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US20210179627A1 - 3-(Carboxymethyl)-8-Amino-2-Oxo-1,3-Diaza-Spiro-[4.5]-Decane Derivatives - Google Patents

3-(Carboxymethyl)-8-Amino-2-Oxo-1,3-Diaza-Spiro-[4.5]-Decane Derivatives Download PDF

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US20210179627A1
US20210179627A1 US17/188,884 US202117188884A US2021179627A1 US 20210179627 A1 US20210179627 A1 US 20210179627A1 US 202117188884 A US202117188884 A US 202117188884A US 2021179627 A1 US2021179627 A1 US 2021179627A1
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methyl
phenyl
diazaspiro
decan
oxo
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US17/188,884
Inventor
Sven Kuehnert
Rene Michael KOENIGS
Florian Jakob
Achim Kless
Paul Ratcliffe
Ruth Jostock
Thomas Koch
Klaus Linz
Wolfgang Schroeder
Klaus Schiene
Anita WEGERT
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Gruenenthal GmbH
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Gruenenthal GmbH
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Priority to US17/188,884 priority Critical patent/US20210179627A1/en
Publication of US20210179627A1 publication Critical patent/US20210179627A1/en
Priority to US18/103,319 priority patent/US20230174540A1/en
Abandoned legal-status Critical Current

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    • 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
    • A61K31/4164—1,3-Diazoles
    • A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
    • 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
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
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    • C07D401/02—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 two hetero rings
    • C07D401/06—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 two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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    • 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
    • C07D401/02—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 two hetero rings
    • C07D401/12—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 two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D403/06—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 only aliphatic carbon atoms
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    • 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
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    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
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    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • 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
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
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    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • C07D417/02—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 two hetero rings
    • C07D417/12—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 two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06008—Dipeptides with the first amino acid being neutral
    • C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
    • C07K5/06026—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing 0 or 1 carbon atom, i.e. Gly or Ala

Definitions

  • the invention relates to 3-(carboxymethyl)-8-amino-2-oxo-1,3-diaza-spiro-[4.5]-decane derivatives, their preparation and use in medicine, particularly in various neurological disorders, including but not limited to pain, neurodegenerative disorders, neuroinflammatory disorders, neuropsychiatric disorders, substance abuse/dependence.
  • Opioid receptors are a group of Gi/o protein-coupled receptors which are widely distributed in the human body.
  • the opioid receptors are currently subdivided into four major classes, i.e. the three classical opioid receptors mu-opioid (MOP) receptor, kappa-opioid (KOP) receptor, and delta-opioid (DOP) receptor as well as the opioid receptor-like (ORL-1) receptor, which was more recently discovered based on its high homology with said classical opioid receptors.
  • MOP mu-opioid
  • KOP kappa-opioid
  • DOP delta-opioid
  • ORL-1 opioid receptor-like receptor
  • ORL-1 receptor After identification of the endogenous ligand of the ORL-1 receptor, known as nociceptin/orphanin FQ, a highly basic 17 amino acid peptide isolated from tissue extracts in 1995, the ORL-1 receptor was renamed “nociceptin opioid peptide receptor” and abbreviated as “NOP-receptor”.
  • the classical opioid receptors (MOP, KOP and DOP) as well as the NOP receptor are widely distributed/expressed in the human body, including in the brain, the spinal cord, on peripheral sensory neurons and the intestinal tract, wherein the distribution pattern differs between the different receptor classes.
  • Nociceptin acts at the molecular and cellular level in very much the same way as opioids. However, its pharmacological effects sometimes differ from, and even oppose those of opioids. NOP-receptor activation translates into a complex pharmacology of pain modulation, which, depending on route of administration, pain model and species involved, leads to either pronociceptive or antinociceptive activity. Furthermore, the NOP receptor system is upregulated under conditions of chronic pain. Systemic administration of selective NOP receptor agonists was found to exert a potent and efficacious analgesia in non-human primate models of acute and inflammatory pain in the absence of side effects.
  • NOP receptors The activation of NOP receptors has been demonstrated to be devoid of reinforcing effects but to inhibit opioid-mediated reward in rodents and non-human primates (Review: Schroeder et al, Br J Pharmacol 2014; 171 (16): 3777-3800, and references therein).
  • NOP receptor agonists might be useful inter alia in the treatment of neuropsychiatric disorders (Witkin et al, Pharmacology & Therapeutics, 141 (2014) 283-299; Jenck et al., Proc. Natl. Acad. Sci. USA 94, 1997, 14854-14858).
  • the DOP receptor is also implicated to modulate not only pain but also neuropsychiatric disorders (Mabrouk et al, 2014; Pradhan et al., 2011).
  • MOP receptor agonists show only reduced effectiveness under conditions of chronic and neuropathic pain.
  • peripherally restricted opioid receptor ligands that do not easily cross the blood-brain barrier and therefore distribute poorly to the central nervous system (see for instance WO 2015/192039).
  • peripherally acting compounds might combine effective analgesia with limited side-effects.
  • a further approach has been to provide multi-opioid receptor analgesics that modulate more than one of the opioid receptor subtypes to provide additive or synergistic analgesia and/or reduced side effects like abuse liability or tolerance.
  • medicaments which are effective in the treatment of pain and which have advantages compared to the compounds of the prior art.
  • medicaments should contain such a small dose of active ingredient that satisfactory pain therapy can be ensured without the occurrence of intolerable treatment-emergent adverse events.
  • a first aspect of the invention relates to 3-(carboxymethyl)-8-amino-2-oxo-1,3-diaza-spiro-[4.5]-decane derivatives according to general formula (I)
  • R 1 and R 2 independently of one another mean
  • —C 1 -C 6 -alkyl linear or branched, saturated or unsaturated, unsubstituted or substituted with one, two, three or four substituents independently of one another selected from the group consisting of —F, —Cl, —Br, —I, —OH, —OCH 3 , —CN and —CO 2 CH 3 ; a 3-12-membered cycloalkyl moiety, saturated or unsaturated, unsubstituted or substituted with one, two, three or four substituents independently of one another selected from the group consisting of —F, —Cl, —Br, —I, —OH, —OCH 3 , —CN and —CO 2 CH 3 ; wherein said 3-12-membered cycloalkyl moiety is optionally connected through —C 1 -C 6 -alkylene-, linear or branched, saturated or unsaturated, unsubstituted; or a 3-12-
  • —C 1 -C 6 -alkyl linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted; wherein said —C 1 -C 6 -alkyl is optionally connected through —C( ⁇ O)—, —C( ⁇ O)O—, or —S( ⁇ O) 2 —; a 3-12-membered cycloalkyl moiety, saturated or unsaturated, unsubstituted, mono- or polysubstituted; wherein said 3-12-membered cycloalkyl moiety is optionally connected through —C 1 -C 6 -alkylene-, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted; or wherein said 3-12-membered cycloalkyl moiety is optionally connected through —C( ⁇ O)—, —C( ⁇ O)O—, —C( ⁇ O)O—CH 2
  • —C 1 -C 6 -alkyl linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted; a 3-12-membered cycloalkyl moiety, saturated or unsaturated, unsubstituted, mono- or polysubstituted; wherein said 3-12-membered cycloalkyl moiety is optionally connected through —C 1 -C 6 -alkylene-, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted; a 3-12-membered heterocycloalkyl moiety, saturated or unsaturated, unsubstituted, mono- or polysubstituted; wherein said 3-12-membered heterocycloalkyl moiety is optionally connected through —C 1 -C 6 -alkylene-, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted;
  • —C 1 -C 6 -alkyl linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted; a 3-12-membered cycloalkyl moiety, saturated or unsaturated, unsubstituted, mono- or polysubstituted; wherein said 3-12-membered cycloalkyl moiety is optionally connected through —C 1 -C 6 -alkylene-, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted; a 3-12-membered heterocycloalkyl moiety, saturated or unsaturated, unsubstituted, mono- or polysubstituted; wherein said 3-12-membered heterocycloalkyl moiety is optionally connected through —C 1 -C 6 -alkylene-, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted;
  • —C 1 -C 6 -alkyl linear or branched, saturated or unsaturated, unsubstituted or substituted with one, two, three or four substituents independently of one another selected from the group consisting of —F, —Cl, —Br, —I, —CN, —OH, —NH 2 , and —O—C 1 -C 6 -alkyl; a 3-12-membered cycloalkyl moiety, saturated or unsaturated, unsubstituted; wherein said 3-12-membered cycloalkyl moiety is optionally connected through —C 1 -C 6 -alkylene-, linear or branched, saturated or unsaturated, unsubstituted or substituted with one, two, three or four substituents independently of one another selected from the group consisting of —F, —Cl, —Br, —I, —CN, —OH, —NH 2 , —C 1 -C
  • aryl includes but is not limited to phenyl and naphthyl.
  • heteroaryl includes but is not limited to -1,2-benzodioxole, -pyrazinyl, -pyridazinyl, -pyridinyl, -pyrimidinyl, -thienyl, -imidazolyl, -benzimidazolyl, -thiazolyl, -1,3,4-thiadiazolyl, -benzothiazolyl, -oxazolyl, -benzoxazolyl, -pyrazolyl, -quinolinyl, -isoquinolinyl, -quinazolinyl, -indolyl, -indolinyl, -benzo[c][1,2,5]oxadiazolyl, -imidazo[1,2-a]pyrazinyl, or -1H-pyrrolo[2,3-b]pyri
  • cycloalkyl includes but is not limited to -cyclopropyl, -cyclobutyl, -cyclopentyl and -cyclohexyl.
  • heterocycloalkyl includes but is not limited to -aziridinyl, -azetidinyl, -pyrrolidinyl, -piperidinyl, -piperazinyl, -morpholinyl, -sulfamorpholinyl, -oxiridinyl, -oxetanyl, tetrahydropyranyl, and -pyranyl.
  • asymmetric group such as —C( ⁇ O)O— or —C( ⁇ O)O—CH 2 —
  • said asymmetric group may be arranged in either direction.
  • R 4 when R 4 is connected to the core structure through —C( ⁇ O)O—, the arrangement may be either R 4 —C( ⁇ O)O-core or core-C( ⁇ O)O—R 4 .
  • R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , and R 20 independently of one another mean —H, —F, —OH, or —C 1 -C 6 -alkyl: preferably —H.
  • R 1 means —H; and R 2 means —C 1 -C 6 -alkyl, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted.
  • R 1 means —H and R 2 means —CH 3 .
  • R 1 means —CH 3 ; and R 2 means —C 1 -C 6 -alkyl, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted.
  • R 1 means —CH 3 and R 2 means —CH 3 .
  • R 1 and R 2 together with the nitrogen atom to which they are attached form a ring and mean —(CH 2 ) 3-6 —.
  • R 1 and R 2 together with the nitrogen atom to which they are attached form a ring and mean —(CH 2 ) 3 —.
  • R 3 means —C 1 -C 6 -alkyl, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted.
  • R 3 means —C 1 -C 6 -alkyl, linear or branched, saturated or unsaturated, unsubstituted or monosubstituted with —OCH 3 .
  • R 3 means a 6-14-membered aryl moiety, unsubstituted, mono- or polysubstituted, optionally connected through —C 1 -C 6 -alkylene-, linear or branched, saturated or unsaturated, unsubstituted.
  • R 3 means -phenyl unsubstituted, mono- or polysubstituted.
  • R 3 means -phenyl unsubstituted, mono- or disubstituted with —F, —Cl, —CH 3 , —CF 3 , —OH, —OCH 3 , —OCF 3 or —OCH 2 OCH 3 , preferably —F.
  • R 3 means -benzyl unsubstituted, mono- or polysubstituted.
  • R 3 means -benzyl unsubstituted, mono- or disubstituted with —F, —Cl, —CH 3 , —CF 3 , —OH, —OCH 3 , —OCF 3 or —OCH 2 OCH 3 , preferably —F.
  • R 3 means a 5-14-membered heteroaryl moiety, unsubstituted, mono- or polysubstituted.
  • R 3 means -thienyl or -pyridinyl, in each case unsubstituted, mono- or polysubstituted. More preferably, R 3 means -thienyl, -pyridinyl, -imidazolyl or benzimidazolyl, in each case unsubstituted or monosubstituted with —F, —Cl or —CH 3 .
  • R 4 means —H.
  • R 4 means —C 1 -C 6 -alkyl, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted.
  • R 4 means —C 1 -C 6 -alkyl, linear or branched, saturated or unsaturated, unsubstituted or monosubstituted with a substituent selected from the group consisting of —F, —Cl, —Br, —I, —CN, —CF 3 , —OH, —O—C 1 -C 4 -alkyl, —OCF 3 , —O—(CH 2 CH 2 —O) 1-30 —H, —O—(CH 2 CH 2 —O) 1-30 —CH 3 , —OC( ⁇ O)C 1 -C 4 -alkyl, —C( ⁇ O)C 1 -C 4 -alkyl, —C( ⁇ O)C 1 -C 4 -alkyl,
  • R 4 means —C 1 -C 6 -alkyl, linear or branched, saturated or unsaturated, unsubstituted or monosubstituted with —O—C 1 -C 4 -alkyl or —C( ⁇ O)N(C 1 -C 4 -alkyl) 2 .
  • R 4 means a 3-12-membered cycloalkyl moiety, saturated or unsaturated, unsubstituted, mono- or polysubstituted; wherein the 3-12-membered cycloalkyl moiety is connected through —C 1 -C 6 -alkylene-, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted.
  • R 4 means a 3-12-membered cycloalkyl moiety, saturated or unsaturated, unsubstituted, mono- or polysubstituted; wherein said 3-12-membered cycloalkyl moiety is connected through —CH 2 — or —CH 2 CH 2 —.
  • R 4 means a 3-12-membered cycloalkyl moiety, saturated or unsaturated, unsubstituted or substituted with one, two, three or four substituents independently of one another selected from the group consisting of —F, —Cl, —Br, —I, —CN, —OH, —C 1 -C 4 -alkyl, —O—C 1 -C 4 -alkyl, —C( ⁇ O)OH, —C( ⁇ O)OC 1 —C 4 -alkyl, —C( ⁇ O)NH 2 , —C( ⁇ O)NHC 1 —C 4 -alkyl, —C( ⁇ O)N(C 1 -C 4 -alkyl) 2 , —S( ⁇ O)C 1 -C 4 -alkyl and —S( ⁇ O) 2 C 1 -C 4 -alkyl; wherein said 3-12-membered cycloalkyl mo
  • R 4 means a 3-12-membered heterocycloalkyl moiety, saturated or unsaturated, unsubstituted, mono- or polysubstituted; wherein said 3-12-membered heterocycloalkyl moiety is connected through —C 1 -C 6 -alkylene-, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted.
  • R 4 means a 3-12-membered heterocycloalkyl moiety, saturated or unsaturated, unsubstituted, mono- or polysubstituted; wherein said 3-12-membered heterocycloalkyl moiety is connected through —CH 2 — or —CH 2 CH 2 —.
  • R 4 means -oxetanyl, -tetrahydrofuranyl or -tetrahydropyranyl, in each case unsubstituted or substituted with one, two, three or four substituents independently of one another selected from the group consisting of —F, —Cl, —Br, —I, —CN, —OH, —C 1 -C 4 -alkyl, —O—C 1 -C 4 -alkyl, —C( ⁇ O)OH, —C( ⁇ O)OC 1 —C 4 -alkyl, —C( ⁇ O)NH 2 , —C( ⁇ O)NHC 1 —C 4 -alkyl, —C( ⁇ O)N(C 1 -C 4 -alkyl) 2 , —S( ⁇ O)C 1 -C 4 -alkyl and —S( ⁇ O) 2 C 1 -C 4 -alkyl; wherein said -
  • R 4 means a 6-14-membered aryl moiety, unsubstituted, mono- or polysubstituted; wherein said 6-14-membered aryl moiety is connected through —C 1 -C 6 -alkylene-, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted.
  • R 4 means -phenyl, unsubstituted, mono- or polysubstituted; wherein said -phenyl is connected through —CH 2 — or —CH 2 CH 2 —.
  • R 4 means -phenyl, unsubstituted or substituted with one, two, three or four substituents independently of one another selected from the group consisting of —F, —Cl, —Br, —I, —CN, —OH, —C 1 -C 4 -alkyl, —O—C 1 -C 4 -alkyl, —C( ⁇ O)OH, —C( ⁇ O)OC 1 —C 4 -alkyl, —C( ⁇ O)NH 2 , —C( ⁇ O)NHC 1 —C 4 -alkyl, —C( ⁇ O)N(C 1 -C 4 -alkyl) 2 , —S( ⁇ O)C 1 -C 4 -alkyl and —S( ⁇ O) 2 C 1 -C 4 -alkyl; wherein said -phenyl is connected through —CH 2 — or —CH 2 CH 2 —.
  • R 4 means a 5-14-membered heteroaryl moiety, unsubstituted, mono- or polysubstituted; wherein said 5-14-membered heteroaryl moiety is connected through —C 1 -C 6 -alkylene-, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted.
  • R 4 means a 5-14-membered heteroaryl moiety, unsubstituted, mono- or polysubstituted; wherein said -phenyl is connected through —CH 2 — or —CH 2 CH 2 —.
  • R 4 means -pyridinyl, -pyrimidinyl, -pyrazinyl, or -pyrazolinyl, in each case unsubstituted or substituted with one, two, three or four substituents independently of one another selected from the group consisting of —F, —Cl, —Br, —I, —CN, —OH, —C 1 -C 4 -alkyl, —O—C 1 -C 4 -alkyl, —C( ⁇ O)OH, —C( ⁇ O)OC 1 —C 4 -alkyl, —C( ⁇ O)NH 2 , —C( ⁇ O)NHC 1 —C 4 -alkyl, —C( ⁇ O)N(C 1 -C 4 -alkyl) 2 , —S( ⁇ O)C 1 -C 4 -alkyl and —S( ⁇ O) 2 C 1 -C 4 -alkyl; wherein
  • R 5 means —H.
  • R 5 means —C 1 -C 6 -alkyl, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted.
  • R 5 means —C 1 -C 6 -alkyl, linear or branched, saturated, unsubstituted, mono- or polysubstituted.
  • R 5 means —C 1 -C 6 -alkyl, linear or branched, saturated, unsubstituted or monosubstituted with a substituent selected from the group consisting of —F, —Cl, —Br, —I, —CN, —OH, —O—C 1 -C 6 -alkyl, —C( ⁇ O)OH, —C( ⁇ O)OC 1 —C 4 -alkyl, —C( ⁇ O)NH 2 , —C( ⁇ O)NHC 1 —C 4 -alkyl, —C( ⁇ O)N(C 1 -C 4 -alkyl) 2 , —S( ⁇ O)C 1 -C 4 -alkyl, —S( ⁇ O) 2 C 1 -C 4 -alkyl, —C( ⁇ O)—C 3-12 heterocycloalkyl, —NH—C( ⁇ O)—C 1 -C 4 -alkyl,
  • R 5 means a 3-12-membered cycloalkyl moiety, saturated or unsaturated, unsubstituted, mono- or polysubstituted, wherein said 3-12-membered cycloalkyl moiety is optionally connected through —C 1 -C 6 -alkylene-, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted.
  • R 5 means a 3-6-membered cycloalkyl moiety, saturated, unsubstituted, mono- or polysubstituted, wherein said 3-12-membered cycloalkyl moiety is optionally connected through —C 1 -C 6 -alkylene-, linear or branched, saturated, unsubstituted; more preferably -cyclopropyl, -cyclobutyl, -cyclopentyl or -cyclohexyl, unsubstituted or monosubstituted with —F, —OH, —CN or —C 1 -C 4 -alkyl, wherein said -cyclopropyl, -cyclobutyl -cyclopentyl or -cyclohexyl is optionally connected through —CH 2 — or —CH 2 CH 2 —.
  • R 5 means a 3-12-membered heterocycloalkyl moiety, saturated or unsaturated, unsubstituted, mono- or polysubstituted; wherein said 3-12-membered heterocycloalkyl moiety is optionally connected through —C 1 -C 6 -alkylene-, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted.
  • R 5 means a 4-6-membered heterocycloalkyl moiety, saturated or unsaturated, unsubstituted, mono- or polysubstituted. More preferably, R 5 means -hetero-cyclobutyl or -tetrahydro-2H-thiopyranyl dioxide, unsubstituted.
  • R 5 means a 5-14-membered heteroaryl moiety, unsubstituted, mono- or polysubstituted; wherein said 5-14-membered heteroaryl moiety is optionally connected through —C 1 -C 6 -alkylene-, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted.
  • R 5 means a 5-6-membered heteroaryl moiety, unsubstituted, mono- or polysubstituted, wherein said 5-6-membered heteroaryl moiety is optionally connected through —CH 2 —.
  • R 5 means a 5-6-membered heteroaryl moiety, unsubstituted or substituted with one, two, three or four substituents independently of one another selected from the group consisting of —F, —Cl, —Br, —I, —CN, —OH, —C 1 -C 4 -alkyl, —O—C 1 -C 4 -alkyl, —C( ⁇ O)OH, —C( ⁇ O)OC 1 —C 4 -alkyl, —C( ⁇ O)NH 2 , —C( ⁇ O)NHC 1 —C 4 -alkyl, —C( ⁇ O)N(C 1 -C 4 -alkyl) 2 , —S( ⁇ O)C 1 -C 4 -alkyl, —S( ⁇ O) 2 C 1 -C 4 -alkyl and —S—C 1 -C 4 -alkyl, wherein said 5-6-membered
  • R 5 means -oxazolyl, -isoxazolyl, -pyrazolyl, -pyridinyl, -pyridazinyl, -pyrazinyl, -thiazolyl, -thiadiazolyl, -imidazolyl or -pyrimidinyl, in each case unsubstituted or substituted with one, two, three or four substituents independently of one another selected from the group consisting of —F, —Cl, Br, —I, —CN, —OH, —C 1 -C 4 -alkyl, —O—C 1 -C 4 -alkyl, —C( ⁇ O)OH, —C( ⁇ O)OC 1 —C 4 -alkyl, —C( ⁇ O)NH 2 , —C( ⁇ O)NHC 1 —C 4 -alkyl, —C( ⁇ O)N(C 1 -C 4 -alkyl
  • R 5 means a 6-14-membered aryl moiety, unsubstituted, mono- or polysubstituted; wherein said 6-14-membered aryl moiety is optionally connected through —C 1 -C 6 -alkylene-, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted.
  • R 5 means -phenyl, unsubstituted or substituted with one, two, three or four substituents independently of one another selected from the group consisting of —F, —Cl, Br, —I, —CN, —OH, —C 1 -C 4 -alkyl, —O—C 1 -C 4 -alkyl, —C( ⁇ O)OH, —C( ⁇ O)OC 1 —C 4 -alkyl, —C( ⁇ O)NH 2 , —C( ⁇ O)NHC 1 —C 6 -alkyl, —C( ⁇ O)N(C 1 -C 4 -alkyl) 2 , S( ⁇ O)C 1 -C 4 -alkyl, —S( ⁇ O) 2 C 1 -C 4 -alkyl and —S—C 1 -C 4 -alkyl, wherein said -phenyl is optionally connected through —CH 2 —.
  • X means NR 6 and R 5 and R 6 together with the nitrogen atom to which they are attached form a 3-12-membered heterocycloalkyl moiety, saturated or unsaturated, unsubstituted, mono- or polysubstituted.
  • X means NR 6 and R 5 and R 6 together with the nitrogen atom to which they are attached form a 5-6-membered heterocycloalkyl moiety, saturated or unsaturated, unsubstituted, mono- or polysubstituted.
  • X means NR 6 and R 5 and R 6 together with the nitrogen atom to which they are attached form -pyrrolidinyl, -piperidinyl, -piperazinyl, -morpholinyl, -thiomorpholinyl, -thiomorpholinyl dioxide or -(methylsulfonyl)piperazinyl, in each case unsubstituted or substituted with one, two, three or four substituents independently of one another selected from the group consisting of ⁇ O, —OH, —CH 2 —OH and —C( ⁇ O)NH 2 , wherein said -pyrrolidinyl, -piperidinyl, piperazinyl, -morpholinyl, -thiomorpholinyl, -thiomorpholinyl dioxide or -(methylsulfonyl)piperazinyl is optionally condensed with an imidazole moiety, unsubstituted.
  • R 5 means
  • —C 1 -C 6 -alkyl linear or branched, saturated or unsaturated, unsubstituted or substituted with one, two, three or four substituents independently of one another selected from the group consisting of —F, —Cl, —Br, —I, —CN, —O—CH 3 , —O—(CH 2 —CH 2 —O) 1-10 —H, —O—(CH 2 CH 2 —O) 1-10 —CH 3 , —C( ⁇ O)OH, —C( ⁇ O)OCH 3 , —C( ⁇ O)NH 2 , —C( ⁇ O)NHCH 3 , —C( ⁇ O)N(CH 3 ) 2 , —OH, —S( ⁇ O)CH 3 , —S( ⁇ O) 2 CH 3 , unsubstituted —C( ⁇ O)-morpholinyl, —NH—C( ⁇ O)—CH 3 , —N(CH 3
  • X means NR 6 and R 6 means —H or —C 1 -C 6 -alkyl, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted.
  • R 6 means —H or —CH 3 .
  • the compound according to the invention has a structure according to any of general formulas (II-A) to (VIII-C):
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and X are defined as above, R C means —H, —OH, —F, —CN or —C 1 -C 4 -alkyl; R D means —H or —F; or a physiologically acceptable salt thereof.
  • the substructure of the compounds according to general formula (I) represented by R 5 , X, R 9 and R 10 i.e.
  • R 1 means —H or —CH 3
  • R 2 means —CH 3 , —CH 2 CH 3 or —CH 2 —C(H)(CH 3 ) 2
  • R 3 means -phenyl, -thienyl or -pyridinyl, in each case unsubstituted or monosubstituted with —F
  • R 4 means
  • —C 1 -C 6 -alkyl linear or branched, saturated, unsubstituted or substituted with one, two, three or four substituents independently of one another selected from the group consisting of —F, —Cl, —Br, —I, —CN, —OH, ⁇ O, —N(CH 3 ) 2 and —O—CH 3 ; or -cyclopropyl, -cyclobutyl, -cyclopentyl or -cyclohexyl, unsubstituted or monosubstituted with —F, —OH, —CN or —CH 3 , wherein said -cyclopropyl, -cyclobutyl, -cyclopentyl or -cyclohexyl is connected through —CH 2 — or —CH 2 CH 2 —; -oxetanyl unsubstituted or monosubstituted with —F, —OH, —CN or
  • —C 1 -C 6 -alkyl linear or branched, saturated or unsaturated, unsubstituted or substituted with one, two, three or four substituents independently of one another selected from the group consisting of —F, —Cl, —Br, —I, —CN, —O—CH 3 , —O—(CH 2 —CH 2 —O) 1-10 —H, —O—(CH 2 CH 2 —O) 1-10 —CH 3 , —C( ⁇ O)OH, —C( ⁇ O)OCH 3 , —C( ⁇ O)NH 2 , —C( ⁇ O)NHCH 3 , —C( ⁇ O)N(CH 3 ) 2 , —OH, —S( ⁇ O)CH 3 , —S( ⁇ O) 2 CH 3 , unsubstituted —C( ⁇ O)-morpholinyl, —NH—C( ⁇ O)—CH 3 , —N(CH 3
  • R 1 means —H or —CH 3 ; and/or R 2 means —CH 3 , —CH 2 CH 3 or —CH 2 —C(H)(CH 3 ) 2 ; and/or R 3 means -phenyl, -thienyl or -pyridinyl, in each case unsubstituted; preferably, R 3 means phenyl unsubstituted; and/or R 4 means
  • —C 1 -C 6 -alkyl linear or branched, saturated, unsubstituted or substituted with one, two, three or four substituents independently of one another selected from the group consisting of —F, —Cl, —Br, —I, —CN, —OH, ⁇ O, —N(CH 3 ) 2 and —O—CH 3 ; or -cyclopropyl, -cyclobutyl, -cyclopentyl or -cyclohexyl, unsubstituted or monosubstituted with —F, —OH, —CN or —CH 3 , wherein said -cyclopropyl, -cyclobutyl, -cyclopentyl or -cyclohexyl is connected through —CH 2 — or —CH 2 CH 2 —; preferably, R 4 means -cyclobutyl, unsubstituted or monosubstituted with —OH, wherein
  • —C 1 -C 6 -alkyl linear or branched, saturated or unsaturated, unsubstituted or substituted with one, two, three or four substituents independently of one another selected from the group consisting of —F, —Cl, —Br, —I, —CN, —O—CH 3 , —O—(CH 2 —CH 2 —O) 1-10 —H, —O—(CH 2 CH 2 —O) 1-10 —CH 3 , —C( ⁇ O)OH, —C( ⁇ O)OCH 3 , —C( ⁇ O)NH 2 , —C( ⁇ O)NHCH 3 , —C( ⁇ O)N(CH 3 ) 2 , —OH, —S( ⁇ O)CH 3 , —S( ⁇ O) 2 CH 3 , unsubstituted —C( ⁇ O)-morpholinyl, —NH—C( ⁇ O)—CH 3 , —N(CH 3
  • the compound according to the invention is selected from the group consisting of
  • SC_1001 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-N-[2-[2-[2-[2-[2-[2-[2-[2-[2-(2-methoxy-ethoxy)-ethoxy]-ethoxy]-ethoxy]-ethoxy]-ethoxy]-ethyl]-acetamide
  • SC_1002 CIS-6-[[2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3-yl]-acetyl]amino]-pyridine-2-carboxylic acid methyl ester
  • SC_1003 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,
  • —C 1 -C 4 -alkyl can be linear or branched, saturated or unsaturated.
  • Linear saturated alkyl includes methyl, ethyl, n-propyl, n-butyl, n-pentyl and n-hexyl.
  • branched saturated alkyl include but are not limited to iso-propyl, sec-butyl, and tert-butyl.
  • linear unsaturated alkyl include but are not limited to vinyl, propenyl, allyl, and propargyl.
  • —C 1 -C 4 -alkyl can be unsubstituted, mono- or polysubstituted.
  • substituted alkyl examples include but are not limited to —CH 2 CH 2 OH, —CH 2 CH 2 OCH 3 , —CH 2 CH 2 CH 2 OCH 3 , —CH 2 CH 2 S( ⁇ O) 2 CH 3 , —CH 2 C( ⁇ O)NH 2 , —C(CH 3 ) 2 C( ⁇ O)NH 2 , —CH 2 C(CH 3 ) 2 C( ⁇ O)NH 2 , and —CH 2 CH 2 C( ⁇ O)N(CH 3 ) 2 .
  • —C 1 -C 6 -alkylene- “—C 1 -C 4 -alkylene” and any other alkylene residue can be unsubstituted, mono- or polysubstituted.
  • saturated alkylene examples include but are not limited to —CH 2 —, —CH(CH 3 )—, —C(CH 3 ) 2 —, —CH 2 CH 2 —, —CH(CH 3 )CH 2 —, —CH 2 CH(CH 3 )—, —CH(CH 3 )—CH(CH 3 )—, —C(CH 3 ) 2 CH 2 —, —CH 2 C(CH 3 ) 2 —, —CH(CH 3 )C(CH 3 ) 2 —, —C(CH 3 ) 2 CH(CH 3 )—, C(CH 3 ) 2 C(CH 3 ) 2 —, —CH 2 CH 2 CH 2 —, and —C(CH 3 ) 2 CH 2 CH 2 —.
  • unsaturated alkylene examples include but are not limited to —CH ⁇ CH—, —C ⁇ C—, —C(CH 3 ) ⁇ CH—, —CH ⁇ C(CH 3 )—, —C(CH 3 ) ⁇ C(CH 3 )—, ⁇ CH 2 CH ⁇ CH—, —CH ⁇ CHCH 2 —, —CH ⁇ CH—CH ⁇ CH—, and —CH ⁇ CH—C ⁇ C—.
  • —C 1 -C 6 -alkylene- “—C 1 -C 4 -alkylene” and any other alkylene residue can be unsubstituted, mono- or polysubstituted. Examples of substituted —C 1 -C 6 -alkylene- include but are not limited to —CHF—, —CF 2 —, —CHOH— and —C( ⁇ O)—.
  • moieties may be connected through —C 1 -C 6 -alkylene-. i.e. the moieties may not be directly bound to the core structure of compound according to general formula (I), but may be connected to the core structure of compound according to general formula (I) or its periphery through a —C 1 -C 6 -alkylene- linker.
  • 3-12-membered cycloalkyl moiety means a non-aromatic, monocyclic, bicyclic or tricyclic moiety comprising 3 to 12 ring carbon atoms but no heteroatoms in the ring.
  • preferred saturated 3-12-membered cycloalkyl moieties according to the invention include but are not limited to cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, hydrindane, and decaline.
  • Examples of preferred unsaturated 3-12-membered cycloalkyl moiety moieties according to the invention include but are not limited to cyclopropene, cyclobutene, cyclopentene, cyclopentadiene, cyclohexene, 1,3-cyclohexadiene, and 1,4-cyclohexadiene.
  • the 3-12-membered cycloalkyl moiety which is bonded to the compound according to the invention, in its periphery may optionally be condensed with a 3-12-membered heterocycloalkyl moiety, saturated or unsaturated, unsubstituted, mono- or polysubstituted; and/or with a 6-14-membered aryl moiety, unsubstituted, mono- or polysubstituted; and/or with a 5-14-membered heteroaryl moiety, unsubstituted, mono- or polysubstituted.
  • the ring atoms of the condensed moieties are not included in the 3 to 12 ring atoms of the 3-12-membered cycloalkyl moiety.
  • 3-12-membered cycloalkyl moieties condensed with 3-12-membered heterocycloalkyl moieties include but are not limited to octahydro-1H-indol, decahydroquinoline, decahydroisoquinoline, octahydro-2H-benzo[b][1,4]oxazin, and decahydro-quinoxalin, which in each case are connected through the 3-12-membered cycloalkyl moiety.
  • 3-12-membered cycloalkyl moieties condensed with 6-14-membered aryl moieties include but are not limited to 2,3-dihydro-1H-indene and tetraline, which in each case are connected through the 3-12-membered cycloalkyl moiety.
  • 3-12-membered cycloalkyl moieties condensed with 5-14-membered heteroaryl moieties include but are not limited to 5,6,7,8-tetrahydroquinoline and 5,6,7,8-tetrahydroquinazoline, which in each case are connected through the 3-12-membered cycloalkyl moiety.
  • the 3-12-membered cycloalkyl moiety may optionally be connected through —C 1 -C 6 -alkylene-. i.e. the 3-12-membered cycloalkyl moiety may not be directly bound to the compound according to general formula (I) but may be connected thereto through a —C 1 -C 6 -alkylene- linker.
  • Examples include but are not limited to —CH 2 -cyclopropyl, —CH 2 -cyclobutyl, —CH 2 -cyclopentyl, —CH 2 -cyclohexyl, —CH 2 CH 2 -cyclopropyl, —CH 2 CH 2 -cyclobutyl, —CH 2 CH 2 -cyclopentyl, and —CH 2 CH 2 -cyclohexyl.
  • the 3-12-membered cycloalkyl moiety can be unsubstituted, mono- or polysubstituted.
  • substituted 3-12-membered cycloalkyl moieties include but are not limited to —CH 2 -1-hydroxy-cyclobutyl.
  • “3-12-membered heterocycloalkyl moiety” means a non-aromatic, monocyclic, bicyclic or tricyclic moiety comprising 3 to 12 ring atoms, wherein each cycle comprises independently of one another 1, 2, 3, 4 or more heteroatoms independently of one another selected from the group consisting of nitrogen, oxygen and sulfur, whereas sulfur may be oxidized (S( ⁇ O) or S( ⁇ O) 2 ), whereas the remaining ring atoms are carbon atoms, and whereas bicyclic or tricyclic systems may share common heteroatom(s).
  • Examples of preferred saturated 3-12-membered heterocycloalkyl moieties according to the invention include but are not limited to aziridin, azetidine, pyrrolidine, imidazolidine, pyrazolidine, piperidine, piperazine, triazolidine, tetrazolidine, oxiran, oxetane, tetrahydrofurane, tetrahydropyrane, thiirane, thietane, tetra-hydrothiophene, diazepane, oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, thiadiazoli-dine, morpholine, thiomorpholine.
  • Examples of preferred unsaturated 3-12-membered heterocycloalkyl moiety moieties according to the invention include but are not limited to oxazoline, pyrazoline, imidazoline, isoxazoline, thiazoline, isothiazoline, and dihydropyran.
  • the 3-12-membered heterocycloalkyl moiety which is bonded to the compound according to the invention, in its periphery may optionally be condensed with a 3-12-membered cycloalkyl moiety, saturated or unsaturated, unsubstituted, mono- or polysubstituted; and/or with a 6-14-membered aryl moiety, unsubstituted, mono- or polysubstituted; and/or with a 5-14-membered heteroaryl moiety, unsubstituted, mono- or polysubstituted.
  • the ring atoms of the condensed moieties are not included in the 3 to 12 ring atoms of the 3-12-membered heterocycloalkyl moieties.
  • 3-12-membered heterocycloalkyl moieties condensed with 3-12-membered cycloalkyl moieties include but are not limited to octahydro-1H-indol, decahydroquinoline, decahydroisoquinoline, octahydro-2H-benzo[b][1,4]oxazin, and decahydro-quinoxalin, which in each case are connected through the 3-12-membered heterocycloalkyl moiety.
  • An examples of a 3-12-membered heterocycloalkyl moiety condensed with a 6-14-membered aryl moiety includes but is not limited to 1,2,3,4-tetrahydroquinoline, which is connected through the 3-12-membered heterocycloalkyl moiety.
  • An example of a 3-12-membered heterocycloalkyl moiety condensed with a 5-14-membered heteroaryl moieties includes but is not limited to 5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazine, which is connected through the 3-12-membered heterocycloalkyl moiety.
  • the 3-12-membered heterocycloalkyl moiety may optionally be connected through —C 1 -C 6 -alkylene-. i.e. the 3-12-membered heterocycloalkyl moiety may not be directly bound to the compound according to general formula (I) but may be connected thereto through a —C 1 -C 6 -alkylene- linker. Said linker may be connected to a carbon ring atom or to a hetero ring atom of the 3-12-membered heterocycloalkyl moiety.
  • Examples include but are not limited to —CH 2 -oxetane, —CH 2 -pyrrolidine, —CH 2 -piperidine, —CH 2 -morpholine, —CH 2 CH 2 -oxetane, —CH 2 CH 2 -pyrrolidine, —CH 2 CH 2 -piperidine, and —CH 2 CH 2 -morpholine.
  • the 3-12-membered heterocycloalkyl moiety can be unsubstituted, mono- or polysubstituted.
  • substituted 3-12-membered heterocycloalkyl moieties include but are not limited to 2-carboxamido-N-pyrrolidinyl-, 3,4-dihydroxy-N-pyrrolidinyl, 3-hydroxy-N-pyrimidinyl, 3,4-dihydroxy-N-pyrimidinyl, 3-oxo-N-piperazinyl, -tetrahydro-2H-thiopyranyl dioxide and thiomorpholinyl dioxide.
  • 6-14-membered aryl moiety means an aromatic, monocyclic, bicyclic or tricyclic moiety comprising 6 to 14 ring carbon atoms but no heteroatoms in the ring.
  • 6-14-membered aryl moieties according to the invention include but are not limited to benzene, naphthalene, anthracen, and phenanthren.
  • the 6-14-membered aryl moiety, which is bonded to the compound according to the invention, in its periphery may optionally be condensed with a 3-12-membered cycloalkyl moiety, saturated or unsaturated, unsubstituted, mono- or polysubstituted; and/or with a 3-12-membered heterocycloalkyl moiety, saturated or unsaturated, unsubstituted, mono- or polysubstituted; and/or with a 5-14-membered heteroaryl moiety, unsubstituted, mono- or polysubstituted.
  • the ring atoms of the condensed moieties are not included in the 6 to 14 ring carbon atoms of the 6-14-membered heterocycloalkyl moieties.
  • 6-14-membered aryl moieties condensed with 3-12-membered cycloalkyl moieties include but are not limited to 2,3-dihydro-1H-indene and tetraline, which in each case are connected through the 6-14-membered aryl moiety.
  • 6-14-membered aryl moiety condensed with a 3-12-membered heterocycloalkyl moiety includes but is not limited to 1,2,3,4-tetrahydroquinoline, which is connected through the 6-14-membered aryl moiety.
  • 6-14-membered aryl moieties condensed with 5-14-membered heteroaryl moieties include but are not limited to quinoline, isoquinoline, phenazine and phenoxacine, which in each case are connected through the 6-14-membered aryl moiety.
  • the 6-14-membered aryl moiety may optionally be connected through —C 1 -C 6 -alkylene-, i.e. the 6-14-membered aryl moiety may not be directly bound to the compound according to general formula (I) but may be connected thereto through a —C 4 -C 6 -alkylene- linker.
  • Said linker may be connected to a carbon ring atom or to a hetero ring atom of the 6-14-membered aryl moiety. Examples include but are not limited to —CH 2 —C 6 H 5 , —CH 2 CH 2 —C 6 H 5 and —CH ⁇ CH—C 6 H 5 .
  • the 6-14-membered aryl moiety can be unsubstituted, mono- or polysubstituted.
  • substituted 6-14-membered aryl moieties include but are not limited to 2-fluorophenyl, 3-fluorophenyl, 2-methoxyphenyl and 3-methoxyphenyl.
  • “5-14-membered heteroaryl moiety” means an aromatic, monocyclic, bicyclic or tricyclic moiety comprising 6 to 14 ring atoms, wherein each cycle comprises independently of one another 1, 2, 3, 4 or more heteroatoms independently of one another selected from the group consisting of nitrogen, oxygen and sulfur, whereas the remaining ring atoms are carbon atoms, and whereas bicyclic or tricyclic systems may share common heteroatom(s).
  • Examples of preferred 5-14-membered heteroaryl moieties according to the invention include but are not limited to pyrrole, pyrazole, imidazole, triazole, tetrazole, furane, thiophene, oxazole, isoxazole, thiazole, isothiazole, pyridine, pyridazine, pyrimidine, pyrazine, indolicine, 9H-chinolicine, 1,8-naphthyridine, purine, imidazo[1,2-a]pyrazine, and pteridine.
  • the 5-14-membered heteroaryl moiety which is bonded to the compound according to the invention, in its periphery may optionally be condensed with a 3-12-membered cycloalkyl moiety, saturated or unsaturated, unsubstituted, mono- or polysubstituted; and/or with a 3-12-membered heterocycloalkyl moiety, saturated or unsaturated, unsubstituted, mono- or polysubstituted; and/or with a 6-14-membered aryl moiety, unsubstituted, mono- or poly substituted.
  • the ring atoms of the condensed moieties are not included in the 6 to 14 ring carbon atoms of the 6-14-membered heterocycloalkyl moieties.
  • 5-14-membered heteroaryl moieties condensed with 3-12-membered cycloalkyl moieties include but are not limited to 5,6,7,8-tetrahydroquinoline and 5,6,7,8-tetrahydroquinazoline, which in each case are connected through the 5-14-membered heteroaryl moiety.
  • 5-14-membered heteroaryl moiety condensed with a 3-12-membered heterocycloalkyl moiety includes but is not limited to 5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazine, which is connected through the 5-14-membered heteroaryl moiety.
  • 5-14-membered heteroaryl moieties condensed with 6-14-membered aryl moieties include but are not limited to quinoline, isoquinoline, phenazine and phenoxacine, which in each case are connected through the 5-14-membered heteroaryl moiety.
  • the 5-14-membered heteroaryl moiety may optionally be connected through —C 1 -C 6 -alkylene-. i.e. the 5-14-membered heteroaryl moiety may not be directly bound to the compound according to general formula (I) but may be connected thereto through a —C 1 -C 6 -alkylene- linker. Said linker may be connected to a carbon ring atom or to a hetero ring atom of the 5-14-membered heteroaryl moiety.
  • Examples include but are not limited to —CH 2 -oxazole, —CH 2 -isoxazole, —CH 2 -imidazole, —CH 2 -pyridine, —CH 2 -pyrimidine, —CH 2 -pyridazine, —CH 2 CH 2 -oxazole, —CH 2 CH 2 -isoxazole, —CH 2 CH 2 -imidazole, —CH 2 CH 2 -pyridine, —CH 2 CH 2 -pyrimidine, and —CH 2 CH 2 -pyridazine.
  • the 5-14-membered heteroaryl moiety can be unsubstituted, mono- or polysubstituted.
  • 5-14-membered heteroaryl moieties include but are not limited to 2-methoxy-4-pyridinyl, 2-methoxy-5-pyridinyl, 3-methoxy-4-pyridinyl, 3-methoxy-6-pyridinyl, 4-methoxy-2-pyridinyl, 2-methylsulfonyl-5-pyridinyl, 3-methylsulfonyl-6-pyridinyl, 3-methoxy-6-pyridazinyl, 2-nitrilo-5-pyrimidinyl, 4-hydroxy-2-pyrimidinyl, 4-methoxy-pyrimidinyl, and 2-methoxy-6-pyrazinyl.
  • the compounds according to the invention have a structure according to general formula (I′)
  • R 1 to R 5 , R 9 to R 20 , and X are defined as above, or a physiologically acceptable salt thereof.
  • the excess of the cis-isomer so designated is at least 50% de, more preferably at least 75% de, yet more preferably at least 90% de, most preferably at least 95% de and in particular at least 99% de.
  • the compounds according to the invention have a structure according to general formula (IX)
  • R C means —H or —OH
  • R 3 means -phenyl or -3-fluorophenyl
  • R 5 means —H, —CH 3 , —CH 2 CH 2 OH, or —CH 2 C( ⁇ O)NH 2
  • R 6 means —H or —CH 3 ; or R 5 and R 6 together with the nitrogen atom to which they are attached form a ring and mean —(CH 2 ) 5 —, wherein said ring is unsubstituted or substituted with one or two substituents independently of one another selected from the group consisting of —CH 3 , —OH, —S( ⁇ O) 2 CH 3 and —C( ⁇ O)NH 2
  • R 9 and R 10 independently of one another mean —H or —CH 3 ; or a physiologically acceptable salt thereof.
  • the compounds according to the invention are in the form of the free bases.
  • the compounds according to the invention are in the form of the physiologically acceptable salts.
  • salt is to be understood as being any form of the compound in which it assumes an ionic form or is charged and is coupled with a counter-ion (a cation or anion) or is in solution.
  • the term is also to be understood as meaning complexes of the compound with other molecules and ions, in particular complexes which are associated via ionic interactions.
  • Preferred salts are physiologically acceptable, in particular physiologically acceptable salts with anions or acids or also a salt formed with a physiologically acceptable acid.
  • Physiologically acceptable salts with anions or acids are salts of the particular compound in question with inorganic or organic acids which are physiologically acceptable, in particular when used in humans and/or mammals.
  • physiologically acceptable salts of particular acids include but are not limited to salts of hydrochloric acid, sulfuric acid, and acetic acid.
  • the invention also includes isotopic isomers of a compound according to 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.
  • Certain compounds according to the invention are useful for modulating a pharmacodynamic response from one or more opioid receptors (mu, delta, kappa, NOP/ORL-1) either centrally or peripherally, or both.
  • the pharmacodynamic response may be attributed to the compound either stimulating (agonizing) or inhibiting (antagonizing) the one or more receptors.
  • Certain compounds according to the invention may antagonize one opioid receptor, while also agonizing one or more other receptors.
  • Compounds according to the invention having agonist activity may be either full agonists or partial agonists.
  • agonists compounds that bind to receptors and mimic the regulatory effects of endogenous ligands are defined as “agonists”.
  • antagonists Compounds that bind to a receptor but produce no regulatory effect, but rather block the binding of ligands to the receptor, are defined as “antagonists”.
  • the compounds according to the invention are agonists at the mu opioid (MOP) and/or kappa opioid (KOP) and/or delta opioid (DOP) and/or nociceptin opioid (NOP/ORL-1) receptors.
  • MOP mu opioid
  • KOP kappa opioid
  • DOP delta opioid
  • NOP/ORL-1 nociceptin opioid
  • the compounds according to the invention potently bind to the MOP and/or KOP and/or DOP and/or NOP receptors.
  • the compounds according to the invention can be modulators at the MOP and/or KOP and/or DOP and/or NOP receptors, and therefore the compounds according to the invention can be used/administered to treat, ameliorate, or prevent pain.
  • the compounds according to the invention are agonists of one or more opioid receptors. In some embodiments, the compounds according to the invention are agonists of the MOP and/or KOP and/or DOP and/or NOP receptors.
  • the compounds according to the invention are antagonists of one or more opioid receptors. In some embodiments, the compounds according to the invention are antagonists of the MOP and/or KOP and/or DOP and/or NOP receptors.
  • the compounds according to the invention have both, (i) agonist activity at the NOP receptor; and (ii) agonist activity at one or more of the MOP, KOP, and DOP receptors.
  • the compounds according to the invention have both, (i) agonist activity at the NOP receptor; and (ii) antagonist activity at one or more of the MOP, KOP, and DOP receptors.
  • the compounds according to the invention have both, (i) antagonist activity at the NOP receptor; and (ii) agonist activity at one or more of the MOP, KOP, and DOP receptors.
  • the compounds according to the invention have both, (i) antagonist activity at the NOP receptor; and (ii) antagonist activity at one or more of the MOP, KOP, and DOP receptors.
  • the compounds according to the invention have selective agonist activity at the NOP receptor. In some embodiments, preferably with respect to receptors of the peripheral nervous system, the compounds according to the invention
  • the compounds according to the invention have balanced agonist activity at the NOP receptor as well as at the MOP receptor. In some embodiments, preferably with respect to receptors of the peripheral nervous system, the compounds according to the invention
  • the compounds according to the invention have balanced agonist activity at the NOP receptor as well as at the KOP receptor. In some embodiments, preferably with respect to receptors of the peripheral nervous system, the compounds according to the invention
  • the compounds according to the invention have balanced agonist activity at the NOP receptor as well as at the DOP receptor. In some embodiments, preferably with respect to receptors of the peripheral nervous system, the compounds according to the invention
  • the compounds according to the invention have selective agonist activity at the KOP receptor. In some embodiments, preferably with respect to receptors of the peripheral nervous system, the compounds according to the invention
  • the compounds according to the invention have agonist activity at the MOP receptor, agonist activity at the KOP receptor, and antagonist activity at the DOP receptor. In some embodiments, preferably with respect to receptors of the peripheral nervous system, the compounds according to the invention
  • the compounds according to the invention have selective agonist activity at the NOP receptor. In some embodiments, preferably with respect to receptors of the central nervous system, the compounds according to the invention
  • the compounds according to the invention have selective antagonist activity at the NOP receptor. In some embodiments, preferably with respect to receptors of the central nervous system, the compounds according to the invention
  • the compounds according to the invention have antagonist activity at the NOP receptor as well as agonist activity at the DOP receptor. In some embodiments, preferably with respect to receptors of the central nervous system, the compounds according to the invention
  • no significant activity means that the activity (agonist/antagonist) of the given compound at this receptor is lower by a factor of 1000 or more compared to its activity (agonist/antagonist) at one or more of the other opioid receptors.
  • a further aspect of the invention relates to the compounds according to the invention as medicaments.
  • a further aspect of the invention relates to the compounds according to the invention for use in the treatment of pain.
  • a further aspect of the invention relates to a method of treating pain comprising the administration of a pain alleviating amount of a compound according to the invention to a subject in need thereof, preferably to a human.
  • the pain is preferably acute or chronic.
  • the pain is preferably nociceptive or neuropathic.
  • a further aspect of the invention relates to the compounds according to the invention for use in the treatment of neurodegenerative disorders, neuroinflammatory disorders, neuropsychiatric disorders, and substance abuse/dependence.
  • a further aspect of the invention relates to a method of treating any one of the aforementioned disorders, diseases or conditions comprising the administration of a therapeutically effective amount of a compound according to the invention to a subject in need thereof, preferably to a human.
  • Another aspect of the invention relates to a pharmaceutical composition which contains a physiologically acceptable carrier and at least one compound according to the invention.
  • the composition according to the invention is solid, liquid or pasty; and/or contains the compound according to the invention in an amount of from 0.001 to 99 wt. %, preferably from 1.0 to 70 wt. %, based on the total weight of the composition.
  • composition according to the invention can optionally contain suitable additives and/or auxiliary substances and/or optionally further active ingredients.
  • physiologically acceptable carriers examples include fillers, solvents, diluents, colorings and/or binders. These substances are known to the person skilled in the art (see H. P. Fiedler, Lexikon der Hilfsstoffe fur Pharmazie, Kosmetik and angrenzende füre, Editio Cantor Aulendoff).
  • the pharmaceutical composition according to the invention contains the compound according to the invention in an amount of preferably from 0.001 to 99 wt. %, more preferably from 0.1 to 90 wt. %, yet more preferably from 0.5 to 80 wt. %, most preferably from 1.0 to 70 wt. % and in particular from 2.5 to 60 wt. %, based on the total weight of the pharmaceutical composition.
  • the pharmaceutical composition according to the invention is preferably for systemic, topical or local administration, preferably for oral administration.
  • Another aspect of the invention relates to a pharmaceutical dosage form which contains the pharmaceutical composition according to the invention.
  • the pharmaceutical dosage form according to the invention is produced for administration twice daily, for administration once daily or for administration less frequently than once daily.
  • Administration is preferably systemic, in particular oral.
  • the pharmaceutical dosage form according to the invention can be administered, for example, as a liquid dosage form in the form of injection solutions, drops or juices, or as a semi-solid dosage form in the form of granules, tablets, pellets, patches, capsules, plasters/spray-on plasters or aerosols.
  • auxiliary substances etc. and the amounts thereof to be used depend on whether the form of administration is to be administered orally, perorally, parenterally, intravenously, intraperitoneally, intradermally, intramuscularly, intranasally, buccally, rectally or locally, for example to the skin, the mucosa or into the eyes.
  • compositions in the form of tablets, dragees, capsules, granules, drops, juices and syrups are suitable for oral administration, and solutions, suspensions, readily reconstitutable dry preparations and also sprays are suitable for parenteral, topical and inhalatory administration.
  • the amount of the compounds according to the invention to be administered to the patient varies in dependence on the weight of the patient, on the type of administration, on the indication and on the severity of the disease. Usually, from 0.00005 mg/kg to 50 mg/kg, preferably from 0.001 mg/kg to 10 mg/kg, of at least one compound according to the invention is administered.
  • Another aspect of the invention relates to a process for the preparation of the compounds according to the invention. Suitable processes for the synthesis of the compounds according to the invention are known in principle to the person skilled in the art.
  • the compounds according to the invention can be obtained via different synthesis routes. Depending on the synthesis route, different intermediates are prepared and subsequently further reacted.
  • the synthesis of the compounds according to the invention proceeds via a synthesis route which comprises the preparation of an intermediate according to general formula (IIIa):
  • R 1 , R 2 and R 3 are defined as above.
  • the synthesis of the compounds according to the invention proceeds via a synthesis route which comprises the preparation of an intermediate according to general formula (IIIb):
  • R 1 , R 2 and R 3 are defined as above and PG is a protecting group.
  • the protecting group is -p-methoxybenzyl. Therefore, in another preferred embodiment, the synthesis of the compounds according to the invention proceeds via a synthesis route which comprises the preparation of an intermediate according to general formula (IIIc):
  • R 1 , R 2 and R 3 are defined as above.
  • the -p-methoxybenzyl moiety represents a protecting group which can be cleaved in the course of the synthesis route.
  • the synthesis of the compounds according to the invention proceeds via a synthesis route which comprises the preparation of
  • RT room temperature (23 ⁇ 7° C.)
  • M are indications of concentration in mol/l
  • aq.” means aqueous
  • anhydr.” means anhydrous
  • sat.” means saturated
  • sol.” means solution
  • cone.” means concentrated.
  • the mixing ratios of solvents or eluents for chromatography are specified in v/v.
  • CIS refers to the relative configuration of compounds described herein, in which both nitrogen atoms are drawn on the same face of the cyclohexane ring as described in the following exemplary structure. Two depictions are possible:
  • TRANS refers to compounds, in which both nitrogen atoms are on opposite faces of the cyclohexane ring as described in the following exemplary structure. Two depictions are possible:
  • Step 1 CIS-1-((1-(benzyloxy)cyclobutyl)methyl)-3-(3,4-dimethoxybenzyl)-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
  • Step 2 CIS-8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
  • Step 1 1-((CIS-8-(dimethylamino)-3-(4-methoxybenzyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl)methyl)cyclobutanecarbonitrile
  • Step 2 1-((CIS-8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl)methyl) cyclobutanecarboxamide
  • Step 3 1-((cis-8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl)methyl)cyclobutane carbonitrile
  • reaction mixture was allowed to stir another 2 h at reflux, then cooled to RT, diluted with water (150 mL) and the layers partitioned. The aqueous layer was extracted with EtOAc (3 ⁇ 300 mL). The combined organic layers were dried over Na 2 SO 4 and then concentrated in vacuo. The residue was filtered through a plug of silica gel using a DCM/MeOH (19/1 v/v) mixture.
  • Step 1 1-Cyclobutylmethyl-3-(4-methoxy-benzyl)-9,12-dioxa-1,3-diaza-dispiro[4.2.4.2]tetradecan-2-one
  • Step 2 1-Cyclobutylmethyl-3-(4-methoxy-benzyl)-1,3-diaza-spiro[4.5]decane-2,8-dione
  • Step 3 1-(cyclobutylmethyl)-8-(isobutyl(methyl)amino)-3-(4-methoxybenzyl)-2-oxo-1,3-diazaspiro[4.5]decane-8-carbonitrile
  • Step 4 CIS-1-(cyclobutylmethyl)-8-(isobutyl(methyl)amino)-3-(4-methoxybenzyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
  • Step 5 CIS-1-(Cyclobutyl-methyl)-8-(methyl-(2-methyl-propyl)-amino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
  • KOtBu (57.0 g, 508.4 mmol) was added to the solution of 2-(pyridin-2-yl)acetonitrile (50.0 g, 423.7 mmol) and ethyl acrylate (89.0 g, 889.8 mmol) in THF (500 mL) at 0° C. and stirred for 16 h at RT. The reaction mixture was quenched with sat. aq. NH 4 Cl and extracted with EtOAc (2 ⁇ 500 mL).
  • Step 1 8-(pyridin-2-yl)-1,4-dioxaspiro[4.5]decane-8-carbonitrile
  • Step 3 methyl 8-(pyridin-2-yl)-1,4-dioxaspiro[4.5]decan-8-ylcarbamate
  • Step 1 8-(Dimethylamino)-1,4-dioxaspiro 4.5]decane-8-carbonitrile
  • Dimethylamine hydrochloride 52 g, 0.645 mol was added to the solution of 1,4-dioxaspiro-[4.5]-decan-8-one (35 g, 0.224 mmol) in MeOH (35 mL) at RT under argon atmosphere. The solution was stirred for 10 min and 40 wt % aq. dimethylamine (280 mL, 2.5 mol) and KCN (32 g, 0.492 mol) were sequentially added. The reaction mixture was stirred for 48 h at RT, then diluted with water (100 mL) and extracted with EtOAc (2 ⁇ 200 mL).
  • Step 2 N,N-dimethyl-8-phenyl-1,4-dioxaspiro[4.5]decan-8-amine
  • Step 1 9,12-Dioxa-2,4-diazadispiro[4.2.4 ⁇ circumflex over ( ) ⁇ 8 ⁇ 0.2 ⁇ circumflex over ( ) ⁇ 5 ⁇ ]tetradecane-1,3-dione
  • Step 2 2-[(4-Methoxyphenyl)-methyl]-9,12-dioxa-2,4-diazadispiro[4.2.4 ⁇ circumflex over ( ) ⁇ 8 ⁇ 0.2 ⁇ circumflex over ( ) ⁇ 5 ⁇ ]tetradecane-1,3-dione
  • Step 3 2-[(4-Methoxyphenyl)-methyl]-9,12-dioxa-2,4-diazadispiro[4.2.4 ⁇ circumflex over ( ) ⁇ 8 ⁇ 0.2 ⁇ circumflex over ( ) ⁇ 5 ⁇ ]tetradecan-3-one
  • Step 4 3-[(4-Methoxyphenyl)-methyl]-1,3-diazaspiro[4.5]decane-2,8-dione
  • Step 1 CIS-8-(dimethylamino)-1-isobutyl-3-(4-methoxybenzyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
  • CIS-8-Dimethylamino-8-[3-(methoxymethyloxy)-phenyl]-3-[(4-methoxyphenyl)-methyl]-1,3-diazaspiro[4.5]decan-2-one (INT-968) was converted into CIS-1-(cyclobutylmethyl)-8-(dimethylamino)-3-(4-methoxybenzyl)-8-(3-(methoxymethoxy)phenyl)-1,3-diazaspiro[4.5]decan-2-one.
  • Step 2 CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-8-(3-hydroxyphenyl)-3-[(4-methoxyphenyl)-methyl]-1,3-diazaspiro[4.5]decan-2-one
  • Step 1 8-(dimethylamino)-3-(4-methoxybenzyl)-2-oxo-1,3-diazaspiro[4.5]decane-8-carbonitrile
  • Dimethylamine hydrochloride (76.4 g, 936.4 mmol) was added to a solution of 3-[(4-methoxyphenyl)-methyl]-1,3-diazaspiro[4.5]decane-2,8-dione (INT-966) (90 g, 312.13 mmol) in MeOH (180 mL) at RT under argon atmosphere. The solution was stirred for 15 min and 40 wt % aq. dimethylamine (780 mL) and KCN (48.76 g, 749.11 mmol) were sequentially added. The reaction mixture was stirred for 48 h and the completion of the reaction was monitored by NMR.
  • reaction mixture was diluted with water (1.0 L) and the organic product was extracted with ethyl acetate (2 ⁇ 2.0 L). The combined organic layer was dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure to afford 90 g (85%) of 8-(dimethylamino)-3-(4-methoxybenzyl)-2-oxo-1,3-diazaspiro[4.5]decane-8-carbonitrile as an off white solid (TLC system: TLC system: 10% MeOH in DCM; Rf: 0.35, 0.30).
  • Step 2 CIS-8-Dimethylamino-8-(3-fluorophenyl)-3-[(4-methoxyphenyl)-methyl]-1,3-diazaspiro[4.5]decan-2-one
  • Step 1 8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4,5]decane-2,4-dione
  • Step 2 8-(dimethylamino)-8-phenyl-1, 3-diazaspiro [4, 5] decan-2-one
  • Step 3 CIS-8-Dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
  • Step 1 CIS-2-[8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl]-acetic acid tert-butyl ester
  • Step 2 cis-2-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl)-acetic acid trifluoroacetic acid salt
  • CIS-2-[8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl]-acetic acid tert-butyl ester 200 mg, 0.4 mmol was dissolved in TFA (5 mL) and heated to reflux overnight. After cooling to RT all volatiles are removed in vacuo. The residue was taken up in THF (1 mL) and added dropwise to diethyl ether (20 mL).
  • CIS-2-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl)-acetic acid (INT-977) trifluoroacetic acid salt (119 mg, 0.35 mmol) was dissolved in DCM (5 mL). Triethylamine (0.21 mL, 1.6 mmol), dimethylamine (0.54 mL, 1.1 mmol) and T3P (0.63 mL, 1.1 mmol) were sequentially added. The reaction mixture was stirred at RT overnight, then diluted with 1 M aq. Na 2 CO 3 (5 mL).
  • Step 1 CIS-8-(dimethylamino)-3-(4-methoxybenzyl)-1-((1-methylcyclobutyl)methyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
  • Step 2 CIS-8-Dimethylamino-1-[(1-methyl-cyclobutyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
  • Step 1 CIS-8-(dimethylamino)-1-isobutyl-3-(4-methoxybenzyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
  • CIS-8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-975) was converted into CIS-8-(dimethylamino)-1-isobutyl-3-(4-methoxybenzyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one.
  • Step 2 CIS-1-(Cyclobutyl-methyl)-8-(ethyl-methyl-amino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
  • step 2 CIS-8-(dimethylamino)-1-isobutyl-3-(4-methoxybenzyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one was converted into CIS-1-(Cyclobutyl-methyl)-8-(ethyl-methyl-amino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-984).
  • Step 1 CIS-3-benzyl-1-(cyclobutylmethyl)-8-(methylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
  • N-Iodosuccinimide (3.11 g, 13.92 mmol) was added to the solution of CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-8-phenyl-3-[phenyl-methyl]-1,3-diazaspiro[4.5]decan-2-one (INT-950) (4 g, 9.28 mmol) in a mixture of acetonitrile and THF (1:1 v/v, 80 mL) and the resulting mixture was stirred at RT for 16 h. The reaction mixture was basified with 2N aq. NaOH to pH10 and the organic product was extracted with DCM (3 ⁇ 10 mL).
  • Step 2 CIS-3-benzyl-1-(cyclobutylmethyl)-8-(ethyl(methyl)amino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
  • Step 3 CIS-1-(Cyclobutyl-methyl)-8-(ethyl-methyl-amino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-986)
  • step 2 CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-8-phenyl-3-[(4-methoxyphenyl)-methyl]-1,3-diazaspiro[4.5]decan-2-one (INT-952) was converted into CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-987).
  • Step 1 CIS-8-(dimethylamino)-1-[2-(1-methoxycyclobutyl)ethyl]-3-[(4-methoxyphenyl)methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
  • Step 2 CIS-8-(dimethylamino)-1-(2-(1-methoxycyclobutyl)ethyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-988)
  • CIS-8-Dimethylamino-1-(2-methyl-propyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-241) (0.9 g, 2.73 mmol) was added to a solution of NaH (60 wt % in mineral oil, 1.64 g, 41.03 mmol) in DMF (20 mL) at RT. The reaction mixture was stirred at RT for 15 min, then cooled to 0° C. and ethyl 2-bromoacetate (4.56 g, 27.35 mmol) was added dropwise. The resulting mixture was stirred at RT for 2 days. The reaction completion was monitored by TLC. The reaction mixture was quenched with water and concentrated under reduced pressure.
  • Step 1 ethyl 2-(cis-8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3 yl)acetate
  • KOtBu (1M in THF) 54.90 mL, 54.95 mmol was added to a solution of CIS-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-976) (10 g, 36.63 mmol) in THF (950 mL) under argon atmosphere at 0° C. and the reaction mixture was stirred for 15 min. A solution of ethyl bromoacetate (5.06 mL, 43.96 mmol) in THF (50 mL) was added. The reaction mixture was warmed up to RT and stirred for 48 h. The reaction completion was monitored by TLC.
  • Step 2 2-(cis-8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)acetic acid
  • Step 3 2-(cis-8-(dimethylamino)-1-((1-hydroxycyclobutyl)methyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)acetic acid
  • Step 1 CIS-tert-butyl 2-[8-(dimethylamino)-1-[(1-methylcyclobutyl)methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]acetate
  • CIS -8-Dimethylamino-1-[(1-methyl-cyclobutyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-982) (2.8 g, 7.9 mmol) was dissolved in THF (110 mL) and the solution was cooled to 0° C. Lithium diisopropylamide solution in THF/heptane/ethylbenzene (2M, 16 mL) was added dropwise. The reaction mixture was stirred for 30 min and t-butyl-bromoacetate was added dropwise at the same temperature. The reaction mixture was concentrated in vacuo, water was added and the resulting mixture was extracted with DCM (3 ⁇ 250 mL).
  • Step 2 CIS-2-[8-Dimethylamino-1-[(1-methyl-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetic acid; 2,2,2-trifluoro-acetic acid salt
  • Step 1 and step 2 ethyl-(8-phenyl-1,4-dioxa-spiro[4.5]dec-8-yl)-amine hydrochloride (INT-1004)
  • Step 3 4-ethylamino-4-phenyl-cyclohexanone (INT-1005)
  • Step 4 mixture of CIS- and TRANS-8-ethylamino-8-phenyl-1,3-diaza-spiro[4.5]decane-2,4-dione (INT-1006 and INT-1007)
  • Step 5 CIS-8-ethylamino-8-phenyl-1,3-diaza-spiro[4.5]decane-2,4-dione (INT-1006)
  • the solid material was filtered off and washed with MeOH/DCM (1:5, 50 ml) to get 8-ethylamino-8-phenyl-1,3-diaza-spiro[4.5]decane-2,4-dione tartrate (7.5 g) as a white solid.
  • the solid was suspended in sat. aq. NaHCO 3 (pH8) and the resulting mixture was extracted with 25% MeOH-DCM (2 ⁇ 800 ml). Combined organic extracts were washed with water (300 ml), brine (300 ml) and dried over anhydrous Na 2 SO 4 .
  • Step 6 CIS-8-ethylamino-8-phenyl-1,3-diaza-spiro[4.5]decan-2-one (INT-1008)
  • Step 1 tert-butyl CIS-2-(8-(dimethylamino)-1-((1-hydroxycyclobutyl)methyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)acetate
  • Step 2 CIS-2-(8-(dimethylamino)-1-((1-hydroxycyclobutyl)methyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)acetic acid hydrochloride
  • Step 1 tert-butyl CIS-2-(8-(dimethylamino)-2,4-dioxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)acetate
  • Step 2 sodium CIS-2-(8-(dimethylamino)-1-((1-hydroxycyclobutyl)methyl)-2,4-dioxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)acetate (INT-1020)
  • Titanium ethoxide (58.45 g, 256.4 mmol) was added to a solution of 1,4-dioxaspiro[4.5]decan-8-one (20 g, 128.20 mmol) and 2-methylpropane-2-sulfinamide (15.51 g, 128.20 mmol) in THF (200 mL) at RT and the reaction mixture was stirred at RT for 18 h. The reaction mixture was cooled to 0° C. and quenched by dropwise addition of sat. aq. NaHCO 3 (500 mL) over a period of 30 min. The organic product was extracted with EtOAc (3 ⁇ 100 mL).
  • Step 2 2-methyl-N-(8-phenyl-1,4-dioxaspiro[4.5]decan-8-yl)propane-2-sulfinamide
  • Phenylmagnesium bromide (1M in THF, 116 mL, 116 mmol) was added dropwise to a solution of 2-methyl-N-(1,4-dioxaspiro[4.5]decan-8-ylidene)propane-2-sulfinamide (10 g, 38.61 mmol) in THF (500 mL) at ⁇ 10° C. under argon atmosphere. The reaction mixture was stirred for 2 h at ⁇ 10° C. to 0° C. The reaction completion was monitored by TLC. The reaction mixture was quenched with sat. aq. NH 4 Cl (50 mL) at 0° C. and the organic product was extracted with EtOAc (3 ⁇ 100 mL).
  • Step 4 8-phenyl-N-((tetrahydrofuran-3-yl)methyl)-1,4-dioxaspiro[4.5]decan-8-amine
  • Step 5 N-methyl-8-phenyl-N-((tetrahydrofuran-3-yl)methyl)-1,4-dioxaspiro[4.5]decan-8-amine)
  • Step 6 4-(methyl((tetrahydrofuran-3-yl)methyl)amino)-4-phenylcyclohexanone
  • Step 7 8-(methyl((tetrahydrofuran-3-yl)methyl)amino)-8-phenyl-1,3-diazaspiro[4.5]decane-2,4-dione
  • Step 8 CIS-8-(methyl((tetrahydrofuran-3-yl)methyl)amino)-8-phenyl-1,3-diazaspiro[4.5]decane-2,4-dione
  • Diastereomeric mixture of 8-(methyl((tetrahydrofuran-3-yl)methyl)amino)-8-phenyl-1,3-diazaspiro[4.5]decane-2,4-dione (1.0 g) was separated by reverse phase preparative HPLC to afford 400 mg of isomer 1 (CIS-8-(methyl((tetrahydrofuran-3-yl)methyl)amino)-8-phenyl-1,3-diazaspiro[4.5]decane-2,4-dione) and 60 mg of isomer 2 (TRANS-8-(methyl((tetrahydrofuran-3-yl)methyl)amino)-8-phenyl-1,3-diazaspiro[4.5]decane-2,4-dione) and 300 mg of mixture of both isomers.
  • Reverse phase preparative HPLC conditions mobile phase: 10 mM ammonium bicarbonate in H 2 O/acetonitrile, column: X-BRIDGE-C 18 (150*30), 5 ⁇ m, gradient (T/B %): 0/35, 8/55, 8.1/98, 10/98, 10.1/35, 13/35, flow rate: 25 ml/min, diluent: mobile phase+THF.
  • Step 9 CIS-8-(methyl((tetrahydrofuran-3-yl)methyl)amino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-1026)
  • Step 1 CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-8-(3-fluorophenyl)-3-[(4-methoxyphenyl)-methyl]-1,3-diazaspiro[4.5]decan-2-one
  • Step 2 CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-8-(3-fluorophenyl)-1,3-diazaspiro[4.5]decan-2-one
  • Step 1 CIS-[8-dimethylamino-2-oxo-8-phenyl-1-(2-trimethylsilanyl-ethoxymethyl)-1,3-diaza-spiro[4.5]dec-3-yl]-acetic acid tert-butyl ester
  • Step 2 CIS-[8-dimethylamino-2-oxo-8-phenyl-1-(2-trimethylsilanyl-ethoxymethyl)-1,3-diaza-spiro[4.5]dec-3-yl]-acetic acid tert-butyl ester
  • Step 3 CIS-[8-methylamino-2-oxo-8-phenyl-1-(2-trimethylsilanyl-ethoxymethyl)-1,3-diaza-spiro[4.5]dec-3-yl]-acetic acid tert-butyl ester
  • Step 4 CIS-(8-methylamino-2-oxo-8-phenyl-1,3-diaza-spiro[4.5]dec-3-yl)-acetic acid (INT-1034)
  • Step 1 CIS -(8-dimethylamino-1-oxetan-3-ylmethyl-2-oxo-8-phenyl-1,3-diaza-spiro[4.5]dec-3-yl)-acetic acid oxetan-3-ylmethyl ester
  • Step 1 CIS-(8-dimethylamino-2-oxo-8-phenyl-1,3-diaza-spiro[4.5]dec-3-yl)-acetic acid tert-butyl ester (INT-1033) was converted into CIS-(8-dimethylamino-1-oxetan-3-ylmethyl-2-oxo-8-phenyl-1,3-diaza-spiro[4.5]dec-3-yl)-acetic acid oxetan-3-ylmethyl ester.
  • Step 2 CIS-(8-dimethylamino-1-oxetan-3-ylmethyl-2-oxo-8-phenyl-1,3-diaza-spiro[4.5]dec-3-yl)-acetic acid (INT-1035)
  • Step 1 9,12-dioxa-2,4-diazadispiro[4.2.4 ⁇ circumflex over ( ) ⁇ 8 ⁇ 0.2 ⁇ circumflex over ( ) ⁇ 5 ⁇ ]tetradecan-3-one
  • Lithiumaluminiumhydride (2.2 equiv., 292 mmol) was suspended in THF (400 mL) and the suspension was cooled to 0° C.
  • 8-(Dimethylamino)-8-(m-tolyl)-1,3-diazaspiro[4.5]decan-2-one (B, 75 mg, 0.261 mmol) (step 1 of INT-965) was added portionwise at 0° C.
  • the reaction mixture was stirred 1.5 h at 0° C., then overnight at RT and then 2 h at 40° C.
  • the reaction mixture was cooled down to 0° C., quenched carefully with sat. aq.
  • Step 3 8-(dimethylamino)-2-oxo-1,3-diazaspiro[4.5]decane-8-carbonitrile (INT-1037)
  • Step 1 T RANS-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decane-2,4-dione
  • the resulting solid was dried under reduced pressure to get CIS-8-dimethylamino-8-phenyl-1,3-diaza-spiro[4.5]decane-2,4-dione (223 g, 0.776 mol, 65%) as a white solid.
  • the filtrate was collected from multiple batches (450 g) which contained a mixture of cis and trans isomers.
  • the filtrate was concentrated under reduced pressure and solid obtained was filtered and washed with water (1 L) and hexane (1 L). Solid material was dried under reduced pressure to get 100 g of a mixture of cis and trans (major) isomers.
  • Step 2 TRANS-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-1059)
  • TRANS-8-dimethylamino-8-phenyl-1,3-diaza-spiro[4.5]decane-2,4-dione was treated with LiAlH 4 to be converted into TRANS-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-1059). Mass: m/z 274.2 (M+H) + .
  • Step 3 1-aminomethyl-N′,N′-dimethyl-4-phenyl-N-(2,2,2-trifluoroethyl)cyclohexane-1,4-diamine
  • Step 4 CIS- and TRANS-8-dimethylamino-8-phenyl-1-(2,2,2-trifluoro-ethyl)-1,3-diaza-spiro[4.5]decan-2-one (INT-1068 and INT-1069)
  • HPLC: 98.53%, Column: Xbridge C-18 (100 ⁇ 4.6), 5p, Diluent: MeOH, Mobile phase: A) 0.05% TFA in water; B) ACN flow rate: 1 ml/min, R t 5.17 min.
  • CIS-2-[1-(cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetamide (SC_1195) (50 mg, 0.1255 mmol), 4-bromopyrimidine-2-carbonitrile (0.1882 mmol), 4,5-XantPhos (0.0188 mmol), Cs 2 CO 3 (0.2509 mmol) and Pd 2 (dba) 3 (0.0063 mmol) were dissolved in 1,4-dioxane (6 mL). The reaction mixture was degassed by three consecutive vacuum/nitrogen-refill cycles and then stirred at 90° C. for 18 h.
  • reaction mixture was warmed to RT and stirred for 4 h.
  • the reaction mixture was quenched with water and the organic product was extracted with DCM (3 ⁇ 20 mL).
  • the combined organic layer was washed with sat. aq. NaHCO 3 (10 mL), brine (10 mL) and dried over anhydr.
  • CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-987) (0.2 g, 0.57 mmol) was added to a solution of NaH (60% in mineral oil) (0.15 g, 3.47 mmol) in DMF (5 mL) at RT and the reaction mixture was stirred at RT for 1 h. The reaction mixture was cooled to 0° C. and 2-bromo-N-methylacetamide (0.52 g, 3.47 mmol) in DMF (2 mL) was added dropwise. the resulting mixture was stirred for 30 min at 0° C. and then at RT for 16 h.
  • N-Iodosuccinimide (71.8 mg, 0.319 mmol) was added to a solution of CIS-2-[8-dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(oxetan-3-yl)-acetamide (SC_1301) (100 mg, 0.213 mmol) in a mixture of acetonitrile and THF (1:1 v/v, 5 mL) at 0° C. and the resulting mixture was stirred at RT for 16 h.
  • the reaction mixture was basified with 2N NaOH solution to pH10 and the organic product was extracted with ethyl acetate (10 mL ⁇ 3). The combined organic extracts were dried over anhydr. Na 2 SO 4 and concentrated under reduced pressure.
  • the resulting crude product was purified by preparative reverse phase HPLC to give 50 mg of the desired product as a formiate.
  • the isolated product was diluted with water (5 mL) and basified with sat. aq. NaHCO 3 .
  • the product was extracted with EtOAc (10 mL ⁇ 2), combined organic layer was dried over anhydr.
  • KOtBu (187 mg, 1.67 mmol) was added to a solution of CIS-1-(cyclobutyl-methyl)-8-dimethylamino-8-(3-fluorophenyl)-1,3-diazaspiro[4.5]decan-2-one (INT-1031) (400 mg, 1.1 mmol) in dry THF (9 mL) at 0° C. The mixture was stirred for 15 min at this temperature and t-butyl-bromoacetate (0.246 mL, 1.67 mmol) was added subsequently. After stirring for 1 h at 0° C., the reaction was quenched with water, diluted with EtOAc and stirred for 5 min at RT.
  • Step 1 tert-butyl TRANS-2-(1-(cyclopropylmethyl)-8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)acetate
  • Step 2 TRANS-2-(1-(cyclopropylmethyl)-8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)acetamide (INT-1363)
  • hMOP human mu-opioid receptor
  • hKOP human kappa-opioid receptor
  • hDOP human delta-opioid receptor
  • hNOP human nociceptin/orphanin FQ peptide receptor
  • the hMOP receptor binding assay was performed as homogeneous SPA-assay (scintillation proximity assay) using the assay buffer 50 mM TRIS-HCl (pH 7.4) supplemented with 0.052 mg/ml bovine serum albumin (Sigma-Aldrich Co., St. Louis, Mo.).
  • the final assay volume 250 ⁇ l/well included 1 nM of [N-allyl-2,3- 3 H]naloxone as ligand (PerkinElmer Life Sciences, Inc. Boston, Mass., USA), and either test compound in dilution series or 25 ⁇ M unlabeled naloxone for determination of unspecific binding.
  • the test compound was diluted with 25% DMSO in H 2 O to yield a final 0.5% DMSO concentration, which also served as a respective vehicle control.
  • the assay was started by adding wheat germ agglutinin coated SPA beads (GE Healthcare UK Ltd., Buckinghamshire, UK) which had been preloaded with hMOP receptor membranes (PerkinElmer Life Sciences, Inc. Boston, Mass., USA). After incubation for 90 minutes at RT and centrifugation for 20 minutes at 500 rpm the signal rate was measured by means of a 1450 Microbeta Trilux ⁇ -counter (PerkinElmer Life Sciences/Wallac, Turku, Finland). Half-maximal inhibitory concentration (IC50) values reflecting 50% displacement of [ 3 H]naloxone-specific receptor binding were calculated by nonlinear regression analysis and Ki values were calculated by using the Cheng-Prusoff equation, (Cheng and Prusoff, 1973).
  • the hKOP receptor binding assay is run as homogeneous SPA-assay (scintillation proximity assay) using the assay buffer 50 mM TRIS-HCl (pH 7.4) supplemented with 0.076 mg BSA/ml.
  • the final assay volume of 250 ⁇ l per well includes 2 nM of [ 3 H]U69,593 as ligand, and either test compound in dilution series or 100 ⁇ M unlabeled naloxone for determination of unspecific binding.
  • the test compound is diluted with 25% DMSO in H 2 O to yield a final 0.5% DMSO concentration which serves as respective vehicle control, as well.
  • the assays are started by the addition of wheat germ agglutinin coated SPA beads (1 mg SPA beads/250 ⁇ l final assay volume per well) which has been preloaded for 15 minutes at room temperature with hKOP receptor membranes (14.8 ⁇ g/250 ⁇ l final assay volume per well). After short mixing on a mini-shaker, the microtiter plates are covered with a lid and the assay plates are incubated for 90 minutes at room temperature. After this incubation, the microtiter plates are sealed with a topseal and centrifuged for 20 minutes at 500 rpm. The signal rate is measured after a short delay of 5 minutes by means of a 1450 Microbeta Trilux ⁇ -counter (PerkinElmer Life Sciences/Wallac.
  • the hDOP receptor binding assay is performed as homogeneous SPA-assay using the assay buffer 50 mM TRIS-HCl, 5 mM MgCl 2 (pH 7.4).
  • the final assay volume (250 ⁇ l/well) includes 1 nM of [Tyrosyl-3,5- 3 H]2-D-Ala-deltorphin II as ligand, and either test compound in dilution series or 10 ⁇ M unlabeled naloxone for determination of unspecific binding.
  • the test compound is diluted with 25% DMSO in H 2 O to yield a final 0.5% DMSO concentration which serves as respective vehicle control, as well.
  • the assays are started by the addition of wheat germ agglutinin coated SPA beads (1 mg SPA beads/250 ⁇ l final assay volume per well) which has been preloaded for 15 minutes at room temperature with hDOP receptor membranes (15.2 ⁇ g/250 ⁇ l final assay volume per well). After short mixing on a mini-shaker, the microtiter plates are covered with a lid and the assay plates are incubated for 120 minutes at room temperature and centrifuged for 20 minutes at 500 rpm. The signal rate is measured by means of a 1450 Microbeta Trilux ⁇ -counter (PerkinElmer Life Sciences/Wallac. Turku, Finland).
  • IC50 Half-maximal inhibitory concentration
  • the hNOP receptor binding assay was performed as homogeneous SPA-assay (scintillation proximity assay) using the assay buffer 50 mM TRIS-HCl, 10 mM MgCl 2 , 1 mM EDTA (pH 7.4).
  • the final assay volume 250 ⁇ l/well included 0.5 nM of [leucyl- 3 H]nociceptin as ligand (PerkinElmer Life Sciences, Inc. Boston, Mass., USA), and either test compound in dilution series or 1 ⁇ M unlabeled nociceptin for determination of unspecific binding.
  • the test compound was diluted with 25% DMSO in H 2 O to yield a final 0.5% DMSO concentration, which also served as a respective vehicle control.
  • the assay was started by adding wheat germ agglutinin coated SPA beads (GE Healthcare UK Ltd., Buckinghamshire, UK) which had been preloaded with hMOP receptor membranes (PerkinElmer Life Sciences, Inc. Boston, Mass., USA). After incubation for 60 minutes at RT and centrifugation for 20 minutes at 500 rpm the signal rate was measured by means of a 1450 Microbeta Trilux ⁇ -counter (PerkinElmer Life Sciences/Wallac. Turku, Finland). Half-maximal inhibitory concentration (IC50) values reflecting 50% displacement of [ 3 H]nociceptin-specific receptor binding were calculated by nonlinear regression analysis and Ki values were calculated by using the Cheng-Prusoff equation, (Cheng and Prusoff, 1973).
  • the [ 35 S]GTP ⁇ S assays are carried out essentially as described by Gillen et al (2000). They are run as homogeneous scintillation proximity (SPA) assays in microtiter luminescence plates, where each well contains 1.5 mg of WGA-coated SPA-beads.
  • SPA scintillation proximity
  • hNOP hMOP
  • hDOP hKOP receptor expressing cell membranes from CHO-K1 or HEK293 cells
  • 10 or 5 ⁇ g membrane protein per assay are incubated with 0.4 nM [ 35 S]GTP ⁇ S and serial concentrations of receptor-specific agonists in buffer containing 20 mM HEPES pH 7.4, 100 mM NaCl, 10 mM MgCl2, 1 mM EDTA, 1 mM dithiothreitol, 1.28 mM NaN 3 , and 10 ⁇ M GDP for 45 min at room temperature.
  • microtiter plates are then centrifuged for 10 min at 830 to sediment the SPA beads.
  • the microtiter plates are sealed and the bound radioactivity [cpm] is determined after a delay of 15 min by means of a 1450 Microbeta Trilux (PerkinElmer, Waltham, Mass.).
  • the unstimulated basal binding activity (UBS obs [cpm]) is determined from 12 unstimulated incubates and is set as 100% basal binding.
  • the arithmetic mean of the observed total [ 35 S]GTP ⁇ S binding (TB obs [cpm]) of all incubates (duplicates) stimulated by the receptor-specific agonists i.e. N/OFQ, SNC80, DAMGO, or U69,593
  • TB obs [%] percent total binding relative to the basal binding activity (i.e. 100% binding).
  • the potency (EC 50 ) of the respective agonist and its maximal achievable total [ 35 S]GTP ⁇ S binding (TB calc [%]) above its calculated basal binding (UBS calc [%]) are determined from its transformed data (TB obs [%]) by means of nonlinear regression analysis with XLfit for each individual concentration series. Then the difference between the calculated unstimulated [ 35 S]GTP ⁇ S binding (UBS calc [%]) and the maximal achievable total [ 35 S]GTP ⁇ S binding (TB calc [%]) by each tested agonist is determined (i.e. B1 calc [%]).
  • the percentage efficacies of test compounds at the hDOP, hMOP, or hKOP receptor are determined versus the calculated maximal enhancement of [ 35 S]GTP ⁇ S binding by the full agonists SNC80 (B1 calc-SNC80 [%]), DAMGO (B1 calc-DAMGO [%]) and U69,593 (B1 calc-U69,593 [%]) which are set as 100% relative efficacy at each receptor, respectively.

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Abstract

The invention relates to 3-(carboxymethyl)-8-amino-2-oxo-1,3-diaza-spiro-[4.5]-decane derivatives, their preparation and their use in medicine, particularly in the treatment of pain.

Description

  • This application is a continuation of U.S. Non-Provisional patent application Ser. No. 17/007,557, filed Aug. 31, 2020, which is a continuation of U.S. Non-Provisional patent application Ser. No. 16/454,489, filed Jun. 27, 2019; now U.S. Pat. No. 10,807,989, which is a continuation of U.S. Non-Provisional patent application Ser. No. 16/212,723, filed Dec. 7, 2018, abandoned, which is a continuation of U.S. Non-Provisional patent application Ser. No. 15/980,181, filed May 15, 2018, abandoned, which is a continuation of U.S. Non-Provisional patent application Ser. No. 15/405,919, filed Jan. 13, 2017, abandoned, which claims foreign priority of European Patent Application No. 16 151 014.4, filed Jan. 13, 2016, the disclosures of which are incorporated herein by reference.
  • The invention relates to 3-(carboxymethyl)-8-amino-2-oxo-1,3-diaza-spiro-[4.5]-decane derivatives, their preparation and use in medicine, particularly in various neurological disorders, including but not limited to pain, neurodegenerative disorders, neuroinflammatory disorders, neuropsychiatric disorders, substance abuse/dependence.
  • Opioid receptors are a group of Gi/o protein-coupled receptors which are widely distributed in the human body. The opioid receptors are currently subdivided into four major classes, i.e. the three classical opioid receptors mu-opioid (MOP) receptor, kappa-opioid (KOP) receptor, and delta-opioid (DOP) receptor as well as the opioid receptor-like (ORL-1) receptor, which was more recently discovered based on its high homology with said classical opioid receptors. After identification of the endogenous ligand of the ORL-1 receptor, known as nociceptin/orphanin FQ, a highly basic 17 amino acid peptide isolated from tissue extracts in 1995, the ORL-1 receptor was renamed “nociceptin opioid peptide receptor” and abbreviated as “NOP-receptor”.
  • The classical opioid receptors (MOP, KOP and DOP) as well as the NOP receptor are widely distributed/expressed in the human body, including in the brain, the spinal cord, on peripheral sensory neurons and the intestinal tract, wherein the distribution pattern differs between the different receptor classes.
  • Nociceptin acts at the molecular and cellular level in very much the same way as opioids. However, its pharmacological effects sometimes differ from, and even oppose those of opioids. NOP-receptor activation translates into a complex pharmacology of pain modulation, which, depending on route of administration, pain model and species involved, leads to either pronociceptive or antinociceptive activity. Furthermore, the NOP receptor system is upregulated under conditions of chronic pain. Systemic administration of selective NOP receptor agonists was found to exert a potent and efficacious analgesia in non-human primate models of acute and inflammatory pain in the absence of side effects. The activation of NOP receptors has been demonstrated to be devoid of reinforcing effects but to inhibit opioid-mediated reward in rodents and non-human primates (Review: Schroeder et al, Br J Pharmacol 2014; 171 (16): 3777-3800, and references therein).
  • Besides the involvement of the NOP receptor in nociception, results from preclinical experiments suggest that NOP receptor agonists might be useful inter alia in the treatment of neuropsychiatric disorders (Witkin et al, Pharmacology & Therapeutics, 141 (2014) 283-299; Jenck et al., Proc. Natl. Acad. Sci. USA 94, 1997, 14854-14858). Remarkably, the DOP receptor is also implicated to modulate not only pain but also neuropsychiatric disorders (Mabrouk et al, 2014; Pradhan et al., 2011).
  • Strong opioids acting at the MOP receptor site are widely used to treat moderate to severe acute and chronic pain. However, the therapeutic window of strong opioids is limited by severe side effects such as nausea and vomiting, constipation, dizziness, somnolence, respiratory depression, physical dependence and abuse. Furthermore, it is known that MOP receptor agonists show only reduced effectiveness under conditions of chronic and neuropathic pain.
  • It is known that some of the above mentioned side-effects of strong opioids are mediated by activation of classic opioid-receptors within the central nervous system. Furthermore, peripheral opioid receptors, when activated, can inhibit transmission of nociceptive signals shown in both, clinical and animal studies (Gupta et ah, 2001; Kalso et ah, 2002; Stein et al., 2003; Zollner et ah, 2008).
  • Thus, to avoid CNS-mediated adverse effects after systemic administration, one approach has been to provide peripherally restricted opioid receptor ligands that do not easily cross the blood-brain barrier and therefore distribute poorly to the central nervous system (see for instance WO 2015/192039). Such peripherally acting compounds might combine effective analgesia with limited side-effects.
  • Another approach has been to provide compounds which interact with both the NOP receptor and the MOP receptor. Such compounds have for instance been described in WO 2004/043967, WO 2012/013343 and WO 2009/118168.
  • A further approach has been to provide multi-opioid receptor analgesics that modulate more than one of the opioid receptor subtypes to provide additive or synergistic analgesia and/or reduced side effects like abuse liability or tolerance.
  • On the one hand, it would be desirable to provide analgesics that selectively act on the NOP receptor system but less pronounced on the classic opioid receptor system, especially MOP receptor system, whereas it would be desirable to distinguish between central nervous activity and peripheral nervous activity. On the other hand, it would be desirable to provide analgesics that act on the NOP receptor system and also to a balanced degree on the MOP receptor system, whereas it would be desirable to distinguish between central nervous activity and peripheral nervous activity.
  • There is a need for medicaments which are effective in the treatment of pain and which have advantages compared to the compounds of the prior art. Where possible, such medicaments should contain such a small dose of active ingredient that satisfactory pain therapy can be ensured without the occurrence of intolerable treatment-emergent adverse events.
  • It is an object of the invention to provide pharmacologically active compounds, preferably analgesics that have advantages compared to the prior art.
  • This object has been achieved by the subject-matter of the patent claims.
  • A first aspect of the invention relates to 3-(carboxymethyl)-8-amino-2-oxo-1,3-diaza-spiro-[4.5]-decane derivatives according to general formula (I)
  • Figure US20210179627A1-20210617-C00001
  • wherein
    R1 and R2 independently of one another mean
    • —H;
  • —C1-C6-alkyl, linear or branched, saturated or unsaturated, unsubstituted or substituted with one, two, three or four substituents independently of one another selected from the group consisting of —F, —Cl, —Br, —I, —OH, —OCH3, —CN and —CO2CH3;
    a 3-12-membered cycloalkyl moiety, saturated or unsaturated, unsubstituted or substituted with one, two, three or four substituents independently of one another selected from the group consisting of —F, —Cl, —Br, —I, —OH, —OCH3, —CN and —CO2CH3; wherein said 3-12-membered cycloalkyl moiety is optionally connected through —C1-C6-alkylene-, linear or branched, saturated or unsaturated, unsubstituted; or
    a 3-12-membered heterocycloalkyl moiety, saturated or unsaturated, unsubstituted or substituted with one, two, three or four substituents independently of one another selected from the group consisting of —F, —Cl, —Br, —I, —OH, —OCH3, —CN and —CO2CH3; wherein said 3-12-membered heterocycloalkyl moiety is optionally connected through —C1-C6-alkylene-, linear or branched, saturated or unsaturated, unsubstituted;
    or
    R1 and R2 together with the nitrogen atom to which they are attached form a ring and mean —(CH2)3-6—; —(CH2)2—O—(CH2)2—; or —(CH2)2—NRA—(CH2)2—, wherein RA means —H or —C1-C6-alkyl, linear or branched, saturated or unsaturated, unsubstituted or substituted with one, two, three or four substituents independently of one another selected from the group consisting of —F, —Cl, —Br and —I;
    preferably with the proviso that R1 and R2 do not simultaneously mean —H;
    R3 means
    —C1-C6-alkyl, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted;
    a 3-12-membered cycloalkyl moiety, saturated or unsaturated, unsubstituted, mono- or polysubstituted; wherein said 3-12-membered cycloalkyl moiety is optionally connected through —C1-C6-alkylene-, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted;
    a 3-12-membered heterocycloalkyl moiety, saturated or unsaturated, unsubstituted, mono- or polysubstituted; wherein said 3-12-membered heterocycloalkyl moiety is optionally connected through —C1-C6-alkylene-, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted;
    a 6-14-membered aryl moiety, unsubstituted, mono- or polysubstituted; wherein said 6-14-membered aryl moiety is optionally connected through —C1-C6-alkylene-, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted; or a 5-14-membered heteroaryl moiety, unsubstituted, mono- or polysubstituted; wherein said 5-14-membered heteroaryl moiety is optionally connected through —C1-C6-alkylene-, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted;
    R4 means
    • —H;
  • —C1-C6-alkyl, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted; wherein said —C1-C6-alkyl is optionally connected through —C(═O)—, —C(═O)O—, or —S(═O)2—;
    a 3-12-membered cycloalkyl moiety, saturated or unsaturated, unsubstituted, mono- or polysubstituted; wherein said 3-12-membered cycloalkyl moiety is optionally connected through —C1-C6-alkylene-, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted; or wherein said 3-12-membered cycloalkyl moiety is optionally connected through —C(═O)—, —C(═O)O—, —C(═O)O—CH2—, or —S(═O)2—;
    a 3-12-membered heterocycloalkyl moiety, saturated or unsaturated, unsubstituted, mono- or polysubstituted; wherein said 3-12-membered heterocycloalkyl moiety is optionally connected through —C1-C6-alkylene-, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted; or wherein said 3-12-membered heterocycloalkyl moiety is optionally connected through —C(═O)—, —C(═O)O—, —C(═O)O—CH2—, or —S(═O)2—;
    a 6-14-membered aryl moiety, unsubstituted, mono- or polysubstituted; wherein said 6-14-membered aryl moiety is optionally connected through —C1-C6-alkylene-, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted; or wherein said 6-14-membered aryl moiety is optionally connected through —C(═O)—, —C(═O)O—, —C(═O)O—CH2—, or —S(═O)2—; or
    a 5-14-membered heteroaryl moiety, unsubstituted, mono- or polysubstituted; wherein said 5-14-membered heteroaryl moiety is optionally connected through —C1-C6-alkylene-, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted; or wherein said 5-14-membered heteroaryl moiety is optionally connected through —C(═O)—, —C(═O)O—, —C(═O)O—CH2—, or —S(═O)2—;
    X means —O—, —S— or —NR6—;
    R5 means
    • —H;
  • —C1-C6-alkyl, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted;
    a 3-12-membered cycloalkyl moiety, saturated or unsaturated, unsubstituted, mono- or polysubstituted; wherein said 3-12-membered cycloalkyl moiety is optionally connected through —C1-C6-alkylene-, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted;
    a 3-12-membered heterocycloalkyl moiety, saturated or unsaturated, unsubstituted, mono- or polysubstituted; wherein said 3-12-membered heterocycloalkyl moiety is optionally connected through —C1-C6-alkylene-, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted;
    a 6-14-membered aryl moiety, unsubstituted, mono- or polysubstituted; wherein said 6-14-membered aryl moiety is optionally connected through —C1-C6-alkylene-, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted; or
    a 5-14-membered heteroaryl moiety, unsubstituted, mono- or polysubstituted; wherein said 5-14-membered heteroaryl moiety is optionally connected through —C1-C6-alkylene-, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted; in case X means NR6, R6 means
    • —H;
  • —C1-C6-alkyl, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted;
    a 3-12-membered cycloalkyl moiety, saturated or unsaturated, unsubstituted, mono- or polysubstituted; wherein said 3-12-membered cycloalkyl moiety is optionally connected through —C1-C6-alkylene-, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted;
    a 3-12-membered heterocycloalkyl moiety, saturated or unsaturated, unsubstituted, mono- or polysubstituted; wherein said 3-12-membered heterocycloalkyl moiety is optionally connected through —C1-C6-alkylene-, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted;
    a 6-14-membered aryl moiety, unsubstituted, mono- or polysubstituted; wherein said 6-14-membered aryl moiety is optionally connected through —C1-C6-alkylene-, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted; or
    a 5-14-membered heteroaryl moiety, unsubstituted, mono- or polysubstituted; wherein said 5-14-membered heteroaryl moiety is optionally connected through —C1-C6-alkylene-, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted;
    or in case X means NR6, R5 and R6 together with the nitrogen atom to which they are attached form a 3-12-membered heterocycloalkyl moiety, saturated or unsaturated, unsubstituted, mono- or polysubstituted;
    R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19, and R20 independently of one another mean —H, —F, —Cl, —Br, —I, —OH, or —C1-C6-alkyl, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted;
    wherein “mono- or polysubstituted” means that one or more hydrogen atoms are replaced by a substituent independently of one another selected from the group consisting of —F, —Cl, —Br, —I, —CN, —R21, —C(═O)R21, —C(═O)OR21, —C(═O)NR21R22, —O—(CH2CH2—O)1-30—H, —O—(CH2CH2—O)1-30—CH3, ═O, —OR21, —OC(═O)R21, —OC(═O)OR21, —OC(═O)NR21R22, —NO2, —NR21R22, —NR21—(CH2)1-6—C(═O)R22, —NR21—(CH2)1-6—C(═O)OR22, —NR23—(CH2)1-6—C(═O)NR21R22, —NR21C(═O)R22, —NR21C(═O)—OR22, —NR23C(═O)NR21R22, —NR21S(═O)2R22, —SR21, —S(═O)R21, —S(═O)2R21, —S(═O)2OR21, and —S(═O)2NR21R22;
    wherein
    R21, R22 and R23 independently of one another mean
    • —H;
  • —C1-C6-alkyl, linear or branched, saturated or unsaturated, unsubstituted or substituted with one, two, three or four substituents independently of one another selected from the group consisting of —F, —Cl, —Br, —I, —CN, —OH, —NH2, and —O—C1-C6-alkyl;
    a 3-12-membered cycloalkyl moiety, saturated or unsaturated, unsubstituted; wherein said 3-12-membered cycloalkyl moiety is optionally connected through —C1-C6-alkylene-, linear or branched, saturated or unsaturated, unsubstituted or substituted with one, two, three or four substituents independently of one another selected from the group consisting of —F, —Cl, —Br, —I, —CN, —OH, —NH2, —C1-C6-alkyl and —O—C1-C6-alkyl;
    a 3-12-membered heterocycloalkyl moiety, saturated or unsaturated, unsubstituted; wherein said 3-12-membered heterocycloalkyl moiety is optionally connected through —C1-C6-alkylene-, linear or branched, saturated or unsaturated, unsubstituted or substituted with one, two, three or four substituents independently of one another selected from the group consisting of —F, —Cl, —Br, —I, —CN, —OH, —NH2, —C1-C6-alkyl and —O—C1-C6-alkyl;
    a 6-14-membered aryl moiety, unsubstituted, mono- or polysubstituted; wherein said 6-14-membered aryl moiety is optionally connected through —C1-C6-alkylene-, linear or branched, saturated or unsaturated, unsubstituted or substituted with one, two, three or four substituents independently of one another selected from the group consisting of —F, —Cl, —Br, —I, —CN, —OH, —NH2, —C1-C6-alkyl and —O—C1-C6-alkyl;
    a 5-14-membered heteroaryl moiety, unsubstituted, mono- or polysubstituted; wherein said 5-14-membered heteroaryl moiety is optionally connected through —C1-C6-alkylene-, linear or branched, saturated or unsaturated, unsubstituted or substituted with one, two, three or four substituents independently of one another selected from the group consisting of —F, —Cl, —Br, —I, —CN, —OH, —NH2, —C1-C6-alkyl and —O—C1-C6-alkyl;
    or R21 and R22 within —C(═O)NR21R22, —OC(═O)NR21R22, —NR21R22, —NR23—(CH2)1-6—C(═O)NR21R22, —NR23C(═O)NR21R22, or —S(═O)2NR21R22 together with the nitrogen atom to which they are attached form a ring and mean —(CH2)3-6—; —(CH2)2—O—(CH2)2—; or —(CH2)2—NRB—(CH2)2—, wherein RB means —H or —C1-C6-alkyl, linear or branched, saturated or unsaturated, unsubstituted or substituted with one, two, three or four substituents independently of one another selected from the group consisting of —F, —Cl, —Br and —I;
    or a physiologically acceptable salt thereof.
  • Preferably, aryl includes but is not limited to phenyl and naphthyl. Preferably, heteroaryl includes but is not limited to -1,2-benzodioxole, -pyrazinyl, -pyridazinyl, -pyridinyl, -pyrimidinyl, -thienyl, -imidazolyl, -benzimidazolyl, -thiazolyl, -1,3,4-thiadiazolyl, -benzothiazolyl, -oxazolyl, -benzoxazolyl, -pyrazolyl, -quinolinyl, -isoquinolinyl, -quinazolinyl, -indolyl, -indolinyl, -benzo[c][1,2,5]oxadiazolyl, -imidazo[1,2-a]pyrazinyl, or -1H-pyrrolo[2,3-b]pyridinyl. Preferably, cycloalkyl includes but is not limited to -cyclopropyl, -cyclobutyl, -cyclopentyl and -cyclohexyl. Preferably, heterocycloalkyl includes but is not limited to -aziridinyl, -azetidinyl, -pyrrolidinyl, -piperidinyl, -piperazinyl, -morpholinyl, -sulfamorpholinyl, -oxiridinyl, -oxetanyl, tetrahydropyranyl, and -pyranyl.
  • When a moiety is connected through an asymmetric group such as —C(═O)O— or —C(═O)O—CH2—, said asymmetric group may be arranged in either direction. For example, when R4 is connected to the core structure through —C(═O)O—, the arrangement may be either R4—C(═O)O-core or core-C(═O)O—R4.
  • In preferred embodiments of the compound according to the invention, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19, and R20 independently of one another mean —H, —F, —OH, or —C1-C6-alkyl: preferably —H.
  • In a preferred embodiment of the compound according to the invention, R1 means —H; and R2 means —C1-C6-alkyl, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted. Preferably, R1 means —H and R2 means —CH3.
  • In another preferred embodiment of the compound according to the invention, R1 means —CH3; and R2 means —C1-C6-alkyl, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted. Preferably, R1 means —CH3 and R2 means —CH3.
  • In still another preferred embodiment of the compound according to the invention, R1 and R2 together with the nitrogen atom to which they are attached form a ring and mean —(CH2)3-6—. Preferably, R1 and R2 together with the nitrogen atom to which they are attached form a ring and mean —(CH2)3—.
  • In yet another preferred embodiment,
      • R1 means —H or —CH3; and
      • R2 means a 3-12-membered cycloalkyl moiety, saturated or unsaturated, unsubstituted; wherein said 3-12-membered cycloalkyl moiety is connected through —CH2—, unsubstituted; preferably —CH2-cycloalkyl, —CH2-cyclobutyl or —CH2-cyclopentyl; or R2 means a 3-12-membered heterocycloalkyl moiety, saturated or unsaturated, unsubstituted; wherein said 3-12-membered heterocycloalkyl moiety is connected through —CH2—, unsubstituted; preferably —CH2-oxetanyl or —CH2-tetrahydrofuranyl.
  • In a preferred embodiment of the compound according to the invention, R3 means —C1-C6-alkyl, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted. Preferably, R3 means —C1-C6-alkyl, linear or branched, saturated or unsaturated, unsubstituted or monosubstituted with —OCH3.
  • In another preferred embodiment of the compound according to the invention, R3 means a 6-14-membered aryl moiety, unsubstituted, mono- or polysubstituted, optionally connected through —C1-C6-alkylene-, linear or branched, saturated or unsaturated, unsubstituted. In a preferred embodiment, R3 means -phenyl unsubstituted, mono- or polysubstituted. More preferably, R3 means -phenyl unsubstituted, mono- or disubstituted with —F, —Cl, —CH3, —CF3, —OH, —OCH3, —OCF3 or —OCH2OCH3, preferably —F. In another preferred embodiment, R3 means -benzyl unsubstituted, mono- or polysubstituted. More preferably, R3 means -benzyl unsubstituted, mono- or disubstituted with —F, —Cl, —CH3, —CF3, —OH, —OCH3, —OCF3 or —OCH2OCH3, preferably —F.
  • In still another preferred embodiment of the compound according to the invention, R3 means a 5-14-membered heteroaryl moiety, unsubstituted, mono- or polysubstituted. Preferably, R3 means -thienyl or -pyridinyl, in each case unsubstituted, mono- or polysubstituted. More preferably, R3 means -thienyl, -pyridinyl, -imidazolyl or benzimidazolyl, in each case unsubstituted or monosubstituted with —F, —Cl or —CH3.
  • In a preferred embodiment of the compound according to the invention, R4 means —H.
  • In another preferred embodiment of the compound according to the invention, R4 means —C1-C6-alkyl, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted. Preferably, R4 means —C1-C6-alkyl, linear or branched, saturated or unsaturated, unsubstituted or monosubstituted with a substituent selected from the group consisting of —F, —Cl, —Br, —I, —CN, —CF3, —OH, —O—C1-C4-alkyl, —OCF3, —O—(CH2CH2—O)1-30—H, —O—(CH2CH2—O)1-30—CH3, —OC(═O)C1-C4-alkyl, —C(═O)C1-C4-alkyl, —C(═O)OH, —C(═O)OC1—C4-alkyl, —C(═O)NH2, —C(═O)NHC1—C4-alkyl, —C(═O)NHC1—C4-alkylene-CN, —C(═O)NHC1—C4-alkylene-O—C1-C4-alkyl, —C(═O)N(C1-C4-alkyl)2; —S(═O)C1-C4-alkyl, and —S(═O)2C1-C4-alkyl; or with —C(═O)NR21R22 wherein R21 and R22 together with the nitrogen atom to which they are attached form a ring and mean —(CH2)3-6—, —(CH2)2—O—(CH2)2—, or —(CH2)2—NRB—(CH2)2—, wherein RB means —H or —C1-C6-alkyl; or with —C(═O)NH-3-12-membered cycloalkyl, saturated or unsaturated, unsubstituted or monosubstituted with —F, —Cl, —Br, —I, —CN, or —OH; or with —C(═O)NH-3-12-membered heterocycloalkyl, saturated or unsaturated, unsubstituted or monosubstituted with —F, —Cl, —Br, —I, —CN, or —OH. More preferably, R4 means —C1-C6-alkyl, linear or branched, saturated or unsaturated, unsubstituted or monosubstituted with —O—C1-C4-alkyl or —C(═O)N(C1-C4-alkyl)2.
  • In still another preferred embodiment of the compound according to the invention, R4 means a 3-12-membered cycloalkyl moiety, saturated or unsaturated, unsubstituted, mono- or polysubstituted; wherein the 3-12-membered cycloalkyl moiety is connected through —C1-C6-alkylene-, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted. Preferably, R4 means a 3-12-membered cycloalkyl moiety, saturated or unsaturated, unsubstituted, mono- or polysubstituted; wherein said 3-12-membered cycloalkyl moiety is connected through —CH2— or —CH2CH2—. More preferably, R4 means a 3-12-membered cycloalkyl moiety, saturated or unsaturated, unsubstituted or substituted with one, two, three or four substituents independently of one another selected from the group consisting of —F, —Cl, —Br, —I, —CN, —OH, —C1-C4-alkyl, —O—C1-C4-alkyl, —C(═O)OH, —C(═O)OC1—C4-alkyl, —C(═O)NH2, —C(═O)NHC1—C4-alkyl, —C(═O)N(C1-C4-alkyl)2, —S(═O)C1-C4-alkyl and —S(═O)2C1-C4-alkyl; wherein said 3-12-membered cycloalkyl moiety is connected through —CH2— or —CH2CH2—.
  • In a preferred embodiment of the compound according to the invention, R4 means a 3-12-membered heterocycloalkyl moiety, saturated or unsaturated, unsubstituted, mono- or polysubstituted; wherein said 3-12-membered heterocycloalkyl moiety is connected through —C1-C6-alkylene-, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted. Preferably, R4 means a 3-12-membered heterocycloalkyl moiety, saturated or unsaturated, unsubstituted, mono- or polysubstituted; wherein said 3-12-membered heterocycloalkyl moiety is connected through —CH2— or —CH2CH2—. More preferably, R4 means -oxetanyl, -tetrahydrofuranyl or -tetrahydropyranyl, in each case unsubstituted or substituted with one, two, three or four substituents independently of one another selected from the group consisting of —F, —Cl, —Br, —I, —CN, —OH, —C1-C4-alkyl, —O—C1-C4-alkyl, —C(═O)OH, —C(═O)OC1—C4-alkyl, —C(═O)NH2, —C(═O)NHC1—C4-alkyl, —C(═O)N(C1-C4-alkyl)2, —S(═O)C1-C4-alkyl and —S(═O)2C1-C4-alkyl; wherein said -oxetanyl, -tetrahydrofuranyl or -tetrahydropyranyl is connected through —CH2— or —CH2CH2—.
  • In yet another preferred embodiment of the compound according to the invention, R4 means a 6-14-membered aryl moiety, unsubstituted, mono- or polysubstituted; wherein said 6-14-membered aryl moiety is connected through —C1-C6-alkylene-, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted. Preferably, R4 means -phenyl, unsubstituted, mono- or polysubstituted; wherein said -phenyl is connected through —CH2— or —CH2CH2—. More preferably, R4 means -phenyl, unsubstituted or substituted with one, two, three or four substituents independently of one another selected from the group consisting of —F, —Cl, —Br, —I, —CN, —OH, —C1-C4-alkyl, —O—C1-C4-alkyl, —C(═O)OH, —C(═O)OC1—C4-alkyl, —C(═O)NH2, —C(═O)NHC1—C4-alkyl, —C(═O)N(C1-C4-alkyl)2, —S(═O)C1-C4-alkyl and —S(═O)2C1-C4-alkyl; wherein said -phenyl is connected through —CH2— or —CH2CH2—.
  • In a further preferred embodiment of the compound according to the invention, R4 means a 5-14-membered heteroaryl moiety, unsubstituted, mono- or polysubstituted; wherein said 5-14-membered heteroaryl moiety is connected through —C1-C6-alkylene-, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted. Preferably, R4 means a 5-14-membered heteroaryl moiety, unsubstituted, mono- or polysubstituted; wherein said -phenyl is connected through —CH2— or —CH2CH2—. More preferably, R4 means -pyridinyl, -pyrimidinyl, -pyrazinyl, or -pyrazolinyl, in each case unsubstituted or substituted with one, two, three or four substituents independently of one another selected from the group consisting of —F, —Cl, —Br, —I, —CN, —OH, —C1-C4-alkyl, —O—C1-C4-alkyl, —C(═O)OH, —C(═O)OC1—C4-alkyl, —C(═O)NH2, —C(═O)NHC1—C4-alkyl, —C(═O)N(C1-C4-alkyl)2, —S(═O)C1-C4-alkyl and —S(═O)2C1-C4-alkyl; wherein said -pyridinyl, -pyrimidinyl, -pyrazinyl, or -pyrazolinyl is connected through —CH2— or —CH2CH2—.
  • In a preferred embodiment of the compound according to the invention, R5 means —H.
  • In another preferred embodiment of the compound according to the invention, R5 means —C1-C6-alkyl, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted. Preferably, R5 means —C1-C6-alkyl, linear or branched, saturated, unsubstituted, mono- or polysubstituted. More preferably, R5 means —C1-C6-alkyl, linear or branched, saturated, unsubstituted or monosubstituted with a substituent selected from the group consisting of —F, —Cl, —Br, —I, —CN, —OH, —O—C1-C6-alkyl, —C(═O)OH, —C(═O)OC1—C4-alkyl, —C(═O)NH2, —C(═O)NHC1—C4-alkyl, —C(═O)N(C1-C4-alkyl)2, —S(═O)C1-C4-alkyl, —S(═O)2C1-C4-alkyl, —C(═O)—C3-12heterocycloalkyl, —NH—C(═O)—C1-C4-alkyl, —N(C1-C4-alkyl)2 and NH—S(═O)2—C1-C4-alkyl.
  • In still another preferred embodiment of the compound according to the invention, R5 means a 3-12-membered cycloalkyl moiety, saturated or unsaturated, unsubstituted, mono- or polysubstituted, wherein said 3-12-membered cycloalkyl moiety is optionally connected through —C1-C6-alkylene-, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted. Preferably, R5 means a 3-6-membered cycloalkyl moiety, saturated, unsubstituted, mono- or polysubstituted, wherein said 3-12-membered cycloalkyl moiety is optionally connected through —C1-C6-alkylene-, linear or branched, saturated, unsubstituted; more preferably -cyclopropyl, -cyclobutyl, -cyclopentyl or -cyclohexyl, unsubstituted or monosubstituted with —F, —OH, —CN or —C1-C4-alkyl, wherein said -cyclopropyl, -cyclobutyl -cyclopentyl or -cyclohexyl is optionally connected through —CH2— or —CH2CH2—.
  • In a preferred embodiment of the compound according to the invention, R5 means a 3-12-membered heterocycloalkyl moiety, saturated or unsaturated, unsubstituted, mono- or polysubstituted; wherein said 3-12-membered heterocycloalkyl moiety is optionally connected through —C1-C6-alkylene-, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted. Preferably, R5 means a 4-6-membered heterocycloalkyl moiety, saturated or unsaturated, unsubstituted, mono- or polysubstituted. More preferably, R5 means -hetero-cyclobutyl or -tetrahydro-2H-thiopyranyl dioxide, unsubstituted.
  • In yet another preferred embodiment of the compound according to the invention, R5 means a 5-14-membered heteroaryl moiety, unsubstituted, mono- or polysubstituted; wherein said 5-14-membered heteroaryl moiety is optionally connected through —C1-C6-alkylene-, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted. Preferably, R5 means a 5-6-membered heteroaryl moiety, unsubstituted, mono- or polysubstituted, wherein said 5-6-membered heteroaryl moiety is optionally connected through —CH2—. More preferably, R5 means a 5-6-membered heteroaryl moiety, unsubstituted or substituted with one, two, three or four substituents independently of one another selected from the group consisting of —F, —Cl, —Br, —I, —CN, —OH, —C1-C4-alkyl, —O—C1-C4-alkyl, —C(═O)OH, —C(═O)OC1—C4-alkyl, —C(═O)NH2, —C(═O)NHC1—C4-alkyl, —C(═O)N(C1-C4-alkyl)2, —S(═O)C1-C4-alkyl, —S(═O)2C1-C4-alkyl and —S—C1-C4-alkyl, wherein said 5-6-membered heteroaryl moiety is optionally connected through —CH2—. Still more preferably, R5 means -oxazolyl, -isoxazolyl, -pyrazolyl, -pyridinyl, -pyridazinyl, -pyrazinyl, -thiazolyl, -thiadiazolyl, -imidazolyl or -pyrimidinyl, in each case unsubstituted or substituted with one, two, three or four substituents independently of one another selected from the group consisting of —F, —Cl, Br, —I, —CN, —OH, —C1-C4-alkyl, —O—C1-C4-alkyl, —C(═O)OH, —C(═O)OC1—C4-alkyl, —C(═O)NH2, —C(═O)NHC1—C4-alkyl, —C(═O)N(C1-C4-alkyl)2, S(═O)C1-C4-alkyl, —S(═O)2C1-C4-alkyl and —S—C1-C4-alkyl, wherein said -oxazolyl, -isoxazolyl, -pyrazolyl, -pyridinyl, -pyridazinyl, -pyrazinyl, -thiazolyl, -thiadiazolyl, -imidazolyl or -pyrimidinyl is optionally connected through —CH2—.
  • In a further preferred embodiment of the compound according to the invention, R5 means a 6-14-membered aryl moiety, unsubstituted, mono- or polysubstituted; wherein said 6-14-membered aryl moiety is optionally connected through —C1-C6-alkylene-, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted. Preferably, R5 means -phenyl, unsubstituted or substituted with one, two, three or four substituents independently of one another selected from the group consisting of —F, —Cl, Br, —I, —CN, —OH, —C1-C4-alkyl, —O—C1-C4-alkyl, —C(═O)OH, —C(═O)OC1—C4-alkyl, —C(═O)NH2, —C(═O)NHC1—C6-alkyl, —C(═O)N(C1-C4-alkyl)2, S(═O)C1-C4-alkyl, —S(═O)2C1-C4-alkyl and —S—C1-C4-alkyl, wherein said -phenyl is optionally connected through —CH2—.
  • In a preferred embodiment of the compound according to the invention, X means NR6 and R5 and R6 together with the nitrogen atom to which they are attached form a 3-12-membered heterocycloalkyl moiety, saturated or unsaturated, unsubstituted, mono- or polysubstituted. Preferably, X means NR6 and R5 and R6 together with the nitrogen atom to which they are attached form a 5-6-membered heterocycloalkyl moiety, saturated or unsaturated, unsubstituted, mono- or polysubstituted. More preferably, X means NR6 and R5 and R6 together with the nitrogen atom to which they are attached form -pyrrolidinyl, -piperidinyl, -piperazinyl, -morpholinyl, -thiomorpholinyl, -thiomorpholinyl dioxide or -(methylsulfonyl)piperazinyl, in each case unsubstituted or substituted with one, two, three or four substituents independently of one another selected from the group consisting of ═O, —OH, —CH2—OH and —C(═O)NH2, wherein said -pyrrolidinyl, -piperidinyl, piperazinyl, -morpholinyl, -thiomorpholinyl, -thiomorpholinyl dioxide or -(methylsulfonyl)piperazinyl is optionally condensed with an imidazole moiety, unsubstituted.
  • In a preferred embodiment of the compound according to the invention R5 means
    • —H;
  • —C1-C6-alkyl, linear or branched, saturated or unsaturated, unsubstituted or substituted with one, two, three or four substituents independently of one another selected from the group consisting of —F, —Cl, —Br, —I, —CN, —O—CH3, —O—(CH2—CH2—O)1-10—H, —O—(CH2CH2—O)1-10—CH3, —C(═O)OH, —C(═O)OCH3, —C(═O)NH2, —C(═O)NHCH3, —C(═O)N(CH3)2, —OH, —S(═O)CH3, —S(═O)2CH3, unsubstituted —C(═O)-morpholinyl, —NH—C(═O)—CH3, —N(CH3)2 and NH—S(═O)2—CH3;
    -cyclopropyl, -cyclobutyl, -cyclopentyl or -cyclohexyl, unsubstituted or monosubstituted with —F, —OH, —CN or —CH3, wherein said -cyclopropyl, -cyclobutyl, cyclopentyl or cyclohexyl is optionally connected through —CH2— or —CH2CH2—;
    -heterocyclobutyl, -heterocyclopentyl, or -heterocyclohexyl, in each case unsubstituted or substituted with one, two, three or four substituents independently of one another selected from the group consisting of —F, —Cl, —Br, —I, —CN, —O—CH3, —O—(CH2—CH2—O)MO-H, —O—(CH2CH2—O)1-10—CH3, —C1-C4-alkyl, —C(═O)OH, —C(═O)OCH3, —C(═O)NH2, —C(═O)NHCH3, —C(═O)N(CH3)2, ═O, —OH, —SCH3, —S(═O)CH3, —S(═O)2CH3, unsubstituted —C(═O)-morpholinyl, —NH—C(═O)—CH3, —N(CH3)2 and NH—S(═O)2—CH3; wherein said -heterocyclobutyl, -heterocyclopentyl, or -heterocyclohexyl is optionally connected through —CH2— or —CH2CH2—;
    -oxazolyl, -isoxazolyl, -pyrazolyl, -pyridinyl, -pyridazinyl, -pyrazinyl, -thiazolyl, -thiadiazolyl, -imidazolyl, -pyrimidinyl, or 5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazine, in each case unsubstituted or substituted with one, two, three or four substituents independently of one another selected from the group consisting of —F, —Cl, Br, —I, —CN, —OH, —CH3, —O—CH3, —C(═O)OH, —C(═O)OCH3, —C(═O)NH2, —C(═O)NHCH3, —C(═O)N(CH3)2, S(═O)CH3, —S(═O)2CH3 and —S—CH3, wherein said -oxazolyl, -isoxazolyl, -pyrazolyl, -pyridinyl, -pyridazinyl, -pyrazinyl, -thiazolyl, -thiadiazolyl, -imidazolyl, -pyrimidinyl, or 5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazine is optionally connected through —CH2—; or
    -phenyl, unsubstituted or substituted with one, two, three or four substituents independently of one another selected from the group consisting of —F, —Cl, Br, —I, —CN, —OH, —CH3, —O—CH3, —C(═O)OH, —C(═O)OCH3, —C(═O)NH2, —C(═O)NHCH3, —C(═O)N(CH3)2, S(═O)CH3, —S(═O)2CH3 and —S—CH3, wherein said -phenyl is optionally connected through —CH2—;
    in case X means NR6, R6 means —H or —CH3;
    or in case X means NR6, R5 and R6 together with the nitrogen atom to which they are attached form a -pyrrolidinyl, -piperidinyl, -piperazinyl, -morpholinyl, -thiomorpholinyl, -thiomorpholinyl dioxide or -(methylsulfonyl)piperazinyl, in each case unsubstituted or substituted with one, two, three or four substituents independently of one another selected from the group consisting of ═O, —OH, —CH2—OH, —C(═O)NH2, and —S(═O)2CH3, wherein said -pyrrolidinyl, -piperidinyl, -piperazinyl, -morpholinyl, -thiomorpholinyl, -thiomorpholinyl dioxide or -(methylsulfonyl)piperazinyl is optionally condensed with an imidazole moiety, unsubstituted;
  • In a preferred embodiment of the compound according to the invention, X means NR6 and R6 means —H or —C1-C6-alkyl, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted. Preferably, R6 means —H or —CH3.
  • In preferred embodiments, the compound according to the invention has a structure according to any of general formulas (II-A) to (VIII-C):
  • Figure US20210179627A1-20210617-C00002
    Figure US20210179627A1-20210617-C00003
    Figure US20210179627A1-20210617-C00004
    Figure US20210179627A1-20210617-C00005
  • wherein in each case
    R1, R2, R3, R4, R5, R6 and X are defined as above,
    RC means —H, —OH, —F, —CN or —C1-C4-alkyl;
    RD means —H or —F;
    or a physiologically acceptable salt thereof.
  • Preferably, the substructure of the compounds according to general formula (I) represented by R5, X, R9 and R10, i.e.
  • Figure US20210179627A1-20210617-C00006
  • or the corresponding substructure of any of above general formulas (II-A) to (VIII-C) has preferably a meaning selected from the group consisting of:
  • Figure US20210179627A1-20210617-C00007
    Figure US20210179627A1-20210617-C00008
    Figure US20210179627A1-20210617-C00009
    Figure US20210179627A1-20210617-C00010
    Figure US20210179627A1-20210617-C00011
    Figure US20210179627A1-20210617-C00012
    Figure US20210179627A1-20210617-C00013
    Figure US20210179627A1-20210617-C00014
    Figure US20210179627A1-20210617-C00015
    Figure US20210179627A1-20210617-C00016
    Figure US20210179627A1-20210617-C00017
    Figure US20210179627A1-20210617-C00018
  • In a particularly preferred embodiment of the compound according to the invention
  • R1 means —H or —CH3;
    R2 means —CH3, —CH2CH3 or —CH2—C(H)(CH3)2;
    R3 means -phenyl, -thienyl or -pyridinyl, in each case unsubstituted or monosubstituted with —F;
    R4 means
    • —H;
  • —C1-C6-alkyl, linear or branched, saturated, unsubstituted or substituted with one, two, three or four substituents independently of one another selected from the group consisting of —F, —Cl, —Br, —I, —CN, —OH, ═O, —N(CH3)2 and —O—CH3; or
    -cyclopropyl, -cyclobutyl, -cyclopentyl or -cyclohexyl, unsubstituted or monosubstituted with —F, —OH, —CN or —CH3, wherein said -cyclopropyl, -cyclobutyl, -cyclopentyl or -cyclohexyl is connected through —CH2— or —CH2CH2—;
    -oxetanyl unsubstituted or monosubstituted with —F, —OH, —CN or —CH3, wherein said -oxetanyl is connected through —CH2— or —CH2CH2—;
    X means —O— or —NR6—;
    R5 means
    • —H;
  • —C1-C6-alkyl, linear or branched, saturated or unsaturated, unsubstituted or substituted with one, two, three or four substituents independently of one another selected from the group consisting of —F, —Cl, —Br, —I, —CN, —O—CH3, —O—(CH2—CH2—O)1-10—H, —O—(CH2CH2—O)1-10—CH3, —C(═O)OH, —C(═O)OCH3, —C(═O)NH2, —C(═O)NHCH3, —C(═O)N(CH3)2, —OH, —S(═O)CH3, —S(═O)2CH3, unsubstituted —C(═O)-morpholinyl, —NH—C(═O)—CH3, —N(CH3)2 and NH—S(═O)2—CH3;
    -cyclopropyl, -cyclobutyl, -cyclopentyl or -cyclohexyl, unsubstituted or monosubstituted with —F, —OH, —CN or —CH3, wherein said -cyclopropyl, -cyclobutyl, cyclopentyl or cyclohexyl is optionally connected through —CH2— or —CH2CH2—;
    -heterocyclobutyl, -heterocyclopentyl, or -heterocyclohexyl, in each case unsubstituted or substituted with one, two, three or four substituents independently of one another selected from the group consisting of —F, —Cl, —Br, —I, —CN, —O—CH3, —O—(CH2—CH2—O)MO-H, —O—(CH2CH2—O)1-10—CH3, —C1-C4-alkyl, —C(═O)OH, —C(═O)OCH3, —C(═O)NH2, —C(═O)NHCH3, —C(═O)N(CH3)2, ═O, —OH, —SCH3, —S(═O)CH3, —S(═O)2CH3, unsubstituted —C(═O)-morpholinyl, —NH—C(═O)—CH3, —N(CH3)2 and NH—S(═O)2—CH3; wherein said -heterocyclobutyl, -heterocyclopentyl, or -heterocyclohexyl is optionally connected through —CH2— or —CH2CH2—;
    -oxazolyl, -isoxazolyl, -pyrazolyl, -pyridinyl, -pyridazinyl, -pyrazinyl, -thiazolyl, -thiadiazolyl, -imidazolyl, -pyrimidinyl, or 5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazine, in each case unsubstituted or substituted with one, two, three or four substituents independently of one another selected from the group consisting of —F, —Cl, Br, —I, —CN, —OH, —CH3, —O—CH3, —C(═O)OH, —C(═O)OCH3, —C(═O)NH2, —C(═O)NHCH3, —C(═O)N(CH3)2, S(═O)CH3, —S(═O)2CH3 and —S—CH3, wherein said -oxazolyl, -isoxazolyl, -pyrazolyl, -pyridinyl, -pyridazinyl, -pyrazinyl, -thiazolyl, -thiadiazolyl, -imidazolyl, -pyrimidinyl, or 5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazine is optionally connected through —CH2—; or
    -phenyl, unsubstituted or substituted with one, two, three or four substituents independently of one another selected from the group consisting of —F, —Cl, Br, —I, —CN, —OH, —CH3, —O—CH3, —C(═O)OH, —C(═O)OCH3, —C(═O)NH2, —C(═O)NHCH3, —C(═O)N(CH3)2, S(═O)CH3, —S(═O)2CH3 and —S—CH3, wherein said -phenyl is optionally connected through —CH2—;
    in case X means NR6, R6 means —H or —CH3;
    or in case X means NR6, R5 and R6 together with the nitrogen atom to which they are attached form a -pyrrolidinyl, -piperidinyl, -piperazinyl, -morpholinyl, -thiomorpholinyl, -thiomorpholinyl dioxide or -(methylsulfonyl)piperazinyl, in each case unsubstituted or substituted with one, two, three or four substituents independently of one another selected from the group consisting of ═O, —OH, —CH2—OH, —C(═O)NH2, and —S(═O)2CH3, wherein said -pyrrolidinyl, -piperidinyl, -piperazinyl, -morpholinyl, -thiomorpholinyl, -thiomorpholinyl dioxide or -(methylsulfonyl)piperazinyl is optionally condensed with an imidazole moiety, unsubstituted; and
    R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19, and R20 mean —H.
  • In a particularly preferred embodiment of the compound according to the invention
  • R1 means —H or —CH3; and/or
    R2 means —CH3, —CH2CH3 or —CH2—C(H)(CH3)2; and/or
    R3 means -phenyl, -thienyl or -pyridinyl, in each case unsubstituted; preferably, R3 means phenyl unsubstituted; and/or
    R4 means
    • —H;
  • —C1-C6-alkyl, linear or branched, saturated, unsubstituted or substituted with one, two, three or four substituents independently of one another selected from the group consisting of —F, —Cl, —Br, —I, —CN, —OH, ═O, —N(CH3)2 and —O—CH3; or
    -cyclopropyl, -cyclobutyl, -cyclopentyl or -cyclohexyl, unsubstituted or monosubstituted with —F, —OH, —CN or —CH3, wherein said -cyclopropyl, -cyclobutyl, -cyclopentyl or -cyclohexyl is connected through —CH2— or —CH2CH2—; preferably, R4 means -cyclobutyl, unsubstituted or monosubstituted with —OH, wherein said -cyclobutyl is connected through —CH2—; and/or
    X means —O— or —NR6—; and/or
    R5 means
    • —H;
  • —C1-C6-alkyl, linear or branched, saturated or unsaturated, unsubstituted or substituted with one, two, three or four substituents independently of one another selected from the group consisting of —F, —Cl, —Br, —I, —CN, —O—CH3, —O—(CH2—CH2—O)1-10—H, —O—(CH2CH2—O)1-10—CH3, —C(═O)OH, —C(═O)OCH3, —C(═O)NH2, —C(═O)NHCH3, —C(═O)N(CH3)2, —OH, —S(═O)CH3, —S(═O)2CH3, unsubstituted —C(═O)-morpholinyl, —NH—C(═O)—CH3, —N(CH3)2 and NH—S(═O)2—CH3; preferably, R5 means —C1-C6-alkyl, linear or branched, saturated or unsaturated, unsubstituted or monosubstituted with —OH;
    -cyclopropyl, -cyclobutyl, -cyclopentyl or -cyclohexyl, unsubstituted or monosubstituted with —F, —OH, —CN or —CH3, wherein said -cyclopropyl, -cyclobutyl, cyclopentyl or cyclohexyl is optionally connected through —CH2— or —CH2CH2—;
    -heterocyclobutyl, -tetrahydro-2H-thiopyranyl dioxide, —CH2-heterocyclobutyl or —CH2-tetrahydro-2H-thiopyranyl dioxide, in each case unsubstituted;
    -oxazolyl, -isoxazolyl, -pyrazolyl, -pyridinyl, -pyridazinyl, -pyrazinyl, -thiazolyl, -thiadiazolyl, -imidazolyl or -pyrimidinyl, in each case unsubstituted or substituted with one, two, three or four substituents independently of one another selected from the group consisting of —F, —Cl, Br, —I, —CN, —OH, —CH3, —O—CH3, —C(═O)OH, —C(═O)OCH3, —C(═O)NH2, —C(═O)NHCH3, —C(═O)N(CH3)2, S(═O)CH3, —S(═O)2CH3 and —S—CH3, wherein said -oxazolyl, -isoxazolyl, -pyrazolyl, -pyridinyl, -pyridazinyl, -pyrazinyl, -thiazolyl, -thiadiazolyl, -imidazolyl or -pyrimidinyl is optionally connected through —CH2—; preferably, R5 means -pyridinyl unsubstituted; or
    -phenyl, unsubstituted or substituted with one, two, three or four substituents independently of one another selected from the group consisting of —F, —Cl, Br, —I, —CN, —OH, —CH3, —O—CH3, —C(═O)OH, —C(═O)OCH3, —C(═O)NH2, —C(═O)NHCH3, —C(═O)N(CH3)2, S(═O)CH3, —S(═O)2CH3 and —S—CH3, wherein said -phenyl is optionally connected through —CH2—; and/or
    in case X means NR6, R6 means —H or —CH3;
    or in case X means NR6, R5 and R6 together with the nitrogen atom to which they are attached form a -pyrrolidinyl, -piperidinyl, -piperazinyl, -morpholinyl, -thiomorpholinyl, -thiomorpholinyl dioxide or -(methylsulfonyl)piperazinyl, in each case unsubstituted or substituted with one, two, three or four substituents independently of one another selected from the group consisting of ═O, —OH, —CH2—OH and —C(═O)NH2, wherein said -pyrrolidinyl, -piperidinyl, -piperazinyl, -morpholinyl, -thiomorpholinyl, -thiomorpholinyl dioxide or -(methylsulfonyl)piperazinyl is optionally condensed with an imidazole moiety, unsubstituted; and/or
    R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19, and R20 mean —H.
  • Preferably, the compound according to the invention is selected from the group consisting of
  •
    SC_1001 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-[2-[2-[2-[2-[2-[2-(2-methoxy-ethoxy)-ethoxy]-ethoxy]-
    ethoxy]-ethoxy]-ethoxy]-ethyl]-acetamide
    SC_1002 CIS-6-[[2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-acetyl]amino]-pyridine-2-carboxylic acid methyl ester
    SC_1003 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-[(1R)-2-hydroxy-1-methyl-ethyl]-acetamide
    SC_1004 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-[(1S)-2-hydroxy-1-methyl-ethyl]-acetamide
    SC_1005 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-methyl-N-(methylcarbamoyl-methyl)-acetamide
    SC_1006 CIS-6-[[2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-acetyl]amino]-nicotinic acid methyl ester
    SC_1007 CIS-2-[[2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-acetyl]-methyl-amino]-2-methyl-propionamide
    SC_1008 CIS-2-[[2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-acetyl]amino]-N,2-dimethyl-propionamide
    SC_1009 CIS-2-[[2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-acetyl]-methyl-amino]-N,2-dimethyl-propionamide
    SC_1010 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-[(dimethyl-carbamoyl)-methyl]-N-methyl-acetamide
    SC_1011 CIS-2-[[2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-acetyl]amino]-2-methyl-propionamide
    SC_1012 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-(5-methoxy-pyridin-2-yl)-acetamide
    SC_1013 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-(6-methoxy-pyridin-2-yl)-acetamide
    SC_1014 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-(4-methoxy-pyridin-2-yl)-acetamide
    SC_1015 CIS-6-[[2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-acetyl]amino]-N-methyl-pyridine-2-carboxylic acid
    amide
    SC_1016 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-[(3-hydroxy-cyclobutyl)-methyl]-acetamide
    SC_1017 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-[(3-hydroxy-cyclobutyl)-methyl]-acetamide
    SC_1018 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-[(1-hydroxy-cyclopropyl)-methyl]-acetamide
    SC_1019 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-(3-morpholin-4-yl-3-oxo-propyl)-acetamide
    SC_1020 CIS-N-(1-Cyano-cyclopropyl)-2-[1-(cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-
    phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetamide
    SC_1021 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-[(3-hydroxy-cyclopentyl)-methyl]-acetamide
    SC_1022 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-[[(2R)-2-hydroxy-cyclohexyl]-methyl]-acetamide
    SC_1023 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-[2-[2-[2-(2-methoxy-ethoxy)-ethoxy]-ethoxy]-ethyl]-
    acetamide
    SC_1024 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-[(1-hydroxy-cyclohexyl)-methyl]-acetamide
    SC_1025 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-[2-[2-[2-[2-(2-methoxy-ethoxy)-ethoxy]-ethoxy]-
    ethoxy]-ethyl]-acetamide
    SC_1026 CIS-N-(6-Cyano-pyridin-2-yl)-2-[1-(cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-
    phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetamide
    SC_1027 CIS-2-[[2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-acetyl]amino]-nicotinic acid methyl ester
    SC_1028 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-(3-methoxy-pyridin-2-yl)-acetamide
    SC_1029 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-[2-[2-[2-[2-[2-(2-methoxy-ethoxy)-ethoxy]-ethoxy]-
    ethoxy]-ethoxy]-ethyl]-acetamide
    SC_1030 CIS-N-(4-Cyano-pyridin-2-yl)-2-[1-(cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-
    phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetamide
    SC_1031 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-(5-methoxy-pyrimidin-2-yl)-acetamide
    SC_1032 CIS-2-[[2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-acetyl]amino]-isonicotinic acid methyl ester
    SC_1033 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-(2-methoxy-pyridin-4-yl)-acetamide
    SC_1034 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-(6-fluoro-pyridin-3-yl)-acetamide
    SC_1035 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-(2-methyl-pyrimidin-5-yl)-acetamide
    SC_1036 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-(5-methyl-pyrimidin-2-yl)-acetamide
    SC_1037 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-(3-fluoro-pyridin-2-yl)-acetamide
    SC_1038 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-(3-fluoro-pyridin-4-yl)-acetamide
    SC_1039 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-(6-methoxy-pyridin-3-yl)-acetamide
    SC_1040 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-(2-methyl-pyridin-3-yl)-acetamide
    SC_1041 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-(4-methyl-pyridin-3-yl)-acetamide
    SC_1042 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-(3-methyl-pyridin-4-yl)-acetamide
    SC_1043 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-(6-methyl-pyridin-3-yl)-acetamide
    SC_1044 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-(5-fluoro-pyridin-2-yl)-acetamide
    SC_1045 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-(5-methyl-pyridin-2-yl)-acetamide
    SC_1046 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-(4-methyl-pyridin-2-yl)-acetamide
    SC_1047 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-(3-methyl-pyridin-2-yl)-acetamide
    SC_1048 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-(3-methoxy-pyridin-4-yl)-acetamide
    SC_1049 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-(6-methoxy-pyridazin-3-yl)-acetamide
    SC_1050 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-(5-methylsulfonyl-pyridin-2-yl)-acetamide
    SC_1051 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-(5-methoxy-pyridin-2-yl)-acetamidc
    SC_1052 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-(6-methylsulfonyl-pyridin-3-yl)-acetamide
    SC_1053 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-(6-methoxy-pyrazin-2-yl)-acetamide
    SC_1054 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-(4-methoxy-pyridin-2-yl)-acetamide
    SC_1055 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-(4-methoxy-pyrimidin-2-yl)-acetamide
    SC_1056 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-(oxazol-5-yl-methyl)-acetamide
    SC_1057 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-(oxazol-2-yl-methyl)-acetamide
    SC_1058 CIS-1-(Cyclobutyl-methyl)-3-[2-[(3S,4S)-3,4-dihydroxy-piperidin-1-yl]-2-oxo-
    ethyl]-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
    SC_1059 CIS-1-(Cyclobutyl-methyl)-3-[2-[(3S,4S)-3,4-dihydroxy-pyrrolidin-1-yl]-2-oxo-
    ethyl]-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
    SC_1060 CIS-1-(Cyclobutyl-methyl)-3-[2-[(3S,4R)-3,4-dihydroxy-pyrrolidin-1-yl]-2-oxo-
    ethyl]-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
    SC_1061 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-cyclopropyl-acetamide
    SC_1062 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-(2-hydroxy-ethyl)-N-methyl-acetamide
    SC_1063 CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-3-[2-(3-hydroxy-piperidin-1-yl)-2-
    oxo-ethyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
    SC_1064 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-[(1-hydroxy-cyclobutyl)-methyl]-acetamide
    SC_1065 CIS-2-[[2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-acetyl]amino]-N,N-dimethyl-acetamide
    SC_1066 CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-3-[2-oxo-2-(5,6,7,8-tetrahydro-
    [1,2,4]triazolo[1,5-a]pyrazin-7-yl)-ethyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
    SC_1067 CIS-3-[[2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-acetyl]amino]-N,N-dimethyl-propionamide
    SC_1068 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-[2-[2-[2-[2-[2-[2-[2-(2-methoxy-ethoxy)-ethoxy]-
    ethoxy]-ethoxy]-ethoxy]-ethoxy]-ethoxy]-ethyl]-acetamide
    SC_1069 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-(4-methoxy-pyrimidin-5-yl)-acetamide
    SC_1070 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-(2-methoxy-pyrimidin-5-yl)-acetamide
    SC_1072 CIS-N-(5-Cyano-pyridin-2-yl)-2-[1-(cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-
    phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetamide
    SC_1073 CIS-2-[[2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-acetyl]amino]-N-methyl-pyridine-4-carboxylic acid
    amide
    SC_1074 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-(5-methoxy-pyrimidin-4-yl)-acetamide
    SC_1075 CIS-N-(2-Cyano-pyrimidin-5-yl)-2-[1-(cyclobutyl-methyl)-8-dimethylamino-2-oxo-
    8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetamide
    SC_1076 CIS-6-[[2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-acetyl]amino]-pyridine-2-carboxylic acid amide
    SC_1077 CIS-N-(3-Cyano-pyridin-2-yl)-2-[1-(cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-
    phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetamide
    SC_1078 CIS-2-[[2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-acetyl]amino]-acetamide
    SC_1079 CIS-6-[[2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-acetyl]amino]-pyridine-3-carboxylic acid amide
    SC_1080 CIS-N-(4-Cyano-pyrimidin-2-yl)-2-[1-(cyclobutyl-methyl)-8-dimethylamino-2-oxo-
    8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetamide
    SC_1081 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-([1,3,4]thiadiazol-2-yl)-acetamide
    SC_1082 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-thiazol-2-yl-acetamide
    SC_1083 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-(5-methyl-isoxazol-3-yl)-acetamide
    SC_1084 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-isoxazol-3-yl-acetamide
    SC_1085 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-(1-methyl-1H-pyrazol-3-yl)-acetamide
    SC_1086 CIS-N-(4-Cyano-5-methylsulfanyl-1H-pyrazol-3-yl)-2-[1-(cyclobutyl-methyl)-8-
    dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetamide
    SC_1087 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-(5-methoxy-pyrazin-2-yl)-acetamide
    SC_1088 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-(pyridazin-4-yl-methyl)-acetamide
    SC_1089 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-[(2-hydroxyphenyl)-methyl]-acetamide
    SC_1090 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-[(1-methyl-1H-imidazol-4-yl)-methyl]-acetamide
    SC_1091 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-[(4-methyl-pyridin-3-yl)-methyl]-acetamide
    SC_1092 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-(pyrimidin-2-yl-methyl)-acetamide
    SC_1093 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-(pyridazin-3-yl-methyl)-acetamide
    SC_1094 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-(pyrimidin-4-yl-methyl)-acetamide
    SC_1095 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-(pyrazin-2-yl-methyl)-acetamide
    SC_1096 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-(oxazol-4-yl-methyl)-acetamide
    SC_1097 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-[(2-methyl-pyridin-3-yl)-methyl]-acetamide
    SC_1098 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-[(2-methoxy-pyridin-3-yl)-methyl]-acetamide
    SC_1099 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-[(4-methoxy-pyridin-3-yl)-methyl]-acetamide
    SC_1100 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-[(6-methyl-pyridin-2-yl)-methyl]-acetamide
    SC_1101 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-[(6-methoxy-pyridin-2-yl)-methyl]-acetamide
    SC_1102 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-[(2-methoxyphenyl)-methyl]-acetamide
    SC_1103 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-(o-tolyl-methyl)-acetamide
    SC_1104 CIS-6-[[2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-acetyl]amino]-N-methyl-pyridine-3-carboxylic acid
    amide
    SC_1105 CIS-2-[[2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-acetyl]amino]-pyridine-4-carboxylic acid amide
    SC_1106 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-(6-methoxy-pyrimidin-4-yl)-acetamide
    SC_1107 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-(2-methoxy-pyrimidin-4-yl)-acetamide
    SC_1109 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-(4-hydroxy-pyrimidin-5-yl)-acetamide
    SC_1110 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-(2-hydroxy-pyrimidin-5-yl)-acetamide
    SC_1111 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-(5-hydroxy-pyridin-2-yl)-acetamide
    SC_1112 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-(1,1-dioxo-thian-4-yl)-acetamide
    SC_1113 CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-3-[2-(1,1-dioxo-[1,4]thiazinan-4-yl)-2-
    oxo-ethyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
    SC_1114 CIS-2-[8-Dimethylamino-1-(2-methoxy-ethyl)-2-oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-pyrimidin-4-yl-acetamide
    SC_1115 CIS-2-[8-Dimethylamino-1-(2-methoxy-ethyl)-2-oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-methyl-acetamide
    SC_1117 CIS-N-(5-Cyano-pyrimidin-4-yl)-2-[1-(cyclobutyl-methyl)-8-dimethylamino-2-oxo-
    8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetamide
    SC_1118 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-(5-methylsulfanyl-pyridin-2-yl)-acetamide
    SC_1119 ClS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-(4-methoxy-pyrimidin-2-yl)-acetamide
    SC_1120 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-(6-methylsulfanyl-pyridin-2-yl)-acetamide
    SC_1121 CIS-2-[8-Dimethylamino-1-(2-methoxy-ethyl)-2-oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-(2-hydroxy-ethyl)-acetamide
    SC_1122 CIS-2-[[2-[8-Dimethylamino-1-(2-methoxy-ethyl)-2-oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-acetyl]amino]-acetamide
    SC_1123 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-methyl-acetamide
    SC_1124 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-(2-hydroxy-ethyl)-acetamide
    SC_1125 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-(6-hydroxy-pyridin-2-yl)-acetamide
    SC_1126 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-[(2-methoxy-pyrimidin-5-yl)-methyl]-acetamide
    SC_1127 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-[(4-methoxy-pyrimidin-2-yl)-methyl]-acetamide
    SC_1128 CIS-N-(2-Cyano-pyrimidin-4-yl)-2-[1-(cyclobutyl-methyl)-8-dimethylamino-2-oxo-
    8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetamide
    SC_1129 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-[6-(methylsulfinyl)-pyridin-2-yl]-acetamide
    SC_1130 CIS-2-[[2-[1-(Cyclobutyl-methyl)-8-methylamino-2-oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-acetyl]amino]-2-methyl-propionamide
    SC_1131 CIS-2-[[2-[1-(Cyclobutyl-methyl)-8-methylamino-2-oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-acetyl]amino]-N-methyl-acetamide
    SC_1132 CIS-2-[[2-[1-(Cyclobutyl-methyl)-8-methylamino-2-oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-acetyl]amino]-acetamide
    SC_1133 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-[2-[2-(2-methoxy-ethoxy)-ethoxy]-ethyl]-acetamide
    SC_1134 CIS-N-(Carbamoyl-methyl)-2-[1-(cyclobutyl-methyl)-8-methylamino-2-oxo-8-
    phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-methyl-acetamide
    SC_1135 CIS-2-[1-(Cyclobutyl-methyl)-8-methylamino-2-oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-methyl-N-(methylcarbamoyl-methyl)-acetamide
    SC_1136 CIS-2-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-(2-methylsulfonyl-ethyl)-acetamide
    SC_1137 CIS-2-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-pyrimidin-5-yl-acetamide
    SC_1138 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-(6-methylsulfonyl-pyridin-2-yl)-acetamide
    SC_1139 CIS-2-[8-Dimethylamino-1-[(dimethyl-carbamoyl)-methyl]-2-oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-(2-hydroxy-ethyl)-acetamide
    SC_1140 CIS-2-[[2-[1-(Cyclobutyl-methyl)-8-methylamino-2-oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-acetyl]-methyl-amino]-2-methyl-propionamide
    SC_1141 CIS-1-(Cyclobutyl-methyl)-3-[2-(1,1-dioxo-[1,4]thiazinan-4-yl)-2-oxo-ethyl]-8-
    methylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
    SC_1142 CIS-2-[1-(Cyclobutyl-methyl)-8-methylamino-2-oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-[2-[2-[2-[2-[2-[2-(2-methoxy-ethoxy)-ethoxy]-ethoxy]-
    ethoxy]-ethoxy]-ethoxy]-ethyl]-acetamide
    SC_1143 CIS-2-[[2-[1-(Cyclobutyl-methyl)-8-methylamino-2-oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-acetyl]amino]-N,N-dimethyl-acetamide
    SC_1144 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-(5-hydroxy-pyrimidin-2-yl)-acetamide
    SC_1145 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-(4-methylsulfonyl-pyridin-2-yl)-acetamide
    SC_1146 CIS-2-[[2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-acetyl]amino]-N-methyl-acetamide
    SC_1147 CIS-N-(Carbamoyl-methyl)-2-[1-(cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-
    phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-methyl-acetamide
    SC_1148 CIS-2-(8-Dimethylamino-2-oxo-8-phenyl-1-propyl-1,3-diazaspiro[4.5]decan-3-yl)-
    N-methyl-acetamide
    SC_1149 CIS-2-[8-Dimethylamino-1-(3-methoxy-propyl)-2-oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-methyl-acetamide
    SC_1150 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-[4-(methylsulfinyl)-pyridin-2-yl]-acetamide
    SC_1151 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-(3-hydroxy-pyridin-2-yl)-acetamide
    SC_1152 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-(2-methylsulfonyl-ethyl)-acetamide
    SC_1154 CIS-1-(Cyclobutyl-methyl)-3-[2-[(3S,4R)-3,4-dihydroxy-pyrrolidin-1-yl]-2-oxo-
    ethyl]-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
    SC_1155 CIS-2-[1-(Cyclobutyl-methyl)-8-methylamino-2-oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-(2-hydroxy-ethyl)-acetamide
    SC_1156 CIS-2-[8-Dimethylamino-1-[(dimethyl-carbamoyl)-methyl]-2-oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-pyrimidin-4-yl-acetamide
    SC_1157 CIS-2-[8-Dimethylamino-1-[(dimethyl-carbamoyl)-methyl]-2-oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-methyl-acetamide
    SC_1158 CIS-2-[[2-[8-Dimethylamino-1-(2-methyl-propyl)-2-oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-acetyl]amino]-acetamide
    SC_1159 CIS-2-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-acetamide
    SC_1160 CIS-2-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-methyl-acetamide
    SC_1161 CIS-2-[[2-[8-Dimethylamino-1-(3-methoxy-propyl)-2-oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-acetyl]amino]-acetamide
    SC_1162 CIS-2-[8-Dimethylamino-1-(2-methyl-propyl)-2-oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-methyl-acetamide
    SC_1163 CIS-1-(Cyclobutyl-methyl)-3-[2-[(3S,4R)-3,4-dihydroxy-pyrrolidin-1-yl]-2-oxo-
    ethyl]-8-methylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
    SC_1164 CIS-2-[8-Dimethylamino-1-[(1-methyl-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-methyl-acetamide
    SC_1165 CIS-2-[8-Dimethylamino-1-[(1-methyl-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-pyrimidin-4-yl-acetamide
    SC_1166 CIS-2-[[2-[8-Dimethylamino-1-[(1-methyl-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-acetyl]amino]-acetamide
    SC_1167 CIS-2-[8-Dimethylamino-1-[(1-methyl-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-(2-hydroxy-ethyl)-acetamide
    SC_1168 CIS-2-[[2-[1-(Cyclopropyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-acetyl]amino]-acetamide
    SC_1169 CIS-2-[1-(Cyclobutyl-methyl)-8-(ethyl-methyl-amino)-2-oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-methyl-acetamide
    SC_1171 CIS-2-[[2-(8-Dimethylamino-2-oxo-8-phenyl-1-propyl-1,3-diazaspiro[4.5]decan-3-
    yl)-acetyl]amino]-acetamide
    SC_1172 CIS-2-[[2-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-
    1,3-diazaspiro[4.5]decan-3-yl]-acetyl]amino]-acetamide
    SC_1173 CIS-2-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-(2-hydroxy-ethyl)-acetamide
    SC_1174 CIS-2-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-(1,1-dioxo-thian-4-yl)-acetamide
    SC_1175 CIS-2-[1-(Cyclopropyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-methyl-acetamide
    SC_1176 CIS-2-[1-[(1-Cyano-cyclobutyl)-methyl]-8-dimethylamino-2-oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-methyl-acetamide
    SC_1177 CIS-2-[1-(Cyclobutyl-methyl)-8-(ethyl-methyl-amino)-2-oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-(2-hydroxy-ethyl)-acetamide
    SC_1178 CIS-2-[[2-[1-(Cyclobutyl-methyl)-8-(ethyl-methyl-amino)-2-oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-acetyl]amino]-acetamide
    SC_1179 CIS-2-[[2-[1-(Cyclobutyl-methyl)-8-methylamino-2-oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-acetyl]amino]-N,2-dimethyl-propionamide
    SC_1180 CIS-2-[8-Dimethylamino-1-(3-methoxy-propyl)-2-oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-(2-hydroxy-ethyl)-acetamide
    SC_1181 CIS-2-[8-Dimethylamino-1-(3-methoxy-propyl)-2-oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-methyl-N-(methylcarbamoyl-methyl)-acetamide
    SC_1182 CIS-8-Dimethylamino-1-(3-methoxy-propyl)-3-[2-oxo-2-(3-oxo-piperazin-1-yl)-
    ethyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
    SC_1183 CIS-N-(Carbamoyl-methyl)-2-[8-dimethylamino-1-(3-methoxy-propyl)-2-oxo-8-
    phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-methyl-acetamide
    SC_1184 CIS-2-[8-Dimethylamino-1-(3-methoxy-propyl)-2-oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-[(3-hydroxy-cyclobutyl)-methyl]-acetamide
    SC_1185 CIS-2-[8-Dimethylamino-1-(3-methoxy-propyl)-2-oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-[(3-hydroxy-cyclobutyl)-methyl]-acetamide
    SC_1186 CIS-2-[8-Dimethylamino-1-(3-methoxy-propyl)-2-oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-[(3-hydroxy-cyclopentyl)-methyl]-acetamide
    SC_1187 CIS-2-[8-Dimethylamino-1-(3-methoxy-propyl)-2-oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-pyridazin-4-yl-acetamide
    SC_1188 CIS-2-[8-Dimethylamino-1-(3-methoxy-propyl)-2-oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-(6-methoxy-pyridin-2-yl)-acetamide
    SC_1189 CIS-N-(2-Cyanoethyl)-2-[8-dimethylamino-1-(3-methoxy-propyl)-2-oxo-8-phenyl-
    1,3-diazaspiro[4.5]decan-3-yl]-acetamide
    SC_1190 CIS-2-[8-Dimethylamino-1-(3-methoxy-propyl)-2-oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-pyrimidin-5-yl-acetamide
    SC_1191 CIS-2-[8-Dimethylamino-1-(3-methoxy-propyl)-2-oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-pyrimidin-4-yl-acetamide
    SC_1192 CIS-2-[1-(Cyclobutyl-methyl)-8-(ethyl-methyl-amino)-2-oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-(6-methoxy-pyridin-2-yl)-acetamide
    SC_1193 CIS-2-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-pyridin-3-yl-acetamide
    SC_1195 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-acetamide
    SC_1196 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-pyrimidin-4-yl-acetamide
    SC_1197 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-(2-methoxy-cthyl)-acetamide
    SC_1198 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-(2-hydroxy-cthyl)-acetamide
    SC_1199 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-[2-[2-[2-[2-[2-[2-(2-methoxy-ethoxy)-ethoxy]-ethoxy]-
    ethoxy]-ethoxy]-ethoxy]-ethyl]-acetamide
    SC_1201 CIS-2-[1-(Cyclobutyl-methyl)-8-methylamino-2-oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-methyl-acetamide
    SC_1203 CIS-(2S)-1-[2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-acetyl]-pyrrolidine-2-carboxylic acid amide
    SC_1204 CIS-2-[[2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-acetyl]amino]-N,N-dimethyl-acetamide
    SC_1205 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-(oxetan-3-yl)-acetamide
    SC_1206 CIS-2-[[2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-acetyl]amino]-acetamide
    SC_1207 CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-3-[2-oxo-2-(3-oxo-piperazin-1-yl)-
    ethyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
    SC_1208 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-(1,1-dioxo-thian-4-yl)-acetamide
    SC_1209 CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-3-[2-[2-(hydroxymethyl)-morpholin-4-
    yl]-2-oxo-ethyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
    SC_1210 CIS-N-(Carbamoyl-methyl)-2-[1-(cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-
    phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-methyl-acetamide
    SC_1211 CIS-N-(Cyano-methyl)-2-[1-(cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-
    1,3-diazaspiro[4.5]decan-3-yl]-acetamide
    SC_1212 CIS-N-(2-Acetylamino-ethyl)-2-[1-(cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-
    phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetamide
    SC_1213 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-(2-methylsulfonyl-ethyl)-acetamide
    SC_1214 CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-3-[2-(1,1-dioxo-[1,4]thiazinan-4-yl)-2-
    oxo-ethyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
    SC_1215 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-[(1,1-dioxo-thian-4-yl)-methyl]-acetamide
    SC_1216 CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-3-[2-(4-methylsulfonyl-piperazin-1-
    yl)-2-oxo-ethyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
    SC_1217 CIS-N-(2-Cyanoethyl)-2-[1-(cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-
    1,3-diazaspiro[4.5]decan-3-yl]-acetamide
    SC_1218 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-(2-hydroxy-2-methyl-propyl)-acetamide
    SC_1219 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-(2-morpholin-4-yl-2-oxo-ethyl)-acetamide
    SC_1220 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-[2-(2-hydroxy-ethoxy)-ethyl]-acetamide
    SC_1222 CIS-2-[[2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-acetyl]amino]-N-methyl-acetamide
    SC_1223 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-[2-(methanesulfonamido)-ethyl]-acetamide
    SC_1224 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-[(1-hydroxy-cyclopentyl)-methyl]-acetamide
    SC_1225 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-[(4-hydroxy-cyclohexyl)-methyl]-acetamide
    SC_1226 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-[2-(2-methoxy-ethoxy)-ethyl]-acetamide
    SC_1227 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-[2-(dimethylamino)ethyl]-acetamide
    SC_1228 CIS-2-[1-(Cyclobutyl-methyl)-8-[methyl-(2-methyl-propyl)-amino]-2-oxo-8-phenyl-
    1,3-diazaspiro[4.5]decan-3-yl]-N-methyl-acetamide
    SC_1229 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-methyl-acetamide
    SC_1230 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-pyrimidin-4-yl-acetamide
    SC_1231 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-(6-methyl-pyridin-2-yl)-acetamide
    SC_1232 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-pyridazin-3-yl-acetamide
    SC_1233 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-pyrimidin-5-yl-acetamide
    SC_1234 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-pyridazin-4-yl-acetamide
    SC_1235 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-(6-methoxy-pyrimidin-4-yl)-acetamide
    SC_1236 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-(2-methyl-pyridin-4-yl)-acetamide
    SC_1300 CIS-2-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-pyridin-4-yl-acetamide
    SC_1301 CIS-2-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-(oxetan-3-yl)-acetamide
    SC_1302 CIS-2-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-(2-methoxy-ethyl)-acetamide
    SC_1303 CIS-2-[1-[(1-Hydroxy-cyclobutyl)-methyl]-8-methylamino-2-oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-(oxetan-3-yl)-acetamide
    SC_1304 CIS-2-[1-[(1-Hydroxy-cyclobutyl)-methyl]-8-methylamino-2-oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-(2-methoxy-ethyl)-acetamide
    SC_1305 CIS-2-[8-Dimethylamino-1-(3-methoxy-propyl)-2-oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-(4-methoxy-pyridin-2-yl)-acetamide
    SC_1306 CIS-2-[8-Dimethylamino-1-(3-methoxy-propyl)-2-oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-(pyrimidin-4-yl-methyl)-acetamide
    SC_1308 CIS-8-Dimethylamino-3-[2-(1,1-dioxo-[1,4]thiazinan-4-yl)-2-oxo-ethyl]-8-phenyl-1-
    propyl-1,3-diazaspiro[4.5]decan-2-one
    SC_1309 CIS-2-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-pyridin-2-yl-acetamide
    SC_1310 CIS-2-[1-[(1-Cyano-cyclobutyl)-methyl]-8-dimethylamino-2-oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-acetamide
    SC_1311 CIS-2-[[2-[1-[(1-Cyano-cyclobutyl)-methyl]-8-dimethylamino-2-oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-acetyl]amino]-acetamide
    SC_1312 CIS-2-[1-[(1-Hydroxy-cyclobutyl)-methyl]-8-methylamino-2-oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-methyl-acetamide
    SC_1313 CIS-3-[2-(1,1-Dioxo-[1,4]thiazinan-4-yl)-2-oxo-ethyl]-8-methylamino-8-phenyl-1-
    propyl-1,3-diazaspiro[4.5]decan-2-one
    SC_1317 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-pyridin-2-yl-acetamide
    SC_1318 CIS-8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-3-(2-morpholin-4-yl-2-
    oxo-ethyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
    SC_1319 CIS-2-[1-[(1-Hydroxy-cyclobutyl)-methyl]-8-methylamino-2-oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-acetamide
    SC_1320 CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-3-(2-morpholin-4-yl-2-oxo-ethyl)-8-
    phenyl-1,3-diazaspiro[4.5]decan-2-one
    SC_1321 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-(4-methylsulfanyl-pyridin-2-yl)-acetamide
    SC_1322 CIS-3-[2-(1,1-Dioxo-[1,4]thiazinan-4-yl)-2-oxo-ethyl]-8-methylamino-8-phenyl-1,3-
    diazaspiro[4.5]decan-2-one
    SC_1323 CIS-2-(8-Methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-acetamide
    SC_1324 CIS-2-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-acetamide
    SC_1325 CIS-3-[2-(1,1-Dioxo-[1,4]thiazinan-4-yl)-2-oxo-ethyl]-8-ethylamino-8-phenyl-1,3-
    diazaspiro[4.5]decan-2-one
    SC_1326 TRANS-3-[2-(1,1-Dioxo-[1,4]thiazinan-4-yl)-2-oxo-ethyl]-8-ethylamino-8-phenyl-
    1,3-diazaspiro[4.5]decan-2-one
    SC_1327 CIS-2-[1-(Cyclobutyl-methyl)-8-methylamino-2-oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-methyl-acetamide
    SC_1328 CIS-2-(8-Ethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-acetamide
    SC_1329 TRANS-2-(8-Ethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-acetamide
    SC_1330 CIS-2-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-N-(2-
    hydroxy-ethyl)-N-methyl-acetamide
    SC_1331 CIS-8-Dimethylamino-3-[2-(1,1-dioxo-[1,4]thiazinan-4-yl)-2-oxo-ethyl]-1-[(1-
    hydroxy-cyclobutyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decane-2,4-dione
    SC_1332 CIS-2-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-N-phenyl-
    acetamide
    SC_1333 CIS-N-(Carbamoyl-methyl)-2-[1-(cyclopropyl-methyl)-8-dimethylamino-2-oxo-8-
    phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-methyl-acetamide
    SC_1334 CIS-2-(8-Dimethylamino-2,4-dioxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-N-
    phenyl-acetamide
    SC_1335 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-acetamide
    SC_1336 CIS-2-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-[2-[2-[2-(2-methoxy-ethoxy)-ethoxy]-ethoxy]-ethyl]-
    acetamide
    SC_1337 CIS-3-[2-(1,1-Dioxo-[1,4]thiazinan-4-yl)-2-oxo-ethyl]-1-[(1-hydroxy-cyclobutyl)-
    methyl]-8-methylamino-8-phenyl-1,3-diazaspiro[4.5]decane-2,4-dione
    SC_1338 CIS-2-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-N-[2-[2-[2-
    (2-methoxy-ethoxy)-ethoxy]-ethoxy]-ethyl]-acetamide
    SC_1339 CIS-N-(Carbamoyl-methyl)-N-methyl-2-(8-methylamino-2-oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl)-acetamide
    SC_1340 CIS-N-(Carbamoyl-methyl)-2-(8-dimethylamino-2-oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl)-N-methyl-acetamide
    SC_1341 CIS-N-(Carbamoyl-methyl)-2-[8-dimethylamino-1-(oxetan-3-yl-methyl)-2-oxo-8-
    phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-methyl-acetamide
    SC_1342 CIS-N-(2-Hydroxy-ethyl)-N-methyl-2-(8-methylamino-2-oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl)-acetamide
    SC_1343 CIS-2-[1-(Cyclopropyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-acetamide
    SC_1344 CIS-2-[1-(Cyclopropyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-(2-hydroxy-ethyl)-acetamide
    SC_1345 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-8-(3-fluorophenyl)-2-oxo-1,3-
    diazaspiro[4.5]decan-3-yl]-N-(2-hydroxy-ethyl)-N-methyl-acetamide
    SC_1346 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-8-(3-fluorophenyl)-2-oxo-1,3-
    diazaspiro[4.5]decan-3-yl]-acetic acid tert-butyl ester
    SC_1347 CIS-2-[1-(Cyclopropyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-(2-hydroxy-ethyl)-N-methyl-acetamide
    SC_1348 CIS-2-[1-(Cyclopropyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-(2-methylsulfonyl-ethyl)-acetamide
    SC_1349 CIS-N-(Carbamoyl-methyl)-2-[1-(cyclobutyl-methyl)-8-dimethylamino-8-(3-
    fluorophenyl)-2-oxo-1,3-diazaspiro[4.5]decan-3-yl]-N-methyl-acetamide
    SC_1350 CIS-1-[2-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-acetyl]-piperidine-4-carboxylic acid amide
    SC_1351 CIS-8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-3-[2-(4-methylsulfonyl-
    piperidin-1-yl)-2-oxo-ethyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
    SC_1352 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-8-(3-fluorophenyl)-2-oxo-1,3-
    diazaspiro[4.5]decan-3-yl]-N-(2-hydroxy-ethyl)-acetamide
    SC_1353 TRANS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-(2-hydroxy-ethyl)-acetamide
    SC_1354 TRANS-N-(Carbamoyl-methyl)-2-[1-(cyclobutyl-methyl)-8-dimethylamino-2-oxo-
    8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-methyl-acetamide
    SC_1355 CIS-8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-3-[2-(4-hydroxy-4-
    methyl-piperidin-1-yl)-2-oxo-ethyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
    SC_1356 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-8-(4-fluorophenyl)-2-oxo-1,3-
    diazaspiro[4.5]decan-3-yl]-N-(2-hydroxy-ethyl)-acetamide
    SC_1357 TRANS-1-(Cyclopropyl-methyl)-8-dimethylamino-3-(2-morpholin-4-yl-2-oxo-
    ethyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
    SC_1358 TRANS-8-Dimethylamino-3-(2-morpholin-4-yl-2-oxo-ethyl)-8-phenyl-1,3-
    diazaspiro[4.5]decan-2-one
    SC_1359 CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-8-(4-fluorophenyl)-2-oxo-1,3-
    diazaspiro[4.5]decan-3-yl]-N-(2-hydroxy-ethyl)-N-methyl-acetamide
    SC_1360 CIS-N-(Carbamoyl-methyl)-2-[1-(cyclobutyl-methyl)-8-dimethylamino-8-(4-
    fluorophenyl)-2-oxo-1,3-diazaspiro[4.5]decan-3-yl]-N-methyl-acetamide
    SC_1361 CIS-1-(Cyclopropyl-methyl)-8-dimethylamino-3-[2-(4-hydroxy-4-methyl-piperidin-
    1-yl)-2-oxo-ethyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
    SC_1362 CIS-1-[2-[1-(Cyclopropyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-acetyl]-piperidine-4-carboxylic acid amide
    SC_1363 TRANS-2-[1-(Cyclopropyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-acetamide
    SC_1364 TRANS-2-[1-(Cyclopropyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-methyl-acetamide
    SC_1365 TRANS-1-(Cyclopropyl-methyl)-8-dimethylamino-3-[2-(1,1-dioxo-[1,4]thiazinan-4-
    yl)-2-oxo-ethyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
    SC_1366 CIS-1-(Cyclopropyl-methyl)-8-dimethylamino-3-[2-(4-methylsulfonyl-piperidin-1-
    yl)-2-oxo-ethyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
    SC_1368 CIS-8-Dimethylamino-3-[2-(1,1-dioxo-[1,4]thiazinan-4-yl)-2-oxo-ethyl]-1-[(1-
    hydroxy-cyclobutyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
    SC_1369 TRANS-2-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-
    acetamide
    SC_1370 TRANS-8-Dimethylamino-3-[2-(1,1-dioxo-[1,4]thiazinan-4-yl)-2-oxo-ethyl]-8-
    phenyl-1,3-diazaspiro[4.5]decan-2-one
    SC_1371 CIS-8-(dimethylamino)-8-phenyl-1-(2,2,2-trifluoroethyl)-3-(2-
    (trifluoromethyl)pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one
    SC_1372 CIS-8-(dimethylamino)-8-phenyl-3-(2-(trifluoromethyl)pyrimidin-5-yl)-1-(3,3,3-
    trifluoropropyl)-1,3-diazaspiro[4.5]decan-2-one

    and the physiologically acceptable salts thereof.
  • According to the invention, unless expressly stated otherwise, “—C1-C4-alkyl”, “—C1-C6-alkyl” and any other alkyl residues can be linear or branched, saturated or unsaturated. Linear saturated alkyl includes methyl, ethyl, n-propyl, n-butyl, n-pentyl and n-hexyl. Examples of branched saturated alkyl include but are not limited to iso-propyl, sec-butyl, and tert-butyl. Examples of linear unsaturated alkyl include but are not limited to vinyl, propenyl, allyl, and propargyl.
  • According to the invention, unless expressly stated otherwise, “—C1-C4-alkyl”, “—C1-C6-alkyl” and any other alkyl residues can be unsubstituted, mono- or polysubstituted. Examples of substituted alkyl include but are not limited to —CH2CH2OH, —CH2CH2OCH3, —CH2CH2CH2OCH3, —CH2CH2S(═O)2CH3, —CH2C(═O)NH2, —C(CH3)2C(═O)NH2, —CH2C(CH3)2C(═O)NH2, and —CH2CH2C(═O)N(CH3)2.
  • According to the invention, unless expressly stated otherwise, “—C1-C6-alkylene-”. “—C1-C4-alkylene” and any other alkylene residue can be unsubstituted, mono- or polysubstituted. Examples of saturated alkylene include but are not limited to —CH2—, —CH(CH3)—, —C(CH3)2—, —CH2CH2—, —CH(CH3)CH2—, —CH2CH(CH3)—, —CH(CH3)—CH(CH3)—, —C(CH3)2CH2—, —CH2C(CH3)2—, —CH(CH3)C(CH3)2—, —C(CH3)2CH(CH3)—, C(CH3)2C(CH3)2—, —CH2CH2CH2—, and —C(CH3)2CH2CH2—. Examples of unsaturated alkylene include but are not limited to —CH═CH—, —C≡C—, —C(CH3)═CH—, —CH═C(CH3)—, —C(CH3)═C(CH3)—, −CH2CH═CH—, —CH═CHCH2—, —CH═CH—CH═CH—, and —CH═CH—C≡C—.
  • According to the invention, unless expressly stated otherwise, “—C1-C6-alkylene-”. “—C1-C4-alkylene” and any other alkylene residue can be unsubstituted, mono- or polysubstituted. Examples of substituted —C1-C6-alkylene- include but are not limited to —CHF—, —CF2—, —CHOH— and —C(═O)—.
  • According to the invention, moieties may be connected through —C1-C6-alkylene-. i.e. the moieties may not be directly bound to the core structure of compound according to general formula (I), but may be connected to the core structure of compound according to general formula (I) or its periphery through a —C1-C6-alkylene- linker.
  • According to the invention, “3-12-membered cycloalkyl moiety” means a non-aromatic, monocyclic, bicyclic or tricyclic moiety comprising 3 to 12 ring carbon atoms but no heteroatoms in the ring. Examples of preferred saturated 3-12-membered cycloalkyl moieties according to the invention include but are not limited to cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, hydrindane, and decaline. Examples of preferred unsaturated 3-12-membered cycloalkyl moiety moieties according to the invention include but are not limited to cyclopropene, cyclobutene, cyclopentene, cyclopentadiene, cyclohexene, 1,3-cyclohexadiene, and 1,4-cyclohexadiene. The 3-12-membered cycloalkyl moiety, which is bonded to the compound according to the invention, in its periphery may optionally be condensed with a 3-12-membered heterocycloalkyl moiety, saturated or unsaturated, unsubstituted, mono- or polysubstituted; and/or with a 6-14-membered aryl moiety, unsubstituted, mono- or polysubstituted; and/or with a 5-14-membered heteroaryl moiety, unsubstituted, mono- or polysubstituted. Under these circumstances, the ring atoms of the condensed moieties are not included in the 3 to 12 ring atoms of the 3-12-membered cycloalkyl moiety. Examples of 3-12-membered cycloalkyl moieties condensed with 3-12-membered heterocycloalkyl moieties include but are not limited to octahydro-1H-indol, decahydroquinoline, decahydroisoquinoline, octahydro-2H-benzo[b][1,4]oxazin, and decahydro-quinoxalin, which in each case are connected through the 3-12-membered cycloalkyl moiety. Examples of 3-12-membered cycloalkyl moieties condensed with 6-14-membered aryl moieties include but are not limited to 2,3-dihydro-1H-indene and tetraline, which in each case are connected through the 3-12-membered cycloalkyl moiety. Examples of 3-12-membered cycloalkyl moieties condensed with 5-14-membered heteroaryl moieties include but are not limited to 5,6,7,8-tetrahydroquinoline and 5,6,7,8-tetrahydroquinazoline, which in each case are connected through the 3-12-membered cycloalkyl moiety.
  • According to the invention, the 3-12-membered cycloalkyl moiety may optionally be connected through —C1-C6-alkylene-. i.e. the 3-12-membered cycloalkyl moiety may not be directly bound to the compound according to general formula (I) but may be connected thereto through a —C1-C6-alkylene- linker. Examples include but are not limited to —CH2-cyclopropyl, —CH2-cyclobutyl, —CH2-cyclopentyl, —CH2-cyclohexyl, —CH2CH2-cyclopropyl, —CH2CH2-cyclobutyl, —CH2CH2-cyclopentyl, and —CH2CH2-cyclohexyl.
  • According to the invention, unless expressly stated otherwise, the 3-12-membered cycloalkyl moiety can be unsubstituted, mono- or polysubstituted. Examples of substituted 3-12-membered cycloalkyl moieties include but are not limited to —CH2-1-hydroxy-cyclobutyl.
  • According to the invention, “3-12-membered heterocycloalkyl moiety” means a non-aromatic, monocyclic, bicyclic or tricyclic moiety comprising 3 to 12 ring atoms, wherein each cycle comprises independently of one another 1, 2, 3, 4 or more heteroatoms independently of one another selected from the group consisting of nitrogen, oxygen and sulfur, whereas sulfur may be oxidized (S(═O) or S(═O)2), whereas the remaining ring atoms are carbon atoms, and whereas bicyclic or tricyclic systems may share common heteroatom(s). Examples of preferred saturated 3-12-membered heterocycloalkyl moieties according to the invention include but are not limited to aziridin, azetidine, pyrrolidine, imidazolidine, pyrazolidine, piperidine, piperazine, triazolidine, tetrazolidine, oxiran, oxetane, tetrahydrofurane, tetrahydropyrane, thiirane, thietane, tetra-hydrothiophene, diazepane, oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, thiadiazoli-dine, morpholine, thiomorpholine. Examples of preferred unsaturated 3-12-membered heterocycloalkyl moiety moieties according to the invention include but are not limited to oxazoline, pyrazoline, imidazoline, isoxazoline, thiazoline, isothiazoline, and dihydropyran. The 3-12-membered heterocycloalkyl moiety, which is bonded to the compound according to the invention, in its periphery may optionally be condensed with a 3-12-membered cycloalkyl moiety, saturated or unsaturated, unsubstituted, mono- or polysubstituted; and/or with a 6-14-membered aryl moiety, unsubstituted, mono- or polysubstituted; and/or with a 5-14-membered heteroaryl moiety, unsubstituted, mono- or polysubstituted. Under these circumstances, the ring atoms of the condensed moieties are not included in the 3 to 12 ring atoms of the 3-12-membered heterocycloalkyl moieties. Examples of 3-12-membered heterocycloalkyl moieties condensed with 3-12-membered cycloalkyl moieties include but are not limited to octahydro-1H-indol, decahydroquinoline, decahydroisoquinoline, octahydro-2H-benzo[b][1,4]oxazin, and decahydro-quinoxalin, which in each case are connected through the 3-12-membered heterocycloalkyl moiety. An examples of a 3-12-membered heterocycloalkyl moiety condensed with a 6-14-membered aryl moiety includes but is not limited to 1,2,3,4-tetrahydroquinoline, which is connected through the 3-12-membered heterocycloalkyl moiety. An example of a 3-12-membered heterocycloalkyl moiety condensed with a 5-14-membered heteroaryl moieties includes but is not limited to 5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazine, which is connected through the 3-12-membered heterocycloalkyl moiety.
  • According to the invention, the 3-12-membered heterocycloalkyl moiety may optionally be connected through —C1-C6-alkylene-. i.e. the 3-12-membered heterocycloalkyl moiety may not be directly bound to the compound according to general formula (I) but may be connected thereto through a —C1-C6-alkylene- linker. Said linker may be connected to a carbon ring atom or to a hetero ring atom of the 3-12-membered heterocycloalkyl moiety. Examples include but are not limited to —CH2-oxetane, —CH2-pyrrolidine, —CH2-piperidine, —CH2-morpholine, —CH2CH2-oxetane, —CH2CH2-pyrrolidine, —CH2CH2-piperidine, and —CH2CH2-morpholine.
  • According to the invention, unless expressly stated otherwise, the 3-12-membered heterocycloalkyl moiety can be unsubstituted, mono- or polysubstituted. Examples of substituted 3-12-membered heterocycloalkyl moieties include but are not limited to 2-carboxamido-N-pyrrolidinyl-, 3,4-dihydroxy-N-pyrrolidinyl, 3-hydroxy-N-pyrimidinyl, 3,4-dihydroxy-N-pyrimidinyl, 3-oxo-N-piperazinyl, -tetrahydro-2H-thiopyranyl dioxide and thiomorpholinyl dioxide.
  • According to the invention, “6-14-membered aryl moiety” means an aromatic, monocyclic, bicyclic or tricyclic moiety comprising 6 to 14 ring carbon atoms but no heteroatoms in the ring. Examples of preferred 6-14-membered aryl moieties according to the invention include but are not limited to benzene, naphthalene, anthracen, and phenanthren. The 6-14-membered aryl moiety, which is bonded to the compound according to the invention, in its periphery may optionally be condensed with a 3-12-membered cycloalkyl moiety, saturated or unsaturated, unsubstituted, mono- or polysubstituted; and/or with a 3-12-membered heterocycloalkyl moiety, saturated or unsaturated, unsubstituted, mono- or polysubstituted; and/or with a 5-14-membered heteroaryl moiety, unsubstituted, mono- or polysubstituted. Under these circumstances, the ring atoms of the condensed moieties are not included in the 6 to 14 ring carbon atoms of the 6-14-membered heterocycloalkyl moieties. Examples of 6-14-membered aryl moieties condensed with 3-12-membered cycloalkyl moieties include but are not limited to 2,3-dihydro-1H-indene and tetraline, which in each case are connected through the 6-14-membered aryl moiety. An example of a 6-14-membered aryl moiety condensed with a 3-12-membered heterocycloalkyl moiety includes but is not limited to 1,2,3,4-tetrahydroquinoline, which is connected through the 6-14-membered aryl moiety. Examples of 6-14-membered aryl moieties condensed with 5-14-membered heteroaryl moieties include but are not limited to quinoline, isoquinoline, phenazine and phenoxacine, which in each case are connected through the 6-14-membered aryl moiety.
  • According to the invention, the 6-14-membered aryl moiety may optionally be connected through —C1-C6-alkylene-, i.e. the 6-14-membered aryl moiety may not be directly bound to the compound according to general formula (I) but may be connected thereto through a —C4-C6-alkylene- linker. Said linker may be connected to a carbon ring atom or to a hetero ring atom of the 6-14-membered aryl moiety. Examples include but are not limited to —CH2—C6H5, —CH2CH2—C6H5 and —CH═CH—C6H5.
  • According to the invention, unless expressly stated otherwise, the 6-14-membered aryl moiety can be unsubstituted, mono- or polysubstituted. Examples of substituted 6-14-membered aryl moieties include but are not limited to 2-fluorophenyl, 3-fluorophenyl, 2-methoxyphenyl and 3-methoxyphenyl.
  • According to the invention, “5-14-membered heteroaryl moiety” means an aromatic, monocyclic, bicyclic or tricyclic moiety comprising 6 to 14 ring atoms, wherein each cycle comprises independently of one another 1, 2, 3, 4 or more heteroatoms independently of one another selected from the group consisting of nitrogen, oxygen and sulfur, whereas the remaining ring atoms are carbon atoms, and whereas bicyclic or tricyclic systems may share common heteroatom(s). Examples of preferred 5-14-membered heteroaryl moieties according to the invention include but are not limited to pyrrole, pyrazole, imidazole, triazole, tetrazole, furane, thiophene, oxazole, isoxazole, thiazole, isothiazole, pyridine, pyridazine, pyrimidine, pyrazine, indolicine, 9H-chinolicine, 1,8-naphthyridine, purine, imidazo[1,2-a]pyrazine, and pteridine. The 5-14-membered heteroaryl moiety, which is bonded to the compound according to the invention, in its periphery may optionally be condensed with a 3-12-membered cycloalkyl moiety, saturated or unsaturated, unsubstituted, mono- or polysubstituted; and/or with a 3-12-membered heterocycloalkyl moiety, saturated or unsaturated, unsubstituted, mono- or polysubstituted; and/or with a 6-14-membered aryl moiety, unsubstituted, mono- or poly substituted. Under these circumstances, the ring atoms of the condensed moieties are not included in the 6 to 14 ring carbon atoms of the 6-14-membered heterocycloalkyl moieties. Examples of 5-14-membered heteroaryl moieties condensed with 3-12-membered cycloalkyl moieties include but are not limited to 5,6,7,8-tetrahydroquinoline and 5,6,7,8-tetrahydroquinazoline, which in each case are connected through the 5-14-membered heteroaryl moiety. An examples of a 5-14-membered heteroaryl moiety condensed with a 3-12-membered heterocycloalkyl moiety includes but is not limited to 5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazine, which is connected through the 5-14-membered heteroaryl moiety. Examples of 5-14-membered heteroaryl moieties condensed with 6-14-membered aryl moieties include but are not limited to quinoline, isoquinoline, phenazine and phenoxacine, which in each case are connected through the 5-14-membered heteroaryl moiety.
  • According to the invention, the 5-14-membered heteroaryl moiety may optionally be connected through —C1-C6-alkylene-. i.e. the 5-14-membered heteroaryl moiety may not be directly bound to the compound according to general formula (I) but may be connected thereto through a —C1-C6-alkylene- linker. Said linker may be connected to a carbon ring atom or to a hetero ring atom of the 5-14-membered heteroaryl moiety. Examples include but are not limited to —CH2-oxazole, —CH2-isoxazole, —CH2-imidazole, —CH2-pyridine, —CH2-pyrimidine, —CH2-pyridazine, —CH2CH2-oxazole, —CH2CH2-isoxazole, —CH2CH2-imidazole, —CH2CH2-pyridine, —CH2CH2-pyrimidine, and —CH2CH2-pyridazine.
  • According to the invention, unless expressly stated otherwise, the 5-14-membered heteroaryl moiety can be unsubstituted, mono- or polysubstituted. Examples of 5-14-membered heteroaryl moieties include but are not limited to 2-methoxy-4-pyridinyl, 2-methoxy-5-pyridinyl, 3-methoxy-4-pyridinyl, 3-methoxy-6-pyridinyl, 4-methoxy-2-pyridinyl, 2-methylsulfonyl-5-pyridinyl, 3-methylsulfonyl-6-pyridinyl, 3-methoxy-6-pyridazinyl, 2-nitrilo-5-pyrimidinyl, 4-hydroxy-2-pyrimidinyl, 4-methoxy-pyrimidinyl, and 2-methoxy-6-pyrazinyl.
  • Preferably, the compounds according to the invention have a structure according to general formula (I′)
  • Figure US20210179627A1-20210617-C00019
  • wherein R1 to R5, R9 to R20, and X are defined as above, or a physiologically acceptable salt thereof.
  • In one preferred embodiment, the excess of the cis-isomer so designated is at least 50% de, more preferably at least 75% de, yet more preferably at least 90% de, most preferably at least 95% de and in particular at least 99% de.
  • Preferably, the compounds according to the invention have a structure according to general formula (IX)
  • Figure US20210179627A1-20210617-C00020
  • wherein
    RC means —H or —OH;
    R3 means -phenyl or -3-fluorophenyl;
    R5 means —H, —CH3, —CH2CH2OH, or —CH2C(═O)NH2;
    R6 means —H or —CH3;
    or R5 and R6 together with the nitrogen atom to which they are attached form a ring and mean —(CH2)5—, wherein said ring is unsubstituted or substituted with one or two substituents independently of one another selected from the group consisting of —CH3, —OH, —S(═O)2CH3 and —C(═O)NH2;
    R9 and R10 independently of one another mean —H or —CH3;
    or a physiologically acceptable salt thereof.
  • In a preferred embodiment, the compounds according to the invention are in the form of the free bases.
  • In another preferred embodiment, the compounds according to the invention are in the form of the physiologically acceptable salts.
  • For the purposes of the description, a “salt” is to be understood as being any form of the compound in which it assumes an ionic form or is charged and is coupled with a counter-ion (a cation or anion) or is in solution. The term is also to be understood as meaning complexes of the compound with other molecules and ions, in particular complexes which are associated via ionic interactions. Preferred salts are physiologically acceptable, in particular physiologically acceptable salts with anions or acids or also a salt formed with a physiologically acceptable acid.
  • Physiologically acceptable salts with anions or acids are salts of the particular compound in question with inorganic or organic acids which are physiologically acceptable, in particular when used in humans and/or mammals. Examples of physiologically acceptable salts of particular acids include but are not limited to salts of hydrochloric acid, sulfuric acid, and acetic acid.
  • The invention also includes isotopic isomers of a compound according to 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 2H (deuterium), 3H (tritium), 13C and 14C.
  • Certain compounds according to the invention are useful for modulating a pharmacodynamic response from one or more opioid receptors (mu, delta, kappa, NOP/ORL-1) either centrally or peripherally, or both. The pharmacodynamic response may be attributed to the compound either stimulating (agonizing) or inhibiting (antagonizing) the one or more receptors. Certain compounds according to the invention may antagonize one opioid receptor, while also agonizing one or more other receptors. Compounds according to the invention having agonist activity may be either full agonists or partial agonists.
  • As used herein, compounds that bind to receptors and mimic the regulatory effects of endogenous ligands are defined as “agonists”. Compounds that bind to a receptor but produce no regulatory effect, but rather block the binding of ligands to the receptor, are defined as “antagonists”.
  • In certain embodiments, the compounds according to the invention are agonists at the mu opioid (MOP) and/or kappa opioid (KOP) and/or delta opioid (DOP) and/or nociceptin opioid (NOP/ORL-1) receptors.
  • The compounds according to the invention potently bind to the MOP and/or KOP and/or DOP and/or NOP receptors.
  • The compounds according to the invention can be modulators at the MOP and/or KOP and/or DOP and/or NOP receptors, and therefore the compounds according to the invention can be used/administered to treat, ameliorate, or prevent pain.
  • In some embodiments, the compounds according to the invention are agonists of one or more opioid receptors. In some embodiments, the compounds according to the invention are agonists of the MOP and/or KOP and/or DOP and/or NOP receptors.
  • In some embodiments, the compounds according to the invention are antagonists of one or more opioid receptors. In some embodiments, the compounds according to the invention are antagonists of the MOP and/or KOP and/or DOP and/or NOP receptors.
  • In some embodiments, the compounds according to the invention have both, (i) agonist activity at the NOP receptor; and (ii) agonist activity at one or more of the MOP, KOP, and DOP receptors.
  • In some embodiments, the compounds according to the invention have both, (i) agonist activity at the NOP receptor; and (ii) antagonist activity at one or more of the MOP, KOP, and DOP receptors.
  • In some embodiments, the compounds according to the invention have both, (i) antagonist activity at the NOP receptor; and (ii) agonist activity at one or more of the MOP, KOP, and DOP receptors.
  • In some embodiments, the compounds according to the invention have both, (i) antagonist activity at the NOP receptor; and (ii) antagonist activity at one or more of the MOP, KOP, and DOP receptors.
  • In some embodiments, preferably with respect to receptors of the peripheral nervous system, the compounds according to the invention have selective agonist activity at the NOP receptor. In some embodiments, preferably with respect to receptors of the peripheral nervous system, the compounds according to the invention
      • have agonist activity at the NOP receptor, but no significant activity at the MOP receptor;
      • have agonist activity at the NOP receptor, but no significant activity at the KOP receptor;
      • have agonist activity at the NOP receptor, but no significant activity at the DOP receptor;
      • have agonist activity at the NOP receptor, but no significant activity at the MOP receptor as well as no significant activity at the KOP receptor;
      • have agonist activity at the NOP receptor, but no significant activity at the MOP receptor as well as no significant activity at the DOP receptor; or
      • have agonist activity at the NOP receptor, but no significant activity at the MOP receptor as well as no significant activity at the KOP receptor as well as no significant activity at the DOP receptor.
  • In some embodiments, preferably with respect to receptors of the peripheral nervous system, the compounds according to the invention have balanced agonist activity at the NOP receptor as well as at the MOP receptor. In some embodiments, preferably with respect to receptors of the peripheral nervous system, the compounds according to the invention
      • have agonist activity at the NOP receptor as well as agonist activity at the MOP receptor;
      • have agonist activity at the NOP receptor as well as agonist activity at the MOP receptor as well as agonist activity at the KOP receptor;
      • have agonist activity at the NOP receptor as well as agonist activity at the MOP receptor as well as agonist activity at the DOP receptor;
      • can be regarded as opioid pan agonists, i.e. have agonist activity at the NOP receptor as well as agonist activity at the MOP receptor as well as agonist activity at the KOP receptor as well as agonist activity at the DOP receptor;
      • have agonist activity at the NOP receptor as well as agonist activity at the MOP receptor, but no significant activity at the KOP receptor;
      • have agonist activity at the NOP receptor as well as agonist activity at the MOP receptor, but no significant activity at the DOP receptor; or
      • have agonist activity at the NOP receptor as well as agonist activity at the MOP receptor, but no significant activity at the KOP receptor as well as no significant activity at the DOP receptor.
  • In some embodiments, preferably with respect to receptors of the peripheral nervous system, the compounds according to the invention have balanced agonist activity at the NOP receptor as well as at the KOP receptor. In some embodiments, preferably with respect to receptors of the peripheral nervous system, the compounds according to the invention
      • have agonist activity at the NOP receptor as well as agonist activity at the KOP receptor;
      • have agonist activity at the NOP receptor as well as agonist activity at the KOP receptor as well as agonist activity at the MOP receptor;
      • have agonist activity at the NOP receptor as well as agonist activity at the KOP receptor as well as agonist activity at the DOP receptor;
      • have agonist activity at the NOP receptor as well as agonist activity at the KOP receptor, but no significant activity at the MOP receptor;
      • have agonist activity at the NOP receptor as well as agonist activity at the KOP receptor, but no significant activity at the DOP receptor; or
      • have agonist activity at the NOP receptor as well as agonist activity at the KOP receptor, but no significant activity at the MOP receptor as well as no significant activity at the DOP receptor.
  • In some embodiments, preferably with respect to receptors of the peripheral nervous system, the compounds according to the invention have balanced agonist activity at the NOP receptor as well as at the DOP receptor. In some embodiments, preferably with respect to receptors of the peripheral nervous system, the compounds according to the invention
      • have agonist activity at the NOP receptor as well as agonist activity at the DOP receptor;
      • have agonist activity at the NOP receptor as well as agonist activity at the DOP receptor, but no significant activity at the MOP receptor;
      • have agonist activity at the NOP receptor as well as agonist activity at the DOP receptor, but no significant activity at the KOP receptor; or
      • have agonist activity at the NOP receptor as well as agonist activity at the DOP receptor, but no significant activity at the MOP receptor as well as no significant activity at the KOP receptor.
  • In some embodiments, preferably with respect to receptors of the peripheral nervous system, the compounds according to the invention have selective agonist activity at the KOP receptor. In some embodiments, preferably with respect to receptors of the peripheral nervous system, the compounds according to the invention
      • have agonist activity at the KOP receptor, but no significant activity at the MOP receptor;
      • have agonist activity at the KOP receptor, but no significant activity at the NOP receptor;
      • have agonist activity at the KOP receptor, but no significant activity at the DOP receptor;
      • have agonist activity at the KOP receptor, but no significant activity at the MOP receptor as well as no significant activity at the NOP receptor;
      • have agonist activity at the KOP receptor, but no significant activity at the MOP receptor as well as no significant activity at the DOP receptor; or
      • have agonist activity at the KOP receptor, but no significant activity at the MOP receptor as well as no significant activity at the NOP receptor as well as no significant activity at the DOP receptor.
  • In some embodiments, preferably with respect to receptors of the peripheral nervous system, the compounds according to the invention have agonist activity at the MOP receptor, agonist activity at the KOP receptor, and antagonist activity at the DOP receptor. In some embodiments, preferably with respect to receptors of the peripheral nervous system, the compounds according to the invention
      • have agonist activity at the MOP receptor as well as agonist activity at the KOP receptor as well as antagonist activity at the DOP receptor;
      • have agonist activity at the MOP receptor as well as agonist activity at the KOP receptor as well as antagonist activity at the DOP receptor as well as agonist activity at the NOP receptor;
      • have agonist activity at the MOP receptor as well as agonist activity at the KOP receptor as well as antagonist activity at the DOP receptor as well as antagonist activity at the NOP receptor; or
      • have agonist activity at the MOP receptor as well as agonist activity at the KOP receptor as well as antagonist activity at the DOP receptor, no significant activity at the NOP receptor.
  • In some embodiments, preferably with respect to receptors of the central nervous system, the compounds according to the invention have selective agonist activity at the NOP receptor. In some embodiments, preferably with respect to receptors of the central nervous system, the compounds according to the invention
      • have agonist activity at the NOP receptor, but no significant activity at the MOP receptor;
      • have agonist activity at the NOP receptor, but no significant activity at the KOP receptor;
      • have agonist activity at the NOP receptor, but no significant activity at the DOP receptor;
      • have agonist activity at the NOP receptor, but no significant activity at the MOP receptor as well as no significant activity at the KOP receptor;
      • have agonist activity at the NOP receptor, but no significant activity at the MOP receptor as well as no significant activity at the DOP receptor; or
      • have agonist activity at the NOP receptor, but no significant activity at the MOP receptor as well as no significant activity at the KOP receptor as well as no significant activity at the DOP receptor.
  • In some embodiments, preferably with respect to receptors of the central nervous system, the compounds according to the invention have selective antagonist activity at the NOP receptor. In some embodiments, preferably with respect to receptors of the central nervous system, the compounds according to the invention
      • have antagonist activity at the NOP receptor, but no significant activity at the MOP receptor;
      • have antagonist activity at the NOP receptor, but no significant activity at the KOP receptor;
      • have antagonist activity at the NOP receptor, but no significant activity at the DOP receptor;
      • have antagonist activity at the NOP receptor, but no significant activity at the MOP receptor as well as no significant activity at the KOP receptor;
      • have antagonist activity at the NOP receptor, but no significant activity at the MOP receptor as well as no significant activity at the DOP receptor; or
      • have antagonist activity at the NOP receptor, but no significant activity at the MOP receptor as well as no significant activity at the KOP receptor as well as no significant activity at the DOP receptor.
  • In some embodiments, preferably with respect to receptors of the central nervous system, the compounds according to the invention have antagonist activity at the NOP receptor as well as agonist activity at the DOP receptor. In some embodiments, preferably with respect to receptors of the central nervous system, the compounds according to the invention
      • have antagonist activity at the NOP receptor as well as agonist activity at the DOP receptor;
      • have antagonist activity at the NOP receptor as well as agonist activity at the DOP receptor, but no significant activity at the MOP receptor;
      • have antagonist activity at the NOP receptor as well as agonist activity at the DOP receptor, but no significant activity at the KOP receptor; or
      • have antagonist activity at the NOP receptor as well as agonist activity at the DOP receptor, but no significant activity at the MOP receptor as well as no significant activity at the KOP receptor.
  • For the purpose of the specification, “no significant activity” means that the activity (agonist/antagonist) of the given compound at this receptor is lower by a factor of 1000 or more compared to its activity (agonist/antagonist) at one or more of the other opioid receptors.
  • A further aspect of the invention relates to the compounds according to the invention as medicaments.
  • A further aspect of the invention relates to the compounds according to the invention for use in the treatment of pain. A further aspect of the invention relates to a method of treating pain comprising the administration of a pain alleviating amount of a compound according to the invention to a subject in need thereof, preferably to a human. The pain is preferably acute or chronic. The pain is preferably nociceptive or neuropathic.
  • A further aspect of the invention relates to the compounds according to the invention for use in the treatment of neurodegenerative disorders, neuroinflammatory disorders, neuropsychiatric disorders, and substance abuse/dependence. A further aspect of the invention relates to a method of treating any one of the aforementioned disorders, diseases or conditions comprising the administration of a therapeutically effective amount of a compound according to the invention to a subject in need thereof, preferably to a human.
  • Another aspect of the invention relates to a pharmaceutical composition which contains a physiologically acceptable carrier and at least one compound according to the invention.
  • Preferably, the composition according to the invention is solid, liquid or pasty; and/or contains the compound according to the invention in an amount of from 0.001 to 99 wt. %, preferably from 1.0 to 70 wt. %, based on the total weight of the composition.
  • The pharmaceutical composition according to the invention can optionally contain suitable additives and/or auxiliary substances and/or optionally further active ingredients.
  • Examples of suitable physiologically acceptable carriers, additives and/or auxiliary substances are fillers, solvents, diluents, colorings and/or binders. These substances are known to the person skilled in the art (see H. P. Fiedler, Lexikon der Hilfsstoffe fur Pharmazie, Kosmetik and angrenzende Gebiete, Editio Cantor Aulendoff).
  • The pharmaceutical composition according to the invention contains the compound according to the invention in an amount of preferably from 0.001 to 99 wt. %, more preferably from 0.1 to 90 wt. %, yet more preferably from 0.5 to 80 wt. %, most preferably from 1.0 to 70 wt. % and in particular from 2.5 to 60 wt. %, based on the total weight of the pharmaceutical composition.
  • The pharmaceutical composition according to the invention is preferably for systemic, topical or local administration, preferably for oral administration.
  • Another aspect of the invention relates to a pharmaceutical dosage form which contains the pharmaceutical composition according to the invention.
  • In one preferred embodiment, the pharmaceutical dosage form according to the invention is produced for administration twice daily, for administration once daily or for administration less frequently than once daily. Administration is preferably systemic, in particular oral.
  • The pharmaceutical dosage form according to the invention can be administered, for example, as a liquid dosage form in the form of injection solutions, drops or juices, or as a semi-solid dosage form in the form of granules, tablets, pellets, patches, capsules, plasters/spray-on plasters or aerosols. The choice of auxiliary substances etc. and the amounts thereof to be used depend on whether the form of administration is to be administered orally, perorally, parenterally, intravenously, intraperitoneally, intradermally, intramuscularly, intranasally, buccally, rectally or locally, for example to the skin, the mucosa or into the eyes.
  • Pharmaceutical dosage forms in the form of tablets, dragees, capsules, granules, drops, juices and syrups are suitable for oral administration, and solutions, suspensions, readily reconstitutable dry preparations and also sprays are suitable for parenteral, topical and inhalatory administration. Compounds according to the invention in a depot, in dissolved form or in a plaster, optionally with the addition of agents promoting penetration through the skin, are suitable percutaneous administration preparations.
  • The amount of the compounds according to the invention to be administered to the patient varies in dependence on the weight of the patient, on the type of administration, on the indication and on the severity of the disease. Usually, from 0.00005 mg/kg to 50 mg/kg, preferably from 0.001 mg/kg to 10 mg/kg, of at least one compound according to the invention is administered.
  • Another aspect of the invention relates to a process for the preparation of the compounds according to the invention. Suitable processes for the synthesis of the compounds according to the invention are known in principle to the person skilled in the art.
  • Preferred synthesis routes are described below:
  • The compounds according to the invention can be obtained via different synthesis routes. Depending on the synthesis route, different intermediates are prepared and subsequently further reacted.
  • In a preferred embodiment, the synthesis of the compounds according to the invention proceeds via a synthesis route which comprises the preparation of an intermediate according to general formula (IIIa):
  • Figure US20210179627A1-20210617-C00021
  • wherein R1, R2 and R3 are defined as above.
  • In another preferred embodiment, the synthesis of the compounds according to the invention proceeds via a synthesis route which comprises the preparation of an intermediate according to general formula (IIIb):
  • Figure US20210179627A1-20210617-C00022
  • wherein R1, R2 and R3 are defined as above and PG is a protecting group.
  • Preferably the protecting group is -p-methoxybenzyl. Therefore, in another preferred embodiment, the synthesis of the compounds according to the invention proceeds via a synthesis route which comprises the preparation of an intermediate according to general formula (IIIc):
  • Figure US20210179627A1-20210617-C00023
  • wherein R1, R2 and R3 are defined as above.
  • As already indicated, in general formula (IIIc), the -p-methoxybenzyl moiety represents a protecting group which can be cleaved in the course of the synthesis route.
  • In yet another preferred embodiment, the synthesis of the compounds according to the invention proceeds via a synthesis route which comprises the preparation of
      • an intermediate according to general formula (IIIa) and according to general formula (IIIb); or
      • an intermediate according to general formula (IIIa) and according to general formula (IIIc); or
      • an intermediate according to general formula (IIIb) and according to general formula (IIIc); or
      • an intermediate according to general formula (IIIa), according to general formula (IIIb) and according to general formula (IIIc).
  • The following examples further illustrate the invention but are not to be construed as limiting its scope.
    • EXAMPLES
  • “RT” means room temperature (23±7° C.), “M” are indications of concentration in mol/l, “aq.” means aqueous, “anhydr.” means anhydrous, “sat.” means saturated, “sol.” means solution, “cone.” means concentrated.
    • Further Abbreviations
    • brine saturated aqueous sodium chloride solution
    • CC column chromatography
    • cHex cyclohexane
    • DCM dichloromethane
    • DIPEA N,N-diisopropylethylamine
    • DMF N,N-dimethylformamide
    • EDCl 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide
    • Et ethyl
    • ether diethyl ether
    • EE ethyl acetate
    • EtOAc ethyl acetate
    • EtOH ethanol
    • h hour(s)
    • H2O water
    • HATU O-(7-aza-benzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate
    • LDA Lithium-di-isoproyl-amid
    • Me methyl
    • m/z mass-to-charge ratio
    • MeOH methanol
    • MeCN acetonitrile
    • min minutes
    • MS mass spectrometry
    • NBS N-bromo-succinimide
    • NEt3 triethylamine
    • Pd2(dba)3 tris(dibenzylideneacetone)dipalladium(0)
    • PE petroleum ether (60-80° C.)
    • RM reaction mixture
    • RT room temperature
    • T3P 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide
    • tBME tert-butyl methyl ether
    • THF tetrahydrofuran
    • TFA trifluoroacetic acid
    • v/v volume to volume
    • w/w weight to weight
    • XantPhos 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene
  • The yields of the compounds prepared were not optimised. All temperatures are uncorrected.
  • All starting materials, which are not explicitly described, were either commercially available (the details of suppliers such as for example Acros, Aldrich, Bachem, Butt park, Enamine, Fluka, Lancaster, Maybridge, Merck, Sigma, TCI, Oakwood, etc. can be found in the Symyx® Available Chemicals Database of MDL, San Ramon, US or the SciFinder® Database of the ACS, Washington D.C., US, respectively, for example) or the synthesis thereof has already been described precisely in the specialist literature (experimental guidelines can be found in the Reaxys® Database of Elsevier, Amsterdam, NL or the SciFinder® Database of the ACS, Washington D.C., US, respectively, for example) or can be prepared using the conventional methods known to the person skilled in the art.
  • The mixing ratios of solvents or eluents for chromatography are specified in v/v.
  • All the intermediate products and exemplary compounds were analytically characterised by mass spectrometry (MS, m/z for [M+H]+). In addition 1H-NMR and 13C spectroscopy was carried out for all the exemplary compounds and selected intermediate products.
  • Remark Regarding Stereochemistry
  • CIS refers to the relative configuration of compounds described herein, in which both nitrogen atoms are drawn on the same face of the cyclohexane ring as described in the following exemplary structure. Two depictions are possible:
  • Figure US20210179627A1-20210617-C00024
  • TRANS refers to compounds, in which both nitrogen atoms are on opposite faces of the cyclohexane ring as described in the following exemplary structure. Two depictions are possible:
  • Figure US20210179627A1-20210617-C00025
    • Synthesis of Intermediates Synthesis of INT-799: CIS-8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
  • Figure US20210179627A1-20210617-C00026
    • Step 1: CIS-1-((1-(benzyloxy)cyclobutyl)methyl)-3-(3,4-dimethoxybenzyl)-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
  • NaOH (1.42 g, 35.5 mmol) was added to a solution of CIS-3-(3,4-dimethoxybenzyl)-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-794) (3 g, 7.09 mmol) in DMSO (90 mL) under argon atmosphere and the reaction mixture was stirred at 80° C. for 30 min. ((1-(Bromomethyl)cyclobutoxy)methyl)benzene (5.4 g, 21.3 mmol) was added and stirring was continued for 2 days at 80° C. The reaction completion was monitored by TLC. The reaction mixture was diluted with water (500 mL) and extracted with diethyl ether (4×300 mL). The combined organic extracts were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography (230-400 mesh silica gel; 65-70% EtOAc in petroleum ether as eluent) to afford 2.5 g (59%) of CIS-1-((1-(benzyloxy)cyclobutyl)methyl)-3-(3,4-dimethoxybenzyl)-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (TLC system: 10% MeOH in DCM; Rf: 0.8).
    • Step 2: CIS-8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
  • TFA (12 mL) was added to CIS-1-((1-(benzyloxy)cyclobutyl)methyl)-3-(3,4-dimethoxybenzyl)-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (2.5 g, 4.18 mmol) at 0° C. and the resulting mixture was stirred at 70° C. for 6 h. The reaction completion was monitored by LCMS. The reaction mixture was concentrated under reduced pressure. To the residue sat. aq. NaHCO3 was added (until pH 10) and the organic product was extracted with DCM (3×150 mL). The combined organic extracts were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography (230-400 mesh silica gel; 5% MeOH in DCM as eluent) to afford 500 mg (33%) of CIS-8-dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-799) (TLC system: 10% MeOH in DCM; Rf: 0.5). [M+H]+ 358.2
    • Synthesis of INT-951: CIS-1-[(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl)-methyl]-cyclobutane-1-carbonitrile
  • Figure US20210179627A1-20210617-C00027
    • Step 1: 1-((CIS-8-(dimethylamino)-3-(4-methoxybenzyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl)methyl)cyclobutanecarbonitrile
  • NaH (50% in mineral oil) (2.44 g, 50.89 mmol) was added to a solution of CIS-8-dimethylamino-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-975) (5 g, 12.72 mmol) in DMF (100 mL) at 0° C. portionwise over 10 min. 1-(Bromomethyl)cyclobutanecarbonitrile (4.4 g, 25.44 mmol) was added dropwise over 10 minutes at 0° C. The reaction mixture was allowed to stir at RT for 3 h, then quenched with water and the organic product was extracted with ethyl acetate (3×200 mL). The combined organic extracts were dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford 5 g (crude) of 1-((CIS-8-(dimethylamino)-3-(4-methoxybenzyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl)methyl)cyclobutane-carbonitrile as gummy brown liquid. The material was used for the next step without further purification.
    • Step 2: 1-((CIS-8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl)methyl) cyclobutanecarboxamide
  • TFA (100 mL) was added to 1-((CIS-8-(dimethylamino)-3-(4-methoxybenzyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl)methyl)cyclobutanecarbonitrile (5 g, 10.28 mmol) at 0° C. and the reaction mixture at mixture was stirred at RT for 2 days. The reaction mixture was concentrated in vacuo. To the residue sat. aq. NaHCO3 was added (until pH 10) and the organic product was extracted with dichloromethane (3×150 mL). The combined organic extracts were dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford 3.5 g (crude) of 1-((CIS-8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl)methyl) cyclobutanecarboxamide. The material was used for the next step without further purification.
    • Step 3: 1-((cis-8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl)methyl)cyclobutane carbonitrile
  • Thionyl chloride (35 mL) was added to 1-((cis-8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl)methyl)cyclobutanecarboxamide (3.5 g, 9.11 mmol) at RT and the resulting mixture was stirred at reflux for 2 h. The reaction mixture was concentrated in vacuo. To the residue sat. aq. NaHCO3 was added (until pH 10) and the organic product was extracted with dichloromethane (3×150 mL). The combined organic layer was dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography to afford 1.3 g (34% after three steps) of CIS-1-[(8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl)-methyl]-cyclobutane-1-carbonitrile (INT-951). [M+H]+ 367.2.
    • Synthesis of INT-952: CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-8-phenyl-3-[(4-methoxyphenyl)-methyl]-1,3-diazaspiro[4.5]decan-2-one
  • Figure US20210179627A1-20210617-C00028
  • To a solution of CIS-8-dimethylamino-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-975) (10 g, 25 mmol) in THF (500 mL) was added KOtBu (7.1 g, 63 mmol) at 50° C. The reaction mixture was heated up to reflux, cyclobutylmethylbromide (11.3 g, 76 mmol) was added in one portion, and stirring was continued at reflux for 12 h. KOtBu (7.1 g) and cyclobutylmethylbromide (11.3 g) were added again. The reaction mixture was allowed to stir another 2 h at reflux, then cooled to RT, diluted with water (150 mL) and the layers partitioned. The aqueous layer was extracted with EtOAc (3×300 mL). The combined organic layers were dried over Na2SO4 and then concentrated in vacuo. The residue was filtered through a plug of silica gel using a DCM/MeOH (19/1 v/v) mixture. The filtrate was concentrated in vacuo and the resulting solid was recrystallized from hot ethanol to yield 7.8 g of CIS-1-(cyclobutyl-methyl)-8-dimethylamino-8-phenyl-3-[(4-methoxyphenyl)-methyl]-1,3-diazaspiro[4.5]decan-2-one (INT-952). [M+H]+ 461.3.
    • Synthesis of INT-953: CIS-1-(Cyclobutyl-methyl)-8-(methyl-(2-methyl-propyl)-amino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
  • Figure US20210179627A1-20210617-C00029
    • Step 1: 1-Cyclobutylmethyl-3-(4-methoxy-benzyl)-9,12-dioxa-1,3-diaza-dispiro[4.2.4.2]tetradecan-2-one
  • To a stirred solution of 3-(4-methoxy-benzyl)-9,12-dioxa-1,3-diaza-dispiro[4.2.4.2]tetradecan-2-one (4 g, 12.04 mmol) in anhydrous DMF (60 ml) was added NaH (1.38 g, 60% dispersion in oil, 36.14 mmol) at RT. The reaction mixture was stirred for 10 min, bromomethylcyclobutane (3 ml, 26.5 mmol) was added dropwise and stirring was continued for 50 h. TLC analysis showed complete consumption of the starting material. The reaction mixture was quenched with sat. aq. NH4Cl (50 ml) and extracted with EtOAc (3×200 ml). The combined organic phase was dried over Na2SO4 and concentrated under reduced pressure. The resulting residue was purified column chromatography (neutral aluminum oxide, EtOAc—petroleum ether (2:8)) to give 1-cyclobutylmethyl-3-(4-methoxy-benzyl)-9,12-dioxa-1,3-diaza-dispiro[4.2.4.2]tetradecan-2-one (2.4 g, 50%, white solid). TLC system: EtOAc—pet ether (6:4); Rf=0.48.
    • Step 2: 1-Cyclobutylmethyl-3-(4-methoxy-benzyl)-1,3-diaza-spiro[4.5]decane-2,8-dione
  • To a stirred solution of 1-cyclobutylmethyl-3-(4-methoxy-benzyl)-9,12-dioxa-1,3-diaza-dispiro[4.2.4.2]tetradecan-2-one (1 g, 2.5 mmol) in MeOH (7 ml) was added 10% aq. HCl (8 ml) at 0° C. The reaction mixture was warmed up to RT and stirred for 16 h. TLC analysis showed complete consumption of the starting material. The reaction mixture was quenched with sat. aq. NaHCO3 (30 ml) and extracted with EtOAc (3×50 ml). The combined organic phase was dried over Na2SO4 and concentrated under reduced pressure. The resulting residue was purified by column chromatography (silica gel, 230-400 mesh, EtOAc—pet ether (1:3)→(3:7)) to give 1-cyclobutylmethyl-3-(4-methoxy-benzyl)-1,3-diaza-spiro[4.5]decane-2,8-dione (650 mg, 73%, colorless viscous oil). TLC system: EtOAc—pet ether (6:4); Rf=0.40.
    • Step 3: 1-(cyclobutylmethyl)-8-(isobutyl(methyl)amino)-3-(4-methoxybenzyl)-2-oxo-1,3-diazaspiro[4.5]decane-8-carbonitrile
  • To a stirred solution of N-isobutyl-N-methylamine (1.34 ml, 11.23 mmol) and MeOH/H2O (8 ml, 1:1, v/v) was added 4N aq. HCl (1.5 ml) and the reaction mixture was stirred for 10 min at 0° C. (ice bath). A solution of 1-cyclobutylmethyl-3-(4-methoxy-benzyl)-1,3-diaza-spiro[4.5]decane-2,8-dione (1 g, 2.80 mmol) in MeOH (7 ml) and KCN (548 mg, 8.42 mmol) were added and the reaction mixture was stirred at 45° C. for 20 h. TLC analysis showed complete consumption of the starting material. The reaction mixture was diluted with water (30 ml), extracted with EtOAc (3×30 ml), the combined organic phase was dried over Na2SO4 and concentrated under reduced pressure to give 1-(cyclobutylmethyl)-8-(isobutyl(methyl)amino)-3-(4-methoxybenzyl)-2-oxo-1,3-diazaspiro[4.5]decane-8-carbonitrile (1.3 g, viscous yellow oil). TLC system: EtOAc—pet ether (1:1); Rf=0.45. The product was used for the next step without additional purification.
    • Step 4: CIS-1-(cyclobutylmethyl)-8-(isobutyl(methyl)amino)-3-(4-methoxybenzyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
  • A round bottom flask containing 1-(cyclobutylmethyl)-8-(isobutyl(methyl)amino)-3-(4-methoxybenzyl)-2-oxo-1,3-diazaspiro[4.5]decane-8-carbonitrile (1.3 g, 2.81 mmol) was cooled in an ice bath (0° C.) and a solution of phenylmagnesium bromide (26 ml, 2M in THF) was added slowly at 0° C.-5° C. The ice bath was removed and the reaction mixture was stirred for 30 min, then diluted with sat. aq. NH4Cl (25 ml) and extracted with EtOAc (4×30 ml). The combined organic phase was dried over Na2SO4 and concentrated under reduced pressure to give pale yellow viscous oil. This residue was purified by column chromatography (silica gel, 230-400 mesh, eluent: EtOAc—pet ether (15:85)→(2:4)) to give CIS-1-(cyclobutylmethyl)-8-(isobutyl(methyl)amino)-3-(4-methoxybenzyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (135 mg, 10%, white solid). TLC system: EtOAc—pet ether (1:1); Rf=0.6
    • Step 5: CIS-1-(Cyclobutyl-methyl)-8-(methyl-(2-methyl-propyl)-amino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
  • A round bottom flask containing CIS-1-(cyclobutylmethyl)-8-(isobutyl(methyl)amino)-3-(4-methoxybenzyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (130 mg, 0.25 mmol) was cooled in an ice bath and a mixture of TFA/CH2Cl2 (2.6 ml, 1:1, v/v) was added slowly at 0° C.-5° C. The reaction mixture was warmed to RT and stirred for 20 h, then quenched with methanolic NH3 (10 ml, 10% in MeOH) and concentrated under reduced pressure to give pale yellow viscous oil. This residue was purified twice by column chromatography (silica gel, 230-400 mesh, eluent: MeOH—CHCl3 (1:99)→(2:98)) to give CIS-1-(cyclobutyl-methyl)-8-(methyl-(2-methyl-propyl)-amino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-953) (65 mg, 66%, white solid). TLC system: MeOH—CHCl3 (5:95); Rf=0.25; [M+H]+ 384.3
    • Synthesis of INT-958: 4-Oxo-1-pyridin-2-yl-cyclohexane-1-carbonitrile
  • Figure US20210179627A1-20210617-C00030
    • Step 1: Ethyl 5-cyano-2-oxo-5-(pyridin-2-yl)cyclohexanecarboxylate
  • KOtBu (57.0 g, 508.4 mmol) was added to the solution of 2-(pyridin-2-yl)acetonitrile (50.0 g, 423.7 mmol) and ethyl acrylate (89.0 g, 889.8 mmol) in THF (500 mL) at 0° C. and stirred for 16 h at RT. The reaction mixture was quenched with sat. aq. NH4Cl and extracted with EtOAc (2×500 mL). The combined organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure to afford 68.0 g (60%; crude) of ethyl 5-cyano-2-oxo-5-(pyridin-2-yl)cyclohexanecarboxylate as a brown liquid (TLC system: 50% ethyl acetate in petroleum ether; Rf: 0.65).
    • Step 2: 4-Oxo-1-pyridin-2-yl-cyclohexane-1-carbonitrile
  • A solution of ethyl 5-cyano-2-oxo-5-(pyridin-2-yl)cyclohexanecarboxylate (68.0 g, 250.0 mmol) was added to a mixture of cone. aq. HCl and glacial acetic acid (170 mL/510 mL) at 0° C. The reaction mixture was heated to 100° C. for 16 h. All volatiles were evaporated under reduced pressure. The residue was diluted with sat. aq. NaHCO3 and extracted with ethyl acetate (3×300 mL). The combined organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure to afford 44.0 g (88%) of 4-oxo-1-pyridin-2-yl-cyclohexane-1-carbonitrile INT-958 as a brown solid (TLC system: 50% ethyl acetate in pet ether; Rf: 0.45). [M+H]+ 201.1
    • Synthesis of INT-961: 4-Dimethylamino-4-pyridin-2-yl-cyclohexan-1-one
  • Figure US20210179627A1-20210617-C00031
    • Step 1: 8-(pyridin-2-yl)-1,4-dioxaspiro[4.5]decane-8-carbonitrile
  • A solution of 4-oxo-1-pyridin-2-yl-cyclohexane-1-carbonitrile (INT-958) (44.0 g, 220.0 mmol), ethylene glycol (27.0 g, 440.0 mmol) and PTSA (4.2 g, 22.0 mmol) in toluene (450 mL) was heated to 120° C. for 16 h using Dean Stark apparatus. All volatiles were evaporated under reduced pressure. The residue was diluted with sat. aq. NaHCO3 and extracted with ethyl acetate (3×300 mL). The combined organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure to afford 45.0 g (85%) of 8-(pyridin-2-yl)-1,4-dioxaspiro[4.5]decane-8-carbonitrile as a light brown solid (TLC system: 50% ethyl acetate in petroleum ether; Rf: 0.55).
    • Step 2: 8-(pyridin-2-yl)-1,4-dioxaspiro[4.5]decane-8-carboxamide
  • Potassium carbonate (50.0 g, 368.84 mmol) and 30% aq. H2O2 (210.0 mL, 1844.2 mmol) were added to the solution of 8-(pyridin-2-yl)-1,4-dioxaspiro[4.5]decane-8-carbonitrile (45.0 g, 184.42 mmol) in DMSO (450 mL) at 0° C. and the resulting mixture was stirred at RT for 14 h. The reaction mixture was diluted with water (1.5 L) and stirred for 1 h. The precipitated solid was separated by filtration, washed with water, petroleum ether and dried under reduced pressure to get 32.0 g (66%) of 8-(pyridin-2-yl)-1,4-dioxaspiro[4.5]decane-8-carboxamide as a white solid. (TLC system: 10% MeOH in DCM Rf: 0.35).
    • Step 3: methyl 8-(pyridin-2-yl)-1,4-dioxaspiro[4.5]decan-8-ylcarbamate
  • A mixture of 8-(pyridin-2-yl)-1,4-dioxaspiro[4.5]decane-8-carboxamide (25.0 g, 95.41 mmol), sodium hypochlorite (5 wt % aq. solution, 700 mL, 477.09 mmol) and KF—Al2O3 (125.0 g) in methanol (500 mL) was heated to 80° C. for 16 h. The reaction mixture was filtered through celite and the solid residue was washed with methanol. The combined filtrate was concentrated under reduced pressure. The residue was diluted with water and extracted with ethyl acetate (3×500 mL). The combined organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure to afford 18.0 g (66%) of methyl 8-(pyridin-2-yl)-1,4-dioxaspiro[4.5]decan-8-ylcarbamate as a light brown solid. (TLC system: 5% MeOH in DCM Rf: 0.52.)
    • Step 4: 8-(pyridin-2-yl)-1,4-dioxaspiro[4.5]decan-8-amine
  • A suspension of methyl 8-(pyridin-2-yl)-1,4-dioxaspiro[4.5]decan-8-ylcarbamate (18.0 g, 61.64 mmol) in 10 wt % aq. NaOH (200 mL) was heated to 100° C. for 24 h. The reaction mixture was filtered through celite pad, the solid residue was washed with water and the combined filtrate was extracted with EtOAc (4×200 mL). The combined organic layer washed with brine, dried over Na2SO4 and concentrated under reduced pressure to afford 12.5 g (88%) of 8-(pyridin-2-yl)-1,4-dioxaspiro[4.5]decan-8-amine as a light brown semi-solid. (TLC system: 5% MeOH in DCM Rf: 0.22.).
    • Step 5: 4-Dimethylamino-4-pyridin-2-yl-cyclohexan-1-one
  • Sodium cyanoborohydride (13.7 g, 0.213 mol) was added portionwise to a solution of 8-(pyridin-2-yl)-1,4-dioxaspiro[4.5]decan-8-amine (12.5 g, 53.418 mmol) and 35 wt % aq. formaldehyde (45 mL, 0.534 mol) in acetonitrile (130 mL) at 0° C. The reaction mixture was warmed up to room temperature and stirred for 16 h. The reaction mixture was quenched with sat. aq. NH4Cl and concentrated under reduced pressure. The residue was dissolved in water and extracted with EtOAc (3×200 mL). The combined organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure to afford 10.5 g (72%) of 4-dimethylamino-4-pyridin-2-yl-cyclohexan-1-one (INT-961) as a light brown solid. (TLC system: 5% MeOH in DCM Rf: 0.32.). [M+H]+ 219.1
    • Synthesis of INT-965: 4-Dimethylamino-4-phenyl-cyclohexan-1-one
  • Figure US20210179627A1-20210617-C00032
    • Step 1: 8-(Dimethylamino)-1,4-dioxaspiro 4.5]decane-8-carbonitrile
  • Dimethylamine hydrochloride (52 g, 0.645 mol) was added to the solution of 1,4-dioxaspiro-[4.5]-decan-8-one (35 g, 0.224 mmol) in MeOH (35 mL) at RT under argon atmosphere. The solution was stirred for 10 min and 40 wt % aq. dimethylamine (280 mL, 2.5 mol) and KCN (32 g, 0.492 mol) were sequentially added. The reaction mixture was stirred for 48 h at RT, then diluted with water (100 mL) and extracted with EtOAc (2×200 mL). The combined organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford 44 g of 8-(dimethylamino)-1,4-dioxaspiro-[4.5]-decane-8-carbonitrile (93%) as a white solid.
    • Step 2: N,N-dimethyl-8-phenyl-1,4-dioxaspiro[4.5]decan-8-amine
  • 8-(Dimethylamino)-1,4-dioxaspiro[4.5]decane-8-carbonitrile (35 g, 0.167 mol) in THF (350 mL) was added to the solution of 3M phenylmagnesium bromide in diethyl ether (556 mL, 1.67 mol) dropwise at -10° C. under argon atmosphere. The reaction mixture was stirred for 4 h at -10° C. to 0° C. and then at RT for 18 h. The reaction completion was monitored by TLC. The reaction mixture was cooled to 0° C., diluted with sat. aq. NH4Cl (1 L) and extracted with EtOAc (2×600 mL). The combined organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford 60 g of, N N-dimethyl-8-phenyl-1, 4-dioxaspiro-[4.5]-decan-8-amine as a liquid.
    • Step 3: 4-(dimethylamino)-4-phenylcyclohexanone
  • A solution of N,N-dimethyl-8-phenyl-1,4-dioxaspiro[4.5]decan-8-amine (32 g, 0.123 mol) in 6N aq. HCl (320 mL) was stirred at 0° C. for 2 h and then at RT for 18 h. The reaction completion was monitored by TLC. The reaction mixture was extracted with DCM (2×150 mL). The aqueous layer was basified to pH 10 with solid NaOH and extracted with ethyl acetate (2×200 mL). The combined organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The solid residue was washed with hexane and dried in vacuo to afford 7 g of 4-dimethylamino-4-phenyl-cyclohexan-1-one (INT-965) (25% over 2 steps) as a brown solid. [M+H]+ 218.1
    • Synthesis of INT-966: 3-[(4-Methoxyphenyl)-methyl]-1,3-diazaspiro[4.5]decane-2,8-dione
  • Figure US20210179627A1-20210617-C00033
    • Step 1: 9,12-Dioxa-2,4-diazadispiro[4.2.4{circumflex over ( )}{8}0.2{circumflex over ( )}{5}]tetradecane-1,3-dione
  • KCN (93.8 g, 1441.6 mmol) and (NH4)2CO3 (271.8 g, 1729.9 mmol) were added to the solution of 1,4-dioxaspiro[4.5]decan-8-one (150 g, 961 mmol) in MeOH:H2O (1:1 v/v) (1.92 L) at RT under argon atmosphere. The reaction mixture was stirred at 60° C. for 16 h. The reaction completion was monitored by TLC. The reaction mixture was cooled to 0° C., the precipitated solid was filtered off and dried in vacuo to afford 120 g (55%) of 9,12-dioxa-2,4-diazadispiro[4.2.4{circumflex over ( )}{8}0.2{circumflex over ( )}{5}]tetradecane-1,3-dione. The filtrate was extracted with DCM (2×1.5 L). The combined organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford additional 30 g (14%) of 9,12-dioxa-2,4-diazadispiro[4.2.4{circumflex over ( )}{8}0.2{circumflex over ( )}{5}]tetradecane-1,3-dione (TLC system: 10% Methanol in DCM; Rf: 0.4).
    • Step 2: 2-[(4-Methoxyphenyl)-methyl]-9,12-dioxa-2,4-diazadispiro[4.2.4{circumflex over ( )}{8}0.2{circumflex over ( )}{5}]tetradecane-1,3-dione
  • Cs2CO3 (258.7 g, 796.1 mmol) was added to the solution of 73a (150 g, 663.4 mmol) in MeCN (1.5 L) under argon atmosphere and the reaction mixture was stirred for 30 min. A solution of p-methoxybenzyl bromide (96 mL, 663.4 mmol) was added. The reaction mixture was stirred at RT for 48 h. The reaction completion was monitored by TLC. The reaction mixture was quenched with sat. aq. NH4Cl (1.0 L) and the organic product was extracted with EtOAc (2×1.5 L). The combined organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was washed with diethyl ether and pentane and dried under reduced pressure to afford 151 g (65%) of 2-[(4-Methoxyphenyl)-methyl]-9,12-dioxa-2,4-diazadispiro[4.2.4{circumflex over ( )}{8}0.2{circumflex over ( )}{5}]tetradecane-1,3-dione as an off white solid (TLC system: 10% MeOH in DCM; Rf: 0.6).
    • Step 3: 2-[(4-Methoxyphenyl)-methyl]-9,12-dioxa-2,4-diazadispiro[4.2.4{circumflex over ( )}{8}0.2{circumflex over ( )}{5}]tetradecan-3-one
  • AlCl3 (144.3 g, 1082.6 mmol) was added to a solution of LiAlH4 (2M in THF) (433 mL, 866.10 mmol) in THF (4.5 L) at 0° C. under argon atmosphere and the resulting mixture was stirred at RT for 1 h. 2-[(4-Methoxyphenyl)-methyl]-9,12-dioxa-2,4-diazadispiro[4.2.4{circumflex over ( )}{8}0.2{circumflex over ( )}{5}]tetradecane-1,3-dione (150 g, 433.05 mmol) was added at 0° C. The reaction mixture was stirred at RT for 16 h. The reaction completion was monitored by TLC. The reaction mixture was cooled to 0° C., quenched with sat. aq. NaHCO3 (500 mL) and filtered through celite pad. The filtrate was extracted with EtOAc (2×2.0 L). The combined organic layer was dried over anhydrous Na2SO4 and concentrated in vacuo to afford 120 g (84%) of 2-[(4-methoxyphenyl)-methyl]-9,12-dioxa-2,4-diazadispiro[4.2.4{circumflex over ( )}{8}0.2{circumflex over ( )}{5}]tetradecan-3-one as an off-white solid. (TLC system: 10% MeOH in DCM, Rf: 0.5).
    • Step 4: 3-[(4-Methoxyphenyl)-methyl]-1,3-diazaspiro[4.5]decane-2,8-dione
  • A solution of 2-[(4-methoxyphenyl)-methyl]-9,12-dioxa-2,4-diazadispiro[4.2.4{circumflex over ( )}{8}0.2{circumflex over ( )}{5}]tetradecan-3-one (120 g, 361.03 mmol) in 6N aq. HCl (2.4 L) was stirred at 0° C. for 2 h and then at RT for 18 h. The reaction completion was monitored by TLC. The reaction mixture was extracted with DCM (2×2.0 L). The aqueous layer was basified to pH 10 with 50% aq. NaOH and then extracted with DCM (2×2.0 L). Combined organic extracts were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The solid residue was washed with hexane and dried in vacuo to afford 90 g of 3-[(4-Methoxyphenyl)-methyl]-1,3-diazaspiro[4.5]decane-2,8-dione (INT-966) as an off-white solid (TLC system: 10% MeOH in DCM; Rf: 0.4) [M+H]+ 289.11.
    • Synthesis of INT-971: CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-8-(3-hydr oxyphenyl)-3-[(4-methoxyphenyl)-methyl]-1,3-diazaspiro[4.5]decan-2-one
  • Figure US20210179627A1-20210617-C00034
    • Step 1: CIS-8-(dimethylamino)-1-isobutyl-3-(4-methoxybenzyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
  • In analogy to the method described for INT-951 step 1 CIS-8-Dimethylamino-8-[3-(methoxymethyloxy)-phenyl]-3-[(4-methoxyphenyl)-methyl]-1,3-diazaspiro[4.5]decan-2-one (INT-968) was converted into CIS-1-(cyclobutylmethyl)-8-(dimethylamino)-3-(4-methoxybenzyl)-8-(3-(methoxymethoxy)phenyl)-1,3-diazaspiro[4.5]decan-2-one.
    • Step 2: CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-8-(3-hydroxyphenyl)-3-[(4-methoxyphenyl)-methyl]-1,3-diazaspiro[4.5]decan-2-one
  • TFA (0.2 mL) was added to the solution of CIS-1-(cyclobutylmethyl)-8-(dimethylamino)-3-(4-methoxybenzyl)-8-(3-methoxyphenyl)-1,3-diazaspiro[4.5]decan-2-one (300 mg, 0.57 mmol) in DCM (1.5 mL) at 0° C. The reaction mixture was stirred at 0° C. for 3 h. The reaction completion was monitored by TLC. The reaction mixture was quenched with sat. aq. NaHCO3 and the organic product was extracted with DCM (3×10 mL). The combined organic extracts were dried over anhydrous Na2SO4 and concentrated under reduced pressure. Purification of the residue by preparative TLC (3% MeOH in DCM as mobile phase) yielded 50 mg (18%) of CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-8-(3-hydroxyphenyl)-3-[(4-methoxyphenyl)-methyl]-1,3-diazaspiro[4.5]decan-2-one (INT-971) as an off white solid. (TLC system: 10% MeOH in DCM; Rf: 0.20) [M+H]+ 478.3
    • Synthesis of INT-974: CIS-8-Dimethylamino-8-(3-fluorophenyl)-3-[(4-methoxyphenyl)-methyl]-1,3-diazaspiro[4.5]decan-2-one
  • Figure US20210179627A1-20210617-C00035
    • Step 1: 8-(dimethylamino)-3-(4-methoxybenzyl)-2-oxo-1,3-diazaspiro[4.5]decane-8-carbonitrile
  • Dimethylamine hydrochloride (76.4 g, 936.4 mmol) was added to a solution of 3-[(4-methoxyphenyl)-methyl]-1,3-diazaspiro[4.5]decane-2,8-dione (INT-966) (90 g, 312.13 mmol) in MeOH (180 mL) at RT under argon atmosphere. The solution was stirred for 15 min and 40 wt % aq. dimethylamine (780 mL) and KCN (48.76 g, 749.11 mmol) were sequentially added. The reaction mixture was stirred for 48 h and the completion of the reaction was monitored by NMR. The reaction mixture was diluted with water (1.0 L) and the organic product was extracted with ethyl acetate (2×2.0 L). The combined organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford 90 g (85%) of 8-(dimethylamino)-3-(4-methoxybenzyl)-2-oxo-1,3-diazaspiro[4.5]decane-8-carbonitrile as an off white solid (TLC system: TLC system: 10% MeOH in DCM; Rf: 0.35, 0.30).
    • Step 2: CIS-8-Dimethylamino-8-(3-fluorophenyl)-3-[(4-methoxyphenyl)-methyl]-1,3-diazaspiro[4.5]decan-2-one
  • 3-Fluorophenylmagnesium bromide (1M in THF) (220 mL, 219.17 mmol) was added dropwise to a solution of 8-(dimethylamino)-3-(4-methoxybenzyl)-2-oxo-1,3-diazaspiro[4.5]decane-8-carbonitrile (15 g, 43.83 mmol) in THF (300 mL) at 0° C. under argon atmosphere. The reaction mixture was stirred for 16 h at RT. The reaction completion was monitored by TLC. The reaction mixture was cooled to 0° C., quenched with sat. aq. NH4Cl (200 mL) and the organic product was extracted with EtOAc (2×200 mL). The combined organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The reaction was carried out in 4 batches (15 g x 2 and 5 g x 2) and the batches were combined for purification. Purification of the crude product by flash column chromatography on silica gel (230-400 mesh) (2 times) (0-20% methanol in DCM) eluent and subsequently by washing with pentane yielded 5.6 g (11%) of CIS-8-dimethylamino-8-(3-fluorophenyl)-3-[(4-methoxyphenyl)-methyl]-1,3-diazaspiro[4.5]decan-2-one (INT-974) as an off-white solid. (TLC system: 5% MeOH in DCM in presence of ammonia; Rf: 0.1). [M+H]+ 412.2
    • Synthesis of INT-975: CIS-8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
  • Figure US20210179627A1-20210617-C00036
  • KOtBu (1M in THF) (29.30 mL, 29.30 mmol) was added to the solution of CIS-8-Dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one INT-976 (8.0 g, 29.30 mmol) in THF (160 mL) under argon atmosphere and the reaction mixture was stirred for 30 min. 4-Methoxybenzyl bromide (4.23 mL, 29.30 mmol) was added and stirring was continued at RT for 4 h. The reaction completion was monitored by TLC. The reaction mixture was diluted with sat. aq. NH4Cl (150 mL) and the organic product was extracted with EtOAc (2×150 mL). The combined organic layer was dried over anhydrous Na2SO4 and concentrated in vacuo. The reaction was carried out in 2 batches (8 g x 2) and the batches were combined for purification. Purification of the crude product by flash column chromatography on silica gel (0-10% methanol in DCM) and subsequently by washing with pentane yielded 11 g (47%) of CIS-8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-975) as a white solid. [M+H]+ 394.2
    • Synthesis of INT-976: CIS-8-Dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
  • Figure US20210179627A1-20210617-C00037
    • Step 1: 8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4,5]decane-2,4-dione
  • In a sealed tube 4-dimethylamino-4-phenyl-cyclohexan-1-one (INT-965) (2 g, 9.22 mmol) was suspended in 40 mL EtOH/H2O (1:1 v/v) at RT under argon atmosphere. (NH4)2CO3 (3.62 g, 23.04 mmol) and KCN (0.6 g, 9.22 mmol) were added. The reaction mixture was stirred at 60° C. for 18 h. The reaction mixture was cooled to 0° C. and diluted with ice-water and filtered through a glass filter. The solid residue was dried under reduced pressure to afford 8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4,5]decane-2,4-dione (1.8 g, 86%) as an off white crystalline solid (TLC: 80% EtOAc in hexane; Rf: 0.25).
    • Step 2: 8-(dimethylamino)-8-phenyl-1, 3-diazaspiro [4, 5] decan-2-one
  • LiAlH4 (2M in THF) (70 mL, 139.4 mmol) was added to the solution of 8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4,5]decane-2,4-dione (10 g, 34.8 mmol) in THF/Et2O (2:1 v/v) (400 mL) at 0° C. under argon atmosphere. The reaction mixture was stirred for 4 h at 60° C. The reaction completion was monitored by TLC. The reaction mixture was cooled to 0° C., quenched with saturated Na2SO4 solution (100 mL) and filtered through Celite pad. The filtrate was dried over anhydrous Na2SO4 and concentrated in vacuo to afford 5.7 g (59%) of 8-(dimethylamino)-8-phenyl-1, 3-diazaspiro [4, 5] decan-2-one as an off white solid. (TLC system: 10% MeOH in DCM, Rf: 0.3).
    • Step 3: CIS-8-Dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
  • A mixture of CIS- and TRANS-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4,5]decan-2-one (8 g, 29.30 mmol) was purified by preparative chiral SFC (column: Chiralcel AS-H, 60% CO2, 40% (0.5% DEA in MeOH)) to get 5 g of CIS-8-Dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-976) as a white solid. [M+H]+ 274.2.
    • Synthesis of INT-977: CIS-2-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl)-acetic acid; 2,2,2-trifluoro-acetic acid salt
  • Figure US20210179627A1-20210617-C00038
    • Step 1: CIS-2-[8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl]-acetic acid tert-butyl ester
  • A solution of CIS-8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-975) (5.0 g, 12.7 mmol) in THF (18 mL) was cooled to 0° C. and treated with LDA solution (2M in THF/heptane/ether, 25.4 mL, 50.8 mmol). The resulting mixture was allowed to warm up to RT over 30 min. The solution was then cooled to 0° C. again and tert-butyl-bromoacetate (5.63 mL, 38.1 mmol) was added. The reaction mixture was stirred at RT for 16 h, quenched with water and extracted with DCM (3×). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. Purification of the residue by column chromatography on silica gel provided CIS-2-[8-dimethylamino-3-[(4-methoxyphenyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl]-acetic acid tert-butyl ester (4.4 g).
    • Step 2: cis-2-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl)-acetic acid trifluoroacetic acid salt
  • CIS-2-[8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl]-acetic acid tert-butyl ester (200 mg, 0.4 mmol) was dissolved in TFA (5 mL) and heated to reflux overnight. After cooling to RT all volatiles are removed in vacuo. The residue was taken up in THF (1 mL) and added dropwise to diethyl ether (20 mL). The resulting precipitate was filtered off and dried under reduced pressure to give CIS-2-(8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl)-acetic acid; 2,2,2-trifluoro-acetic acid salt (INT-977) (119 mg) as a white solid. [M+H]+ 332.2
    • Synthesis of INT-978: CIS-2-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl)-N,N-dimethyl-acetamide
  • Figure US20210179627A1-20210617-C00039
  • CIS-2-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl)-acetic acid (INT-977) trifluoroacetic acid salt (119 mg, 0.35 mmol) was dissolved in DCM (5 mL). Triethylamine (0.21 mL, 1.6 mmol), dimethylamine (0.54 mL, 1.1 mmol) and T3P (0.63 mL, 1.1 mmol) were sequentially added. The reaction mixture was stirred at RT overnight, then diluted with 1 M aq. Na2CO3 (5 mL). The aqueous layer was extracted with DCM (3×5 mL), the combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel to yield CIS-2-(8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl)-N,N-dimethyl-acetamide (INT-978) (39 mg) as a white solid. [M+H]+ 359.2
    • Synthesis of INT-982: CIS-8-Dimethylamino-1-[(1-methyl-cyclobutyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
  • Figure US20210179627A1-20210617-C00040
    • Step 1: CIS-8-(dimethylamino)-3-(4-methoxybenzyl)-1-((1-methylcyclobutyl)methyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
  • A solution of NaOH (2.85 g, 71.2 mmol) in DMSO (25 mL) was stirred at RT for 10 min. CIS-8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-975) (7.00 g, 17.8 mmol) was added and stirring was continued for 15 min. 1-(Bromo-methyl)-1-methyl-cyclobutane (8.7 g, 53.4 mmol) was added at 0° C. The reaction mixture was heated to 60° C. for 16 h. After cooling down to RT, water (100 mL) was added and the mixture was extracted with DCM (3×150 mL). The combined organic layers were washed with water (70 mL), brine (100 mL), dried over Na2SO4 and concentrated under reduced pressure. Purification of the residue by column chromatography on silica gel provided CIS-8-(dimethylamino)-3-(4-methoxybenzyl)-1-((1-methylcyclobutyl)methyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (6.5 g) as a light yellow solid.
    • Step 2: CIS-8-Dimethylamino-1-[(1-methyl-cyclobutyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
  • To the solution of CIS-8-Dimethylamino-1-[(1-methyl-cyclobutyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (6.66 g, 14.0 mmol) in DCM (65 mL) was added TFA (65 mL) and the resulting mixture was stirred at RT for 16 h. The reaction mixture was concentrated under reduced pressure. The residue was taken up in DCM (100 mL) and water (60 mL) and basified with 2M aq. NaOH to pH 10. The organic layer was separated and washed with brine (40 mL), dried over MgSO4, filtered and concentrated under reduced pressure. Crystallization of the residue from EtOAc provided CIS-8-Dimethylamino-1-[(1-methyl-cyclobutyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-982) (3.41 g) as an off-white solid. [M+H]+ 356.3
    • Synthesis of INT-984: CIS-1-(Cyclobutyl-methyl)-8-(ethyl-methyl-amino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
  • Figure US20210179627A1-20210617-C00041
    • Step 1: CIS-8-(dimethylamino)-1-isobutyl-3-(4-methoxybenzyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
  • In analogy to the method described for INT-951 step 1 CIS-8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-975) was converted into CIS-8-(dimethylamino)-1-isobutyl-3-(4-methoxybenzyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one.
    • Step 2: CIS-1-(Cyclobutyl-methyl)-8-(ethyl-methyl-amino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
  • In analogy to the method described for INT-982 step 2 CIS-8-(dimethylamino)-1-isobutyl-3-(4-methoxybenzyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one was converted into CIS-1-(Cyclobutyl-methyl)-8-(ethyl-methyl-amino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-984).
    • Synthesis of INT-986: CIS-1-(Cyclobutyl-methyl)-8-(ethyl-methyl-amino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
  • Figure US20210179627A1-20210617-C00042
    • Step 1: CIS-3-benzyl-1-(cyclobutylmethyl)-8-(methylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
  • N-Iodosuccinimide (3.11 g, 13.92 mmol) was added to the solution of CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-8-phenyl-3-[phenyl-methyl]-1,3-diazaspiro[4.5]decan-2-one (INT-950) (4 g, 9.28 mmol) in a mixture of acetonitrile and THF (1:1 v/v, 80 mL) and the resulting mixture was stirred at RT for 16 h. The reaction mixture was basified with 2N aq. NaOH to pH10 and the organic product was extracted with DCM (3×10 mL). The combined organic extracts were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was stirred vigorously with a mixture of 10 wt % aq. citric acid (5 mL) and DCM (10 mL) at RT for 10 min. The reaction mixture was basified with 5N aq. NaOH to pH10 and extracted with DCM (3×10 mL). The combined organic layer was dried over anhydrous Na2SO4 and concentrated in vacuo to give 3.5 g (crude) of CIS-3-benzyl-1-(cyclobutylmethyl)-8-(methylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one as semi solid (TLC system: 10% MeOH in DCM; Rf: 0.60.).
    • Step 2: CIS-3-benzyl-1-(cyclobutylmethyl)-8-(ethyl(methyl)amino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
  • Sodium cyanoborohydride (1.56 g, 25.17 mmol, 3 equiv.) was added to the solution of CIS-3-benzyl-1-(cyclobutylmethyl)-8-(methylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (3.5 g, 8.39 mmol), acetaldehyde (738 mg, 16.78 mmol, 2 equiv.) and acetic acid (0.5 mL) in methanol (20 mL). The reaction mixture was stirred at RT for 3 h, then quenched with sat. aq. NaHCO3 and the organic product was extracted with DCM (3×50 mL). The combined organic extracts were dried over anhydrous Na2SO4 and concentrated in vacuo. Purification of the residue by flash column chromatography on silica gel (230-400 mesh) (20-25% ethyl acetate in petroleum ether) yielded 2.3 g (62%) of CIS-3-benzyl-1-(cyclobutylmethyl)-8-(ethyl(methyl)amino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one as a solid. (TLC system: 50% EtOAc in Pet. Ether; Rf: 0.65).
    • Step 3: CIS-1-(Cyclobutyl-methyl)-8-(ethyl-methyl-amino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-986)
  • Sodium metal (1.18 g, 51.68 mmol, 10 equiv.) was added to liquid ammonia (25 mL) at -78° C. The resulting mixture was stirred for 10 min at −78° C. A solution of CIS-3-benzyl-1-(cyclobutylmethyl)-8-(ethyl(methyl)amino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (2.3 g, 5.16 mmol) in THF (25 mL) was added at −78° C. The reaction mixture was stirred for 15 min, then quenched with sat. aq. NH4Cl, warmed to RT and stirred for 1 h. The organic product was extracted with DCM (3×50 mL). The combined organic layer was washed with water, brine and concentrated under reduced pressure to afford 1.30 g (72%) of CIS-1-(cyclobutylmethyl)-8-(ethyl(methyl)amino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-986) as an off-white solid. (TLC system: 10% MeOH in DCM Rf: 0.15.). [M+H]+ 356.3
    • Synthesis of INT-987: CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
  • Figure US20210179627A1-20210617-C00043
  • In analogy to the method as described for INT-982 step 2 CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-8-phenyl-3-[(4-methoxyphenyl)-methyl]-1,3-diazaspiro[4.5]decan-2-one (INT-952) was converted into CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-987).
    • Synthesis of INT-988: CIS-8-(dimethylamino)-1-(2-(1-methoxycyclobutyl)ethyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
  • Figure US20210179627A1-20210617-C00044
    • Step 1: CIS-8-(dimethylamino)-1-[2-(1-methoxycyclobutyl)ethyl]-3-[(4-methoxyphenyl)methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
  • Sodium hydroxide (78.06 mg, 4.0 equiv.) was suspended in DMSO (3.5 mL), stirred for 10 minutes, 8-(dimethylamino)-3-[(4-methoxyphenyl)methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-975) (192.0 mg, 1.0 equiv.) was added, the reaction mixture was stirred for 5 min followed by addition of 2-(1-methoxycyclobutyl)ethyl 4-methylbenzenesulfonate (416.2 mg, 3.0 equiv.) in DMSO (1.5 mL). The resulting mixture was stirred overnight at 50° C. The reaction mixture was quenched with water and extracted with DCM (3×20 mL). The combined organic phases were washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The residue (283 mg yellow oil) was purified by column chromatography on silica gel (eluent DCM/EtOH 98/2 to 96/4) to give 8-(dimethylamino)-1-[2-(1-methoxycyclobutyl)ethyl]-3-[(4-methoxyphenyl)methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one 163 mg (66%).
    • Step 2: CIS-8-(dimethylamino)-1-(2-(1-methoxycyclobutyl)ethyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-988)
  • In analogy to the method described for INT-982 step 2 CIS-8-(dimethylamino)-1-[2-(1-methoxycyclobutyl)ethyl]-3-[(4-methoxyphenyl)methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one was converted into CIS-8-(dimethylamino)-1-(2-(1-methoxycyclobutyl)ethyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-988). Mass: m/z 386.3 (M+H)+.
    • Synthesis of INT-992: CIS-2-[8-Dimethylamino-1-(2-methyl-propyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetic acid
  • Figure US20210179627A1-20210617-C00045
  • CIS-8-Dimethylamino-1-(2-methyl-propyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-241) (0.9 g, 2.73 mmol) was added to a solution of NaH (60 wt % in mineral oil, 1.64 g, 41.03 mmol) in DMF (20 mL) at RT. The reaction mixture was stirred at RT for 15 min, then cooled to 0° C. and ethyl 2-bromoacetate (4.56 g, 27.35 mmol) was added dropwise. The resulting mixture was stirred at RT for 2 days. The reaction completion was monitored by TLC. The reaction mixture was quenched with water and concentrated under reduced pressure. The residue was diluted with small amount of water and acidified by acetic acid. The resulting mixture was concentrated under reduced pressure again. The crude product was purified by silica gel flash chromatography using 230-400 mesh (25 vol % MeOH in DCM) to afford 1.1 g of CIS-2-[8-dimethylamino-1-(2-methyl-propyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetic acid (INT-992) as a solid. [M+H]+ 388.3
    • Synthesis of INT-994: CIS-2-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetic acid
  • Figure US20210179627A1-20210617-C00046
    • Step 1: ethyl 2-(cis-8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3 yl)acetate
  • KOtBu (1M in THF) (54.90 mL, 54.95 mmol) was added to a solution of CIS-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-976) (10 g, 36.63 mmol) in THF (950 mL) under argon atmosphere at 0° C. and the reaction mixture was stirred for 15 min. A solution of ethyl bromoacetate (5.06 mL, 43.96 mmol) in THF (50 mL) was added. The reaction mixture was warmed up to RT and stirred for 48 h. The reaction completion was monitored by TLC. Solvent was evaporated under reduced pressure and the crude product was purified by column chromatography to yield the desired product in 2 fractions: fraction 1: 2.2 g ethyl 2-(cis-8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)acetate (68% pure according to LCMS) as an off-white solid and Fraction 2: 3.2 g of ethyl 2-(cis-8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)acetate (32% pure according to LCMS) as well as 1.1 g of unreacted starting material. Fraction 1 was used further without additional purification.
    • Step 2: 2-(cis-8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)acetic acid
  • A mixture of ethyl-2-(CIS-8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)acetate (68% pure, 2.2 g, 6.128 mmol) and powdered NaOH (981 mg, 24.513 mmol) in toluene (40 mL) was stirred at 80° C. for 3 h under argon atmosphere. Ester hydrolysis was monitored by LCMS. Toluene was evaporated under reduced pressure and the resulting crude product (2.4 g) was further purified by reverse phase prep. HPLC to yield 0.93 g of 2-(CIS-8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)acetic acid.
    • Step 3: 2-(cis-8-(dimethylamino)-1-((1-hydroxycyclobutyl)methyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)acetic acid
  • To a solution of 2-(CIS-8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)acetic acid (1.5 g, 4.532 mmol) in toluene (45 mL) was added in one portion powdered NaOH (725.08 mg, 18.127 mmol) under argon atmosphere at RT. The reaction mixture was stirred at 80° C. for 4 h. Toluene was evaporated under reduced pressure to get the residue which was dissolved in DMSO (45 mL) under argon atmosphere. The solution was stirred at 55° C. for 1 h. To the reaction mixture was added dropwise a solution of 1-oxaspiro[2.3]hexane (1.144 g, 13.596 mmol) in DMSO (12 mL) via syring pump (flow rate 10 mL/h). The reaction mixture was stirred at 55° C. for 65 h. The reaction progress was monitored by LCMS. DMSO was evaporated in vacuo. The residue was dissolved in water (50 mL), cooled to 0° C. and pH was adjusted to 3-4 with acetic acid. The resulting mixture was concentrated under reduced pressure and the crude product was purified by column chromatography (elution with 8-10% MeOH in DCM) to yield 750 mg (78%) of 2-(cis-8-(dimethylamino)-1-((1-hydroxycyclobutyl)methyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)acetic acid (INT-994) as an off-white solid. [M+H]+ 416.2
    • Synthesis of INT-998: CIS-2-[8-Dimethylamino-1-[(1-methyl-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetic acid; 2,2,2-trifluoro-acetic acid salt
  • Figure US20210179627A1-20210617-C00047
    • Step 1: CIS-tert-butyl 2-[8-(dimethylamino)-1-[(1-methylcyclobutyl)methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]acetate
  • CIS -8-Dimethylamino-1-[(1-methyl-cyclobutyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-982) (2.8 g, 7.9 mmol) was dissolved in THF (110 mL) and the solution was cooled to 0° C. Lithium diisopropylamide solution in THF/heptane/ethylbenzene (2M, 16 mL) was added dropwise. The reaction mixture was stirred for 30 min and t-butyl-bromoacetate was added dropwise at the same temperature. The reaction mixture was concentrated in vacuo, water was added and the resulting mixture was extracted with DCM (3×250 mL). The combined organic layers were dried over Na2SO4, concentrated in vacuo and the residue was purified by flash chromatography to yield CIS-tert-butyl 2-[8-(dimethylamino)-1-[(1-methylcyclobutyl)methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]acetate (1670 mg) as a white solid.
    • Step 2: CIS-2-[8-Dimethylamino-1-[(1-methyl-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetic acid; 2,2,2-trifluoro-acetic acid salt
  • CIS-tert-butyl 2-[8-(dimethylamino)-1-[(1-methylcyclobutyl)methyl]-2-oxo-8-phenyl-1,3-diaza-spiro[4.5]decan-3-yl]acetate (2250 mg, 4.8 mmol) was treated with TFA (18 mL) at RT. After stirring for 10 min, all volatiles were removed in vacuo. The residue was triturated with diethyl ether (30 mL) using ultrasonic bath, the solid rest was dried under reduced pressure to yield CIS-2-[8-dimethylamino-1-[(1-methyl-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetic acid; 2,2,2-trifluoro-acetic acid salt (INT-998) (2.2 g) as a brown solid. [M+H]+ 413.3
    • Synthesis of INT-1008: CIS-8-ethylamino-8-phenyl-1,3-diaza-spiro[4.5]decan-2-one
  • Figure US20210179627A1-20210617-C00048
    • Step 1 and step 2: ethyl-(8-phenyl-1,4-dioxa-spiro[4.5]dec-8-yl)-amine hydrochloride (INT-1004)
  • A mixture of 1,4-dioxa-spiro[4.5]decan-8-one (25.0 g, 160.25 mmol, 1.0 eq.) and 2M solution of EtNH2 in THF (200 ml, 2.5 eq. 400.64 mmol) in EtOH (30 mL) was stirred at RT for 48 h. The reaction mixture was concentrated under argon atmosphere. The residue was diluted with ether (60 mL) and added to the freshly prepared PhLi solution [prepared by addition of 2.5M n-BuLi in THF (70.5 mL, 1.1 eq. 176.27 mmol) to a solution of bromobenzene (27.675 g, 1.1 eq. 176.275 mmol) in ether (100 mL) at −30° C. and stirred at RT for 1 h] at RT. The reaction mixture was stirred at RT for 1.5 h, then cooled down to 0° C. and quenched with sat. aq. NH4Cl (100 mL). The resulting mixture was extracted with EtOAc (2×750 mL), combined organic extracts were washed with water (3×350 mL), brine (300 mL), dried over Na2SO4 and concentrated under reduced pressure. The crude product was dissolved in ethylmethyl ketone (100 mL) and TMSCl (37.5 mL) was added at 0° C. The reaction mixture was stirred at RT for 16 h, the precipitate formed was filtered off and washed with acetone and THF to give ethyl-(8-phenyl-1,4-dioxa-spiro[4.5]dec-8-yl)-amine hydrochloride as an off-white solid. This reaction was done in 2 batches of 25 g scale and the yield is given for 2 combined batches. Yield: 18% (17.1 g, 57.575 mmol). LCMS: m/z 262.2 (M+H)+.
    • Step 3: 4-ethylamino-4-phenyl-cyclohexanone (INT-1005)
  • To a solution of ethyl-(8-phenyl-1,4-dioxa-spiro[4.5]dec-8-yl)-amine hydrochloride (10.1 g, 34.0 mmol, 1 eq.) in water (37.5 mL) was added cone. HCl (62.5 mL) at 0° C. and the reaction mixture was stirred at RT for 16 h. The reaction mixture was basified with 1N aq. NaOH to pH 14 at 0° C. and extracted with DCM (2×750 mL). Organic layer was washed with water (400 mL), brine (400 mL), dried over Na2SO4 and concentrated under reduced pressure to yield 4-ethylamino-4-phenyl-cyclohexanone which was used in the next step without further purification. This reaction was carried out in another batch of 15.1 g scale and yield is given for 2 combined batches. Yield: 92% (17.0 g, 78.34 mmol).
    • Step 4: mixture of CIS- and TRANS-8-ethylamino-8-phenyl-1,3-diaza-spiro[4.5]decane-2,4-dione (INT-1006 and INT-1007)
  • To a solution of 4-ethylamino-4-phenyl-cyclohexanone (17 g, 78.341 mmol, 1.0 eq.) in EtOH (250 mL) and water (200 mL) was added (NH4)2CO3 (18.8 g, 195.85 mmol, 2.5 eq.) and the reaction mixture was stirred at RT for 15 min. KCN (5.09 g, 78.341 mmol, 1.0 eq.) was and the resulting mixture was stirred at 60° C. for 18 h. The reaction mixture was cooled to RT, the precipitate was filtered off, washed with water (250 mL), EtOH (300 mL), hexane (200 mL) and dried under reduced pressure to yield CIS- and TRANS-mixture 8-ethylamino-8-phenyl-1,3-diaza-spiro[4.5]decane-2,4-dione (13.0 g, 45.29 mmol, 58%) as a white solid. Yield: 58% (13 g, 45.296 mmol) LC-MS: m/z [M+1]+=288.2.
    • Step 5: CIS-8-ethylamino-8-phenyl-1,3-diaza-spiro[4.5]decane-2,4-dione (INT-1006)
  • To a solution of cis and trans mixture of 8-ethylamino-8-phenyl-1,3-diaza-spiro[4.5]decane-2,4-dione (12 g) in MeOH/DCM (1:1 v/v, 960 mL) was added a solution of L-tartaric acid in MeOH (25 mL). The resulting mixture was stirred at RT for 2 h and then kept in refrigerator for 16 h. The solid material was filtered off and washed with MeOH/DCM (1:5, 50 ml) to get 8-ethylamino-8-phenyl-1,3-diaza-spiro[4.5]decane-2,4-dione tartrate (7.5 g) as a white solid. The solid was suspended in sat. aq. NaHCO3 (pH8) and the resulting mixture was extracted with 25% MeOH-DCM (2×800 ml). Combined organic extracts were washed with water (300 ml), brine (300 ml) and dried over anhydrous Na2SO4. The solvent was evaporated under reduced pressure and the residue was triturated with 20% DCM-hexane to afford CIS-8-ethylamino-8-phenyl-1,3-diaza-spiro[4.5]decane-2,4-dione as a white solid. This step was done in 2 batches (12 g & 2.4 g) and yield is given for 2 combined batches. Yield: 31.2% (5.0 g, 17.421 mmol) LC-MS: m/z [M+1]+=288.0.
    • Step 6: CIS-8-ethylamino-8-phenyl-1,3-diaza-spiro[4.5]decan-2-one (INT-1008)
  • To a slurry of LiAlH4 (793 mg, 20.905 mmol, 3.0 eq.) in THF (15 mL) was added a suspension of cis-8-ethylamino-8-phenyl-1,3-diaza-spiro[4.5]decane-2,4-dione (2.0 g, 6.968 mmol, 1.0 eq.) in THF (60 mL) at 0° C. and the reaction mixture was stirred at 65° C. for 16 h. The resulting mixture was cooled to 0° C., quenched with sat. aq. Na2SO4 (20 ml), stirred at RT for 1 h and filtered through celite. The celite layer was washed with 15% MeOH-DCM (500 ml). The combined filtrate was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The resulting crude product was triturated with 15% DCM-Hexane to afford CIS-8-ethylamino-8-phenyl-1,3-diaza-spiro[4.5]decan-2-one (INT-1008) (1.6 g, 5.86 mmol, 84%) as a white solid. Yield: 84% (1.6 g, 5.86 mmol) LC-MS: m/z [M+H]+=274.2.
    • Synthesis of INT-1019: CIS-2-(8-(dimethylamino)-1-((1-hydroxycyclobutyl)methyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)acetic acid hydrochloride
  • Figure US20210179627A1-20210617-C00049
    • Step 1: tert-butyl CIS-2-(8-(dimethylamino)-1-((1-hydroxycyclobutyl)methyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)acetate
  • The solution of CIS-8-(dimethylamino)-1-((1-hydroxycyclobutyl)methyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-799) (1.8 g, 5.042 mmol) in THF (40 mL) was cooled down to 0° C. and KOtBu (1 M in THF, 5.55 mL, 5.546 mmol) was added. The resulting mixture was stirred for 10 min followed by the dropwise addition of tert-butyl bromoacetate (1.081 g, 5.546 mmol). The ice bath was removed and the reaction mixture was stirred for 2 h, then quenched with sat. aq. NH4Cl (40 mL) and extracted with EtOAc (2×80 mL). The combined organic extracts were dried over anhydr. Na2SO4 and concentrated under reduced pressure. Crude product was purified by column chromatography (silica gel 100-200 mesh, 0-4% MeOH in DCM as eluent) to afford 1.7 g of tert-butyl CIS-2-(8-(dimethylamino)-1-((1-hydroxycyclobutyl)methyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)acetate as an off white solid.
    • Step 2: CIS-2-(8-(dimethylamino)-1-((1-hydroxycyclobutyl)methyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)acetic acid hydrochloride
  • 4N HCl in dioxane (30 mL) was added to the solution of tert-butyl CIS-2-(8-(dimethylamino)-1-((1-hydroxycyclobutyl)methyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)acetate (1.7 g, 3.609 mmol) in 1,4 dioxane (10 mL). The resulting mixture was stirred at RT for 16 h and then concentrated under reduced pressure to afford 1.5 g of CIS-2-(8-(dimethylamino)-1-((1-hydroxycyclobutyl)methyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)acetic acid hydrochloride (INT-1019) as a hygroscopic solid. TLC Rf (10% MeOH in DCM)=0.2. LC-MS: m/z [M+H]+=416.3.
    • Synthesis of INT-1020: sodium CIS-2-(8-(dimethylamino)-1-((1-hydroxycyclobutyl)methyl)-2,4-dioxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)acetate
  • Figure US20210179627A1-20210617-C00050
    • Step 1: tert-butyl CIS-2-(8-(dimethylamino)-2,4-dioxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)acetate
  • To the suspension of tert-butyl CIS-2-(8-(dimethylamino)-2,4-dioxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)acetate (INT-1018) (0.5 g, 1.74 mmol) in DMF (11 mL) was added portionwise sodium hydride (60% in mineral oil, 70 mg, 1.74 mmol, 1 equiv.). The reaction mixture was stirred until the evolution of hydrogen was over and a clear solution was formed (ca. 40 min). Tert-butyl bromoacetate (257 μL, 1.74 mmol, 1 equiv.) was added, the reaction mixture was stirred at RT overnight, quenched with ca. 40 mL water and stirred for 2 h. The precipitate was filtered off, washed with water, hexane and dried under reduced pressure to give tert-butyl CIS-2-(8-(dimethylamino)-2,4-dioxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)acetate (653 mg, 93%) which was used further without additional purification. LC-MS: m/z [M+H]+=402.2.
    • Step 2: sodium CIS-2-(8-(dimethylamino)-1-((1-hydroxycyclobutyl)methyl)-2,4-dioxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)acetate (INT-1020)
  • Sodium hydroxide (135 mg, 3.37 mmol, 4 equiv.) was suspended in dimethyl sulfoxide (1.8 mL, 25.26 mmol, 30 equiv.) and the mixture was stirred at RT for 10 min. Tert-butyl CIS-2-(8-(dimethylamino)-2,4-dioxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)acetate (338 mg, 0.84 mmol, 1 equiv.) was added, the reaction mixture was stirred 5 min at RT and then heated up to 50° C. [1-[Tert-butyl(dimethyl)silyl]oxycyclobutyl]methyl 4-methylbenzenesulfonate (936 mg, 2.53 mmol, 3 equiv.) was added and the reaction mixture was stirred at 60° C. for 3 days. The resulting mixture was cooled down to RT, diluted with water (5 mL), extracted with EtOAc (1×10 mL) and the aqueous phase was concentrated under reduced pressure to give crude sodium CIS-2-(8-(dimethylamino)-1-((1-hydroxycyclobutyl)methyl)-2,4-dioxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)acetate (INT-1020) (473 mg) which was used in the next step without further purification. LC-MS: m/z [M+H]+=452.2.
    • Synthesis of INT-1026: CIS-8-(methyl((tetrahydrofuran-3-yl)methyl)amino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
  • Figure US20210179627A1-20210617-C00051
    • Step 1: 2-methyl-N-(1,4-dioxaspiro[4.5]decan-8-ylidene)propane-2-sulfinamide
  • Titanium ethoxide (58.45 g, 256.4 mmol) was added to a solution of 1,4-dioxaspiro[4.5]decan-8-one (20 g, 128.20 mmol) and 2-methylpropane-2-sulfinamide (15.51 g, 128.20 mmol) in THF (200 mL) at RT and the reaction mixture was stirred at RT for 18 h. The reaction mixture was cooled to 0° C. and quenched by dropwise addition of sat. aq. NaHCO3 (500 mL) over a period of 30 min. The organic product was extracted with EtOAc (3×100 mL). The combined organic extracts were dried over anhydrous Na2SO4 and concentrated in vacuo to afford 10 g (crude) of 2-methyl-N-(1,4-dioxaspiro[4.5]decan-8-ylidene)propane-2-sulfinamide as a white solid (TLC system: 30% Ethyl acetate in hexane; Rf: 0.30).
    • Step 2: 2-methyl-N-(8-phenyl-1,4-dioxaspiro[4.5]decan-8-yl)propane-2-sulfinamide
  • Phenylmagnesium bromide (1M in THF, 116 mL, 116 mmol) was added dropwise to a solution of 2-methyl-N-(1,4-dioxaspiro[4.5]decan-8-ylidene)propane-2-sulfinamide (10 g, 38.61 mmol) in THF (500 mL) at −10° C. under argon atmosphere. The reaction mixture was stirred for 2 h at −10° C. to 0° C. The reaction completion was monitored by TLC. The reaction mixture was quenched with sat. aq. NH4Cl (50 mL) at 0° C. and the organic product was extracted with EtOAc (3×100 mL). The combined organic extracts were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography (silica gel 230-400 mesh; 40-60% ethyl acetate in hexane) to yield 6.0 g (46%) of 2-methyl-N-(8-phenyl-1,4-dioxaspiro[4.5]decan-8-yl)propane-2-sulfinamide as a liquid (TLC system: 70% Ethyl acetate in hexane; Rf: 0.30).
    • Step 3: 8-phenyl-1,4-dioxaspiro[4.5]decan-8-amine hydrochloride
  • 2N solution of HCl in diethyl ether (17.80 mL, 35.60 mmol) was added to a solution of 2-methyl-N-(8-phenyl-1,4-dioxaspiro[4.5]decan-8-yl)propane-2-sulfinamide (6.0 g, 17.80 mmol) in DCM (60 mL) at 0° C. The reaction mixture was stirred at RT for 2 h. The reaction mixture was concentrated in vacuo. The residue was washed with diethyl ether to yield 3 g (crude) of 8-phenyl-1,4-dioxaspiro[4.5]decan-8-amine hydrochloride as a brown solid (TLC system: 5% MeOH in DCM; Rf: 0.10).
    • Step 4: 8-phenyl-N-((tetrahydrofuran-3-yl)methyl)-1,4-dioxaspiro[4.5]decan-8-amine
  • Sodium cyanoborohydride (2.17 g, 33.45 mmol) was added to a solution of 8-phenyl-1,4-dioxaspiro[4.5]decan-8-amine hydrochloride (3.0 g, 11.15 mmol) and tetrahydrofuran-3-carbaldehyde (4.46 mL, 22.30 mmol) and acetic acid (0.05 mL) in methanol (30 mL) at 0° C. The reaction mixture was stirred at RT for 16 h. The reaction mixture was concentrated in vacuo at 30° C. and to the residue sat. aq. NaHCO3 was added. The organic product was extracted with DCM (3×30 mL). The combined organic extracts were dried over anhydrous Na2SO4 and solvent was concentrated under reduced pressure to get 3 g (crude) of 8-phenyl-N-((tetrahydrofuran-3-yl)methyl)-1,4-dioxaspiro[4.5]decan-8-amine as a semi-solid (TLC system: 10% MeOH in DCM; Rf: 0.22).
    • Step 5: N-methyl-8-phenyl-N-((tetrahydrofuran-3-yl)methyl)-1,4-dioxaspiro[4.5]decan-8-amine)
  • Sodium cyanoborohydride (1.76 g, 28.39 mmol) was added to a solution of 8-phenyl-N-((tetrahydrofuran-3-yl)methyl)-1,4-dioxaspiro[4.5]decan-8-amine (3.0 g, 9.46 mmol), 37% formaldehyde in water (7.70 mL, 94.60 mmol) and acetic acid (0.05 mL) in methanol (30 mL) at 0° C. The reaction mixture was stirred at RT for 16 h. The reaction mixture was concentrated in vacuo and to the residue sat. aq. NaHCO3 was added. The organic product was extracted with DCM (3×30 mL). The combined organic extracts were dried over anhydrous Na2SO4 and solvent was concentrated under reduced pressure. The resulting residue was purified by column chromatography (silica gel 230-400 mesh; 5-6% MeOH in DCM) to yield 2.50 g (83%) of N-methyl-8-phenyl-N-((tetrahydrofuran-3-yl)methyl)-1,4-dioxaspiro[4.5]decan-8-amine as a semi solid (TLC system: 10% MeOH in DCM; Rf: 0.25).
    • Step 6: 4-(methyl((tetrahydrofuran-3-yl)methyl)amino)-4-phenylcyclohexanone
  • 5% sulfuric acid in water (25 mL) was added to N-methyl-8-phenyl-N-((tetrahydrofuran-3-yl)methyl)-1,4-dioxaspiro[4.5]decan-8-amine (2.50 g, 7.55 mmol) at 0° C. and the resulting mixture was stirred at RT for 24 h. The reaction mixture was quenched with sat. aq. NaHCO3 and the organic product was extracted with DCM (2×50 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated in vacuo to afford 2.0 g (crude) of 4-(methyl((tetrahydrofuran-3-yl)methyl)amino)-4-phenylcyclohexanone as a thick liquid (TLC system: 10% MeOH in DCM, Rf: 0.20).
    • Step 7: 8-(methyl((tetrahydrofuran-3-yl)methyl)amino)-8-phenyl-1,3-diazaspiro[4.5]decane-2,4-dione
  • 4-(methyl((tetrahydrofuran-3-yl)methyl)amino)-4-phenylcyclohexanone (1.50 g, 5.22 mmol) was suspended in 30 mL of EtOH:H2O (1:1 v/v) at RT under argon atmosphere. (NH4)2CO3 (1.9 g, 13.05 mmol) and KCN (0.34 g, 5.22 mmol) were added. The reaction mixture was heated to 70° C. for 16 h. The reaction mixture was diluted with ice-water and the organic product was extracted with DCM (2×50 mL). The combined organic layer was dried over anhydrous Na2SO4 and concentrated in vacuo to give 1.0 g (crude) of 8-(methyl((tetrahydrofuran-3-yl)methyl)amino)-8-phenyl-1,3-diazaspiro[4.5]decane-2,4-dione as a solid (TLC system: 70% Ethyl acetate in hexane; Rf: 0.18).
    • Step 8: CIS-8-(methyl((tetrahydrofuran-3-yl)methyl)amino)-8-phenyl-1,3-diazaspiro[4.5]decane-2,4-dione
  • Diastereomeric mixture of 8-(methyl((tetrahydrofuran-3-yl)methyl)amino)-8-phenyl-1,3-diazaspiro[4.5]decane-2,4-dione (1.0 g) was separated by reverse phase preparative HPLC to afford 400 mg of isomer 1 (CIS-8-(methyl((tetrahydrofuran-3-yl)methyl)amino)-8-phenyl-1,3-diazaspiro[4.5]decane-2,4-dione) and 60 mg of isomer 2 (TRANS-8-(methyl((tetrahydrofuran-3-yl)methyl)amino)-8-phenyl-1,3-diazaspiro[4.5]decane-2,4-dione) and 300 mg of mixture of both isomers. Reverse phase preparative HPLC conditions: mobile phase: 10 mM ammonium bicarbonate in H2O/acetonitrile, column: X-BRIDGE-C18 (150*30), 5 μm, gradient (T/B %): 0/35, 8/55, 8.1/98, 10/98, 10.1/35, 13/35, flow rate: 25 ml/min, diluent: mobile phase+THF.
    • Step 9: CIS-8-(methyl((tetrahydrofuran-3-yl)methyl)amino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-1026)
  • LiAlH4 (1M in THF) (4.48 mL, 4.48 mmol) was added to a solution of CIS-8-(methyl((tetrahydrofuran-3-yl)methyl)amino)-8-phenyl-1,3-diazaspiro[4.5]decane-2,4-dione (isomer-1) (0.4 g, 1.12 mmol) in THF:Et2O (2:1 v/v, 15 mL) at 0° C. under argon atmosphere. The reaction mixture was stirred at 65° C. for 16 h. The mixture was cooled to 0° C., quenched with sat. aq. Na2SO4 (1000 mL) and filtered through celite pad. The filtrate was dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography (silica gel 230-400 mesh; 5-6% MeOH in DCM) to yield 0.3 g (78%) of CIS-8-(methyl((tetrahydrofuran-3-yl)methyl)amino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-1026) as an off white solid. (TLC system: 10% MeOH in DCM, Rf: 0.2). LC-MS: m/z [M+1]+=344.2.
    • Synthesis of INT-1031: CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-8-(3-fluorophenyl)-1,3-diazaspiro[4.5]decan-2-one
  • Figure US20210179627A1-20210617-C00052
    • Step 1: CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-8-(3-fluorophenyl)-3-[(4-methoxyphenyl)-methyl]-1,3-diazaspiro[4.5]decan-2-one
  • In analogy to the method described for INT-952 CIS-8-dimethylamino-8-(3-fluorophenyl)-3-[(4-methoxyphenyl)-methyl]-1,3-diazaspiro[4.5]decan-2-one (INT-974) was converted into CIS-1-(cyclobutyl-methyl)-8-dimethylamino-8-(3-fluorophenyl)-3-[(4-methoxyphenyl)-methyl]-1,3-diazaspiro[4.5]decan-2-one.
    • Step 2: CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-8-(3-fluorophenyl)-1,3-diazaspiro[4.5]decan-2-one
  • In analogy to the method described for INT-982 step 2 1-(cyclobutyl-methyl)-8-dimethylamino-8-(3-fluorophenyl)-3-[(4-methoxyphenyl)-methyl]-1,3-diazaspiro[4.5]decan-2-one was converted into 1-(cyclobutyl-methyl)-8-dimethylamino-8-(3-fluorophenyl)-1,3-diazaspiro[4.5]decan-2-one (INT-1031).
    • Synthesis of INT-1032: CIS-2-[1-(cyclobutylmethyl)-8-(dimethylamino)-8-(3-fluorophenyl)-2-oxo-1,3-diazaspiro[4.5]decan-3-yl]acetic acid trifluoroacetate
  • Figure US20210179627A1-20210617-C00053
  • In analogy to the method described for INT-998 step 2 2-[1-(cyclobutyl-methyl)-8-dimethylamino-8-(3-fluorophenyl)-2-oxo-1,3-diazaspiro[4.5]decan-3-yl]-acetic acid tert-butyl ester (SC_1346) was converted into 2-[1-(cyclobutylmethyl)-8-(dimethylamino)-8-(3-fluorophenyl)-2-oxo-1,3-diazaspiro[4.5]decan-3-yl]acetic acid trifluoroacetate (INT-10322).
    • Synthesis of INT-1034: CIS-(8-methylamino-2-oxo-8-phenyl-1,3-diaza-spiro[4.5]dec-3-yl)-acetic acid
  • Figure US20210179627A1-20210617-C00054
    • Step 1: CIS-[8-dimethylamino-2-oxo-8-phenyl-1-(2-trimethylsilanyl-ethoxymethyl)-1,3-diaza-spiro[4.5]dec-3-yl]-acetic acid tert-butyl ester
  • In analogy to the method described for INT-988 Step 1 CIS-8-dimethylamino-8-phenyl-1,3-diaza-spiro[4.5]decan-2-one (INT-967) was converted into CIS-[8-dimethylamino-2-oxo-8-phenyl-1-(2-trimethylsilanyl-ethoxymethyl)-1,3-diaza-spiro[4.5]dec-3-yl]-acetic acid tert-butyl ester (INT-1033). LC-MS: m/z [M+H]+=388.3
    • Step 2: CIS-[8-dimethylamino-2-oxo-8-phenyl-1-(2-trimethylsilanyl-ethoxymethyl)-1,3-diaza-spiro[4.5]dec-3-yl]-acetic acid tert-butyl ester
  • To a suspension of CIS-(8-dimethylamino-2-oxo-8-phenyl-1,3-diaza-spiro[4.5]dec-3-yl)-acetic acid tert-butyl ester (INT-1033) (8.1 g, 20.90 mmol, 1.0 eq.) in DMF (300 mL) was added NaH (603 mg, 25.11 mmol, 1.2 eq.) at RT and the reaction mixture was stirred for 40 min. Trimethylsilylethoxymethyl chloride (SEMCl) was added (4.06 ml, 23.02 mmol, 1.1 eq). The resulting mixture was stirred at RT for 16 h, then diluted with ice-water (100 mL) and extracted with ethyl acetate (2×500 mL). The combined organic layer was washed with water (150 mL), brine (200 mL), dried over Na2SO4 and concentrated under reduced pressure. The resulting crude product was purified by column chromatography (silica gel, 30% ethyl acetate/hexane) to yield CIS-[8-dimethylamino-2-oxo-8-phenyl-1-(2-trimethylsilanyl-ethoxymethyl)-1,3-diaza-spiro[4.5]dec-3-yl]-acetic acid tert-butyl ester (4.0 g, 7.736 mmol, 37%) as a light yellow dense sticky liquid. LC-MS: m/z [M+H]+=518.3
    • Step 3: CIS-[8-methylamino-2-oxo-8-phenyl-1-(2-trimethylsilanyl-ethoxymethyl)-1,3-diaza-spiro[4.5]dec-3-yl]-acetic acid tert-butyl ester
  • In analogy to the method described for INT-986 Step 1 CIS-[8-dimethylamino-2-oxo-8-phenyl-1-(2-trimethylsilanyl-ethoxymethyl)-1,3-diaza-spiro[4.5]dec-3-yl]-acetic acid tert-butyl ester was converted into CIS-[8-methylamino-2-oxo-8-phenyl-1-(2-trimethylsilanyl-ethoxymethyl)-1,3-diaza-spiro[4.5]dec-3-yl]-acetic acid tert-butyl ester. LC-MS: m/z [M+H]+=504.2
    • Step 4: CIS-(8-methylamino-2-oxo-8-phenyl-1,3-diaza-spiro[4.5]dec-3-yl)-acetic acid (INT-1034)
  • To a solution of CIS-[8-methylamino-2-oxo-8-phenyl-1-(2-trimethylsilanyl-ethoxymethyl)-1,3-diaza-spiro[4.5]dec-3-yl]-acetic acid tert-butyl ester (1.6 g, 3.180 mmol, 1.0 eq.) in MeOH (48 mL) was added 2N aq. HCl (48 mL) and the mixture was stirred at RT for 16 h. The reaction mixture concentrated under reduced pressure, diluted with MeOH (40 mL), basified with 1M aq. LiOH (pH12) and stirred at RT for 16 h. The reaction mixture was concentrated under reduced pressure and acidified to pH-6 with aq. NaHSO4. The reaction mixture was extracted with 20% MeOH/DCM (5×200 ml). The combined organic layer was dried over anhydr. Na2SO4 and concentrated under reduced pressure to yield CIS-(8-methylamino-2-oxo-8-phenyl-1,3-diaza-spiro[4.5]dec-3-yl)-acetic acid (INT-1034) (850 mg, 0.681 mmol, 84%) as an off white solid. The product was used in the next step without further purification. LC-MS: m/z [M+H]+=318.2
    • Synthesis of INT-1035: CIS-(8-dimethylamino-1-oxetan-3-ylmethyl-2-oxo-8-phenyl-1,3-diaza-spiro[4.5]dec-3-yl)-acetic acid
  • Figure US20210179627A1-20210617-C00055
    • Step 1: CIS -(8-dimethylamino-1-oxetan-3-ylmethyl-2-oxo-8-phenyl-1,3-diaza-spiro[4.5]dec-3-yl)-acetic acid oxetan-3-ylmethyl ester
  • In analogy to the method described for INT-986 Step 1 CIS-(8-dimethylamino-2-oxo-8-phenyl-1,3-diaza-spiro[4.5]dec-3-yl)-acetic acid tert-butyl ester (INT-1033) was converted into CIS-(8-dimethylamino-1-oxetan-3-ylmethyl-2-oxo-8-phenyl-1,3-diaza-spiro[4.5]dec-3-yl)-acetic acid oxetan-3-ylmethyl ester.
    • Step 2: CIS-(8-dimethylamino-1-oxetan-3-ylmethyl-2-oxo-8-phenyl-1,3-diaza-spiro[4.5]dec-3-yl)-acetic acid (INT-1035) Synthesis of INT-1037: 8-(dimethylamino)-2-oxo-1,3-diazaspiro[4.5]decane-8-carbonitrile
  • Figure US20210179627A1-20210617-C00056
    • Step 1: 9,12-dioxa-2,4-diazadispiro[4.2.4{circumflex over ( )}{8}0.2{circumflex over ( )}{5}]tetradecan-3-one
  • Lithiumaluminiumhydride (2.2 equiv., 292 mmol) was suspended in THF (400 mL) and the suspension was cooled to 0° C. 8-(Dimethylamino)-8-(m-tolyl)-1,3-diazaspiro[4.5]decan-2-one (B, 75 mg, 0.261 mmol) (step 1 of INT-965) was added portionwise at 0° C. The reaction mixture was stirred 1.5 h at 0° C., then overnight at RT and then 2 h at 40° C. The reaction mixture was cooled down to 0° C., quenched carefully with sat. aq. Na2SO4, EtOAc (400 mL) was added and the resulting mixture was stirred for 2 h and then left without stirring for 2 h at RT. The precipitate was filtered off and washed with EtOAc and MeOH. The resulting solid residue was suspended in methanol and stirred at RT overnight. The precipitate was filtered off and disposed. The filtrate was concentrated under reduced pressure, the residue was suspended thoroughly in water (50 mL) at 40° C., the precipitate was filtered off and dried under reduced pressure to yield 9,12-dioxa-2,4-diazadispiro[4.2.4{circumflex over ( )}{8}0.2{circumflex over ( )}{5}]tetradecan-3-one (11.4 g, 41%). Mass: m/z 213.2 (M+H)+.
    • Step 2: 1,3-diazaspiro[4.5]decane-2,8-dione
  • In analogy to the method described for INT-1003 step 3 9,12-dioxa-2,4-diazadispiro[4.2.4{circumflex over ( )}{8}0.2{circumflex over ( )}{5}]tetradecan-3-one was treated with cone. aq. HCl to be converted into 1,3-diazaspiro[4.5]decane-2,8-dione. Mass: m/z 169.1 (M+H)+.
    • Step 3: 8-(dimethylamino)-2-oxo-1,3-diazaspiro[4.5]decane-8-carbonitrile (INT-1037)
  • In analogy to the method described for INT-965 step 1 1,3-diazaspiro[4.5]decane-2,8-dione was treated with dimethyl amine and potassium cyanide to be converted into 8-(dimethylamino)-2-oxo-1,3-diazaspiro[4.5]decane-8-carbonitrile (INT-1037). Mass: m/z 223.2 (M+H)+.
    • Synthesis of INT-1038: CIS-8-(dimethylamino)-8-(m-tolyl)-1,3-diazaspiro[4.5]decan-2-one
  • Figure US20210179627A1-20210617-C00057
  • To the suspension of 8-(dimethylamino)-2-oxo-1,3-diazaspiro[4.5]decane-8-carbonitrile (200 mg, 0.90 mmol) in THF (4 mL) at RT was added dropwise 1M bromo(m-tolyl)magnesium in THF (4 equiv., 3.6 mmol, 3.6 mL) and the reaction mixture was stirred for 1 h at RT. Additional portion of 1M bromo(m-tolyl)magnesium in THF (1 equiv., 0.8 mL) was added. The reaction mixture was stirred at RT overnight, then quenched with methanol/water. Solid NH4Cl and DCM were added to the resulting mixture and the precipitate was filtered off. The organic phase of the filtrate was separated and the aqueous phase was extracted with DCM (3×). The combined organic phases were dried over anhydr. Na2SO4 and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (DCM/MeOH, 100/0 to 65/35) to yield CIS-8-(dimethylamino)-8-(m-tolyl)-1,3-diazaspiro[4.5]decan-2-one (INT-1038) (81 mg, 31%). Mass: m/z 288.2 (M+H)+.
    • Synthesis of INT-1059: TRANS-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
  • Figure US20210179627A1-20210617-C00058
    • Step 1: T RANS-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decane-2,4-dione
  • To a stirred solution of 4-dimethylamino-4-phenyl-cyclohexanone (250.0 g, 1.15 mol, 1.0 eq.) in EtOH (2.5 L) and water (2.1 L) was added (NH4)2CO3 (276.2 g, 2.87 mol, 2.5 eq.) and the reaction mixture was stirred at RT for 15 min. KCN (74.92 g, 1.15 mol, 1.0 eq.) was added. The reaction mixture was stirred at 60° C. for 18 h and then filtered in hot condition to get white solid which was washed with water (2.5 L), ethanol (1 L) and hexane (2.5 L). The resulting solid was dried under reduced pressure to get CIS-8-dimethylamino-8-phenyl-1,3-diaza-spiro[4.5]decane-2,4-dione (223 g, 0.776 mol, 65%) as a white solid. The filtrate was collected from multiple batches (450 g) which contained a mixture of cis and trans isomers. The filtrate was concentrated under reduced pressure and solid obtained was filtered and washed with water (1 L) and hexane (1 L). Solid material was dried under reduced pressure to get 100 g of a mixture of cis and trans (major) isomers. Crude material was partially dissolved in hot MeOH (600 mL) and cooled to RT, filtered through sintered funnel, washed with MeOH (200 mL) followed by ether (150 mL) and dried to get TRANS-8-dimethylamino-8-phenyl-1,3-diaza-spiro[4.5]decane-2,4-dione (50 g, 0.174 mmol, -9-10%).
    • Step 2: TRANS-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-1059)
  • In analogy to the method described for INT-976 step 2 TRANS-8-dimethylamino-8-phenyl-1,3-diaza-spiro[4.5]decane-2,4-dione was treated with LiAlH4 to be converted into TRANS-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-1059). Mass: m/z 274.2 (M+H)+.
    • Synthesis of INT-1068 and INT-1069: CIS- and TRANS-8-(dimethylamino)-8-phenyl-1-(2,2,2-trifluoroethyl)-1,3-diazaspiro[4.5]decan-2-one
  • Figure US20210179627A1-20210617-C00059
    • Step 1: 1-amino-4-dimethylamino-4-phenyl-cyclohexanecarbonitrile
  • To a stirred solution of 4-dimethylamino-4-phenyl-cyclohexanone (50 g, 230.096 mmol) in MeOH (400 mL) was added NH4Cl (24.6 g, 460.8 mmol) followed by NH4OH (400 mL) at RT and the reaction mixture was stirred for 15 min. NaCN (22.5 g, 460.83 mmol) was added and the resulting mixture was stirred for 16 h at RT. The reaction mixture was extracted with DCM (3×750 mL). Combined organic layer was washed with water (750 mL), brine (750 mL), dried over Na2SO4 and concentrated under reduced pressure. The residue was triturated with DCM/hexane to get crude 1-amino-4-dimethylamino-4-phenyl-cyclohexanecarbonitrile (50 g, 90%) as an off white solid which was used in next step without further purification. LC-MS: m/z [M+H]+=244.2 (MW calc. 244.09).
    • Step 2: N-(1-cyano-4-dimethylamino-4-phenyl-cyclohexyl)-2,2,2-trifluoroacetamide
  • To a solution of 1-amino-4-dimethylamino-4-phenyl-cyclohexanecarbonitrile (5.0 g, 20.57 mmol, 1.0 eq.) in THF (100 ml) were added DIPEA (10.72 ml, 61.71 mmol, 3.0 eq), trifluoroacetic acid (1.89 ml, 24.69 mmol, 1.2 eq) and T3P (18.2 ml, 30.85 mmol, 1.5 eq) at 0° C. The reaction mixture was stirred at RT for 16 h, then diluted with water (100 ml) and extracted with 10% MeOH in DCM (2×250 mL). Combined organic layer was washed with brine (100 mL), dried over Na2SO4 and concentrated under reduced pressure to get crude N-(1-cyano-4-dimethylamino-4-phenyl-cyclohexyl)-2,2,2-trifluoroacetamide as a light yellow sticky material which was used in the next step without further purification. LC-MS: m/z [M+1]+=339.9 (MW calc. 339.36).
    • Step 3: 1-aminomethyl-N′,N′-dimethyl-4-phenyl-N-(2,2,2-trifluoroethyl)cyclohexane-1,4-diamine
  • To suspension of LiAlH4 (4.03 g, 106.19 mmol, 6.0 eq.) in dry THF (40 mL) was added N-(1-cyano-4-dimethylamino-4-phenyl-cyclohexyl)-2,2,2-trifluoro-acetamide (6.0 g, 17.69 mmol, 1.0 eq.) in dry THF (100 mL) dropwise at 0° C. The reaction mixture was stirred at RT for 16 h, then quenched with sat. aq. Na2SO4 at 0° C., excess THF was added and the resulting mixture was stirred at RT for 2 h. The resulting suspension was filtered through celite and the filter cake was washed with 10% MeOH in DCM (150 mL). Combined filtrate was concentrated under reduced pressure to yield crude 1-aminomethyl-N′,N′-dimethyl-4-phenyl-N-(2,2,2-trifluoro-ethyl)-cyclohexane-1,4-diamine (4.2 g, crude) as a light yellow sticky material which was directly used in the next step without further purification. LC-MS: m/z [M+1]+=330.0 (MW calc. 329.40).
    • Step 4: CIS- and TRANS-8-dimethylamino-8-phenyl-1-(2,2,2-trifluoro-ethyl)-1,3-diaza-spiro[4.5]decan-2-one (INT-1068 and INT-1069)
  • To a solution of 1-aminomethyl-N′,N′-dimethyl-4-phenyl-N-(2,2,2-trifluoro-ethyl)-cyclohexane-1,4-diamine (4.2 g, 12.76 mmol, 1.0 eq.) in toluene (60 ml) was added KOH (4.29 g, 76.56 mmol, 6.0 eq.) in water (120 ml) at 0° C. followed by addition of COCl2 (15.6 ml, 44.66 mmol, 3.5 eq., 20% in toluene) at 0° C. and stirred at RT for 16 h. Reaction mixture was basified with sat NaHCO3 solution and extracted with DCM (2*200 ml). Combined organic layer was dried over Na2SO4 and concentrated under reduced pressure to get crude product which was purified by prep HPLC to get CIS-8-dimethylamino-8-phenyl-1-(2,2,2-trifluoro-ethyl)-1,3-diaza-spiro[4.5]decan-2-one (INT-1068) (1.5 g) (major isomer, polar spot on TLC) and TRANS-8-dimethylamino-8-phenyl-1-(2,2,2-trifluoro-ethyl)-1,3-diaza-spiro[4.5]decan-2-one (INT-1069) as minor isomer (non-polar spot on TLC) (120 mg, 92.93% by HPLC) as off-white solids. CIS-isomer: LC-MS: m/z [M+1]+=356.2 (MW calc.=355.40). HPLC: 98.53%, Column: Xbridge C-18 (100×4.6), 5p, Diluent: MeOH, Mobile phase: A) 0.05% TFA in water; B) ACN flow rate: 1 ml/min, Rt=5.17 min. 1HNMR (DMSO-de, 400 MHz), δ (ppm)=7.43-7.27 (m, 5H), 6.84 (s, 1H), 3.30-3.25 (m, 4H), 2.66-2.63 (d, 2H, J=12.72 Hz), 1.89 (s, 6H), 1.58-1.51 (m, 2H), 1.46-1.43 (m, 2H), 1.33-1.23 (m, 2H).
  • To a solution of CIS-(8-dimethylamino-1-oxetan-3-ylmethyl-2-oxo-8-phenyl-1,3-diaza-spiro[4.5]dec-3-yl)-acetic acid oxetan-3-ylmethyl ester (300 mg, 0.636 mmol, 1.0 eq.) in THF/H2O (8 mL, 1.5:1) was added LiOH (160 mg, 3.821 mmol, 6.0 eq.). The reaction mixture was stirred at RT for 16 h, concentrated under reduced pressure, neutralized with aq. NaHSCfi to pH-6 and extracted with 5% MeOH/DCM (3×200 mL). the combined organic extract was dried over Na2SO4 and concentrated under reduced pressure. The residue was triturated with 15% DCM-Hexane to yield CIS-(8-dimethylamino-1-oxetan-3-ylmethyl-2-oxo-8-phenyl-1,3-diaza-spiro[4.5]dec-3-yl)-acetic acid (INT-1035) (210 mg, 0.523 mmol, 82%) as an off-white solid.
  • For further intermediates the synthesis in analogy to previously described methods is given in the following table. The syntheses of the building blocks and intermediates have either been described previously within this application or can be performed in analogy to the herein described methods or by methods known to the person, skilled in the art. Such a person will also know which building blocks and intermediates need to be chosen for synthesis of each exemplary compound.
  • Inter- in analogy m/z
    mediate Chemical Name Chemical structure to method [M + H]+
    INT-241 CIS-8- (dimethylamino)-1- isobutyl-8-phenyl-1,3- diazaspiro[4.5]decan-2- one
    Figure US20210179627A1-20210617-C00060
         		INT-982 330.3
    INT-794 CIS-3-(3,4- dimethoxybenzyl)-8- (dimethylamino)-8- phenyl-1,3- diazaspiro[4.5]decan-2- one
    Figure US20210179627A1-20210617-C00061
         		INT-975 424.3
    INT-796 CIS-8-Dimethylamino- 3-[(4-methoxyphenyl)- methyl]-8-(3-methoxy- propyl)-1,3- diazaspiro[4.5]decan-2- one
    Figure US20210179627A1-20210617-C00062
         		INT-974 390.3
    INT-797 CIS-8-(Ethyl-methyl- amino)-8-phenyl-1,3- diazaspiro[4.5]decan-2- one
    Figure US20210179627A1-20210617-C00063
         		INT-976 288.2
    INT-949 CIS-8-Dimethylamino- 1-ethyl-8-phenyl-1,3- diazaspiro[4.5]decan-2- one
    Figure US20210179627A1-20210617-C00064
         		INT-984 302.2
    INT-950 CIS-1-(Cyclobutyl- methyl)-8- dimethylamino-8- phenyl-3-[phenyl- methyl]-1,3- diazaspiro[4.5]decan-2- one
    Figure US20210179627A1-20210617-C00065
         		INT-952 432.3
    INT-954 4-Dimethylamino-4-(5- methyl-thiophen-2-yl)- cyclohexan-1-one
    Figure US20210179627A1-20210617-C00066
         		INT-965 238.1
    INT-955 4-Dimethylamino-4- thiophen-2-yl- cyclohexan-1-one
    Figure US20210179627A1-20210617-C00067
         		INT-965 224.1
    INT-956 1-(1-Methyl-1H- pyrazol-3-yl)-4-oxo- cyclohexane-1- carbonitrile
    Figure US20210179627A1-20210617-C00068
         		INT-958 204.1
    INT-957 4-Oxo-1-pyrazin-2-yl- cyclohexane-1- carbonitrile
    Figure US20210179627A1-20210617-C00069
         		INT-958 202.1
    INT-959 4-Dimethylamino-4-(1- methyl-1H-pyrazol-3- yl)-cyclohexan-1-one
    Figure US20210179627A1-20210617-C00070
         		INT-961 222.2
    INT-960 4-Dimethylamino-4- pyrazin-2-yl- cyclohexan-1-one
    Figure US20210179627A1-20210617-C00071
         		INT-961 220.1
    INT-962 4-Dimethylamino-4-(3- methoxyphenyl)- cyclohexan-1-one
    Figure US20210179627A1-20210617-C00072
         		INT-965 248.2
    INT-963 CIS-3-Benzyl-8- dimethylamino-8- phenyl-1,3- diazaspiro[4.5]decan-2- one
    Figure US20210179627A1-20210617-C00073
         		INT-975 364.2
    INT-964 4-(Ethyl-methyl- amino)-4-phenyl- cyclohexan-1-one
    Figure US20210179627A1-20210617-C00074
         		INT-965 232.2
    INT-967 CIS-8-Dimethylamino- 8-[4- (methoxymethyloxy)- phenyl]-3-[(4- methoxyphenyl)- methyl]-1,3- diazaspiro[4.5]decan-2- one
    Figure US20210179627A1-20210617-C00075
         		INT-974 454.3
    INT-968 CIS-8-Dimethylamino- 8-[3- (methoxymethyloxy)- phenyl]-3-[(4- methoxyphenyl)- methyl]-1,3- diazaspiro[4.5]decan-2- one
    Figure US20210179627A1-20210617-C00076
         		INT-974 454.3
    INT-969 CIS-1-(Cyclobutyl- methyl)-8- dimethylamino-8-(4- hydroxyphenyl)-3-[(4- methoxyphenyl)- methyl]-1,3- diazaspiro[4.5]decan-2- one
    Figure US20210179627A1-20210617-C00077
         		INT-971 478.3
    INT-970 CIS-8-Dimethylamino- 8-(4-methoxyphenyl)- 3-[(4-methoxyphenyl)- methyl]-1,3- diazaspiro[4.5]decan-2- one
    Figure US20210179627A1-20210617-C00078
         		SC_2017 424.3
    INT-972 CIS-8-Dimethylamino- 8-(3-methoxyphenyl)- 3-[(4-methoxyphenyl)- methyl]-1,3- diazaspiro[4.5]decan-2- one
    Figure US20210179627A1-20210617-C00079
         		SC_2017 424.3
    INT-973 CIS-8-Dimethylamino- 8-(4-fluorophenyl)-3- [(4-methoxyphenyl)- methyl]-1,3- diazaspiro[4.5]decan-2- one
    Figure US20210179627A1-20210617-C00080
         		INT-974 412.2
    INT-979 CIS-8-Dimethylamino- 1-(3-methoxy-propyl)- 8-phenyl-1,3- diazaspiro[4.5]decan-2- one
    Figure US20210179627A1-20210617-C00081
         		INT-984 346.2
    INT-980 CIS-8-Dimethylamino- 1-(2-methoxy-ethyl)-8- phenyl-1,3- diazaspiro[4.5]decan-2- one
    Figure US20210179627A1-20210617-C00082
         		INT-984 332.2
    INT-981 CIS-8-Dimethylamino- 8-phenyl-1-propyl-1,3- diazaspiro[4.5]decan-2- one
    Figure US20210179627A1-20210617-C00083
         		INT-984 316.2
    INT-983 CIS-1-(Cyclopropyl- methyl)-8- dimethylamino-8- phenyl-1,3- diazaspiro[4.5]decan-2- one
    Figure US20210179627A1-20210617-C00084
         		INT-984 328.2
    INT-985 CIS-1-(Cyclobutyl- methyl)-8-(methyl- propyl-amino)-8- phenyl-1,3- diazaspiro[4.5]decan-2- one
    Figure US20210179627A1-20210617-C00085
         		INT-986 370.3
    INT-989 CIS-2-[1-[(1-Cyano- cyclobutyl)-methyl]-8- dimethylamino-2-oxo- 8-phenyl-1,3- diazaspiro[4.5]decan-3- yl]-acetic acid
    Figure US20210179627A1-20210617-C00086
         		INT-992 425.2
    INT-990 CIS-2-[8- Dimethylamino-1-(3- methoxy-propyl)-2- oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3- yl]-acetic acid
    Figure US20210179627A1-20210617-C00087
         		INT-992 404.2
    INT-991 CIS-2-[1-(Cyclopropyl- methyl)-8- dimethylamino-2-oxo- 8-phenyl-1,3- diazaspiro[4.5]decan-3- yl]-acetic acid
    Figure US20210179627A1-20210617-C00088
         		INT-992 386.2
    INT-993 CIS-2-[1-(Cyclobutyl- methyl)-8- dimethylamino-2-oxo- 8-phenyl-1,3- diazaspiro[4.5]decan-3- yl]-acetic acid
    Figure US20210179627A1-20210617-C00089
         		INT-992 400.3
    INT-995 CIS-2-(8- Dimethylamino-2-oxo- 8-phenyl-1-propyl-1,3- diazaspiro[4.5]decan-3- yl)-acetic acid
    Figure US20210179627A1-20210617-C00090
         		INT-992 374.2
    INT-996 CIS-2-[8- Dimethylamino-1- [(dimethyl-carbamoyl)- methyl]-2-oxo-8- phenyl-1,3- diazaspiro[4.5]decan-3- yl]-acetic acid; 2,2,2- trifluoro-acetic acid salt
    Figure US20210179627A1-20210617-C00091
         		INT-998 417.2
    INT-997 CIS-2-[8- Dimethylamino-1-(2- methoxy-ethyl)-2-oxo- 8-phenyl-1,3- diazaspiro[4.5]decan-3- yl]-acetic acid; 2,2,2- trifluoro-acetic acid
    Figure US20210179627A1-20210617-C00092
         		INT-998 390.2
    INT-999 CIS-2-[1-(Cyclobutyl- methyl)-8- dimethylamino-2-oxo- 8-phenyl-1,3- diazaspiro[4.5]decan-3- yl]-acetic acid; 2,2,2- trifluoro-acetic acid salt
    Figure US20210179627A1-20210617-C00093
         		INT-998 400.3
    INT-1000 4-benzyl-4- (dimethylamino) cyclohexanone
    Figure US20210179627A1-20210617-C00094
         		INT-965 232.3
    INT-1001 CIS-8-benzyl-8- (dimethylamino)-1,3- diazaspiro[4.5]decan-2- one
    Figure US20210179627A1-20210617-C00095
         		INT-976 288.2
    INT-1002 TRANS-8-benzyl-8- (dimethylamino)-1,3- diazaspiro[4.5]decan-2- one
    Figure US20210179627A1-20210617-C00096
         		INT-976 288.2
    INT-1009 CIS-8- (dimethylamino)-8- (thiophen-2-yl)-1,3- diazaspiro[4.5]decan-2- one
    Figure US20210179627A1-20210617-C00097
         		INT-976 280.1
    INT-1010 TRANS-8- (dimethylamino)-8- (thiophen-2-yl)-1,3- diazaspiro[4.5]decan-2- one
    Figure US20210179627A1-20210617-C00098
         		INT-976 280.1
    INT-1011 4-(dimethylamino)-4- (1-methyl-1H- benzo[d]imidazol-2- yl)cyclohexanone
    Figure US20210179627A1-20210617-C00099
         		INT-965 272.2
    INT-1012 CIS-8- (dimethylamino)-8-(1- methyl-1H- benzo[d]imidazol-2-yl)- 1,3- diazaspiro[4.5]decan-2- one
    Figure US20210179627A1-20210617-C00100
         		INT-976 328.2
    INT-1013 TRANS-8- (dimethylamino)-8-(1- methyl-1H- benzo[d]imidazol-2-yl)- 1,3- diazaspiro [4.5]decan-2- one
    Figure US20210179627A1-20210617-C00101
         		INT-976 328.2
    INT-1014 CIS-2-(8- (dimethylamino)-2- oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3- yl)acetic acid trifluoroacetate salt
    Figure US20210179627A1-20210617-C00102
         		steps 1 and 2 of INT- 994 332.2
    INT-1015 CIS-2-(8-(ethylamino)- 2-oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3- yl)acetic acid trifluoroacetate salt
    Figure US20210179627A1-20210617-C00103
         		steps 1 and 2 of INT- 994 332.2
    INT-1016 TRANS-8- (ethylamino)-8-phenyl- 1,3- diazaspiro[4.5]decan-2- one
    Figure US20210179627A1-20210617-C00104
         		INT-1008 274.2
    INT-1017 TRANS-2-(8- (ethylamino)-2-oxo-8- phenyl-1,3- diazaspiro[4.5]decan-3- yl)acetic acid trifluoroacetate salt
    Figure US20210179627A1-20210617-C00105
         		steps 1 and 2 of INT- 994 332.2
    INT-1018 CIS-8- (dimethylamino)-8- phenyl-1,3- diazaspiro[4.5]decane- 2,4-dione
    Figure US20210179627A1-20210617-C00106
         		INT-976 288.2
    INT-1024 CIS-8- (dimethylamino)-8-(3- fluorophenyl)-1,3- diazaspiro[4.5]decan-2- one
    Figure US20210179627A1-20210617-C00107
         		INT-977 (step 2) 292.2
    INT-1025 CIS-8- (dimethylamino)-8-(4- fluorophenyl)-1,3- diazaspiro[4.5]decan-2- one
    Figure US20210179627A1-20210617-C00108
         		INT-974, INT-977 (step 2) 292.2
    INT-1039 CIS-8- (dimethylamino)-8-(3- (trifluoromethoxy) phenyl)-1,3- diazaspiro[4.5]decan-2- one
    Figure US20210179627A1-20210617-C00109
         		INT-1038 358.2
    INT-1040 (CIS)-8- (dimethylamino)-8-(3- (trifluoromethyl)phenyl)- 1,3- diazaspiro[4.5]decan-2- one
    Figure US20210179627A1-20210617-C00110
         		INT-1038 342.2
    INT-1041 (CIS)-8- (dimethylamino)-8-(3- methoxyphenyl)-1,3- diazaspiro[4.5]decan-2- one
    Figure US20210179627A1-20210617-C00111
         		INT-1038 304.2
    INT-1042 (CIS)-8-(5- chlorothiophen-2-yl)-8- (dimethylamino)-1,3- diazaspiro[4.5]decan-2- one
    Figure US20210179627A1-20210617-C00112
         		INT-1038 314.1
    INT-1043 (CIS)-8- (dimethylamino)-8-(3- fluoro-5- methylphenyl)-1,3- diazaspiro[4.5]decan-2- one
    Figure US20210179627A1-20210617-C00113
         		INT-1038 306.2
    INT-1044 (CIS)-8-(3- chlorophenyl)-8- (dimethylamino)-1,3- diazaspiro[4.5]decan-2- one
    Figure US20210179627A1-20210617-C00114
         		INT-1038 308.2
    INT-1047 (CIS)-8- (methyl(oxetan-3- ylmethyl)amino)-8- phenyl-1,3- diazaspiro[4.5]decan-2- one
    Figure US20210179627A1-20210617-C00115
         		INT-1026 330.5
    INT-1057 CIS-1- (cyclobutylmethyl)-8- (dimethylamino)-8-(4- fluorophenyl)-1,3- diazaspiro[4.5]decan-2- one
    Figure US20210179627A1-20210617-C00116
         		INT-1031 360.3
    INT-1058 CIS-2-(1- (cyclobutylmethyl)-8- (dimethylamino)-8-(4- fluorophenyl)-2-oxo- 1,3- diazaspiro[4.5]decan-3- yl)acetic acid trifluoroacetate
    Figure US20210179627A1-20210617-C00117
         		INT-998 418.3
    INT-1060 TRANS-2-(8- (dimethylamino)-2- oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3- yl)acetic acid trifluoroacetate salt
    Figure US20210179627A1-20210617-C00118
         		steps 1 and 2 of INT- 994 332.2
    INT-1061 TRANS-1- (cyclopropyl-methyl)- 8-dimethylamino-8- phenyl-1,3- diazaspiro[4.5]decan-2- one
    Figure US20210179627A1-20210617-C00119
         		INT-984 328.2
    INT-1062 TRANS-2-[1- (cyclopropyl-methyl)- 8-dimethylamino-2- oxo-8-phenyl-1,3- diazaspiro[4.5]decan-3- yl]-acetic acid trifluoroacetate salt
    Figure US20210179627A1-20210617-C00120
         		INT-998 386.2
    INT-1063 CIS-1- (cyclopropylmethyl)-8- (dimethylamino)-8-(3- fluorophenyl)-1,3- diazaspiro[4.5]decan-2- one
    Figure US20210179627A1-20210617-C00121
         		INT-1031 346.2
    INT-1066 TRANS-1- (cyclobutylmethyl)-8- (dimethylamino)-8- phenyl-1,3- diazaspiro[4.5]decan-2- one
    Figure US20210179627A1-20210617-C00122
         		INT-987 342.3
    INT-1067 TRANS-2-[1- (cyclobutyl-methyl)-8- dimethylamino-2-oxo- 8-phenyl-1,3- diazaspiro[4.5]decan-3- yl]-acetic acid; 2,2,2- trifluoro-acetic acid salt
    Figure US20210179627A1-20210617-C00123
         		INT-998 400.3
    INT-1070 CIS-8- (dimethylamino)-8- phenyl-1-(3,3,3- trifluoropropyl)-1,3- diazaspiro[4.5]decan-2- one
    Figure US20210179627A1-20210617-C00124
         		INT-1068 360.2
    INT-1074 CIS-8- (dimethylamino)-8-(3- fluorophenyl)-1-((1- hydroxycyclobutyl) methyl)-1,3- diazaspiro[4.5]decan-2- one
    Figure US20210179627A1-20210617-C00125
         		INT-1031 376.2
    Figure US20210179627A1-20210617-C00126
    • Synthesis of Exemplary Compounds Synthesis of SC_1051: CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(5-methoxy-pyridin-2-yl)-acetamide
  • Figure US20210179627A1-20210617-C00127
  • Into a dry reaction vessel were added successively 1 mL of a solution of CIS-2-[1-(cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetic acid (INT-993) (0.1 M in DCM), 2 mL of a solution of 5-methoxy-pyridin-2-amine (0.2 M in DCM), 0.07 ml of triethylamine and 0.118 mL of a solution of T3P (1.7 M, 50% in EtOAc). The reaction mixture was stirred at RT overnight, then quenched with 3 mL aq. Na2CO3 (1 M) and stirred at RT for 1 h. The organic layer was separated and the aq. layer was extracted with DCM (2×). The combined organic layers were concentrated under reduced pressure and the resulting crude product was purified by HPLC to obtain CIS-2-[1-(cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(5-methoxy-pyridin-2-yl)-acetamide (SC_1051). [M+H]+ 506.3
    • Synthesis of SC_1073: CIS-2-[[2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetyl]amino]-N-methyl-pyridine-4-carboxylic acid amide
  • Figure US20210179627A1-20210617-C00128
  • To a mixture of CIS-2-[1-(cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetic acid trifluoroacetate (INT-999) (100 mg, 0.19 mmol) and 2-amino-N-methylisonicotinamide (118 mg, 0.78 mmol) in DCM (6 ml) were added HATU (148 mg, 0.39 mmol) and DIPEA (0.13 ml, 0.78 mmol) at RT and the reaction mixture was stirred at same temperature for 16 h. The reaction mixture was washed with 1M aq. Na2CO3 (1 mL) and 2M aq. NaOH (1 mL). The combined aqueous layers were extracted with DCM (3×5 mL). The combined organic layers were washed with water (3 mL) and brine (3 ml), dried over magnesium sulfate, filtered and concentrated in vacuum. Column chromatography (silica gel, cHex/tBuOMe/1N methanolic ammonia 1:1:0.05) of the crude product provided CIS-2-[[2-[1-(cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetyl]amino]-N-methyl-pyridine-4-carboxylic acid amide (SC_1073) (27 mg). [M+H]+ 533.3
    • Synthesis of SC_1076: CIS-6-[[2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetyl]amino]-pyridine-2-carboxylic acid amide
  • Figure US20210179627A1-20210617-C00129
  • CIS-N-(6-Cyano-pyridin-2-yl)-2-[1-(cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetamide (SC_1026) (30 mg, 0.06 mmol) was dissolved in DMSO (0.2 mL) and potassium carbonate (17 mg, 0.12 mmol) and hydrogen peroxide (30% in water, 0.12 mmol) were added at 0° C. The resulting mixture was stirred for 18 h, then water was added and the reaction mixture was extracted with DCM (3×5 mL). The combined organic layers were dried over Na2SO4, concentrated in vacuo and the resulting crude product was purified by flash chromatography to yield CIS-6-[[2-[1-(cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetyl]amino]-pyridine-2-carboxylic acid amide SC_1076 (14 mg) as a white solid. [M+H]+ 519.3
    • Synthesis of SC_1110: CIS-2-[1-(cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(2-hydroxy-pyrimidin-5-yl)-acetamide
  • Figure US20210179627A1-20210617-C00130
  • A solution of CIS-2-[1-(cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(2-methoxy-pyrimidin-5-yl)-acetamide (SC_1070) (80 mg, 0.16 mmol) in DCM (12 mL) was cooled to 0° C. and treated with a boron tribromide solution (1M in DCM, 1.26 mL, 1.26 mmol). After stirring at RT for 16 h the reaction mixture was quenched with MeOH, diluted with water and extracted with DCM (3×). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuum. The resulting crude product was purified by column chromatography (reversed phase silica gel C18, water/MeCN 100:0->20:80) to yield CIS-2-[1-(cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(2-hydroxy-pyrimidin-5-yl)-acetamide (SC_1110) (17 mg). [M+H]+ 493.3
    • Synthesis of SC_1128: CIS-N-(2-Cyano-pyrimidin-4-yl)-2-[1-(cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetamide
  • Figure US20210179627A1-20210617-C00131
  • CIS-2-[1-(cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetamide (SC_1195) (50 mg, 0.1255 mmol), 4-bromopyrimidine-2-carbonitrile (0.1882 mmol), 4,5-XantPhos (0.0188 mmol), Cs2CO3 (0.2509 mmol) and Pd2(dba)3 (0.0063 mmol) were dissolved in 1,4-dioxane (6 mL). The reaction mixture was degassed by three consecutive vacuum/nitrogen-refill cycles and then stirred at 90° C. for 18 h. Water (2 mL) was added and the resulting mixture was extracted with ethyl acetate (3×6 mL). The combined organic layers were dried over Na2SO4, concentrated in vacuo and purified by flash chromatography to yield CIS-N-(2-cyano-pyrimidin-4-yl)-2-[1-(cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetamide (SC_1128) (43 mg) as a white solid. [M+H]+ 502.3
    • Synthesis of SC_1129: CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-[6-(methylsulfinyl)-pyridin-2-yl]-acetamide
  • Figure US20210179627A1-20210617-C00132
  • CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(6-methylsulfanyl-pyridin-2-yl)-acetamide SC_1120 (30.0 mg) was dissolved in 1,1,1,3,3,3-hexafluoropropan-2-ol (0.303 mL) and hydrogen peroxide (30% in water, 12 μL) was added. The resulting mixture was stirred at 60° C. for 1 h. Then sat. aq. Na2S2O3 (2 mL) was added and the aqueous layer was extracted with DCM (3×5 mL). The combined organic layers were dried over Na2SO4, concentrated in vacuo and purified by flash chromatography to yield CIS-2-[1-(cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-[6-(methylsulfinyl)-pyridin-2-yl]-acetamide (SC_1129) (8 mg) as a white solid. [M+H]+ 538.3
    • Synthesis of SC_1136: CIS-2-[8-dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(2-methylsulfonyl-ethyl)-acetamide
  • Figure US20210179627A1-20210617-C00133
  • 50% Propylphosphonic anhydride (T3P) solution in EtOAc (0.766 mL, 1.204 mmol) was added to a solution of crude CIS-2-[8-dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetic acid (INT-994) (250 mg, 0.602 mmol), 2-(methylsulfonyl)ethanamine hydrochloride (115.4 mg, 0.723 mmol) and diisopropylethylamine (0.410 mL, 2.408 mmol) in DCM (15 mL) at 0° C. The reaction mixture was warmed to RT and stirred for 4 h. The reaction mixture was quenched with water and the organic product was extracted with DCM (3×20 mL). The combined organic layer was washed with sat. aq. NaHCO3 (10 mL), brine (10 mL) and dried over anhydr. Na2SO4 and concentrated under reduced pressure The crude product was purified by preparative HPLC to give 56 mg (25%) of CIS-2-[8-dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(2-methylsulfonyl-ethyl)-acetamide (SC_1136) as an off-white solid. (TLC system: 10% MeOH in DCM Rf: 0.62). [M+H]+ 521.3
    • Synthesis of SC_1138: CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(6-methylsulfonyl-pyridin-2-yl)-acetamide
  • Figure US20210179627A1-20210617-C00134
  • CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(6-methylsulfanyl-pyridin-2-yl)-acetamide (SC_1120) (22 mg) was dissolved in a water/methanol (500 μL/500 μL) and oxone (39 mg) was added. The resulting mixture was stirred at RT for 18 h. Then 2N aq. NaOH (2 mL) was added and the aqueous layer was extracted with DCM (3×5 mL). The combined organic layers were dried over Na2SO4, concentrated in vacuo and the residue was purified by flash chromatography to yield CIS-2-[1-(cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(6-methylsulfonyl-pyridin-2-yl)-acetamide (SC_1138) (14 mg) as a white solid. [M+H]+ 554.3
    • Synthesis of SC_1149: CIS-2-[8-Dimethylamino-1-(3-methoxy-propyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-methyl-acetamide
  • Figure US20210179627A1-20210617-C00135
  • CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-987) (0.2 g, 0.57 mmol) was added to a solution of NaH (60% in mineral oil) (0.15 g, 3.47 mmol) in DMF (5 mL) at RT and the reaction mixture was stirred at RT for 1 h. The reaction mixture was cooled to 0° C. and 2-bromo-N-methylacetamide (0.52 g, 3.47 mmol) in DMF (2 mL) was added dropwise. the resulting mixture was stirred for 30 min at 0° C. and then at RT for 16 h. The reaction completion was monitored by TLC. The reaction mixture was quenched with sat. aq. NH4Cl and the organic product was extracted with EtOAc (2×10 mL). The combined organic extracts were dried over anhydrous Na2SO4 and concentrated under reduced pressure. Purified of the crude product by preparative TLC using 5% MeOH in DCM as a mobile phase gave 45 g (18%) of CIS-2-[8-dimethylamino-1-(3-methoxy-propyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-methyl-acetamide (SC_1149) as an off-white solid. (TLC system: 10% MeOH in DCM; Rf: 0.3). [M+H]+ 417.3
    • Synthesis of SC_1303: CIS-2-[1-[(1-Hydroxy-cyclobutyl)-methyl]-8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(oxetan-3-yl)-acetamide
  • Figure US20210179627A1-20210617-C00136
  • N-Iodosuccinimide (71.8 mg, 0.319 mmol) was added to a solution of CIS-2-[8-dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(oxetan-3-yl)-acetamide (SC_1301) (100 mg, 0.213 mmol) in a mixture of acetonitrile and THF (1:1 v/v, 5 mL) at 0° C. and the resulting mixture was stirred at RT for 16 h. The reaction mixture was basified with 2N NaOH solution to pH10 and the organic product was extracted with ethyl acetate (10 mL×3). The combined organic extracts were dried over anhydr. Na2SO4 and concentrated under reduced pressure. The resulting crude product was purified by preparative reverse phase HPLC to give 50 mg of the desired product as a formiate. The isolated product was diluted with water (5 mL) and basified with sat. aq. NaHCO3. The product was extracted with EtOAc (10 mL×2), combined organic layer was dried over anhydr. Na2SO4 and concentrated in vacuo to yield 42 mg (43%) of CIS-2-[1-[(1-hydroxy-cyclobutyl)-methyl]-8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(oxetan-3-yl)-acetamide (SC_1303) as an off-white solid (TLC system: 5% MeOH in DCM; Rf: 0.42.). [M+H]+ 457.3
    • Synthesis of SC_1308: CIS-8-Dimethylamino-3-[2-(1,1-dioxo-[1,4]thiazinan-4-yl)-2-oxo-ethyl]-8-phenyl-1-propyl-1,3-diazaspiro[4.5]decan-2-one
  • Figure US20210179627A1-20210617-C00137
  • 50 wt % solution of T3P (2.32 g, 3.65 mmol) in EtOAc was added to a suspension of CIS-2-(8-dimethylamino-2-oxo-8-phenyl-1-propyl-1,3-diazaspiro[4.5]decan-3-yl)-acetic acid hydrochlorid (INT-995) (600 mg, 1.46 mmol), thiomorpholin-1,1-dioxide (237 mg, 1.76 mmol) and diisopropylethylamine (1.27 mL, 7.30 mmol) in THF (10 mL) at 0° C. The reaction mixture was warmed to RT and stirred for 16 h. The reaction mixture was quenched with water, the organic product was extracted with EtOAc (3×25 mL). The combined organic extracts were washed with water, brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure to give the crude compound. Purification by flash silica column chromatography using 4-5% methanol in DCM as eluent yielded 250 mg (34%) of CIS-8-dimethylamino-3-[2-(1,1-dioxo-[1,4]thiazinan-4-yl)-2-oxo-ethyl]-8-phenyl-1-propyl-1,3-diazaspiro[4.5]decan-2-one (SC_1308) as a solid (TLC system: 10% MeOH in DCM Rf: 0.30). [M+H]+ 491.3
    • Synthesis of SC_1324: CIS-2-(8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)acetamide
  • Figure US20210179627A1-20210617-C00138
  • The suspension of TFA salt of CIS-(8-dimethylamino-2-oxo-8-phenyl-1,3-diaza-spiro[4.5]dec-3-yl)-acetic acid (500 mg, 1.12 mmol, 1.0 eq.) in THF (40 ml) was cooled to 0° C. and DIPEA (0.78 ml, 4.48 mmol, 4.0 eq.), 1-hydroxy-1H-benzotriazole ammonium salt (287 mg, 1.68 mmol, 1.5 eq.) and EDCl (321 mg, 1.68 mmol, 1.5 eq.) were sequentially added. The resulting mixture was stirred at RT for 16 h and then concentrated under reduced pressure. Crude product was purified by column chromatography (neutral alumina; 0.5% NH3 in 20% MeOH/DCM) to yield CIS-2-(8-dimethylamino-2-oxo-8-phenyl-1,3-diaza-spiro[4.5]dec-3-yl)-acetamide (SC_1324) (250 mg, 0.75 mmol, 67%) as an off-white solid. [M+H]+ 331.2
    • Synthesis of SC_1332: CIS-2-(8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-N-phenylacetamide
  • Figure US20210179627A1-20210617-C00139
  • KOtBu (1M in THF) (1.4 mL, 1.37 mmol) was added to the solution of CIS-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (250 mg, 0.915 mmol) in THF (15 mL) under argon atmosphere at 0° C. and the reaction mixture was stirred for 30 min. 2-Bromo-N-phenylacetamide (312 mg, 1.46 mmol) was added, the ice bath was removed and the reaction mixture was stirred for 4 h. Sat. aq. NH4Cl (10 mL) was added and the resulting mixture was extracted with EtOAc (2×50 mL). The combined organic extracts were dried over anhydr. Na2SO4 and concentrated under reduced pressure. The crude product was purified by reverse phase preparative HPLC to give 60 mg (16%) of CIS-2-(8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-N-phenylacetamide (SC_1332) as a white solid. 1H NMR (CDCl3): δ 8.32 (br s, 1H), 7.50-7.48 (d, 2H), 7.39-7.36 (m, 2H), 7.33-7.26 (m, 5H), 7.12-7.08 (t, 1H), 5.90 (br s, 1H), 3.90 (s, 2H), 3.25 (s, 2H), 2.12 (m, 4H), 1.99 (s, 6H), 1.94-1.91 (m, 2H), 1.58-1.53 (m, 2H). [M+H]+ 407.2
    • Synthesis of SC-1346: CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-8-(3-fluorophenyl)-2-oxo-1,3-diazaspiro[4.5]decan-3-yl]-acetic acid tert-butyl ester
  • Figure US20210179627A1-20210617-C00140
  • KOtBu (187 mg, 1.67 mmol) was added to a solution of CIS-1-(cyclobutyl-methyl)-8-dimethylamino-8-(3-fluorophenyl)-1,3-diazaspiro[4.5]decan-2-one (INT-1031) (400 mg, 1.1 mmol) in dry THF (9 mL) at 0° C. The mixture was stirred for 15 min at this temperature and t-butyl-bromoacetate (0.246 mL, 1.67 mmol) was added subsequently. After stirring for 1 h at 0° C., the reaction was quenched with water, diluted with EtOAc and stirred for 5 min at RT. The layers were separated and the aqueous layer was extracted two times with ethyl acetate. The combined organic extracts were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was purified by flash chromatography (silica, 0.5 M NH3 in MeOH/DCM gradient) to yield 395 mg (75%) of CIS-2-[1-(cyclobutyl-methyl)-8-dimethylamino-8-(3-fluorophenyl)-2-oxo-1,3-diazaspiro[4.5]decan-3-yl]-acetic acid tert-butyl ester (SC_1346) as a white solid. 1H NMR (600 MHz, DMSO) δ 7.43-7.36 (m, 1H), 7.17 (d, 1H), 7.13 (dt, 1H), 7.09 (td, 1H), 3.75 (d, 2H), 3.21 (s, 2H), 3.05 (d, 2H), 2.67-2.61 (m, 2H), 2.08-2.00 (m, 2H), 1.99 (d, 7H), 1.98-1.93 (m, 2H), 1.83-1.75 (m, 2H), 1.75-1.65 (m, 2H), 1.39 (d, 8H), 1.38-1.29 (m, 5H). [M+H]+ 474.3
    • of SC-1357: TRANS-1-(cyclopropylmethyl)-8-(dimethylamino)-3-(2-morpholino-2-oxoethyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
  • Figure US20210179627A1-20210617-C00141
  • To a solution of TRANS-2-(1-(cyclopropylmethyl)-8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)acetic acid trifluoroacetate (300 mg, 0.6 mmol, 1.0 eq.) in DCM (10 mL) were added DIPEA (0.62 mL, 3.6 mmol, 6.0 eq.) and HATU (296 mg, 0.78 mmol, 1.3 eq.) followed by morpholine (102 mg, 1.08 mmol, 1.8 eq.) at 0° C. The reaction mixture was stirred at RT for 16 h, then quenched with water (25 mL) and extracted with DCM (50 mL×2). Combined organic layer was washed with brine (25 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting crude product was purified by prep HPLC to get TRANS-1-cyclopropylmethyl-8-dimethylamino-3-(2-morpholin-4-yl-2-oxo-ethyl)-8-phenyl-1,3-diaza-spiro[4.5]decan-2-one (SC-1357) (55 mg, 0.12 mmol, 20%) as a white solid. 1HNMR (DMSO-d6. 400 MHz), δ (ppm)=7.44-7.29 (m, 5H), 3.96 (s, 2H), 3.56 (bs, 4H), 3.42-3.40 (m, 4H), 3.29 (s, 2H), 2.67 (bs, 2H), 2.55-2.54 (d, 2H, J=6.36 Hz), 1.92 (s, 6H), 1.56-0.144 (m, 6H), 0.51-0.48 (m, 1H), 0.16-0.14 (m, 2H), (−0.26)-(−0.27) (m, 2H). [M+H]+ 455.1
    • Synthesis of INT-1363: TRANS-2-(1-(cyclopropylmethyl)-8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)acetamide
  • Figure US20210179627A1-20210617-C00142
    • Step 1: tert-butyl TRANS-2-(1-(cyclopropylmethyl)-8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)acetate
  • In analogy to the method described for INT-1019 step 1 TRANS-1-(cyclopropylmethyl)-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-1061) was converted into tert-butyl TRANS-2-(1-(cyclopropylmethyl)-8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)acetate. LC-MS: m/z [M+H]+=442.3
    • Step 2: TRANS-2-(1-(cyclopropylmethyl)-8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)acetamide (INT-1363)
  • A mixture of TRANS-(1-cyclopropylmethyl-8-dimethylamino-2-oxo-8-phenyl-1,3-diaza-spiro[4.5]dec-3-yl)-acetic acid tert-butyl ester (250 mg, 0.56 mmol, 1.0 eq.) and 7M NH3 in MeOH (5 mL) was heated in sealed tube at 90° C. for 16 h, then cooled down to RT and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel basified with aq. NH3; 10% MeOH in DCM) to yield 2-(1-cyclopropylmethyl-8-dimethylamino-2-oxo-8-phenyl-1,3-diaza-spiro[4.5]dec-3-yl)-acetamide (77 mg, 0.2 mmol, 35%) as a white solid. LC-MS: m/z [M+1]+=385.2 (MW calc. 384.52); 1H NMR at 100° C. (DMSO-d6, 400 MHz), δ (ppm)=7.40-7.29 (m, 5H), 6.76 (bs, 2H), 3.68 (s, 2H), 3.33 (s, 2H), 2.61-2.60 (m, 4H), 2.00 (s, 6H), 1.61-0.153 (m, 6H), 0.58-0.56 (m, 1H), 0.22-0.20 (m, 2H), (−0.16)-(−0.18) (m, 2H).
  • For further exemplary compounds the last synthesis step in analogy to previously described methods is given in the following table. The syntheses of the building blocks and intermediates have either been described previously within this application or can be performed in analogy to the herein described methods or by methods known to the person, skilled in the art. Such a person will also know which building blocks and intermediates need to be chosen for synthesis of each exemplary compound.
  •
    in analogy m/z
    Example Chemical Name Reactant I Reactant II to method [M + H]+
    SC_1001 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 2,5,8,11,14,17,20- SC_1308 721.5
    8-dimethylamino-2-oxo-8- heptaoxadocosan-22-amine
    phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-
    [2-[2-[2-[2-[2-[2-(2-methoxy-
    ethoxy)-ethoxy]-ethoxy]-
    ethoxy]-ethoxy]-ethoxy]-ethyl]-
    acetamide
    SC_1002 CIS-6-[[2-[1-(Cyclobutyl- INT 993 methyl SC_1308 534.3
    methyl)-8-dimethylamino-2- 6-aminopicolinate
    oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-
    acetyl]amino]-pyridine-2-
    carboxylic acid methyl ester
    SC_1003 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 (R)-2-aminopropan-1-ol SC_1308 457.3
    8-dimethylamino-2-oxo-8-
    phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-
    [(1R)-2-hydroxy-1-methyl-
    ethyl]-acetamide
    SC_1004 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 (S)-2-aminopropan-1-ol SC_1308 457.3
    8-dimethylamino-2-oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-
    [(1S)-2-hydroxy-1-methyl-
    ethyl]-acetamide
    SC_1005 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 N-methyl-2- SC_1308 484.3
    8-dimethylamino-2-oxo-8- (methylamino)acetamide
    phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-
    methyl-N-(methylcarbamoyl-
    methyl)-acetamide
    SC_1006 CIS-6-[[2-[1-(Cyclobutyl- INT 993 methyl SC_1308 534.3
    methyl)-8-dimethylamino-2- 6-aminonicotinate
    oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-
    acetyl]amino]-nicotinic acid
    methyl ester
    SC_1007 CIS-2-[[2-[1-(Cyclobutyl- INT 993 2-methyl-2- SC_1308 498.3
    methyl)-8-dimethylamino-2- (methylamino)propanamide
    oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-
    acetyl]-methyl-amino]-2-
    methyl-propionamide
    SC_1008 CIS-2-[[2-[1-(Cyclobutyl- INT 993 2-amino-N,2- SC_1308 498.3
    methyl)-8-dimethylamino-2- dimethylpropanamide
    oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-
    acetyl]amino]-N,2-dimethyl-
    propionamide
    SC_1009 CIS-2-[[2-[1-(Cyclobutyl- INT 993 N,2-dimethyl-2- SC_1308 512.4
    methyl)-8-dimethylamino-2- (methylamino)propanamide
    oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-
    acetyl]-methyl-amino]-N,2-
    dimethyl-propionamide
    SC_1010 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 N,N-dimethyl-2- SC_1308 498.3
    8-dimethylamino-2-oxo-8- (methylamino)acetamide
    phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-
    [(dimethyl-carbamoyl)-methyl]-
    N-methyl-acetamide
    SC_1011 CIS-2-[[2-[1-(Cyclobutyl- INT 993 2-amino-2- SC_1308 484.3
    methyl)-8-dimethylamino-2- methylpropanamide
    oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-
    acetyl]amino]-2-methyl-
    propionamide
    SC_1012 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 5-methoxypyridin- SC_1308 506.3
    8-dimethylamino-2-oxo-8-phenyl-1,3- 2-amine
    diazaspiro[4.5]decan-3-yl]-N-
    (5-methoxy-pyridin-2-yl)-
    acetamide
    SC_1013 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 6-methoxypyridin- SC_1308 506.3
    8-dimethylamino-2-oxo-8- 2-amine
    phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-
    (6-methoxy-pyridin-2-yl)-
    acetamide
    SC_1014 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 4-methoxypyridin- SC_1308 506.3
    8-dimethylamino-2-oxo-8- 2-amine
    phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-
    (4-methoxy-pyridin-2-yl)-
    acetamide
    SC_1015 CIS-6-[[2-[1-(Cyclobutyl- INT 999 6-amino-N- SC_1073 533.3
    methyl)-8-dimethylamino-2- methylpicolinamide
    oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-
    acetyl]amino]-N-methyl-
    pyridine-2-carboxylic acid
    amide
    SC_1016 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 cis-3- SC_1308 483.3
    8-dimethylamino-2-oxo-8- (aminomethyl)cyclobutanol
    phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-
    [(3-hydroxy-cyclobutyl)-
    methyl]-acetamide
    SC_1017 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 trans-3- SC_1308 483.3
    8-dimethylamino-2-oxo-8- (aminomethyl)cyclobutanol
    phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-
    [(3-hydroxy-cyclobutyl)-
    methyl]-acetamide
    SC_1018 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 1- SC_1308 469.3
    8-dimethylamino-2-oxo-8- (aminomethyl)cyclopropanol
    phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-
    [(1-hydroxy-cyclopropyl)-
    methyl]-acetamide
    SC_1019 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 3-amino-1- SC_1308 540.3
    8-dimethylamino-2-oxo-8- morpholinopropan-1-one
    phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-
    (3-morpholin-4-yl-3-oxo-
    propyl)-acetamide
    SC_1020 CIS-N-(1-Cyano-cyclopropyl)- INT 993 1- SC_1308 464.3
    2-[1-(cyclobutyl-methyl)-8- aminocyclopropane-
    dimethylamino-2-oxo-8-phenyl- carbonitrile
    1,3-diazaspiro[4.5]decan-3-yl]-
    acetamide
    SC_1021 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 3- SC_1308 497.3
    8-dimethylamino-2-oxo-8- (aminomethyl)cyclopentanol
    phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-
    [(3-hydroxy-cyclopentyl)-
    methyl]-acetamide
    SC_1022 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 (1R)-2- SC_1308 511.4
    8-dimethylamino-2-oxo-8- (aminomethyl)cyclohexanol
    phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-
    [[(2R)-2-hydroxy-cyclohexyl]-
    methyl]-acetamide
    SC_1023 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 2,5,8,11-tetraoxatridecan- SC_1308 589.4
    8-dimethylamino-2-oxo-8- 13-amine
    phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-
    [2-[2-[2-(2-methoxy-ethoxy)-
    ethoxy]-ethoxy]-ethyl]-
    acetamide
    SC_1024 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 1- SC_1308 511.4
    8-dimethylamino-2-oxo-8- (aminomethyl)cyclohexanol
    phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-
    [(1-hydroxy-cyclohexyl)-
    methyl]-acetamide
    SC_1025 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 2,5,8,11,14- SC_1308 633.4
    8-dimethylamino-2-oxo-8- pentaoxahexadecan-16-
    phenyl-1,3- amine
    diazaspiro[4.5]decan-3-yl]-N-
    [2-[2-[2-[2-(2-methoxy-ethoxy)-
    ethoxy]-ethoxy]-ethoxy]-ethyl]-
    acetamide
    SC_1026 CIS-N-(6-Cyano-pyridin-2-yl)- INT 993 6-aminopicolinonitrile SC_1308 501.3
    2-[1-(cyclobutyl-methyl)-8-
    dimethylamino-2-oxo-8-phenyl-
    1,3-diazaspiro[4.5]decan-3-yl]-
    acetamide
    SC_1027 CIS-2-[[2-[1-(Cyclobutyl- INT 993 methyl SC_1308 534.3
    methyl)-8-dimethylamino-2- 2-aminonicotinate
    oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-
    acetyl]amino]-nicotinic acid
    methyl ester
    SC_1028 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 3-methoxypyridin- SC_1308 506.3
    8-dimethylamino-2-oxo-8- 2-amine
    phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-
    (3-methoxy-pyridin-2-yl)-
    acetamide
    SC_1029 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 2,5,8,11,14,17- SC_1308 677.4
    8-dimethylamino-2-oxo-8- hexaoxanonadecan-19-
    phenyl-1,3- amine
    diazaspiro[4.5]decan-3-yl]-N-
    [2-[2-[2-[2-[2-(2-methoxy-
    ethoxy)-ethoxy]-ethoxy]-
    ethoxy]-ethoxy]-ethyl]-
    acetamide
    SC_1030 CIS-N-(4-Cyano-pyridin-2-yl)- INT 993 2-aminoisonicotinonitrile SC_1308 501.3
    2-[1-(cyclobutyl-methyl)-8-
    dimethylamino-2-oxo-8-phenyl-
    1,3-diazaspiro[4.5]decan-3-yl]-
    acetamide
    SC_1031 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 5-methoxypyrimidin-2- SC 1308 507.3
    8-dimethylamino-2-oxo-8- amine
    phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-
    (5-methoxy-pyrimidin-2-yl)-
    acetamide
    SC_1032 CIS-2-[[2-[1-(Cyclobutyl- INT 993 methyl SC_1308 534.3
    methyl)-8-dimethylamino-2- 2-aminoisonicotinate
    oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-
    acetyl]amino]-isonicotinic acid
    methyl ester
    SC_1033 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 2-methoxypyridin- SC_1051 506.3
    8-dimethylamino-2-oxo-8- 4-amine
    phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-
    (2-methoxy-pyridin-4-yl)-
    acetamide
    SC_1034 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 6-fluoropyridin- SC_1051 494.3
    8-dimethylamino-2-oxo-8- 3-amine
    phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-
    (6-fluoro-pyridin-3-yl)-
    acetamide
    SC_1035 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 2-methylpyrimidin- SC_1051 491.3
    8-dimethylamino-2-oxo-8-phenyl-1,3- 5-amine
    diazaspiro[4.5]decan-3-yl]-N-
    (2-methyl-pyrimidin-5-yl)-
    acetamide
    SC_1036 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 5-methylpyrimidin- SC_1051 491.3
    8-dimethylamino-2-oxo-8- 2-amine
    phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-
    (5-methyl-pyrimidin-2-yl)-
    acetamide
    SC_1037 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 3-fluoropyridin- SC_1051 494.3
    8-dimethylamino-2-oxo-8- 2-amine
    phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-
    (3-fluoro-pyridin-2-yl)-
    acetamide
    SC_1038 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 3-fluoropyridin- SC_1051 494.3
    8-dimethylamino-2-oxo-8- 4-amine
    phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-
    (3-fluoro-pyridin-4-yl)-
    acetamide
    SC_1039 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 6-methoxypyridin- SC_1051 506.3
    8-dimethylamino-2-oxo-8- 3-amine
    phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-
    (6-methoxy-pyridin-3-yl)-
    acetamide
    SC_1040 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 2-methylpyridin- SC_1051 490.3
    8-dimethylamino-2-oxo-8- 3-amine
    phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-
    (2-methyl-pyridin-3-yl)-
    acetamide
    SC_1041 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 4-methylpyridin- SC_1051 490.3
    8-dimethylamino-2-oxo-8- 3-amine
    phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-
    (4-methyl-pyridin-3-yl)-
    acetamide
    SC_1042 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 3-methylpyridin- SC_1051 490.3
    8-dimethylamino-2-oxo-8- 4-amine
    phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-
    (3-methyl-pyridin-4-yl)-
    acetamide
    SC_1043 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 6-methylpyridin- SC_1051 490.3
    8-dimethylamino-2-oxo-8- 3-amine
    phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-
    (6-methyl-pyridin-3-yl)-
    acetamide
    SC_1044 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 5-fluoropyridin- SC_1051 494.3
    8-dimethylamino-2-oxo-8- 2-amine
    phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-
    (5-fluoro-pyridin-2-yl)-
    acetamide
    SC_1045 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 5-methylpyridin- SC_1051 490.3
    8-dimethylamino-2-oxo-8- 2-amine
    phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-
    (5-methyl-pyridin-2-yl)-
    acetamide
    SC_1046 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 4-methylpyridin- SC_1051 490.3
    8-dimethylamino-2-oxo-8- 2-amine
    phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-
    (4-methyl-pyridin-2-yl)-
    acetamide
    SC_1047 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 3-methylpyridin- SC_1051 490.3
    8-dimethylamino-2-oxo-8- 2-amine
    phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-
    (3-methyl-pyridin-2-yl)-
    acetamide
    SC_1048 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 3-methoxypyridin- SC_1051 506.3
    8-dimethylamino-2-oxo-8- 4-amine
    phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-
    (3-methoxy-pyridin-4-yl)-
    acetamide
    SC_1049 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 6-methoxypyridazin-3- SC_1051 507.3
    8-dimethylamino-2-oxo-8- amine
    phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-
    (6-methoxy-pyridazin-3-yl)-
    acetamide
    SC_1050 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 5-(methylsulfonyl)pyridin- SC_1051 554.3
    8-dimethylamino-2-oxo-8- 2-amine
    phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-
    (5-methylsulfonyl-pyridin-2-yl)-
    acetamide
    SC_1052 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 6-(methylsulfonyl)pyridin- SC_1051 554.3
    8-dimethylamino-2-oxo-8- 3-amine
    phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-
    (6-methylsulfonyl-pyridin-3-yl)-
    acetamide
    SC_1053 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 6-methoxypyrazin- SC_1051 507.3
    8-dimethylamino-2-oxo-8-phenyl-1,3- 2-amine
    diazaspiro[4.5]decan-3-yl]-N-
    (6-methoxy-pyrazin-2-yl)-
    acetamide
    SC_1054 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 4-methoxypyridin- SC_1051 506.3
    8-dimethylamino-2-oxo-8- 2-amine
    phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-
    (4-methoxy-pyridin-2-yl)-
    acetamide
    SC_1055 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 4-methoxypyrimidin- SC_1051 507.3
    8-dimethylamino-2-oxo-8- 2-amine
    phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-
    (4-methoxy-pyrimidin-2-yl)-
    acetamide
    SC_1056 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 oxazol-5- SC_1051 480.3
    8-dimethylamino-2-oxo-8- ylmethanamine
    phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-
    (oxazol-5-yl-methyl)-acetamide
    SC_1057 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 oxazol-2- SC_1051 480.3
    8-dimethylamino-2-oxo-8- ylmethanamine
    phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-
    (oxazol-2-yl-methyl)-acetamide
    SC_1058 CIS-1-(Cyclobutyl-methyl)-3- INT 993 (3S,4S)- SC_1051 499.3
    [2-[(3S,4S)-3,4-dihydroxy- piperidine-3,4-diol
    piperidin-1-yl]-2-oxo-ethyl]-8-
    dimethylamino-8-phenyl-1,3-
    diazaspiro[4.5]decan-2-one
    SC_1059 CIS-1-(Cyclobutyl-methyl)-3- INT 993 (3S,4S)- SC_1051 485.3
    [2-[(3S,4S)-3,4-dihydroxy- pyrrolidine-3,4-diol
    pyrrolidin-1-yl]-2-oxo-ethyl]-8-
    dimethylamino-8-phenyl-1,3-
    diazaspiro[4.5]decan-2-one
    SC_1060 CIS-1-(Cyclobutyl-methyl)-3- INT 993 (3S,4R)- SC_1051 485.3
    [2-[(3S,4R)-3,4-dihydroxy- pyrrolidine-3,4-diol
    pyrrolidin-1-yl]-2-oxo-ethyl]-8-
    dimethylamino-8-phenyl-1,3-
    diazaspiro[4.5]decan-2-one
    SC_1061 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 cyclopropanamine SC_1051 439.3
    8-dimethylamino-2-oxo-8-
    phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-
    cyclopropyl-acetamide
    SC_1062 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 2- SC_1051 457.3
    8-dimethylamino-2-oxo-8- (methylamino)ethanol
    phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-
    (2-hydroxy-ethyl)-N-methyl-
    acetamide
    SC_1063 CIS-1-(Cyclobutyl-methyl)-8- INT 993 piperidin-3-ol SC_1051 483.3
    dimethylamino-3-[2-(3-
    hydroxy-piperidin-1-yl)-2-oxo
    ethyl]-8-phenyl-1,3-
    diazaspiro[4.5]decan-2-one
    SC_1064 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 1- SC_1051 483.3
    8-dimethylamino-2-oxo-8-phenyl-1,3- (aminomethyl)cyclobutanol
    diazaspiro[4.5]decan-3-yl]-N-
    [(1-hydroxy-cyclobutyl)-
    methyl]-acetamide
    SC_1065 CIS-2-[[2-[1-(Cyclobutyl- INT 993 2-amino-N,N- SC_1051 484.3
    methyl)-8-dimethylamino-2- dimethylacetamide
    oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-
    acetyl]amino]-N,N-dimethyl-
    acetamide
    SC_1066 CIS-1-(Cyclobutyl-methyl)-8- INT 993 5,6,7,8-tetrahydro- SC_1051 506.3
    dimethylamino-3-[2-oxo-2- [1,2,4]triazolo[1,5-
    (5,6,7,8-tetrahydro- a]pyrazine
    [1,2,4]triazolo[1,5-a]pyrazin-7-
    yl)-ethyl]-8-phenyl-1,3-
    diazaspiro[4.5]decan-2-one
    SC_1067 CIS-3-[[2-[1-(Cyclobutyl- INT 993 3-amino-N,N- SC_1051 498.3
    methyl)-8-dimethylamino-2- dimethylpropanamide
    oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-
    acetyl]amino]-N,N-dimethyl-
    propionamide
    SC_1068 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 2,5,8,11,14, SC_1308 765.5
    8-dimethylamino-2-oxo-8- 17,20,23-octa-
    phenyl-1,3- oxapentacosan-25-amine
    diazaspiro[4.5]decan-3-yl]-N-
    [2-[2-[2-[2-[2-[2-[2-(2-
    methoxy-ethoxy)-ethoxy]-
    ethoxy]-ethoxy]-ethoxy]-
    ethoxy]-ethoxy]-ethyl]-
    acetamide
    SC_1069 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 4-methoxypyrimidin-5- SC_1308 507.3
    8-dimethylamino-2-oxo-8- amine
    phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-
    (4-methoxy-pyrimidin-5-yl)-
    acetamide
    SC_1070 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 2-methoxypyrimidin-5- SC_1308 507.3
    8-dimethylamino-2-oxo-8- amine
    phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-
    (2-methoxy-pyrimidin-5-yl)-
    acetamide
    SC_1072 CIS-N-(5-Cyano-pyridin-2-yl)- INT 993 6-aminonicotinonitrile SC_1308 501.3
    2-[1-(cyclobutyl-methyl)-8-
    dimethylamino-2-oxo-8-phenyl-
    1,3-diazaspiro[4.5]decan-3-yl]-
    acetamide
    SC_1074 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 5-methoxypyrimidin-4- SC_1308 507.3
    8-dimethylamino-2-oxo-8-phenyl-1,3- amine
    diazaspiro[4.5]decan-3-yl]-N-
    (5-methoxy-pyrimidin-4-yl)-
    acetamide
    SC_1075 CIS-N-(2-Cyano-pyrimidin-5- INT 993 5-aminopyrimidine-2- SC_1308 502.3
    yl)-2-[1-(cyclobutyl-methyl)-8- carbonitrile
    dimethylamino-2-oxo-8-phenyl-
    1,3-diazaspiro[4.5]decan-3-yl]-
    acetamide
    SC_1077 CIS-N-(3-Cyano-pyridin-2-yl)- INT 993 2-aminonicotinonitrile SC_1308 501.3
    2-[1-(cyclobutyl-methyl)-8-
    dimethylamino-2-oxo-8-phenyl-
    1,3-diazaspiro[4.5]decan-3-yl]-
    acetamide
    SC_1078 CIS-2-[[2-[1-(Cyclobutyl- INT 993 2-aminoacetamide SC_1308 456.3
    methyl)-8-dimethylamino-2-
    oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-
    acetyl]amino]-acetamide
    SC_1079 CIS-6-[[2-[1-(Cyclobutyl- SC_1072 — SC_1076 519.3
    methyl)-8-dimethylamino-2-
    oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-
    acetyl]amino]-pyridine-3-
    carboxylic acid amide
    SC_1080 CIS-N-(4-Cyano-pyrimidin-2- INT 993 2-aminopyrimidine-4- SC_1308 502.3
    yl)-2-[1-(cyclobutyl-methyl)-8- carbonitrile
    dimethylamino-2-oxo-8-phenyl-
    1,3-diazaspiro[4.5]decan-3-yl]-
    acetamide
    SC_1081 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 1,3,4-thiadiazol-2-amine SC_1051 483.2
    8-dimethylamino-2-oxo-8-
    phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-
    ([1,3,4]thiadiazol-2-yl)-
    acetamide
    SC_1082 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 thiazol-2-amine SC_1051 482.3
    8-dimethylamino-2-oxo-8-
    phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-
    thiazol-2-yl-acetamide
    SC_1083 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 5-methylisoxazol- SC_1051 480.3
    8-dimethylamino-2-oxo-8- 3-amine
    phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-
    (5-methyl-isoxazol-3-yl)-
    acetamide
    SC_1084 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 isoxazol-3-amine SC_1051 466.3
    8-dimethylamino-2-oxo-8-
    phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-
    isoxazol-3-yl-acetamide
    SC_1085 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 1-methyl-1H-pyrazol- SC_1051 479.3
    8-dimethylamino-2-oxo-8- 3-amine
    phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-
    (1-methyl-1H-pyrazol-3-yl)-
    acetamide
    SC_1086 CIS-N-(4-Cyano-5- INT 993 3-amino-5-(methylthio)-1H- SC_1051 536.3
    methylsulfanyl-1H-pyrazol-3- pyrazole-4-carbonitrile
    yl)-2-[1-(cyclobutyl-methyl)-8-
    dimethylamino-2-oxo-8-phenyl-
    1,3-diazaspiro[4.5]decan-3-yl]-
    acetamide
    SC_1087 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 5-methoxypyrazin- SC_1051 507.3
    8-dimethylamino-2-oxo-8- 2-amine
    phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-
    (5-methoxy-pyrazin-2-yl)-
    acetamide
    SC_1088 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 pyridazin-4- SC_1051 491.3
    8-dimethylamino-2-oxo-8- ylmethanamine
    phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-
    (pyridazin-4-yl-methyl)-
    acetamide
    SC_1089 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 2-(aminomethyl)phenol SC_1051 505.3
    8-dimethylamino-2-oxo-8-
    phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-
    [(2-hydroxyphenyl)-methyl]-
    acetamide
    SC_1090 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 (1-methyl-1H-imidazol- SC_1051 493.3
    8-dimethylamino-2-oxo-8- 4-yl)methanamine
    phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-
    [(1-methyl-1H-imidazol-4-yl)-
    methyl]-acetamide
    SC_1091 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 (4-methylpyridin-3- SC_1051 504.3
    8-dimethylamino-2-oxo-8- yl)methanamine
    phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-
    [(4-methyl-pyridin-3-yl)-
    methyl]-acetamide
    SC_1092 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 pyrimidin-2- SC_1051 491.3
    8-dimethylamino-2-oxo-8-phenyl-1,3- ylmethanamine
    diazaspiro[4.5]decan-3-yl]-N-
    (pyrimidin-2-yl-methyl)-
    acetamide
    SC_1093 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 pyridazin-3- SC_1051 491.3
    8-dimethylamino-2-oxo-8-phenyl-1,3- ylmethanamine
    diazaspiro[4.5]decan-3-yl]-N-
    (pyridazin-3-yl-methyl)-
    acetamide
    SC_1094 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 pyrimidin-4- SC_1051 491.3
    8-dimethylamino-2-oxo-8- ylmethanamine
    phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-
    (pyrimidin-4-yl-methyl)-
    acetamide
    SC_1095 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 pyrazin-2- SC_1051 491.3
    8-dimethylamino-2-oxo-8- ylmethanamine
    phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-
    (pyrazin-2-yl-methyl)-acetamide
    SC_1096 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 oxazol-4- SC_1051 480.3
    8-dimethylamino-2-oxo-8- ylmethanamine
    phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-
    (oxazol-4-yl-methyl)-acetamide
    SC_1097 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 (2-methylpyridin-3- SC_1051 504.3
    8-dimethylamino-2-oxo-8- yl)methanamine
    phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-
    [(2-methyl-pyridin-3-yl)-
    methyl]-acetamide
    SC_1098 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 (2-methoxypyridin-3- SC_1051 520.3
    8-dimethylamino-2-oxo-8-phenyl-1,3- yl)methanamine
    diazaspiro[4.5]decan-3-yl]-N-
    [(2-methoxy-pyridin-3-yl)-
    methyl]-acetamide
    SC_1099 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 (4-methoxypyridin-3- SC_1051 520.3
    8-dimethylamino-2-oxo-8- yl)methanamine
    phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-
    [(4-methoxy-pyridin-3-yl)-
    methyl]-acetamide
    SC_1100 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 (6-methylpyridin-2- SC_1051 504.3
    8-dimethylamino-2-oxo-8- yl)methanamine
    phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-
    [(6-methyl-pyridin-2-yl)-
    methyl]-acetamide
    SC_1101 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 (6-methoxypyridin-2- SC_1051 520.3
    8-dimethylamino-2-oxo-8- yl)methanamine
    phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-
    [(6-methoxy-pyridin-2-yl)-
    methyl]-acetamide
    SC_1102 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 (2- SC_1051 519.3
    8-dimethylamino-2-oxo-8- methoxyphenyl)methanamine
    phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-
    [(2-methoxyphenyl)-methyl]-
    acetamide
    SC_1103 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 o-tolylmethanamine SC_1051 503.3
    8-dimethylamino-2-oxo-8-
    phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-
    (o-tolyl-methyl)-acetamide
    SC_1104 CIS-6-[[2-[1-(Cyclobutyl- INT 999 6-amino-N- SC_1073 533.3
    methyl)-8-dimethylamino-2- methylnicotinamide
    oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-
    acetyl]amino]-N-methyl-
    pyridine-3-carboxylic acid
    amide
    SC_1105 CIS-2-[[2-[1-(Cyclobutyl- SC 1030 — SC_1076 519.3
    methyl)-8-dimethylamino-2-
    oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-
    acetyl]amino]-pyridine-4-
    carboxylic acid amide
    SC_1106 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 6-methoxypyrimidin- SC_1308 507.3
    8-dimethylamino-2-oxo-8- 4-amine
    phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-
    (6-methoxy-pyrimidin-4-yl)-
    acetamide
    SC_1107 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 2-methoxypyrimidin- SC_1308 507.3
    8-dimethylamino-2-oxo-8- 4-amine
    phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-
    (2-methoxy-pyrimidin-4-yl)-
    acetamide
    SC_1109 CIS-2-[1-(Cyclobutyl-methyl)- SC 1069 SC_1110 493.3
    8-dimethylamino-2-oxo-8-
    phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-
    (4-hydroxy-pyrimidin-5-yl)-
    acetamide
    SC_1111 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 6-aminopyridin-3-ol SC_1308 492.3
    8-dimethylamino-2-oxo-8-
    phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-
    (5-hydroxy-pyridin-2-yl)-
    acetamide
    SC_1112 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 4-aminotetrahydro-2H- SC_1308 531.3
    8-dimethylamino-2-oxo-8- thiopyran 1,1-dioxide
    phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-
    (1,1-dioxo-thian-4-yl)-
    acetamide
    SC_1113 CIS-1-(Cyclobutyl-methyl)-8- INT 993 thiomorpholine SC_1308 517.3
    dimethylamino-3-[2-(1,1-dioxo- 1,1-dioxide
    [1,4]thiazinan-4-yl)-2-oxo-
    ethyl]-8-phenyl-1,3-
    diazaspiro[4.5]decan-2-one
    SC_1114 CIS-2-[8-Dimethylamino-1-(2- INT 997 pyrimidin-4-amine SC_1308 467.3
    methoxy-ethyl)-2-oxo-8-phenyl-
    1,3-diazaspiro[4.5]decan-3-yl]-
    N-pyrimidin-4-yl-acetamide
    SC_1115 CIS-2-[8-Dimethylamino-1-(2- INT 997 methylamine SC_1308 403.3
    methoxy-ethyl)-2-oxo-8-phenyl-
    1,3-diazaspiro[4.5]decan-3-yl]-
    N-methyl-acetamide
    SC_1117 CIS-N-(5-Cyano-pyrimidin-4- INT 993 4-aminopyrimidine-5- SC_1308 502.3
    yl)-2-[1-(cyclobutyl-methyl)-8- carbonitrile
    dimethylamino-2-oxo-8-phenyl-
    1,3-diazaspiro[4.5]decan-3-yl]-
    acetamide
    SC_1118 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 5-(methylthio)pyridin- SC_1308 522.3
    8-dimethylamino-2-oxo-8- 2-amine
    phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-
    (5-methylsulfanyl-pyridin-2-yl)-
    acetamide
    SC_1119 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 4-methoxypyrimidin- SC_1308 507.3
    8-dimethylamino-2-oxo-8- 2-amine
    phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-
    (4-methoxy-pyrimidin-2-yl)-
    acetamide
    SC_1120 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 6-(methylthio)pyridin- SC_1308 522.3
    8-dimethylamino-2-oxo-8- 2-amine
    phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-
    (6-methylsulfanyl-pyridin-2-yl)-
    acetamide
    SC_1121 CIS-2-[8-Dimethylamino-1-(2- INT 997 2-aminoethanol SC_1308 433.3
    methoxy-ethyl)-2-oxo-8-phenyl-
    1,3-diazaspiro[4.5]decan-3-yl]-
    N-(2-hydroxy-ethyl)-acetamide
    SC_1122 CIS-2-[[2-[8-Dimethylamino-1- INT 997 2-aminoacetamide SC_1308 446.3
    (2-methoxy-ethyl)-2-oxo-8-
    phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-
    aoetyl]amino]-acetamide
    SC_1123 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 methylamine SC_1308 413.3
    8-dimethylamino-2-oxo-8-
    phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-
    methyl-acetamide
    SC_1124 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 2-aminoethanol SC_1308 443.3
    8-dimethylamino-2-oxo-8-
    phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-
    (2-hydroxy-ethyl)-acetamide
    SC_1125 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 6-aminopyridin-2-ol SC_1308 492.3
    8-dimethylamino-2-oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-
    (6-hydroxy-pyridin-2-yl)-
    acetamide
    SC_1126 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 (2-methoxypyrimidin-5- SC_1308 521.3
    8-dimethylamino-2-oxo-8-phenyl-1,3- yl)methanamine
    diazaspiro[4.5]decan-3-yl]-N-
    [(2 methoxy-pyrimidin-5-yl)-
    methyl]-acetamide
    SC_1127 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 (4-methoxypyrimidin-2- SC_1308 521.3
    8-dimethylamino-2-oxo-8- yl)methanamine
    phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-
    [(4-methoxy-pyrimidin-2-yl)-
    methyl]-acetamide
    SC_1130 CIS-2-[[2-[1-(Cyclobutyl- SC 1011 2-amino-2- SC_1303 470.3
    methyl)-8-methylamino-2-oxo- methylpropanamide
    8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-
    acetyl]amino]-2-methyl-
    propionamide
    SC_1131 CIS-2-[[2-[1-(Cyclobutyl- SC 1222 — SC_1303 456.3
    methyl)-8-methylamino-2-oxo-
    8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-
    acetyl]amino]-N-methyl-
    acetamide
    SC_1132 CIS-2-[[2-[1-(Cyclobutyl- SC 1078 — SC_1303 442.3
    methyl)-8-methylamino-2-oxo-
    8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-
    acetyl]amino]-acetamide
    SC_1133 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 2-(2-(2- SC_1308 545.4
    8-dimethylamino-2-oxo-8- methoxyethoxy)ethoxy)-
    phenyl-1,3- ethanamine
    diazaspiro[4.5]decan-3-yl]-N-
    [2-[2-(2-methoxy-ethoxy)-
    ethoxy]-ethyl]-acetamide
    SC_1134 CIS-N-(Carbamoyl-methyl)-2- SC 1146 2-(methylamino)acetamide SC_1303 456.3
    [1-(cyclobutyl-methyl)-8-
    methylamino-2-oxo-8-phenyl-
    1,3-diazaspiro[4.5]decan-3-yl]-
    N-methyl-acetamide
    SC_1135 CIS-2-[1-(Cyclobutyl-methyl)- SC 1005 N-methyl-2- SC_1303 470.3
    8-methylamino-2-oxo-8-phenyl- (methylamino)acetamide
    1,3-diazaspiro[4.5]decan-3-yl]-
    N-methyl-N-(methylcarbamoyl-
    methyl)-acetamide
    SC_1137 CIS-2-[8-Dimethylamino-1-[(1- INT 994 pyrimidin-5-amine SC_1136 493.3
    hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-
    pyrimidin-5-yl-acetamide
    SC_1139 CIS-2-[8-Dimethylamino-1- INT 996 2-aminoethanol SC_1308 460.3
    [(dimethyl-carbamoyl)-methyl]-2-oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-
    (2-hydroxy-ethyl)-acetamide
    SC_1140 CIS-2-[[2-[1-(Cyclobutyl- SC 1007 — SC_1303 484.3
    methyl)-8-methylamino-2-oxo-
    8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-
    acetyl]-methyl-amino]-2-
    methyl-propionamide
    SC_1141 CIS-1-(Cyclobutyl-methyl)-3- SC 1214 — SC_1303 503.3
    [2-(1,1-dioxo-[1,4]thiazinan-4-
    yl)-2-oxo-ethyl]-8-
    methylamino-8-phenyl-1,3-
    diazaspiro[4.5]decan-2-one
    SC_1142 CIS-2-[1-(Cyclobutyl-methyl)- SC 1199 — SC_1303 707.5
    8-methylamino-2-oxo-8-phenyl-
    1,3-diazaspiro[4.5]decan-3-yl]-
    N-[2-[2-[2-[2-[2-[2-(2-methoxy-
    ethoxy)-ethoxy]-ethoxy]-
    ethoxy]-ethoxy]-ethoxy]-ethyl]-
    acetamide
    SC_1143 CIS-2-[[2-[1-(Cyclobutyl- SC 1065 — SC_1303 470.3
    methyl)-8-methylamino-2-oxo-
    8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-
    acetyl]amino]-N,N-dimethyl-
    acetamide
    SC_1144 CIS-2-[1-(Cyclobutyl-methyl)- SC 1070 — SC_1110 493.3
    8-dimethylamino-2-oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-
    (5-hydroxy-pyrimidin-2-yl)-
    acetamide
    SC_1145 CIS-2-[1-(Cyclobutyl-methyl)- SC_1321 — SC_1138 554.3
    8-dimethylamino-2-oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-
    (4-methylsulfonyl-pyridin-2-yl)-
    acetamide
    SC_1146 CIS-2-[[2-[1-(Cyclobutyl- INT 993 2-amino-N- SC_1308 470.3
    methyl)-8-dimethylamino-2- methylacetamide
    oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-
    acetyl]amino]-N-methyl-
    acetamide
    SC_1147 CIS-N-(Carbamoyl-methyl)-2- INT 993 2- SC_1308 470.3
    [1-(cyclobutyl-methyl)-8- (methylamino)acetamide
    dimethylamino-2-oxo-8-phenyl-
    1,3-diazaspiro[4.5]decan-3-yl]-
    N-methyl-acetamide
    SC_1148 CIS-2-(8-Dimethylamino-2- INT 995 methylamine SC_1136 387.3
    oxo-8-phenyl-1-propyl-1,3-
    diazaspiro[4.5]decan-3-yl)-N-
    methyl-acetamide
    SC_1150 CIS-2-[1-(Cyclobutyl-methyl)- SC_1321 — SC_1129 538.3
    8-dimethylamino-2-oxo-8-
    phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-
    [4-(methylsulfinyl)-pyridin-2-
    yl]-acetamide
    SC_1151 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 2-aminopyridin-3-ol SC_1308 492.3
    8-dimethylamino-2-oxo-8-
    phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-
    (3-hydroxy-pyridin-2-yl)-
    acetamide
    SC_1152 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 2- SC_1308 505.3
    8-dimethylamino-2-oxo-8- (methylsulfonyl)ethanamine
    phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-
    (2-methylsulfonyl-ethyl)-
    acetamide
    SC_1154 CIS-1-(Cyclobutyl-methyl)-3- INT 993 (3S,4R)-pyrrolidine- SC_1308 485.3
    [2-[(3S,4R)-3,4-dihydroxy- 3,4-diol
    pyrrolidin-1-yl]-2-oxo-ethyl]-8-
    dimethylamino-8-phenyl-1,3-
    diazaspiro[4.5]decan-2-one
    SC_1155 CIS-2-[1-(Cyclobutyl-methyl)- SC 1198 — SC_1303 429.3
    8-methylamino-2-oxo-8-phenyl-
    1,3-diazaspiro[4.5]decan-3-yl]-
    N-(2-hydroxy-ethyl)-acetamide
    SC_1156 CIS-2-[8-Dimethylamino-1- INT 996 pyrimidin-4-amine SC_1308 494.3
    [(dimethyl-carbamoyl)-methyl]-
    2-oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-
    pyrimidin-4-yl-acetamide
    SC_1157 CIS-2-[8-Dimethylamino-1- INT 996 methylamine SC_1308 430.3
    [(dimethyl-carbamoyl)-methyl]-
    2-oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-
    methyl-acetamide
    SC_1158 CIS-2-[[2-[8-Dimethylamino-1- INT 992 2-aminoacetamide SC_1136 444.3
    (2-methyl-propyl)-2-oxo-8-
    phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-
    acetyl]amino]-acetamide
    SC_1159 CIS-2-[8-Dimethylamino-1-[(1- INT 994 NH4Cl SC_1136 415.3
    hydroxy-cyclobutyl)-methyl]-2-
    oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-
    acetamide
    SC_1160 CIS-2-[8-Dimethylamino-1-[(1- INT 994 methylamine SC_1136 429.3
    hydroxy-cyclobutyl)-methyl]-2-
    oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-
    methyl-acetamide
    SC_1161 CIS-2-[[2-[8-Dimethylamino-1- INT 987 N-(2-amino-2-oxoethyl)- SC_1149 460.3
    (3-methoxy-propyl)-2-oxo-8- 2-bromoacetamide
    phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-
    acetyl]amino]-acetamide
    SC_1162 CIS-2-[8-Dimethylamino-1-(2- INT 984 2-bromo-N- SC_1149 401.3
    methyl-propyl)-2-oxo-8-phenyl- methylacetamide
    1,3-diazaspiro[4.5]decan-3-yl]-
    N-methyl-acetamide
    SC_1163 CIS-1-(Cyclobutyl-methyl)-3- SC 1154 — SC_1303 471.3
    [2-[(3S,4R)-3,4-dihydroxy-
    pyrrolidin-1-yl]-2-oxo-ethyl]-8-
    methylamino-8-phenyl-1,3-
    diazaspiro[4.5]decan-2-one
    SC_1164 CIS-2-[8-Dimethylamino-1-[(1- INT 998 methylamine SC_1308 427.3
    methyl-cyclobutyl)-methyl]-2-
    oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-
    methyl-acetamide
    SC_1165 CIS-2-[8-Dimethylamino-1-[(1- INT 998 pyrimidin-4-amine SC_1308 491.3
    methyl-cyclobutyl)-methyl]-2-
    oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-
    pyrimidin-4-yl-acetamide
    SC_1166 CIS-2-[[2-[8-Dimethylamino-1- INT 998 2-aminoacetamide SC_1308 470.3
    [(1-methyl-cyclobutyl)-methyl]-
    2-oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-
    acetyl]amino]-acetamide
    SC_1167 CIS-2-[8-Dimethylamino-1-[(1- INT 998 2-aminoethanol SC_1308 457.3
    methyl-cyclobutyl)-methyl]-2-
    oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-
    (2-hydroxy-ethyl)-acetamide
    SC_1168 CIS-2-[[2-[1-(Cyclopropyl- INT 983 N-(2-amino-2-oxoethyl)- SC_1149 442.3
    methyl)-8-dimethylamino-2- 2-bromoacetamide
    oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-
    acetyl]amino]-acetamide
    SC_1169 CIS-2-[1-(Cyclobutyl-methyl)- INT 986 2-bromo-N- SC_1149 427.3
    8-(ethyl-methyl-amino)-2-oxo- methylacetamide
    8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-
    methyl-acetamide
    SC_1171 CIS-2-[[2-(8-Dimethylamino-2- INT 995 2-aminoacetamide SC_1308 430.3
    oxo-8-phenyl-1-propyl-1,3-
    diazaspiro[4.5]decan-3-yl)-
    acetyl]amino]-acetamide
    SC_1172 CIS-2-[[2-[8-Dimethylamino-1- INT 994 2-aminoacetamide SC_1308 472.3
    [(1-hydroxy-cyclobutyl)-
    methyl]-2-oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-
    acetyl]amino]-acetamide
    SC_1173 CIS-2-[8-Dimethylamino-1-[(1- INT 994 2-aminoethanol SC_1308 459.3
    hydroxy-cyclobutyl)-methyl]-2-
    oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-
    (2-hydroxy-ethyl)-acetamide
    SC_1174 CIS-2-[8-Dimethylamino-1-[(1- INT 994 4-aminotetrahydro-2H- SC_1308 547.3
    hydroxy-cyclobutyl)-methyl]-2- thiopyran 1,1-dioxide
    oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-
    (1,1-dioxo-thian-4-yl)-
    acetamide
    SC_1175 CIS-2-[1-(Cyclopropyl-methyl)- INT 983 2-bromo-N- SC_1149 399.3
    8-dimethylamino-2-oxo-8- methylacetamide
    phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-
    methyl-acetamide
    SC_1176 CIS-2-[1-[(1-Cyano- INT 951 2-bromo-N- SC_1149 438.3
    cyclobutyl)-methyl]-8- methylacetamide
    dimethylamino-2-oxo-8-phenyl-
    1,3-diazaspiro[4.5]decan-3-yl]-
    N-methyl-acetamide
    SC_1177 CIS-2-[1-(Cyclobutyl-methyl)- INT 998 2-aminoethanol SC_1308 457.3
    8-(ethyl-methyl-amino)-2-oxo-
    8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-
    (2-hydroxy-ethyl)-acetamide
    SC_1178 CIS-2-[[2-[1-(Cyclobutyl- INT 998 2-aminoacetamide SC_1308 470.3
    methyl)-8-(ethyl-methyl-
    amino)-2-oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-
    acetyl]amino]-acetamide
    SC_1179 CIS-2-[[2-[1-(Cyclobutyl- SC 1008 — SC_1303 484.3
    methyl)-8-methylamino-2-oxo-
    8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-
    acetyl]amino]-N,2-dimethyl-
    propionamide
    SC_1180 CIS-2-[8-Dimethylamino-1-(3- INT 990 2-aminoethanol SC_1308 447.3
    methoxy-propyl)-2-oxo-8-
    phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-
    (2-hydroxy-ethyl)-acetamide
    SC_1181 CIS-2-[8-Dimethylamino-1-(3- INT 990 N-methyl-2- SC_1308 488.3
    methoxy-propyl)-2-oxo-8- (methylamino)acetamide
    phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-
    methyl-N-(methylcarbamoyl-
    methyl)-acetamide
    SC_1182 CIS-8-Dimethylamino-1-(3- INT 990 piperazin-2-one SC_1308 486.3
    methoxy-propyl)-3-[2-oxo-2-(3-
    oxo-piperazin-1-yl)-ethyl]-8-phenyl-1,3-
    diazaspiro[4.5]decan-2-one
    SC_1183 CIS-N-(Carbamoyl-methyl)-2- INT 990 2-(methylamino)acetamide SC_1308 474.3
    [8-dimethylamino-1-(3-
    methoxy-propyl)-2-oxo-8-
    phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-
    methyl-acetamide
    SC_1184 CIS-2-[8-Dimethylamino-1-(3- INT 990 cis-3- SC_1073 487.3
    methoxy-propyl)-2-oxo-8- (aminomethyl)cyclobutanol
    phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-
    [(3-hydroxy-cyclobutyl)-
    methyl]-acetamide
    SC_1185 CIS-2-[8-Dimethylamino-1-(3- INT 990 trans-3- SC_1073 487.3
    methoxy-propyl)-2-oxo-8- (aminomethyl)cyclobutanol
    phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-
    [(3-hydroxy-cyclobutyl)-
    methyl]-acetamide
    SC_1186 CIS-2-[8-Dimethylamino-1-(3- INT 990 3- SC_1073 501.3
    methoxy-propyl)-2-oxo-8- (aminomethyl)cyclopentanol
    phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-
    [(3-hydroxy-cyclopentyl)-
    methyl]-acetamide
    SC_1187 CIS-2-[8-Dimethylamino-1-(3- INT 990 pyridazin-4-amine SC_1308 481.3
    methoxy-propyl)-2-oxo-8-
    phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-
    pyridazin-4-yl-acetamide
    SC_1188 CIS-2-[8-Dimethylamino-1-(3- INT 990 6-methoxypyridin- SC_1308 510.3
    methoxy-propyl)-2-oxo-8- 2-amine
    phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-
    (6-methoxy-pyridin-2-yl)-
    acetamide
    SC_1189 CIS-N-(2-Cyanoethyl)-2-[8- INT 990 3- SC_1308 456.3
    dimethylamino-1-(3-methoxy- aminopropanenitrile
    propyl)-2-oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-
    acetamide
    SC_1190 CIS-2-[8-Dimethylamino-1-(3- INT 990 pyrimidin-5-amine SC_1308 481.3
    methoxy-propyl)-2-oxo-8-
    phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-
    pyrimidin-5-yl-acetamide
    SC_1191 CIS-2-[8-Dimethylamino-1-(3- INT 990 pyrimidin-4-amine SC_1308 481.3
    methoxy-propyl)-2-oxo-8-
    phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-
    pyrimidin-4-yl-acetamide
    SC_1192 CIS-2-[1-(Cyclobutyl-methyl)- INT 999 6-methoxypyridin- SC_1073 520.3
    8-(ethyl-methyl-amino)-2-oxo- 2-amine
    8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-
    (6-methoxy-pyridin-2-yl)-
    acetamide
    SC_1193 CIS-2-[8-Dimethylamino-1-[(1- INT 995 pyridin-3-amine SC_1308 492.3
    hydroxy-cyclobutyl)-methyl]-2-
    oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-
    pyridin-3-yl-acetamide
    SC_1195 CIS-2-[1-(Cyclobutyl-methyl)- INT 999 NH4Cl SC_1073 399.3
    8-dimethylamino-2-oxo-8-
    phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-
    acetamide
    SC_1196 CIS-2-[1-(Cyclobutyl-methyl)- INT 999 pyrimidin-4-amine SC_1073 477.3
    8-dimethylamino-2-oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-
    pyrimidin-4-yl-acetamide
    SC_1197 CIS-2-[1-(Cyclobutyl-methyl)- INT 999 2-methoxyethanamine SC_1073 457.3
    8-dimethylamino-2-oxo-8-
    phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-
    (2-methoxy-ethyl)-acetamide
    SC_1198 CIS-2-[1-(Cyclobutyl-methyl)- INT 999 2-aminoethanol SC_1073 443.3
    8-dimethylamino-2-oxo-8-
    phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-
    (2-hydroxy-ethyl)-acetamide
    SC_1199 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 2,5,8,11,14,17,20- SC_1308 721.5
    8-dimethylamino-2-oxo-8- heptaoxadocosan-
    phenyl-1,3- 22-amine
    diazaspiro[4.5]decan-3-yl]-N-
    [2-[2-[2-[2-[2-[2-(2-methoxy-
    ethoxy)-ethoxy]-ethoxy]-
    ethoxy]-ethoxy]-ethoxy]-ethyl]-
    acetamide
    SC_1201 CIS-2-[1-(Cyclobutyl-methyl)- SC 1229 — SC_1303 399.3
    8-methylamino-2-oxo-8-phenyl-
    1,3-diazaspiro[4.5]decan-3-yl]-
    N-methyl-acetamide
    SC_1203 CIS-(2S)-1-[2-[1-(Cyclobutyl- INT 993 (S)-pyrrolidine-2- SC_1308 196.3
    methyl)-8-dimethylamino-2- carboxamide
    oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-
    acetyl]-pyrrolidine-2-carboxylic
    acid amide
    SC_1204 CIS-2-[[2-[1-(Cyclobutyl- INT 993 2-amino-N,N- SC_1308 484.3
    methyl)-8-dimethylamino-2- dimethylacetamide
    oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-
    acetyl]amino]-N,N-dimethyl-
    acetamide
    SC_1205 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 oxetan-3-amine SC_1308 455.3
    8-dimethylamino-2-oxo-8-
    phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-
    (oxetan-3-yl)-acetamide
    SC_1206 CIS-2-[[2-[1-(Cyclobutyl- INT 993 2-aminoacetamide SC_1308 456.3
    methyl)-8-dimethylamino-2-
    oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-
    acetyl]amino]-acetamide
    SC_1207 CIS-1-(Cyclobutyl-methyl)-8- INT 999 piperazin-2-one SC_1073 482.3
    dimethylamino-3-[2-oxo-2-(3-
    oxo-piperazin-1-yl)-ethyl]-8-
    phenyl-1,3-
    diazaspiro[4.5]decan-2-one
    SC_1208 CIS-2-[1-(Cyclobutyl-methyl)- INT 999 4-aminotetrahydro-2H- SC_1073 531.3
    8-dimethylamino-2-oxo-8- thiopyran 1,1-dioxide
    phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-
    (1,1-dioxo-thian-4-yl)-
    acetamide
    SC_1209 CIS-1-(Cyclobutyl-methyl)-8- INT 999 morpholin-2- SC_1073 499.3
    dimethylamino-3-[2-[2- ylmethanol
    (hydroxymethyl)-morpholin-4-
    yl]-2-oxo-ethyl]-8-phenyl-1,3-
    diazaspiro[4.5]decan-2-one
    SC_1210 CIS-N-(Carbamoyl-methyl)-2- INT 993 2- SC_1308 470.3
    [1-(cyclobutyl-methyl)-8- (methylamino)acetamide
    dimethylamino-2-oxo-8-phenyl-
    1,3-diazaspiro[4.5]decan-3-yl]-
    N-methyl-acetamide
    SC_1211 CIS-N-(Cyano-methyl)-2-[1- INT 993 2-aminoacetonitrile SC_1308 438.3
    (cyclobutyl-methyl)-8-
    dimethylamino-2-oxo-8-phenyl-
    1,3-diazaspiro[4.5]decan-3-yl]-
    acetamide
    SC_1212 CIS-N-(2-Acetylamino-ethyl)-2- INT 993 N-(2- SC_1308 484.3
    [1-(cyclobutyl-methyl)-8- aminoethyl)acetamide
    dimethylamino-2-oxo-8-phenyl-
    1,3-diazaspiro[4.5]decan-3-yl]-
    acetamide
    SC_1213 CIS-2-[1-(Cyclobutyl-methyl)- INT 999 2-(methylsulfonyl)ethan- SC_1073 505.3
    8-dimethylamino-2-oxo-8- amine
    phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-
    (2-methylsulfonyl-ethyl)-
    acetamide
    SC_1214 CIS-1-(Cyclobutyl-methyl)-8- INT 999 thiomorpholine SC_1073 517.3
    dimethylamino-3-[2-(1,1-dioxo- 1,1-dioxide
    [1,4]thiazinan-4-yl)-2-oxo-
    ethyl]-8-phenyl-1,3-
    diazaspiro[4.5]decan-2-one
    SC_1215 CIS-2-[1-(Cyclobutyl-methyl)- INT 999 4-(aminomethyl)tetra- SC_1073 545.3
    8-dimethylamino-2-oxo-8- hydro-2H-thiopyran 1,1-
    phenyl-1,3- dioxide
    diazaspiro[4.5]decan-3-yl]-N-
    [(1,1-dioxo-thian-4-yl)-methyl]-
    acetamide
    SC_1216 CIS-1-(Cyclobutyl-methyl)-8- INT 999 1-(methylsulfonyl)- SC_1073 546.3
    dimethylamino-3-[2-(4- piperazine
    methylsulfonyl-piperazin-1-yl)-
    2-oxo-ethyl]-8-phenyl-1,3-
    diazaspiro[4.5]decan-2-one
    SC_1217 CIS-N-(2-Cyanoethyl)-2-[1- INT 993 3-aminopropanenitrile SC_1308 452.3
    (cyclobutyl-methyl)-8-
    dimethylamino-2-oxo-8-phenyl-
    1,3-diazaspiro[4.5]decan-3-yl]-
    acetamide
    SC_1218 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 1-amino-2-methylpropan- SC_1308 471.3
    8-dimethylamino-2-oxo-8- 2-ol
    phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-
    (2-hydroxy-2-methyl-propyl)-
    acetamide
    SC_1219 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 2-amino-1- SC_1308 526.3
    8-dimethylamino-2-oxo-8- morpholinoethanone
    phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-
    (2-morpholin-4-yl-2-oxo-ethyl)-
    acetamide
    SC_1220 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 2-(2-aminoethoxy)ethanol SC_1308 487.3
    8-dimethylamino-2-oxo-8-
    phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-
    [2-(2-hydroxy-ethoxy)-ethyl]-
    acetamide
    SC_1222 CIS-2-[[2-[1-(Cyclobutyl- INT 993 2-amino-N- SC_1308 470.3
    methyl)-8-dimethylamino-2- methylacetamide
    oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-
    acetyl]amino]-N-methyl-
    acetamide
    SC_1223 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 N-(2-aminoethyl)- SC_1308 520.3
    8-dimethylamino-2-oxo-8- methanesulfonamide
    phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-
    [2-(methanesulfonamido)-
    ethyl]-acetamide
    SC_1224 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 1-(aminomethyl)- SC_1308 497.3
    8-dimethylamino-2-oxo-8- cyclopentanol
    phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-
    [(1-hydroxy-cyclopentyl)-
    methyl]-acetamide
    SC_1225 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 4- SC_1308 511.4
    8-dimethylamino-2-oxo-8- (aminomethyl)cyclohexanol
    phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-
    [(4-hydroxy-cyclohexyl)-
    methyl]-acetamide
    SC_1226 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 2-(2-methoxyethoxy)- SC_1308 501.3
    8-dimethylamino-2-oxo-8- ethanamine
    phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-
    [2-(2-methoxy-ethoxy)-ethyl]-
    acetamide
    SC_1227 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 N1,N1-dimethylethane- SC_1308 470.3
    8-dimethylamino-2-oxo-8- 1,2-diamine
    phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-
    [2-(dimethylamino)ethyl]-
    acetamide
    SC_1228 CIS-2-[1-(Cyclobutyl-methyl)- INT 953 2-bromo-N- SC_1149 455.3
    8-[methyl-(2-methyl-propyl)- methylacetamide
    amino]-2-oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-
    methyl-acetamide
    SC_1229 CIS-2-[1-(Cyclobutyl-methyl)- INT 999 methylamine SC_1073 413.3
    8-dimethylamino-2-oxo-8-
    phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-
    methyl-acetamide
    SC_1230 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 pyrimidin-4-amine SC_1051 477.3
    8-dimethylamino-2-oxo-8-
    phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-
    pyrimidin-4-yl-acetamide
    SC_1231 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 6-methylpyridin- SC_1051 490.3
    8-dimethylamino-2-oxo-8- 2-amine
    phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-
    (6-methyl-pyridin-2-yl)-
    acetamide
    SC_1232 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 pyridazin-3-amine SC_1051 477.3
    8-dimethylamino-2-oxo-8-
    phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-
    pyridazin-3-yl-acetamide
    SC_1233 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 pyrimidin-5-amine SC_1051 477.3
    8-dimethylamino-2-oxo-8-
    phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-
    pyrimidin-5-yl-acetamide
    SC_1234 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 pyridazin-4-amine SC_1051 477.3
    8-dimethylamino-2-oxo-8-
    phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-
    pyridazin-4-yl-acetamide
    SC_1235 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 6-methoxypyrimidin- SC_1051 507.3
    8-dimethylamino-2-oxo-8-phenyl-1,3- 4-amine
    diazaspiro[4.5]decan-3-yl]-N-
    (6-methoxy-pyrimidin-4-yl)-
    acetamide
    SC_1236 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 2-methylpyridin- SC_1051 490.3
    8-dimethylamino-2-oxo-8- 4-amine
    phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-
    (2-methyl-pyridin-4-yl)-
    acetamide
    SC_1300 CIS-2-[8-Dimethylamino-1-[(1- INT 994 pyridin-4-amine SC_1308 492.3
    hydroxy-cyclobutyl)-methyl]-2-
    oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-
    pyridin-4-yl-acetamide
    SC_1301 CIS-2-[8-Dimethylamino-1-[(1- INT 994 oxetan-3-amine SC_1308 471.3
    hydroxy-cyclobutyl)-methyl]-2-
    oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-
    (oxetan-3-yl)-acetamide
    SC_1302 CIS-2-[8-Dimethylamino-1-[(1- INT 994 2-methoxyethanamine SC_1308 473.3
    hydroxy-cyclobutyl)-methyl]-2-
    oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-
    (2-methoxy-ethyl)-acetamide
    SC_1304 CIS-2-[1-[(1-Hydroxy- SC 1301 — SC_1303 459.3
    cyclobutyl)-methyl]-8-
    methylamino-2-oxo-8-phenyl-
    1,3-diazaspiro[4.5]decan-3-yl]-
    N-(2-methoxy-ethyl)-acetamide
    SC_1305 CIS-2-[8-Dimethylamino-1-(3- SC 1302 — SC_1308 510.3
    methoxy-propyl)-2-oxo-8-
    phenyl-1,3-
    diazaspiro[4.5] decan-3-yl]-N-
    (4-methoxy-pyridin-2-yl)-
    acetamide
    SC_1306 CIS-2-[8-Dimethylamino-1-(3- INT 990 pyrimidin-4- SC_1073 495.3
    methoxy-propyl)-2-oxo-8- ylmethanamine
    phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-
    (pyrimidin-4-yl-methyl)-
    acetamide
    SC_1309 CIS-2-[8-Dimethylamino-1-[(1- SC 1159 — SC_1128 492.3
    hydroxy-cyclobutyl)-methyl]-2-
    oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-
    pyridin-2-yl-acetamide
    SC_1310 CIS-2-[1-[(1-Cyano- INT 989 NH4Cl SC_1308 424.3
    cyclobutyl)-methyl]-8-
    ditnethylamino-2-oxo-8-phenyl-
    1,3-diazaspiro[4.5]decan-3-yl]-
    acetamide
    SC_1311 CIS-2-[[2-[1-[(1-Cyano- INT 989 2-aminoacetamide SC_1308 481.3
    cyclobutyl)-methyl]-8-
    dimethylamino-2-oxo-8-phenyl-
    1,3-diazaspiro[4.5]decan-3-yl]-
    acetyl]amino]-acetamide
    SC_1312 CIS-2-[1-[(1-Hydroxy- SC 1160 — SC_1303 415.3
    cyclobutyl)-methyl]-8-
    methylamino-2-oxo-8-phenyl-
    1,3-diazaspiro[4.5]decan-3-yl]-
    N-methyl-acetamide
    SC_1313 CIS-3-[2-(1,1-Dioxo- SC 1308 — SC_1303 477.2
    [1,4]thiazinan-4-yl)-2-oxo-
    ethyl]-8-methylamino-8-phenyl-1-propyl-1,3-
    diazaspiro[4.5]decan-2-one
    SC_1317 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 pyridin-2-amine SC_1051 476.3
    8-dimethylamino-2-oxo-8-
    phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-
    pyridin-2-yl-acetamide
    SC_1318 CIS-8-Dimethylamino-1-[(1- INT 994 morpholine SC_1136 485.3
    hydroxy-cyclobutyl)-methyl]-3-
    (2-morpholin-4-yl-2-oxo-ethyl)-
    8-phenyl-1,3-
    diazaspiro[4.5]decan-2-one
    SC_1319 CIS-2-[1-[(1-Hydroxy- SC 1159 — SC_1303 401.2
    cyclobutyl)-methyl]-8-
    methylamino-2-oxo-8-phenyl-
    1,3-diazaspiro[4.5]decan-3-yl]-
    acetamide
    SC_1320 CIS-1-(Cyclobutyl-methyl)-8- INT 993 morpholine SC_1308 469.3
    dimethylamino-3-(2-morpholin-
    4-yl-2-oxo-ethyl)-8-phenyl-1,3-
    diazaspiro[4.5]decan-2-one
    SC_1321 CIS-2-[1-(Cyclobutyl-methyl)- INT 993 4-(methylthio)pyridin- SC_1073 522.3
    8-dimethylamino-2-oxo-8- 2-amine
    phenyl-1,3-
    diazaspiro[4.5]decan-3-yl]-N-
    (4-methylsulfanyl-pyridin-2-yl)-
    acetamide
    in analogy m/z
    Example Chemical name Reactant I Reactant II to method 1H NMR data (M + H)+
    SC_1322 CIS-3-[2-(1,1- INT-1014 thiomorpholin- SC_1308 1HNMR (DMSO-d6, 400 435.3
    Dioxo- 1,1-dioxide (for step 1), MHz), δ (ppm) = 7.40 (d,
    [1,4]thiazinan-4- SC_1303 2H, J = 7.2 Hz), 7.31 (t, 2H,
    yl)-2-oxo-ethyl]- (for step 2) J = 7.44 Hz), 7.18 (t, 1H, J =
    8-methylamino-8- 6.78 Hz), 6.61 (bs, 1H),
    phenyl-1,3- 3.98 (s, 2H), 3.82 (bs, 4H),
    diazaspiro[4.5]decan- 3.21 (bs, 4H), 3.09 (s, 2H),
    2-one 1.95 (t, 2H, J = 11.74 Hz),
    1.85 (bs, 5H), 1.65 (bs, 2H),
    1.48 (bs, 2H).
    SC_1323 CIS-2-(8- SC_1324 SC_1303 1HNMR (DMSO-d6, 400 317.2
    Methylamino-2- MHz), δ (ppm) = 7.41 (d,
    oxo-8-phenyl-1,3- 2H, J = 7.60 Hz), 7.30 (t,
    diazaspiro[4.5]decan- 2H, J = 7.60 Hz), 7.23 (s,
    3-yl)-acetamide 1H), 7.18 (t, 1H, J = 7.08
    Hz), 6.95 (s, 1H), 6.58 (s,
    1H), 3.58 (s, 2H), 3.21 (s,
    2H), 1.96-1.80 (m, 7H),
    1.69-1.66 (m, 2H), 1.47 (d,
    2H, J = 11.76 Hz).
    SC_1324 CIS-2-(8- INT-1014 procedure — 331.2
    Dimethylamino-2- described
    oxo-8-phenyl-1,3-
    diazaspiro[4.5]decan-
    3-yl)-acetamide
    SC_1325 CIS-3-[2-(1,1- INT-1015 thiomorpholin- SC_1308 1HNMR (DMSO-d6, 400 449.4
    Dioxo- 1,1-dioxide (for step 1), MHz), δ (ppm) = 7.42 (d,
    [1,4]thiazinan-4- SC_1303 2H, J = 7.2 Hz), 7.29 (t, 2H,
    yl)-2-oxo-ethyl]- (for step 2) J = 7.2 Hz), 7.17 (t, 1H),
    8-ethylamino-8- 6.61 (s, 1H), 5.75 (s, 1H),
    phenyl-1,3- 3.98 (s, 2H), 3.82 (s, 4H),
    diazaspiro[4.5]decan- 3.21 (s, 4H), 3.09 (s, 2H),
    2-one 2.07-1.93 (m, 4H), 1.87-
    1.83 (m, 2H), 1.69-1.66 (m,
    2H), 1.48-1.45 (m, 2H),
    0.92 (t, 3H, J = 6.8 Hz).
    SC_1326 TRANS-3-[2- INT-1017 thiomorpholin- SC_1308 1HNMR (DMSO-d6, 400 449.2
    (1,1-Dioxo- 1,1-dioxide (for step 1), MHz), δ (ppm) = 7.50 (d,
    [1,4]thiazinan-4- SC_1303 2H, J = 7.4 Hz), 7.30 (t, 2H,
    yl)-2-oxo-ethyl]- (for step 2) J = 7.2 Hz), 7.18-7.15 (m,
    8-ethylamino-8- 2H), 4.00 (s, 2H), 3.84 (bs,
    phenyl-1,3- 4H), 3.24 (s, 2H), 3.19 (s,
    diazaspiro[4.5]decan- 2H), 3.11 (s, 2H), 2.07-
    2-one 1.44(m, 11H), 0.91 (t, 3H, J =
    6.6 Hz).
    SC_1327 CIS-2-[1- INT-998 methylamine SC_1308 1H NMR (DMSO-d6): δ 399.3
    (Cyclobutyl- (step 1) (for step 1), 7.71-7.70 (m, 1H), 7.43 (d,
    methyl)-8- SC_1303 2H), 7.30 (t, 2H), 7.18 (t,
    methylamino-2- (for step 2) 1H), 3.64 (s, 2H), 3.21 (s,
    oxo-8-phenyl-1,3- 2H), 3.08 (d, 2H), 2.57-2.54
    diazaspiro[4.5]decan- (m, 4H), 2.25 (m, 1H),
    3-yl]-N- 2.11-2.06 (m, 2H), 1.97-
    methyl-acetamide 1.82 (m, 7H), 1.80-1.67 (m,
    4H), 1.59 (m, 2H), 1.36-
    1.35 (m, 2H).
    SC_1328 CIS-2-(8- INT-1015 SC_1324 1HNMR (DMSO-d6, 400 331.1
    Ethylamino-2- MHz), δ (ppm) = 7.43 (d,
    oxo-8-phenyl-1,3- 2H, J = 7.6 Hz), 7.29 (t, 2H,
    diazaspiro[4.5]decan- J = 7.2 Hz), 7.22 (s, 1H),
    3-yl)-acetamide 7.17 (t, 1H, J = 6.8 Hz), 6.95
    (s, 1H), 6.58 (s, 1H), 3.58
    (s, 2H), 3.20 (s, 2H),
    2.07-2.05 (m, 2H), 1.93 (t,
    2H, J = 11.2), 1.85-1.82 (m,
    2H), 1.69-1.67 (m, 2H,),
    1.48-1.45 (m, 2H), 0.92 (t,
    3H, J = 6.8 Hz).
    SC_1329 TRANS-2-(8- INT-1017 SC_1324 1HNMR (DMSO-d6, 400 331.2
    Ethylamino-2- MHz), δ (ppm) = 7.49 (d,
    oxo-8-phenyl-1,3- 2H, J = 7.56 Hz), 7.29 (t,
    diazaspiro[4.5]decan- 2H, J = 7.66 Hz), 7.24 (s,
    3-yl)-acetamide 1H), 7.16 (t, 1H), 7.24 Hz),
    7.11 (bs, 1H), 6.98 (bs, 1H),
    3.59 (s, 2H), 3.17 (s, 2H),
    2.09-1.95 (m, 4H).
    SC_1330 CIS-2-(8- INT-1014 2- SC_1308 1HNMR (DMSO-d6, 400 389.2
    Dimethylamino-2- (methylamino)- MHz at 100° C.), δ (ppm) =
    oxo-8-phenyl-1,3- ethanol 7.34-7.23 (m, 5H), 6.41 (s,
    diazaspiro[4.5]decan- 1H), 4.4 (bs, 1H), 3.89 (s,
    3-yl)-N-(2- 2H), 3.53-3.52 (m, 2H),
    hydroxy-ethyl)-N- 3.34 (t, 2H, J = 5.56 Hz),
    methyl-acetamide 3.13 (s, 2H), 2.89 (s, 2H),
    2.31-2.27 (m, 2H), 2.01 (s,
    6H), 1.89-1.78 (m, 4H),
    1.46-1.41 (m, 2H).
    SC_1331 CIS-8- INT-1020 1,4-thiazinane SC_1308 1H NMR (600 MHz, 547.3
    Dimethylamino-3- 1,1-dioxide DMSO) δ 7.35 (qd, 4H),
    [2-(1,1-dioxo- 7.26 (tt, 1H), 4.40 (s, 2H),
    [1,4]thiazinan-4- 3.89 (dt, 4H), 3.26 (t, 2H),
    yl)-2-oxo-ethyl]- 3.11 (d, 2H), 2.64-2.58
    1-[(1-hydroxy- (m, 2H), 2.45 (td, 2H), 2.14
    cyclobutyl)- (tt, 2H), 2.03 (td, 2H), 1.98
    methyl]-8-phenyl-1,3- (s, 6H), 1.97-1.88 (m,
    diazaspiro[4.5]decane- 2H), 1.70-1.63 (m, 1H),
    2,4-dione 1.58-1.47 (m, 3H).
    SC_1332 CIS-2-(8- INT-976 procedure 1H NMR (CDCl3): δ 8.32 407.2
    Dimethylamino-2- described (br s, 1H), 7.50-7.48 (d,
    oxo-8-phenyl-1,3- 2H), 7.39-7.36 (m, 2H),
    diazaspiro[4.5]decan- 7.33-7.26 (m, 5H), 7.12-
    3-yl)-N- 7.08 (t, 1H), 5.90 (br s, 1H),
    phenyl-acetamide 3.90 (s, 2H), 3.25 (s, 2H),
    2.12 (m, 4H), 1.99 (s, 6H),
    1.94-1.91 (m, 2H), 1.58-1.53
    (m, 2H).
    SC_1333 CIS-N- INT-991 2- SC_1308 1HNMR (DMSO-d6, 400 388.3
    (Carbamoyl- methylamino- MHz at 100° C.), δ (ppm) =
    methyl)-2-[1- acetamide•HCl 7.34-7.23 (m, 5H), 6.85 (bs,
    (cyclopropyl- 2H), 3.94 (s, 2H), 3.88 (s,
    methyl)-8- 2H), 3.26 (s, 2H), 3.00-2.99
    dimethylamino-2- (m, 2H), 2.95 (s, 3H), 2.61
    oxo-8-phenyl-1,3- (d, 2H, J = 13.2 Hz), 2.22 (t,
    diazaspiro[4.5]decan- 2H, J = 12 Hz), 2.06 (s, 6H),
    3-yl]-N- 1.47-1.38 (m, 4H), 0.98 (m,
    methyl-acetamide 1H), 0.48 (d, 2H, J = 7.6
    Hz), 0.28 (d, 2H, 4.8 Hz).
    SC_1334 CIS-2-(8- INT-1018 2-Bromo-N- SC_1332 1H NMR (DMSO-d6): δ 421.2
    Dimethylamino- phenylacet- 10.19 (s, 1H), 8.80 (br s, 1H),
    2,4-dioxo-8- amide 7.52-7.520 (d, 2H), 7.42-
    phenyl-1,3- 7.34 (m, 4H), 7.31-7.27 (m,
    diazaspiro[4.5]decan- 3H), 7.06-7.02 (t, 1H), 4.11
    3-yl)-N- (s, 2H), 2.49-2.45 (m, 2H),
    phenyl-acetamide 2.03-1.93 (m, 8H), 1.71-
    1.68 (m, 2H), 1.60-1.54 (m,
    2H).
    SC_1335 CIS-2-[1- INT-998 NH4Cl SC_1308 1H NMR (DMSO-d6): δ 399.3
    (Cyclobutyl- 7.36-7.22 (m, 6H), 6.93 (br
    methyl)-8- s, 1H), 3.61 (s, 2H), 3.18 (s,
    dimethylamino-2- 2H), 3.04 (d, 2H), 2.66-2.63
    oxo-8-phenyl-1,3- (m, 2H), 2.54-2.52 (m, 1H),
    diazaspiro[4.5]decan- 2.07-1.93 (m, 10H), 1.81-
    3-yl]- 1.67 (m, 4H), 1.39-1.29 (m,
    acetamide 4H).
    SC_1336 CIS-2-[8- INT-1019 2,5,8,11- SC_1308 1H NMR (DMSO-d6): δ 605.3
    Dimethylamino-1- tetraoxatridecan- 7.37-7.33 (m, 2H), 7.28-
    [(1-hydroxy- 13-amine 7.26 (m, 3H), 6.67 (t, 1H),
    cyclobutyl)- 6.31 (br, s, 1H), 3.83 (s,
    methyl]-2-oxo-8- 2H), 3.65-3.59 (m, 10H),
    phenyl-1,3- 3.55-3.52 (m, 4H), 3.46-
    diazaspiro[4.5]decan- 3.42 (m, 2H), 3.37 (s, 5H),
    3-yl]-N-[2-[2- 3.29 (s, 2H), 2.68-2.65 (m,
    [2-(2-methoxy- 2H), 2.20-2.06 (m, 12H),
    ethoxy)-ethoxy]- 1.78-1.71 (m, 1H), 1.59-
    ethoxy]-ethyl]- 1.56 (m, 2H), 1.48-1.37 (m,
    acetamide 3H).
    SC_1337 CIS-3-[2-(1,1- SC_1331 SC_1303 1H NMR (600 MHz, 533.3
    Dioxo- DMSO) δ 7.46 (d, 2H), 7.33
    [1,4]thiazinan-4- (t, 2H), 7.21 (t, 1H), 4.42 (s,
    yl)-2-oxo-ethyl]- 2H), 3.90 (dt, 4H), 3.49 (s,
    1-[(1-hydroxy- 2H), 3.28 (t, 2H), 3.12 (t,
    cyclobutyl)- 2H), 2.47 (dd, 2H), 2.35-
    methyl]-8- 2.25 (m, 2H), 2.15-2.08
    methylamino-8- (m, 2H), 1.98-1.89 (m,
    phenyl-1,3- 6H), 1.84 (d, 2H), 1.71-
    diazaspiro[4.5]decane- 1.63 (m, 1H), 1.58-1.48
    2,4-dione (m, 3H).
    SC_1338 CIS-2-(8- INT-976 2-bromo-N- SC_1332 1H NMR (DMSO-d6): δ 521.3
    Dimethylamino-2- (2,5,8,11- 7.78 (t, 1H), 7.37-7.23 (m,
    oxo-8-phenyl-1,3- tetraoxatridecan- 5H), 6.89 (br s, 1H), 3.60
    diazaspiro[4.5]decan- 13-yl)acetamide (s, 2H), 3.49-3.47 (m, 10H),
    3-yl)-N-[2-[2- 3.43-3.37 (m, 4H), 3.22-
    [2-(2-methoxy- 3.17 (m, 5H), 3.08 (s, 2H),
    ethoxy)-ethoxy]- 2.30 (br m, 2H), 1.92-1.74
    ethoxy]-ethyl]- (m, 10H), 1.38 (br m, 2H).
    acetamide
    SC_1339 CIS-N- INT-1034 2- SC_1308 1HNMR (DMSO-d6, 400 388.3
    (Carbamoyl- methylamino- MHz at 100° C.), δ (ppm) =
    methyl)-N- acetamide•HCl 7.43 (d, 2H, J = 7.52 Hz),
    methyl-2-(8- 7.31 (t, 2H, J = 7.44 Hz),
    methylamino-2- 7.18 (t, 1H, J = 7.20 Hz),
    oxo-8-phenyl-1,3- 6.8 (bs, 2H), 3.88 (s, 4H),
    diazaspiro[4.5]decan- 3.25 (s, 2H), 2.95 (3H,
    3-yl)-acetamide merged with DMSO water),
    1.97-1.85 (m, 7H), 1.77-
    1.50 (m, 4H).
    SC_1340 CIS-N- INT-1014 2- SC_1308 1HNMR (DMSO-d6, 400 402.1
    (Carbamoyl- methylamino- MHz at 100° C.), δ (ppm) =
    methyl)-2-(8- acetamide•HCl 7.33-7.23 (m, 5H), 6.84 (bs,
    dimethylamino-2- 2H), 6.45 (s, 1H), 3.87 (s,
    oxo-8-phenyl-1,3- 4H), 3.13 (s, 2H), 2.95 (3H,
    diazaspiro[4.5]decan- merged with DMSO water),
    3-yl)-N- 2.32-2.27 (m, 2H), 2.01 (s,
    methyl-acetamide 6H), 1.88-1.77 (m, 4H),
    1.46-1.41 (m, 2H).
    SC_1341 CIS-N- INT-1035 2- SC_1308 1HNMR (DMSO-d6, 400 472.3
    (Carbamoyl- methylamino- MHz at 100° C.), δ (ppm) =
    methyl)-2-[8- acetamide•HCl 7.33-7.24 (m, 5H), 6.8 (bs,
    dimethylamino-1- 2H), 4.63 (t, 2H, J = 5.6
    (oxetan-3-yl- Hz), 4.39 (s, 2H), 3.93-3.87
    methyl)-2-oxo-8- (m, 4H), 3.36 (d, 2H, J = 6.8
    phenyl-1,3- Hz), 3.24 (m, 3H), 2.95 (s,
    diazaspiro[4.5]decan- 3H), 2.66-2.60 (m, 2H),
    3-yl]-N- 2.06-2.03 (m, 8H), 1.44-
    methyl-acetamide 1.37 (m, 4H).
    CIS-N-(2- INT-1034 2- SC_1308 1HNMR (DMSO-d6, 400 375.0
    SC_1342 Hydroxy-ethyl)- (methylamino)- MHz at 100° C.), δ (ppm) =
    N-methyl-2-(8- ethanol 7.41 (d, 2H, J = 7.48 Hz),
    methylamino-2- 7.31 (t, 2H, J = 7.60 Hz),
    oxo-8-phenyl-1,3- 7.18 (t, 1H), J = 7.18 Hz),
    diazaspiro[4.5]decan- 6.24 (s, 1H), 4.58-4.36 (m,
    3-yl)- 1H), 3.92 (bs, 2H), 3.52 (bs,
    acetamide 2H), 3.34 (t, 2H, J = 5.72
    Hz), 3.24 (s, 2H), 2.96-2.84
    (m, 3H), 1.97-1.84 (m, 7H),
    1.74-1.49 (m, 4H).
    SC_1343 CIS-2-[1- INT-991 ammonium SC_1308 1H NMR (DMSO d6): δ 385.3
    (Cyclopropyl- chloride 7.34-7.25 (m, 6H), 6.96 (s,
    methyl)-8- 1H), 3.63 (s, 2H), 3.22 (m,
    dimethylamino-2- 2H), 2.93 (d, 2H), 2.67-2.64
    oxo-8-phenyl-1,3- (m, 2H), 2.16 (t, 2H), 1.97
    diazaspiro[4.5]decan- (s, 6H), 1.43-1.31 (m, 4H),
    3-yl]- 0.93 (m, 1H), 0.46-0.45 (m,
    acetamide 2H), 0.26 (m, 2H).
    SC_1344 CIS-2-[1- INT-991 2- SC_1308 1H NMR (DMSO d6): δ 429.3
    (Cyclopropyl- aminoethanol 7.77-7.75 (m, 1H), 7.36-
    methyl)-8- 7.33 (m, 4H), 7.26-7.23 (m,
    dimethylamino-2- 1H), 4.65-4.63 (m, 1H),
    oxo-8-phenyl-1,3- 3.67 (s, 2H), 3.39-3.35 (m,
    diazaspiro[4.5]decan- 2H), 3.21 (s, 2H), 3.12-3.09
    3-yl]-N-(2- (m, 2H), 2.94-2.93 (m, 2H),
    hydroxy-ethyl)- 2.67-2.64 (m, 2H), 2.19-
    acetamide 2.14 (t, 2H), 1.97 (s, 6H),
    1.42-1.31 (m, 4H), 0.93-
    0.92 (s, 1H), 0.48-0.44 (m,
    2H), 0.27-0.25 (m, 2H).
    SC_1345 CIS-2-[1- INT-1032 2- SC_1308 1H NMR (600 MHz, 475.3
    (Cyclobutyl- (methylamino)- DMSO) δ 7.39 (td, 1H),
    methyl)-8- ethanol 7.16 (dd, 1H), 7.13 (dt, 2H),
    dimethylamino-8- 7.08 (td, 1H), 3.99 (s, 1H),
    (3-fluorophenyl)- 3.91 (s, 1H), 3.52 (q, 1H),
    2-oxo-1,3- 3.45 (d, 1H), 3.40-3.36
    diazaspiro[4.5]decan- (m, 0H), 3.34-3.28 (m,
    3-yl]-N-(2- 2H), 3.19 (d, 2H), 3.05 (dd,
    hydroxy-ethyl)-N- 2H), 2.96 (s, 2H), 2.80 (s,
    methyl-acetamide 2H), 2.66-2.60 (m, 3H),
    2.07-1.93 (m, 3H), 1.99
    (s, 7H), 1.85-1.74 (m,
    2H), 1.75-1.65 (m, 3H),
    1.40-1.28 (m, 5H).
    SC_1346 CIS-2-[1- INT-1031 tert-butyl- procedure 1H NMR (600 MHz, 474.3
    (Cyclobutyl- bromo acetate described DMSO) δ 7.43-7.36 (m,
    methyl)-8- 1H), 7.17 (d, 1H), 7.13 (dt,
    dimethylamino-8- 1H), 7.09 (td, 1H), 3.75 (d,
    (3-fluorophenyl)- 2H), 3.21 (s, 2H), 3.05 (d,
    2-oxo-1,3- 2H), 2.67-2.61 (m, 2H),
    diazaspiro[4.5]decan- 2.08-2.00 (m, 2H), 1.99
    3-yl]-acetic (d, 7H), 1.98-1.93 (m,
    acid tert-butyl 2H), 1.83-1.75 (m, 2H),
    ester 1.75-1.65 (m, 2H), 1.39
    (d, 8H), 1.38-1.29 (m, 5H).
    SC_1347 CIS-2-[1- INT-991 2- SC_1308 1H NMR (DMSO): δ 7.36- 444.3
    (Cyclopropyl- (methylamino)- 7.32 (m, 4H), 7.26-7.23 (m,
    methyl)-8- ethanol 1H), 4.83-4.63 (m, 1H),
    dimethylamino-2- 3.99-3.91 (m, 2H), 3.50-
    oxo-8-phenyl-1,3- 3.44 (m, 2H), 3.32-3.28 (m,
    diazaspiro[4.5]decan- 2H), 3.22-3.20 (m, 2H),
    3-yl]-N-(2- 2.95-2.92 (m, 3H), 2.79 (s,
    hydroxy-ethyl)-N- 2H), 2.67-2.65 (m, 2H),
    methyl-acetamide 2.20-2.15 (m, 2H), 1.97(s,
    6H), 1.42-1.30 (m, 4H),
    0.93-0.90 (s, 1H), 0.47-0.43
    (m, 2H), 0.27-0.25 (m, 2H).
    SC_1348 CIS-2-[1- INT-991 2- SC_1308 1H NMR (DMSO): δ 8.05- 491.3
    (Cyclopropyl- (methyl- 8.02 (m, 1H), 7.37-7.32 (m,
    methyl)-8- sulfonyl)ethanamine 4H), 7.26-7.22 (m, 1H),
    dimethylamino-2- 3.67 (s, 2H), 3.49-3.44 (m,
    oxo-8-phenyl-1,3- 2H), 3.25-3.21 (m, 4H),
    diazaspiro[4.5]decan- 2.98-2.93 (m, 5H), 2.67-
    3-yl]-N-(2- 2.64 (m, 2H), 2.19-2.13 (m,
    methylsulfonyl- 2H), 1.97 (s, 6H), 1.45-1.31
    ethyl)-acetamide (m, 4H), 0.95-0.91 (s, 1H),
    0.48-0.44 (m, 2H), 0.28-
    0.24 (m, 2H).
    SC_1349 CIS-N- INT-1032 2- SC_1308 1H NMR (600 MHz, 488.3
    (Carbamoyl- methylamino- DMSO) δ 7.39 (td, 1H),
    methyl)-2-[1- acetamide 7.31 (s, 1H), 7.19-7.05
    (cyclobutyl- hydrochloride (m, 3H), 6.99 (s, 1H), 4.00-
    methyl)-8- 3.78 (m, 4H), 3.18 (d,
    dimethylamino-8- 2H), 3.07-3.02 (m, 2H),
    (3-fluorophenyl)- 2.94 (s, 2H), 2.76 (s, 1H),
    2-oxo-1,3- 2.66-2.59 (m, 2H), 2.06-
    diazaspiro[4.5]decan- 1.93 (m, 9H), 1.84-1.73
    3-yl]-N- (m, 2H), 1.70 (dt, 2H), 1.43-
    methyl-acetamide 1.28 (m, 4H) (mixture of
    amide rotamers)
    SC_1350 CIS-1-[2-[8- INT-1019 piperidine-4- SC_1308 1H NMR (DMSO d6): δ 526.4
    Dimethylamino-1- carboxamide 7.37-7.25 (m, 6H), 6.77 (s,
    [(1-hydroxy- 1H), 6.02 (s, 1H), 4.26-4.23
    cyclobutyl)- (m, 1H), 4.02-3.91 (m, 2H),
    methyl]-2-oxo-8- 3.79-3.75 (m, 1H), 3.31 (m,
    phenyl-1,3- 2H), 3.10 (s, 2H), 3.00-2.93
    diazaspiro[4.5]decan- (t, 1H), 2.68-2.65 (m, 2H),
    3-yl]-acetyl]- 2.60-2.58 (m, 2H), 2.32-
    piperidine-4- 2.27 (m, 2H), 2.06-2.03 (m,
    carboxylic acid 4H), 1.91-1.83 (m, 8H),
    amide 1.67-1.61 (m, 2H), 1.49-
    1.40 (m, 2H), 1.36-1.30 (m,
    4H).
    SC_1351 CIS-8- INT-1019 4- SC_1308 1H NMR (DMSO d6): δ 561.3
    Dimethylamino-1- (methyl- 7.37-7.23 (m, 5H), 6.00 (s,
    [(1-hydroxy- sulfonyl)piperidine 1H), 4.45-4.41 (m, 1H),
    cyclobutyl)- 4.08-3.91 (m, 3H), 3.17 (s,
    methyl]-3-[2-(4- 3H), 3.10-2.99 (m, 2H),
    methylsulfonyl- 2.92 (s, 3H), 2.73-2.65 (m,
    piperidin-1-yl)-2- 3H), 2.06-1.83 (m, 15H),
    oxo-ethyl]-8- 1.64-1.46 (m, 4H), 1.40-
    phenyl-1,3- 1.30 (m, 4H).
    diazaspiro[4.5]decan-
    2-one
    SC_1352 CIS-2-[1- INT-1032 2- SC_1308 1H NMR (600 MHz, 461.3
    (Cyclobutyl- aminoethanol DMSO) δ 7.73 (t, 1H), 7.39
    methyl)-8- (td, 1H), 7.19-7.05 (m,
    dimethylamino-8- 3H), 4.66 (t, 1H), 3.67 (s,
    (3-fluorophenyl)- 2H), 3.43-3.35 (m, 2H),
    2-oxo-1,3- 3.18 (s, 2H), 3.11 (q, 2H),
    diazaspiro[4.5]decan- 3.05 (d, 2H), 2.65-2.58
    3-yl]-N-(2- (m, 2H), 2.55-2.45 (m,
    hydroxy-ethyl)- 1H), 2.07-1.93 (m, 10H),
    acetamide 1.84-1.73 (m, 2H), 1.74-
    1.64 (m, 2H), 1.41-1.29
    (m, 4H).
    SC_1353 TRANS-2-[1- INT-1067 2- SC_1357 1HNMR at 100° C. (DMSO- 443.1
    (Cyclobutyl- aminoethanol d6, 400 MHz), δ (ppm) =
    methyl)-8- 7.44-7.38 (m, 5H), 7.29 (t,
    dimethylamino-2- 1H, J = 6.48 Hz), 4.29 (bs,
    oxo-8-phenyl-1,3- 1H), 3.69 (s, 2H), 3.48-3.44
    diazaspiro[4.5]decan- (m, 2H), 3.28 (s, 2H), 3.21-
    3-yl]-N-(2- 3.17 (m, 2H), 2.69-2.67(m,
    hydroxy-ethyl)- 2H), 2.58-2.55 (d, 2H, J =
    acetamide 11.6 Hz), 2.19-2.12 (m,
    1H), 1.98 (s, 6H), 1.82-1.74
    (m, 2H), 1.71-1.60 (m, 4H),
    1.58-1.46 (m, 6H).
    SC_1354 TRANS-N- INT-1067 2- SC_1357 1HNMR at 100° C. (DMSO- 470.4
    (Carbamoyl- methylamino- d6, 400 MHz), δ (ppm) =
    methyl)-2-[1- acetamide 7.40-7.28 (m, 5H), 6.87 (bs,
    (cyclobutyl- hydrochloride 2H), 3.94-3.90 (m, 4H),
    methyl)-8- 3.29 (s, 2H), 3.68-3.66 (m,
    dimethylamino-2- 2H), 2.58-2.55 (m, 2H),
    oxo-8-phenyl-1,3- 2.15-2.13 (m, 1H), 1.98 (s,
    diazaspiro[4.5]decan- 6H), 1.77 (bs, 2H), 1.64-
    3-yl]-N- 1.61 (m, 4H), 1.46-1.27 (m,
    methyl-acetamide 6H).
    SC_1355 CIS-8- INT-1019 4- SC_1308 1H NMR (DMSO d6): δ 513.4
    Dimethylamino-1- methylpiperidin- 7.36-7.32 (m, 4H), 7.26-
    [(1-hydroxy- 4-ol 7.23 (m, 1H), 6.02 (s, 1H),
    cyclobutyl)- 4.37 (s, 1H), 3.96-3.95 (m,
    methyl]-3-[2-(4- 2H), 3.90-3.80 (m, 1H),
    hydroxy-4- 3.50-3.40 (m, 1H), 3.30 (m,
    methyl-piperidin- 1H), 3.10 (s, 2H), 3.00-2.93
    1-yl)-2-oxo- (m, 1H), 2.68-2.65 (m, 2H),
    ethyl]-8-phenyl- 2.09-2.04 (m, 4H), 1.97 (s,
    1,3- 6H), 1.90-1.86 (m, 2H),
    diazaspiro[4.5]decan- 1.64-1.61 (m, 1H), 1.48-
    2-one 1.40 (m, 5H), 1.37-1.30 (m,
    4H), 1.22 (m, 2H), 1.11 (s,
    3H).
    SC_1356 CIS-2-[1- INT-1058 2- SC_1308 1H NMR (600 MHz, 461.3
    (Cyclobutyl- aminoethanol DMSO) δ 7.72 (t, 1H), 7.40-
    methyl)-8- 7.33 (m, 2H), 7.15 (t, 2H),
    dimethylamino-8- 4.81 (tdd, 0.15H), 4.65
    (4-fluorophenyl)- (ddq, 0.75H), 3.66 (s, 2H),
    2-oxo-1,3- 3.48 (q), 3.25 (q), 3.17 (s,
    diazaspiro[4.5]decan- 2H), 3.11 (q, 2H), 3.05 (d,
    3-yl]-N-(2- 2H), 2.66-2.60 (m, 2H),
    hydroxy-ethyl)- 2.57-2.47 (m, 1H), 2.06-
    acetamide 1.92 (m, 10H), 1.85-1.73
    (m, 2H), 1.75-1.63 (m,
    2H), 1.40-1.28 (m, 4H).
    Not all signals could be
    intergrated due to overlap
    with solvent peaks; two
    rotamers observed in
    spectrum.
    SC_1357 TRANS-1- INT-1062 morpholine procedure 1HNMR (DMSO-d6, 400 455.1
    (Cyclopropyl- described MHz), δ (ppm) = 7.44-7.29
    methyl)-8- (m, 5H), 3.96 (s, 2H), 3.56
    dimethylamino-3- (bs, 4H), 3.42-3.40 (m, 4H),
    (2-morpholin-4- 3.29 (s, 2H), 2.67 (bs, 2H),
    yl-2-oxo-ethyl)-8- 2.55-2.54 (d, 2H, J = 6.36
    phenyl-1,3- Hz), 1.92 (s, 6H), 1.56-.144
    diazaspiro[4.5]decan- (m, 6H), 0.51-0.48 (m, 1H),
    2-one 0.16-0.14 (m, 2H), (−0.26)-
    (−0.27) (m, 2H).
    SC_1358 TRANS-8- INT-1060 morpholine SC_1357 1HNMR (DMSO-d6, 400 401.3
    Dimethylamino-3- MHz at 100° C.), δ (ppm) =
    (2-morpholin-4- 7.39-7.36 (m, 4H), 7.26-
    yl-2-oxo-ethyl)-8- 7.23 (m, 1H), 6.35 (m, 1H),
    phenyl-1,3- 3.91 (s, 2H), 3.59 (t, 4H, J =
    diazaspiro[4.5]decan- 4.8 Hz), 3.45 (t, 4H, J = 4.8
    2-one Hz), 3.27 (s, 2H), 2.18-2.15
    (m, 2H), 2.0-1.99 (m, 8H),
    1.78-1.73 (m, 2H), 1.48-
    1.43 (m, 2H).
    SC_1359 CIS-2-[1- INT-1058 2- SC_308 1H NMR (600 MHz, 475.3
    (Cyclobutyl- (methylamino)ethanol DMSO) δ 7.37 (dd, 2H),
    methyl)-8- 7.15 (t, 2H), 4.82 (t, 0.2H),
    dimethylamino-8- 4.63 (t, 0.2H), 3.98 (s, 1H),
    (4-fluorophenyl)- 3.91 (s, 1H), 3.51 (q, 1H),
    2-oxo-1,3- 3.45 (q, 1H), 3.37-3.26
    diazaspiro[4.5]decan- (m, 2H), 3.18 (d, 2H), 3.04
    3-yl]-N-(2- (dd, 2H), 2.96 (s, 1H), 2.80
    hydroxy-ethyl)-N- (s, 2H), 2.64 (d, 2H), 2.56-
    methyl-acetamide 2.47 (m, 1H), 2.08-2.00
    (m, 2H), 2.00-1.91 (m,
    8H), 1.79 (ddt, 2H), 1.75-
    1.65 (m, 2H), 1.37 (d, 2H),
    1.31 (td, 2H). Two rotamers
    are observed.
    SC_1360 CIS-N- INT-1058 2- SC_1308 1H NMR (600 MHz, 488.3
    (Carbamoyl- methylamino- DMSO) δ 7.46 (s, 0.4H),
    methyl)-2-[1- acetamide 7.37 (dd, 2H), 7.30 (s,
    (cyclobutyl- hydrochloride 0.6H), 7.20-7.12 (m, 2H),
    methyl)-8- 6.99 (s, 0.6H), 3.97 (s, 1H),
    dimethylamino-8- 3.90 (s, 1H), 3.83 (d, 2H),
    (4-fluorophenyl)- 3.18 (d, 2H), 3.04 (dd, 2H),
    2-oxo-1,3- 2.94 (s, 2H), 2.76 (s, 1H),
    diazaspiro[4.5]decan- 2.67-2.60 (m, 2H), 2.57-
    3-yl]-N- 2.47 (m, 1H), 2.07-1.92
    methyl-acetamide (m, 10H), 1.83-1.74 (m,
    2H), 1.74-1.63 (m, 2H),
    1.40-1.27 (m, 4H). Two
    rotamers are observed.
    SC_1361 CIS-1- INT-991 4- SC_1308 1H NMR (DMSO d6): δ 483.4
    (Cyclopropyl- hydrochloride methylpiperidin- 7.36-7.33 (m, 4H), 7.25-
    methyl)-8- 4-ol 7.23 (m, 1H), 4.37 (s, 1H),
    dimethylamino-3- 3.92-3.84 (m, 3H), 3.48-
    [2-(4-hydroxy-4- 3.46 (m, 1H), 3.25-3.21 (m,
    methyl-piperidin- 3H), 2.99-2.92 (m, 3H),
    1-yl)-2-oxo- 2.67-2.64 (m, 2H), 2.20-
    ethyl]-8-phenyl- 2.15 (t, 2H), 1.97 (s, 6H),
    1,3- 1.44-1.21 (m, 8H), 1.11 (s,
    diazaspiro[4.5]decan- 3H), 0.93-0.92 (m, 1H),
    2-one 0.47-0.45 (m, 2H), 0.44-
    0.43 (m, 2H).
    SC_1362 CIS-1-[2-[1- INT-991 piperidine-4- SC_1308 1H NMR (DMSO): δ 7.34- 496.4
    (Cyclopropyl- hydrochloride carboxamide 7.32 (m, 4H), 7.25-7.24 (m,
    methyl)-8- 2H), 6.77 (s, 1H), 4.21-4.29
    dimethylamino-2- (m, 1H), 3.94-3.86 (m, 2H),
    oxo-8-phenyl-1,3- 3.78 (m, 1H), 3.22 (s, 2H),
    diazaspiro[4.5]decan- 2.96-2.93 (m, 3H), 2.67-
    3-yl]-acetyl]- 2.57 (m, 2H), 2.50 (t, 1H),
    piperidine-4- 2.30 (m, 1H), 2.20-2.15 (m,
    carboxylic acid 2H), 1.97 (s, 6H), 1.69-1.67
    amide (m, 2H), 1.42-1.31 (m, 6H),
    0.92 (m, 1H), 0.47-0.43 (m,
    2H), 0.27-0.24 (m, 2H).
    SC_1363 TRANS-2-[1- INT-1061 t-butyl- procedure 1HNMR at 100° C. (DMSO- 385.2
    (Cyclopropyl- bromoacetate described d6, 400 MHz), δ (ppm) =
    methyl)-8- (step 1), 7N 7.40-7.29 (m, 5H), 6.76 (bs,
    dimethylamino-2- ammonia in 2H), 3.68 (s, 2H), 3.33 (s,
    oxo-8-phenyl-1,3- methanol 2H), 2.61-2.60 (m, 4H),
    diazaspiro[4.5]decan- (step 2) 2.00 (s, 6H), 1.61-.153 (m,
    3-yl]- 6H), 0.58-0.56 (m, 1H),
    acetamide 0.22-0.20 (m, 2H), (−0.16)-
    (−0.18) (m, 2H).
    SC_1364 TRANS-2-[1- INT-1062 methylamine SC_1357 1HNMR at 100° C. (DMSO- 399.2
    (Cyclopropyl- d6, 400 MHz), δ (ppm) =
    methyl)-8- 7.43-7.27 (m, 6H), 3.68 (s,
    dimethylamino-2- 2H), 3.32 (s, 2H), 2.64-2.58
    oxo-8-phenyl-1,3- (m, 7H), 1.99 (s, 6H), 1.66-
    diazaspiro[4.5]decan- .152 (m, 6H), 0.58-0.56 (m,
    3-yl]-N- 1H), 0.23-0.19 (m, 2H),
    methyl-acetamide (−0.15)-(−0.17) (m, 2H).
    SC_1365 TRANS-1- INT-1062 1,4-thiazinane SC_1357 1HNMR at 100° C. (DMSO- 503.3
    (Cyclopropyl- 1,1-dioxide d6, 400 MHz), δ (ppm) =
    methyl)-8- 7.40-7.28 (m, 5H), 4.06 (s,
    dimethylamino-3- 2H), 3.90-3.88 (m, 4H),
    [2-(1,1-dioxo- 3.34 (s, 2H), 3.14 (bs, 4H),
    [1,4]thiazinan-4- 2.66-2.60 (m, 4H), 1.99 (s,
    yl)-2-oxo-ethyl]- 6H), 1.63-.152 (m, 6H),
    8-phenyl-1,3- 0.58-0.56 (m, 1H), 0.23-
    diazaspiro[4.5]decan- 0.20 (m, 2H), (−0.16)-
    2-one (−0.17) (m, 2H).
    SC_1366 CIS-1- INT-991 4- SC_1308 1H NMR (DMSO d6): δ 531.4
    (Cyclopropyl- hydrochloride (methyl- 7.36-7.32 (m, 4H), 7.26-
    methyl)-8- sulfonyl)piperidine 7.23 (m, 1H), 4.40 (m, 1H),
    dimethylamino-3- 4.04-3.88 (m, 3H), 3.31 (m,
    [2-(4- 1H), 3.02 (s, 2H), 2.94 (t,
    methylsulfonyl- 1H), 2.94-2.92 (m, 5H),
    piperidin-1-yl)-2- 2.67-2.50 (m, 3H), 2.20-
    oxo-ethyl]-8- 2.15 (m, 2H), 2.08-1.97 (m,
    phenyl-1,3- 8H), 1.56 (m, 1H), 1.42-
    diazaspiro[4.5]decan- 1.31 (m, 5H), 0.92 (m, 1H),
    2-one 0.47-0.43 (m, 2H), 0.27-
    0.24 (m, 2H).
    SC_1368 CIS-8- INT-1019 1,4-thiazinane SC_1308 1H NMR (600 MHz, 533.3
    Dimethylamino-3- 1,1-dioxide DMSO) δ 7.35 (d, 4H), 7.29-
    [2-(1,1-dioxo- 7.22 (m, 1H), 4.09 (s,
    [1,4]thiazinan-4- 2H), 3.83 (dt, 4H), 3.25-
    yl)-2-oxo-ethyl]- 3.19 (m, 2H), 3.15-3.05
    1-[(1-hydroxy- (m, 4H), 2.72-2.65 (m,
    cyclobutyl)- 2H), 2.12-2.04 (m, 6H),
    methyl]-8-phenyl- 1.99 (s, 6H), 1.88 (dt, 2H),
    1,3- 1.68-1.59 (m, 1H), 1.50
    diazaspiro[4.5]decan- (d, 2H), 1.43-1.29 (m,
    2-one 3H).
    SC_1369 TRANS-2-(8- INT-1060 t-butyl- SC_1363 1HNMR (DMSO-d6, 400 331.2
    Dimethylamino-2- bromoacetate MHz at 100° C.), δ (ppm) =
    oxo-8-phenyl-1,3- (step 1), 7N 7.37-7.24 (m, 5H), 6.74 (bs,
    diazaspiro[4.5]decan- ammonia in 2H), 6.38 (s, 1H), 3.62 (s,
    3-yl)-acetamide methanol 2H), 3.27 (s, 2H), 2.19-2.14
    (step 2) (m, 2H), 2.01-1.96 (m, 8H),
    1.78-1.73 (m, 2H), 1.48-
    1.43 (m, 2H).
    SC_1370 TRANS-8- INT-1060 1,4-thiazinane SC_1357 1HNMR (DMSO-d6, 400 449.2
    Dimethylamino-3- 1,1-dioxide MHz at 100° C.), δ (ppm) =
    [2-(1,1-dioxo- 7.37-7.24 (m, 5H), 6.41 (s,
    [1,4]thiazinan-4- 1H), 4.0 (s, 2H), 3.89 (bs,
    yl)-2-oxo-ethyl]- 4H), 3.28 (s, 2H), 3.14 (bs,
    8-phenyl-1,3- 4H), 2.15 (m, 2H), 1.99 (m,
    diazaspiro[4.5]decan- 8H), 1.78-1.73 (m, 2H),
    2-one 1.48-1.43 (m, 2H).
    SC_1371 CIS-8- INT-1068 t-butyl- SC_1363 413.2
    (dimethylamino)- bromoacetate
    8-phenyl-1-(2,2,2- (step 1), 7N
    trifluoroethyl)-3- ammonia in
    (2- methanol
    (trifluoromethyl)pyrim- (step 2)
    idin-5-yl)-1,3-
    diazaspiro[4.5]decan-
    2-one
    SC_1372 CIS-8- INT-1070 t-butyl- SC_1363
    (dimethylamino)- bromoacetate
    8-phenyl-3-(2- (step 1), 7N
    (trifluoromethyl)pyrim- ammonia in
    idin-5-yl)-1-(3,3,3- methanol
    trifluoropropyl)-1,3- (step 2)
    diazaspiro[4.5]decan-
    2-one
  • Chemical Structure of all Examples
  • Figure US20210179627A1-20210617-C00143
    Figure US20210179627A1-20210617-C00144
    Figure US20210179627A1-20210617-C00145
    Figure US20210179627A1-20210617-C00146
    Figure US20210179627A1-20210617-C00147
    Figure US20210179627A1-20210617-C00148
    Figure US20210179627A1-20210617-C00149
    Figure US20210179627A1-20210617-C00150
    Figure US20210179627A1-20210617-C00151
    Figure US20210179627A1-20210617-C00152
    Figure US20210179627A1-20210617-C00153
    Figure US20210179627A1-20210617-C00154
    Figure US20210179627A1-20210617-C00155
    Figure US20210179627A1-20210617-C00156
    Figure US20210179627A1-20210617-C00157
    Figure US20210179627A1-20210617-C00158
    Figure US20210179627A1-20210617-C00159
    Figure US20210179627A1-20210617-C00160
  • Figure US20210179627A1-20210617-C00161
    Figure US20210179627A1-20210617-C00162
    Figure US20210179627A1-20210617-C00163
    Figure US20210179627A1-20210617-C00164
    Figure US20210179627A1-20210617-C00165
    Figure US20210179627A1-20210617-C00166
    Figure US20210179627A1-20210617-C00167
    Figure US20210179627A1-20210617-C00168
    Figure US20210179627A1-20210617-C00169
    Figure US20210179627A1-20210617-C00170
    Figure US20210179627A1-20210617-C00171
    Figure US20210179627A1-20210617-C00172
    Figure US20210179627A1-20210617-C00173
    Figure US20210179627A1-20210617-C00174
    Figure US20210179627A1-20210617-C00175
    Figure US20210179627A1-20210617-C00176
    Figure US20210179627A1-20210617-C00177
    Figure US20210179627A1-20210617-C00178
    Figure US20210179627A1-20210617-C00179
    Figure US20210179627A1-20210617-C00180
    Figure US20210179627A1-20210617-C00181
    Figure US20210179627A1-20210617-C00182
    Figure US20210179627A1-20210617-C00183
  • Pharmacological Investigations
  • Functional investigation on the human mu-opioid receptor (hMOP), human kappa-opioid receptor (hKOP), human delta-opioid receptor (hDOP), and human nociceptin/orphanin FQ peptide receptor (hNOP)
  • Human Mu-Opioid Peptide (hMOP) Receptor Binding Assay
  • The hMOP receptor binding assay was performed as homogeneous SPA-assay (scintillation proximity assay) using the assay buffer 50 mM TRIS-HCl (pH 7.4) supplemented with 0.052 mg/ml bovine serum albumin (Sigma-Aldrich Co., St. Louis, Mo.). The final assay volume (250 μl/well) included 1 nM of [N-allyl-2,3-3H]naloxone as ligand (PerkinElmer Life Sciences, Inc. Boston, Mass., USA), and either test compound in dilution series or 25 μM unlabeled naloxone for determination of unspecific binding. The test compound was diluted with 25% DMSO in H2O to yield a final 0.5% DMSO concentration, which also served as a respective vehicle control. The assay was started by adding wheat germ agglutinin coated SPA beads (GE Healthcare UK Ltd., Buckinghamshire, UK) which had been preloaded with hMOP receptor membranes (PerkinElmer Life Sciences, Inc. Boston, Mass., USA). After incubation for 90 minutes at RT and centrifugation for 20 minutes at 500 rpm the signal rate was measured by means of a 1450 Microbeta Trilux β-counter (PerkinElmer Life Sciences/Wallac, Turku, Finland). Half-maximal inhibitory concentration (IC50) values reflecting 50% displacement of [3H]naloxone-specific receptor binding were calculated by nonlinear regression analysis and Ki values were calculated by using the Cheng-Prusoff equation, (Cheng and Prusoff, 1973).
  • Human Kappa-Opioid Peptide (hKOP) Receptor Binding Assay
  • The hKOP receptor binding assay is run as homogeneous SPA-assay (scintillation proximity assay) using the assay buffer 50 mM TRIS-HCl (pH 7.4) supplemented with 0.076 mg BSA/ml. The final assay volume of 250 μl per well includes 2 nM of [3H]U69,593 as ligand, and either test compound in dilution series or 100 μM unlabeled naloxone for determination of unspecific binding. The test compound is diluted with 25% DMSO in H2O to yield a final 0.5% DMSO concentration which serves as respective vehicle control, as well. The assays are started by the addition of wheat germ agglutinin coated SPA beads (1 mg SPA beads/250 μl final assay volume per well) which has been preloaded for 15 minutes at room temperature with hKOP receptor membranes (14.8 μg/250 μl final assay volume per well). After short mixing on a mini-shaker, the microtiter plates are covered with a lid and the assay plates are incubated for 90 minutes at room temperature. After this incubation, the microtiter plates are sealed with a topseal and centrifuged for 20 minutes at 500 rpm. The signal rate is measured after a short delay of 5 minutes by means of a 1450 Microbeta Trilux β-counter (PerkinElmer Life Sciences/Wallac. Turku, Finland). Half-maximal inhibitory concentration (IC50) values reflecting 50% displacement of [3H]U69.593-specific receptor binding are calculated by nonlinear regression analysis and Ki values are calculated by using the Cheng-Prusoff equation, (Cheng and Prusoff, 1973).
  • Human Delta-Opioid Peptide (hDOP) Receptor Binding Assay
  • The hDOP receptor binding assay is performed as homogeneous SPA-assay using the assay buffer 50 mM TRIS-HCl, 5 mM MgCl2 (pH 7.4). The final assay volume (250 μl/well) includes 1 nM of [Tyrosyl-3,5-3H]2-D-Ala-deltorphin II as ligand, and either test compound in dilution series or 10 μM unlabeled naloxone for determination of unspecific binding. The test compound is diluted with 25% DMSO in H2O to yield a final 0.5% DMSO concentration which serves as respective vehicle control, as well. The assays are started by the addition of wheat germ agglutinin coated SPA beads (1 mg SPA beads/250 μl final assay volume per well) which has been preloaded for 15 minutes at room temperature with hDOP receptor membranes (15.2 μg/250 μl final assay volume per well). After short mixing on a mini-shaker, the microtiter plates are covered with a lid and the assay plates are incubated for 120 minutes at room temperature and centrifuged for 20 minutes at 500 rpm. The signal rate is measured by means of a 1450 Microbeta Trilux β-counter (PerkinElmer Life Sciences/Wallac. Turku, Finland). Half-maximal inhibitory concentration (IC50) values reflecting 50% displacement of [Tyrosyl-3,5-3H]2-D-Ala-deltorphin II-specific receptor binding are calculated by nonlinear regression analysis and Ki values are calculated by using the Cheng-Prusoff equation, (Cheng and Prusoff, 1973).
  • Human Nociceptin/Orphanin FQ Peptide (hNOP) Receptor Binding Assay
  • The hNOP receptor binding assay was performed as homogeneous SPA-assay (scintillation proximity assay) using the assay buffer 50 mM TRIS-HCl, 10 mM MgCl2, 1 mM EDTA (pH 7.4). The final assay volume (250 μl/well) included 0.5 nM of [leucyl-3H]nociceptin as ligand (PerkinElmer Life Sciences, Inc. Boston, Mass., USA), and either test compound in dilution series or 1 μM unlabeled nociceptin for determination of unspecific binding. The test compound was diluted with 25% DMSO in H2O to yield a final 0.5% DMSO concentration, which also served as a respective vehicle control. The assay was started by adding wheat germ agglutinin coated SPA beads (GE Healthcare UK Ltd., Buckinghamshire, UK) which had been preloaded with hMOP receptor membranes (PerkinElmer Life Sciences, Inc. Boston, Mass., USA). After incubation for 60 minutes at RT and centrifugation for 20 minutes at 500 rpm the signal rate was measured by means of a 1450 Microbeta Trilux β-counter (PerkinElmer Life Sciences/Wallac. Turku, Finland). Half-maximal inhibitory concentration (IC50) values reflecting 50% displacement of [3H]nociceptin-specific receptor binding were calculated by nonlinear regression analysis and Ki values were calculated by using the Cheng-Prusoff equation, (Cheng and Prusoff, 1973).
  • hNOP hMOP
    Example Ki [nM] Ki [nM]
    SC_1001 33 206
    SC_1002 2.1 160
    SC_1003 3.7 102
    SC_1004 3.6 84
    SC_1005 6.3 115.5
    SC_1006 2.2 150
    SC_1007 29.5 190
    SC_1008 5.4 117.5
    SC_1009 17 390
    SC_1010 9.8 175
    SC_1011 9.1 112.5
    SC_1012 1.8 47.5
    SC_1013 1 220
    SC_1014 2.6 175
    SC_1015 1.3 140
    SC_1016 3.1 76.5
    SC_1017 2.6 130
    SC_1018 2.8 106.5
    SC_1019 4.6 170
    SC_1020 2 86
    SC_1021 1.6 94
    SC_1022 2.1 20.5
    SC_1023 13 270
    SC_1024 3.7 26.5
    SC_1025 22 125
    SC_1026 2 67.3
    SC_1027 7.6 55
    SC_1028 4.8 104
    SC_1029 52.3 303.3
    SC_1030 3.1 74.5
    SC_1031 3.6 43
    SC_1032 4.9 69.5
    SC_1033 3.9 75.5
    SC_1034 2.1 47
    SC_1035 1.3 21.5
    SC_1036 2.7 39
    SC_1037 1.8 45
    SC_1038 1.6 41.5
    SC_1039 1.3 34.5
    SC_1040 1.1 15
    SC_1041 1.7 20.5
    SC_1042 1.8 57
    SC_1043 1.1 21.5
    SC_1044 1.7 43
    SC_1045 1.6 44.5
    SC_1046 2.3 54
    SC_1047 2.5 49
    SC_1048 1 43.5
    SC_1049 2.9 48.5
    SC_1050 0.8 40
    SC_1051 1.6 36.5
    SC_1052 1.6 24.5
    SC_1053 2.7 53
    SC_1054 2.6 74.5
    SC_1055 2.5 29
    SC_1056 3.3 10
    SC_1057 1.9 11
    SC_1058 2.9 78
    SC_1059 7.4 45
    SC_1060 5.1 40.5
    SC_1061 2.2 12.6
    SC_1062 2.6 47.5
    SC_1063 1.6 22
    SC_1064 4.2 33
    SC_1065 4.8 26.5
    SC_1066 1.9 23
    SC_1067 7.5 31.5
    SC_1068 68.5 360
    SC_1069 1.4 16.5
    SC_1070 1 13.5
    SC_1071 3.6 38.5
    SC_1072 2.8 62
    SC_1073 3.5 25
    SC_1074 5.9 37
    SC_1075 1.5 19.5
    SC_1076 0.8 72
    SC_1077 1.8 20.5
    SC_1078 1.3 23.3
    SC_1079 1.7 26.2
    SC_1080 6.4 19.5
    SC_1081 1.9 64
    SC_1082 1 81.5
    SC_1083 1.5 44
    SC_1084 1.1 59
    SC_1085 3.8 71
    SC_1086 0.8 16.5
    SC_1087 2.4 28.2
    SC_1088 2 19.5
    SC_1089 1.4 16.5
    SC_1090 3 27.5
    SC_1091 1.3 15.5
    SC_1092 1.8 26.5
    SC_1093 4.2 43
    SC_1094 2.8 10.4
    SC_1095 1.8 12.5
    SC_1096 1.6 12
    SC_1097 1.6 15
    SC_1098 1.5 10
    SC_1099 1.5 4.5
    SC_1100 1 2.3
    SC_1101 3.4 6
    SC_1102 2 4.4
    SC_1103 0.4 7.2
    SC_1104 1.2 23
    SC_1105 4 50.5
    SC_1106 11 122
    SC_1107 1.8 45
    SC_1109 2.8 16
    SC_1110 9.8 31.5
    SC_1111 1.6 30
    SC_1112 1.3 30.5
    SC_1113 0.8 30
    SC_1114 109.5 850
    SC_1115 140 145
    SC_1117 4.1 37.5
    SC_1118 2.4 114.3
    SC_1119 6.5 73.5
    SC_1120 2.9 125
    SC_1121 115 630
    SC_1122 124.5 480
    SC_1123 2.6 24.8
    SC_1124 1.8 33.8
    SC_1125 2.2 23
    SC_1126 3.5 29.5
    SC_1127 2.6 2.7
    SC_1128 1.9 72
    SC_1129 1.7 37.3
    SC_1130 68.5 160
    SC_1131 34.5 215
    SC_1132 23.5 410
    SC_1133 6.4 25.5
    SC_1134 26 140
    SC_1135 73 370
    SC_1136 14 57.5
    SC_1137 5.8 99
    SC_1138 0.9 23.5
    SC_1139 215 515
    SC_1140 51.5 150
    SC_1141 4.8 165
    SC_1142 265 1200
    SC_1143 17 200
    SC_1144 9.8 73.5
    SC_1145 3.4 60.5
    SC_1146 2.2 21.2
    SC_1147 2.6 34.2
    SC_1148 40 18.8
    SC_1149 62 102.5
    SC_1150 4.9 55.5
    SC_1151 1.6 13.5
    SC_1152 0.9 13.7
    SC_1153 1.6 37
    SC_1154 4.5 29
    SC_1155 14.1 114.5
    SC_1156 155 1215
    SC_1157 170 1120
    SC_1158 12.5 144.5
    SC_1159 22.5 81.5
    SC_1160 20 84.5
    SC_1161 60 86
    SC_1162 15.3 47.5
    SC_1163 30.5 119
    SC_1164 8.2 16.5
    SC_1165 5.7 63.5
    SC_1166 17 72.5
    SC_1167 18 92
    SC_1168 37 125
    SC_1169 36.5 370
    SC_1171 43 130
    SC_1172 27.5 106
    SC_1173 38.5 120
    SC_1174 12.9 195
    SC_1175 28.5 9.6
    SC_1176 9 56
    SC_1177 39 660
    SC_1178 16 390
    SC_1179 87.5 180
    SC_1180 80 230
    SC_1181 125 435
    SC_1182 47.5 320
    SC_1183 130 185
    SC_1184 110 153.3
    SC_1185 47 165
    SC_1186 95.5 355
    SC_1187 43 127.5
    SC_1188 9.1 175
    SC_1189 70.5 75.5
    SC_1190 11.2 123.5
    SC_1191 29 150
    SC_1192 17 680
    SC_1193 9.9 41
    SC_1195 4.4 6.2
    SC_1196 2.1 64.8
    SC_1197 5.4 60
    SC_1198 4.9 47
    SC_1199 35 230
    SC_1201 13.3 123.7
    SC_1203 5.2 47.5
    SC_1204 2.5 77.2
    SC_1205 2.2 37
    SC_1206 1.2 61.5
    SC_1207 2.9 38
    SC_1208 1.8 90
    SC_1209 3.2 46
    SC_1210 4.4 83.5
    SC_1211 2.4 18.7
    SC_1212 4.8 37.7
    SC_1213 1.8 31.7
    SC_1214 1 56.7
    SC_1215 3.9 25
    SC_1216 1.2 49
    SC_1217 2.2 25.7
    SC_1218 5.2 59
    SC_1219 4.2 73.7
    SC_1220 4 51
    SC_1221 17 180
    SC_1222 2.6 63
    SC_1223 2.5 43.5
    SC_1224 1.6 15
    SC_1225 1.8 49.5
    SC_1226 2.6 12.5
    SC_1227 4.6 63
    SC_1228 665 1740
    SC_1229 2.8 22.5
    SC_1230 1.5 36.5
    SC_1231 2 51.5
    SC_1232 1.4 32.5
    SC_1233 0.5 26.5
    SC_1234 1.8 53.5
    SC_1236 3.3 83
    SC_1300 13 130
    SC_1301 23 44
    SC_1302 27 66.5
    SC_1303 145 215
    SC_1304 280 400
    SC_1305 19 105.5
    SC_1306 59 45
    SC_1308 22 97
    SC_1309 12.5 100
    SC_1310 8.1 17
    SC_1311 11.5 44
    SC_1312 295 520
    SC_1313 305 1015
    SC_1317 1.4 53.5
    SC_1318 89 960
    SC_1319 4 71
    SC_1320 4 51
    SC_1321 17 180
    SC_1322 6% @1 μM 9% @1 μM
    SC_1323 12% @1 μM  7% @1 μM
    SC_1324 330 6025
    SC_1325 0% @1 μM 5% @1 μM
    SC_1326 0% @1 μM 625
    SC_1327 11 120
    SC_1328 2% @1 μM 6% @1 μM
    SC_1329 0% @1 μM 4% @1 μM
    SC_1330 465 18% @1 μM 
    SC_1331 10 38
    SC_1332 52 1950
    SC_1333 36 300
    SC_1334 195 1605
    SC_1335 2 24
    SC_1336 — —
    SC_1337 23 —
    SC_1338 475 14% @1 μM 
    SC_1339 1110 9% @1 μM
    SC_1340 230 14% @1 μM 
    SC_1341 170 2905
    SC_1342 1140 10% @1 μM 
    SC_1343 12 95
    SC_1344 13 145
    SC_1345 1 185
    SC_1346 2 400
    SC_1347 31 615
    SC_1348 8 97
    SC_1349 1 165
    SC_1350 8 510
    SC_1351 1 235
    SC_1352 1 135
    SC_1353 66 80.5
    SC_1354 465 210
    SC_1355 7 325
    SC_1356 11 86
    SC_1357 100 15.5
    SC_1358 73 51.5
    SC_1359 10 260
    SC_1360 15 180
    SC_1361 13 255
    SC_1362 6 240
    SC_1363 185 225
    SC_1364 230 73.5
    SC_1365 160 4.4
    SC_1366 1 205
    SC_1368 7 360
    SC_1369 465 1805
    SC_1370 100 11
  • Protocol for [35S]GTPγS Functional NOP/MOP/KOP/DOP Assays
  • Cell membrane preparations of CHO-K1 cells transfected with the human MOP receptor (Art.-No. RBHOMM) or the human DOP receptor (Art.-No. RBHODM), and HEK293 cells transfected with the human NOP receptor (Art.-No. RBHORLM) or the human KOP receptor (Art.-No. 6110558) are available from PerkinElmer (Waltham, Mass.). Membranes from CHO-K1 cells transfected with the human nociceptin/orphanin FQ peptide (hNOP) receptor (Art.-No. 93-0264C2, DiscoveRx Corporation, Freemont, Calif.) are also used. [35S]GTPγS (Art.-No. NEG030H; Lot-No. #0112, #0913, #1113 calibrated to 46.25 TBq/mmol) is available from PerkinElmer (Waltham, Mass.).
  • The [35S]GTPγS assays are carried out essentially as described by Gillen et al (2000). They are run as homogeneous scintillation proximity (SPA) assays in microtiter luminescence plates, where each well contains 1.5 mg of WGA-coated SPA-beads. To test the agonistic activity of test compounds on recombinant hNOP, hMOP, hDOP, and hKOP receptor expressing cell membranes from CHO-K1 or HEK293 cells, 10 or 5 μg membrane protein per assay are incubated with 0.4 nM [35S]GTPγS and serial concentrations of receptor-specific agonists in buffer containing 20 mM HEPES pH 7.4, 100 mM NaCl, 10 mM MgCl2, 1 mM EDTA, 1 mM dithiothreitol, 1.28 mM NaN3, and 10 μM GDP for 45 min at room temperature. The microtiter plates are then centrifuged for 10 min at 830 to sediment the SPA beads. The microtiter plates are sealed and the bound radioactivity [cpm] is determined after a delay of 15 min by means of a 1450 Microbeta Trilux (PerkinElmer, Waltham, Mass.).
  • The unstimulated basal binding activity (UBSobs [cpm]) is determined from 12 unstimulated incubates and is set as 100% basal binding. For determination of the potency and the efficacy, the arithmetic mean of the observed total [35S]GTPγS binding (TBobs [cpm]) of all incubates (duplicates) stimulated by the receptor-specific agonists (i.e. N/OFQ, SNC80, DAMGO, or U69,593) are transformed in percent total binding (TBobs [%]) relative to the basal binding activity (i.e. 100% binding). The potency (EC50) of the respective agonist and its maximal achievable total [35S]GTPγS binding (TBcalc [%]) above its calculated basal binding (UBScalc [%]) are determined from its transformed data (TBobs [%]) by means of nonlinear regression analysis with XLfit for each individual concentration series. Then the difference between the calculated unstimulated [35S]GTPγS binding (UBScalc [%]) and the maximal achievable total [35S]GTPγS binding (TBcalc [%]) by each tested agonist is determined (i.e. B1calc [%]). This difference (B1calc [%]) as a measure of the maximal achievable enhancement of [35S]GTPγS binding by a given agonist is used to calculate the relative efficacy of test compounds versus the maximal achievable enhancement by a receptor-specific full agonist, e.g. N/OFQ (B1calc-N/OFQ [%]) which is set as 100% relative efficacy for the hNOP receptor. Likewise, the percentage efficacies of test compounds at the hDOP, hMOP, or hKOP receptor are determined versus the calculated maximal enhancement of [35S]GTPγS binding by the full agonists SNC80 (B1calc-SNC80 [%]), DAMGO (B1calc-DAMGO [%]) and U69,593 (B1calc-U69,593 [%]) which are set as 100% relative efficacy at each receptor, respectively.
  • The foregoing description and examples have been set forth merely to illustrate the invention and are not intended to be limiting. Since modifications of the described embodiments incorporating the spirit and substance of the invention may occur to persons skilled in the art, the invention should be construed broadly to include all variations within the scope of the appended claims and equivalents thereof.

Claims (32)

1. A compound according to general formula (I)
Figure US20210179627A1-20210617-C00184
wherein
R1 and R2 independently of one another mean
—H;
—C1-C6-alkyl, linear or branched, saturated or unsaturated, unsubstituted or substituted with one, two, three or four substituents independently of one another selected from the group consisting of —F, —Cl, —Br, —I, —OH, —OCH3, —CN and —CO2CH3;
a 3-12-membered cycloalkyl moiety, saturated or unsaturated, unsubstituted or substituted with one, two, three or four substituents independently of one another selected from the group consisting of —F, —Cl, —Br, —I, —OH, —OCH3, —CN and —CO2CH3; wherein said 3-12-membered cycloalkyl moiety is optionally connected through —C1-C6-alkylene-, linear or branched, saturated or unsaturated, unsubstituted; or
a 3-12-membered heterocycloalkyl moiety, saturated or unsaturated, unsubstituted or substituted with one, two, three or four substituents independently of one another selected from the group consisting of —F, —Cl, —Br, —I, —OH, —OCH3, —CN and —CO2CH3; wherein said 3-12-membered heterocycloalkyl moiety is optionally connected through —C1-C6-alkylene-, linear or branched, saturated or unsaturated, unsubstituted;
or
R1 and R2 together with the nitrogen atom to which they are attached form a ring and mean —(CH2)3-6—; —(CH2)2—O—(CH2)2—; or —(CH2)2—NRA—(CH2)2—, wherein RA means —H or —C1-C6-alkyl, linear or branched, saturated or unsaturated, unsubstituted or substituted with one, two, three or four substituents independently of one another selected from the group consisting of —F, —Cl, —Br and —I;
R3 means
—C1-C6-alkyl, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted;
a 3-12-membered cycloalkyl moiety, saturated or unsaturated, unsubstituted, mono- or polysubstituted; wherein said 3-12-membered cycloalkyl moiety is optionally connected through —C1-C6-alkylene-, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted;
a 3-12-membered heterocycloalkyl moiety, saturated or unsaturated, unsubstituted, mono- or polysubstituted; wherein said 3-12-membered heterocycloalkyl moiety is optionally connected through —C1-C6-alkylene-, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted;
a 6-14-membered aryl moiety, unsubstituted, mono- or polysubstituted; wherein said 6-14-membered aryl moiety is optionally connected through —C1-C6-alkylene-, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted; or
a 5-14-membered heteroaryl moiety, unsubstituted, mono- or polysubstituted; wherein said 5-14-membered heteroaryl moiety is optionally connected through —C1-C6-alkylene-, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted;
R4 means
—H;
—C1-C6-alkyl, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted; wherein said —C1-C6-alkyl is optionally connected through —C(═O)—, —C(═O)O—, or —S(═O)2—;
a 3-12-membered cycloalkyl moiety, saturated or unsaturated, unsubstituted, mono- or polysubstituted; wherein said 3-12-membered cycloalkyl moiety is optionally connected through —C1-C6-alkylene-, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted; or wherein said 3-12-membered cycloalkyl moiety is optionally connected through —C(═O)—, —C(═O)O—, —C(═O)O—CH2—, or —S(═O)2—;
a 3-12-membered heterocycloalkyl moiety, saturated or unsaturated, unsubstituted, mono- or polysubstituted; wherein said 3-12-membered heterocycloalkyl moiety is optionally connected through —C1-C6-alkylene-, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted; or wherein said 3-12-membered heterocycloalkyl moiety is optionally connected through —C(═O)—, —C(═O)O—, —C(═O)O—CH2—, or —S(═O)2—;
a 6-14-membered aryl moiety, unsubstituted, mono- or polysubstituted; wherein said 6-14-membered aryl moiety is optionally connected through —C1-C6-alkylene-, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted; or wherein said 6-14-membered aryl moiety is optionally connected through —C(═O)—, —C(═O)O—, —C(═O)O—CH2—, or —S(═O)2—; or
a 5-14-membered heteroaryl moiety, unsubstituted, mono- or polysubstituted; wherein said 5-14-membered heteroaryl moiety is optionally connected through —C1-C6-alkylene-, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted; or wherein said 5-14-membered heteroaryl moiety is optionally connected through —C(═O)—, —C(═O)O—, —C(═O)O—CH2—, or —S(═O)2—;
X means —O—, —S— or —NR6—;
R5 means
—H;
—C1-C6-alkyl, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted;
a 3-12-membered cycloalkyl moiety, saturated or unsaturated, unsubstituted, mono- or polysubstituted; wherein said 3-12-membered cycloalkyl moiety is optionally connected through —C1-C6-alkylene-, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted;
a 3-12-membered heterocycloalkyl moiety, saturated or unsaturated, unsubstituted, mono- or polysubstituted; wherein said 3-12-membered heterocycloalkyl moiety is optionally connected through —C1-C6-alkylene-, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted;
a 6-14-membered aryl moiety, unsubstituted, mono- or polysubstituted; wherein said 6-14-membered aryl moiety is optionally connected through —C1-C6-alkylene-, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted; or
a 5-14-membered heteroaryl moiety, unsubstituted, mono- or polysubstituted; wherein said 5-14-membered heteroaryl moiety is optionally connected through —C1-C6-alkylene-, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted;
in case X means NR6, R6 means
—H;
—C1-C6-alkyl, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted;
a 3-12-membered cycloalkyl moiety, saturated or unsaturated, unsubstituted, mono- or polysubstituted; wherein said 3-12-membered cycloalkyl moiety is optionally connected through —C1-C6-alkylene-, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted;
a 3-12-membered heterocycloalkyl moiety, saturated or unsaturated, unsubstituted, mono- or polysubstituted; wherein said 3-12-membered heterocycloalkyl moiety is optionally connected through —C1-C6-alkylene-, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted;
a 6-14-membered aryl moiety, unsubstituted, mono- or polysubstituted; wherein said 6-14-membered aryl moiety is optionally connected through —C1-C6-alkylene-, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted; or
a 5-14-membered heteroaryl moiety, unsubstituted, mono- or polysubstituted; wherein said 5-14-membered heteroaryl moiety is optionally connected through —C1-C6-alkylene-, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted;
or in case X means NR6, R5 and R6 together with the nitrogen atom to which they are attached form a 3-12-membered heterocycloalkyl moiety, saturated or unsaturated, unsubstituted, mono- or polysubstituted;
R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19, and R20 independently of one another mean —H, —F, —Cl, —Br, —I, —OH, or —C1-C6-alkyl, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted;
wherein “mono- or polysubstituted” means that one or more hydrogen atoms are replaced by a substituent independently of one another selected from the group consisting of —F, —Cl, —Br, —I, —CN, —R21, —C(═O)R21, —C(═O)OR21, —C(═O)NR21R22, —O—(CH2CH2—O)1-30—H, —O—(CH2CH2—O)1-3O—CH3, ═O, —OR21, —OC(═O)R21, —OC(═O)OR21, —OC(═O)NR21R22, —NO2, —NR21R22, —NR21—(CH2)1-6—C(═O)R22, —NR21—(CH2)1-6—C(═O)OR22, —NR23—(CH2)1-6—C(═O)NR21R22, —NR21C(═O)R22, —NR21C(═O)—OR22, —NR23C(═O)NR21R22, NR21S(═O)2R22, —SR21, —S(═O)R21, —S(═O)2R21, —S(═O)2OR21, and —S(═O)2NR21R22;
wherein
R21, R22 and R23 independently of one another mean
—H;
C1-C6-alkyl, linear or branched, saturated or unsaturated, unsubstituted or substituted with one, two, three or four substituents independently of one another selected from the group consisting of —F, —Cl, —Br, —I, —CN, —OH, —NH2, and —O—C1-C6-alkyl;
a 3-12-membered cycloalkyl moiety, saturated or unsaturated, unsubstituted; wherein said 3-12-membered cycloalkyl moiety is optionally connected through —C1-C6-alkylene-, linear or branched, saturated or unsaturated, unsubstituted or substituted with one, two, three or four substituents independently of one another selected from the group consisting of —F, —Cl, —Br, —I, —CN, —OH, —NH2, —C1-C6-alkyl and —O—C1-C6-alkyl;
a 3-12-membered heterocycloalkyl moiety, saturated or unsaturated, unsubstituted; wherein said 3-12-membered heterocycloalkyl moiety is optionally connected through —C1-C6-alkylene-, linear or branched, saturated or unsaturated, unsubstituted or substituted with one, two, three or four substituents independently of one another selected from the group consisting of —F, —Cl, —Br, —I, —CN, —OH, —NH2, —C1-C6-alkyl and —O—C1-C6-alkyl;
a 6-14-membered aryl moiety, unsubstituted, mono- or polysubstituted; wherein said 6-14-membered aryl moiety is optionally connected through —C1-C6-alkylene-, linear or branched, saturated or unsaturated, unsubstituted or substituted with one, two, three or four substituents independently of one another selected from the group consisting of —F, —Cl, —Br, —I, —CN, —OH, —NH2, —C1-C6-alkyl and —O—C1-C6-alkyl;
a 5-14-membered heteroaryl moiety, unsubstituted, mono- or polysubstituted; wherein said 5-14-membered heteroaryl moiety is optionally connected through —C1-C6-alkylene-, linear or branched, saturated or unsaturated, unsubstituted or substituted with one, two, three or four substituents independently of one another selected from the group consisting of —F, —Cl, —Br, —I, —CN, —OH, —NH2, —C1-C6-alkyl and —O—C1-C6-alkyl;
or R21 and R22 within —C(═O)NR21R22, —OC(═O)NR21R22, —NR21R22, —NR23—(CH2)1-6—C(═O)NR21R22, —NR23C(═O)NR21R22, or —S(═O)2NR21R22 together with the nitrogen atom to which they are attached form a ring and mean —(CH2)3-6—; —(CH2)2—O—(CH2)2—; or —(CH2)2—NRB—(CH2)2—, wherein RB means —H or —C1-C6-alkyl, linear or branched, saturated or unsaturated, unsubstituted or substituted with one, two, three or four substituents independently of one another selected from the group consisting of —F, —Cl, —Br and —I;
or a physiologically acceptable salt thereof.
2. The compound according to claim 1, wherein R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19, and R20 independently of one another mean —H, —F, —OH, or —C1-C6-alkyl.
3. The compound according to claim 1, wherein R1 means —H; and R2 means —C1-C6-alkyl, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted.
4. The compound according to claim 1, wherein R1 means —CH3; and R2 means —C1-C6-alkyl, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted.
5. The compound according to claim 1, wherein R1 means —H or —CH3; and wherein R2 means —CH2-cycloalkyl, —CH2-cyclobutyl, —CH2-cyclopentyl, —CH2-oxetanyl or —CH2— tetrahydrofuranyl.
6. The compound according to claim 1, wherein R1 and R2 together with the nitrogen atom to which they are attached form a ring and mean —(CH2)3-6—.
7. The compound according to claim 1, wherein R3 means —C1-C6-alkyl, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted.
8. The compound according to claim 1, wherein R3 means a 6-14-membered aryl moiety, unsubstituted, mono- or polysubstituted.
9. The compound according to claim 1, wherein R3 means a 5-14-membered heteroaryl moiety, unsubstituted, mono- or polysubstituted.
10. The compound according to claim 1, wherein R4 means —H.
11. The compound according to claim 1, wherein R4 means —C1-C6-alkyl, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted.
12. The compound according to claim 1, wherein R4 means a 3-12-membered cycloalkyl moiety, saturated or unsaturated, unsubstituted, mono- or polysubstituted; wherein the 3-12-membered cycloalkyl moiety is connected through —C1-C6-alkylene-, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted.
13. The compound according to claim 1, wherein R4 means a 3-12-membered heterocycloalkyl moiety, saturated or unsaturated, unsubstituted, mono- or polysubstituted; wherein said 3-12-membered heterocycloalkyl moiety is connected through —C1-C6-alkylene-, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted.
14. The compound according to claim 1, wherein R4 means a 6-14-membered aryl moiety, unsubstituted, mono- or polysubstituted; wherein said 6-14-membered aryl moiety is connected through —C1-C6-alkylene-, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted.
15. The compound according to claim 1, wherein R4 means a 5-14-membered heteroaryl moiety, unsubstituted, mono- or polysubstituted; wherein said 5-14-membered heteroaryl moiety is connected through —C1-C6-alkylene-, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted.
16. The compound according to claim 1, wherein R5 means —H.
17. The compound according to claim 1, wherein R5 means —C1-C6-alkyl, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted.
18. The compound according to claim 1, wherein R5 means a 3-12-membered cycloalkyl moiety, saturated or unsaturated, unsubstituted, mono- or polysubstituted, wherein said 3-12-membered cycloalkyl moiety is optionally connected through —C1-C6-alkylene-, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted.
19. The compound according to claim 1, wherein R5 means a 3-12-membered heterocycloalkyl moiety, saturated or unsaturated, unsubstituted, mono- or polysubstituted; wherein said 3-12-membered heterocycloalkyl moiety is optionally connected through —C1-C6-alkylene-, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted.
20. The compound according to claim 1, wherein R5 means a 5-14-membered heteroaryl moiety, unsubstituted, mono- or polysubstituted; wherein said 5-14-membered heteroaryl moiety is optionally connected through —C1-C6-alkylene-, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted.
21. The compound according to claim 1, wherein X means NR6 and R5 and R6 together with the nitrogen atom to which they are attached form a 3-12-membered heterocycloalkyl moiety, saturated or unsaturated, unsubstituted, mono- or polysubstituted.
22. The compound according to claim 1, wherein X means NR6 and R6 means —H or —C1-C6-alkyl, linear or branched, saturated or unsaturated, unsubstituted, mono- or polysubstituted.
23. The compound according to claim 1, which has a structure according to any of general formulas (II-A) to (VIII-C):
Figure US20210179627A1-20210617-C00185
Figure US20210179627A1-20210617-C00186
Figure US20210179627A1-20210617-C00187
Figure US20210179627A1-20210617-C00188
wherein in each case
R1, R2, R3, R4, R5, R6 and X are defined as in claim 1,
RC means —H, —OH, —F, —CN or —C1-C4-alkyl;
RD means —H or —F;
or a physiologically acceptable salt thereof.
24. The compound according to claim 1, wherein the substructure
Figure US20210179627A1-20210617-C00189
has a meaning selected from the group consisting of:
Figure US20210179627A1-20210617-C00190
Figure US20210179627A1-20210617-C00191
Figure US20210179627A1-20210617-C00192
Figure US20210179627A1-20210617-C00193
Figure US20210179627A1-20210617-C00194
Figure US20210179627A1-20210617-C00195
Figure US20210179627A1-20210617-C00196
Figure US20210179627A1-20210617-C00197
25. The compound according to claim 1, wherein
R1 means —H or —CH3;
R2 means —CH3, —CH2CH3 or —CH2—C(H)(CH3)2;
R3 means -phenyl, -thienyl or -pyridinyl, in each case unsubstituted or monosubstituted with —F;
R4 means
—H;
—C1-C6-alkyl, linear or branched, saturated, unsubstituted or substituted with one, two, three or four substituents independently of one another selected from the group consisting of —F, —Cl, —Br, —I, —CN, —OH, ═O, —N(CH3)2 and —O—CH3; or
-cyclopropyl, -cyclobutyl, -cyclopentyl or -cyclohexyl, unsubstituted or monosubstituted with —F, —OH, —CN or —CH3, wherein said -cyclopropyl, -cyclobutyl, -cyclopentyl or -cyclohexyl is connected through —CH2— or —CH2CH2—;
-oxetanyl unsubstituted or monosubstituted with —F, —OH, —CN or —CH3, wherein said -oxetanyl is connected through —CH2— or —CH2CH2—;
X means —O— or —NR6—;
R5 means
—H;
C1-C6-alkyl, linear or branched, saturated or unsaturated, unsubstituted or substituted with one, two, three or four substituents independently of one another selected from the group consisting of —F, —Cl, —Br, —I, —CN, —O—CH3, —O—(CH2—CH2—O)1-10—H, —O—(CH2CH2—O)1-10—CH3, —C(═O)OH, —C(═O)OCH3, —C(═O)NH2, —C(═O)NHCH3, —C(═O)N(CH3)2, —OH, —S(═O)CH3, —S(═O)2CH3, unsubstituted —C(═O)-morpholinyl, —NH—C(═O)—CH3, —N(CH3)2 and NH—S(═O)2—CH3;
-cyclopropyl, -cyclobutyl, -cyclopentyl or -cyclohexyl, unsubstituted or monosubstituted with —F, —OH, —CN or —CH3, wherein said -cyclopropyl, -cyclobutyl, cyclopentyl or cyclohexyl is optionally connected through —CH2— or —CH2CH2—;
-heterocyclobutyl, -heterocyclopentyl, or -heterocyclohexyl, in each case unsubstituted or substituted with one, two, three or four substituents independently of one another selected from the group consisting of —F, —Cl, —Br, —I, —CN, —O—CH3, —O—(CH2—CH2—O)1-10—H, —O—(CH2CH2—O)1-10—CH3, —C1-C4-alkyl, —C(═O)OH, —C(═O)OCH3, —C(═O)NH2, —C(═O)NHCH3, —C(═O)N(CH3)2, ═O, —OH, —SCH3, —S(═O)CH3, —S(═O)2CH3, unsubstituted —C(═O)-morpholinyl, —NH—C(═O)—CH3, —N(CH3)2 and NH—S(═O)2—CH3; wherein said -hetero-cyclobutyl, -heterocyclopentyl, or -heterocyclohexyl is optionally connected through —CH2— or —CH2CH2—;
-oxazolyl, -isoxazolyl, -pyrazolyl, -pyridinyl, -pyridazinyl, -pyrazinyl, -thiazolyl, -thiadiazolyl, -imidazolyl, -pyrimidinyl, or 5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazine, in each case unsubstituted or substituted with one, two, three or four substituents independently of one another selected from the group consisting of —F, —Cl, Br, —I, —CN, —OH, —CH3, —O—CH3, —C(═O)OH, —C(═O)OCH3, —C(═O)NH2, —C(═O)NHCH3, —C(═O)N(CH3)2, S(═O)CH3, —S(═O)2CH3 and —S—CH3, wherein said -oxazolyl, -isoxazolyl, -pyrazolyl, -pyridinyl, -pyridazinyl, -pyrazinyl, -thiazolyl, -thiadiazolyl, -imidazolyl, -pyrimidinyl, or 5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazine is optionally connected through —CH2—; or
-phenyl, unsubstituted or substituted with one, two, three or four substituents independently of one another selected from the group consisting of —F, —Cl, Br, —I, —CN, —OH, —CH3, —O—CH3, —C(═O)OH, —C(═O)OCH3, —C(═O)NH2, —C(═O)NHCH3, —C(═O)N(CH3)2, S(═O)CH3, —S(═O)2CH3 and —S—CH3, wherein said -phenyl is optionally connected through —CH2—;
in case X means NR6, R6 means —H or —CH3;
or in case X means NR6, R5 and R6 together with the nitrogen atom to which they are attached form a -pyrrolidinyl, -piperidinyl, -piperazinyl, -morpholinyl, -thiomorpholinyl, -thiomorpholinyl dioxide or -(methylsulfonyl)piperazinyl, in each case unsubstituted or substituted with one, two, three or four substituents independently of one another selected from the group consisting of ═O, —OH, —CH2—OH, —C(═O)NH2, and —S(═O)2CH3, wherein said -pyrrolidinyl, -piperidinyl, -piperazinyl, -morpholinyl, -thiomorpholinyl, -thiomorpholinyl dioxide or -(methylsulfonyl)piperazinyl is optionally condensed with an imidazole moiety, unsubstituted; and
R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19, and R20 mean —H.
26. The compound according to claim 1, which has a structure according to general formula (I1)
Figure US20210179627A1-20210617-C00198
wherein R1 to R5, R9 to R20, and X are defined as in claim 1,
or a physiologically acceptable salt thereof.
27. The compound according to claim 1, which has a structure according to general formula (IX)
Figure US20210179627A1-20210617-C00199
wherein
RC means —H or —OH;
R3 means -phenyl or -3-fluorophenyl;
R5 means —H, —CH3, —CH2CH2OH, or —CH2C(═O)NH2;
R6 means —H or —CH3;
or R5 and R6 together with the nitrogen atom to which they are attached form a ring and mean —(CH2)5—, wherein said ring is unsubstituted or substituted with one or two substituents independently of one another selected from the group consisting of —CH3, —OH, —S(═O)2CH3 and —C(═O)NH2;
R9 and R10 independently of one another mean —H or —CH3;
or a physiologically acceptable salt thereof.
28. The compound according to claim 1, which is selected from the group consisting of
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-[2-[2-[2-[2-[2-[2-(2-methoxy-ethoxy)-ethoxy]-ethoxy]-ethoxy]-ethoxy]-ethoxy]-ethyl]-acetamide;
CIS-6-[[2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetyl]amino]-pyridine-2-carboxylic acid methyl ester;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-[(1R)-2-hydroxy-1-methyl-ethyl]-acetamide;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-[(1S)-2-hydroxy-1-methyl-ethyl]-acetamide;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-methyl-N-(methylcarbamoyl-methyl)-acetamide;
CIS-6-[[2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetyl]amino]-nicotinic acid methyl ester;
CIS-2-[[2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetyl]-methyl-amino]-2-methyl-propionamide;
CIS-2-[[2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetyl]amino]-N,2-dimethyl-propionamide;
CIS-2-[[2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetyl]-methyl-amino]-N,2-dimethyl-propionamide;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-[(dimethyl-carbamoyl)-methyl]-N-methyl-acetamide;
CIS-2-[[2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetyl]amino]-2-methyl-propionamide;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(5-methoxy-pyridin-2-yl)-acetamide;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(6-methoxy-pyridin-2-yl)-acetamide;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(4-methoxy-pyridin-2-yl)-acetamide;
CIS-6-[[2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetyl]amino]-N-methyl-pyridine-2-carboxylic acid amide;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-[(3-hydroxy-cyclobutyl)-methyl]-acetamide;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-[(3-hydroxy-cyclobutyl)-methyl]-acetamide;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-[(1-hydroxy-cyclopropyl)-methyl]-acetamide;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(3-morpholin-4-yl-3-oxo-propyl)-acetamide;
CIS-N-(1-Cyano-cyclopropyl)-2-[1-(cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetamide;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-[(3-hydroxy-cyclopentyl)-methyl]-acetamide;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-[[(2R)-2-hydroxy-cyclohexyl]-methyl]-acetamide;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-[2-[2-[2-(2-methoxy-ethoxy)-ethoxy]-ethoxy]-ethyl]-acetamide;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-[(1-hydroxy-cyclohexyl)-methyl]-acetamide;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-[2-[2-[2-[2-(2-methoxy-ethoxy)-ethoxy]-ethoxy]-ethoxy]-ethyl]-acetamide;
CIS-N-(6-Cyano-pyridin-2-yl)-2-[1-(cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetamide;
CIS-2-[[2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetyl]amino]-nicotinic acid methyl ester;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(3-methoxy-pyridin-2-yl)-acetamide;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-[2-[2-[2-[2-[2-(2-methoxy-ethoxy)-ethoxy]-ethoxy]-ethoxy]-ethoxy]-ethyl]-acetamide;
CIS-N-(4-Cyano-pyridin-2-yl)-2-[1-(cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetamide;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(5-methoxy-pyrimidin-2-yl)-acetamide;
CIS-2-[[2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetyl]amino]-isonicotinic acid methyl ester;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(2-methoxy-pyridin-4-yl)-acetamide;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(6-fluoro-pyridin-3-yl)-acetamide;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(2-methyl-pyrimidin-5-yl)-acetamide;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(5-methyl-pyrimidin-2-yl)-acetamide;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(3-fluoro-pyridin-2-yl)-acetamide;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(3-fluoro-pyridin-4-yl)-acetamide;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(6-methoxy-pyridin-3-yl)-acetamide;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(2-methyl-pyridin-3-yl)-acetamide;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(4-methyl-pyridin-3-yl)-acetamide;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(3-methyl-pyridin-4-yl)-acetamide;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(6-methyl-pyridin-3-yl)-acetamide;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(5-fluoro-pyridin-2-yl)-acetamide;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(5-methyl-pyridin-2-yl)-acetamide;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(4-methyl-pyridin-2-yl)-acetamide;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(3-methyl-pyridin-2-yl)-acetamide;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(3-methoxy-pyridin-4-yl)-acetamide;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(6-methoxy-pyridazin-3-yl)-acetamide;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(5-methylsulfonyl-pyridin-2-yl)-acetamide;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(5-methoxy-pyridin-2-yl)-acetamide;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(6-methylsulfonyl-pyridin-3-yl)-acetamide;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(6-methoxy-pyrazin-2-yl)-acetamide;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(4-methoxy-pyridin-2-yl)-acetamide;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(4-methoxy-pyrimidin-2-yl)-acetamide;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(oxazol-5-yl-methyl)-acetamide;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(oxazol-2-yl-methyl)-acetamide;
CIS-1-(Cyclobutyl-methyl)-3-[2-[(3S,4S)-3,4-dihydroxy-piperidin-1-yl]-2-oxo-ethyl]-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
CIS-1-(Cyclobutyl-methyl)-3-[2-[(3S,4S)-3,4-dihydroxy-pyrrolidin-1-yl]-2-oxo-ethyl]-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
CIS-1-(Cyclobutyl-methyl)-3-[2-[(3S,4R)-3,4-dihydroxy-pyrrolidin-1-yl]-2-oxo-ethyl]-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-cyclopropyl-acetamide;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(2-hydroxy-ethyl)-N-methyl-acetamide;
CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-3-[2-(3-hydroxy-piperidin-1-yl)-2-oxo-ethyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-[(1-hydroxy-cyclobutyl)-methyl]-acetamide;
CIS-2-[[2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetyl]amino]-N,N-dimethyl-acetamide;
CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-3-[2-oxo-2-(5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazin-7-yl)-ethyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
CIS-3-[[2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetyl]amino]-N,N-dimethyl-propionamide;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-[2-[2-[2-[2-[2-[2-[2-(2-methoxy-ethoxy)-ethoxy]-ethoxy]-ethoxy]-ethoxy]-ethoxy]-ethoxy]-ethyl]-acetamide;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(4-methoxy-pyrimidin-5-yl)-acetamide;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(2-methoxy-pyrimidin-5-yl)-acetamide;
CIS-N-(5-Cyano-pyridin-2-yl)-2-[1-(cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetamide;
CIS-2-[[2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetyl]amino]-N-methyl-pyridine-4-carboxylic acid amide;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(5-methoxy-pyrimidin-4-yl)-acetamide;
CIS-N-(2-Cyano-pyrimidin-5-yl)-2-[1-(cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetamide;
CIS-6-[[2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetyl]amino]-pyridine-2-carboxylic acid amide;
CIS-N-(3-Cyano-pyridin-2-yl)-2-[1-(cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetamide;
CIS-2-[[2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetyl]amino]-acetamide;
CIS-6-[[2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetyl]amino]-pyridine-3-carboxylic acid amide;
CIS-N-(4-Cyano-pyrimidin-2-yl)-2-[1-(cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetamide;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-([1,3,4]thiadiazol-2-yl)-acetamide;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-thiazol-2-yl-acetamide;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(5-methyl-isoxazol-3-yl)-acetamide;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-isoxazol-3-yl-acetamide;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(1-methyl-1H-pyrazol-3-yl)-acetamide;
CIS-N-(4-Cyano-5-methylsulfanyl-1H-pyrazol-3-yl)-2-[1-(cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetamide;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(5-methoxy-pyrazin-2-yl)-acetamide;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(pyridazin-4-yl-methyl)-acetamide;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-[(2-hydroxyphenyl)-methyl]-acetamide;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-[(1-methyl-1H-imidazol-4-yl)-methyl]-acetamide;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-[(4-methyl-pyridin-3-yl)-methyl]-acetamide;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(pyrimidin-2-yl-methyl)-acetamide;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(pyridazin-3-yl-methyl)-acetamide;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(pyrimidin-4-yl-methyl)-acetamide;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(pyrazin-2-yl-methyl)-acetamide;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(oxazol-4-yl-methyl)-acetamide;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-[(2-methyl-pyridin-3-yl)-methyl]-acetamide;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-[(2-methoxy-pyridin-3-yl)-methyl]-acetamide;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-[(4-methoxy-pyridin-3-yl)-methyl]-acetamide;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-[(6-methyl-pyridin-2-yl)-methyl]-acetamide;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-[(6-methoxy-pyridin-2-yl)-methyl]-acetamide;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-[(2-methoxyphenyl)-methyl]-acetamide;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(o-tolyl-methyl)-acetamide;
CIS-6-[[2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetyl]amino]-N-methyl-pyridine-3-carboxylic acid amide;
CIS-2-[[2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetyl]amino]-pyridine-4-carboxylic acid amide;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(6-methoxy-pyrimidin-4-yl)-acetamide;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(2-methoxy-pyrimidin-4-yl)-acetamide;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(4-hydroxy-pyrimidin-5-yl)-acetamide;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(2-hydroxy-pyrimidin-5-yl)-acetamide;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(5-hydroxy-pyridin-2-yl)-acetamide;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(1,1-dioxo-thian-4-yl)-acetamide;
CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-3-[2-(1,1-dioxo-[1,4]thiazinan-4-yl)-2-oxo-ethyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
CIS-2-[8-Dimethylamino-1-(2-methoxy-ethyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-pyrimidin-4-yl-acetamide;
CIS-2-[8-Dimethylamino-1-(2-methoxy-ethyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-methyl-acetamide;
CIS-N-(5-Cyano-pyrimidin-4-yl)-2-[1-(cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetamide;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(5-methylsulfanyl-pyridin-2-yl)-acetamide;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(4-methoxy-pyrimidin-2-yl)-acetamide;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(6-methylsulfanyl-pyridin-2-yl)-acetamide;
CIS-2-[8-Dimethylamino-1-(2-methoxy-ethyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(2-hydroxy-ethyl)-acetamide;
CIS-2-[[2-[8-Dimethylamino-1-(2-methoxy-ethyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetyl]amino]-acetamide;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-methyl-acetamide;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(2-hydroxy-ethyl)-acetamide;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(6-hydroxy-pyridin-2-yl)-acetamide;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-[(2-methoxy-pyrimidin-5-yl)-methyl]-acetamide;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-[(4-methoxy-pyrimidin-2-yl)-methyl]-acetamide;
CIS-N-(2-Cyano-pyrimidin-4-yl)-2-[1-(cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetamide;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-[6-(methylsulfinyl)-pyridin-2-yl]-acetamide;
CIS-2-[[2-[1-(Cyclobutyl-methyl)-8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetyl]amino]-2-methyl-propionamide;
CIS-2-[[2-[1-(Cyclobutyl-methyl)-8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetyl]amino]-N-methyl-acetamide;
CIS-2-[[2-[1-(Cyclobutyl-methyl)-8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetyl]amino]-acetamide;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-[2-[2-(2-methoxy-ethoxy)-ethoxy]-ethyl]-acetamide;
CIS-N-(Carbamoyl-methyl)-2-[1-(cyclobutyl-methyl)-8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-methyl-acetamide;
CIS-2-[1-(Cyclobutyl-methyl)-8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-methyl-N-(methylcarbamoyl-methyl)-acetamide;
CIS-2-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(2-methylsulfonyl-ethyl)-acetamide;
CIS-2-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-pyrimidin-5-yl-acetamide;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(6-methylsulfonyl-pyridin-2-yl)-acetamide;
CIS-2-[8-Dimethylamino-1-[(dimethyl-carbamoyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(2-hydroxy-ethyl)-acetamide;
CIS-2-[[2-[1-(Cyclobutyl-methyl)-8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetyl]-methyl-amino]-2-methyl-propionamide;
CIS-1-(Cyclobutyl-methyl)-3-[2-(1,1-dioxo-[1,4]thiazinan-4-yl)-2-oxo-ethyl]-8-methylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
CIS-2-[1-(Cyclobutyl-methyl)-8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-[2-[2-[2-[2-[2-[2-(2-methoxy-ethoxy)-ethoxy]-ethoxy]-ethoxy]-ethoxy]-ethoxy]-ethyl]-acetamide;
CIS-2-[[2-[1-(Cyclobutyl-methyl)-8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetyl]amino]-N,N-dimethyl-acetamide;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(5-hydroxy-pyrimidin-2-yl)-acetamide;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(4-methylsulfonyl-pyridin-2-yl)-acetamide;
CIS-2-[[2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetyl]amino]-N-methyl-acetamide;
CIS-N-(Carbamoyl-methyl)-2-[1-(cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-methyl-acetamide;
CIS-2-(8-Dimethylamino-2-oxo-8-phenyl-1-propyl-1,3-diazaspiro[4.5]decan-3-yl)-N-methyl-acetamide;
CIS-2-[8-Dimethylamino-1-(3-methoxy-propyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-methyl-acetamide;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-[4-(methylsulfinyl)-pyridin-2-yl]-acetamide;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(3-hydroxy-pyridin-2-yl)-acetamide;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(2-methylsulfonyl-ethyl)-acetamide;
CIS-1-(Cyclobutyl-methyl)-3-[2-[(3S,4R)-3,4-dihydroxy-pyrrolidin-1-yl]-2-oxo-ethyl]-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
CIS-2-[1-(Cyclobutyl-methyl)-8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(2-hydroxy-ethyl)-acetamide;
CIS-2-[8-Dimethylamino-1-[(dimethyl-carbamoyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-pyrimidin-4-yl-acetamide;
CIS-2-[8-Dimethylamino-1-[(dimethyl-carbamoyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-methyl-acetamide;
CIS-2-[[2-[8-Dimethylamino-1-(2-methyl-propyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetyl]amino]-acetamide;
CIS-2-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetamide;
CIS-2-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-methyl-acetamide;
CIS-2-[[2-[8-Dimethylamino-1-(3-methoxy-propyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetyl]amino]-acetamide;
CIS-2-[8-Dimethylamino-1-(2-methyl-propyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-methyl-acetamide;
CIS-1-(Cyclobutyl-methyl)-3-[2-[(3S,4R)-3,4-dihydroxy-pyrrolidin-1-yl]-2-oxo-ethyl]-8-methylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
CIS-2-[8-Dimethylamino-1-[(1-methyl-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-methyl-acetamide;
CIS-2-[8-Dimethylamino-1-[(1-methyl-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-pyrimidin-4-yl-acetamide;
CIS-2-[[2-[8-Dimethylamino-1-[(1-methyl-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetyl]amino]-acetamide;
CIS-2-[8-Dimethylamino-1-[(1-methyl-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(2-hydroxy-ethyl)-acetamide;
CIS-2-[[2-[1l-(Cyclopropyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetyl]amino]-acetamide;
CIS-2-[1-(Cyclobutyl-methyl)-8-(ethyl-methyl-amino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-methyl-acetamide;
CIS-2-[[2-(8-Dimethylamino-2-oxo-8-phenyl-1-propyl-1,3-diazaspiro[4.5]decan-3-yl)-acetyl]amino]-acetamide;
CIS-2-[[2-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetyl]amino]-acetamide;
CIS-2-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(2-hydroxy-ethyl)-acetamide;
CIS-2-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(1,1-dioxo-thian-4-yl)-acetamide;
CIS-2-[1-(Cyclopropyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-methyl-acetamide;
CIS-2-[1-1[(1-Cyano-cyclobutyl)-methyl]-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-methyl-acetamide;
CIS-2-[1-(Cyclobutyl-methyl)-8-(ethyl-methyl-amino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(2-hydroxy-ethyl)-acetamide;
CIS-2-[[2-[1-(Cyclobutyl-methyl)-8-(ethyl-methyl-amino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetyl]amino]-acetamide;
CIS-2-[[2-[1-(Cyclobutyl-methyl)-8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetyl]amino]-N,2-dimethyl-propionamide;
CIS-2-[8-Dimethylamino-1-(3-methoxy-propyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(2-hydroxy-ethyl)-acetamide;
CIS-2-[8-Dimethylamino-1-(3-methoxy-propyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-methyl-N-(methylcarbamoyl-methyl)-acetamide;
CIS-8-Dimethylamino-1-(3-methoxy-propyl)-3-[2-oxo-2-(3-oxo-piperazin-1-yl)-ethyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
CIS-N-(Carbamoyl-methyl)-2-[8-dimethylamino-1-(3-methoxy-propyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-methyl-acetamide;
CIS-2-[8-Dimethylamino-1-(3-methoxy-propyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-[(3-hydroxy-cyclobutyl)-methyl]-acetamide;
CIS-2-[8-Dimethylamino-1-(3-methoxy-propyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-[(3-hydroxy-cyclobutyl)-methyl]-acetamide;
CIS-2-[8-Dimethylamino-1-(3-methoxy-propyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-[(3-hydroxy-cyclopentyl)-methyl]-acetamide;
CIS-2-[8-Dimethylamino-1-(3-methoxy-propyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-pyridazin-4-yl-acetamide;
CIS-2-[8-Dimethylamino-1-(3-methoxy-propyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(6-methoxy-pyridin-2-yl)-acetamide;
CIS-N-(2-Cyanoethyl)-2-[8-dimethylamino-1-(3-methoxy-propyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetamide;
CIS-2-[8-Dimethylamino-1-(3-methoxy-propyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-pyrimidin-5-yl-acetamide;
CIS-2-[8-Dimethylamino-1-(3-methoxy-propyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-pyrimidin-4-yl-acetamide;
CIS-2-[1-(Cyclobutyl-methyl)-8-(ethyl-methyl-amino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(6-methoxy-pyridin-2-yl)-acetamide;
CIS-2-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-pyridin-3-yl-acetamide;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetamide;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-pyrimidin-4-yl-acetamide;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(2-methoxy-ethyl)-acetamide;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(2-hydroxy-ethyl)-acetamide;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-[2-[2-[2-[2-[2-[2-(2-methoxy-ethoxy)-ethoxy]-ethoxy]-ethoxy]-ethoxy]-ethoxy]-ethyl]-acetamide;
CIS-2-[1-(Cyclobutyl-methyl)-8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-methyl-acetamide;
CIS-(2S)-1-[2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetyl]-pyrrolidine-2-carboxylic acid amide;
CIS-2-[[2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetyl]amino]-N,N-dimethyl-acetamide;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(oxetan-3-yl)-acetamide;
CIS-2-[[2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetyl]amino]-acetamide;
CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-3-[2-oxo-2-(3-oxo-piperazin-1-yl)-ethyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(1,1-dioxo-thian-4-yl)-acetamide;
CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-3-[2-[2-(hydroxymethyl)-morpholin-4-yl]-2-oxo-ethyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
CIS-N-(Carbamoyl-methyl)-2-[1-(cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-methyl-acetamide;
CIS-N-(Cyano-methyl)-2-[1-(cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetamide;
CIS-N-(2-Acetylamino-ethyl)-2-[1-(cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetamide;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(2-methylsulfonyl-ethyl)-acetamide;
CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-3-[2-(1,1-dioxo-[1,4]thiazinan-4-yl)-2-oxo-ethyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-[(1,1-dioxo-thian-4-yl)-methyl]-acetamide;
CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-3-[2-(4-methylsulfonyl-piperazin-1-yl)-2-oxo-ethyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
CIS-N-(2-Cyanoethyl)-2-[1-(cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetamide;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(2-hydroxy-2-methyl-propyl)-acetamide;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(2-morpholin-4-yl-2-oxo-ethyl)-acetamide;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-[2-(2-hydroxy-ethoxy)-ethyl]-acetamide;
CIS-2-[[2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetyl]amino]-N-methyl-acetamide;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-[2-(methanesulfonamido)-ethyl]-acetamide;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-[(1-hydroxy-cyclopentyl)-methyl]-acetamide;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-[(4-hydroxy-cyclohexyl)-methyl]-acetamide;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-[2-(2-methoxy-ethoxy)-ethyl]-acetamide;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-[2-(dimethylamino)ethyl]-acetamide;
CIS-2-[1-(Cyclobutyl-methyl)-8-[methyl-(2-methyl-propyl)-amino]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-methyl-acetamide;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-methyl-acetamide;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-pyrimidin-4-yl-acetamide;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(6-methyl-pyridin-2-yl)-acetamide;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-pyridazin-3-yl-acetamide;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-pyrimidin-5-yl-acetamide;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-pyridazin-4-yl-acetamide;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(6-methoxy-pyrimidin-4-yl)-acetamide;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(2-methyl-pyridin-4-yl)-acetamide;
CIS-2-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-pyridin-4-yl-acetamide;
CIS-2-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(oxetan-3-yl)-acetamide;
CIS-2-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(2-methoxy-ethyl)-acetamide;
CIS-2-[1-[(1-Hydroxy-cyclobutyl)-methyl]-8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(oxetan-3-yl)-acetamide;
CIS-2-[1-[(1-Hydroxy-cyclobutyl)-methyl]-8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(2-methoxy-ethyl)-acetamide;
CIS-2-[8-Dimethylamino-1-(3-methoxy-propyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(4-methoxy-pyridin-2-yl)-acetamide;
CIS-2-[8-Dimethylamino-1-(3-methoxy-propyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(pyrimidin-4-yl-methyl)-acetamide;
CIS-8-Dimethylamino-3-[2-(1,1-dioxo-[1,4]thiazinan-4-yl)-2-oxo-ethyl]-8-phenyl-1-propyl-1,3-diazaspiro[4.5]decan-2-one;
CIS-2-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-pyridin-2-yl-acetamide;
CIS-2-[1-[(1-Cyano-cyclobutyl)-methyl]-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetamide;
CIS-2-[[2-[1-[(1-Cyano-cyclobutyl)-methyl]-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetyl]amino]-acetamide;
CIS-2-[1-[(1-Hydroxy-cyclobutyl)-methyl]-8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-methyl-acetamide;
CIS-3-[2-(1,1-Dioxo-[1,4]thiazinan-4-yl)-2-oxo-ethyl]-8-methylamino-8-phenyl-1-propyl-1,3-diazaspiro[4.5]decan-2-one;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-pyridin-2-yl-acetamide;
CIS-8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-3-(2-morpholin-4-yl-2-oxo-ethyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
CIS-2-[1-[(1-Hydroxy-cyclobutyl)-methyl]-8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetamide;
CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-3-(2-morpholin-4-yl-2-oxo-ethyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(4-methylsulfanyl-pyridin-2-yl)-acetamide;
CIS-3-[2-(1,1-Dioxo-[1,4]thiazinan-4-yl)-2-oxo-ethyl]-8-methylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
CIS-2-(8-Methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-acetamide;
CIS-2-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-acetamide;
CIS-3-[2-(1,1-Dioxo-[1,4]thiazinan-4-yl)-2-oxo-ethyl]-8-ethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
TRANS-3-[2-(1,1-Dioxo-[1,4]thiazinan-4-yl)-2-oxo-ethyl]-8-ethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
CIS-2-[1-(Cyclobutyl-methyl)-8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-methyl-acetamide;
CIS-2-(8-Ethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-acetamide;
TRANS-2-(8-Ethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-acetamide;
CIS-2-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-N-(2-hydroxy-ethyl)-N-methyl-acetamide;
CIS-8-Dimethylamino-3-[2-(1,1-dioxo-[1,4]thiazinan-4-yl)-2-oxo-ethyl]-1-[(1-hydroxy-cyclobutyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decane-2,4-dione;
CIS-2-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-N-phenyl-acetamide;
CIS-N-(Carbamoyl-methyl)-2-[1-(cyclopropyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-methyl-acetamide;
CIS-2-(8-Dimethylamino-2,4-dioxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-N-phenyl-acetamide;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetamide;
CIS-2-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-[2-[2-[2-(2-methoxy-ethoxy)-ethoxy]-ethoxy]-ethyl]-acetamide;
CIS-3-[2-(1,1-Dioxo-[1,4]thiazinan-4-yl)-2-oxo-ethyl]-1-[(1-hydroxy-cyclobutyl)-methyl]-8-methylamino-8-phenyl-1,3-diazaspiro[4.5]decane-2,4-dione;
CIS-2-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-N-[2-[2-[2-(2-methoxy-ethoxy)-ethoxy]-ethoxy]-ethyl]-acetamide;
CIS-N-(Carbamoyl-methyl)-N-methyl-2-(8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-acetamide;
CIS-N-(Carbamoyl-methyl)-2-(8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-N-methyl-acetamide;
CIS-N-(Carbamoyl-methyl)-2-[8-dimethylamino-1-(oxetan-3-yl-methyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-methyl-acetamide;
CIS-N-(2-Hydroxy-ethyl)-N-methyl-2-(8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-acetamide;
CIS-2-[1-(Cyclopropyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetamide;
CIS-2-[1-(Cyclopropyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(2-hydroxy-ethyl)-acetamide;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-8-(3-fluorophenyl)-2-oxo-1,3-diazaspiro[4.5]decan-3-yl]-N-(2-hydroxy-ethyl)-N-methyl-acetamide;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-8-(3-fluorophenyl)-2-oxo-1,3-diazaspiro[4.5]decan-3-yl]-acetic acid tert-butyl ester;
CIS-2-[1-(Cyclopropyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(2-hydroxy-ethyl)-N-methyl-acetamide;
CIS-2-[1-(Cyclopropyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(2-methylsulfonyl-ethyl)-acetamide;
CIS-N-(Carbamoyl-methyl)-2-[1-(cyclobutyl-methyl)-8-dimethylamino-8-(3-fluorophenyl)-2-oxo-1,3-diazaspiro[4.5]decan-3-yl]-N-methyl-acetamide;
CIS-1-[2-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetyl]-piperidine-4-carboxylic acid amide;
CIS-8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-3-[2-(4-methylsulfonyl-piperidin-1-yl)-2-oxo-ethyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-8-(3-fluorophenyl)-2-oxo-1,3-diazaspiro[4.5]decan-3-yl]-N-(2-hydroxy-ethyl)-acetamide;
TRANS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-(2-hydroxy-ethyl)-acetamide;
TRANS-N-(Carbamoyl-methyl)-2-[1-(cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-methyl-acetamide;
CIS-8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-3-[2-(4-hydroxy-4-methyl-piperidin-1-yl)-2-oxo-ethyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-8-(4-fluorophenyl)-2-oxo-1,3-diazaspiro[4.5]decan-3-yl]-N-(2-hydroxy-ethyl)-acetamide;
TRANS-1-(Cyclopropyl-methyl)-8-dimethylamino-3-(2-morpholin-4-yl-2-oxo-ethyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
TRANS-8-Dimethylamino-3-(2-morpholin-4-yl-2-oxo-ethyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
CIS-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-8-(4-fluorophenyl)-2-oxo-1,3-diazaspiro[4.5]decan-3-yl]-N-(2-hydroxy-ethyl)-N-methyl-acetamide;
CIS-N-(Carbamoyl-methyl)-2-[1-(cyclobutyl-methyl)-8-dimethylamino-8-(4-fluorophenyl)-2-oxo-1,3-diazaspiro[4.5]decan-3-yl]-N-methyl-acetamide;
CIS-1-(Cyclopropyl-methyl)-8-dimethylamino-3-[2-(4-hydroxy-4-methyl-piperidin-1-yl)-2-oxo-ethyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
CIS-1-[2-[1-(Cyclopropyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetyl]-piperidine-4-carboxylic acid amide;
TRANS-2-[1-(Cyclopropyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-acetamide;
TRANS-2-[1-(Cyclopropyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-methyl-acetamide;
TRANS-1-(Cyclopropyl-methyl)-8-dimethylamino-3-[2-(1,1-dioxo-[1,4]thiazinan-4-yl)-2-oxo-ethyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
CIS-1-(Cyclopropyl-methyl)-8-dimethylamino-3-[2-(4-methylsulfonyl-piperidin-1-yl)-2-oxo-ethyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
CIS-8-Dimethylamino-3-[2-(1,1-dioxo-[1,4]thiazinan-4-yl)-2-oxo-ethyl]-1-[(1-hydroxy-cyclobutyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
TRANS-2-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-acetamide;
TRANS-8-Dimethylamino-3-[2-(1,1-dioxo-[1,4]thiazinan-4-yl)-2-oxo-ethyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
CIS-8-(dimethylamino)-8-phenyl-1-(2,2,2-trifluoroethyl)-3-(2-(trifluoromethyl)pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one;
CIS-8-(dimethylamino)-8-phenyl-3-(2-(trifluoromethyl)pyrimidin-5-yl)-1-(3,3,3-trifluoropropyl)-1,3-diazaspiro[4.5]decan-2-one
and the physiologically acceptable salts thereof.
29. The compound according to claim 1 adapted for use in the treatment of pain.
30. A medicament comprising a compound according to claim 1.
31. A method of treating pain in a patient in need thereof, said method comprising administering to said patient an effective amount therefor of at least one compound according to claim 1.
32. A method of treating a disorder selected from the group consisting of neurodegenerative disorders, neuroinflammatory disorders, neuropsychiatric disorders, and substance abuse/dependence, said method comprising administering to a patient in need thereof an effective amount therefor of at least one compound according to claim 1.
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