US20230303573A1 - 3-((Hetero-)Aryl)-8-Amino-2-Oxo-1,3-Diaza-Spiro-[4.5]-Decane Derivatives - Google Patents

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

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US20230303573A1
US20230303573A1 US17/986,207 US202217986207A US2023303573A1 US 20230303573 A1 US20230303573 A1 US 20230303573A1 US 202217986207 A US202217986207 A US 202217986207A US 2023303573 A1 US2023303573 A1 US 2023303573A1
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decan
diazaspiro
cis
phenyl
dimethylamino
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Sven Kuehnert
Rene Koenigs
Achim Kless
Anita WEGERT
Ingo Konetzki
Paul Ratcliffe
Ruth Jostock
Thomas Koch
Klaus Linz
Wolfgang Schroeder
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Gruenenthal GmbH
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Gruenenthal GmbH
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    • A61K31/4164—1,3-Diazoles
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Definitions

  • the invention relates to 3-((hetero-)aryl)-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-((hetero-)aryl)-8-amino-2-oxo-1,3-diaza-spiro-[4.5]-decane derivatives according to general formula (I)
  • heteroaryl means “heteroaryl or aryl”.
  • 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]
  • 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 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 -alkcyl, 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 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 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 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 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 5 means -phenyl, 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; —CF 3 ; -3-12-membered cycloalkyl, saturated or unsaturated, unsubstituted, mono- or polysubstituted; preferably -cyclopropyl, saturated, unsubstituted; -3-12-membered heterocycloalkyl, saturated or unsaturated, unsubstituted, mono-or polysubstituted; preferably -pyrrolidinyl, -piperidinyl, -morpholinyl, -piperazinyl,
  • R 5 means -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, in each case unsubstituted, mono- or polysubstituted, mono- or polysubstituted
  • R 5 means -pyrazinyl, -pyridazinyl, -pyridinyl, -pyrimidinyl, or -thienyl, 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; -CF 3 ; -3-12-membered cycloalkyl, saturated or unsaturated, unsubstituted, mono- or polysubstituted; preferably -cyclopropyl, saturated, unsubstituted; -3-12-membered heterocycloalkyl, saturated or unsaturated, unsubstituted, mono- or polysubstituted; preferably -pyrrolidinyl, -piperidinyl, -morpholinyl, -piperazinyl
  • R 5 means a bicyclic 9-10-membered heteroaryl moiety, unsubstituted, mono- or polysubstituted.
  • R 5 means imidazo[1,2-a]pyrazine, unsubstituted or monosubstituted with -C 1 -C 4 -alkyl.
  • R 5 means -phenyl, -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, in each case unsubstituted or substituted with one, two, three or four
  • the compound according to the invention has a structure according to any of general formulas (II-A) to (VIII-C):
  • R 5 is selected from the group consisting of:
  • the compound according to the invention is selected from the group consisting of
  • SC_3001 cis-5-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carbonitrile
  • SC_3002 cis-5-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-pyrazine-2-carbonitrile
  • SC_3003 cis-5-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-4-methoxy-pyrimidine-2-carbonitrile
  • SC_3004 cis-5-[8-Dimethylamino-1-(2-methoxy-ethyl)-2-ox
  • “-C 1 -C 4 -alkyl”, “-C 1 -C 6 -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.
  • 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 .
  • 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—.
  • 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, -CH2-cyclobutyl, -CH2-cyclopentyl, -CH2-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.
  • 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, tetrahydrothiophene, 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 1 -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 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.
  • 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 compound according to the invention has a structure according to general formula (I′)
  • 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 compound according to the invention has a structure according to general formula (IX) or (X)
  • the compound according to the invention has a structure according to general formula (XI)
  • 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 semisolid 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
  • 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 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 (35g, 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 ⁇ 8 ⁇ .2 ⁇ 5 ⁇ ]tetradecane-1,3-dione
  • Step 2 2-[(4-Methoxyphenyl)-methyl]-9,12-dioxa-2,4-diazadispiro[4.2.4 ⁇ 8 ⁇ .2 ⁇ 5 ⁇ ] tetradecane-1,3-dione
  • Step 3 2-[(4-Methoxyphenyl)-methyl]-9,12-dioxa-2,4-diazadispiro[4.2.4 ⁇ 8 ⁇ .2 ⁇ 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 90g (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.
  • Step2 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-(Cyclobutylmethyl)-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 pH ⁇ 10 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)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-976) (1250 mg, 4.6 mmol), 5-bromo-2-chloro-pyrimidine (1.5 equiv., 6.7 mmol, 1327 mg), Cs 2 CO 3 (2 equiv., 9.15 mmol, 2980 mg), XantPhos (0.15 equiv., 0.69 mmol, 397 mg) and Pd 2 (dba) 3 (0.05 equiv., 0.23 mmol, 209 mg) were dissolved in dry 1,4-dioxane (120 equiv., 549 mmol, 47 mL) under nitrogen atmosphere and stirred at 90° C.
  • Methyl CIS-5-[8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]pyrimidine-2-carboxylate (INT-990) (950 mg, 2.32 mmol) was suspended in a mixture of MeOH (140 equiv., 325 mmol, 13 mL) and THF (70 equiv., 162 mmol, 13 mL). Lithium hydroxide 2M aq. sol. (1.3 mL) was added. The reaction mixture was stirred 5 days at RT. Additional 1.3 mL of lithium hydroxide 2M aq. sol.
  • 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 Cis and Trans Mixture of 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)
  • Step 6 CIS-8-ethylamino-8-phenyl-1,3-diaza-spiro[4.5]Decan-2-One (INT-1008)
  • 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-C18 (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 9,12-dioxa-2,4-diazadispiro[4.2.4 ⁇ 8 ⁇ .2 ⁇ 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 TRANS-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decane-2,4-dione
  • 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), 5 ⁇ , Diluent: MeOH, Mobile phase: A) 0.05% TFA in water; B) ACN flow rate: 1 ml/min, R t 5.17 min.
  • Step 1 Lithium 4-(cis-1-(cyclobutylmethyl)-8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)benzoate
  • Step 2 cis-4-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro [4.5]decan-3-yl]-N,N-dimethyl-benzamide (SC_3028)
  • Lithium 4-(cis-1-(cyclobutylmethyl)-8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro [4.5]decan-3-yl)benzoate (80 mg, 0.17 mmol) was suspended in DCM (1 mL) and triethylamine (0.23 mL, 1.7 mmol) and dimethylamine (2M solution in THF, 0.17 mL) and T3P (0.20 mL, 0.34 mmol) were sequentially added. The resulting mixture was stirred for 18 h at RT. Water (10 mL) was added and the mixture was extracted with DCM (3 ⁇ 20 mL).
  • N-iodosuccinimide 150 mg, 0.67 mmol was added to a suspension of cis-5-[8-(dimethylamino)-l-(3-methoxypropyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-4-methoxy-pyrimidine-2-carbonitrile SC_3040 (214 mg, 0.44 mmol) in acetonitrile/THF (2/1 v/v, 10 mL) at RT and the resulting mixture was stirred for 16 h at RT. The reaction mixture was basified with 2N NaOH solution to pH ⁇ 10 and the organic product was extracted with DCM (10 mL ⁇ 3).
  • Step 1 5-(cis-1-(2-(tert-Butyldimethylsilyloxy)ethyl)-8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)pyrimidine-2-carbonitrile
  • reaction mixture was diluted with water (15 mL) and extracted with diethyl ether (3 x 25 mL). The combined organic extracts were dried over anhydrous Na 2 SO 4 , the solvents were removed under reduced pressure and the residue was purified by flash chromatography on silica gel to afford 5-(cis-1-(2-(tert-butyldimethylsilyloxy)ethyl)-8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)pyrimidine-2-carbonitrile (100 mg, 34%) as a white solid.
  • Step 2 cis-5-[8-Dimethylamino-1-(2-hydroxy-ethyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carbonitrile (SC_3025)
  • Step 2 CIS-8-dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-3-(2-morpholin-4-yl-pyrimidin-5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (SC_3097)
  • N-Iodosuccinimide (162 mg, 0.72 mmol) was added to the solution CIS-8-(dimethylamino)-1-((1-hydroxycyclobutyl)methyl)-3-(2-morpholinopyrimidin-5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (SC-3097) (250 mg, 0.48 mmol) in acetonitrile (8.0 mL) and THF (8.0 mL) at 0° C. and the resulting mixture was stirred for 16 h at RT. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in EtOAc (2 ⁇ 30 mL), the organic layer was washed with 2N aq.
  • Preparative reverse phase HPLC conditions column: Luna-PhenylHexyl-C18 (150*19mm) 5 ⁇ m; mobile phase: 10 mM ammonium bicarbonate/acetonitrile, gradient (T/%B): 0/50, 7/85, 7.1/98, 9/98, 9.1/50, 12/50; flow Rate: 25 ml/min; diluent: mobile phase + THF.
  • tert-butyl piperazine-1-carboxylate was reacted with 5-bromo-2-chloropyrimidine to be converted into tert-butyl 4-(5-bromopyrimidin-2-yl)piperazine-1-c arboxylate.
  • Step 2 Tert-butyl 4-(5-((cis)-8-(dimethylamino)-1-((1-hydroxycyclobutyl)methyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)pyrimidin-2-yl)piperazine-1-carboxylate
  • Step 3 CIS-8-(dimethylamino)-1-((1-hydroxycyclobutyl)methyl)-8-phenyl-3-(2-(piperazin-1-yl)pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one hydrochloride (SC_3100)
  • Step 1 CIS-2-(8-(dimethylamino)-1-(2-(1-methoxycyclobutyl)ethyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)benzonitrile
  • Step 2 CIS-2-[8-Dimethylamino-1-[2-(1-methoxy-cyclobutyl)-ethyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-benzamide SC_3109
  • reaction mixture was then quenched with 10 mL water, extracted with DCM (3 ⁇ 10 mL), the combined organic extracts were dried over Na 2 SO 4 and concentrated under reduced pressure (24 mg crude product).
  • the aqueous phase was concentrated to dryness (91 mg), suspended in DCM, the precipitate was filtered off and the organic solution was concentrated under reduced pressure to give additional 56 mg of the crude product.
  • Step 1 CIS-2-(8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)benzonitrile
  • Step 2 CIS-2-(8-(dimethylamino)-1-((1-hydroxycyclobutyl)methyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)benzonitrile
  • Step 3 CIS- 2-(1-((1-hydroxycyclobutyl)methyl)-8-(methylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)benzonitrile (SC_3112)
  • CIS-3-(2-chloropyrimidin-5-yl)-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-989) (100 mg, 0.259 mmol) was placed into a reaction vial for microvawe reactor (5 mL), the vial was flushed with nitrogen, anhydrous n-butanol (50 equiv., 13.0 mmol, 1.2 mL), diisopropylethylamine (5 equiv., 1.30 mmol, 0.224 mL) and piperazine-2-one (1.2 equiv., 0.311 mmol, 31 mg) were added, the vial was sealed and the reaction mixture was stirred for 2.5 h at 140° C.
  • CIS-3-(2-chloropyrimidin-5-yl)-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-989) (1 equiv., 0.47 mmol, 180 mg), Pd(PPh 3 ) 4 (0.1 equiv., 0,047 mmol, 54 mg) and (3-cyanophenyl)boronic acid (1.5 equiv., 0.70 mmol, 103 mg) were dissolved in degassed dry tetrahydrofurane (9.5 mL) and sodium carbonate 1M aq. sol. (1.9 equiv., 0.89 mmol, 0.89 mL) was added.
  • Step 1 CIS-8-(methylamino)-8-phenyl-3-(2-(trifluoromethyl)pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one
  • Step 2 CIS-1-(4-methoxybenzyl)-8-(methylamino)-8-phenyl-3-(2-(trifluoromethyl)pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one
  • reaction mixture was allowed to warm up to RT and stirred for 16 h. The reaction progress was monitored by LCMS. The reaction mixture was diluted with water (150 mL) and the organic product was extracted with EtOAc (3 ⁇ 60mL). The combined organic extracts were dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure.
  • Step 3 CIS-8-((cyclopropylmethyl)(methyl)amino)-1-(4-methoxybenzyl)-8-phenyl-3-(2-(trifluoromethyl)pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one
  • Step 4 CIS-8-((cyclopropylmethyl)(methyl)amino)-8-phenyl-3-(2-(trifluoromethyl)pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one (SC_3132)
  • TFA (4.2 mL) was added drop wise to a solution of CIS-8-((cyclopropylmethyl)(methyl)amino)-1-(4-methoxybenzyl)-8-phenyl-3-(2-(trifluoromethyl)pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one (210mg, 0.363mmol) in DCM (0.05 mL) at 0° C. under argon atmosphere. The reaction mixture was allowed to warm up to RT and stirred for 16 h. The reaction progress was monitored by LCMS. The excess of TFA was evaporated under reduced pressure and the residual amount of TFA was removed as an azeotropic mixture with DCM (2 ⁇ 5mL).
  • Methyl CIS-5-(8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)pyrimidine-2-carboxylate (INT-990) (100 mg, 0.244 mmol) was dissolved in 7N NH 3 in methanol (25 equiv. NH 3 , 0.9 mL) in a microwave reactor vial. The reaction vessel was sealed, the reaction mixture was stirred for 5 days at RT and then concentrated under reduced pressure.
  • CIS-3-(2-chloropyrimidin-5-yl)-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-989) (200 mg, 0.52 mmol), tributyl(2-pyridyl)stannane (1.5 equiv., 0.78 mmol, 286 mg) and Pd(PPh 3 ) 4 (0.1 equiv., 0.052 mmol, 60 mg) were dissolved in degassed anhydrous DMF (150 equiv., 77.7 mmol, 6 mL) under nitrogen atmosphere.
  • DMF degassed anhydrous DMF
  • Step 1 CIS-2-(2-(8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)phenoxy)acetonitrile
  • Step 2 CIS-2-(2-(8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)phenoxy)acetic acid (SC_3169)
  • Step 1 CIS-tert-butyl 4-(5-(8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)pyrimidine-2-carbonyl)piperazine-1-carboxylate
  • Step 2 CIS-8-(dimethylamino)-8-phenyl-3-(2-(piperazine-1-carbonyl)pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one (SC_3173)
  • Et 3 N (0.39 g, 3.89mmol) was added to the solution of CIS-3-(2-chloropyrimidin-5-yl)-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-989) (0.5 g, 1.29mmol) and piperidin-4-ol (0.32 g, 3.24mmol) in DMF (10mL) at RT.
  • the reaction mixture was stirred at 130° C. for 16 h, cooled down to RT and concentrated under reduced pressure. The residue was diluted with 10% aq. NaOH and the organic product was extracted with 1 ⁇ 9 v/v MeOH/DCM.
  • CIS-3-(2-chloropyrimidin-5-yl)-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-989) (150 mg, 0.38 mmol), Pd(t-Bu 3 P) 2 (0.1 equiv., 0.02 mmol, 10 mg) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indolin-2-one (2 equiv., 0.78 mmol, 201 mg) were dissolved in degassed anhydrous THF (80 equiv., 31 mmol, 2.5 mL) and 1M aq.
  • degassed anhydrous THF 80 equiv., 31 mmol, 2.5 mL
  • Step 1 CIS-8-(dimethylamino)-3-(2-((2-methoxyethyl)amino)pyrimidin-5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
  • Step 2 CIS-8-(dimethylamino)-3-(2-((2-hydroxyethyl)amino)pyrimidin-5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (SC_3221)
  • BBr 3 (1M in DCM) (2.2mL, 2.22mmol) was added to the solution of CIS-8-(dimethylamino)-3-(2-((2-methoxyethyl)amino)pyrimidin-5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (0.55 g, 1.06 mmol) in DCM (20 mL) at -78° C. over 15 min. The reaction mixture was stirred at RT for 4 h, then quenched with water and concentrated under reduced pressure.
  • Microwave reactor vial was loaded with CIS-3-(2-chloropyrimidin-5-yl)-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-989) (250 mg, 0.65 mmol), flushed with nitrogen, 7N solution of NH 3 in methanol (108 equiv., 70 mmol, 10 mL) and dioxane (37 equiv., 24 mmol, 2 mL) were added, the vial was sealed and the reaction mixture was stirred at 115° C. for 12 h in the microwave reactor. The reaction mixture was then cooled down to 4° C. overnight.
  • Step 2 CIS-8-(dimethylamino)-8-phenyl-3-(6-(piperazin-1-yl)pyridin-3-yl)-1,3-diazaspiro[4.5]decan-2-one (SC_3242)
  • CIS-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-976) (80 mg, 0.29 mmol), 4-(5-bromopyrimidin-2-yl)piperazine (2 equiv., 0.56 mmol, 142 mg) and potassium phosphate (4 equiv., 1.17 mmol, 248 mg) were suspended in N,N′-dimethylethylenediamine (18 equiv., 5.27 mmol, 0.6 mL) under nitrogen atmosphere. The reaction mixture was stirred at 80° C. for 2 h, diluted with water (10 mL) and extracted with DCM (3 ⁇ 15 mL).
  • CIS-8-amino-1-((1-hydroxycyclobutyl)methyl)-8-phenyl-3-(2-(trifluoromethyl)pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one 70 mg, 0.15 mmol
  • Acetic acid 0.1 equiv., 0.015 mmol, 0.8 ⁇ L
  • acetaldehyde 1.1 equiv., 0.16 mmol, 9 ⁇ L
  • Reverse phase preparative HPLC conditions mobile phase: 10 mM ammonium bicarbonate in H 2 O/acetonitrile; column: X-BRIDGE-C18 (150*19), 5 ⁇ m; mobile phase gradient (min/%B): 0/30, 8/82, 8.1/100, 10/100, 10.1/30, 12/30; flow rate: 19 ml/min; diluent: mobile phase + THF.
  • Enantiomeric mixture of CIS-8-(methyl((tetrahydrofuran-3-yl)methyl)amino)-8-phenyl-3-(2-(trifluoromethyl)pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one (100mg) was separated by chiral SFC to afford 35 mg of enantiomer 1 (SC-3292) and 40 mg of enantiomer 2 (SC-3293) as off-white solids.
  • Preparative SFC conditions column: Chiralpak IA (250 ⁇ 30) mm, 5 ⁇ m;% CO 2 : 50.0%; % co-solvent: 50.0% (100% Methanol); total flow: 70.0 g/min; back pressure: 100.0 bar; UV: 256 nm; stack time: 13.5 min; load/inj.: 9.5 mg; no. of injections: 11.
  • Step 1 5-bromo-2-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)pyrimidine
  • Step 2 CIS-3-(2-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)pyrimidin-5-yl)-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (SC_3313)
  • 1,4-Dioxane (1.5 mL) was added via syringe and the reaction mixture was stirred at 110° C. in the microwave reactor for 10 h.
  • the resulting mixture was cooled down to RT, solution of Xanthphos (19 mg, 0.033 mmol, 0.15 equiv.) and Pd 2 (dba) 3 (10 mg, 0.011 mmol, 0.05 equiv.) in 1,4 dioxane (1 mL) was added, and the reaction mixture was stirred at 130°C in the microwave reactor for further 10 h.
  • the resulting suspension was cooled to RT, quenched with water and extracted with DCM (3x). The combined organic layer was dried over Na 2 SO 4 and concentrated under reduced pressure.
  • Step 1 CIS-2-(3-(8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)pyridin-4-yl)acetonitrile
  • CIS-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-976) was reacted with (3-bromo-pyridin-4-yl)-acetonitrile to be converted into CIS-2-(3-(8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)pyridin-4-yl)acetonitrile.
  • Step 2 CIS-2-(3-(8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)pyridin-4-yl)acetamide (SC_3340)
  • Step 1 CIS-7-(8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-3-((2-(trimethylsilyl)ethoxy)methyl)benzo[d]oxazol-2(3H)-one
  • Step 2 CIS-8-(dimethylamino)-3-(2-hydroxybenzo[d]oxazol-7-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (SC_3352)
  • Step 1 CIS-8-(dimethylamino)-8-phenyl-3-(1-tosyl-1H-indol-3-yl)-1,3-diazaspiro[4.5]decan-2-one
  • Step 2 CIS-8-(dimethylamino)-3-(1H-indol-3-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (SC_3357)
  • Step 1 CIS-4-(8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-1-(4-methoxybenzyl)indoline-2,3-dione
  • Step 2 CIS-4-(8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-1-(4-methoxybenzyl)indolin-2-one
  • Step 3 CIS-4-(8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)indolin-2-one (SC_3396)
  • SC_3104 cis-1-(Cyclobutyl-methyl)-8-methylamino-3-[4-methyl-6-(trifluoromethyl)-pyridin-3-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
  • SC_3103 SC_3099 1H NMR (DMSO-d6): ⁇ 8.59 (s, 1H), 7.81 (s, 1H), 7.44 (d, 2H), 7.30 (t, 2H), 7.17 (t, 1H), 3.76 (s, 2H), 3.21 (d, 2H), 2.61-2.57 (m, 1H), 2.32 (s, 3H), 2.29-2.17 (m, 3H), 2.03-1.97 (m, 2H), 1.91-1.88 (m, 5H), 1.84-1.67 (m, 6H), 1.51-1.48 (m, 2H).
  • SC_3107 cis-1-(Cyclopropyl-methyl)-8-dimethylamino-3 -(2-fluoro-4-methylsulfonyl-phenyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one INT-983 1-bromo-2-fluoro-4-(methylsulfonyl)benzene (step 1), (Bromomethyl)cyclopropane (step 2) SC3103 (step 1), SC_3105 (step 2) 1H NMR (DMSO-d6): ⁇ 7.85 (t, 1H), 7.79-7.76 (m, 1H), 7.72-7.69 (m, 1H), 7.37-7.33 (m, 4H), 7.27-7.24 (m, 1H), 3.81 (s, 2H), 3.24 (s, 3H), 3.07 (d, 2H), 2.71-2.68 (m, 2H), 2.28-2.22 (m, 2H), 1.99 (s, 6H), 1.5
  • SC_3108 cis-2-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-benzamide; formic acid SC_3071 SC_3016 1H NMR (600 MHz, DMSO) ⁇ 7.59 - 7.55 (s, 1H), 7.47 - 7.39 (m, 2H), 7.39 - 7.31 (m, 5H), 7.30 - 7.21 (m, 3H), 3.77 - 3.73 (s, 2H), 3.21 - 3.17 (s, 1H), 2.72 - 2.66 (d, 2H), 2.17 - 2.09 (m, 5H), 2.02 - 1.99 (s, 6H), 1.95 - 1.86 (m, 2H), 1.71 - 1.60 (m, 3H), 1.49 - 1.37 (m, 3H) 477.3 SC_3109 cis-2-[8-[
  • SC_3115 cis-2-[8-Ethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-benzonitrile
  • step 1 SC_3112 (step 1, step 2)
  • SC_3117 cis-2-[8-Dimethylamino-1-(oxetan-3-yl-methyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-benzamide
  • SC_3274 toluene-4-sulfonic acid oxetan-3-ylmethyl ester step 1) SC_3105 (step 1), SC_3016 (step 2)
  • SC_3124 cis-8-Dimethylamino-8-phenyl-3-(2-piperazin-1-yl-pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one INT-989 Piperazine-2-one SC_3120 1H NMR (600 MHz, DMSO) ⁇ 8.52 (s, 2H), 7.41 - 7.31 (m, 5H), 3.59 - 3.54 (m, 4H), 3.52 (s, 2H), 2.76 - 2.70 (m, 4H), 2.55 (s, 3H), 2.49 - 2.33 (m, 2H), 1.96 (s, 6H),1.93 - 1.83 (m, 4H), 1.51- 1.43 (s, 2H).
  • SC_3136 cis-3-[2-(4-Acetyl-piperazin-1-yl)-pyrimidin-5-yl]-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3124 acetyl chloride SC_3130 478.3 SC_3137 cis-8-Dimethylamino-8-phenyl-3-(2-pyridin-4-yl-pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one INT-989 pyridine-4-boronic acid SC_3129 1HNMR (600 MHz, DMSO) ⁇ 9.16 (s, 2H), 8.70 (d, 1H), 8.18 (s, 1H), 7.91 (s, 1H), 7.42 - 7.35 (m, 4H), 7.28 (tt, 1H), 3.73 (s, 2H), 2.49 - 2.37 (m, 2H), 1.98 (s,
  • SC_3138 cis-8-Dimethylamino-8-phenyl-3-(2-pyridin-3-yl-pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one INT-989 pyridine-3-boronic acid SC_3129 1HNMR (600 MHz, DMSO) ⁇ 9.43 (dd, 1H), 9.13 (s, 2H), 8.65 (dd, 1H), 8.58 (dt,1H), 7.52 (ddd, 1H), 7.42 - 7.36 (m, 4H), 7.28 (ddd, 1H), 3.72 (s, 2H), 1.98 (s, 6H), 2.02 - 1.89 (m, 4H), 1.57 - 1.46 (m, 4H).
  • SC_3142 cis-4-[5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-pyrimidin-2-yl] -benzonitrile INT-989 4-cyanophenylboronic acid SC_3129 1HNMR (600 MHz, DMSO) ⁇ 9.15 (s, 2H), 8.49 - 8.43 (m, 2H), 7.99 - 7.92 (m, 2H), 7.89 (s, 1H), 7.38 (m, 4H), 7.28 (td, 1H), 3.73 (s, 2H), 2.48 - 2.35 (m, 1H), 2.03 - 1.90 (m, 10H), 1.55 - 1.48 (m,2H).
  • SC_3151 cis-5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-N-(2-hydroxy-ethyl)-N-methyl-pyrimidine-2-carboxylic acid amide INT-991 2-(methylamino)ethanol SC_3133 1HNMR (600 MHz, DMSO) ⁇ 9.03 (d, 2H), 7.86 (s, 1H), 7.40 - 7.23 (m, 5H), 3.69 (s, 2H), 3.61 (q, 1H), 3.50 (t, 1H), 3.45 (d, 1H), 3.17 (t, 1H), 3.01 and 2.83 (both s, together 3H, amide rotamers), 2.49 - 2.36 (m, 2H), 2.00 - 1.89 (m, 8H), 1.89 - 1.73 (m, 2H), 1.55 - 1.47 (m, 2H).
  • SC_3152 cis-5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-2-morpholin-4-yl-isonicotinonitrile INT-976 5-bromo-2-morpholino-pyridine-4-carbonitrile SC_3103 1H NMR (600 MHz, DMSO) ⁇ 8.24 (s, 1H), 7.67 - 7.30 (m, 5H), 7.29 (s, 1H), 3.70 - 3.65 (m, 4H), 3.51 - 3.44 (m, 4H), 2.37 - 2.22 (m, 2H), 2.10 - 1.87 (m, 10H), 1.53 - 1.31 (m, 2H).
  • SC_3155 cis-4-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-3-fluoro-benzonitrile INT-976 4-bromo-3-fluoro-benzonitrile SC_3103 1H NMR (600 MHz, DMSO) ⁇ 7.85 - 7.79 (m, 2H), 7.73 (s, 1H), 7.62 (dd, 1H), 7.40 - 7.31 (m, 4H), 7.26 (tt, 1H), 3.69 (s, 2H), 2.40 - 2.31 (m, 2H), 1.95 (s, 6H), 1.94 - 1.87 (m, 2H), 1.87 - 1.75 (m, 2H), 1.52 - 1.46 (m, 2H).
  • SC_3164 cis-4-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-3-fluoro-benzamide
  • SC_3155 SC_3016 1H NMR (600 MHz, DMSO) ⁇ 7.95 (s, 1H), 7.72 - 7.64 (m, 2H), 7.61 (t, 1H), 7.54 - 7.50 (m, 1H), 7.40 - 7.32 (m, 5H), 7.26 (tt, 1H), 3.62 (s, 2H), 2.41 - 2.31 (m, 2H), 1.96 (s, 6H), 1.93 - 1.88 (m, 2H), 1.86 - 1.75 (m, 2H), 1.53 - 1.45 (m, 2H).
  • SC_3175 cis-5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-2-morpholin-4-yl-pyridine-4-carboxylic acid amide
  • SC_3152 SC_3016 480.6
  • SC_3176 cis-8-Dimethylamino-3-[2-(3,5-dimethyl-isoxazol-4-yl)-pyrimidin-5-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one INT-989 (3,5-dimethylisoxazol-4-yl)boronic acid SC_3129
  • 1HNMR 600 MHz, DMSO) ⁇ 9.05 (s, 2H), 7.80 (s, 1H), 7.43 - 7.34 (m, 4H), 7.28 (tt, 1H), 3.68 (s, 2H), 2.69 (s, 3H), 2.47 (s, 3
  • SC_3180 cis-8-Dimethylamino-8-phenyl-3-(2-phenyl-thiazol-4-yl)-1,3-diazaspiro[4.5]decan-2-one INT-976 4-bromo-2-phenylthiazole SC_3103 1HNMR (DMSO-d6): ⁇ 7.89-7.87 (m, 2H), 7.55 (br s, 1H), 7.43-7.35 (m, 8H), 7.29-7.26 (m, 1H), 3.82 (s, 2H), 2.45 (br m, 2H), 1.96-1.79 (m, 10H), 1.53-1.50 (m, 2H).
  • SC_3217 cis-8-Dimethylamino-3-[4-methyl-6-(trifluoromethyl)-pyridin-3-yl]-8-thiophen-2-yl-1,3-diazaspiro[4.5]decan-2-one INT-997 5-bromo-4-methyl-2-(trifluoromethyl)pyridine
  • SC_3103 1H NMR (600 MHz, DMSO) ⁇ 8.58 (s, 1H), 7.80 (s, 1H), 7.45 (s, 1H), 7.42 (dd, 1H), 7.05 (dd, 1H), 6.95 (dd, 1H), 3.67 (s, 2H), 2.33 (s, 3H), 2.32 - 2.25 (m, 2H), 2.04 (s, 6H), 2.00 - 1.92 (m, 2H), 1.89 - 1.76 (m, 2H), 1.62 (dt, 2H).
  • SC_3218 cis-8-Dimethylamino-3-[2-(1,1-dioxo-[1,4]thiazinan-4-yl)-4-(trifluoromethyl)-pyrimidin-5-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one INT-976 4-[5-bromo-4-(trifluoromethyl)pyrimidin-2-yl]-1,4-thiazinane1,1-dioxide (prepared as SC_3097 step 1) SC_3103 1H NMR (600 MHz, DMSO) ⁇ 8.65 (s, 1H), 7.42 (s, 1H), 7.41 - 7.31 (m, 5H), 7.25 (tt, 1H), 4.23 (t, 4H), 3.22 (t, 4H), 2.40 - 2.26 (m, 2H), 1.97 - 1.88 (m, 8H), 1.87 - 1.75 (m, 2H), 1.54 - 1.42 (
  • SC_3226 cis-3-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-benzamide INT-976 5-bromo-4-methyl-2-(trifluoromethyl)pyridine SC_3103 (step 1), SC_3016 (step 2) 487.3 SC_3227 cis-8-Dimethylamino-3-[3-fluoro-5-(trifluoromethyl)-pyridin-2-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one INT-976 2-bromo-3-fluoro-5-(trifluoromethyl)pyridine SC_3186 417.1 SC_3228 cis-8-Dimethylamino-3-(5-methyl-pyrazin-2-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one INT-976 2-bromo-5-methylpyrazine SC_
  • SC_3244 cis-8-Dimethylamino-3-[2-(1,1-dioxo-[1,4]thiazinan-4-yl)-4-methyl-pyrimidin-5-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one INT-976 4-(5-bromo-4-methyl-pyrimidin-2-yl)-1,4-thiazinane1,1-dioxide SC_3103 1H NMR (600 MHz, DMSO) ⁇ 8.20 (s, 1H), 7.36 (h, 4H), 7.30 - 7.17 (m, 2H), 4.23 - 4.17 (m, 4H), 3.13 (t, 4H), 2.44 - 2.28 (m, 2H), 2.24 (s, 3H), 1.97 (s, 6H), 1.91 (d, 4H), 1.55 - 1.44 (m, 2H).
  • SC_3245 cis-8-Dimethylamino-8-phenyl-3-[2-(trifluoromethyl)-pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2-one INT-976 5-bromo-2-(trifluoromethyl)-pyrimidine SC_3103 1HNMR (600 MHz, DMSO) ⁇ 9.17 (s, 2H), 8.03 (s, 1H), 7.38 (s, 4H), 7.28 (tt, 1H), 3.73 (s, 2H), 2.49 - 2.35 (m, 2H), 1.97 (s, 6H), 1.97 - 1.92 (m, 2H), 1.90 - 1.73 (m, 2H), 1.55 - 1.49 (m, 2H).
  • SC_3246 cis-2-[8-Dimethylamino-1-(3-methoxy-propyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-5-carbonitrile INT-979 2-chloropyrimidine-5-carbonitrile SC_3103 1HNMR (600 MHz, DMSO) ⁇ 9.02 (s, 2H), 7.40 - 7.31 (m, 5H), 3.86 (s, 2H), 3.26 (s, 3H), 3.29 - 3.19 (m, 2H), 2.73 - 2.67 (m, 2H), 2.16 (td, 2H), 2.00 (s, 7H), 1.83 (dt, 2H), 1.50 - 1.40 (m, 5H).
  • SC_3248 cis-8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-8-phenyl-3-[2-(trifluoromethyl)-pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2-one
  • SC_3245 [1-[tert-butyl(dimethyl)silyl]-oxycyclobutyl]methyl 4-methylbenzenesulfonate INT-988 (step 1)
  • 1HNMR 600 MHz, DMSO) ⁇ 9.24 (s, 2H), 7.38 (d, 4H), 7.27 (p, 1H), 3.89 (s, 2H), 2.73 - 2.67 (m, 2H), 2.26 (ddd, 2H), 2.19 (tt, 2H), 2.08 (s, 1H), 2.00 (s, 6H), 1.92 (qd, 2H), 1.73 - 1.64 (m, 1H), 1.60 - 1.50 (m, 3H),
  • SC_3254 cis-8-Dimethylamino-1-[(2-methoxyphenyl)-methyl]-3-(2-methyl-pyrimidin-5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
  • SC_3253 2-methoxybenzyl bromide SC_3105 1H NMR (DMSO-d6): ⁇ 8.90 (s, 2H), 7.39-7.34 (m, 3H), 7.28-7.22 (m, 4H), 6.95-6.87 (m, 2H), 4.58 (s, 2H), 3.89 (s, 3H), 3.63 (s, 2H), 2.68-2.64 (m, 5H), 2.35-2.28 (m, 2H), 2.01(s, 6H), 1.49-1.43 (m, 4H).
  • SC_3259 cis-8-Dimethylamino-3-(2-methyl-pyrimidin-5-yl)-8-phenyl-1-(pyridin-2-yl-methyl)-1,3-diazaspiro[4.5]decan-2-one
  • SC_3253 2-(bromomethyl)pyridine
  • SC_3263 cis-8-Dimethylamino-3-(3-fluorophenyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one INT-976 1-bromo-3-fluoro-benzene SC_3103 1H NMR (600 MHz, DMSO) ⁇ 7.58 - 7.50 (m, 2H), 7.41 - 7.33 (m, 4H), 7.33 - 7.23 (m, 3H), 6.77 - 6.71 (m, 1H), 3.58 (s, 2H), 2.48 - 2.31 (m, 2H), 1.97 (s, 6H), 1.92 - 1.80 (m, 4H), 1.47 (t, 2H).
  • SC_3270 cis-8-Methylamino-1-(oxetan-3-yl-methyl)-8-phenyl-3-[2-(trifluoromethyl)-pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2-one
  • SC_3245 oxetan-3-ylmethyl 4-methylbenzenesulfonate (step 2)
  • SC_3099 for step 1)
  • SC_3105 for step 2)
  • 1H NMR (DMSO-d6) ⁇ 9.24 (s, 2H), 7.49 (d, 2H), 7.34 (t, 2H), 7.21 (t, 1H), 4.66-4.62 (m, 2H), 4.44 (t, 2H), 3.87 (s, 2H), 3.55 (d, 2H), 3.28-3.23 (m, 1H), 2.36 (m, 1H), 2.20-2.14 (m, 2H), 1.95-1.91 (m, 5H), 1.84-1.77 (m, 2H),
  • SC_3271 cis-1-(Cyclopropyl-methyl)-8-methylamino-8-phenyl-3-[2-(trifluoromethyl)-pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2-one
  • SC_3245 bromomethyl)-cyclopropane SC_3099 (for step 1), SC_3105 (for step 2)
  • 1H NMR (DMSO-d6) ⁇ 9.26 (s, 2H), 7.50 (d, 2H), 7.35 (t, 2H), 7.22 (t, 1H), 3.89 (s, 2H), 3.13 (d, 2H), 2.29-2.23 (m, 3H), 1.92-1.82 (m, 7H), 1.47-1.44 (m, 2H), 1.08-1.05 (m, 1H), 0.52-0.48 (m, 2H), 0.36-0.36-0.32 (m, 2H).
  • SC_3272 cis-4-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-benzonitrile INT-976 4-bromobenzonitrile SC_3103 1H NMR (600 MHz, DMSO) ⁇ 7.82 - 7.71 (m, 3H), 7.72 - 7.67 (m, 2H), 7.41 - 7.33 (m, 4H), 7.30 - 7.23 (m, 1H), 3.63 (s, 2H), 2.45 - 2.39 (m, 2H), 1.97 (s, 6H), 1.95 - 1.72 (m, 4H), 1.51 - 1.44 (m, 2H).
  • SC_3278 cis-8-Dimethylamino-3-[2-(methyl-tetrahydro-pyran-4-yl-amino)-pyrimidin-5-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one INT-989 N-methyltetrahydro-2H-pyran-4-amine SC_3120 1H NMR (DMSO-d6): ⁇ 8.50 (s, 2H), 7.39-7.35 (m, 5H), 7.27-7.24 (m, 1H), 4.74-4.67 (m, 1H), 3.94-3.90 (m, 2H), 3.50 (s, 2H), 3.39 (t, 2H), 2.93 (s, 3H), 2.35 (m, 2H), 1.99-1.71 (m, 12H), 1.50-1.44 (m, 4H).
  • SC_3282 cis-2-[[5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-pyrimidin-2-yl]amino]-acetamide
  • SC_3103 for step 1)
  • SC_3100 step 3 for step 2)
  • 1H NMR (DMSO-d6) ⁇ 8.45 (s, 2H), 7.39-7.33 (m, 5H), 7.27-7.22 (m, 2H), 6.92 (s, 1H), 6.86 (t, 1H), 3.74 (d, 2H), 3.51 (s, 2H), 2.46-2.28 (m, 2H), 1.95-1.86 (m, 10H), 1.45 (m, 2H).
  • SC_3286 cis-N-[5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-pyrimidin-2-yl]-benzamide
  • SC_3239 benzoyl chloride
  • SC_3240 1H NMR (600 MHz, DMSO) ⁇ 10.84 (s, 1H), 8.91 (s, 2H), 7.98 - 7.93 (m, 2H), 7.62 - 7.55 (m, 1H), 7.50 (t, 2H), 7.39 (d, 4H), 7.28 (dt, 1H), 3.67 (s, 2H), 2.48 - 2.32 (m, 2H), 2.05 - 1.76 (m, 10H), 1.55 - 1.49 (m, 2H).
  • SC_3288 cis-1-(Cyclopropyl-methyl)-8-dimethylamino-3-[2-(methylsulfonyl-methyl)-phenyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one INT-984 1-bromo-2-(methylsulfonylmethy1)benzene SC_3103 1H NMR (CDCl3): ⁇ 7.49 (d, 1H), 7.41-7.22 (m, 8H), 4.45 (s, 2H), 3.64 (s, 2H), 3.15 (d, 2H), 2.79 (s, 3H), 2.71-2.67 (m, 2H), 2.37 (t, 2H), 2.06 (s, 6H), 1.67-1.64 (m, 2H), 1.55-1.44 (m, 2H), 1.10-1.06 (m, 1H), 0.57-0.52 (m, 2H), 0.39-0.35 (m, 2H).
  • SC_3294 cis-8-Dimethylamino-8-(3-fluorophenyl)-3-(4-methyl-2-morpholin-4-yl-pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one INT-1024 4-(5-bromo-4-methyl-pyrimidin-2-yl)morpholine SC_3103 1H NMR (600 MHz, DMSO) ⁇ 8.13 (s, 1H), 7.40 (td, 1H), 7.22 - 7.11 (m, 4H), 7.08 (td, 1H), 3.69 - 3.60 (m, 8H), 2.34 - 2.31 (m, 2H), 2.20 (s, 3H), 1.96 (s, 6H), 1.96 - 1.70 (m, 4H), 1.56 - 1.43 (m, 2H).
  • SC_3305 cis-8-[Methyl-(tetrahydro-furan-3-yl-methyl)-amino]-3-(2-morpholin-4-yl-pyrimidin-5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (enantiomer 2)
  • enantiomer 2 INT-1026 4-(5-bromopyrimidin-2-yl)morpholine step 2 of SC_3097 (for synthesis), SC_3292 and SC_3293 (for separation of enantiomers)
  • 1H NMR (DMSO-d6) ⁇ 8.56 (s, 2H), 7.66 (broad s, 1H), 7.35-7.24 (m, 5H), 3.63-3.49 (m, 12H), 3.31 (m, 1H), 2.27 (m, 3H), 2.11-1.84 (m, 10H), 1.42 (m, 3H).
  • SC_3311 cis-8-Dimethylamino-3-(5-methylsulfonyl-pyridin-2-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one INT-976 2-bromo-5-methylsulfonylpyridine
  • SC_3103 1H NMR (600 MHz, DMSO) ⁇ 8.66 (dd, 1H), 8.39 (dd, 1H), 8.14 (dd, 1H), 8.06 (s, 1H), 7.42 - 7.33 (m, 4H), 7.28 (t, 1H), 3.77 (s, 2H), 3.21 (s, 3H), 2.46 - 2.32 (m, 2H), 2.03 - 1.68 (m, 10H), 1.52 - 1.46 (m, 2H).
  • SC_3312 cis-6-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-nicotinonitrile INT-976 6-bromopyridine-3-carbonitrile SC_3103 1H NMR (600 MHz, DMSO) ⁇ 8.66 (d, 1H), 8.34 (d, 1H), 8.08 (dd, 1H), 7.41 - 7.33 (m, 4H), 7.28 (t, 1H), 3.74 (s, 2H), 2.46 - 2.30 (m, 2H), 1.96 (s, 6H), 1.94 - 1.73 (m, 4H), 1.51 - 1.44 (m, 2H).
  • SC_3317 cis-2-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-benzamide INT-976 2-bromobenzonitrile SC_3103 (step 1), SC_3016 (step 2) 1H NMR (600 MHz, DMSO) ⁇ 7.50 (s, 1H), 7.42 (dd, 1H), 7.42 - 7.32 (m, 5H), 7.31 (d, 1H), 7.26 (t, 1H), 7.23 - 7.13 (m, 3H), 3.53 (s, 2H), 2.41 - 2.27 (m, 2H), 1.96 (s, 6H), 1.90 (t, 2H), 1.86 - 1.68 (m, 2H), 1.52 - 1.48 (m, 2H).
  • SC_3320 cis-8-Dimethylamino-3-(4-methyl-2-morpholin-4-yl-pyrimidin-5-yl)-8-thiophen-2-yl-1,3-diazaspiro[4.5]decan-2-one INT-997 4-(5-bromo-4-methyl-pyrimidin-2-yl)morpholine SC_3319 1H NMR (600 MHz, DMSO) ⁇ 8.15 (d, 1H), 7.41 (dt, 1H), 7.13 (s, 1H), 7.05 (ddd, 1H), 6.94 (dd, 1H), 3.71 - 3.60 (m, 8H), 3.44 (s, 2H), 2.32 - 2.24 (m, 2H), 2.21 (s, 3H), 2.04 (s, 6H), 1.98 - 1.88 (m, 2H), 1.87 - 1.75 (m, 2H), 1.62 - 1.54 (m, 2H).
  • SC_3322 cis-8-Dimethylamino-8-phenyl-3-(1H-pyrrolo [2,3-b]pyridin-5-yl)-1,3-diazaspiro[4.5]decan-2-one INT-976 tert-butyl 5-bromopyrrolo[2,3-b]pyridine-1-carboxylate (step 1) SC_3103 (for step 1), SC_3173 (for step 2) 1H NMR (600 MHz, DMSO) ⁇ 11.45 (s, 1H), 8.38 (s, 1H), 8.00 (d, 1H), 7.85 - 7.81 (m, 1H), 7.70 - 7.66 (m, 2H), 7.57 - 7.53 (m, 3H), 7.41 (t, 1H), 6.35 (dd, 1H), 3.54 (s, 2H), 2.75 - 2.41 (m, 8H, overlapps with solvent residual peak), 2.30 - 2.26 (m, 2H), 1.89 (d, 2H), 1.
  • SC_3323 cis-N-[5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-pyrimidin-2-yl]-acetamide (enantiomer 1)
  • SC_3239 acetyl chloride SC_3240 1H NMR (600 MHz, DMSO) ⁇ 10.36 (s, 1H), 8.82 (s, 2H), 8.40 (s, rotamer), 7.67 (s, 1H), 7.44 - 7.31 (m, 4H), 7.27 (td, 1H), 3.62 (s, 2H), 2.46 - 2.30 (m, 2H), 2.11 (s, 3H), 2.08 (s, rotamer), 1.96 (s, 6H), 1.97 (s, rotamer), 1.95 - 1.75 (m, 4H), 1.52 - 1.47 (m, 2H).
  • SC_3324 cis-3-[2-(4-Methyl-piperazin-1-yl)-pyrimidin-5-yl]-8-[methyl-(tetrahydro-furan-3-yl-methyl)-amino]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (enantiomer 2) INT-1026 5-bromo-2-(4-methylpiperazin-1-yl)pyrimidine step 2 of SC_3097 (for synthesis), SC_3292 and SC_3293 (for separation of enantiomers) 1H NMR (DMSO-d6): ⁇ 8.52 (s, 2H), 7.64 (broad s, 1H), 7.36-7.23 (m, 5H), 3.66-3.55 (m, 7H), 3.48 (s, 2H), 3.37-3.36 (m, 1H), 2.33-2.13 (m, 11H), 2.01-1.82 (m, 9H), 1.50-1.41 (m, 3H).
  • SC_3326 cis-8-Dimethylamino-3-(4,6-dimethyl-2-morpholin-4-yl-pyrimidin-5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one INT-976 4-(5-bromo-4,6-dimethyl-pyrimidin-2-yl)morpholine SC_3103 465.3 SC_3327 cis-8-Dimethylamino-3-(2-morpholin-4-yl-pyrimidin-5-yl)-8-thiophen-2-yl-1,3-diazaspiro[4.5]decan-2-one INT-1027 morpholine SC_3120 1H NMR (600 MHz, DMSO) ⁇ 8.58 (s, 2H), 7.43 (dd, 1H), 7.40 - 7.32 (m, 1H), 7.07 (dd, 1H), 6.96 (dd, 1H), 3.67 - 3.61 (m, 4H), 3.62 -
  • SC_3330 cis-8-Dimethylamino-3-[2-[(2-hydroxy-ethyl)-methyl-amino]-pyrimidin-5-yl]-8-thiophen-2-yl-1,3-diazaspiro[4.5]decan-2-one INT-1027 2-(methylamino)ethanol SC_3120 1H NMR (600 MHz, DMSO) ⁇ 8.48 (s, 2H), 7.43 (d, 1H), 7.30 (s, 1H), 7.07 (dd, 1H), 6.96 (d, 1H), 3.61 (dd, 2H), 3.58 - 3.51 (m, 4H), 3.09 (s, 3H), 2.34 - 2.22 (m, 2H), 2.04 (s, 6H), 1.96 - 1.76 (m, 4H), 1.56 - 1.50 (m, 2H).
  • SC_3335 cis-3-(Benzothiazol-7-yl)-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one INT-976 7-bromo-benzothiazole SC_3103 407.1
  • SC_3336 cis-8-Dimethylamino-8-(4-fluorophenyl)-3-(4-methyl-2-morpholin-4-yl-pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one INT-1025 4-(5-bromo-4-methyl-pyrimidin-2-yl)morpholine SC_3319 1H NMR (600 MHz, DMSO) ⁇ 8.13 (s, 1H), 7.41 - 7.35 (m, 2H), 7.22 - 7.13 (m, 3H), 3.69 - 3.60 (m, 8H), 2.35 - 2.31 (m, 2H), 2.20 (s, 3H), 1.94
  • SC_3346 cis-8-Dimethylamino-8-phenyl-3-[2-[4-(trifluoromethyl)-1H-[1,2,3]triazol-1-yl]-pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2-one INT-976 3,3,3-trifluoroprop-1-yne, 2-azido-5-bromo-pyrimidine SC_3313 1H NMR (600 MHz, DMSO) ⁇ 9.56 (d, 1H), 9.16 (s, 2H), 7.99 (s, 1H), 7.42 - 7.35 (m, 4H), 7.31 - 7.25 (m, 1H), 3.75 (s, 2H), 2.49 - 2.34 (m, 2H), 2.05 - 1.75 (m, 10H), 1.60 - 1.47 (m, 2H).
  • SC_3351 cis-8-Dimethylamino-3-(1H-indol-4-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one INT-976 4-bromo-1-(toluene-4-sulfonyl)-1H-indole (step 1)
  • SC_3357 1H-NMR (DMSO-d6, 400 MHz at 100 0C), ⁇ (ppm) 10.77 (bs, 1H), 7.37 (bs, 4H), 7.24-7.18 (m, 3H), 7.02-6.94 (m, 2H), 6.81 (bs, 1H), 6.41 (s, 1H), 3.66 (s, 2H), 2.36-2.33 (m, 2H), 2.05-1.96 (m, 10H), 1.60-156 (m, 2H).
  • SC_3358 cis-6-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-5-methyl-nicotinonitrile INT-976 6-chloro-5-methyl-pyridine-3-carbonitrile SC_3103 1H NMR (600 MHz, DMSO) ⁇ 8.64 (s, 1H), 8.12 (s, 1H), 7.76 (s, 1H), 7.39 - 7.34 (m, 4H), 7.27 (s, 1H), 3.71 (s, 2H), 2.43 - 2.15 (m, 5H), 2.11 - 1.70 (m, 10H), 1.52 (s, 2H).
  • SC_3362 cis-6-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-5-fluoro-pyridine-3-carboxylic acid amide
  • SC_3359 SC_3016 1H NMR (600 MHz, DMSO) ⁇ 8.65 - 8.61 (m, 1H), 8.13 (s, 1H), 8.04 (dd, 1H), 7.76 (s, 1H), 7.59 (s, 1H), 7.39 - 7.30 (m, 4H), 7.28 - 7.21 (m, 1H), 3.70 (s, 2H), 2.41 - 2.23 (m, 2H), 1.96 - 1.76 (m, 10H), 1.50 (t, 2H).
  • SC_3366 cis-8-Dimethylamino-3-[4-methyl-6-(trifluoromethyl)-pyridin-3-yl]-8-[3-(trifluoromethyloxy)-phenyl]-1,3-diazaspiro[4.5]decan-2-one INT-1039 5-bromo-4-methyl-2-(trifluoromethyl)pyridine SC_3319 1H NMR (600 MHz, DMSO) ⁇ 8.55 (s, 1H), 7.79 (s, 1H), 7.51 (t, 2H), 7.38 (dd, 1H), 7.26 (d, 2H), 3.62 (s, 2H), 2.40 - 2.34 (m, 2H), 2.31 (s, 3H), 2.01 - 1.77 (m, 10H), 1.58 - 1.49 (m, 2H).
  • SC_3373 cis-N-[5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-pyrimidin-2-yl]-N-methyl-cyclopropanecarboxylic acid amide
  • SC_3371 Cyclopropancarbonyl chlorid SC_3240 1H NMR (600 MHz, DMSO) ⁇ 8.97 (s, 2H), 7.83 - 7.73 (m, 1H), 7.41 - 7.34 (m, 4H), 7.30 - 7.24 (m, 1H), 3.66 (s, 2H), 3.27 (s, 3H), 2.47 - 2.29 (m, 2H), 1.99 - 1.87 (m, 10H), 1.49 (t, 2H), 0.88 - 0.80 (m, 2H), 0.70 (dt, 2H).
  • SC_3374 cis-N-[5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-pyrimidin-2-yl]-N,2,5-trimethyl-2H-pyrazole-3-carboxylic acid amide
  • SC_3371 2,5-dimethylpyrazole-3-carbonyl chloride
  • SC_3240 1H NMR (600 MHz, DMSO) ⁇ 8.83 (s, 2H), 7.77 (s, 1H), 7.41 - 7.32 (m, 4H), 7.27 (td, 1H), 5.48 (s, 1H), 3.80 (s, 3H), 3.61 (s, 2H), 3.40 (s, 3H), 2.46 - 2.31 (m, 2H), 1.96 (s, 3H), 1.96 (s, 6H), 1.94 - 1.74 (m, 5H), 1.52 - 1.42 (m, 2H).
  • SC_3382 cis-N-[5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-pyrimidin-2-yl]-N-methyl-tetrahydro-pyran-4-carboxylic acid amide
  • SC_3240 1H NMR (600 MHz, DMSO) ⁇ 8.97 (s, 2H), 7.80 (s, 1H), 7.42 - 7.34 (m, 4H), 7.31 - 7.25 (m, 1H), 3.79 (ddd, 2H), 3.67 (s, 2H), 3.25 (s, 2H), 3.17 (td, 2H), 3.04 - 2.96 (m, 1H), 2.49 - 2.34 (m, 2H), 1.97 (s, 6H), 1.95 - 1.74 (m, 4H), 1.68 - 1.53 (m, 4H
  • SC_3383 cis-N-[5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-pyrimidin-2-yl]-N,2,2-trimethyl-propionamide SC_3371 pivaloyl chloride SC_3240 1H NMR (600 MHz, DMSO) ⁇ 8.98 (s, 2H), 7.42 - 7.34 (m, 4H), 7.30 - 7.26 (m, 1H), 3.69 (s, 2H), 3.14 (s, 3H), 2.46 - 2.41 (m, 2H), 1.99 - 1.87 (m, 10H), 1.54 - 1.45 (m, 2H), 0.97 (s, 9H).
  • SC_3384 cis-8-Dimethylamino-3-[2-(1-methyl-2-oxo-1,3-dihydro-indol-4-yl)-pyrimidin-5-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one INT-989 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indolin-2-one SC_3208 1H NMR (600 MHz, CDCl3) ⁇ 9.05 (s, 2H), 8.08 (d, 1H), 7.47 - 7.39 (m, 3H), 7.38 - 7.31 (m, 3H), 6.91 (d, 1H), 5.46 (s, 1H), 4.04 (s, 2H), 3.64 (s, 2H), 3.27 (s, 3H), 2.35 - 2.14 (m, 4H), 2.10 (s, 6H), 2.08 - 2.01 (m, 3H), 1.73 -

Abstract

The invention relates to 3-((hetero-)aryl)-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. Pat. Application No. 17/188,860, filed Mar. 1, 2021, which is a continuation of U.S. Pat. Application No. 17/010,089, filed Sep. 2, 2020, abandoned, which is a continuation of U.S. Pat. Application No. 16/450,331, filed Jun. 24, 2019, now U.S. Pat. No. 10,807,988, which is a continuation of U.S. Pat. Application No. 16/207,854, filed Dec. 3, 2018, abandoned, which is a continuation of U.S. Pat. Application No. 15/923,948, filed Mar. 16, 2018, abandoned; which is a continuation of U.S. Pat. Application No. 15/405,485, filed Jan. 13, 2017, abandoned; which claims foreign priority benefit under 35 U.S.C. § 119 of European Patent Application No. 16 151 012.8, filed Jan. 13, 2016, the disclosures of which are incorporated herein by reference.
  • The invention relates to 3-((hetero-)aryl)-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 al., 2001; Kalso et al., 2002; Stein et al., 2003;Zollner et al., 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-((hetero-)aryl)-8-amino-2-oxo-1,3-diaza-spiro-[4.5]-decane derivatives according to general formula (I)
  • Figure US20230303573A1-20230928-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—;
    • R5 means a 6-14-membered aryl moiety, unsubstituted, mono- or polysubstituted; or a 5-14-membered heteroaryl moiety, unsubstituted, mono- or polysubstituted;
    • 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, —C(═O)NH—(CH2CH2—O)1—30—CH3, —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, —CO2H, -C(=O)O-C1-C6-alkyl, —C(═O)NH2, -C(=O)NHC1-C6-alkyl, -C(=O)N(C1-C6-alkyl)2, -O-C1-C6-alkyl and -S(=O)2-C1-C6-alkyl;
    • 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 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, mono- or polysubstituted; 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-alkcylene-, 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—; —(CH2)2—S(═O)2—(CH2)2— or —(CH2)2—NRB—(CH2)2—, wherein RB means —H, -C1-C6-alkyl, -C(=O)-C1-C6-alkyl, or -S(=O)2-C1-C6-alkyl, wherein said -C1-C6-alkyl is 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, —CO2H, -C(=O)O-C1-C6-alkyl and —C(═O)NH2; and wherein said ring is 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 a physiologically acceptable salt thereof.
  • “(Hetero-)aryl” means “heteroaryl or aryl”. 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, 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-alkcyl, 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-alkcyl; 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 -phenyl, 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; —CF3; -3-12-membered cycloalkyl, saturated or unsaturated, unsubstituted, mono- or polysubstituted; preferably -cyclopropyl, saturated, unsubstituted; -3-12-membered heterocycloalkyl, saturated or unsaturated, unsubstituted, mono-or polysubstituted; preferably -pyrrolidinyl, -piperidinyl, -morpholinyl, -piperazinyl, -thiomorpholinyl, or -thiomorpholinyl dioxide, in each case saturated, unsubstituted or monosubstituted with -C1-C4-alkyl; -6-14-membered aryl, unsubstituted, mono- or polysubstituted; preferably -phenyl, unsubstituted; -O-C1-C4-alkyl; -S-C1-C4-alkyl; —C(═O)OH; -C(=O)O-C1-C4-alkyl; —C(═O)NH2; -C(=O)NHC1-C4-alkyl; -C(=O)N(C1-C4-alkyl)2; -C(=O)N(C1-C4-alkyl)(C1-C4-alkyl-OH); -C(=O)NH-(CH2)1-3-3-12-membered cycloalkyl, saturated or unsaturated, unsubstituted or monosubstituted with —OH; preferably -C(=O)NH-(CH2)1-3-cyclobutyl, saturated or unsaturated, unsubstituted or monosubstituted with —OH; -C(=O)-3-12-membered heterocycloalkyl, saturated or unsaturated, unsubstituted, mono- or polysubstituted; preferably -C(=O)-morpholinyl, saturated, unsubstituted; -S(=O)C1-C4-alkyl; -S(=O)2C1-C4-alkyl; and -S(=O)2N(C1-C4-alkyl)2.
  • In another preferred embodiment of the compound according to the invention, R5 means -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, in each case unsubstituted, mono- or polysubstituted; preferably -pyrazinyl, -pyridazinyl, -pyridinyl, -pyrimidinyl, or -thienyl, in each case unsubstituted, mono- or polysubstituted. Preferably, R5 means -pyrazinyl, -pyridazinyl, -pyridinyl, -pyrimidinyl, or -thienyl, 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; -CF3; -3-12-membered cycloalkyl, saturated or unsaturated, unsubstituted, mono- or polysubstituted; preferably -cyclopropyl, saturated, unsubstituted; -3-12-membered heterocycloalkyl, saturated or unsaturated, unsubstituted, mono- or polysubstituted; preferably -pyrrolidinyl, -piperidinyl, -morpholinyl, -piperazinyl, -thiomorpholinyl, or -thiomorpholinyl dioxide, in each case saturated, unsubstituted or monosubstituted with -C1-C4-alkyl; -6-14-membered aryl, unsubstituted, mono- or polysubstituted; preferably -phenyl, unsubstituted; -O-C1-C4-alkyl; -S-C1-C4-alkyl; —C(═O)OH; -C(=O)O-C1-C4-alkyl; —C(═O)NH2; -C(=O)NHC1-C4-alkyl; -C(=O)N(C1-C4-alkyl)2; -C(=O)N(C1-C4-alkyl)(C1-C4-alkyl-OH); -C(=O)NH-(CH2)1-3-3-12-membered cycloalkyl, saturated or unsaturated, unsubstituted or monosubstituted with -OH; preferably -C(=O)NH-(CH2)1-3-cyclobutyl, saturated or unsaturated, unsubstituted or monosubstituted with —OH; -C(=O)-3-12-membered heterocycloalkyl, saturated or unsaturated, unsubstituted, mono- or polysubstituted; preferably -C(=O)-morpholinyl, saturated, unsubstituted; -S(=O)C1-C4-alkyl; -S(=O)2C1-C4-alkyl; and -S(=O)2N(C1-C4-alkyl)2.
  • In still another preferred embodiment of the compound according to the invention, R5 means a bicyclic 9-10-membered heteroaryl moiety, unsubstituted, mono- or polysubstituted. Preferably, R5 means imidazo[1,2-a]pyrazine, unsubstituted or monosubstituted with -C1-C4-alkyl.
  • Preferably, R5 means -phenyl, -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, 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; -C1-C4-alkyl; -CF3; -C1-C4-alkyl-C(=O)NH2; -C1-C4-alkyl-S(=O)2-C1-C4-alkyl;
    • -C(=O)-C1-C4-alkyl; —C(═O)OH; -C(=O)O-C1-C4-alkyl; —C(═O)NH2; -C(=O)NHC1-C4-alkyl; -C(=O)N(C1-C4-alkyl)2; -C(=O)NH(C1-C4-alkyl-OH); -C(=O)N(C1-C4-alkyl)(C1-C4-alkyl-OH); —C(═O)NH—(CH2CH2O)1-30—CH3;
    • —NH2; -NHC1-C4-alkyl; -N(C1-C4-alkyl)2; -NHC1-C4-alkyl-OH; -NCH3C1-C4-alkyl-OH; -NH-C1-C4-alkyl-C(=O)NH2; -NCH3-C1-C4-alkyl-C(=O)NH2; -NHC(=O)-C1-C4-alkyl; -NCH3C(=O)-C1-C4-alkyl;
    • —OH; -O-C1-C4-alkyl; —OCF3; -O-C1-C4-alkyl-CO2H; -O-C1-C4-alkyl-C(=O)O-C1-C4-alkyl; -O-C1-C4-alkyl-CONH2;
    • -S-C1-C4-alkyl; -S(=O)C1-C4-alkyl; -S(=O)2C1-C4-alkyl; and -S(=O)2N(C1-C4-alkyl)2;
    • -3-12-membered cycloalkyl, saturated or unsaturated, unsubstituted, mono- or polysubstituted; wherein said 3-12-membered cycloalkyl is optionally connected through —CH2—, —NH—, —NCH3—, —NH—(CH2)1-3—, —NCH3(CH2)1-3—, —(C═O)—, —NHC(═O)—, —NCH3C(═O)—, —C(═O)NH—(CH2)1-3—, —C(═O)NCH3—(CH2)1-3—;
    • -3-12-membered heterocycloalkyl, saturated or unsaturated, unsubstituted, mono- or polysubstituted; wherein said 3-12-membered heterocycloalkyl is optionally connected through —CH2—, —NH—, —NCH3—, —NH—(CH2)1-3—, —NCH3(CH2)1-3—, —(C═O)—, —NHC(═O)—, —NCH3C(═O)—, —C(═O)NH—(CH2)1-3—, —C(═O)NCH3—(CH2)1-3—;
    • -6-14-membered aryl, unsubstituted, mono- or polysubstituted; wherein said 6-14-membered aryl is optionally connected through —CH2—, —NH—, —NCH3—, —NH—(CH2)1-3—, —NCH3(CH2)1-3—, —(C═O)—, —NHC(═O)—, —NCH3C(═O)—, —C(═O)NH—(CH2)1-3—, —C(═O)NCH3—(CH2)1-3—; or
    • -5-14-membered heteroaryl, unsubstituted, mono- or polysubstituted; wherein said 5-14-membered heteroaryl is optionally connected through —CH2—, —NH—, —NCH3—, —NH—(CH2)1-3—, —NCH3(CH2)1-3—, —(C═O)—, —NHC(═O)—, —NCH3C(═O)—, —C(═O)NH—(CH2)1-3—, —C(═O)NCH3—(CH2)1-3 —.
  • In preferred embodiments, the compound according to the invention has a structure according to any of general formulas (II-A) to (VIII-C):
  • Figure US20230303573A1-20230928-C00002
  • Figure US20230303573A1-20230928-C00003
  • Figure US20230303573A1-20230928-C00004
  • Figure US20230303573A1-20230928-C00005
  • Figure US20230303573A1-20230928-C00006
  • Figure US20230303573A1-20230928-C00007
  • Figure US20230303573A1-20230928-C00008
  • Figure US20230303573A1-20230928-C00009
  • Figure US20230303573A1-20230928-C00010
  • Figure US20230303573A1-20230928-C00011
  • Figure US20230303573A1-20230928-C00012
  • Figure US20230303573A1-20230928-C00013
  • Figure US20230303573A1-20230928-C00014
  • Figure US20230303573A1-20230928-C00015
  • Figure US20230303573A1-20230928-C00016
  • Figure US20230303573A1-20230928-C00017
  • Figure US20230303573A1-20230928-C00018
  • Figure US20230303573A1-20230928-C00019
  • Figure US20230303573A1-20230928-C00020
  • Figure US20230303573A1-20230928-C00021
  • Figure US20230303573A1-20230928-C00022
  • wherein in each case
    • R1, R2, R3, R4, and R5 are defined as above,
    • RC means —H, —OH, —F, —CN or -C1-C4-alkyl; preferably —H or —OH;
    • RD means —H or —F;
    • or a physiologically acceptable salt thereof.
  • Preferably, in the compounds according to general formula (I) or any of the compounds according to general formulas (II-A) to (VIII-C), R5 is selected from the group consisting of:
  • Figure US20230303573A1-20230928-C00023
    Figure US20230303573A1-20230928-C00024
    Figure US20230303573A1-20230928-C00025
    Figure US20230303573A1-20230928-C00026
    Figure US20230303573A1-20230928-C00027
    Figure US20230303573A1-20230928-C00028
    Figure US20230303573A1-20230928-C00029
    Figure US20230303573A1-20230928-C00030
    Figure US20230303573A1-20230928-C00031
    Figure US20230303573A1-20230928-C00032
    Figure US20230303573A1-20230928-C00033
    Figure US20230303573A1-20230928-C00034
    Figure US20230303573A1-20230928-C00035
    Figure US20230303573A1-20230928-C00036
    Figure US20230303573A1-20230928-C00037
    Figure US20230303573A1-20230928-C00038
    Figure US20230303573A1-20230928-C00039
    Figure US20230303573A1-20230928-C00040
    Figure US20230303573A1-20230928-C00041
    Figure US20230303573A1-20230928-C00042
    Figure US20230303573A1-20230928-C00043
    Figure US20230303573A1-20230928-C00044
    Figure US20230303573A1-20230928-C00045
    Figure US20230303573A1-20230928-C00046
    Figure US20230303573A1-20230928-C00047
    Figure US20230303573A1-20230928-C00048
    Figure US20230303573A1-20230928-C00049
    Figure US20230303573A1-20230928-C00050
    Figure US20230303573A1-20230928-C00051
    Figure US20230303573A1-20230928-C00052
    Figure US20230303573A1-20230928-C00053
    Figure US20230303573A1-20230928-C00054
    Figure US20230303573A1-20230928-C00055
    Figure US20230303573A1-20230928-C00056
    Figure US20230303573A1-20230928-C00057
    Figure US20230303573A1-20230928-C00058
    Figure US20230303573A1-20230928-C00059
    Figure US20230303573A1-20230928-C00060
    Figure US20230303573A1-20230928-C00061
    Figure US20230303573A1-20230928-C00062
    Figure US20230303573A1-20230928-C00063
    Figure US20230303573A1-20230928-C00064
    Figure US20230303573A1-20230928-C00065
    Figure US20230303573A1-20230928-C00066
    Figure US20230303573A1-20230928-C00067
    Figure US20230303573A1-20230928-C00068
    Figure US20230303573A1-20230928-C00069
    Figure US20230303573A1-20230928-C00070
    Figure US20230303573A1-20230928-C00071
    Figure US20230303573A1-20230928-C00072
    Figure US20230303573A1-20230928-C00073
    Figure US20230303573A1-20230928-C00074
    Figure US20230303573A1-20230928-C00075
    Figure US20230303573A1-20230928-C00076
    Figure US20230303573A1-20230928-C00077
    Figure US20230303573A1-20230928-C00078
    Figure US20230303573A1-20230928-C00079
    Figure US20230303573A1-20230928-C00080
    Figure US20230303573A1-20230928-C00081
    Figure US20230303573A1-20230928-C00082
    Figure US20230303573A1-20230928-C00083
    Figure US20230303573A1-20230928-C00084
    Figure US20230303573A1-20230928-C00085
    Figure US20230303573A1-20230928-C00086
    Figure US20230303573A1-20230928-C00087
    Figure US20230303573A1-20230928-C00088
    Figure US20230303573A1-20230928-C00089
    Figure US20230303573A1-20230928-C00090
    Figure US20230303573A1-20230928-C00091
    Figure US20230303573A1-20230928-C00092
    Figure US20230303573A1-20230928-C00093
    Figure US20230303573A1-20230928-C00094
    Figure US20230303573A1-20230928-C00095
    Figure US20230303573A1-20230928-C00096
    Figure US20230303573A1-20230928-C00097
    Figure US20230303573A1-20230928-C00098
    Figure US20230303573A1-20230928-C00099
    Figure US20230303573A1-20230928-C00100
    Figure US20230303573A1-20230928-C00101
    Figure US20230303573A1-20230928-C00102
    Figure US20230303573A1-20230928-C00103
    Figure US20230303573A1-20230928-C00104
    Figure US20230303573A1-20230928-C00105
    Figure US20230303573A1-20230928-C00106
    Figure US20230303573A1-20230928-C00107
    Figure US20230303573A1-20230928-C00108
    Figure US20230303573A1-20230928-C00109
    Figure US20230303573A1-20230928-C00110
    Figure US20230303573A1-20230928-C00111
    Figure US20230303573A1-20230928-C00112
    Figure US20230303573A1-20230928-C00113
    Figure US20230303573A1-20230928-C00114
    Figure US20230303573A1-20230928-C00115
    Figure US20230303573A1-20230928-C00116
    Figure US20230303573A1-20230928-C00117
    Figure US20230303573A1-20230928-C00118
    Figure US20230303573A1-20230928-C00119
    Figure US20230303573A1-20230928-C00120
    Figure US20230303573A1-20230928-C00121
    Figure US20230303573A1-20230928-C00122
    Figure US20230303573A1-20230928-C00123
    Figure US20230303573A1-20230928-C00124
    Figure US20230303573A1-20230928-C00125
    Figure US20230303573A1-20230928-C00126
    Figure US20230303573A1-20230928-C00127
    Figure US20230303573A1-20230928-C00128
    Figure US20230303573A1-20230928-C00129
    Figure US20230303573A1-20230928-C00130
    Figure US20230303573A1-20230928-C00131
    Figure US20230303573A1-20230928-C00132
    Figure US20230303573A1-20230928-C00133
    Figure US20230303573A1-20230928-C00134
    Figure US20230303573A1-20230928-C00135
    Figure US20230303573A1-20230928-C00136
    Figure US20230303573A1-20230928-C00137
    Figure US20230303573A1-20230928-C00138
    Figure US20230303573A1-20230928-C00139
    Figure US20230303573A1-20230928-C00140
    Figure US20230303573A1-20230928-C00141
    Figure US20230303573A1-20230928-C00142
    Figure US20230303573A1-20230928-C00143
    Figure US20230303573A1-20230928-C00144
    Figure US20230303573A1-20230928-C00145
    Figure US20230303573A1-20230928-C00146
    Figure US20230303573A1-20230928-C00147
    Figure US20230303573A1-20230928-C00148
    Figure US20230303573A1-20230928-C00149
    Figure US20230303573A1-20230928-C00150
    Figure US20230303573A1-20230928-C00151
    Figure US20230303573A1-20230928-C00152
    Figure US20230303573A1-20230928-C00153
    Figure US20230303573A1-20230928-C00154
    Figure US20230303573A1-20230928-C00155
    Figure US20230303573A1-20230928-C00156
    Figure US20230303573A1-20230928-C00157
    Figure US20230303573A1-20230928-C00158
    Figure US20230303573A1-20230928-C00159
    Figure US20230303573A1-20230928-C00160
    Figure US20230303573A1-20230928-C00161
    Figure US20230303573A1-20230928-C00162
    Figure US20230303573A1-20230928-C00163
    Figure US20230303573A1-20230928-C00164
    Figure US20230303573A1-20230928-C00165
    Figure US20230303573A1-20230928-C00166
    Figure US20230303573A1-20230928-C00167
    Figure US20230303573A1-20230928-C00168
    Figure US20230303573A1-20230928-C00169
    Figure US20230303573A1-20230928-C00170
    Figure US20230303573A1-20230928-C00171
    Figure US20230303573A1-20230928-C00172
    Figure US20230303573A1-20230928-C00173
    Figure US20230303573A1-20230928-C00174
    Figure US20230303573A1-20230928-C00175
    Figure US20230303573A1-20230928-C00176
    Figure US20230303573A1-20230928-C00177
    Figure US20230303573A1-20230928-C00178
    Figure US20230303573A1-20230928-C00179
    Figure US20230303573A1-20230928-C00180
    Figure US20230303573A1-20230928-C00181
    Figure US20230303573A1-20230928-C00182
    Figure US20230303573A1-20230928-C00183
    Figure US20230303573A1-20230928-C00184
    Figure US20230303573A1-20230928-C00185
    Figure US20230303573A1-20230928-C00186
    Figure US20230303573A1-20230928-C00187
    Figure US20230303573A1-20230928-C00188
    Figure US20230303573A1-20230928-C00189
    Figure US20230303573A1-20230928-C00190
    Figure US20230303573A1-20230928-C00191
    Figure US20230303573A1-20230928-C00192
    Figure US20230303573A1-20230928-C00193
    Figure US20230303573A1-20230928-C00194
    Figure US20230303573A1-20230928-C00195
    Figure US20230303573A1-20230928-C00196
    Figure US20230303573A1-20230928-C00197
    Figure US20230303573A1-20230928-C00198
    Figure US20230303573A1-20230928-C00199
    Figure US20230303573A1-20230928-C00200
    Figure US20230303573A1-20230928-C00201
    Figure US20230303573A1-20230928-C00202
    Figure US20230303573A1-20230928-C00203
    Figure US20230303573A1-20230928-C00204
    Figure US20230303573A1-20230928-C00205
    Figure US20230303573A1-20230928-C00206
    Figure US20230303573A1-20230928-C00207
    Figure US20230303573A1-20230928-C00208
    Figure US20230303573A1-20230928-C00209
    Figure US20230303573A1-20230928-C00210
    Figure US20230303573A1-20230928-C00211
    Figure US20230303573A1-20230928-C00212
    Figure US20230303573A1-20230928-C00213
    Figure US20230303573A1-20230928-C00214
    Figure US20230303573A1-20230928-C00215
    Figure US20230303573A1-20230928-C00216
    Figure US20230303573A1-20230928-C00217
    Figure US20230303573A1-20230928-C00218
    Figure US20230303573A1-20230928-C00219
    Figure US20230303573A1-20230928-C00220
    Figure US20230303573A1-20230928-C00221
    Figure US20230303573A1-20230928-C00222
    Figure US20230303573A1-20230928-C00223
    Figure US20230303573A1-20230928-C00224
    Figure US20230303573A1-20230928-C00225
    Figure US20230303573A1-20230928-C00226
    Figure US20230303573A1-20230928-C00227
    Figure US20230303573A1-20230928-C00228
    Figure US20230303573A1-20230928-C00229
    Figure US20230303573A1-20230928-C00230
    Figure US20230303573A1-20230928-C00231
    Figure US20230303573A1-20230928-C00232
    Figure US20230303573A1-20230928-C00233
    Figure US20230303573A1-20230928-C00234
    Figure US20230303573A1-20230928-C00235
    Figure US20230303573A1-20230928-C00236
    Figure US20230303573A1-20230928-C00237
    Figure US20230303573A1-20230928-C00238
    Figure US20230303573A1-20230928-C00239
    Figure US20230303573A1-20230928-C00240
    Figure US20230303573A1-20230928-C00241
    Figure US20230303573A1-20230928-C00242
    Figure US20230303573A1-20230928-C00243
    Figure US20230303573A1-20230928-C00244
    Figure US20230303573A1-20230928-C00245
    Figure US20230303573A1-20230928-C00246
    Figure US20230303573A1-20230928-C00247
    Figure US20230303573A1-20230928-C00248
    Figure US20230303573A1-20230928-C00249
    Figure US20230303573A1-20230928-C00250
    Figure US20230303573A1-20230928-C00251
    Figure US20230303573A1-20230928-C00252
    Figure US20230303573A1-20230928-C00253
    Figure US20230303573A1-20230928-C00254
    Figure US20230303573A1-20230928-C00255
    Figure US20230303573A1-20230928-C00256
    Figure US20230303573A1-20230928-C00257
    Figure US20230303573A1-20230928-C00258
    Figure US20230303573A1-20230928-C00259
    Figure US20230303573A1-20230928-C00260
    Figure US20230303573A1-20230928-C00261
    Figure US20230303573A1-20230928-C00262
    Figure US20230303573A1-20230928-C00263
    Figure US20230303573A1-20230928-C00264
    Figure US20230303573A1-20230928-C00265
    Figure US20230303573A1-20230928-C00266
    Figure US20230303573A1-20230928-C00267
    Figure US20230303573A1-20230928-C00268
    Figure US20230303573A1-20230928-C00269
    Figure US20230303573A1-20230928-C00270
    Figure US20230303573A1-20230928-C00271
    Figure US20230303573A1-20230928-C00272
    Figure US20230303573A1-20230928-C00273
    Figure US20230303573A1-20230928-C00274
    Figure US20230303573A1-20230928-C00275
    Figure US20230303573A1-20230928-C00276
    Figure US20230303573A1-20230928-C00277
    Figure US20230303573A1-20230928-C00278
    Figure US20230303573A1-20230928-C00279
    Figure US20230303573A1-20230928-C00280
    Figure US20230303573A1-20230928-C00281
    Figure US20230303573A1-20230928-C00282
    Figure US20230303573A1-20230928-C00283
    Figure US20230303573A1-20230928-C00284
    Figure US20230303573A1-20230928-C00285
    Figure US20230303573A1-20230928-C00286
    Figure US20230303573A1-20230928-C00287
    Figure US20230303573A1-20230928-C00288
    Figure US20230303573A1-20230928-C00289
    Figure US20230303573A1-20230928-C00290
    Figure US20230303573A1-20230928-C00291
    Figure US20230303573A1-20230928-C00292
    Figure US20230303573A1-20230928-C00293
    Figure US20230303573A1-20230928-C00294
    Figure US20230303573A1-20230928-C00295
    Figure US20230303573A1-20230928-C00296
    Figure US20230303573A1-20230928-C00297
    Figure US20230303573A1-20230928-C00298
    Figure US20230303573A1-20230928-C00299
    Figure US20230303573A1-20230928-C00300
    Figure US20230303573A1-20230928-C00301
    Figure US20230303573A1-20230928-C00302
    Figure US20230303573A1-20230928-C00303
    Figure US20230303573A1-20230928-C00304
    Figure US20230303573A1-20230928-C00305
    Figure US20230303573A1-20230928-C00306
    Figure US20230303573A1-20230928-C00307
    Figure US20230303573A1-20230928-C00308
    Figure US20230303573A1-20230928-C00309
    Figure US20230303573A1-20230928-C00310
    Figure US20230303573A1-20230928-C00311
    Figure US20230303573A1-20230928-C00312
    Figure US20230303573A1-20230928-C00313
    Figure US20230303573A1-20230928-C00314
    Figure US20230303573A1-20230928-C00315
    Figure US20230303573A1-20230928-C00316
    Figure US20230303573A1-20230928-C00317
    Figure US20230303573A1-20230928-C00318
    Figure US20230303573A1-20230928-C00319
    Figure US20230303573A1-20230928-C00320
    Figure US20230303573A1-20230928-C00321
    Figure US20230303573A1-20230928-C00322
    Figure US20230303573A1-20230928-C00323
    Figure US20230303573A1-20230928-C00324
    Figure US20230303573A1-20230928-C00325
    Figure US20230303573A1-20230928-C00326
    Figure US20230303573A1-20230928-C00327
    Figure US20230303573A1-20230928-C00328
    Figure US20230303573A1-20230928-C00329
  • In a particularly preferred embodiment of the compound according to the invention
    • R1 means —H or —CH3;
    • R2 means -C1-C6-alkyl, linear or branched, saturated, unsubstituted; cyclopropyl connected through —CH2—; or tetrahydropyranyl connected through —CH2—;
    • R3 means -phenyl, benzyl, -thienyl or -pyridinyl, 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, —CN, —CH3, —CH2CH3, —CH2F, —CHF2, —CF3, —OCF3, —OH, —OCH3, —C(═O)NH2, C(=O)NHCH3, —C(═O)N(CH3)2, —NH2, —NHCH3, —N(CH3)2, —NHC(═O)CH3, —CH2OH, SOCH3 and SO2CH3; 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-C1-C4-alkyl, -C(=O)NH-C1-C6-alkyl, -C(=O)N(C1-C6-alkyl)2 or —C(═O)NRR′ wherein R and R′ together with the nitrogen atom to which they are attached form a ring and mean —(CH2)3-5—;
    • 3-6-membered cycloalkyl, 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, and -O-C1-C4-alkyl, wherein said 3-6-membered cycloalkyl is connected through -C1-C6-alkylene;
    • 3-6-membered heterocycloalkyl, 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, and -O-C1-C4-alkyl, wherein said 3-6-membered heterocycloalkyl is connected through -C1-C6-alkylene;
    • -phenyl, unsubstituted or monosubstituted with —OCH3; wherein said -phenyl isconnected through -C1-C6-alkylene-; or
    • -pyridyl, unsubstituted, mono- or polysubstituted; wherein said -pyridyl is connected through -C1-C6-alkylene-;
    • R5 means -phenyl, -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, 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; -C1-C4-alkyl; -C1-C4-alkyl-OH; —CF3; -C1-C4-alkyl-CF3; -C1-C4-alkyl-C(=O)NH2; -C1-C4-alkyl-C(=O)NHC1-C6-alkyl; -C1-C4-alkyl-C(=O)N(C1-C6-alkyl)2; -C1-C4-alkyl-S(=O)2-C1-C4-alkyl;
      • -C(=O)-C1-C4-alkyl; —C(═O)OH; -C(=O)O-C1-C4-alkyl; —C(═O)NH2; -C(=O)NHC1-C4-alkyl; -C(=O)N(C1-C4-alkyl)2; -C(=O)NH(C1-C4-alkyl-OH); -C(=O)N(C1-C4-alkyl)(C1-C4-alkyl-OH); —C(═O)NH—(CH2CH2O)1-30—CH3;
      • —NH2; -NHC1-C4-alkyl; -N(C1-C4-alkyl)2; -NHC1-C4-alkyl-OH; -NCH3C1-C4-alkyl-OH; -NH-C1-C4-alkyl-C(=O)NH2; -NCH3-C1-C4-alkyl-C(=O)NH2; -NHC(=O)-C1-C4-alkyl; -NCH3C(=O)-C1-C4-alkyl;
      • —OH; -O-C1-C4-alkyl; —OCF3; -O-C1-C4-alkyl-CO2H; -O-C1-C4-alkyl-C(=O)O-C1-C4-alkyl; -O-C1-C4-alkyl-CONH2;
      • -S-C1-C4-alkyl; -S(=O)C1-C4-alkyl; -S(=O)2C1-C4-alkyl; and -S(=O)2N(C1-C4-alkyl)2;
      • -3-12-membered cycloalkyl, saturated or unsaturated, unsubstituted, mono- or polysubstituted; wherein said 3-12-membered cycloalkyl is optionally connected through —CH2—, —O—, —NH—, —NCH3—, —NH—(CH2)1-3—, —NCH3(CH2)1-3—, —(C═O)—, —NHC(═O)—, —NCH3C(═O)—, —C(═O)NH—(CH2)1-3—, —C(═O)NCH3—(CH2)1-3—;
      • -3-12-membered heterocycloalkyl, saturated or unsaturated, unsubstituted, mono- or polysubstituted; wherein said 3-12-membered heterocycloalkyl is optionally connected through —CH2—, —O—, —NH—, —NCH3—, —NH—(CH2)1-3—, —NCH3(CH2)1-3—, —(C═O)—, —NHC(═O)—, —NCH3C(═O)—, —C(═O)NH—(CH2)1-3—, —C(═O)NCH3—(CH2)1-3—;
      • -6-14-membered aryl, unsubstituted, mono- or polysubstituted; wherein said 6-14-membered aryl is optionally connected through —CH2—, —O—, —NH—, —NCH3—, —NH—(CH2)1-3—, —NCH3(CH2)1-2 3—, —(C═O)—, —NHC(═O)—, —NCH3C(═O)—, —C(═O)NH—(CH2)1-3—, —C(═O)NCH3—(CH2)1-3—; or
      • -5-14-membered heteroaryl, unsubstituted, mono- or polysubstituted; wherein said 5-14-membered heteroaryl is optionally connected through —CH2—, —O—, —NH—, —NCH3—, —NH—(CH2)1—3—, —NCH3(CH2)1-3—, —(C═O)—, —NHC(═O)—, —NCH3C(═O)—, —C(═O)NH—(CH2)1-3—, —C(═O)NCH3—(CH2)1-3—, and
    • 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 -C1-C6-alkyl, linear or branched, saturated, unsubstituted; preferably, R2 means —CH3 or —CH2CH3; more preferably, R1 and R2 both mean —CH3; and/or
    • R3 means -phenyl, -thienyl or -pyridinyl, 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, —CN, —CH3, —CH2CH3, —CH2F, —CHF2, —CF3, —OCF3, —OH, —OCH3, —C(═O)NH2, C(═O)NHCH3,
    • —C(═O)N(CH3)2, —NH2, —NHCH3, —N(CH3)2, —NHC(═O)CH3, —CH2OH, SOCH3 and SO2CH3; preferably, R3 means -phenyl, -thienyl or -pyridinyl, in each case unsubstituted or substituted with —F; more 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, and -O-C1-C4-alkyl; or
    • 3-6-membered cycloalkyl, 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, and -O-C1-C4-alkyl, wherein said 3-6-membered cycloalkyl is connected through -C1-C6-alkylene; preferably, R4 means 3-6-membered cycloalkyl, 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, and -O-C1-C4-alkyl, wherein said 3-6-membered cycloalkyl is connected through —CH2— or —CH2CH2—; more preferably, R4 means -cyclobutyl, unsubstituted or monosubstituted with —OH, wherein said -cyclobutyl is connected through —CH2—; and/or
    • R5 means -phenyl, -pyrazinyl, -pyridazinyl, -pyridinyl, -pyrimidinyl, -thienyl, or imidazo[1,2-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; -C1-C4-alkyl; —CF3; -3-12-membered cycloalkyl, saturated or unsaturated, unsubstituted, mono- or polysubstituted; preferably cyclopropyl, saturated, unsubstituted; -3-12-membered heterocycloalkyl, saturated or unsaturated, unsubstituted, mono- or polysubstituted; preferably -pyrrolidinyl, -morpholinyl, -piperazinyl, -thiomorpholinyl, or -thiomorpholinyl dioxide, in each case saturated, unsubstituted or monosubstituted with -C1-C4-alkyl; -6-14-membered aryl, unsubstituted, mono- or polysubstituted; preferably -phenyl, unsubstituted; -O-C1-C4-alkyl; -S-C1-C4-alkyl; —C(═O)OH; -C(=O)O-C1-C4-alkyl; —C(═O)NH2; -C(=O)NHC1-C4-alkyl; -C(=O)N(C1-C4-alkyl)2; -C(=O)N(C1-C4-alkyl)(C1-C4-alkyl-OH); -C(=O)NH-(CH2)1-3-3-12-membered cycloalkyl, saturated or unsaturated, unsubstituted or monosubstituted with —OH; preferably -C(=O)NH-(CH2)1-3-cyclobutyl, saturated or unsaturated, unsubstituted or monosubstituted with —OH; -C(=O)-3-12-membered heterocycloalkyl, saturated or unsaturated, unsubstituted, mono- or polysubstituted; preferably -C(=O)-morpholinyl, saturated, unsubstituted; -S(=O)C1-C4-alkyl; -S(=O)2C1-C4-alkyl; and -S(=O)2N(C1-C4-alkyl)2; and/or
    • 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_3001 cis-5-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carbonitrile
    SC_3002 cis-5-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-pyrazine-2-carbonitrile
    SC_3003 cis-5-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-4-methoxy-pyrimidine-2-carbonitrile
    SC_3004 cis-5-[8-Dimethylamino-1-(2-methoxy-ethyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carbonitrile
    SC_3005 cis-5-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carboxylic acid amide
    SC_3006 cis-5-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-2-methylsulfonyl-pyrimidine-4-carbonitrile
    SC_3007 cis-5-[1-(2-Methoxy-ethyl)-8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carbonitrile
    SC_3008 cis-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-5-methylsulfonyl-benzonitrile
    SC_3009 cis-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-benzamide
    SC_3010 cis-3-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-benzamide
    SC_3011 cis-5-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carboxylic acid amide
    SC_3012 cis-5-[1-(Cyclobutyl-methyl)-8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-4-methoxy-pyrimidine-2-carbonitrile
    SC_3013 cis-5-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carbonitrile
    SC_3014 cis-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-5-carbonitrile
    SC_3015 cis-8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-3-(2-methoxy-pyrimidin-5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
    SC_3016 cis-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-5-carboxylic acid amide
    SC_3017 cis-4-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-methyl-benzamide
    SC_3018 cis-5-(8-Dimethylamino-2-oxo-8-phenyl-1-propyl-1,3-diazaspiro[4.5]decan-3-yl)-pyrimidine-2-carbonitrile
    SC_3019 cis-5-[8-Dimethylamino-1-(3-methoxy-propyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carbonitrile
    SC_3020 cis-5-[1-(Cyclopropyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carbonitrile
    SC_3021 cis-4-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-benzamide
    SC_3022 cis-1-(Cyclobutyl-methyl)-8-dimethylamino-8-phenyl-3-[2-(trifluoromethyl)-pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2-one
    SC_3023 cis-8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-3-(2-hydroxy-pyrimidin-5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
    SC_3024 cis-5-[8-Dimethylamino-1-(2-methyl-propyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carbonitrile
    SC_3025 cis-5-[8-Dimethylamino-1-(2-hydroxy-ethyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carbonitrile
    SC_3026 cis-5-[1-(Cyclobutyl-methyl)-8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-4-methyl-pyridine-2-carbonitrile
    SC_3027 cis-1-(Cyclobutyl-methyl)-3-(5-methoxy-pyrazin-2-yl)-8-methylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
    SC_3028 cis-4-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N,N-dimethyl-benzamide
    SC_3029 cis-4-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-ethyl-N-(2-hydroxy-ethyl)-benzamide
    SC_3030 cis-2-[1-(Cyclobutyl-methyl)-8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-5-methylsulfonyl-benzonitrile
    SC_3031 cis-1-(Cyclobutyl-methyl)-8-methylamino-3-[2-methylsulfonyl-4-(trifluoromethyl)-phenyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
    SC_3032 cis-4-[1-(Cyclobutyl-methyl)-8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N,N-dimethyl-3-(trifluoromethyl)-benzenesulfonic acid amide
    SC_3033 cis-4-[1-(Cyclobutyl-methyl)-8-(ethyl-methyl-amino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-benzonitrile
    SC_3034 cis-1-(Cyclobutyl-methyl)-8-(ethyl-methyl-amino)-8-phenyl-3-[2-(trifluoromethyl)-pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2-one
    SC_3035 cis-5-[1-(Cyclobutyl-methyl)-8-(ethyl-methyl-amino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carbonitrile
    SC_3036 cis-5-[8-Dimethylamino-1-[(1-methyl-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carbonitrile
    SC_3037 cis-2-[3-(2-Cyano-pyrimidin-5-yl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl]-N,N-dimethyl-acetamide
    SC_3038 cis-1-(Cyclobutyl-methyl)-8-methylamino-8-phenyl-3-[2-(trifluoromethyl)-pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2-one
    SC_3039 cis-5-[8-Dimethylamino-8-(3-fluorophenyl)-1-(4-methoxy-butyl)-2-oxo-1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carbonitrile
    SC_3040 cis-5-[8-Dimethylamino-1-(3-methoxy-propyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-4-methoxy-pyrimidine-2-carbonitrile
    SC_3041 cis-5-[1-[(1-Cyano-cyclobutyl)-methyl]-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carbonitrile
    SC_3042 cis-N-(Cyclobutyl-methyl)-5-[1-(cyclobutyl-methyl)-8-dimethylamino-8-(3-fluorophenyl)-2-oxo-1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carboxylic acid amide
    SC_3043 cis-5-[1-(3-Methoxy-propyl)-8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carbonitrile
    SC_3044 cis-5-[8-Dimethylamino-8-(3-fluorophenyl)-1-methyl-2-oxo-1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carbonitrile
    SC_3045 cis-4-Methoxy-5-[1-(3-methoxy-propyl)-8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carbonitrile
    SC_3046 cis-4-[8-Dimethylamino-1-(2-methoxy-ethyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carbonitrile
    SC_3047 cis-5-[8-Dimethylamino-1-(2-methoxy-ethyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-4-methoxy-pyrimidine-2-carbonitrile
    SC_3048 cis-4-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carbonitrile
    SC_3049 cis-1-(Cyclobutyl-methyl)-8-dimethylamino-3-(6-methylsulfanyl-pyrimidin-4-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
    SC_3050 cis-2-[3-(2-Cyano-pyrimidin-4-yl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl]-N,N-dimethyl-acetamide
    SC_3051 cis-6-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-4-carbonitrile
    SC_3052 cis-2-(8-Dimethylamino-2-oxo-3,8-diphenyl-1,3-diazaspiro[4.5]decan-1-yl)-N,N-dimethyl-acetamide
    SC_3053 cis-1-(Cyclobutyl-methyl)-8-dimethylamino-3,8-diphenyl-1,3-diazaspiro[4.5]decan-2-one
    SC_3054 cis-2-[8-Dimethylamino-1-(2-methoxy-ethyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-5-carbonitrile
    SC_3055 cis-8-Dimethylamino-1-(2-methoxy-ethyl)-3,8-diphenyl-1,3-diazaspiro[4.5]decan-2-one
    SC_3056 cis-5-[8-Dimethylamino-1-(2-methoxy-ethyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-4-methyl-pyridine-2-carbonitrile
    SC_3057 cis-N,N-Dimethyl-2-(8-methylamino-2-oxo-3,8-diphenyl-1,3-diazaspiro[4.5]decan-1-yl)-acetamide
    SC_3058 cis-5-[1-[(1-Cyano-cyclobutyl)-methyl]-8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carbonitrile
    SC_3059 cis-5-[1-[(1-Cyano-cyclobutyl)-methyl]-8-(ethyl-methyl-amino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carbonitrile
    SC_3060 cis-4-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-benzonitrile
    SC_3061 cis-3-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-benzonitrile
    SC_3063 cis-5-[1-[(1-Cyano-cyclobutyl)-methyl]-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-pyridine-2-carbonitrile
    SC_3064 cis-2-[3-(2-Cyano-pyrimidin-5-yl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl]-N-propyl-acetamide
    SC_3065 cis-5-[1-(Cyclobutyl-methyl)-8-(ethyl-methyl-amino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-4-methoxy-pyrimidine-2-carbonitrile
    SC_3066 cis-4-[1-(Cyclobutyl-methyl)-8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-3-methoxy-benzonitrile
    SC_3067 cis-5-[8-Dimethylamino-1-(3-methoxy-propyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-6-methoxy-pyridine-2-carbonitrile
    SC_3068 cis-4-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-benzamide
    SC_3069 cis-5-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-pyridine-2-carbonitrile
    SC_3070 cis-5-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-[(1-hydroxy-cyclobutyl)-methyl]-pyridine-2-carboxylic acid amide
    SC_3071 cis-2-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-benzonitrile
    SC_3072 cis-3-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-benzonitrile
    SC_3073 cis-1-(Cyclobutyl-methyl)-8-dimethylamino-8-phenyl-3-[2-(trifluoromethyl)-pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2-one
    SC_3074 cis-5-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-4-methyl-pyridine-2-carboxylic acid methyl ester
    SC_3075 cis-1-(Cyclobutyl-methyl)-8-dimethylamino-3-(5-methoxy-pyrazin-2-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
    SC_3076 cis-1-(Cyclobutyl-methyl)-8-dimethylamino-3-(2-methoxy-pyrimidin-5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
    SC_3077 cis-4-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-benzonitrile
    SC_3078 cis-5-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-4-methyl-pyridine-2-carbonitrile
    SC_3079 cis-1-(Cyclobutyl-methyl)-8-dimethylamino-3-(5-fluoro-pyrimidin-2-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
    SC_3080 cis-4-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-3-methoxy-benzonitrile
    SC_3081 cis-4-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-benzoic acid methyl ester
    SC_3082 cis-1-(Cyclobutyl-methyl)-8-dimethylamino-8-phenyl-3-(2-pyrrolidin-1-yl-pyrimidin-4-yl)-1,3-diazaspiro[4.5]decan-2-one
    SC_3083 cis-1-(Cyclobutyl-methyl)-8-dimethylamino-8-phenyl-3-(5-pyridin-2-yl-thiophen-2-yl)-1,3-diazaspiro[4.5]decan-2-one
    SC_3084 cis-1-(Cyclobutyl-methyl)-8-dimethylamino-3-[2-methylsulfonyl-4-(trifluoromethyl)-phenyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
    SC_3085 cis-1-(Cyclobutyl-methyl)-8-dimethylamino-8-phenyl-3-[6-(trifluoromethyl)-pyridin-3-yl]-1,3-diazaspiro[4.5]decan-2-one
    SC_3086 cis-1-(Cyclobutyl-methyl)-3-(2,4-dimethoxy-phenyl)-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
    SC_3087 cis-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-4-methylsulfonyl-benzonitrile
    SC_3088 cis-5-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl] -2-fluoro-benzonitrile
    SC_3089 cis-4-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N,N-dimethyl-3-(trifluoromethyl)-benzenesulfonic acid amide
    SC_3090 cis-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-benzonitrile
    SC_3091 cis-1-(Cyclobutyl-methyl)-8-dimethylamino-3-(2-methyl-imidazo[1,2-a]pyrazin-6-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
    SC_3092 cis-1-(Cyclobutyl-methyl)-8-dimethylamino-3-(4-methylsulfonyl-phenyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
    SC_3093 cis-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-5-methoxy-benzonitrile
    SC_3094 cis-1-(Cyclobutyl-methyl)-8-dimethylamino-3,8-diphenyl-1,3-diazaspiro[4.5]decan-2-one
    SC_3096 cis-1-(Cyclobutyl-methyl)-8-dimethylamino-8-phenyl-3-pyrazin-2-yl-1,3-diazaspiro[4.5]decan-2-one
    SC_3097 cis-8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-3-(2-morpholin-4-yl-pyrimidin-5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
    SC_3098 cis-8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-3-[2-(4-methyl-piperazin-1-yl)-pyrimidin-5-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
    SC_3099 cis-1-[(1-Hydroxy-cyclobutyl)-methyl]-8-methylamino-3-(2-morpholin-4-yl-pyrimidin-5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
    SC_3100 cis-8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-8-phenyl-3-(2-piperazin-1-yl-pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one hydrochloride
    SC_3101 cis-1-[(1-Hydroxy-cyclobutyl)-methyl]-8-methylamino-3-[2-(4-methyl-piperazin-1-yl)-pyrimidin-5-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
    SC_3102 cis-1-[(1-Hydroxy-cyclobutyl)-methyl]-8-methylamino-8-phenyl-3-(2-piperazin-1-yl-pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one dihydrochloride
    SC_3103 cis-1-(Cyclobutyl-methyl)-8-dimethylamino-3-[4-methyl-6-(trifluoromethyl)-pyridin-3-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
    SC_3104 cis-1-(Cyclobutyl-methyl)-8-methylamino-3-[4-methyl-6-(trifluoromethyl)-pyridin-3-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
    SC_3105 cis-1-(Cyclopropyl-methyl)-8-dimethylamino-3-(4-methylsulfonyl-phenyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
    SC_3106 cis-1-(Cyclopropyl-methyl)-8-methylamino-3-(4-methylsulfonyl-phenyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
    SC_3107 cis-1-(Cyclopropyl-methyl)-8-dimethylamino-3-(2-fluoro-4-methylsulfonyl-phenyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
    SC_3108 cis-2-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-benzamide; formic acid
    SC_3109 cis-2-[8-Dimethylamino-1-[2-(1-methoxy-cyclobutyl)-ethyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-benzamide
    SC_3110 cis-8-Dimethylamino-1-[2-(1-methoxy-cyclobutyl)-ethyl]-3-(2-methyl-pyrimidin-5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
    SC_3111 cis-5-[1-[(1-Hydroxy-cyclobutyl)-methyl]-8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carbonitrile
    SC_3112 cis-2-[1-[(1-Hydroxy-cyclobutyl)-methyl]-8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-benzonitrile
    SC_3113 cis-4-[1-[(1-Hydroxy-cyclobutyl)-methyl]-8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-3-methoxy-benzonitrile
    SC_3114 cis-4-[8-Ethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-3-methoxy-benzonitrile
    SC_3115 cis-2-[8-Ethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-benzonitrile
    SC_3116 cis-5-[1-[(1-Hydroxy-cyclobutyl)-methyl]-8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-4-methoxy-pyrimidine-2-carbonitrile
    SC_3117 cis-2-[8-Dimethylamino-1-(oxetan-3-yl-methyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-benzamide
    SC_3118 cis-4-Methoxy-5-(8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-pyrimidine-2-carbonitrile
    SC_3119 cis-2-(8-Methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-benzamide
    SC_3120 cis-8-Dimethylamino-3-[2-(3-oxo-piperazin-1-yl)-pyrimidin-5-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
    SC_3121 cis-3-(2-Cyclopropyl-pyrimidin-5-yl)-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
    SC_3122 cis-8-Dimethylamino-3-[4-methyl-6-(trifluoromethyl)-pyridin-3-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
    SC_3123 cis-8-Dimethylamino-3-(2-methylsulfonyl-phenyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
    SC_3124 cis-8-Dimethylamino-8-phenyl-3-(2-piperazin-1-yl-pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one
    SC_3125 trans-2-(8-Ethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-benzamide
    SC_3126 cis--2-(8-Ethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-benzamide
    SC_3127 cis-2-(8-Ethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-benzonitrile
    SC_3128 cis-2-(8-Ethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-benzonitrile
    SC_3129 cis-3-[5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-pyrimidin-2-yl]-benzonitrile
    SC_3130 cis-8-Dimethylamino-3-[2-(4-methylsulfonyl-piperazin-1-yl)-pyrimidin-5-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
    SC_3131 cis-3-[5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-pyrimidin-2-yl]-benzamide
    SC_3132 cis-8-[(Cyclopropyl-methyl)-methyl-amino]-8-phenyl-3-[2-(trifluoromethyl)-pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2-one
    SC_3133 cis-8-Dimethylamino-3-[2-(4-methyl-piperazine-1-carbonyl)-pyrimidin-5-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
    SC_3134 trans-4-(8-Ethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-3-methoxy-benzonitrile
    SC_3135 cis-4-(8-Ethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-3-methoxy-benzonitrile
    SC_3136 cis-3-[2-(4-Acetyl-piperazin-1-yl)-pyrimidin-5-yl]-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
    SC_3137 cis-8-Dimethylamino-8-phenyl-3-(2-pyridin-4-yl-pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one
    SC_3138 cis-8-Dimethylamino-8-phenyl-3-(2-pyridin-3-yl-pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one
    SC_3139 cis-5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-N-(2-hydroxy-ethyl)-pyrimidine-2-carboxylic acid amide
    SC_3140 cis-5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-pyrimidine-2-carboxylic acid amide
    SC_3141 cis-8-Dimethylamino-3-[2-morpholin-4-yl-4-(trifluoromethyl)-pyrimidin-5-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
    SC_3142 cis-4-[5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-pyrimidin-2-yl]-benzonitrile
    SC_3143 cis-5-(8-Ethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-4-methoxy-pyrimidine-2-carbonitrile
    SC_3144 trans-5-(8-Ethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-4-methoxy-pyrimidine-2-carbonitrile
    SC_3145 cis-8-Dimethylamino-3-[2-(morpholine-4-carbonyl)-pyrimidin-5-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
    SC_3146 cis-2-[4-[5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-pyrimidin-2-yl]-piperazin-1-yl]-acetic acid methyl ester
    SC_3147 cis-8-Dimethylamino-3-[2-(methylsulfonyl-methyl)-phenyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
    SC_3148 cis-8-Dimethylamino-3-(4-methyl-2-morpholin-4-yl-pyrimidin-5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
    SC_3149 cis-8-Dimethylamino-3-[2-(1,1-dioxo-[1,4]thiazinan-4-yl)-pyrimidin-5-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
    SC_3150 cis-8-Dimethylamino-3-(4-fluoro-pyridin-3-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
    SC_3151 cis-5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-N-(2-hydroxy-ethyl)-N-methyl-pyrimidine-2-carboxylic acid amide
    SC_3152 cis-5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-2-morpholin-4-yl-isonicotinonitrile
    SC_3153 cis-4-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-benzamide
    SC_3154 cis-8-Dimethylamino-3-(2-fluoro-4-methylsulfonyl-phenyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
    SC_3155 cis-4-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-3-fluoro-benzonitrile
    SC_3156 cis-4-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-3,5-difluoro-benzonitrile
    SC_3157 cis-8-Dimethylamino-3-(2-methoxy-pyrimidin-5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
    SC_3158 cis-3-[2-(Benzylamino)-pyrimidin-5-yl]-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
    SC_3159 cis-8-Dimethylamino-3-[2-(4-fluorophenyl)-pyrimidin-5-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
    SC_3160 trans-8-Benzyl-8-dimethylamino-3-(2-morpholin-4-yl-pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one
    SC_3161 cis-8-Benzyl-8-dimethylamino-3-(2-morpholin-4-yl-pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one
    SC_3162 cis-8-Dimethylamino-8-phenyl-3-(2-pyridin-2-yl-pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one
    SC_3163 cis-4-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-3,5-difluoro-benzamide
    SC_3164 cis-4-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-3-fluoro-benzamide
    SC_3165 cis-8-Benzyl-8-dimethylamino-3-[2-(trifluoromethyl)-pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2-one
    SC_3166 trans-8-Benzyl-8-dimethylamino-3-[2-(trifluoromethyl)-pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2-one
    SC_3167 cis-8-Dimethylamino-8-thiophen-2-yl-3-[2-(trifluoromethyl)-pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2-one
    SC_3168 trans-8-Dimethylamino-8-thiophen-2-yl-3-[2-(trifluoromethyl)-pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2-one
    SC_3169 cis-2-[2-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-phenoxy]-acetic acid
    SC_3170 cis-8-Dimethylamino-8-phenyl-3-(2-piperidin-1-yl-pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one
    SC_3171 cis-8-Dimethylamino-8-phenyl-3-(2-pyrrolidin-1-yl-pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one
    SC_3172 cis-8-Dimethylamino-8-phenyl-3-(2-pyrimidin-5-yl-pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one
    SC_3173 cis-8-Dimethylamino-8-phenyl-3-[2-(piperazine-1-carbonyl)-pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2-one
    SC_3174 trans-8-Benzyl-8-dimethylamino-3-[4-methyl-6-(trifluoromethyl)-pyridin-3-yl]-1,3-diazaspiro[4.5]decan-2-one
    SC_3175 cis-5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-2-morpholin-4-yl-pyridine-4-carboxylic acid amide
    SC_3176 cis-8-Dimethylamino-3-[2-(3,5-dimethyl-isoxazol-4-yl)-pyrimidin-5-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
    SC_3177 cis-3-[2-(Benzothiazol-6-yl)-pyrimidin-5-yl]-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
    SC_3178 cis-8-Dimethylamino-3-[2-fluoro-4-(trifluoromethyl)-phenyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
    SC_3179 cis-8-Dimethylamino-3-(6-morpholin-4-yl-pyridin-3-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
    SC_3180 cis-8-Dimethylamino-8-phenyl-3-(2-phenyl-thiazol-4-yl)-1,3-diazaspiro[4.5]decan-2-one
    SC_3181 cis-8-Dimethylamino-8-phenyl-3-[2-(tetrahydro-pyran-4-ylamino)-pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2-one
    SC_3182 cis-8-Dimethylamino-3-[2-(4-hydroxy-piperidin-1-yl)-pyrimidin-5-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
    SC_3183 cis-8-Dimethylamino-8-phenyl-3-(4-phenyl-thiazol-2-yl)-1,3-diazaspiro[4.5]decan-2-one
    SC_3184 cis-8-Dimethylamino-8-phenyl-3-[2-(1H-pyrrolo[2,3-b]pyridin-1-yl)-pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2-one
    SC_3185 cis-8-Dimethylamino-8-phenyl-3-[2-(3,4,5-trifluoro-phenyl)-pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2-one
    SC_3186 cis-8-Dimethylamino-3-o-tolyl-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
    SC_3187 cis-8-Dimethylamino-3-m-tolyl-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
    SC_3188 cis-8-Dimethylamino-8-phenyl-3-p-tolyl-1,3-diazaspiro[4.5]decan-2-one
    SC_3189 cis-8-Dimethylamino-8-phenyl-3-[4-(trifluoromethyl)-phenyl]-1,3-diazaspiro[4.5]decan-2-one
    SC_3190 cis-8-Dimethylamino-8-phenyl-3-[3-(trifluoromethyloxy)-phenyl]-1,3-diazaspiro[4.5]decan-2-one
    SC_3191 cis-8-Dimethylamino-8-phenyl-3-[4-(trifluoromethyloxy)-phenyl]-1,3-diazaspiro[4.5]decan-2-one
    SC_3192 cis-2-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-benzoic acid methyl ester
    SC_3193 cis-3-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-benzoic acid methyl ester
    SC_3194 cis-4-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-benzoic acid methyl ester
    SC_3195 cis-3-(1,3-Benzodioxol-5-yl)-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
    SC_3196 cis-8-Dimethylamino-8-phenyl-3-quinolin-5-yl-1,3-diazaspiro[4.5]decan-2-one
    SC_3197 cis-3-(2,3-Dihydro-1H-indol-6-yl)-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
    SC_3198 cis-5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-4-methyl-pyridine-2-carboxylic acid methyl ester
    SC_3199 cis-8-Dimethylamino-3-(6-methoxy-4-methyl-pyridin-3-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
    SC_3200 cis-8-Dimethylamino-3-[2-methyl-5-(trifluoromethyl)-2H-pyrazol-3-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
    SC_3201 cis-8-Dimethylamino-3-(3-methoxy-pyridin-2-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
    SC_3202 cis-8-Dimethylamino-8-phenyl-3-[5-(trifluoromethyl)-pyridin-2-yl]-1,3-diazaspiro[4.5]decan-2-one
    SC_3203 cis-5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-nicotinonitrile
    SC_3204 cis-8-Dimethylamino-3-(3-methyl-pyridin-2-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
    SC_3205 cis-8-Dimethylamino-3-(6-methoxy-pyridin-3-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
    SC_3206 cis-8-Dimethylamino-8-phenyl-3-[3-(trifluoromethyl)phenyl]-1,3-diazaspiro[4.5]decan-2-one
    SC_3207 cis-3-(1,3-Benzodioxol-4-yl)-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
    SC_3208 cis-8-Dimethylamino-3-[2-(2-oxo-1,3-dihydro-indol-4-yl)-pyrimidin-5-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
    SC_3209 cis-8-Dimethylamino-3-[2-(3,5-dimethyl-1H-pyrazol-1-yl)-pyrimidin-5-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
    SC_3210 cis-8-Dimethylamino-3-[2-(3-hydroxy-piperidin-1-yl)-pyrimidin-5-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
    SC_3211 cis-8-Dimethylamino-3-[2-(3-hydroxy-piperidin-1-yl)-pyrimidin-5-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
    SC_3212 cis-8-Dimethylamino-3-[2-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-pyrimidin-5-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
    SC_3213 cis-2-[4-[5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-pyrimidin-2-yl]-piperazin-1-yl]-acetic acid
    SC_3214 cis-8-Dimethylamino-3-[2-(1-methyl-1H-pyrrolo [2,3-b]pyridin-4-yl)-pyrimidin-5-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
    SC_3215 cis-8-Benzyl-8-dimethylamino-3-[4-methyl-6-(trifluoromethyl)-pyridin-3-yl]-1,3-diazaspiro[4.5]decan-2-one
    SC_3216 trans-8-Dimethylamino-3-[4-methyl-6-(trifluoromethyl)-pyridin-3-yl]-8-thiophen-2-yl-1,3-diazaspiro[4.5]decan-2-one
    SC_3217 cis-8-Dimethylamino-3-[4-methyl-6-(trifluoromethyl)-pyridin-3-yl]-8-thiophen-2-yl-1,3-diazaspiro[4.5]decan-2-one
    SC_3218 cis-8-Dimethylamino-3-[2-(1,1-dioxo-[1,4]thiazinan-4-yl)-4-(trifluoromethyl)-pyrimidin-5-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
    SC_3219 cis-8-Dimethylamino-8-(1-methyl-1H-benzoimidazol-2-yl)-3-[2-(trifluoromethyl)-pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2-one
    SC_3220 cis-8-Dimethylamino-8-(1-methyl-1H-benzoimidazol-2-yl)-3-[4-methyl-6-(trifluoromethyl)-pyridin-3-yl]-1,3-diazaspiro[4.5]decan-2-one
    SC_3221 cis-8-Dimethylamino-3-[2-(2-hydroxy-ethylamino)-pyrimidin-5-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
    SC_3222 cis-3-[2-(Benzyl-methyl-amino)-pyrimidin-5-yl]-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
    SC_3223 cis-5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-N-[2-[2-[2-(2-methoxy-ethoxy)-ethoxy]-ethoxy]-ethyl]-pyrimidine-2-carboxylic acid amide
    SC_3224 cis-8-Dimethylamino-3-[2-(1H-indazol-1-yl)-pyrimidin-5-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
    SC_3225 cis-8-Dimethylamino-3-[2-[(2-hydroxy-ethyl)-methyl-amino]-pyrimidin-5-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
    SC_3226 cis-3-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-benzamide
    SC_3227 cis-8-Dimethylamino-3-[3-fluoro-5-(trifluoromethyl)-pyridin-2-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
    SC_3228 cis-8-Dimethylamino-3-(5-methyl-pyrazin-2-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
    SC_3229 cis-8-Dimethylamino-3-(5-fluoro-pyrimidin-4-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
    SC_3230 cis-8-Dimethylamino-3-(5-fluoro-pyrimidin-2-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
    SC_3231 cis-8-Dimethylamino-8-phenyl-3-pyrazin-2-yl-1,3-diazaspiro[4.5]decan-2-one
    SC_3232 cis-3-([2,1,3]Benzoxadiazol-5-yl)-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
    SC_3233 cis-2-[2-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-phenoxy]-acetamide
    SC_3234 cis-8-Dimethylamino-8-phenyl-3-(5-pyridin-4-yl-thiophen-2-yl)-1,3-diazaspiro[4.5]decan-2-one
    SC_3235 cis-2-[2-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-phenoxy]-acetic acid methyl ester
    SC_3236 cis-8-Dimethylamino-3-(2-morpholin-4-yl-pyrimidin-4-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
    SC_3237 cis-3-[2-(3,4-Difluoro-phenyl)-pyrimidin-5-yl]-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
    SC_3238 cis-2-[5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-pyrimidin-2-yl]-benzonitrile
    SC_3239 cis-3-(2-Amino-pyrimidin-5-yl)-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
    SC_3240 cis-N-[5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-pyrimidin-2-yl]-cyclopropanecarboxylic acid amide
    SC_3241 cis-2-[4-[5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-pyrimidin-2-yl]-piperazin-1-yl]-acetamide
    SC_3242 cis-8-Dimethylamino-8-phenyl-3-(6-piperazin-1-yl-pyridin-3-yl)-1,3-diazaspiro[4.5]decan-2-one
    SC_3243 cis-8-Dimethylamino-3-[6-(4-methyl-piperazin-1-yl)-pyridin-3-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
    SC_3244 cis-8-Dimethylamino-3-[2-(1,1-dioxo-[1,4]thiazinan-4-yl)-4-methyl-pyrimidin-5-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
    SC_3245 cis-8-Dimethylamino-8-phenyl-3-[2-(trifluoromethyl)-pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2-one
    SC_3246 cis-2-[8-Dimethylamino-1-(3-methoxy-propyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-5-carbonitrile
    SC_3247 cis-8-Dimethylamino-3-[2-(4-methyl-piperazin-1-yl)-pyrimidin-5-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
    SC_3248 cis-8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-8-phenyl-3-[2-(trifluoromethyl)-pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2-one
    SC_3249 cis-2-[1-(3-Methoxy-propyl)-8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-5-carbonitrile
    SC_3250 cis-8-Dimethylamino-8-phenyl-3-[6-(trifluoromethyl)-pyridin-3-yl]-1,3-diazaspiro[4.5]decan-2-one
    SC_3251 cis-5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-pyridine-2-carbonitrile
    SC_3252 cis-8-Dimethylamino-3-(2-morpholin-4-yl-pyrimidin-5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
    SC_3253 cis-8-Dimethylamino-3-(2-methyl-pyrimidin-5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
    SC_3254 cis-8-Dimethylamino-1-[(2-methoxyphenyl)-methyl]-3-(2-methyl-pyrimidin-5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
    SC_3255 cis-1-[(1-Hydroxy-cyclobutyl)-methyl]-8-methylamino-8-phenyl-3-[2-(trifluoromethyl)-pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2-one
    SC_3256 cis-8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-3-(2-methyl-pyrimidin-5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
    SC_3257 cis-1-[(1-Hydroxy-cyclobutyl)-methyl]-8-methylamino-8-phenyl-3-pyrimidin-5-yl-1,3-diazaspiro[4.5]decan-2-one
    SC_3258 cis-5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-4-methyl-pyridine-2-carbonitrile
    SC_3259 cis-8-Dimethylamino-3-(2-methyl-pyrimidin-5-yl)-8-phenyl-1-(pyridin-2-yl-methyl)-1,3-diazaspiro[4.5]decan-2-one
    SC_3260 cis-8-Dimethylamino-8-phenyl-3-pyrimidin-5-yl-1,3-diazaspiro[4.5]decan-2-one
    SC_3261 cis-8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-8-phenyl-3-pyrimidin-5-yl-1,3-diazaspiro[4.5]decan-2-one
    SC_3262 cis-8-Amino-1-[(1-hydroxy-cyclobutyl)-methyl]-8-phenyl-3-[2-(trifluoromethyl)-pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2-one
    SC_3263 cis-8-Dimethylamino-3-(3-fluorophenyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
    SC_3264 cis-8-Dimethylamino-3-(3-methylsulfonyl-phenyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
    SC_3265 cis-8-Dimethylamino-3-(4-methylsulfonyl-phenyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
    SC_3266 cis-8-Dimethylamino-8-phenyl-3-pyridazin-3-yl-1,3-diazaspiro[4.5]decan-2-one
    SC_3267 cis-3-Methoxy-4-(8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-benzonitrile
    SC_3268 cis-8-Dimethylamino-3-(2-fluorophenyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
    SC_3269 cis-8-Dimethylamino-8-phenyl-3-(2-phenyl-pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one
    SC_3270 cis-8-Methylamino-1-(oxetan-3-yl-methyl)-8-phenyl-3-[2-(trifluoromethyl)-pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2-one
    SC_3271 cis-1-(Cyclopropyl-methyl)-8-methylamino-8-phenyl-3-[2-(trifluoromethyl)-pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2-one
    SC_3272 cis-4-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-benzonitrile
    SC_3273 cis-8-Dimethylamino-3-(4-fluorophenyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
    SC_3274 cis-2-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-benzonitrile
    SC_3275 cis-8-Ethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-8-phenyl-3-[2-(trifluoromethyl)-pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2-one
    SC_3276 cis-1-[(1-Hydroxy-cyclobutyl)-methyl]-8-methylamino-3-(2-methyl-pyrimidin-5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
    SC_3277 cis-8-Dimethylamino-3-[2-(morpholin-4-yl-methyl)-pyrimidin-5-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
    SC_3278 cis-8-Dimethylamino-3-[2-(methyl-tetrahydro-pyran-4-yl-amino)-pyrimidin-5-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
    SC_3279 cis-5-[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]-pyrimidine-2-carboxylic acid amide
    SC_3280 cis-1-(Cyclopropyl-methyl)-3-(2-fluoro-4-methylsulfonyl-phenyl)-8-methylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
    SC_3281 cis-2-[[5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-pyrimidin-2-yl]-methyl-amino]-acetamide
    SC_3282 cis-2-[[5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-pyrimidin-2-yl]amino]-acetamide
    SC_3283 cis-1-(Cyclopropyl-methyl)-8-methylamino-3-[4-methyl-6-(trifluoromethyl)-pyridin-3-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
    SC_3284 cis-1-(Cyclopropyl-methyl)-8-dimethylamino-3-[4-methyl-6-(trifluoromethyl)-pyridin-3-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
    SC_3285 cis-N-[5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-pyrimidin-2-yl]-thiophene-2-carboxylic acid amide
    SC_3286 cis-N-[5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-pyrimidin-2-yl]-benzamide
    SC_3287 cis-8-Dimethylamino-8-phenyl-3-(5-phenyl-thiophen-2-yl)-1,3-diazaspiro[4.5]decan-2-one
    SC_3288 cis-1-(Cyclopropyl-methyl)-8-dimethylamino-3-[2-(methylsulfonyl-methyl)-phenyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
    SC_3289 cis-1-(Cyclopropyl-methyl)-8-methylamino-3-[2-(methylsulfonyl-methyl)-phenyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
    SC_3290 cis-8-Dimethylamino-8-(3-fluorophenyl)-3-[2-(methylsulfonyl-methyl)-phenyl]-1,3-diazaspiro[4.5]decan-2-one
    SC_3291 cis-8-Dimethylamino-8-(4-fluorophenyl)-3-[2-(methylsulfonyl-methyl)-phenyl]-1,3-diazaspiro[4.5]decan-2-one
    SC_3292 cis-8-[Methyl-(tetrahydro-furan-3-yl-methyl)-amino]-8-phenyl-3-[2-(trifluoromethyl)-pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2-one (enantiomer 1)
    SC_3293 cis-8-[Methyl-(tetrahydro-furan-3-yl-methyl)-amino]-8-phenyl-3-[2-(trifluoromethyl)-pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2-one (enantiomer 2)
    SC_3294 cis-8-Dimethylamino-8-(3-fluorophenyl)-3-(4-methyl-2-morpholin-4-yl-pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one
    SC_3295 cis-3-[6-(4-Acetyl-piperazin-1-yl)-4-methyl-pyridin-3-yl]-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
    SC_3296 cis-3-[2-(4-Acetyl-piperazin-1-yl)-4-methyl-pyrimidin-5-yl]-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
    SC_3297 cis-8-Dimethylamino-3-(4-methyl-6-pyridin-4-yl-pyridin-3-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
    SC_3298 cis-3-[2-(4-Acetyl-piperazin-1-yl)-4-(trifluoromethyl)-pyrimidin-5-yl]-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
    SC_3299 cis-8-Dimethylamino-3-[2-(3-oxo-piperazin-1-yl)-4-(trifluoromethyl)-pyrimidin-5-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
    SC_3300 cis-8-Dimethylamino-3-isoquinolin-4-yl-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
    SC_3301 cis-8-Dimethylamino-3-isoquinolin-5-yl-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
    SC_3302 cis-8-Dimethylamino-8-phenyl-3-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1,3-diazaspiro[4.5]decan-2-one
    SC_3303 cis-8-Dimethylamino-8-phenyl-3-(2-pyridin-4-yl-thiazol-4-yl)-1,3-diazaspiro[4.5]decan-2-one
    SC_3304 cis-8-[Methyl-(tetrahydro-furan-3-yl-methyl)-amino]-3-(2-morpholin-4-yl-pyrimidin-5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (enantiomer 1)
    SC_3305 cis-8-[Methyl-(tetrahydro-furan-3-yl-methyl)-amino]-3-(2-morpholin-4-yl-pyrimidin-5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (enantiomer 2)
    SC_3306 cis-3-[2-(Azetidin-1-yl)-pyrimidin-5-yl]-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
    SC_3307 cis-3-[2-(3,3-Difluoro-azetidin-1-yl)-pyrimidin-5-yl]-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
    SC_3308 cis-8-Dimethylamino-3-[6-morpholin-4-yl-5-(trifluoromethyl)-pyridin-3-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
    SC_3309 cis-8-Methylamino-3-[6-morpholin-4-yl-5-(trifluoromethyl)-pyridin-3-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
    SC_3310 cis-8-Dimethylamino-8-phenyl-3-[5-(trifluoromethyloxy)-pyridin-2-yl]-1,3-diazaspiro[4.5]decan-2-one
    SC_3311 cis-8-Dimethylamino-3-(5-methylsulfonyl-pyridin-2-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
    SC_3312 cis-6-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-nicotinonitrile
    SC_3313 cis-3-[2-(4-Cyclopropyl-1H-[1,2,3]triazol-1-yl)-pyrimidin-5-yl]-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
    SC_3314 cis-8-Dimethylamino-3-[4-methyl-2-(3-oxo-piperazin-1-yl)-pyrimidin-5-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
    SC_3315 cis-5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-pyridine-2-carboxylic acid amide
    SC_3316 cis-3-[4-(Azetidin-1-yl)-2-methyl-pyrimidin-5-yl]-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
    SC_3317 cis-2-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-benzamide
    SC_3318 cis-8-Dimethylamino-3-[2-(methylsulfonyl-methyl)-phenyl]-8-thiophen-2-yl-1,3-diazaspiro[4.5]decan-2-one
    SC_3319 cis-8-Dimethylamino-8-(3-fluorophenyl)-3-[2-methyl-5-(trifluoromethyl)-2H-pyrazol-3-yl]-1,3-diazaspiro[4.5]decan-2-one
    SC_3320 cis-8-Dimethylamino-3-(4-methyl-2-morpholin-4-yl-pyrimidin-5-yl)-8-thiophen-2-yl-1,3-diazaspiro[4.5]decan-2-one
    SC_3321 cis-8-Dimethylamino-3-(6-methylsulfonyl-pyridin-3-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
    SC_3322 cis-8-Dimethylamino-8-phenyl-3-(1H-pyrrolo[2,3-b]pyridin-5-yl)-1,3-diazaspiro[4.5]decan-2-one
    SC_3323 cis-N-[5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-pyrimidin-2-yl]-acetamide
    SC_3324 cis-3-[2-(4-Methyl-piperazin-1-yl)-pyrimidin-5-yl]-8-[methyl-(tetrahydro-furan-3-yl-methyl)-amino]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (enantiomer 1)
    SC_3325 cis-3-[2-(4-Methyl-piperazin-1-yl)-pyrimidin-5-yl]-8-[methyl-(tetrahydro-furan-3-yl-methyl)-amino]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (enantiomer 2)
    SC_3326 cis-8-Dimethylamino-3-(4,6-dimethyl-2-morpholin-4-yl-pyrimidin-5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
    SC_3327 cis-8-Dimethylamino-3-(2-morpholin-4-yl-pyrimidin-5-yl)-8 thiophen-2-yl-1,3-diazaspiro[4.5]decan-2-one
    SC_3328 cis-6-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-pyridine-3-carboxylic acid amide
    SC_3329 cis-8-Dimethylamino-3-[2-methyl-5-(trifluoromethyl)-2H-pyrazol-3-yl]-8-thiophen-2-yl-1,3-diazaspiro[4.5]decan-2-one
    SC_3330 cis-8-Dimethylamino-3-[2-[(2-hydroxy-ethyl)-methyl-amino]-pyrimidin-5-yl]-8-thiophen-2-yl-1,3-diazaspiro[4.5]decan-2-one
    SC_3331 cis-8-Dimethylamino-3-[2-(2-oxo-1,3-dihydro-indol-4-yl)-pyrimidin-5-yl]-8-thiophen-2-yl-1,3-diazaspiro[4.5]decan-2-one
    SC_3332 cis-8-Dimethylamino-3-[4-methyl-6-(3-oxo-piperazin-1-yl)-pyridin-3-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
    SC_3333 cis-8-Dimethylamino-3-(4-methyl-6-pyridin-2-yl-pyridin-3-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
    SC_3334 cis-8-Dimethylamino-3-(4-methylsulfonyl-pyridin-3-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
    SC_3335 cis-3-(Benzothiazol-7-yl)-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
    SC_3336 cis-8-Dimethylamino-8-(4-fluorophenyl)-3-(4-methyl-2-morpholin-4-yl-pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one
    SC_3337 cis-2-[8-Dimethylamino-3-[4-methyl-6-(trifluoromethyl)-pyridin-3-yl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl]-N,N-dimethyl-acetamide
    SC_3338 cis-8-Dimethylamino-3-[2-(2-methyl-1-oxo-2,3-dihydro-isoindol-4-yl)-pyrimidin-5-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
    SC_3339 cis-2-[[5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-2-methyl-pyrimidin-4-yl]amino]-acetamide
    SC_3340 cis-2-[3-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-pyridin-4-yl]-acetamide
    SC_3341 cis-8-Dimethylamino-3-[4-(methylsulfonyl-methyl)-pyridin-3-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
    SC_3342 cis-8-Dimethylamino-3-[6-(4-methyl-3-oxo-piperazin-1-yl)-pyridin-3-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
    SC_3343 cis-8-Dimethylamino-3-(2,4-dimethyl-pyrimidin-5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
    SC_3344 cis-8-Dimethylamino-3-[2-(1-oxo-2,3-dihydro-isoindol-4-yl)-pyrimidin-5-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; 2,2,2-trifluoro-acetic acid
    SC_3345 cis-8-Dimethylamino-3-[6-[(2-hydroxy-ethyl)-methyl-amino]-5-(trifluoromethyl)-pyridin-3-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
    SC_3346 cis-8-Dimethylamino-8-phenyl-3-[2-[4-(trifluoromethyl)-1H-[1,2,3]triazol-1-yl]-pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2-one
    SC_3347 cis-8-Dimethylamino-3-[2-(4-isopropyl-1H-[1,2,3]triazol-1-yl)-pyrimidin-5-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
    SC_3348 cis-8-Dimethylamino-3-[6-(1,1-dioxo-[1,4]thiazinan-4-yl)-pyridin-3-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
    SC_3349 cis-5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-2-morpholin-4-yl-nicotinonitrile
    SC_3350 cis-8-Dimethylamino-3-(1-methylsulfonyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
    SC_3351 cis-8-Dimethylamino-3-(1H-indol-4-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
    SC_3352 cis-8-Dimethylamino-3-(2-hydroxy-benzooxazol-7-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
    SC_3353 cis-8-Dimethylamino-3-[2-fluoro-4-(trifluoromethyloxy)-phenyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
    SC_3354 cis-4-[5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-pyrimidin-2-yl]-benzamide; 2,2,2-trifluoro-acetic acid
    SC_3355 cis-8-Dimethylamino-3-(1-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
    SC_3356 cis-3-(1-Acetyl-1H-indol-4-yl)-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2–one
    SC_3357 cis-8-Dimethylamino-3-(1H-indol-3-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
    SC_3358 cis-6-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-5-methyl-nicotinonitrile
    SC_3359 cis-6-(8-Dimethlamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-5-fluoro-nicotinonitrile
    SC_3360 cis-8-Dimethylamino-3-[4-methyl-6-(trifluoromethyl)-pyridin-3-yl]-1-(2-oxo-2-pyrrolidin-1-yl-ethyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
    SC_3361 cis-6-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-5-methyl-pyridine-3-carboxylic acid amide
    SC_3362 cis-6-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-5-fluoro-pyridine-3-carboxylic acid amide
    SC_3363 cis-8-Dimethylamino-3-[4-methyl-6-(trifluoromethyl)-pyridin-3-yl]-8-m-tolyl-1,3-diazaspiro[4.5]decan-2-one
    SC_3364 cis-3-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-isonicotinonitrile
    SC_3365 cis-8-Dimethylamino-3-[3-fluoro-5-(2-oxo-1,3-dihydro-indol-4-yl)-pyridin-2-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
    SC_3366 cis-8-Dimethylamino-3-[4-methyl-6-(trifluoromethyl)-pyridin-3-yl]-8-[3-(trifluoromethyloxy)-phenyl]-1,3-diazaspiro[4.5]decan-2-one
    SC_3367 cis-8-Dimethylamino-3-[4-methyl-6-(trifluoromethyl)-pyridin-3-yl]-8-[3-(trifluoromethyl)phenyl]-1,3-diazaspiro[4.5]decan-2-one
    SC_3368 cis-8-Dimethylamino-3-(3-methoxyphenyl)-3-[4-methyl-6-(trifluoromethyl)-pyridin-3-yl]-1,3-diazaspiro[4.5]decan-2-one
    SC_3369 cis-8-(5-Chloro-thiophen-2-yl)-8-dimethylamino-3-[4-methyl-6-(trifluoromethyl)-pyridin-3-yl]-1,3-diazaspiro[4.5]decan-2-one
    SC_3370 cis-8-Dimethylamino-8-(3-fluorophenyl)-3-[4-methyl-6-(trifluoromethyl)-pyrdin-3-yl]-1,3-diazaspiro[4.5]decan-2-one
    SC_3371 cis-8-Dimethylamino-3-(2-methylamino-pyrimidin-5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
    SC_3372 cis-8-(5-Chloro-thiophen-2-yl)-8-dimethylamino-3-(4-methyl-2-morpholin-4-yl-pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one
    SC_3373 cis-N-[5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-pyrimidin-2-yl]-N-methyl-cyclopropanecarboxylic acid amide
    SC_3374 cis-N-[5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-pyrimidin-2-yl]-N,2,5-trimethyl-2H-pyrazole-3-carboxylic acid amide
    SC_3375 cis-3-[4,6-Bis(trifluoromethyl)-pyridin-3-yl]-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
    SC_3376 cis-8-Dimethylamino-3-[2-[(2-hydroxy-ethyl)-methyl-amino]-quinazolin-6-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
    SC_3377 cis-8-Dimethylamino-3-(2-morpholin-4-yl-quinazolin-6-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
    SC_3378 cis-8-[Methyl-(oxetan-3-yl-methyl)-amino]-8-phenyl-3-[2-(trifluoromethyl)-pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2-one
    SC_3379 cis-3-(1-Acetyl-1H-indol-3-yl)-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
    SC_3380 cis-8-Dimethylamino-8-phenyl-3-quinazolin-6-yl-1,3-diazaspiro[4.5]decan-2-one
    SC_3381 cis-5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-2-(2-oxo-1,3-dihydro-indol-4-yl)-isonicotinonitrile
    SC_3382 cis-N-[5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-pyrimidin-2-yl]-N-methyl-tetrahydro-pyran-4-carboxylic acid amide
    SC_3383 cis-N-[5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-pyrimidin-2-yl]-N,2,2-trimethyl-propionamide
    SC_3384 cis-8-Dimethylamino-3-[2-(1-methyl-2-oxo-1,3-dihydro-indol-4-yl)-pyrimidin-5-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
    SC_3385 cis-8-Dimethylamino-3-(2-morpholin-4-yl-1H-benzoimidazol-5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
    SC_3386 cis-8-Dimethylamino-8-(3-fluoro-5-methyl-phenyl)-3-[4-methyl-6-(trifluoromethyl)-pyridin-3-yl]-1,3-diazaspiro[4.5]decan-2-one
    SC_3387 cis-8-Dimethylamino-3-[6-(2-oxo-1,3-dihydro-indol-4-yl)-pyridin-3-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
    SC_3388 cis-8-Dimethylamino-8-(3-hydroxyphenyl)-3-[4-methyl-6-(trifluoromethyl)-pyridin-3-yl]-1,3-diazaspiro[4.5]decan-2-one
    SC_3389 cis-3-[6-(Azetidin-1-yl)-5-(trifluoromethyl)-pyridin-3-yl]-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
    SC_3390 cis-3-[1-(Cyclopropyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-isonicotinonitrile
    SC_3391 cis-3-[3,5-Bis(trifluoromethyl)-pyridin-2-yl]-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
    SC_3392 cis-8-Dimethylamino-3-(5-fluoro-6-morpholin-4-yl-pyridin-3-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
    SC_3393 cis-8-(3-Chlorophenyl)-8-dimethylamino-3-[4-methyl-6-(trifluoromethyl)-pyridin-3-yl]-1,3-diazaspiro[4.5]decan-2-one
    SC_3394 cis-8-Dimethylamino-3-[5-(2-oxo-1,3-dihydro-indol-4-yl)-pyridin-2-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
    SC_3395 cis-8-Dimethylamino-8-phenyl-3-[5-(trifluoromethyl)-[1,3,4]thiadiazol-2-yl]-1,3-diazaspiro[4.5]decan-2-one
    SC_3396 cis-8-Dimethylamino-3-(2-oxo-1,3-dihydro-indol-4-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
    SC_3397 cis-8-Dimethylamino-3-[2-[(2-hydroxy-ethyl)-methyl-amino]-1H-benzoimidazol-5-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
    SC_3398 cis-8-Dimethylamino-3-(5-methyl-6-morpholin-4-yl-pyridin-3-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
    SC_3399 cis-1-(Cyclopropyl-methyl)-8-dimethylamino-8-(3-fluorophenyl)-3-(5-methylsulfonyl-pyridin-2-yl)-1,3-diazaspiro[4.5]decan-2-one
    SC_3400 cis-1-(Cyclopropyl-methyl)-8-(3-fluorophenyl)-8-methylamino-3-(5-methylsulfonyl-pyridin-2-yl)-1,3-diazaspiro[4.5]decan-2-one
    SC_3401 cis-1-(Cyclobutyl-methyl)-8-(3-fluorophenyl)-8-methylamino-3-[2-(trifluoromethyl)-pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2-one
    SC_3402 cis-1-(Cyclopropyl-methyl)-8-dimethylamino-8-(3-fluorophenyl)-3-[2-(trifluoromethyl)-pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2-one
    SC_3403 cis-1-(Cyclopropyl-methyl)-8-(3-fluorophenyl)-8-methylamino-3-[2-(trifluoromethyl)-pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2-one
    SC_3404 cis-8-Dimethylamino-8-(3-fluorophenyl)-3-[2-(trifluoromethyl)-pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2-one
    SC_3405 cis-1-(Cyclopropyl-methyl)-8-dimethylamino-8-(3-fluorophenyl)-3-[2-methyl-5-(trifluoromethyl)-2H-pyrazol-3-yl]-1,3-diazaspiro[4.5]decan-2-one
    SC_3406 cis-1-(Cyclopropyl-methyl)-8-(3-fluorophenyl)-8-methylamino-3-[2-methyl-5-(trifluoromethyl)-2H-pyrazol-3-yl]-1,3-diazaspiro[4.5]decan-2-one
    SC_3407 cis-8-Methylamino-3-(4-methyl-2-morpholin-4-yl-pyrimidin-5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
    SC_3408 cis-3-[5-(Azetidin-1-yl)-3-methyl-pyridin-2-yl]-8-dimethylamino-8-(3-fluorophenyl)-1,3-diazaspiro[4.5]decan-2-one
    SC_3409 cis-8-Dimethylamino-8-(3-fluorophenyl)-3-(5-methylsulfonyl-pyridin-2-yl)-1,3-diazaspiro[4.5]decan-2-one
    SC_3410 cis- 3-(6-(azetidin-1-yl)-4-fluoropyridin-3-yl)-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
    SC_3411 cis-3-(6-(azetidin-1-yl)pyridin-3-yl)-8-(dimethylamino)-8-(3-fluorophenyl)-1,3-diazaspiro[4.5]decan-2-one
    SC_3412 cis-3-(1-(cyclopropanecarbonyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)-8-(dimethylamino)-8-(3-fluorophenyl)-1,3-diazaspiro[4.5]decan-2-one
    SC_3413 cis-8-(dimethylamino)-8-(3-fluorophenyl)-3-(l-(2-hydroxyethyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)-1,3-diazaspiro[4.5]decan-2-one
    SC_3414 cis-3-(1-(cyclopropylmethyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)-8-(dimethylamino)-8-(3-fluorophenyl)-1,3-diazaspiro[4.5]decan-2-one
    SC_3415 cis-8-(dimethylamino)-8-(3-fluorophenyl)-3-(1-(methylsulfonyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)-1,3-diazaspiro[4.5]decan-2-one
    SC_3416 cis-1-(cyclopropylmethyl)-8-(dimethylamino)-8-(3-fluorophenyl)-3-(1-(methylsulfonyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)-1,3-diazaspiro[4.5]decan-2-one
    SC_3417 cis-2-(5-(8-(dimethylamino)-8-(3-fluorophenyl)-2-oxo-1,3-diazaspiro[4.5]decan-3-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)-N,N-dimethylacetamide
    SC_3418 cis-2-(5-(1-(cyclopropylmethyl)-8-(dimethylamino)-8-(3-fluorophenyl)-2-oxo-1,3-diazaspiro[4.5]decan-3-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)-N,N-dimethylacetamide
    SC_3419 cis-8-(dimethylamino)-3-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
    SC_3420 cis-8-(dimethylamino)-3-(3-fluoro-1H-pyrrolo[2,3-b]pyridin-5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
    SC_3421 cis-8-(dimethylamino)-8-phenyl-3-(1H-pyrrolo[2,3-c]pyridin-4-yl)-1,3-diazaspiro[4.5]decan-2-one
    SC_3422 cis-8-(dimethylamino)-8-phenyl-3-(2-(pyridazin-4-yl)pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one
    SC_3423 cis-8-(dimethylamino)-3-(2-(2-oxo-1,2-dihydropyridin-4-yl)pyrimidin-5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
    SC_3424 cis-8-(dimethylamino)-8-(3-fluorophenyl)-3-(1-methyl-3-(thiophen-2-yl)-1H-pyrazol-5-yl)-1,3-diazaspiro[4.5]decan-2-one
    SC_3425 cis-8-(dimethylamino)-8-(3-fluorophenyl)-3-(1-methyl-3-morpholino-1H-pyrazol-5-yl)-1,3-diazaspiro[4.5]decan-2-one
    SC_3426 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_3427 cis-8-(dimethylamino)-8-phenyl-3-(2-(trifluoromethyl)pyrimidin-5-yl)-1-(3,3,3-trifluoropropyl)-1,3-diazaspiro[4.5]decan-2-one
    SC_3428 cis-3-(4-methyl-6-(trifluoromethyl)pyridin-3-yl)-8-(methylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
    SC_3429 cis-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-8-(methylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
    SC_3430 cis-8-(dimethylamino)-8-(3-fluorophenyl)-3-(4-(methylsulfonyl)pyridin-3-yl)-1,3-diazaspiro[4.5]decan-2-one
    SC_3431 cis-8-(dimethylamino)-3-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-8-(3-fluorophenyl)-1,3-diazaspiro[4.5]decan-2-one
    SC_3432 cis-3-(1-cyclopropyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-8-(dimethylamino)-8-(3-fluorophenyl)-1,3-diazaspiro[4.5]decan-2-one
    SC_3433 cis-8-(dimethylamino)-8-(3-fluorophenyl)-3-(1-(oxetan-3-ylmethyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)-1,3-diazaspiro[4.5]decan-2-one
    SC_3434 cis-8-(dimethylamino)-8-(3-fluorophenyl)-3-(1-(2-(methylsulfonyl)ethyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)-1,3-diazaspiro[4.5]decan-2-one
    SC_3435 cis-8-(dimethylamino)-8-(3-fluorophenyl)-3-(4-methyl-2-(methylamino)pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one
    SC_3436 cis-3-(2-cyclopropoxy-4-methylpyrimidin-5-yl)-8-(dimethylamino)-8-(3-fluorophenyl)-1,3-diazaspiro[4.5]decan-2-one
    SC_3437 cis-N-(5-(8-(dimethylamino)-8-(3-fluorophenyl)-2-oxo-1,3-diazaspiro[4.5]decan-3-yl)-4-methylpyrimidin-2-yl)-N-methylcyclopropanecarboxamide
    SC_3438 cis-N-(5-(8-(dimethylamino)-8-(3-fluorophenyl)-2-oxo-1,3-diazaspiro[4.5]decan-3-yl)-4-methylpyrimidin-2-yl)-N-methylpivalamide
    SC_3439 cis-3-(4-(azetidin-1-yl)-2-(trifluoromethyl)pyrimidin-5-yl)-8-(dimethylamino)-8-(3-fluorophenyl)-1,3-diazaspiro[4.5]decan-2-one
    SC_3440 cis-8-(dimethylamino)-8-(3-fluorophenyl)-3-(4-(oxetan-3-ylmethoxy)-2-(trifluoromethyl)pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one
    SC_3441 cis-3-(2-cyclopropyl-4-(2,2,2-trifluoroethoxy)pyrimidin-5-yl)-8-(dimethylamino)-8-(3-fluorophenyl)-1,3-diazaspiro[4.5]decan-2-one
    SC_3442 cis-3-(2-cyclopropyl-4-((2-hydroxyethyl)(methyl)amino)pyrimidin-5-yl)-8-(dimethylamino)-8-(3-fluorophenyl)-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, tetrahydrothiophene, 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 -C1-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 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 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 compound according to the invention has a structure according to general formula (I′)
  • Figure US20230303573A1-20230928-C00330
    • wherein R1 to R5, R11 to R20 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.
  • In a preferred embodiment, the compound according to the invention has a structure according to general formula (IX) or (X)
  • Figure US20230303573A1-20230928-C00331
  • Figure US20230303573A1-20230928-C00332
  • wherein
    • R2 means —H or —CH3;
    • R3 means -phenyl or -3-fluorophenyl;
    • RC means —H or —OH;
    • RE means —H, —CH3, —F, —CF3, -cyclopropyl, -aziridinyl, —OH; -O-C1-C4-alkyl; —OCF3; -O-C1-C4-alkyl-CO2H; -O-C1-C4-alkyl-C(=O)O-C1-C4-alkyl; or -O-C1-C4-alkyl-CONH2;
    • RF means —CF3, -cyclopropyl, —S(═O)2CH3,
    • —NH2; -NHC1-C4-alkyl; -N(C1-C4-alkyl)2; -NHC1-C4-alkyl-OH; -NCH3C1-C4-alkyl-OH; -NH-C1-C4-alkyl-C(=O)NH2; -NCH3-C1-C4-alkyl-C(=O)NH2; -NHC(=O)-C1-C4-alkyl; -NCH3C(=O)-C1-C4-alkyl;
    • -6-14-membered aryl, unsubstituted, mono- or polysubstituted; or
    • -5-14-membered heteroaryl, unsubstituted, mono- or polysubstituted;
    • U means ═CH— or ═N—; and
    • V means ═CH— or ═N—;
    • or a physiologically acceptable salt thereof
  • In a preferred embodiment, the compound according to the invention has a structure according to general formula (XI)
  • Figure US20230303573A1-20230928-C00333
  • wherein
    • R2 means —H or —CH3;
    • R3 means -phenyl or -3-fluorophenyl;
    • RH means —CN; -C1-C4-alkyl; -CF3; -C1-C4-alkyl-C(=O)NH2; -C1-C4-alkyl-S(=O)2-C1-C4-alkyl; -C(=O)-C1-C4-alkyl; —C(═O)OH; -C(=O)O-C1-C4-alkyl; —C(═O)NH2; -C(=O)NHC1-C4-alkyl; -C(=O)N(C1-C4-alkyl)2; -C(=O)NH(C1-C4-alkyl-OH); -C(=O)N(C1-C4-alkyl)(C1-C4-alkyl-OH); —C(═O)NH—(CH2CH2O)1-30—CH3;
    • -3-12-membered cycloalkyl, saturated or unsaturated, unsubstituted, mono- or polysubstituted; wherein said 3-12-membered cycloalkyl is optionally connected through —CH2—, —NH—, —NCH3—, —NH—(CH2)1-3—, —NCH3(CH2)1-3—, —(C═O)—, —NHC(═O)—, —NCH3C(═O)—, —C(═O)NH—(CH2)1-3—, —C(═O)NCH3—(CH2)1-3—; or
    • -3-12-membered heterocycloalkyl, saturated or unsaturated, unsubstituted, mono- or polysubstituted; 6-14-membered aryl, unsubstituted, mono- or polysubstituted; wherein said 3-12-membered heterocycloalkyl is optionally connected through —CH2—, —NH—, —NCH3—, —NH—(CH2)1-3—, —NCH3(CH2)1-3—, —(C═O)—, —NHC(═O)—, —NCH3C(═O)—, —C(═O)NH—(CH2)1-3—, —C(═O)NCH3—(CH2)1- 3—;
    • RG means —CF3, —S(═O)2CH3;
    • —NH2; -NHC1-C4-alkyl; -N(C1-C4-alkyl)2; -NHC1-C4-alkyl-OH; -NCH3C1-C4-alkyl-OH; -NH-C1-C4-alkyl-C(=O)NH2; -NCH3-C1-C4-alkyl-C(=O)NH2; -NHC(=O)-C1-C4-alkyl; -NCH3C(=O)-C1-C4-alkyl;
    • -3-12-membered cycloalkyl, saturated or unsaturated, unsubstituted, mono- or polysubstituted; wherein said 3-12-membered cycloalkyl is optionally connected through —CH2—, —NH—, —NCH3—, —NH—(CH2)1-3—, —NCH3(CH2)1-3—, —(C═O)—, —NHC(═O)—, —NCH3C(═O)—, —C(═O)NH—(CH2)1-3—, —C(═O)NCH3—(CH2)1-3—; or
    • -3-12-membered heterocycloalkyl, saturated or unsaturated, unsubstituted, mono- or polysubstituted; 6-14-membered aryl, unsubstituted, mono- or polysubstituted; wherein said 3-12-membered heterocycloalkyl is optionally connected through —CH2—, —NH—, —NCH3—, —NH—(CH2)1-3—, —NCH3(CH2)1-3—, —(C═O)—, —NHC(═O)—, —NCH3C(═O)—, —C(═O)NH—(CH2)1-3—, —C(═O)NCH3—(CH2)1-3 —;
    • 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 semisolid 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 US20230303573A1-20230928-C00334
  • 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 US20230303573A1-20230928-C00335
  • 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 US20230303573A1-20230928-C00336
  • 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, „sat.“ means saturated, „sol.“ means solution, “conc.” means concentrated.
  • Further abbreviations:
    • brine saturated aqueous sodium chloride solution
    • CC column chromatography
    • cHex cyclohexane
    • dba dibenzylideneacetone
    • DCM dichloromethane
    • DIPEA N,N-diisopropylethylamine
    • DMF N,N-dimethylformamide
    • 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 diisoproylamide
    • Me methyl
    • m/z mass-to-charge ratio
    • MeOH methanol
    • MeCN acetonitrile
    • min minutes
    • MS mass spectrometry
    • NBS N-bromosuccinimide
    • NIS N-iodosuccinimide
    • NEt3 triethylamine
    • PE petroleum ether (60-80°C)
    • RM reaction mixture
    • RT room temperature
    • TFA trifluoroacetic acid
    • T3P 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide
    • tBME tert-butyl methyl ether
    • THF tetrahydrofurane
    • 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 DC, 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 DC, US, repspectively, 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 US20230303573A1-20230928-C00337
  • 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 US20230303573A1-20230928-C00338
    • Synthesis of Intermediates
  • Synthesis of INT-600: 5-(cis-8-(Dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)pyrimidine-2-carbonitrile
  • Figure US20230303573A1-20230928-C00339
  • Cs2CO3 (1.1 g, 3.66 mmol) was added to the solution of CIS-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-976) (0.5 g, 1.83 mmol), Xanthphos (0.158 g, 0.274 mmol), Pd2(dba)3 (0.083 g, 0.091 mmol) and 5-bromopyrimidine-2-carbonitrile (0.52 g, 2.74 mmol) in 1,4-dioxane (20 mL) under argon atmosphere. The reaction mixture was stirred for 16 h at 90°C, then cooled to RT and concentrated under reduced pressure. The residue was suspended in EtOAc (20 mL) and filtered through a plug of celite. The filtrate was concentrated under reduced pressure and the resulting residue was purified by flash chromatography on silica gel to afford 5-(cis-8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)pyrimidine-2-carbonitrile (INT-600) (0.4 g) as a white solid.
  • Synthesis of INT-799: CIS-8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
  • Figure US20230303573A1-20230928-C00340
    • 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 (12mL) 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 (3×150mL). 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 US20230303573A1-20230928-C00341
    • 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 (3×150mL). 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 (3×150mL). 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 US20230303573A1-20230928-C00342
  • 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-(cyclobutylmethyl)-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 US20230303573A1-20230928-C00343
    • 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 (3×200ml). 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 (3×50ml). 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-diazaspiro[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 (3×30ml), 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-methylpropyl)-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 US20230303573A1-20230928-C00344
    • 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 conc. aq. HCl and glacial acetic acid (170mL/510mL) 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 44.0g (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 US20230303573A1-20230928-C00345
    • 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 (3×500mL). The combined organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure to afford 18.0g (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 US20230303573A1-20230928-C00346
    • 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 (35g, 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 (2×200mL). 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 US20230303573A1-20230928-C00347
    • Step 1: 9,12-Dioxa-2,4-diazadispiro[4.2.4^{8}.2^{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^{8}.2^{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^{8}.2^{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^{8}.2^{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^{8}.2^{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^{8}.2^{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^{8}.2^{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^{8}.2^{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^{8}.2^{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 (2×2.0L). The aqueous layer was basified to pH 10 with 50% aq. NaOH and then extracted with DCM (2 × 2.0L). 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-hydroxyphenyl)-3-[(4-methoxyphenyl)-methyl]-1,3-diazaspiro[4.5]decan-2-one
  • Figure US20230303573A1-20230928-C00348
    • 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 US20230303573A1-20230928-C00349
    • 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 90g (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 (2×200mL). The combined organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The reaction was carried out in 4 batches (15 g × 2 and 5 g × 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 US20230303573A1-20230928-C00350
  • 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 (2×150mL). The combined organic layer was dried over anhydrous Na2SO4 and concentrated in vacuo. The reaction was carried out in 2 batches (8 g × 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 US20230303573A1-20230928-C00351
    • 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 US20230303573A1-20230928-C00352
    • 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 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 (3x). The combinded organic layers were dried over Na2SO4, filtered and concentrated inder 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 US20230303573A1-20230928-C00353
  • 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 (3×5mL), 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 US20230303573A1-20230928-C00354
    • 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-(Bromomethyl)-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 residueby 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 US20230303573A1-20230928-C00355
    • 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.
    • Step2: 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 US20230303573A1-20230928-C00356
    • 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-(Cyclobutylmethyl)-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 pH~10 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 pH~10 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 US20230303573A1-20230928-C00357
  • 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 US20230303573A1-20230928-C00358
    • 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-989: CIS-3-(2-chloropyrimidin-5-yl)-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
  • Figure US20230303573A1-20230928-C00359
  • CIS-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-976) (1250 mg, 4.6 mmol), 5-bromo-2-chloro-pyrimidine (1.5 equiv., 6.7 mmol, 1327 mg), Cs2CO3 (2 equiv., 9.15 mmol, 2980 mg), XantPhos (0.15 equiv., 0.69 mmol, 397 mg) and Pd2(dba)3 (0.05 equiv., 0.23 mmol, 209 mg) were dissolved in dry 1,4-dioxane (120 equiv., 549 mmol, 47 mL) under nitrogen atmosphere and stirred at 90° C. overnight. The reaction mixture was cooled down, diluted with water (50 mL), extracted with DCM (3×70 mL), the combined organic phases were dried over Na2SO4 and concentrated under reduced pressure. The residue (2.8 g) was suspended in 10 mL DCM and stirred for 10 min. The resulting precipitate was filtered off and washed with small amount of DCM to give 1213 mg of CIS-3-(2-chloropyrimidin-5-yl)-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-989) as a white solid. The mother liquor was concentrated under reduced pressure (1428 mg), suspended in 3 mL DCM, 3 mL pentane were slowly added and the mixture was stirred for 30 min. The precipitate was filtered off, washed with small amounts of pentane and DCM to give second portion of INT-989 (215 mg) as a light yellow solid. 1H NMR (600 MHz, DMSO) δ 8.94 (s, 2H), 7.88 (s, 1H), 7.41 - 7.33 (m, 4H), 7.27 (tt, 1H), 3.65 (s, 2H), 2.49 - 2.32 (m, 2H), 1.98 - 1.88 (m, 2H), 1.96 (s, 6H), 1.87 - 1.73 (m, 2H), 1.53 -1.47 (m, 2H). Mass: m/z 386.2 (M+H)+.
  • Synthesis of INT-991: lithium CIS-5-(8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)pyrimidine-2-carboxylate
  • Figure US20230303573A1-20230928-C00360
  • Methyl CIS-5-[8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]pyrimidine-2-carboxylate (INT-990) (950 mg, 2.32 mmol) was suspended in a mixture of MeOH (140 equiv., 325 mmol, 13 mL) and THF (70 equiv., 162 mmol, 13 mL). Lithium hydroxide 2M aq. sol. (1.3 mL) was added. The reaction mixture was stirred 5 days at RT. Additional 1.3 mL of lithium hydroxide 2M aq. sol. were added and the reaction mixture was stirred for 2 h at RT. The solvents were removed under reduced pressure. The residue was suspended in EtOAc (10 mL) and stirred overnight. The precipitate was filtered off (1.07 g) and washed with DCM (3 mL), pentane and dried under reduced pressure. The resulting solid (960 mg) containing INT-990 and residual lithium salts was used directly in the next steps. Mass: m/z 394.2 (M-Li)-.
  • Synthesis of INT-1008: CIS-8-ethylamino-8-phenyl-1,3-diaza-spiro[4.5]decan-2-one
  • Figure US20230303573A1-20230928-C00361
    • 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 48h. The reaction mixture was concentrated under argon atmosphere and the residue was diluted with ether (60 ml), and a freshly prepared PhLi solution was added [prepared by addition of 2.5M n-BuLi in THF (70.5 ml, 1.1 eq. 176.27 mmol) to a solution of bromobenzene (27.675g, 1.1 eq. 176.275 mmol) in ether (100 ml) at -30° C. and stirred at RT for 1h). The reaction mixture was stirred at RT for 1.5 h, quenched with saturated NH4Cl solution (100 ml) at 0° C. and extracted with ethyl acetate (2 × 750 ml). The combined organic layer was washed with water (3 × 350 ml), brine (300 ml), dried over Na2SO4 and concentrated under reduced pressure. The resulting residue was dissolved in ethyl methyl ketone (100 ml) and trimethylsilyl chloride (37.5 ml) was added at 0° C. The resulting mixture was stirred at RT for 16 h. The precipitated solid was filtered off and washed with acetone followed by THF to get 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 conc. aq. HCl (62.5 ml) at 0° C. and the resulting mixture was stirred at RT for 16 h. The reaction mixture was basified with aq. NaOH (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 the yield is given for 2 combined batches. Yield: 92% (17.0 g, 78.34 mmol).
    • Step 4: Cis and Trans Mixture of 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 added and stirring was continued at 60° C. for 18 h. The reaction mixture was cooled down to RT. The precipitated solid 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 of 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-diazaspiro[4.5]decane-2,4-dione (12g) in MeOH-DCM (1:1, 960 ml) was added a solution of L-tartaric acid in MeOH (25 ml) and the resulting mixture stirred at RT for 2 h and then kept in refrigerator for 16 h. The precipitated solid was filtered off and washed with MeOH-DCM (1:5, 50 ml) to get tartrate salt of 8-ethylamino-8-phenyl-1,3-diaza-spiro[4.5]decane-2,4-dione (7.5 g) as a white solid. To this solid sat. aq. NaHCO4 was added (pH~8) and the resulting mixture was extracted with 25% MeOH-DCM (2 × 800 ml). Combined organic layer was washed with water (300 ml), brine (300 ml), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was triturated with 20% DCM-hexane and the resulting solid was dried under reduced pressure to afford CIS-8-ethylamino-8-phenyl-1,3-diaza-spiro[4.5]decane-2,4-dione as white solid. This step was done in 2 batches (12 g & 2.4 g) and the 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, 20.91 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, 6.97 mmol, 1.0 eq.) in THF (60 ml) at 0° C. and the reaction mixture was heated to 65° C. for 16 h. The reaction mixture was cooled to 0° C., quenched with sat. aq. Na2SO4 (20 ml), stirred at RT for 1 h and filtered through celite pad. The residue was washed with 15% MeOH-DCM (500 ml). The combined filtrate was dried over anhydrous Na2SO4 and concentrated under reduced pressure to give crude product which 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+1 ]+ = 274.2.
  • Synthesis of INT-1026: CIS-8-(methyl((tetrahydrofuran-3-yl)methyl)amino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
  • Figure US20230303573A1-20230928-C00362
    • 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 (6.0g, 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 US20230303573A1-20230928-C00363
    • 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).
  • [0271] Synthesis of INT-1037: 8-(dimethylamino)-2-oxo-1,3-diazaspiro[4.5]decane-8-carbonitrile
  • Figure US20230303573A1-20230928-C00364
    • Step 1: 9,12-dioxa-2,4-diazadispiro[4.2.4^{8}.2^{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 2h 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^{8}.2^{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^{8}.2^{5}]tetradecan-3-one was treated with conc. 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 US20230303573A1-20230928-C00365
  • 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 (3x). 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 US20230303573A1-20230928-C00366
    • Step 1: TRANS-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 US20230303573A1-20230928-C00367
    • 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-diazaspiro[4.5]decan-2-one (INT-1068) (1.5g) (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), 5 µ, Diluent: MeOH, Mobile phase: A) 0.05% TFA in water; B) ACN flow rate: 1 ml/min, Rt = 5.17 min. 1HNMR (DMSO-d6, 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).
  • 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.
  • Intermediate Chemical Name Chemical Structure in analogy to method m/z
    [M+H]+
    INT-601 CIS-5-(-8-(dimethylamino)-8-(3-fluorophenyl)-2-oxo-1,3-diazaspiro[4.5]decan-3-yl)pyrimidine-2-carbonitrile
    Figure US20230303573A1-20230928-C00368
         		INT-600 395.1
    INT-794 CIS-3-(3,4-dimethoxybenzyl)-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
    Figure US20230303573A1-20230928-C00369
         		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 US20230303573A1-20230928-C00370
         		INT-974 390.3
    INT-797 CIS-8-(Ethyl-methyl-amino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
    Figure US20230303573A1-20230928-C00371
         		INT-976 288.2
    INT-949 CIS-8-Dimethylamino-1-ethyl-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
    Figure US20230303573A1-20230928-C00372
         		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 US20230303573A1-20230928-C00373
         		INT-952 432.3
    INT-954 4-Dimethylamino-4-(5-methyl-thiophen-2-yl)-cyclohexan-1-one
    Figure US20230303573A1-20230928-C00374
         		INT-965 238.1
    INT-955 4-Dimethylamino-4-thiophen-2-yl-cyclohexan-1-one
    Figure US20230303573A1-20230928-C00375
         		INT-965 224.1
    INT-956 1-(1-Methyl-1H-pyrazol-3-yl)-4-oxo-cyclohexane-1-carbonitrile
    Figure US20230303573A1-20230928-C00376
         		INT-958 204.1
    INT-957 4-Oxo-1-pyrazin-2-yl-cyclohexane-1-carbonitrile
    Figure US20230303573A1-20230928-C00377
         		INT-958 202.1
    INT-959 4-Dimethylamino-4-(1-methyl-1H-pyrazol-3-yl)-cyclohexan-1-one
    Figure US20230303573A1-20230928-C00378
         		INT-961 222.2
    INT-960 4-Dimethylamino-4-pyrazin-2-yl-cyclohexan-1-one
    Figure US20230303573A1-20230928-C00379
         		INT-961 220.1
    INT-962 4-Dimethylamino-4-(3-methoxyphenyl)-cyclohexan-1-one
    Figure US20230303573A1-20230928-C00380
         		INT-965 248.2
    INT-963 CIS-3-Benzyl-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
    Figure US20230303573A1-20230928-C00381
         		INT-975 364.2
    INT-964 4-(Ethyl-methyl-amino)-4-phenyl-cyclohexan-1-one
    Figure US20230303573A1-20230928-C00382
         		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 US20230303573A1-20230928-C00383
         		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 US20230303573A1-20230928-C00384
         		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 US20230303573A1-20230928-C00385
         		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 US20230303573A1-20230928-C00386
         		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 US20230303573A1-20230928-C00387
         		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 US20230303573A1-20230928-C00388
         		INT-974 412.2
    INT-979 CIS-8-Dimethylamino-1-(3-methoxy-propyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
    Figure US20230303573A1-20230928-C00389
         		INT-984 346.2
    INT-980 CIS-8-Dimethylamino-1-(2-methoxy-ethyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
    Figure US20230303573A1-20230928-C00390
         		INT-984 332.2
    INT-981 CIS-8-Dimethylamino-8-phenyl-1-propyl-1,3-diazaspiro[4.5]decan-2-one
    Figure US20230303573A1-20230928-C00391
         		INT-984 316.2
    INT-983 CIS-1-(Cyclopropyl-methyl)-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
    Figure US20230303573A1-20230928-C00392
         		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 US20230303573A1-20230928-C00393
         		INT-986 370.3
    INT-990 methyl CIS-5-(8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)pyrimidine-2-carboxylate
    Figure US20230303573A1-20230928-C00394
         		INT-989 410.2
    INT-992 CIS-3-(2-chloro-4-methylpyrimidin-5-yl)-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
    Figure US20230303573A1-20230928-C00395
         		INT-989 400.2
    INT-993 4-benzyl-4-(dimethylamino)cyclohexanone
    Figure US20230303573A1-20230928-C00396
         		INT-965 232.3
    INT-994 CIS-8-benzyl-8-(dimethylamino)-1,3-diazaspiro[4.5]decan-2-one
    Figure US20230303573A1-20230928-C00397
         		INT-976 288.2
    INT-995 TRANS-8-benzyl-8-(dimethylamino)-1,3-diazaspiro[4.5]decan-2-one
    Figure US20230303573A1-20230928-C00398
         		INT-976 288.2
    INT-997 CIS-8-(dimethylamino)-8-(thiophen-2-yl)-1,3-diazaspiro[4.5]decan-2-one
    Figure US20230303573A1-20230928-C00399
         		INT-976 280.1
    INT-998 TRANS-8-(dimethylamino)-8-(thiophen-2-yl)-1,3-diazaspiro[4.5]decan-2-one
    Figure US20230303573A1-20230928-C00400
         		INT-976 280.1
    INT-999 4-(dimethylamino)-4-(1-methyl-1H-benzo[d]imidazol-2-yl)cyclohexanone
    Figure US20230303573A1-20230928-C00401
         		INT-965 272.2
    INT-1000 CIS-8-(dimethylamino)-8-(1-methyl-1H-benzo[d]imidazol-2-yl)-1,3-diazaspiro[4.5]decan-2-one
    Figure US20230303573A1-20230928-C00402
         		INT-976 328.2
    INT-1001 TRANS-8-(dimethylamino)-8-(1-methyl-1H-benzo[d]imidazol-2-yl)-1,3-diazaspiro[4.5]decan-2-one
    Figure US20230303573A1-20230928-C00403
         		INT-976 328.2
    INT-1002 CIS-3-(2-chloropyrimidin-4-yl)-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
    Figure US20230303573A1-20230928-C00404
         		INT-989 386.9
    INT-1009 TRANS-8-ethylamino-8-phenyl-1,3-diaza-spiro[4.5]decan-2-one
    Figure US20230303573A1-20230928-C00405
         		INT-1008 274.2
    INT-1024 CIS-8-(dimethylamino)-8-(3-fluorophenyl)-1,3-diazaspiro[4.5]decan-2-one
    Figure US20230303573A1-20230928-C00406
         		INT-977 (step 2) 292.2
    INT-1025 CIS-8-(dimethylamino)-8-(4-fluorophenyl)-1,3-diazaspiro[4.5]decan-2-one
    Figure US20230303573A1-20230928-C00407
         		INT-974, INT-977 (step 2) 292.2
    INT-1027 CIS-3-(2-chloropyrimidin-5-yl)-8-(dimethylamino)-8-(thiophen-2-yl)-1,3-diazaspiro[4.5]decan-2-one
    Figure US20230303573A1-20230928-C00408
         		INT-989 392.1
    INT-1039 CIS-8-(dimethylamino)-8-(3-(trifluoromethoxy)phenyl)-1,3-diazaspiro[4.5]decan-2-one
    Figure US20230303573A1-20230928-C00409
         		INT-1038 358.2
    INT-1040 (CIS)-8-(dimethylamino)-8-(3-(trifluoromethyl)phenyl)-1,3-diazaspiro[4.5]decan-2-one
    Figure US20230303573A1-20230928-C00410
         		INT-1038 342.2
    INT-1041 (CIS)-8-(dimethylamino)-8-(3-methoxyphenyl)-1,3-diazaspiro[4.5]decan-2-one
    Figure US20230303573A1-20230928-C00411
         		INT-1038 304.2
    INT-1042 (CIS)-8-(5-chlorothiophen-2-yl)-8-(dimethylamino)-1,3-diazaspiro[4.5]decan-2-one
    Figure US20230303573A1-20230928-C00412
         		INT-1038 314.1
    INT-1043 (CIS)-8-(dimethylamino)-8-(3-fluoro-5-methylphenyl)-1,3-diazaspiro[4.5]decan-2-one
    Figure US20230303573A1-20230928-C00413
         		INT-1038 306.2
    INT-1044 (CIS)-8-(3-chlorophenyl)-8-(dimethylamino)-1,3-diazaspiro[4.5]decan-2-one
    Figure US20230303573A1-20230928-C00414
         		INT-1038 308.2
    INT-1045 (CIS)-3-(5-chloro-3-fluoropyridin-2-yl)-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
    Figure US20230303573A1-20230928-C00415
         		INT-989 403.2
    INT-1047 (CIS)-8-(methyl(oxetan-3-ylmethyl)amino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
    Figure US20230303573A1-20230928-C00416
         		INT-1026 330.5
    INT-1048 (CIS)-3-(6-chloropyridin-3-yl)-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
    Figure US20230303573A1-20230928-C00417
         		INT-989 385.2
    INT-1049 (CIS)-3-(5-chloropyridin-2-yl)-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
    Figure US20230303573A1-20230928-C00418
         		INT-989 385.2
    INT-1061 TRANS-1-(cyclopropyl-methyl)-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
    Figure US20230303573A1-20230928-C00419
         		INT-984 328.2
    INT-1063 CIS-1-(cyclopropylmethyl)-8-(dimethylamino)-8-(3-fluorophenyl)-1,3-diazaspiro[4.5]decan-2-one
    Figure US20230303573A1-20230928-C00420
         		INT-1031 346.2
    INT-1066 TRANS-1-(cyclobutylmethyl)-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
    Figure US20230303573A1-20230928-C00421
         		INT-987 342.3
    INT-1070 CIS-8-(dimethylamino)-8-phenyl-1-(3,3,3-trifluoropropyl)-1,3-diazaspiro[4.5]decan-2-one
    Figure US20230303573A1-20230928-C00422
         		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 US20230303573A1-20230928-C00423
         		INT-1031 376.2
    INT-1076 CIS-3-(2-chloro-4-methylpyrimidin-5-yl)-8-(dimethylamino)-8-(3-fluorophenyl)-1,3-diazaspiro[4.5]decan-2-one
    Figure US20230303573A1-20230928-C00424
         		INT-989 418.2
    INT-1077 CIS-3-(4-chloro-2-(trifluoromethyl)pyrimidin-5-yl)-8-(dimethylamino)-8-(3-fluorophenyl)-1,3-diazaspiro[4.5]decan-2-one
    Figure US20230303573A1-20230928-C00425
         		INT-989 472.2
    INT-1078 CIS-3-(4-chloro-2-cyclopropylpyrimidin-5-yl)-8-(dimethylamino)-8-(3-fluorophenyl)-1,3-diazaspiro[4.5]decan-2-one
    Figure US20230303573A1-20230928-C00426
         		INT-989 444.2
    • Synthesis of Exemplary Compounds
  • Synthesis of SC_3013: cis-5-[8-Dimethylamino-1-[(1-hydroxry-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carbonitrile
  • Figure US20230303573A1-20230928-C00427
  • NaH (60% in mineral oil, 0.076 g, 3.19 mmol, 3 equiv.) was added to a solution of 5-(cis-8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)pyrimidine-2-carbonitrile INT_600 (0.4 g, 1.06 mmol) in DMF (5 mL) at 0° C. The mixture was stirred for 30 min at RT and then cooled to 0° C. (1-(Tert-butyldimethylsilyloxy)cyclobutyl)methyl 4-methylbenzenesulfonate (1.18 g, 3.19 mmol, 3 equiv.) was added dropwise over a period of 5 min and the reaction mixture was allowed to warm up to RT and further heated to 70° C. for 16 h. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (3 × 20 mL). The combined organic layers were dried over anhydrous Na2SO4 and the solvent was removed in vacuo. The residue was purified by silica gel flash chromatography to afford CIS-5-[8-dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carbonitrile (0.25 g).
  • Synthesis of SC_3014: cis-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-5-carbonitrile
  • Figure US20230303573A1-20230928-C00428
  • cis-1-(Cyclobutylmethyl)-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one INT-987 (500 mg, 1.464 mmol), 2-chloropyrimidine-5-carbonitrile (409 mg, 2.928 mmol) and Cs2CO3 (954 mg, 2.928 mmol) in 1,4-dioxane (6 ml) were stirred under an nitrogen atmosphere for 18 h at 105° C. The reaction mixture was cooled to RT, 2N aqueous NaOH solution (3 ml) was added and stirring was continued for 10 min. The mixture was extracted first with EtOAc and then with a blend of DCM (30 ml) and methanol (5 ml). The organic layers were combined and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (elution with a DCM/EtOAc gradient) provided cis-2-[1-(cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-5-carbonitrile SC_3014 (57 mg).
  • Synthesis of SC_3016: cis-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-5-carboxylic acid amide
  • Figure US20230303573A1-20230928-C00429
  • cis-2-[1-(Cyclobutylmethyl)-8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]pyrimidine-5-carbonitrile SC_3014 (40 mg, 0.09 mmol) was dissolved in DMSO (1.2 mL) and K2CO3 (25 mg, 0.18 mmol) and hydrogen peroxide (30%, 0.13 mL 1.260 mmol) were added. The reaction mixture was stirred at RT for 20 h, then diluted with 2N NaOH (10 mL) and extracted with DCM (3× 20 mL). The combined organic layers were dried over Na2SO4, concentrated in vacuo. 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]-pyrimidine-5-carboxylic acid amide SC_3016 (40 mg) as a white solid.
  • Synthesis of SC_3022: cis-1-(Cyclobutylmethyl)-8-(dimethylamino)-8-phenyl-3-[2-(trifluoromethyl)pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2-one
  • Figure US20230303573A1-20230928-C00430
  • cis-1-(Cyclobutylmethyl)-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one INT-987 (240 mg, 0.7 mmol), Pd-XPhos Generation 2 (138 mg, 0.17 mmol), Cs2CO3 (457 mg, 1.4 mmol) and 5-bromo-2-(trifluoromethyl)pyrimidine (319 mg, 1.4 mmol) were suspended in anhydrous 1,4-dioxane (3 mL) under nitrogen atmosphere and the resulting mixture was stirred at 100° C. overnight. The reaction mixture was cooled to RT and water (3 mL) was added. The aqueous layer was extracted with DCM (3×10 mL), the combined organic layers were dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash chromatography on silica gel to yield the title compound. Final purification using a strong cation exchange resin gave cis-1-(cyclobutylmethyl)-8-(dimethylamino)-8-phenyl-3-[2-(trifluoromethyl)pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2-one SC_3022 (145 mg) as a white solid.
  • Synthesis of SC_3028: cis-4-[1-(cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N,N-dimethyl-benzamide
  • Figure US20230303573A1-20230928-C00431
    • Step 1: Lithium 4-(cis-1-(cyclobutylmethyl)-8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)benzoate
  • Methyl 4-(cis-1-(cyclobutylmethyl)-8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro [4.5]decan-3-yl)benzoate SC_3081 (400 mg) was dissolved in methanol (5 mL) and DCM (5 mL). Lithium hydroxide solution (2 M in water, 1 mL) was added and the resulting mixture was stirred overnight at RT. All volatiles were removed in vacuo to yield lithium 4-(cis-1-(cyclobutylmethyl)-8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)benzoate (403 mg).
    • Step 2 cis-4-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro [4.5]decan-3-yl]-N,N-dimethyl-benzamide (SC_3028)
  • Lithium 4-(cis-1-(cyclobutylmethyl)-8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro [4.5]decan-3-yl)benzoate (80 mg, 0.17 mmol) was suspended in DCM (1 mL) and triethylamine (0.23 mL, 1.7 mmol) and dimethylamine (2M solution in THF, 0.17 mL) and T3P (0.20 mL, 0.34 mmol) were sequentially added. The resulting mixture was stirred for 18 h at RT. Water (10 mL) was added and the mixture was extracted with DCM (3 × 20 mL). The combined organic layers were dried over Na2SO4, concentrated in vacuo and the residue was purified by flash chromatography to yield cis-4-[1-(cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N,N-dimethyl-benzamide SC_3028 (28 mg) as white solid.
  • Synthesis of SC_3045: cis-4-Methoxy-5-[1-(3-methoxypropyl)-8-(methylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]pyrimidine-2-carbonitrile
  • Figure US20230303573A1-20230928-C00432
  • N-iodosuccinimide (150 mg, 0.67 mmol) was added to a suspension of cis-5-[8-(dimethylamino)-l-(3-methoxypropyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-4-methoxy-pyrimidine-2-carbonitrile SC_3040 (214 mg, 0.44 mmol) in acetonitrile/THF (2/1 v/v, 10 mL) at RT and the resulting mixture was stirred for 16 h at RT. The reaction mixture was basified with 2N NaOH solution to pH~10 and the organic product was extracted with DCM (10 mL × 3). The combined organic extracts were dried over anhydrous Na2SO4, the solvent was removed in vacuo and the residue was purified by preparative flash chromatography to give cis-4-methoxy-5-[1-(3-methoxypropyl)-8-(methylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]pyrimidine-2-carbonitrile SC_3045 (81 mg) as a solid.
  • Synthesis of SC_3064: cis-2-[3-(2-cyano-pyrimidin-5-yl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl]-N-propyl-acetamide
  • Figure US20230303573A1-20230928-C00433
  • Sodium hydroxide (51 mg, 1.3 mmol) was added to anhydrous DMSO (4.5 mL) and stirred for 10 minutes at room temperature. cis-5-[8-(Dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]pyrimidine-2-carbonitrile INT_600 (80 mg, 0.21 mmol) was added and the resulting mixture was stirred at room temperature for 5 min and then heated to 50° C. 2-Bromo-N-propyl-acetamide (153 mg, 0.85 mmol) was added and stirring was continued at 50° C. for one hour. The reaction mixture was quenched with water (25 mL) and extracted with ethyl acetate (2 × 10 mL). The combined organic layers were washed with water (5 mL) and brine (5 mL), dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel to yield cis-2-[3-(2-cyano-pyrimidin-5-yl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl]-N-propyl-acetamide SC_3064 (22 mg) as a solid.
  • Synthesis of SC_3065: 5-(cis-1-(Cyclobutylmethyl)-8-(ethyl(methyl)amino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-4-methoxypyrimidine-2-carbonitrile
  • Figure US20230303573A1-20230928-C00434
  • Cs2CO3 (274 mg, 0.84 mmol) was added to the solution of cis-1-(cyclobutylmethyl)-8-(ethyl(methyl)amino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one INT_986 (150 mg, 0.42 mmol), Xanthphos (36 mg, 0.063 mmol), Pd2(dba)3 (19 mg, 0.0211 mmol) and 5-bromo-4-methoxypyrimidine-2-carbonitrile (135 mg, 0.633 mmol) in 1,4-dioxane (10 mL) under argon atmosphere. The mixture was flushed again with argon for 5 min and the reaction mixture was stirred at 90° C. for 5 h. The reaction mixture was cooled to room temperature. The residue was diluted with water (20 mL) and the organic product was extracted with ethyl acetate (3×10 mL). The combined organic extracts were dried over anhydrous Na2SO4 and the solvent was concentrated under reduced pressure. The residue was purified by preparative TLC (EtOAc / petroleum ether ⅑) to afford a white solid (0.15 g), which was further washed with n-pentane to give 0.1 g of 5-(cis-1-(cyclobutylmethyl)-8-(ethyl(methyl)amino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-4-methoxypyrimidine-2-carbonitrile SC_3065.
  • Synthesis of SC_3008: cis-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-5-methylsulfonyl-benzonitrile
  • Figure US20230303573A1-20230928-C00435
  • cis-2-[1-(Cyclobutylmethyl)-8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-5-methylsulfanyl-benzonitrile (320 mg, 0.66 mmol, prepared from 2-iodo-5-(methylthio)benzonitrile and INT-987 analogously to SC_3022) was dissolved in a mixture of methanol (9 mL) and water (8 mL). Oxone® (807 mg, 1.3 mmol) was added at RT and the resulting mixture was stirred at RT for 18 h. Water (10 mL) was added and the mixture was extracted with DCM (3 × 20 mL). The combined organic layers were dried over Na2SO4, concentrated in vacuo. The residue was purified by flash chromatography on silica gel to yield cis-2-[1-(cyclobutylmethyl)-8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-5-methylsulfonyl-benzonitrile SC_3008 (66 mg) as a white solid.
  • Synthesis of SC_3023: cis-8-Dimethylamino-1-[(1-hydroxry-cyclobutyl)-methyl]-3-(2-hydroxy-pyrimidin-5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
  • Figure US20230303573A1-20230928-C00436
  • Boron tribromide (1M in DCM, 0.38 mL, 0.387 mmol) was added to the solution of cis-8-dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-3-(2-methoxy-pyrimidin-5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3015 (180 mg, 0.387 mmol) in DCM (2 mL) at 0° C. The reaction mixture was stirred for 30 min at 0° C. and then for 16 h at room temperature, quenched with methanol (2 mL), the solvents were removed under reduced pressure and the residue was purified by normal phase preparative HPLC to yield cis-8-dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-3-(2-hydroxy-pyrimidin-5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3023 (60 mg, 34%) as a white solid. 1H NMR (400 MHz, DMSO-d6, δ in ppm): δ 8.43 (s, 2H), 7.35-7.25 (m, 5H), 5.50 (s, 1H), 3.67 (s, 2H), 3.19 (s, 2H), 2.69-2.65 (m, 2H), 2.19-2.10 (m, 4H), 1.98-1.85 (m, 8H), 1.68-1.61 (m, 1H), 1.51-1.39 (m, 5H).
  • Synthesis of SC_3025: cis-5-[8-Dimethylamino-1-(2-hydroxy-ethyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carbonitrile
  • Figure US20230303573A1-20230928-C00437
    • Step 1: 5-(cis-1-(2-(tert-Butyldimethylsilyloxy)ethyl)-8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)pyrimidine-2-carbonitrile
  • NaH (60% in mineral oil, 63.8 mg, 1.59 mmol) was added at 0° C. to the solution of 5-(cis-8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)pyrimidine-2-carbonitrile INT-600 (0.2 g, 0.53 mmol) in DMF (8 mL) for 10 min at 0° C. The reaction mixture was stirred at RT for 30 min, (3-bromopropoxy)(tert-butyl)dimethylsilane (252 mg, 1.06 mmol) was added dropwise over 5 min at 0° C. and the mixture was stirred for further 16 h at RT. The reaction mixture was diluted with water (15 mL) and extracted with diethyl ether (3 x 25 mL). The combined organic extracts were dried over anhydrous Na2SO4, the solvents were removed under reduced pressure and the residue was purified by flash chromatography on silica gel to afford 5-(cis-1-(2-(tert-butyldimethylsilyloxy)ethyl)-8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)pyrimidine-2-carbonitrile (100 mg, 34%) as a white solid.
    • Step 2: cis-5-[8-Dimethylamino-1-(2-hydroxy-ethyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carbonitrile (SC_3025)
  • 1M TBAF solution in THF (0.36 mL, 0.36 mmol) was added to 5-(cis-1-(2-(tert-butyldimethylsilyloxy)ethyl)-8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)pyrimidine-2-carbonitrile (0.1 g, 0.18 mmol) in THF (5 mL) at 0° C. The reaction mixture was stirred at RT for 30 min, diluted with water (10 mL) and extracted with diethyl ether (3×25 mL). The combined organic extracts were washed with sat. aq. NaHCO3, water and brine and dried over anhydrous Na2SO4. The solvents were evaporated under reduced pressure and the residue was purified by preparative TLC (ethyl acetate/n-hexane = 45:55) and then washed with n-pentane (5 mL) to give of cis-5-[8-dimethylamino-1-(2-hydroxy-ethyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carbonitrile (70 mg, 80%) as a white solid. 1H NMR (400 MHz, DMSO-d6, δ in ppm): δ 9.18 (s, 2H), 7.38-7.26 (m, 5H), 4.84 (t, 1H), 3.82 (s, 2H), 3.55-3.51 (m, 2H), 3.26-3.20 (m, 2H), 2.73-2.70 (m, 2H), 2.17-2.11 (m, 2H), 2.00 (s, 6H), 1.57-1.43 (m, 4H).
  • Synthesis of SC_3097: CIS-8-dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-3-(2-morpholin-4-yl-pyrimidin-5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
  • Figure US20230303573A1-20230928-C00438
  • starting from here until the end of the section all procedures were added
    • Step 1: 4-(5-bromopyrimidin-2-yl)morpholine
  • K2CO3 (14.2g, 103mmol) was added to the solution of morpholine (9.0 g, 103 mmol) in acetonitrile (900 mL) and the resulting suspension was stirred at RT for 1 h. 5-Bromo-2-chloropyrimidine (20 g, 103 mmol) was added portionwise. The reaction mixture was stirred for 16 h at 80° C., then cooled down to RT and diluted with EtOAc (100 mL) and water (50 mL). The organic product was extracted with EtOAc (2×100 mL). The combined organic layer was washed with brine (100 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel (100-200 mesh) (20% EtOAc in petroleum ether) to afford 18.0 g (71%) of 4-(5-bromopyrimidin-2-yl)morpholine as an off white solid (TLC system: 30% EtOAc in pet ether, Rf: 0.6).
    • Step 2: CIS-8-dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-3-(2-morpholin-4-yl-pyrimidin-5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (SC_3097)
  • K2CO3 (0.53 g, 3.85 mmol, 2.5 equiv.) was added to the suspension of CIS-8-(dimethylamino)-1-((1-hydroxycyclobutyl)methyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-799) (0.55 g, 1.54 mmol, 1 equiv.) and 4-(5-bromopyrimidin-2-yl)morpholine (0.37 g, 1.54 mmol, 1 equiv.) in dioxane (20 mL) and the resulting suspension was purged with nitrogen for 5 min. Copper(I) iodide (0.29 g, 1.54 mmol, 1 equiv.) and trans-1,2-diaminocyclohexane (0.35 g, 3.085 mmol, 2 equiv.) were sequentially added, the reaction vessel was sealed and the reaction mixture was stirred at 130° C. for 4 h. The reaction mixture was cooled down to RT and diluted with EtOAc (20 mL) and aq. ammonia (10 mL). The organic product was extracted with EtOAc (2×50 mL). The combined organic layer was washed with brine (50 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. Purification of the resulting residue by column chromatography on silica gel (100-200 mesh) (60-70% EtOAc in petroleum ether) afforded 0.35 g (48%) of CIS-8-(dimethylamino)-1-((1-hydroxycyclobutyl)methyl)-3-(2-morpholin-4-yl-pyrimidin-5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (SC_3097) as an off white solid (TLC system: EtOAc, Rf: 0.7). 1H NMR (DMSO-d6): δ 8.60 (s, 2H), 7.36-7.35 (m, 4H), 7.27-7.24 (m, 1H), 5.50 (s, 1H), 3.72 (s, 2H), 3.62-3.61 (m, 8H), 3.21 (s, 2H), 2.70-2.66 (m, 2H), 2.19-2.11 (m, 4H), 1.98 (s, 6H), 1.93-1.85 (m, 2H), 1.66-1.64 (m, 1H), 1.53-1.42 (m, 5H). Mass: m/z 521.3 (M+H)+.
  • Synthesis of SC_3099: CIS-1-[(1-hydroxy-cyclobutyl)-methyl]-8-methylamino-3-(2-morpholin-4-yl-pyrimidin-5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
  • Figure US20230303573A1-20230928-C00439
  • N-Iodosuccinimide (162 mg, 0.72 mmol) was added to the solution CIS-8-(dimethylamino)-1-((1-hydroxycyclobutyl)methyl)-3-(2-morpholinopyrimidin-5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (SC-3097) (250 mg, 0.48 mmol) in acetonitrile (8.0 mL) and THF (8.0 mL) at 0° C. and the resulting mixture was stirred for 16 h at RT. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in EtOAc (2×30 mL), the organic layer was washed with 2N aq. NaOH solution, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by reverse phase prep. HPLC to yield 0.12 g (49%) of CIS-1-((1-hydroxycyclobutyl)methyl)-8-(methylamino)-3-(2-morpholinopyrimidin-5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (SC_3099) as an off white solid (TLC system 5% MeOH in DCM Rf: 0.5.). Preparative reverse phase HPLC conditions: column: Luna-PhenylHexyl-C18 (150*19mm) 5 µm; mobile phase: 10 mM ammonium bicarbonate/acetonitrile, gradient (T/%B): 0/50, 7/85, 7.1/98, 9/98, 9.1/50, 12/50; flow Rate: 25 ml/min; diluent: mobile phase + THF. 1H NMR (DMSO-d6): δ 8.63 (s, 2H), 7.49-7.47 (m, 2H), 7.34-7.30 (t, 2H), 7.21-7.17 (m, 1H), 5.60 (s, 1H), 3.76 (s, 2H), 3.64-3.62 (m, 8H), 3.35 (m, 2H), 2.26-2.20 (m, 3H), 2.12-2.08 (m, 2H), 1.90-1.88 (m, 7H), 1.79-1.73 (m, 2H), 1.65-1.63 (m, 1H), 1.52-1.44 (m, 3H). Mass: m/z 507.3 (M+H)+.
  • Synthesis of SC3100: CIS-8-dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-8-phenyl-3-(2-piperazin-1-yl-pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one hydrochloride
  • Figure US20230303573A1-20230928-C00440
    • Step 1: Tert-butyl 4-(5-bromopyrimidin-2-yl)piperazine-1-carboxylate
  • In analogy to the method described for SC_3097 step 1 tert-butyl piperazine-1-carboxylate was reacted with 5-bromo-2-chloropyrimidine to be converted into tert-butyl 4-(5-bromopyrimidin-2-yl)piperazine-1-c arboxylate.
    • Step 2: Tert-butyl 4-(5-((cis)-8-(dimethylamino)-1-((1-hydroxycyclobutyl)methyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)pyrimidin-2-yl)piperazine-1-carboxylate
  • K2CO3 (0.38 g, 2.8 mmol, 2.5 equiv.) was added to the suspension of CIS-8-(dimethylamino)-1-((1-hydroxycyclobutyl)methyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (0.4 g, 1.12 mmol, 1 equiv.) (INT-799) and tert-butyl 4-(5-bromopyrimidin-2-yl)piperazine-1-carboxylate (0.38 g, 1.12 mmol, 1 equiv.) in dioxane (25 mL) and the resulting mixture was purged with nitrogen for 5 min. Copper(I) iodide (0.21g, 1.12 mmol, 1 equiv.) and trans-1,2-diaminocyclohexane (0.25 g, 2.24 mmol, 2 equiv.) were sequentially added, the reaction vessel was sealed and the reaction mixture was stirred for 10 h at 130° C. The reaction mixture was cooled down to RT and diluted with EtOAc (20 mL) and aq. ammonia (10 mL). The organic product was extracted with e EtOAc (2×50 mL). The combined organic layer was washed with brine (50 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. Purification of the residue by column chromatography on silica gel (100-200 mesh) (60-70% EtOAc in petroleum ether) afforded 0.5 g (72%) of tert-butyl 4-(5-((cis)-8-(dimethylamino)-1-((1-hydroxycyclobutyl)methyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)pyrimidin-2-yl)piperazine-1-carboxylate as an off white solid (TLC system: 1:1 EtOAc/pet ether, Rf: 0.3).
    • Step 3: CIS-8-(dimethylamino)-1-((1-hydroxycyclobutyl)methyl)-8-phenyl-3-(2-(piperazin-1-yl)pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one hydrochloride (SC_3100)
  • 4N HCl in dioxane (2 mL) was added to tert-butyl 4-(5-(cis-8-(dimethylamino)-1-((1-hydroxycyclobutyl)methyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)pyrimidin-2-yl)piperazine-1-carboxylate (0.15 g, 0.24 mmol). The resulting mixture was stirred at 0° C. for 6 h and then concentrated under reduced pressure to give a pale yellow solid which was triturated with n-pentane and lyophilized with water for 16 h to yield 0.14g of CIS-8-(dimethylamino)-1-((1-hydro xycyclobutyl)methyl)-8-phenyl-3-(2-(piperazin-1-yl)pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one hydrochloride (SC_3100) as a pale yellow solid. 1H NMR (DMSO-d6): δ 10.42 (br s, 1H), 9.34 (br s, 2H), 8.63 (s, 2H), 7.70-7.68 (m, 2H), 7.54-7.50 (m, 3H), 3.88-3.86 (m, 4H), 3.77 (m, 4H), 3.16-3.11 (m, 6H), 2.52-2.49 (m, 6H), 2.47 (m, 2H), 2.10-2.07 (m, 2H), 2.00-1.95 (t, 2H), 1.87-1.81 (m, 3H), 1.70-1.68 (m, 2H), 1.58 (m, 1H). Mass: m/z 520.3 (M+H)+.
  • Synthesis of SC_3103: CIS-1-(cyclobutyl-methyl)-8-dimethylamino-3-[4-methyl-6-(trifluoromethyl)-pyridin-3-yl] -8-phenyl-1,3-diazaspiro[4.5]decan-2-one
  • Figure US20230303573A1-20230928-C00441
  • Cs2CO3 (2 g, 6.451mmol) was added to an argon purged solution of CIS-1-(cyclobutylmethyl)-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-987) (1.1 g, 3.225 mmol, 1 equiv.), Xantphos (279 mg, 0.483 mmol, 0.15 equiv.), Pd2(dba)3 (295 mg, 0.322 mmol, 0.1 equiv.) and 5-bromo-4-methyl-2-(trifluoromethyl)pyridine (774 mg, 3.225 mmol, 1 equiv.) in 1,4-dioxane (55 mL). The mixture was purged again with argon for 15 min. The reaction mixture was stirred at 90° C. for 18 h, then cooled down to RT, filtered through Celite and washed with EtOAc (80 mL). The filtrate was concentrated under reduced pressure. The resulting residue was purified by flash chromatography (neutral alumina, 0-3% methanol in DCM) to afford 0.6 g (37%) of CIS-1-(cyclobutylmethyl)-8-(dimethylamino)-3-(4-methyl-6-(trifluoromethyl)pyridin-3-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (SC_3103) as an off white solid. (TLC system: 5% MeOH in DCM; Rf: 0.5). 1H NMR (DMSO-d6): δ 8.56 (s, 1H), 7.80 (s, 1H), 7.34-7.24 (m, 5H), 3.71 (s, 2H), 3.17 (d, 2H), 2.70-2.56 (m, 3H), 2.31 (s, 3H), 2.17-2.11 (m, 2H), 2.03-2.00 (m, 8H), 1.82-1.73 (m, 4H), 1.54-1.41 (m, 4H). Mass: m/z 501.3 (M+H)+.
  • Synthesis of SC_3105: CIS-1-(cyclopropyl-methyl)-8-dimethylamino-3-(4-methylsulfonyl-phenyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
  • Figure US20230303573A1-20230928-C00442
  • NaH (60% in mineral oil) (36.80 mg, 0.92 mmol) was added portionwise to the solution of CIS-8-(dimethylamino)-3-(4-(methylsulfonyl)phenyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (200 mg, 0.46 mmol, prepared from INT-976 and 1-bromo-4-(methylsulfonyl)benzene by analogy with SC_3103) in DMF (30 mL) at 0° C. under argon atmosphere and the resulting mixture was stirred for 10 min. (Bromomethyl)cyclopropane (122 mg, 0.92 mmol) was added dropwise at 0° C., ice bath was removed and the reaction mixture was further stirred for 4 h at room temperature. The reaction progress was monitored by TLC. The reaction mixture was diluted with water (30 mL) and the precipitated solid was filtered. Purification by column chromatography (silica gel 100-200 mesh, 50-60% ethyl acetate in hexane as eluent) to get 80 mg (35%) of CIS-1-(cyclopropylmethyl)-8-(dimethylamino)-3-(4-(methylsulfonyl)phenyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (SC_3105) as off white solid (TLC system: 10% MeOH in DCM; Rf: 0.70). 1H NMR (CDCl3): δ 7.85-7.83 (d, 2H), 7.73-7.71 (d, 2H), 7.39-7.36 (m, 2H), 7.32-7.27 (m, 3H), 3.64 (s, 2H), 3.20 (d, 2H), 3.00 (s, 3H), 2.75-2.71 (m, 2H), 2.43-2.36 (m, 2H), 2.07 (s, 6H), 1.57 (m, 2H), 1.50 (m, 2H), 1.11-1.06 (m, 1H), 0.59-0.54 (m, 2H), 0.41-0.37 (m, 2H). Mass: m/z 482.2 (M+H)+.
  • Synthesis of SC_3109: CIS-2-[8-Dimethylamino-1-[2-(1-methoxy-cyclobutyl)-ethyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-benzamide
  • Figure US20230303573A1-20230928-C00443
    • Step 1: CIS-2-(8-(dimethylamino)-1-(2-(1-methoxycyclobutyl)ethyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)benzonitrile
  • In analogy to the method described for SC_3103 CIS-8-(dimethylamino)-1-(2-(1-methoxycyclobutyl)ethyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one was reacted with 2-bromobenzonitrile to be converted into CIS-2-(8-(dimethylamino)-1-(2-(1-methoxycyclobutyl)ethyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)benzonitrile.
    • Step 2: CIS-2-[8-Dimethylamino-1-[2-(1-methoxy-cyclobutyl)-ethyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-benzamide SC_3109
  • CIS-2-[8-(dimethylamino)-1-[2-(1-methoxycyclobutyl)ethyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]benzonitrile (57.0 mg, 1.0 equiv.) was dissolved in DMSO (1.6 mL), hydrogen peroxide (0.167 mL, 14.0 equiv., 30 mass% in water solution) and K2CO3 (32.4 mg, 2.0 equiv.) were added and the reaction mixture was stirred at RT for 18 h. The reaction mixture was then quenched with 10 mL water, extracted with DCM (3×10 mL), the combined organic extracts were dried over Na2SO4 and concentrated under reduced pressure (24 mg crude product). The aqueous phase was concentrated to dryness (91 mg), suspended in DCM, the precipitate was filtered off and the organic solution was concentrated under reduced pressure to give additional 56 mg of the crude product. The combined crude product was purified by column chromatography on silica gel (DCM/EtOH 95/5) to give 37 mg (62%) of CIS-2-[8-dimethylamino-1-[2-(1-methoxy-cyclobutyl)-ethyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-benzamide (SC_3109) as a white solid. 1H NMR (600 MHz, DMSO) δ 7.52 - 7.48 (s, 1H), 7.47 - 7.31 (m, 7H), 7.29 - 7.23 (m, 1H), 7.25 - 7.22 (s, 1H), 7.24 - 7.18 (m, 1H), 3.68 - 3.65 (s, 3H), 3.13 - 3.10 (s, 2H), 3.09 -3.02 (m, 2H), 2.71 - 2.65 (m, 2H), 2.21 - 2.12 (m, 2H), 2.09 - 1.99 (m, 2H), 2.02 - 1.98 (s, 6H), 1.97 - 1.86 (m, 4H), 1.77 - 1.67 (m, 1H), 1.64 - 1.52 (m, 3H), 1.44 - 1.36 (td, 2H). Mass: m/z 505.32 (M+H)+.
  • Synthesis of SC_3112: CIS- 2-(1-((1-hydroxycyclobutyl)methyl)-8-(methylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)benzonitrile
  • Figure US20230303573A1-20230928-C00444
    • Step 1: CIS-2-(8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)benzonitrile
  • In analogy to the method described for SC_3103 1-bromo-2-cyanobenzene was reacted with CIS-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-976) to be converted into CIS-2-(8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)benzonitrile.
    • Step 2: CIS-2-(8-(dimethylamino)-1-((1-hydroxycyclobutyl)methyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)benzonitrile
  • To a solution of CIS-2-(8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)benzonitrile (500 mg, 1.336 mmol, 1.0 equiv.) in DMSO (16 ml) was added sodium hydroxide (213 mg, 5.334 mmol, 4.0 equiv.) and the mixture was stirred at 60° C. for 30 min. A solution of 1-oxa-spiro[2.3]hexane (237 mg, 6.68 mmol, 5.0 equiv.) in DMSO (4 ml) was added at RT and the reaction mixture was stirred at 55° C. for 16 h. The reaction mixture was diluted with water (100 ml) and extracted with EtOAc (100 ml). The organic layer was washed with water (50 ml) and brine (50 ml), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (EtOAc /Hexane, 7/3) to yield CIS-2-(8-(dimethylamino)-1-((1-hydroxy cyclobutyl)methyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)benzonitrile (200 mg, 0.436 mmol, 32%) as an off white solid. Mass: m/z 459.4 (M+H)+
    • Step 3: CIS- 2-(1-((1-hydroxycyclobutyl)methyl)-8-(methylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)benzonitrile (SC_3112)
  • In analogy to the method described for SC_3099 CIS-2-(8-(dimethylamino)-1-((1-hydroxycyclobutyl)methyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)benzonitrile was reacted with N-iodosuccinimide to be converted into CIS- 2-(1-((1-hydroxycyclobutyl)methyl)-8-(methylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)benzonitrile (SC_3112). Yield: 29%. 1H NMR (DMSO-d6, 400 MHz), δ (ppm) = 7.75 (dd, 1H, J = 7.76 Hz, 1.16 Hz), 7.70-7.65 (m, 1H), 7.50 (d, 1H, J = 8.16 Hz), 7.44-7.42 (m, 2H), 7.35-7.25 (m, 3H), 7.17-7.15 (m, 1H), 5.49 (s, 1H), 3.85 (s, 2H), 3.32 (s, 2H), 2.29-2.23 (m, 2H), 2.12-2.23 (m, 2H), 1.87 (bs, 6H), 1.73-1.46 (m, 6H). Mass: m/z 445.26 (M+H)+.
  • Synthesis of SC_3120: CIS-8-(dimethylamino)-3-(2-(3-oxopiperazin-1-yl)pyrimidin-5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
  • Figure US20230303573A1-20230928-C00445
  • CIS-3-(2-chloropyrimidin-5-yl)-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-989) (100 mg, 0.259 mmol) was placed into a reaction vial for microvawe reactor (5 mL), the vial was flushed with nitrogen, anhydrous n-butanol (50 equiv., 13.0 mmol, 1.2 mL), diisopropylethylamine (5 equiv., 1.30 mmol, 0.224 mL) and piperazine-2-one (1.2 equiv., 0.311 mmol, 31 mg) were added, the vial was sealed and the reaction mixture was stirred for 2.5 h at 140° C. (conventional heating). The reaction mixture was cooled down, transferred into a 1-neck flask and concentrated under reduced pressure. The resulting residue (128 mg) was purified by flash chromatography on aluminium oxide (neutral) (DCM/MeOH gradient 100/0 to 97/3) to yield 65 mg (56%) CIS-8-(dimethylamino)-3-(2-(3-oxopiperazin-1-yl)pyrimidin-5-yl)-8-phenyl-1,3-diazaspiro-[4.5]decan-2-one (SC_3120). 1H NMR (600 MHz, DMSO) δ 8.60 (s, 2H), 8.01 (s, 1H), 7.46 (s, 1H), 7.43 - 7.30 (m, 4H), 7.27 (td, 1H), 4.09 (s, 2H), 3.91 - 3.75 (m, 2H), 3.62 -3.40 (m, 2H), 3.30 - 3.09 (m, 2H), 2.61-2.51 (m, 2H), 2.44 - 2.25 (m, 2H), 1.97 (s, 6H), 1.93-1.80 (m, 2H), 1.55 - 1.41 (m, 2H). Mass: m/z 437.27 (M+H)+.
  • Synthesis of SC_3129: CIS- 3-(5-(8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)pyrimidin-2-yl)benzonitrile
  • Figure US20230303573A1-20230928-C00446
  • CIS-3-(2-chloropyrimidin-5-yl)-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-989) (1 equiv., 0.47 mmol, 180 mg), Pd(PPh3)4 (0.1 equiv., 0,047 mmol, 54 mg) and (3-cyanophenyl)boronic acid (1.5 equiv., 0.70 mmol, 103 mg) were dissolved in degassed dry tetrahydrofurane (9.5 mL) and sodium carbonate 1M aq. sol. (1.9 equiv., 0.89 mmol, 0.89 mL) was added. The resulting clear reaction mixture was stirred overnight at 70° C. Additional portion of Pd(PPh3)4 (0.1 equiv., 0,047 mmol, 54 mg) was added and the reaction was stirred further 12 h at 70° C. The reaction mixture was diluted with EtOAc (50 mL), stirred for 10 min, the precipitate was filtered off and the filtrate was concentrated under reduced pressure. The resulting residue (285 mg) was purified by flash chromatography on silica gel (gradient DCM/MeOH, 100/0 to 80/20) to yield 130 mg (62%) of CIS- 3-(5-(8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)pyrimidin-2-yl)benzonitrile (SC_3129). 1H NMR (600 MHz, DMSO) δ 9.13 (s, 2H), 8.60 (dp, 2H), 7.93 (dt, 1H), 7.88 (s, 1H), 7.72 (dd, 1H), 7.42 - 7.35 (m, 5H), 7.28 (d, 1H), 3.73 (s, 2H), 2.01 - 1.91 (m, 2H), 1.98 (s, 10H), 1.57 - 1.48 (m, 2H). Mass: m/z 453.24 (M+H)+.
  • Synthesis of SC_3130: CIS-8-(dimethylamino)-3-(2-(4-(methylsulfonyl)piperazin-1-yl)pyrimidin-5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
  • Figure US20230303573A1-20230928-C00447
  • CIS-8-(dimethylamino)-8-phenyl-3-(2-(piperazin-1-yl)pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one (SC_3124) (100 mg, 0.23 mmol) was dissolved in DCM (150 equiv., 34 mmol, 2.2 mL) under nitrogen atmosphere. To the resulting solution 4-dimethylaminopyridine (0.05 equiv., 0.012 mmol, 1.4 mg) and diisopropylethylamine (3 equiv., 0.67 mmol, 0.119 mL) were added and the mixture was cooled to 0° C. Methansulfonylchloride (2 equiv., 0.46 mmol, 0.036 mL) was added, ice bath was removed and the reaction mixture was stirred for 2 h at RT. The reaction mixture was quenched with water (5 mL), diluted with DCM (10 mL), the resulting brown suspension was filtered through a glass filter, the filtrate transferred to a separating funnel, the organic phase separated and the aqueous phase extracted with DCM (2×10 mL). The combined organic phases were dried over MgSO4 and concentrated under reduced pressure. The resulting residue (81 mg) was purified by flash chromatography on aluminium oxide (gradient DCM/EtOH 97/3 to 96/4) to yield 51 mg (43%) of CIS-8-(dimethylamino)-3-(2-(4-(methylsulfonyl)piperazin-1-yl)pyrimidin-5-yl)-8-phenyl-1,3-diazaspiro-[4.5]decan-2-one (SC_3130). 1H NMR (600 MHz, DMSO) δ 8.59 (s, 2H), 7.46 (s, 1H), 7.39 (d, 1H), 7.37 (s, 3H), 7.28 (d, 1H), 3.79 - 3.74 (m, 4H), 3.54 (s, 2H), 3.18 - 3.13 (m, 4H), 2.87 (s, 3H), 2.43 - 2.32 (m, 2H), 1.97 (s, 6H), 1.92 - 1.87 (m, 2H), 1.51 - 1.41 (m, 2H). Mass: m/z 514.26 (M+H)+.
  • Synthesis of SC_3132: CIS-8-((cyclopropylmethyl)(methyl)amino)-8-phenyl-3-(2-(trifluoromethyl)pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one
  • Figure US20230303573A1-20230928-C00448
    • Step 1: CIS-8-(methylamino)-8-phenyl-3-(2-(trifluoromethyl)pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one
  • In analogy to the method described for SC_3099 CIS-8-(dimethylamino)-8-phenyl-3-(2-(trifluoromethyl)pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one (SC_3245) was reacted with N-iodosuccinimide to be converted into CIS-8-(methylamino)-8-phenyl-3-(2-(trifluoromethyl)pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one.
    • Step 2: CIS-1-(4-methoxybenzyl)-8-(methylamino)-8-phenyl-3-(2-(trifluoromethyl)pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one
  • NaH (60% in mineral oil) (296.3mg, 7.407 mmol, 1.5 equiv.) was added portionwise to the solution CIS-8-(methylamino)-8-phenyl-3-(2-(trifluoromethyl)pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one (2 g, 4.938 mmol, 1 equiv.) in DMF (20 mL) at 0° C. under argon atmosphere and the resulting mixture was stirred for 10 min. 1-(Bromomethyl)-4-methoxybenzene (1.092 g, 5.432 mmol, 1.1 equiv.) was added dropwise. The reaction mixture was allowed to warm up to RT and stirred for 16 h. The reaction progress was monitored by LCMS. The reaction mixture was diluted with water (150 mL) and the organic product was extracted with EtOAc (3×60mL). The combined organic extracts were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The resulting residue was purified by flash chromatography (silica gel 230-400 mesh; 0-4% MeOH/DCM) to afford 2 g (77%) of CIS-1-(4-methoxybenzyl)-8-(methylamino)-8-phenyl-3-(2-(trifluoromethyl)pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one as an off white solid (TLC system 5% MeOH in DCM Rf: 0.55).
    • Step 3: CIS-8-((cyclopropylmethyl)(methyl)amino)-1-(4-methoxybenzyl)-8-phenyl-3-(2-(trifluoromethyl)pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one
  • (Bromomethyl)cyclopropane (0.461 mL, 4.762 mmol, 5 equiv.) was added dropwise to a mixture of CIS-1-(4-methoxybenzyl)-8-(methylamino)-8-phenyl-3-(2-(trifluoromethyl)pyrimidin-5-yl)-1,3-diazaspiro-[4.5]decan-2-one (500 mg, 0.952 mmol, 1 equiv.) and K2CO3 (657 mg, 4.762 mmol, 5 equiv.) in acetonitrile (20 mL) at RT under argon atmosphere. The reaction vessel was sealed and the mixture was stirred at 95° C. for 24 h. Reaction progress was monitored by LCMS. The reaction mixture was diluted with water (50 mL) and the organic product was extracted with EtOAc (2×50 mL). The combined organic extracts were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The resulting residue was purified by flash chromatography (silica gel 230-400 mesh; 0-40% EtOAc/petroleum ether) to afford 220 mg (39%) of CIS-8-((cyclopropylmethyl)(methyl)amino)-1-(4-methoxybenzyl)-8-phenyl-3-(2-(trifluoromethyl)pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one as an off white solid (TLC 50% EtOAc in petroleum ether, Rf: 0.65) and 230 mg of the unreacted starting material.
    • Step 4: CIS-8-((cyclopropylmethyl)(methyl)amino)-8-phenyl-3-(2-(trifluoromethyl)pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one (SC_3132)
  • TFA (4.2 mL) was added drop wise to a solution of CIS-8-((cyclopropylmethyl)(methyl)amino)-1-(4-methoxybenzyl)-8-phenyl-3-(2-(trifluoromethyl)pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one (210mg, 0.363mmol) in DCM (0.05 mL) at 0° C. under argon atmosphere. The reaction mixture was allowed to warm up to RT and stirred for 16 h. The reaction progress was monitored by LCMS. The excess of TFA was evaporated under reduced pressure and the residual amount of TFA was removed as an azeotropic mixture with DCM (2×5mL). The crude product was purified by preparative HPLC to yield 105 mg (63%) of CIS-8-((cyclopropylmethyl)(methyl)amino)-8-phenyl-3-(2-(trifluoromethyl)pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one (SC_3132) as an off white solid (TLC system 50% EtOAc in pe ether, Rf: 0.35). 1H NMR (DMSO-d6): δ 9.17 (s, 2H), 8.10 (br s, 1H), 7.35-7.33 (m, 4H), 7.25-7.22 (m, 1H), 3.72 (s, 2H), 2.43 (m, 2H), 2.13 (s, 3H), 1.97-1.82 (m, 6H), 1.49 (m, 2H), 0.75-0.71 (m, 1H), 0.41-0.39 (m, 2H), 0.06- -0.01 (m, 2H). Mass: m/z = 460.2 (M+H).
  • Synthesis of SC_3133: CIS-8-Dimethylamino-3-[2-(4-methyl-piperazine-1-carbonyl)-pyrimidin-5-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
  • Figure US20230303573A1-20230928-C00449
  • 1-Methylpiperazine (2 equiv., 0.5 mmol, 55 µL) and [5-[8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]pyrimidine-2-carbonyl]oxylithium (INT-990) (100 mg, 0.25 mmol) were suspended in DCM (1.6 mL), triethylamine (10 equiv., 2.5 mmol, 336 µL) and propylphosphonic anhydride (≥50 wt.% solution in ethyl acetate) (2 equiv., 0.5 mmol, 297 µL) were sequentially added and the reaction mixture was stirred at RT for 2 h. The resulting mixture was quenched with 2M aq. NaOH (2 mL), organic phase was separated and aqueous phase was extracted with dichloromethane (3×10 mL). The combined organic extracts were dried over Na2SO4 and concentrated under reduced pressure. The residue (88 mg) was dissolved in 3 mL DCM and 6 mL pentane were slowly added. The resulting mixture was stirred for 30 min. The precipitate was filtered off and dried under reduced pressure to give 69 mg (58%) of CIS-8-dimethylamino-3-[2-(4-methyl-piperazine-1-carbonyl)-pyrimidin-5-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (SC_3133). 1H NMR (600 MHz, DMSO) δ 9.03 (s, 2H), 7.87 (s, 1H), 7.42 - 7.34 (m, 5H), 7.28 (d, 1H), 3.69 (s, 2H), 3.62 (dd, 2H), 3.17 - 3.12 (m, 2H), 2.57 - 2.51 (m, 2H), 2.36 (t, 2H), 2.25 - 2.21 (m, 2H), 2.21 (s, 3H), 1.98 - 1.89 (m, 2H), 1.96 (s, 6H), 1.56 - 1.46 (m, 2H). Mass: m/z 478.29 (M+H)+.
  • Synthesis of SC_3146: CIS-5-(8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)pyrimidine-2-carboxamide
  • Figure US20230303573A1-20230928-C00450
  • Methyl CIS-5-(8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)pyrimidine-2-carboxylate (INT-990) (100 mg, 0.244 mmol) was dissolved in 7N NH3 in methanol (25 equiv. NH3, 0.9 mL) in a microwave reactor vial. The reaction vessel was sealed, the reaction mixture was stirred for 5 days at RT and then concentrated under reduced pressure. The residue was purified by flash chromatography on neutral aluminum oxide (DCM/ EtOH, gradient 90/10 to 74/26) to yield 38 mg (39%) of CIS-5-(8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)pyrimidine-2-carboxamide (SC_3140). 1H NMR (600 MHz, DMSO) δ 9.07 (s, 2H), 8.02 (d, 1H), 7.93 (s, 1H), 7.59 - 7.55 (m, 1H), 7.38 (d, 4H), 7.28 (ddd, 1H), 3.72 (s, 2H), 2.49 - 2.37 (m, 2H), 1.99 - 1.92 (m, 8H), 1.88 - 1.75 (m, 2H), 1.56 - 1.45 (m, 2H). Mass: m/z 395.22 (M+H)+.
  • Synthesis of SC_3146: methyl CIS-2-(4-(5-(8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)pyrimidin-2-yl)piperazin-1-yl)acetate
  • Figure US20230303573A1-20230928-C00451
  • CIS-8-(dimethylamino)-8-phenyl-3-(2-(piperazin-1-yl)pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one (SC_3124) (200 mg, 0.46 mmol) was dissolved in dry acetonitrile (5 mL) under nitrogen atmosphere, K2CO3 (1.2 equiv., 0.55 mmol, 76 mg) and methyl-2-chloroacetate (1.5 equiv., 0.69 mmol, 0.06 mL) were sequentially added and the reaction mixture was stirred at reflux for 5 h. A new portion of methyl-2-chloroacetate (1.5 equiv., 0.69 mmol, 0.06 mL) was added and the reaction mixture was stirred at reflux overnight. The reaction mixture was concentrated under reduced pressure. The residue was suspended in DCM, the precipitate was filtered off and washed with DCM. The combined filtrate was concentrated under reduced pressure to give 106 mg of crude product. Flash chromatography on silica gel (eluent DCM/EtOH gradient 98/2 to 96/4) yielded 168 mg (72%) of methyl CIS-2-(4-(5-(8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)pyrimidin-2-yl)piperazin-1-yl)acetate (SC_3146). 1H NMR (600 MHz, DMSO) δ 8.54 (s, 2H), 7.42 (s, 1H), 7.37 (m, 4H), 7.27 (m, 1H), 3.63 (t, 7H), 3.52 (s, 2H), 3.27 (s, 2H), 2.54 (t, 4H), 2.45 - 2.30 (m, 2H), 1.96 (s, 6H), 1.93 - 1.83 (m, 4H), 1.52 - 1.42 (m, 2H). Mass: m/z 508.4 (M+H)+.
  • Synthesis of SC_3162: CIS-8-(dimethylamino)-8-phenyl-3-(2-(pyridin-2-yl)pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one
  • Figure US20230303573A1-20230928-C00452
  • CIS-3-(2-chloropyrimidin-5-yl)-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-989) (200 mg, 0.52 mmol), tributyl(2-pyridyl)stannane (1.5 equiv., 0.78 mmol, 286 mg) and Pd(PPh3)4 (0.1 equiv., 0.052 mmol, 60 mg) were dissolved in degassed anhydrous DMF (150 equiv., 77.7 mmol, 6 mL) under nitrogen atmosphere. Cesium fluoride (2.2 equiv., 1.14 mmol, 173 mg) was added and the reaction mixture was stirred at 90° C. overnight. The resulting suspension was cooled down to RT, diluted with water (10 mL), extracted with ethylacetate (30 mL), then DCM (30 mL), the DCM phase was dried over MgSO4 and concentrated under reduced pressure to give 320 mg of crude product. Flash chromatography on silica gel (eluent DCM/0.1N NH3 in MeOH, gradient 95/5 to 70/30) yielded 72 mg (33%) of CIS-8-(dimethylamino)-8-phenyl-3-(2-(pyridin-2-yl)pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one (SC_3162). 1H NMR (600 MHz, DMSO) δ 9.13 (s, 2H), 8.71 - 8.67 (m, 1H), 8.30 (d, 1H), 7.92 (td, 1H), 7.86 (s, 1H), 7.46 (dd, 1H), 7.43 - 7.35 (m, 5H), 7.31 - 7.25 (m, 1H), 3.73 (s, 2H), 2.48 - 2.33 (m, 2H), 2.00 - 1.78 (m, 10H), 1.57 - 1.47 (m, 2H). Mass: m/z 429.2 (M+H)+.
  • Synthesis of SC_3169: CIS-2-(2-(8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)phenoxy)acetic acid
  • Figure US20230303573A1-20230928-C00453
    • Step 1: CIS-2-(2-(8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)phenoxy)acetonitrile
  • In analogy to the method described for SC_3103 CIS-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-976) was reacted with 2-(2-bromophenoxy)acetonitrile to be converted into CIS-2-(2-(8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)phenoxy)acetonitrile.
    • Step 2: CIS-2-(2-(8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)phenoxy)acetic acid (SC_3169)
  • CIS-2-(2-(8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)phenoxy)acetonitrile (134 mg, 0.331 mmol) was dissolved in conc. aq. HCl (1.4 mL, 50 equiv.). The reaction mixture was heated to 100° C. for 2 h and cooled down to RT. The precipitate was filtered off, washed with water (2x) and dried under reduced pressure to give 31 mg (22%) of CIS-2-(2-(8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)phenoxy)acetic acid (SC_3169). 1H NMR (600 MHz, DMSO) δ 7.75 - 7.71 (m, 1H), 7.59 - 7.48 (m, 4H), 7.27 (dd, 1H), 7.15 (ddd, 1H), 6.97 - 6.90 (m, 2H), 4.65 (s, 2H), 3.43 (s, 2H), 2.70 (d, 2H), 2.56 (s, 6H), 2.31 (t, 2H), 1.93 - 1.86 (m, 2H), 1.33 - 1.22 (m, 2H). Mass: m/z 424.2 (M+H)+.
  • Synthesis of SC_3173: CIS-8-(dimethylamino)-8-phenyl-3-(2-(piperazine-1-carbonyl)pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one
  • Figure US20230303573A1-20230928-C00454
    • Step 1: CIS-tert-butyl 4-(5-(8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)pyrimidine-2-carbonyl)piperazine-1-carboxylate
  • In analogy to the method described for SC_3133 lithium CIS-5-(8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)pyrimidine-2-carboxylate (INT-990) was reacted with 1-(tert-butoxycarbonyl)piperazine to be converted into CIS-tert-butyl 4-(5-(8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)pyrimidine-2-carbonyl)piperazine-1-carboxylate.
    • Step 2: CIS-8-(dimethylamino)-8-phenyl-3-(2-(piperazine-1-carbonyl)pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one (SC_3173)
  • CIS-tert-butyl 4-(5-(8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)pyrimidine-2-carbonyl)piperazine-1-carboxylate (230 mg, 0.41 mmol) was dissolved in TFA (2.2 mL, 28.6 mmol, 70 equiv.). The reaction mixture was stirred at RT for 2.5 h and then concentrated under reduced pressure. The residue was dissolved in DCM and aq. sat Na2CO3 was added (until pH 10). The organic phase was separated and the aq. phase was extracted with DCM (2x). The combined organic extracts were dried over MgSO4 and concentrated under reduced pressure. Recrystallization of the residue from DCM/pentane gave 105 mg (56%) of CIS-8-(dimethylamino)-8-phenyl-3-(2-(piperazine-1-carbonyl)pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one (SC_3173). 1H NMR (600 MHz, DMSO) δ 9.04 (s, 2H), 7.89 (s, 1H), 7.42 - 7.32 (m, 4H), 7.31 - 7.26 (m, 1H), 3.69 (s, 2H), 3.65 (t, 2H), 3.21 (t, 2H), 2.90 (t, 2H), 2.79 - 2.74 (m, 2H), 2.43 (s, 2H), 1.98 (s, 9H), 1.89 - 1.75 (m, 1H), 1.53 - 1.47 (m, 2H). Mass: m/z 464.3 (M+H)+.
  • Synthesis of SC_3182: CIS-8-(dimethylamino)-3-(2-(4-hydroxypiperidin-1-yl)pyrimidin-5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
  • Figure US20230303573A1-20230928-C00455
  • Et3N (0.39 g, 3.89mmol) was added to the solution of CIS-3-(2-chloropyrimidin-5-yl)-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-989) (0.5 g, 1.29mmol) and piperidin-4-ol (0.32 g, 3.24mmol) in DMF (10mL) at RT. The reaction mixture was stirred at 130° C. for 16 h, cooled down to RT and concentrated under reduced pressure. The residue was diluted with 10% aq. NaOH and the organic product was extracted with ⅑ v/v MeOH/DCM. The combined organic layer was dried over anhydrous Na2SOa and concentrated in vacuo. The residue was purified by preparative TLC using 10% MeOH/DCM as eluent to afford 130 mg of CIS-8-(dimethylamino)-3-(2-(4-hydroxypiperidin-1-yl)pyrimidin-5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (SC_3182) as an off-white solid (TLC system: 10% MeOH in DCM; Rf: 0.1). 1H NMR (DMSO-d6): δ 8.50 (s, 2H), 7.39-7.26 (m, 6H), 4.68 (d, 1H), 4.19-4.16 (m, 2H), 3.69-3.67 (m, 1H), 3.51 (s, 2H), 3.14 (t, 2H), 2.33 (m, 2H), 1.94-1.71 (m, 12H), 1.45 (m, 2H), 1.30-1.23 (m, 2H). Mass: m/z 451.2 (M+H)+.
  • Synthesis of SC_3186: CIS-8-(dimethylamino)-3-(3-methylpyridin-2-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
  • Figure US20230303573A1-20230928-C00456
  • Compound was synthesized within a parallel array. An argon-flushed dry reaction vessel equipped with a septum was loaded with the solutions of INT-976 (0.1 M, 1 mL) and 1-bromo-2-methylbenzene (0.15 M, 1 mL) in dioxane. To the resulting mixture Cs2CO3 (200 µmol), XantPhos (10 µmol) and Pd2(dba)3 (5 µmol) were added. The reaction vessel was flushed with argon once again, sealed and the reaction mixture was shaken at 100° C. overnight. The resulting mixture was cooled down to RT and the solvent was removed under reduced pressure. The residue was taken up in 3 mL dichloromethane and 3 mL water, the organic phase was separated, the aqueous phase was extracted with dichloromethane (2×3 mL). Combined organic phases were concentrated under reduced pressure. The residue was purified by HPLC to give CIS-8-(dimethylamino)-3-(3-methylpyridin-2-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (SC_3186). Mass: m/z 363.2 (M+H)+.
  • Synthesis of SC_3208: CIS-4-(5-(8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)pyrimidin-2-yl)indolin-2-one
  • Figure US20230303573A1-20230928-C00457
  • CIS-3-(2-chloropyrimidin-5-yl)-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-989) (150 mg, 0.38 mmol), Pd(t-Bu3P)2 (0.1 equiv., 0.02 mmol, 10 mg) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indolin-2-one (2 equiv., 0.78 mmol, 201 mg) were dissolved in degassed anhydrous THF (80 equiv., 31 mmol, 2.5 mL) and 1M aq. Na2CO3 (5.5 equiv., 2.14 mmol, 2.14 mL) was added. The resulting mixture was stirred at 60°C for 8 h and then at RT overnight. The reaction mixture was diluted with water until precipitation occurred. The precipitate was filtered off, suspended in 30 mL DCM, filtered off again, washed with pentane (5 mL) and dried under reduced pressure to give 143 mg (76%) of CIS-4-(5-(8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)pyrimidin-2-yl)indolin-2-one (SC_3208). 1H NMR (600 MHz, DMSO) δ 10.45 (s, 1H), 9.10 (s, 2H), 7.87 (d, 1H), 7.84 - 7.80 (m, 1H), 7.39 (d, 5H), 7.29 (dt, 2H), 6.91 (d, 1H), 3.82 (s, 2H), 3.72 (s, 2H), 2.41 (d, 2H), 2.03 - 1.74 (m, 9H), 1.60 -1.44 (m, 3H). Mass: m/z 484.26 (M+H)+.
  • Synthesis of SC_3221: CIS-8-(dimethylamino)-3-(2-((2-hydroxyethyl)amino)pyrimidin-5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
  • Figure US20230303573A1-20230928-C00458
    • Step 1: CIS-8-(dimethylamino)-3-(2-((2-methoxyethyl)amino)pyrimidin-5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
  • In analogy to the method described for SC_3103 2-methoxyethanamine was reacted with CIS-3-(2-chloropyrimidin-5-yl)-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-989) to be converted into CIS-8-(dimethylamino)-3-(2-((2-methoxyethyl)amino)pyrimidin-5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one.
    • Step 2: CIS-8-(dimethylamino)-3-(2-((2-hydroxyethyl)amino)pyrimidin-5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (SC_3221)
  • BBr3 (1M in DCM) (2.2mL, 2.22mmol) was added to the solution of CIS-8-(dimethylamino)-3-(2-((2-methoxyethyl)amino)pyrimidin-5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (0.55 g, 1.06 mmol) in DCM (20 mL) at -78° C. over 15 min. The reaction mixture was stirred at RT for 4 h, then quenched with water and concentrated under reduced pressure. The residue was purified by preparative reverse phase HPLC to afford 82 mg (19%) of CIS-8-(dimethylamino)-3-(2-((2-hydroxyethyl)amino)pyrimidin-5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (SC_3221) (TLC system: 10% MeOH in DCM (Ammonia atmosphere); Rf: 0.3). 1H NMR (DMSO-d6): δ 8.41 (s, 2H), 7.39-7.24 (m, 6H), 6.70 (t, 1H), 4.64 (br, s, 1H), 3.50-3.45 (m, 4H), 3.28-3.25 (m, 2H), 2.37 (br m, 2H), 1.94-1.86 (m, 10H), 1.45 (m, 2H). Mass: m/z 411.2 (M+H)+
  • Synthesis of SC_3224: CIS-3-(2-(1H-indazol-1-yl)pyrimidin-5-yl)-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
  • Figure US20230303573A1-20230928-C00459
  • K2CO3 (0.53 g, 3.89 mmol) was added to the solution of CIS-3-(2-chloropyrimidin-5-yl)-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (500 mg, 1.29 mmol) and 1H-indazole (306 mg, 2.59 mmol) in DMF (10 mL). The reaction mixture was stirred at 140° C. for 48 h, cooled down to RT and concentrated under reduced pressure. The residue was diluted with DCM (50 mL), filtered through Celite and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography using neutral alumina (0-10% MeOH/DCM) followed by reverse phase HPLC to afford 77 mg (13%) of CIS-3-(2-(1H-indazol-1-yl)pyrimidin-5-yl)-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (SC_3224) as off-white solid (TLC system: 10% MeOH in DCM; Rf: 0.6). 1H NMR (DMSO-d6): δ 9.10 (s, 2H), 8.57-8.55 (d, 1H), 8.41 (s, 1H), 7.89-7.87 (d, 1H), 7.82 (br s, 1H), 7.57-7.53 (t, 1H), 7.39-7.28 (m, 6H), 3.72 (s, 2H), 2.45 (m, 2H), 1.98-1.93 (m, 10H), 1.52 (m, 2H). Mass: m/z 468.2 (M+H)+.
  • Synthesis of SC_3235: CIS-methyl 2-(2-(8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)phenoxy)acetate
  • Figure US20230303573A1-20230928-C00460
  • CIS-2-(2-(8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)phenoxy)acetic acid (120 mg, 0.28 mmol) was dissolved in methanol (1.4 mL, 125 equiv.) and thionyl chloride (4 equiv., 1.13 mmol, 83 µL) was added dropwise. The reaction mixture was stirred at RT overnight, diluted with aq. sat. NaHCO3 and extracted with DCM (3x). The combined organic phases were dried over MgSO4 and concentrated under reduced pressure. The residue (112 mg) was purified by flash chromatography on silica get (gradient DCM/ MeOH 97/3 to 88/12) to give 92 mg (74%) of CIS-methyl 2-(2-(8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)phenoxy)acetate (SC_3235). 1H NMR (600 MHz, DMSO) δ 7.40 -7.33 (m, 4H), 7.29 (dd, 1H), 7.28 - 7.24 (m, 1H), 7.13 (td, 1H), 6.99 - 6.91 (m, 2H), 4.76 (s, 2H), 3.67 (s, 3H), 3.55 (s, 2H), 2.45 - 2.26 (m, 2H), 2.07 (s, 2H), 1.98 (s, 6H), 1.94 - 1.75 (m, 4H), 1.52 - 1.45 (m, 2H). Mass: m/z 438.2 (M+H)+.
  • Synthesis of SC_3238: CIS-2-(5-(8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)pyrimidin-2-yl)benzonitrile
  • Figure US20230303573A1-20230928-C00461
  • CIS-3-(2-chloropyrimidin-5-yl)-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-989) (240 mg, 0.56 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (0.05 equiv., 0.028 mmol, 23 mg) and (2-cyanophenyl)boronic acid (1.125 equiv., 0.63 mmol, 92 mg) were dissolved in degassed 1,2-dimethoxyethane (100 equiv., 56 mmol, 5.8 mL) and Cs2CO3 (3.3 equiv., 1.84 mmol, 600 mg) in water (175 equiv., 98 mmol, 1.8 mL) was added. The resulting clear reaction mixture was stirred 3 days at 60° C. The reaction mixture was diluted with water (15 mL) and extracted with EtOAc (2×15 mL). Combined organic phases were dried over MgSO4 and concentrated under reduced pressure. The residue (355 mg) was purified by flash chromatography on silica get (gradient DCM/ MeOH 95/5 to 70/30) to give 60 mg of product, which was further purified by HPLC to give 15.4 mg (6%) of CIS-2-(5-(8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)pyrimidin-2-yl)benzonitrile (SC_3238). 1H NMR (600 MHz, DMSO) δ 9.17 (s, 2H), 8.27 (dd, 1H), 7.94 (dd, 1H), 7.81 (td, 1H), 7.65 (td, 1H), 7.42 - 7.35 (m, 5H), 7.28 (ddt, 1H), 3.75 (s, 2H), 2.49 - 2.34 (m, 1H), 2.00 - 1.76 (m, 11H), 1.55 -1.51 (m, 2H). Mass: m/z 453.24 (M+H)+.
  • Synthesis of SC_3239: CIS-3-(2-aminopyrimidin-5-yl)-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
  • Figure US20230303573A1-20230928-C00462
  • Microwave reactor vial was loaded with CIS-3-(2-chloropyrimidin-5-yl)-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-989) (250 mg, 0.65 mmol), flushed with nitrogen, 7N solution of NH3 in methanol (108 equiv., 70 mmol, 10 mL) and dioxane (37 equiv., 24 mmol, 2 mL) were added, the vial was sealed and the reaction mixture was stirred at 115° C. for 12 h in the microwave reactor. The reaction mixture was then cooled down to 4° C. overnight. The precipitate formed was filtered off, washed with DCM (small amount), water (2x), ether (2x) and dried under reduced pressure to give 180 mg (76%) of CIS-3-(2-aminopyrimidin-5-yl)-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (SC_3239) as an off-white solid. 1H NMR (600 MHz, DMSO) δ 8.39 (s, 2H), 7.40 - 7.32 (m, 5H), 7.26 (tt, 1H), 6.25 (s, 2H), 3.51 (s, 2H), 2.37 (s, 2H), 2.07 (s, 2H), 1.96 (s, 6H), 1.94 - 1.68 (m, 4H), 1.47 (d, 2H). Mass: m/z 367.23 (M+H)+.
  • Synthesis of SC_3240: CIS-N-(5-(8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)pyrimidin-2-yl)cyclopropanecarboxamide
  • Figure US20230303573A1-20230928-C00463
  • CIS-3-(2-aminopyrimidin-5-yl)-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (SC_3239) (50 mg, 0.14 mmol) and 4-dimethylaminopyridine (1.3 equiv., 0.18 mmol, 22 mg) were dissolved in dry pyridine (200 equiv., 27 mmol, 2.2 mL) under nitrogen atmosphere. Cyclopropancarbonyl chloride (1.3 equiv., 0.18 mmol, 16 µL) was added in one portion and the reaction mixture was stirred at RT for 3 h. Additional portion of cyclopropancarbonyl chloride (3 equiv., 0.42 mmol, 37 µL) was added and the reaction mixture was stirred at 90° C. for 1 h. The reaction mixture was diluted with water (5 mL) and aq. sat. NaHCO3 (5 mL), extracted with DCM (3×10 mL), organic phases were washed with brine, dried over Na2SO4 and the solvent was removed under reduced pressure. The residue was suspended thoroughly in 3 mL DCM, the precipitate was filtered off, washed with ether and dried under reduced pressure to give 47 mg (79%) of CIS-N-(5-(8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)pyrimidin-2-yl)cyclopropanecarboxamide (SC_3240) as a white solid. 1H NMR (600 MHz, DMSO) δ 10.66 (s, 1H), 8.81 (s, 2H), 7.67 (s, 1H), 7.41 - 7.33 (m, 4H), 7.31 - 7.21 (m, 1H), 3.62 (s, 2H), 2.45 -2.32 (m, 2H), 2.01 (td, 1H), 1.96 (s, 6H), 1.93 - 1.78 (m, 3H), 1.52 - 1.47 (m, 2H), 0.82 - 0.72 (m, 4H). Mass: m/z 435.3 (M+H)+.
  • Synthesis of SC_3242: CIS-8-(dimethylamino)-8-phenyl-3-(6-(piperazin-1-yl)pyridin-3-yl)-1,3-diazaspiro[4.5]decan-2-one
  • Figure US20230303573A1-20230928-C00464
    • Step 1: 4-(5-bromopyrimidin-2-yl)piperazine
  • In analogy to the method described for SC_3097 step 1 5-bromo-2-chloro-pyridine was reacted with piperazine to be converted into 4-(5-bromopyrimidin-2-yl)piperazine.
    • Step 2: CIS-8-(dimethylamino)-8-phenyl-3-(6-(piperazin-1-yl)pyridin-3-yl)-1,3-diazaspiro[4.5]decan-2-one (SC_3242)
  • CIS-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-976) (80 mg, 0.29 mmol), 4-(5-bromopyrimidin-2-yl)piperazine (2 equiv., 0.56 mmol, 142 mg) and potassium phosphate (4 equiv., 1.17 mmol, 248 mg) were suspended in N,N′-dimethylethylenediamine (18 equiv., 5.27 mmol, 0.6 mL) under nitrogen atmosphere. The reaction mixture was stirred at 80° C. for 2 h, diluted with water (10 mL) and extracted with DCM (3×15 mL). The combined organic phases contained a precipitate which was filtered off, washed with isopropanol and dried under reduced pressure to give 79 mg (62%) of CIS-8-(dimethyl-amino)-8-phenyl-3-(6-(piperazin-1-yl)pyridin-3-yl)-1,3-diazaspiro[4.5]decan-2-one (SC_3242). 1H NMR (600 MHz, DMSO) δ 8.15 (d, 1H), 7.85 (dd, 1H), 7.41 - 7.33 (m, 4H), 7.32 - 7.23 (m, 2H), 6.74 (d, 1H), 3.51 (s, 2H), 3.30 -3.25 (m, 4H), 2.78 - 2.73 (m, 4H), 2.43 - 2.31 (m, 2H), 1.96 (s, 6H), 1.93 - 1.79 (m, 4H), 1.50 -1.42 (m, 2H). Mass: m/z 435.3 (M+H)+.
  • Synthesis of SC_3275: CIS-8-(ethylamino)-1-((1-hydroxycyclobutyl)methyl)-8-phenyl-3-(2-(trifluoromethyl)pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one
  • Figure US20230303573A1-20230928-C00465
  • CIS-8-amino-1-((1-hydroxycyclobutyl)methyl)-8-phenyl-3-(2-(trifluoromethyl)pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one (70 mg, 0.15 mmol) was dissolved in anhydrous DCM (3.8 mL) under nitrogen atmosphere. Acetic acid (0.1 equiv., 0.015 mmol, 0.8 µL) and acetaldehyde (1.1 equiv., 0.16 mmol, 9 µL) were sequentially added and the resulting mixture was stirred at RT for 1 h. Sodium triacetoxyborohydride (2 equiv., 0.29 mmol, 62 mg) was added and the reaction mixture was stirred at RT overnight and then at 50° C. for 5 h. Additional amounts of acetaldehyde (1.1 equiv., 0.16 mmol, 9 µL) and sodium triacetoxyborohydride (2 equiv., 0.29 mmol, 62 mg) were added and the reaction mixture was stirred further 24 h at 50° C. The resulting mixture was cooled down to RT, quenched with aq. sat. NaHCO3 until pH > 7, diluted with water and extracted with DCM (3x). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The residue (70 mg) was purified by flash chromatography on silica gel (DCM/EtOH gradient 99/1 to 95/5) to yield 43 mg (58%) of CIS-8-(ethylamino)-1-((1-hydroxycyclobutyl)methyl)-8-phenyl-3-(2-(trifluoromethyl)pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one (SC_3275). 1H NMR (600 MHz, DMSO) δ 9.26 (s, 2H), 7.55 - 7.49 (m, 2H), 7.33 (t, 2H), 7.21 (d, 1H), 3.92 (s, 2H), 2.38 (td, 2H), 2.17 - 2.06 (m, 3H), 2.00 - 1.87 (m, 4H), 1.81 (td, 2H), 1.72 - 1.64 (m, 1H), 1.60 - 1.50 (m, 1H), 1.49 - 1.43 (m, 2H), 0.99 (t, 3H). Mass: m/z 504.3 (M+H)+
  • Synthesis of SC_3292 and SC3293: enantiomer 1 and enantiomer 2 of CIS-8-(methyl((tetrahydrofuran-3-yl)methyl)amino)-8-phenyl-3-(2-(trifluoromethyl)pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one
  • Figure US20230303573A1-20230928-C00466
  • Cs2CO3 (0.85 g, 2.61 mmol) was added to an argon purged solution of CIS-8-(methyl((tetrahydrofuran-3-yl)methyl)amino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-1026) (0.3 g, 0.87 mmol), Xanthphos (45 mg, 0.087 mmol), Pd2(dba)3 (80 mg, 0.087 mmol) and 5-bromo-2-(trifluoromethyl)pyrimidine (0.29 g, 1.30 mmol) in 1,4-dioxane (15 mL). The mixture was purged with argon for 5 min and stirred at 90° C. for 16 h. The reaction mixture was cooled to RT, diluted with EtOAc (20 mL), filtered through Celite and the filtrate was concentrated under reduced pressure. The crude product was purified by flash chromatography (silica gel 230-400 mesh; 3% MeOH in DCM) to get the compound which was further purified by reverse phase preparative HPLC to afford 0.1 g (23%) of CIS-8-(methyl((tetrahydrofuran-3-yl)methyl)amino)-8-phenyl-3-(2-(trifluoromethyl)pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one (TLC system: 10% MeOH in DCM; Rf: 0.4) as a mixture of enantiomers. Reverse phase preparative HPLC conditions: mobile phase: 10 mM ammonium bicarbonate in H2O/acetonitrile; column: X-BRIDGE-C18 (150*19), 5 µm; mobile phase gradient (min/%B): 0/30, 8/82, 8.1/100, 10/100, 10.1/30, 12/30; flow rate: 19 ml/min; diluent: mobile phase + THF. Enantiomeric mixture of CIS-8-(methyl((tetrahydrofuran-3-yl)methyl)amino)-8-phenyl-3-(2-(trifluoromethyl)pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one (100mg) was separated by chiral SFC to afford 35 mg of enantiomer 1 (SC-3292) and 40 mg of enantiomer 2 (SC-3293) as off-white solids. Preparative SFC conditions: column: Chiralpak IA (250×30) mm, 5 µm;% CO2: 50.0%; % co-solvent: 50.0% (100% Methanol); total flow: 70.0 g/min; back pressure: 100.0 bar; UV: 256 nm; stack time: 13.5 min; load/inj.: 9.5 mg; no. of injections: 11. SC-3292: 1H NMR (DMSO-d6): δ 9.15 (s, 2H), 8.23 (broad s, 1H), 7.37-7.25 (m, 5H), 3.68-3.58 (m, 5H), 3.37-3.36 (m, 1H), 2.32 (m, 3H), 2.13-1.89 (m, 10H), 1.47 (m, 3H). SC-3293: 1H NMR (DMSO-d6): δ 9.15 (s, 2H), 8.23 (broad s, 1H), 7.37-7.36 (m, 4H), 7.26-7.24 (m, 1H), 3.68-3.56 (m, 5H), 3.37-3.36 (m, 1H), 2.31-2.28 (m, 3H), 2.13-1.86 (m, 10H), 1.48 (m, 3H). Mass: m/z 490.3 (M+H)+.
  • Synthesis of SC_3313: CIS-3-(2-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)pyrimidin-5-yl)-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
  • Figure US20230303573A1-20230928-C00467
    • Step 1: 5-bromo-2-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)pyrimidine
  • 2-Azido-5-bromo-pyrimidine (400 mg, 1.94 mmol) and ethynylcyclopropane (1.3 equiv., 2.522 mmol, 0.21 mL) were dissolved in tert-butanol (5 mL). The solutions of sodium ascorbate (0.1 equiv., 0.194 mmol, 38 mg) in water (2.5 mL) and copper(II) sulfate pentahydrate (0.1 equiv., 0.194 mmol, 48 mg) in water (2.5 mL) were sequentially added. The reaction mixture was stirred under ambient conditions for 18 h, then diluted with 20 mL 1M aq. NH4OH and extracted with EtOAc (3×30 mL). The combined organic extracts were washed with brine, dried over Na2SO4 and concentrated under reduced pressure. Crude product (510 mg) was purified by flash chromatography on silica gel (DCM/EtOH 99/1) to yield 143 mg of 5-bromo-2-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)pyrimidine as a white solid. Mass: m/z 266.0 (M+H)+.
    • Step 2: CIS-3-(2-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)pyrimidin-5-yl)-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (SC_3313)
  • In analogy to the method described for SC_3103 CIS-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-976) was reacted with 5-bromo-2-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)pyrimidine to be converted into CIS-3-(2-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)pyrimidin-5-yl)-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (SC_3313). 1H NMR (600 MHz, DMSO) δ 9.09 (d, 2H), 8.50 (d, 1H), 7.91 (s, 1H), 7.42 - 7.34 (m, 2H), 7.38 (s, 3H), 7.31 - 7.25 (m, 1H), 3.72 (s, 2H), 2.48 - 2.31 (m, 2H), 2.10 - 2.01 (m, 1H), 1.99 - 1.77 (m, 10H), 1.58 - 1.46 (m, 2H), 1.00 - 0.91 (m, 2H), 0.84 (tt, 2H). Mass: m/z 459.3 (M+H)+.
  • Synthesis of SC_3319: CIS-8-(methyl((tetrahydrofuran-3-yl)methyl)amino)-8-phenyl-3-(2-(trifluoromethyl)pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one
  • Figure US20230303573A1-20230928-C00468
  • Cs2CO3 (145 mg, 0.45 mmol, 2 equiv.), CIS-8-(dimethylamino)-8-(3-fluorophenyl)-1,3-diazaspiro[4.5]decan-2-one (INT-1024) (65 mg, 0.223 mmol, 1 equiv.), Xanthphos (19 mg, 0.033 mmol, 0.15 equiv.), Pd2(dba)3 (10 mg, 0.011 mmol, 0.05 equiv.) and 5-bromo-1-methyl-3-(trifluoromethyl)pyrazole (102 mg, 0.446 mmol, 2 equiv.) were loaded into a microwave reactor vial (2-5mL), the vial was sealed and flushed with nitrogen (3x). 1,4-Dioxane (1.5 mL) was added via syringe and the reaction mixture was stirred at 110° C. in the microwave reactor for 10 h. The resulting mixture was cooled down to RT, solution of Xanthphos (19 mg, 0.033 mmol, 0.15 equiv.) and Pd2(dba)3 (10 mg, 0.011 mmol, 0.05 equiv.) in 1,4 dioxane (1 mL) was added, and the reaction mixture was stirred at 130°C in the microwave reactor for further 10 h. The resulting suspension was cooled to RT, quenched with water and extracted with DCM (3x). The combined organic layer was dried over Na2SO4 and concentrated under reduced pressure. The resulting residue was purified by flash chromatography (gradient 0% to 16% MeOH in DCM) to yield 41 mg (42%) of CIS-8-(methyl((tetrahydrofuran-3-yl)methyl)amino)-8-phenyl-3-(2-(trifluoromethyl)pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one (SC_3319). 1H NMR (600 MHz, DMSO) δ 7.71 (s, 1H), 7.41 (q, 1H), 7.21 - 7.12 (m, 2H), 7.09 (td, 1H), 6.63 (s, 1H), 3.75 (s, 2H), 3.55 (s, 2H), 2.42 - 2.27 (m, 2H), 1.99 - 1.89 (m, 8H), 1.88 - 1.73 (m, 2H), 1.56 - 1.49 (m, 2H). Mass: m/z 440.2 (M+H)+.
  • Synthesis of SC_3340: CIS-2-(3-(8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)pyridin-4-yl)acetamide
  • Figure US20230303573A1-20230928-C00469
    • Step 1: CIS-2-(3-(8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)pyridin-4-yl)acetonitrile
  • In analogy to the method described for SC_3097 step 2 CIS-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-976) was reacted with (3-bromo-pyridin-4-yl)-acetonitrile to be converted into CIS-2-(3-(8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)pyridin-4-yl)acetonitrile.
    • Step 2: CIS-2-(3-(8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)pyridin-4-yl)acetamide (SC_3340)
  • To a solution of CIS-2-(3-(8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)pyridin-4-yl)acetonitrile (600 mg, 1.54 mmol, 1.0 equiv.) in EtOH (50 ml) was added NaOH (247 mg, 6.16 mmol, 4.0 equiv.). The reaction mixture was stirred at reflux for 16 h and then concentrated under reduced pressure. The resulting residue was purified by column chromatography (neutral alumina; 4% MeOH in DCM) and finally by preparative HPLC (column: Gemini NX-C18 (50 × 4.6), 3 µm, diluent: DMSO, mobile phase: gradient 0.05% HCOOH in water/ACN flow rate: 1 ml/min) to yield CIS-2-(3-(8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)pyridin-4-yl)acetamide (SC_3340) (40 mg, 0,098 mmol, 4% yield after two steps) as an off white solid. 1HNMR (DMSO, 400 MHz) δ 8.40 (s, 1H), 8.32 (d, 1H, J = 4.92 Hz), 7.49 (s, 1H), 7.36-7.24 (m, 7H), 6.99 (s, 1H), 3.49-3.46 (m, 4H), 2.32 (bs, 2H), 1.94-1.77 (m, 10H), 1.52 (bs, 2H). Mass: m/z 408.2 (M+H)+.
  • Synthesis of SC_3352: CIS-8-(dimethylamino)-3-(2-hydroxybenzo[d]oxazol-7-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
  • Figure US20230303573A1-20230928-C00470
    • Step 1: CIS-7-(8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-3-((2-(trimethylsilyl)ethoxy)methyl)benzo[d]oxazol-2(3H)-one
  • In analogy to the method described for SC_3103 CIS-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-976) was reacted with 7-bromo-3-(2-trimethylsilanyl-ethoxymethyl)-3H-benzooxazol-2-one (prepared from 7-bromobenzo[d]oxazol-2(3H)-one and trimethylsilylethoxymethylchloride following a standart procedure) to be converted into CIS-7-(8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-3-((2-(trimethylsilyl)ethoxy)methyl)benzo[d]oxazol-2(3H)-one. Mass: m/z 537.2 (M+H)+.
    • Step 2: CIS-8-(dimethylamino)-3-(2-hydroxybenzo[d]oxazol-7-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (SC_3352)
  • To a solution of CIS-7-[8-dimethylamino-2-oxo-8-phenyl-1-(2-trimethylsilanyl-ethoxymethyl)-1,3-diaza-spiro[4.5]dec-3-yl]-3H-benzooxazol-2-one (350 mg, 0.65 mmol, 1.0 eq) in 1,4-dioxane (2 mL) was added 4M HCl in dioxane (6 mL) dropwise at 0° C. The reaction mixture was stirred at RT for 48 h and then concentrated under reduced pressure. The residue was taken in DCM (200 mL) and washed with sat. aq. NaHCO3 (100 mL). Organic layer was dried over Na2SO4 and concentrated under reduced pressure to get the crude product which was purified by column chromatography (neutral alumina; 2% MeOH/DCM) to yield CIS-7-(8-dimethylamino-2-oxo-8-phenyl-1,3-diaza-spiro[4.5]dec-3-yl)-3H-benzooxazol-2-one (SC_3352) (85 mg, 0.21 mmol, 32%) as an off white solid. 1HNMR (DMSO-d6, 400 MHz at 100° C.), δ (ppm) = 11.19 (bs, 1H), 7.37-7.23 (m, 6H), 7.14 (s, 1H), 7.04 (t, 1H, J = 8.06), 6.76 (d, 1H, J = 7.68 Hz), 3.69 (s, 2H), 2.38-2.26 (m, 2H), 2.08-1.76 (m, 10H), 1.56-1.51 (m, 2H). Mass: m/z 407.1 (M+H)+.
  • Synthesis of SC_3354: CIS-4-(5-(8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)pyrimidin-2-yl)benzamide trifluoroacetate salt
  • Figure US20230303573A1-20230928-C00471
  • 3-(2-chloropyrimidin-5-yl)-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT 989) (200 mg, 0.52 mmol, 1 equiv.), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (129 mg, 0.52 mmol, 1 equiv.), Pd2(dba)3 (95 mg, 0.10 mmol, 0.2 equiv.), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (X-Phos) (99 mg, 0.21 mmol, 0.4 equiv.) were loaded into microwave reactor vessel and flushed with nitrogen (2x). Anhydrous 1,4-dioxane (9 mL) and sodium carbonate (213 mg, 2.07 mmol, 4 equiv.) were sequentially added. The reaction mixture was stirred 8 h at 120° C. in the microwave reactor and then concentrated under reduced pressure. The residue was suspended in EtOAc/water (1/1, v/v) and filtered through a glass filter. The solid residue was dissolved in MeOH/DCM/TFA, filtered through Celite pad and the filtrate was concentrated under reduced pressure to give 75 mg (25%) of CIS-4-(5-(8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)pyrimidin-2-yl)benzamide trifluoroacetate salt (SC_3354). 1H NMR (600 MHz, DMSO) δ 9.05 (s, 2H), 8.42 (s, 1H), 8.34 (d, 2H), 8.03 (s, 1H), 7.98 (d, 2H), 7.74 - 7.65 (m, 2H), 7.58 (t, 2H), 7.56 - 7.52 (m, 1H), 7.40 (s, 1H), 3.58 (s, 2H), 2.70 (d, 2H), 2.60 (s, 6H), 2.25 (t, 2H), 1.91 (d, 2H), 1.39 (t, 2H). Mass: m/z 471.3 (M+H)+.
  • [0436] Synthesis of SC_3357: CIS-8-(dimethylamino)-3-(1H-indol-3-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
  • Figure US20230303573A1-20230928-C00472
    • Step 1: CIS-8-(dimethylamino)-8-phenyl-3-(1-tosyl-1H-indol-3-yl)-1,3-diazaspiro[4.5]decan-2-one
  • In analogy to the method described for SC_3103 CIS-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-976) was reacted with 3-bromo-1-(toluene-4-sulfonyl)-1H-indole to be converted into CIS-8-(dimethylamino)-8-phenyl-3-(1-tosyl-1H-indol-3-yl)-1,3-diazaspiro[4.5]decan-2-one. Mass: m/z 543.1 (M+H)+.
    • Step 2: CIS-8-(dimethylamino)-3-(1H-indol-3-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (SC_3357)
  • To a solution of 8-dimethylamino-8-phenyl-3-[1-(toluene-4-sulfonyl)-1H-indol-3-yl]-1,3-diaza-spiro[4.5]decan-2-one (275 mg, 0.51 mmol, 1.0 eq.) in EtOH (24 mL) was added 10N aq. NaOH (1.2 mL) at RT. The reaction mixture was heated to reflux for 1.5 h, then concentrated, diluted with water (50 mL) and extracted with EtOAc (150 mL). Organic layer was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography (neutral alumina; 2% MeOH/DCM) to afford CIS-8-dimethylamino-3-(1H-indol-3-yl)-8-phenyl-1,3-diaza-spiro[4.5]decan-2-one (SC_3357) (130 mg, 0.33 mmol, 65%) as light brown solid. 1H NMR (DMSO-d6, 400 MHz at 100° C.), δ (ppm) = 10.55 (bs, 1H), 7.62-7.60 (d, 1H, J = 7.96 Hz), 7.37-7.23 (m, 7H), 7.04 (t, 1H, J = 7.48 Hz), 6.92 (t, 1H, J = 7.44 Hz), 6.71 (bs, 1H), 3.61 (s, 2H), 2.38-2.33 (m, 2H), 2.04-1.82 (m, 10H), 1.59-1.54 (m, 2H). Mass: m/z 389.3 (M+H)+.
  • Synthesis of SC_3379: CIS-3-(1-acetyl-1H-indol-3-yl)-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
  • Figure US20230303573A1-20230928-C00473
  • To a solution of 8-dimethylamino-3-(1H-indol-3-yl)-8-phenyl-1,3-diaza-spiro[4.5]decan-2-one (SC_3357) (150 mg, 0.38 mmol, 1.0 eq.) in DCM (6 mL) were added NaOH (39 mg, 0.96 mmol, 2.5 eq.) and Bu4NHSO4 (129 mg, 0.38 mmol, 1.0 eq.) at 0° C. and the reaction mixture was stirred for 30 min followed by addition of acetyl chloride (54 µl, 0.76 mmol, 2.0 eq.). The reaction mixture was stirred at RT for 16 h, then diluted with DCM (150 ml) and washed with water (50 mL) and brine (50 mL). Organic layer was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography (neutral alumina; 1% MeOH/DCM) followed by prep HPLC to afford 3-(1-acetyl-1H-indol-3-yl)-8-dimethylamino-8-phenyl-1,3-diaza-spiro[4.5]decan-2-one (SC_3379) as off white solid. Note: Two batches of same reactions were done and yield was calculated accordingly. Yield: 13% (45 mg, 0.1 mmol). 1HNMR (DMSO-d6, 400 MHz at 100oC), δ (ppm) = 8.34-8.32 (d, 1H, J = 7.88 Hz), 7.90 (d, 1H, J = 7.36 Hz), 7.67 (s, 1H), 7.37-7.10 (m, 8H), 3.71 (s, 2H), 2.57 (s, 3H), 2.38-2.32 (m, 2H), 2.04-1.88 (m, 10H), 1.61-1.59 (m, 2H). Mass: m/z 431.2 (M+H)+.
  • Synthesis of SC_3388: CIS-8-(dimethylamino)-8-(3-hydroxyphenyl)-3-(4-methyl-6-(trifluoromethyl)pyridin-3-yl)-1,3-diazaspiro[4.5]decan-2-one
  • Figure US20230303573A1-20230928-C00474
  • CIS-8-(dimethylamino)-8-(3-methoxyphenyl)-3-[4-methyl-6-(trifluoromethyl)-3-pyridyl]-1,3-diazaspiro[4.5]decan-2-one (SC_3368) (42 mg, 0.091 mmol) was dissolved in DCM (2 mL) and the solution was cooled to 0° C. Boron tribromide (1M sol. in DCM, 4 equiv., 0.36 mmol, 0.36 mL) was added in one portion. The reaction mixture was allowed to stir at RT overnight, then quenched with methanol and diluted with water. The resulting mixture was extracted with DCM (2x), the combined organic phases weres dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (eluent gradient DCM/EtOH) to yield 16 mg (39%) of CIS-8-(dimethylamino)-8-(3-hydroxyphenyl)-3-(4-methyl-6-(trifluoromethyl)pyridin-3-yl)-1,3-diazaspiro[4.5]decan-2-one (SC_3388). 1H NMR (600 MHz, DMSO) δ 8.57 (s, 1H), 7.80 (s, 1H), 7.52 (s, 1H), 7.14 (t, 1H), 6.77 (d, 1H), 6.74 (s, 1H), 6.66 (dd, 1H), 3.61 (s, 2H), 2.32 (s, 3H), 2.31 - 2.19 (m, 2H), 2.01 - 1.89 (m, 8H), 1.88 - 1.70 (m, 2H), 1.54 (t, 2H). Mass: m/z 449.2 (M+H)+.
  • Synthesis of SC_3396: CIS-4-(8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)indolin-2-one
  • Figure US20230303573A1-20230928-C00475
    • Step 1: CIS-4-(8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-1-(4-methoxybenzyl)indoline-2,3-dione
  • In analogy to the method described for SC_3242 CIS-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-976) was reacted with 4-bromo-1-(4-methoxy-benzyl)-1H-indole-2,3-dione to be converted into CIS-4-(8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-1-(4-methoxybenzyl)indoline-2,3-dione. Mass: m/z 539.2 (M+H)+.
    • Step 2: CIS-4-(8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-1-(4-methoxybenzyl)indolin-2-one
  • To a solution of CIS-4-(8-dimethylamino-2-oxo-8-phenyl-1,3-diaza-spiro[4.5]dec-3-yl)-1-(4-methoxy-benzyl)-1H-indole-2,3-dione (600 mg, 1.11 mmol, 1.0 eq) in EtOH (9 mL) was added hydrazine hydrate (9 mL) at RT. The reaction mixture was stirred at reflux for 16 h, then concentrated, diluted with water (50 mL) and extracted with EtOAc (200 mL). Organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography (neutral alumina, 0.5% MeOH/DCM) to afford 8-dimethylamino-3-[1-(4-methoxy-benzyl)-2-oxo-2,3-dihydro-1H-indol-4-yl]-8-phenyl-1,3-diaza-spiro[4.5]decan-2-one (275 mg, 0.52 mmol, 47%) as a brown solid. Mass: m/z 525.2 (M+H)+.
    • Step 3: CIS-4-(8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)indolin-2-one (SC_3396)
  • A solution of CIS-8-dimethylamino-3-[1-(4-methoxy-benzyl)-2-oxo-2,3-dihydro-1H-indol-4-yl]-8-phenyl-1,3-diaza-spiro[4.5]decan-2-one (275 mg, 0.52 mmol, 1.0 eq.) in TFA (4 mL) was stirred at 90°C in a sealed tube for 16 h. The reaction mixture was cooled to RT, concentrated under reduced pressure, diluted with water (50 mL), basified with sat. aq. NaHCO3 and extracted with EtOAc (200 mL). The organic phase was washed with brine (50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography (neutral alumina, 5% MeOH in DCM) to afford CIS-8-dimethylamino-3-(2-oxo-2,3-dihydro-1H-indol-4-yl)-8-phenyl-1,3-diaza-spiro[4.5]decan-2-one (SC_3396) (60 mg, 0.14 mmol, 28%) as an off-white solid. 1H NMR (DMSO-d6, 400 MHz, 100°C): δ (ppm) = 9.98 (bs, 1H), 7.36-7.22 (m, 5H), 7.09 (t, 1H, J = 7.94 Hz), 6.95-6.88 (m, 2H), 6.59 (d, 1H, J = 7.52 Hz), 3.57 (s, 2H), 3.49 (s, 2H), 2.36-2.31 (m, 2H), 2.03 (s, 6H), 1.97-1.85 (m, 4H), 1.55-1.51 (m, 2H). Mass: m/z 405.3 (M+H)+.
  • The following compounds were prepared in analogy and by combining previously described methods:
  • Example Chemical Name Reactant I Reactant II in analogy to method m/z
    [M+H]+
    SC_3001 cis-5-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carbonitrile INT-987 5-bromopyrimidine-2-carbonitrile SC-3022 445.3
    SC_3002 cis-5-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-pyrazine-2-carbonitrile INT-987 5-bromopyrazine-2-carbonitrile SC-3022 445.3
    SC 3003 cis-5-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-4-methoxy-pyrimidine-2-carbonitrile INT-987 5-bromo-4-methoxypyrimidine-2-carbonitrile SC-3022 475.3
    SC_3004 cis-5-[8-Dimethylamino-1-(2-methoxy-ethyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carbonitrile INT-980 5-bromopyrimidine-2-carbonitrile SC-3022 435.2
    SC 3005 cis-5-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carboxylic acid amide SC_3001 SC_3016 463.3
    SC_3006 cis-5-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-2-methylsulfonyl-pyrimidine-4-carbonitrile INT-987 5-bromo-2-(methylthio)-pyrimidine-4-carbonitrile SC-3022 (step 1); SC_3008 (step 2) 523.2
    SC_3007 cis-5-[1-(2-Methoxy-ethyl)-8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carbonitrile SC_3004 - SC_3045 421.2
    SC_3008 cis-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-5-methylsulfonyl-benzonitrile INT-987 2-iodo-5-(methylthio)benzonitrile (step 1) SC-3022 (step 1); SC_3008 (step 2) 521.3
    SC_3009 cis-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-benzamide SC_3090 - SC_3016 461.3
    SC_3010 cis-3-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-benzamide SC_3072 - SC_3016 461.3
    SC_3011 cis-5-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carboxylic acid amide SC_3013 - SC_3016 479.3
    SC_3012 cis-5-[1-(Cyclobutyl-methyl)-8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-4-methoxy-pyrimidine-2-carbonitrile SC_3003 - SC_3045 461.3
    SC_3013 cis-5-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carbonitrile INT-600 - SC_3013 461.3
    SC_3014 cis-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-5-carbonitrile INT-987 2-chloropyrimidine-5-carbonitrile SC_3014 445.3
    SC_3015 cis-8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-3-(2-methoxy-pyrimidin-5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one INT-976 5-bromo-2-methoxypyrimidine (step 1); 1-(tert-butyldimethyl-silyloxy)cyclobutyl)methyl 4-methylbenzene-sulfonate (step 2) SC_3013 466.3
    SC_3016 cis-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-5-carboxylic acid amide SC_3014 - SC_3016 463.3
    SC_3017 cis-4-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-methyl-benzamide SC_3081 methanamine SC_3028 475.3
    SC_3018 cis-5-(8-Dimethylamino-2-oxo-8-phenyl-1-propyl-1,3-diazaspiro[4.5]decan-3-yl)-pyrimidine-2-carbonitrile INT-600 1-bromopropane SC_3013 419.2
    SC_3019 cis-5-[8-Dimethylamino-1-(3-methoxy-propyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carbonitrile INT-600 1-bromo-3-methoxypropane SC-3013 449.3
    SC_3020 cis-5-[1-(Cyclopropyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carbonitrile INT-600 (bromomethyl)cyclopropane SC-3013 431.2
    SC_3021 cis-4-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-benzamide SC_3081 ammonia SC-3028 461.3
    SC_3022 cis-1-(Cyclobutyl-methyl)-8-dimethylamino-8-phenyl-3-[2-(trifluoromethyl)-pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2-one INT-987 5-bromo-2-(trifluoromethyl)pyrimidine SC_3022 488.3
    SC_3023 cis-8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-3-(2-hydroxy-pyrimidin-5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3015 - SC_3023 452.3
    SC_3024 cis-5-[8-Dimethylamino-1-(2-methyl-propyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carbonitrile INT-600 1-bromo-2-methylpropane SC_3013 433.3
    SC_3025 cis-5-[8-Dimethylamino-1-(2-hydroxy-ethyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carbonitrile INT-600 (3-bromopropoxy)(tert-butyl)dimethylsilane SC-3025 421.2
    SC_3026 cis-5-[1-(Cyclobutyl-methyl)-8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-4-methyl-pyridine-2-carbonitrile SC_3078 - SC_3045 444.3
    SC_3027 cis-1-(Cyclobutyl-methyl)-3-(5-methoxy-pyrazin-2-yl)-8-methylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3075 - SC_3045 436.3
    SC_3028 cis-4-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N,N-dimethyl-benzamide SC_3081 - SC_3028 489.3
    SC_3029 cis-4-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-ethyl-N-(2-hydroxy-ethyl)-benzamide SC_3081 - SC_3028 533.3
    SC_3030 cis-2-[1-(Cyclobutyl-methyl)-8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-5-methylsulfonyl-benzonitrile SC_3008 - SC_3045 507.2
    SC_3031 cis-1-(Cyclobutyl-methyl)-8-methylamino-3-[2-methylsulfonyl-4-(trifluoromethyl)-phenyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3084 - SC_3031 550.2
    SC_3032 cis-4-[1-(Cyclobutyl-methyl)-8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N,N-dimethyl-3-(trifluoromethyl)-benzenesulfonic acid amide SC_3089 - SC_3032 579.3
    SC_3033 cis-4-[1-(Cyclobutyl-methyl)-8-(ethyl-methyl-amino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-benzonitrile INT-797 4-bromobenzonitrile (step 1); (bromomethyl)cyclobutane (step 2) SC_3013 457.3
    SC_3034 cis-1-(Cyclobutyl-methyl)-8-(ethyl-methyl-amino)-8-phenyl-3-[2-(trifluoromethyl)-pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2-one INT-797 5-bromo-2-(trifluoromethyl)pyrimidine (step 1); (bromomethyl)cyclobutane (step 2) SC-3013 502.3
    SC_3035 cis-5-[1-(Cyclobutyl-methyl)-8-(ethyl-methyl-amino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carbonitrile INT-797 5-bromopyrimidine-2-carbonitrile (step 1); (bromomethyl)cyclobutane (step 2) SC_3013 459.3
    SC_3036 cis-5-[8-Dimethylamino-1-[(1-methyl-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carbonitrile INT-982 5-bromopyrimidine-2-carbonitrile SC_3022 459.3
    SC_3037 cis-2-[3-(2-Cyano-pyrimidin-5-yl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl]-N,N-dimethyl-acetamide INT-978 5-bromopyrimidine-2-carbonitrile SC_3065 462.3
    SC_3038 cis-1-(Cyclobutyl-methyl)-8-methylamino-8-phenyl-3-[2-(trifluoromethyl)-pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2-one SC_3022 - SC_3038 474.2
    SC_3039 cis-5-[8-Dimethylamino-8-(3-fluorophenyl)-1-(4-methoxy-butyl)-2-oxo-1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carbonitrile INT-601 1-bromo-4-methoxybutane SC_3064 481.3
    SC_3040 cis-5-[8-Dimethylamino-1-(3-methoxy-propyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-4-methoxy-pyrimidine-2-carbonitrile INT-979 5-bromo-4-methoxypyrimidine-2-carbonitrile SC_3022 479.3
    SC_3041 cis-5-[1-[(1-Cyano-cyclobutyl)-methyl]-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carbonitrile INT_600 (1-cyanocyclobutyl)methyl 4-methylbenzenesulfonate SC_3013 470.3
    SC_3042 cis-N-(Cyclobutyl-methyl)-5-[1-(cyclobutyl-methyl)-8-dimethylamino-8-(3-fluorophenyl)-2-oxo-1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carboxylic acid amide INT-601 (bromomethyl)cyclobutane SC_3064 549.3
    SC_3043 cis-5-[1-(3-Methoxy-propyl)-8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carbonitrile SC_3019 - SC_3043 435.2
    SC_3044 cis-5-[8-Dimethylamino-8-(3-fluorophenyl)-1-methyl-2-oxo-1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carbonitrile INT_600 iodomethane SC_3013 409.2
    SC_3045 cis-4-Methoxy-5-[1-(3-methoxy-propyl)-8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carbonitrile SC_3040 - SC_3045 465.3
    SC_3046 cis-4-[8-Dimethylamino-1-(2-methoxy-ethyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carbonitrile INT-980 4-bromopyrimidine-2-carbonitrile SC_3022 435.2
    SC_3047 cis-5-[8-Dimethylamino-1-(2-methoxy-ethyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-4-methoxy-pyrimidine-2-carbonitrile INT-980 5-bromo-4-methoxypyrimidine-2-carbonitrile SC_3022 465.3
    SC_3048 cis-4-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carbonitrile INT-987 4-bromopyrimidine-2-carbonitrile SC_3022 445.3
    SC_3049 cis-1-(Cyclobutyl-methyl)-8-dimethylamino-3-(6-methylsulfanyl-pyrimidin-4-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one INT-987 4-bromo-6-(methylthio)-pyrimidine SC_3022 466.3
    SC_3050 cis-2-[3-(2-Cyano-pyrimidin-4-yl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl]-N,N-dimethyl-acetamide SC_3022 4-bromopyrimidine-2-carbonitrile SC_3022 462.3
    SC_3051 cis-6-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-4-carbonitrile INT-987 6-bromopyrimidine-4-carbonitrile SC_3022 445.3
    SC_3052 cis-2-(8-Dimethylamino-2-oxo-3,8-diphenyl-1,3-diazaspiro[4.5]decan-1-yl)-N,N-dimethyl-acetamide INT-987 bromobenzene SC_3022 435.3
    SC_3053 cis-1-(Cyclobutyl-methyl)-8-dimethylamino-3,8-diphenyl-1,3-diazaspiro[4.5]decan-2-one INT-987 bromobenzene SC_3022 418.3
    SC_3054 cis-2-[8-Dimethylamino-1-(2-methoxy-ethyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-5-carbonitrile INT-980 5-chloropyrimidine-2-carbonitrile SC_3022 435.2
    SC_3055 cis-8-Dimethylamino-1-(2-methoxy-ethyl)-3,8-diphenyl-1,3-diazaspiro[4.5]decan-2-one INT-980 bromobenzene SC_3022 408.3
    SC_3056 cis-5-[8-Dimethylamino-1-(2-methoxy-ethyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-4-methyl-pyridine-2-carbonitrile INT-980 5-bromo-4-methylpicolinonitrile SC_3022 448.3
    SC_3057 cis-N,N-Dimethyl-2-(8-methylamino-2-oxo-3,8-diphenyl-1,3-diazaspiro[4.5]decan-1-yl)-acetamide SC_3052 - SC_3045 421.3
    SC_3058 cis-5-[1-[(1-Cyano-cyclobutyl)-methyl]-8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carbonitrile SC_3041 - SC_3058 456.2
    SC_3059 cis-5-[1-[(1-Cyano-cyclobutyl)-methyl]-8-(ethyl-methyl-amino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carbonitrile INT-797 5-bromopyrimidine-2-carbo-nitrile (step 1); 1-(bromo-methyl)cyclobutanecarbonitrile (step 2) SC_3013 484.3
    SC_3060 CIS-4-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-benzonitrile INT-987 4-bromobenzonitrile (step 1); (1-(tert-butyldimethylsilyloxy)cyclobutyl)methyl 4-methylbenzene-sulfonate (2 step) SC_3013 459.3
    SC_3061 cis-3-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-benzonitrile INT-987 3-bromobenzonitrile (step 1); (1-(tert-butyldimethylsilyloxy)cyclobutyl)methyl 4-methylbenzene-sulfonate (step 2) SC_3013 459.3
    SC_3063 cis-5-[1-[(1-Cyano-cyclobutyl)-methyl]-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-pyridine-2-carbonitrile INT-987 5-bromopicolinonitrile (step 1); 1-(bromomethyl)cyclo-butanecarbonitrile (step 2) SC_3013 469.3
    SC_3064 cis-2-[3-(2-Cyano-pyrimidin-5-yl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl]-N-propyl-acetamide INT-600 2-bromo-N-propylacetamide SC_3064 476.3
    SC_3065 cis-5-[1-(Cyclobutyl-methyl)-8-(ethyl-methyl-amino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-4-methoxy-pyrimidine-2-carbonitrile INT-986 5-bromo-4-methoxypyrimidine-2-carbonitrile SC_3065 489.3
    SC_3066 cis-4-[1-(Cyclobutyl-methyl)-8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-3-methoxy-benzonitrile SC_3080 - SC_3066 459.3
    SC_3067 cis-5-[8-Dimethylamino-1-(3-methoxy-propyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-6-methoxy-pyridine-2-carbonitrile INT-979 5-bromo-6-methoxypicolinonitrile SC_3022 478.3
    SC_3068 cis-4-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-benzamide SC_3060 - SC_3016 477.3
    SC_3069 cis-5-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-pyridine-2-carbonitrile INT-976 5-bromopicolinonitrile (step 1); 1-(tert-butyldimethyl-silyloxy)cyclobutyl)methyl 4-methylbenzene-sulfonate (step 2) SC_3013 460.3
    SC_3070 cis-5-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-[(1-hydroxy-cyclobutyl)-methyl]-pyridine-2-carboxylic acid amide INT-976 5-bromopicolinonitrile (step 1); 1-(tert-butyldimethyl-silyloxy)cyclobutyl)methyl 4-methylbenzene-sulfonate (step 2) SC_3013 562.3
    SC_3071 cis-2-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-benzonitrile INT-976 2-bromobenzonitrile (step 1); 1-(tert-butyldimethyl-silyloxy)cyclobutyl)methyl 4-methylbenzene-sulfonate (step 2) SC_3013 459.3
    SC_3072 cis-3-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-benzonitrile INT-987 3-iodobenzonitrile SC_3022 443.3
    SC_3073 cis-1-(Cyclobutyl-methyl)-8-dimethylamino-8-phenyl-3-[2-(trifluoromethyl)-pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2-one INT-987 5-bromo-2-(trifluoromethyl)pyrimidine SC_3022 488.3
    SC_3074 cis-5-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-4-methyl-pyridine-2-carboxylic acid methyl ester INT-987 methyl 5-bromo-4-methyl-picolinate SC_3022 491.3
    SC_3075 cis-1-(Cyclobutyl-methyl)-8-dimethylamino-3-(5-methoxy-pyrazin-2-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one INT-987 2-bromo-5-methoxypyrazine SC_3022 450.3
    SC_3076 cis-1-(Cyclobutyl-methyl)-8-dimethylamino-3-(2-methoxy-pyrimidin-5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one INT-987 5-bromo-2-methoxypyrimidine SC_3022 450.3
    SC_3077 cis-4-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-benzonitrile INT-987 4-iodobenzonitrile SC_3022 443.3
    SC_3078 cis-5-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-4-methyl-pyridine-2-carbonitrile INT-987 5-bromo-4-methylpicolinonitrile SC_3022 458.3
    SC_3079 cis-1-(Cyclobutyl-methyl)-8-dimethylamino-3-(5-fluoro-pyrimidin-2-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one INT-987 2-bromo-5-fluoropyrimidine SC_3022 438.3
    SC_3080 cis-4-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-3-methoxy-benzonitrile INT-987 4-bromo-3-methoxybenzonitrile SC_3022 473.3
    SC_3081 cis-4-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-benzoic acid methyl ester INT-987 methyl 4-iodobenzoate SC_3022 476.3
    SC_3082 cis-1-(Cyclobutyl-methyl)-8-dimethylamino-8-phenyl-3-(2-pyrrolidin-1-yl-pyrimidin-4-yl)-1,3-diazaspiro[4.5]decan-2-one INT-987 4-iodo-2-(pyrrolidin-1-yl)pyrimidine SC_3022 489.3
    SC_3083 cis-1-(Cyclobutyl-methyl)-8-dimethylamino-8-phenyl-3-(5-pyridin-2-yl-thiophen-2-yl)-1,3-diazaspiro[4.5]decan-2-one INT-987 2-(5-bromothiophen-2-yl)pyridine SC_3022 501.3
    SC_3084 cis-1-(Cyclobutyl-methyl)-8-dimethylamino-3-[2-methylsulfonyl-4-(trifluoromethyl)-phenyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one INT-987 1-bromo-2-(methylsulfonyl)-4-(trifluoromethyl)benzene SC_3022 564.2
    SC_3085 cis-1-(Cyclobutyl-methyl)-8-dimethylamino-8-phenyl-3-[6-(trifluoromethyl)-pyridin-3-yl]-1,3-diazaspiro[4.5]decan-2-one INT-987 5-bromo-2-(trifluoromethyl)pyridine SC_3022 487.3
    SC_3086 cis-1-(Cyclobutyl-methyl)-3-(2,4-dimethoxy-phenyl)-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one INT-987 1-bromo-2,4-dimethoxybenzene SC_3022 478.3
    SC_3087 cis-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-4-methylsulfonyl-benzonitrile INT_987 2-iodo-4-(methylthio)-benzonitrile (SC_3022) SC_3022/SC_3008 521.3
    SC_3088 cis-5-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-2-fluoro-benzonitrile INT-987 5-bromo-2-fluorobenzonitrile SC_3022 461.3
    SC_3089 cis-4-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N,N-dimethyl-3-(trifluoromethyl)-benzenesulfonic acid amide INT-987 4-bromo-N,N-dimethyl-3-(trifluoromethyl)benzenesulfonamide SC_3022 593.3
    SC_3090 cis-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-benzonitrile INT-987 2-bromobenzonitrile SC_3022 443.3
    SC_3091 cis-1-(Cyclobutyl-methyl)-8-dimethylamino-3-(2-methyl-imidazo[1,2-a]pyrazin-6-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one INT-987 6-bromo-2-methylimidazo[1,2-a]pyrazine SC_3022 473.3
    SC_3092 cis-1-(Cyclobutyl-methyl)-8-dimethylamino-3-(4-methylsulfonyl-phenyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one INT-987 (4-iodophenyl)(methyl)sulfane SC_3022/SC_3008 496.3
    SC_3093 cis-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-5-methoxy-benzonitrile INT-987 2-bromo-5-methoxybenzonitrile SC_3022 473.3
    SC_3094 cis-1-(Cyclobutyl-methyl)-8-dimethylamino-3,8-diphenyl-1,3-diazaspiro[4.5]decan-2-one INT-987 bromobenzene SC_3022 418.3
    SC_3096 cis-1-(Cyclobutyl-methyl)-8-dimethylamino-8-phenyl-3-pyrazin-2-yl-1,3-diazaspiro[4.5]decan-2-one INT-987 2-bromopyrazine SC_3022 420.3
  • Example Chemical name Reactant I Reactant II in analogy to method 1H NMR data m/z
    (M+H)+
    SC_3098 cis-8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-3-[2-(4-methyl-piperazin-1-yl)-pyrimidin-5-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one INT-799 5-bromo-2-(4-methylpiperazin-1-yl)pyrimidine SC_3097 1H NMR (DMSO-d6): δ 8.56 (s, 2H), 7.36-7.35 (m, 4H), 7.27-7.24 (m, 1H), 5.52 (s, 1H), 3.71 (s, 2H), 3.64 (m, 4H), 3.21 (s, 2H), 2.69-2.67 (m, 2H), 2.32 (m, 4H), 2.19-2.11 (m, 7H), 1.98 (s, 6H), 1.92-1.86 (m, 2H), 1.66-1.64 (m, 1H), 1.52-1.42 (m, 5H). 534.4
    SC_3101 cis-1-[(1-Hydroxy-cyclobutyl)-methyl]-8-methylamino-3-[2-(4-methyl-piperazin-1-yl)-pyrimidin-5-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3098 SC_3099 1H NMR (DMSO-d6): δ 8.58 (s, 2H), 7.48 (d, 2H), 7.32 (t, 2H), 7.19 (t, 1H), 5.61 (s, 1H), 3.75 (s, 2H), 3.66-3.64 (m, 4H), 3.30 (s, 2H), 2.35-2.32 (m, 4H), 2.25-2.19 (m, 5H), 2.12-2.07 (m, 2H), 1.90-1.88 (m, 7H), 1.79-1.73 (m, 2H), 1.65-1.63 (m, 1H), 1.50-1.44 (m, 3H) 520.4
    SC_3102 cis-1-[(1-Hydroxy-cyclobutyl)-methyl]-8-methylamino-8-phenyl-3-(2-piperazin-1-yl-pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one dihydrochloride SC_3100 SC_3099 1H NMR (DMSO-d6): δ 9.51 (br s, 2H), 9.15 (br s, 2H), 8.65 (s, 2H), 7.69-7.68 (m, 2H), 7.50-7.41 (m, 3H), 3.88-3.86 (m, 4H), 3.79 (m, 2H), 3.65 (m, 2H), 3.16-3.13 (m, 4H), 2.64-2.62 (m, 2H), 2.38-2.33 (m, 2H), 2.16-2.04 (m, 7H), 1.90-1.84 (m, 2H), 1.76-1.70 (m, 3H), 1.60-1.58 (m, 1H). 506.3
    SC_3104 cis-1-(Cyclobutyl-methyl)-8-methylamino-3-[4-methyl-6-(trifluoromethyl)-pyridin-3-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3103 SC_3099 1H NMR (DMSO-d6): δ 8.59 (s, 1H), 7.81 (s, 1H), 7.44 (d, 2H), 7.30 (t, 2H), 7.17 (t, 1H), 3.76 (s, 2H), 3.21 (d, 2H), 2.61-2.57 (m, 1H), 2.32 (s, 3H), 2.29-2.17 (m, 3H), 2.03-1.97 (m, 2H), 1.91-1.88 (m, 5H), 1.84-1.67 (m, 6H), 1.51-1.48 (m, 2H). 487.3
    SC_3106 cis-1-(Cyclopropyl-methyl)-8-methylamino-3-(4-methylsulfonyl-phenyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3105 SC_3099 1H NMR (DMSO-d6): δ 7.90-7.88 (d, 2H), 7.82-7.80 (d, 2H), 7.50-7.48 (d, 2H), 7.35-7.32 (m, 2H), 7.22-7.19 (m, 1H), 3.80 (s, 2H), 3.14-3.10 (m, 5H), 2.29-2.23 (m, 3H), 1.91-1.79 (m, 7H), 1.42-1.39 (m, 2H), 1.05-1.04 (m, 1H), 0.50-0.47 (m, 2H), 0.34-0.32 (m, 2H). 468.2
    SC_3107 cis-1-(Cyclopropyl-methyl)-8-dimethylamino-3 -(2-fluoro-4-methylsulfonyl-phenyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one INT-983 1-bromo-2-fluoro-4-(methylsulfonyl)benzene (step 1), (Bromomethyl)cyclopropane (step 2) SC3103 (step 1), SC_3105 (step 2) 1H NMR (DMSO-d6): δ 7.85 (t, 1H), 7.79-7.76 (m, 1H), 7.72-7.69 (m, 1H), 7.37-7.33 (m, 4H), 7.27-7.24 (m, 1H), 3.81 (s, 2H), 3.24 (s, 3H), 3.07 (d, 2H), 2.71-2.68 (m, 2H), 2.28-2.22 (m, 2H), 1.99 (s, 6H), 1.53-1.42 (m, 4H), 1.00-0.99 (m, 1H), 0.53-0.49 (m, 2H), 0.34-0.30 (m, 2H). 500.2
    SC_3108 cis-2-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-benzamide; formic acid SC_3071 SC_3016 1H NMR (600 MHz, DMSO) δ 7.59 - 7.55 (s, 1H), 7.47 - 7.39 (m, 2H), 7.39 - 7.31 (m, 5H), 7.30 - 7.21 (m, 3H), 3.77 - 3.73 (s, 2H), 3.21 - 3.17 (s, 1H), 2.72 - 2.66 (d, 2H), 2.17 - 2.09 (m, 5H), 2.02 - 1.99 (s, 6H), 1.95 - 1.86 (m, 2H), 1.71 - 1.60 (m, 3H), 1.49 - 1.37 (m, 3H) 477.3
    SC_3109 cis-2-[8-Dimethylamino-1-[2-(1-methoxy-cyclobutyl)-ethyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-benzamide INT988 2-bromobenzonitrile SC_3097 (step 1), SC_3109 (step 2) 1H NMR (600 MHz, DMSO) δ 7.52 - 7.48 (s, 1H), 7.47 - 7.31 (m, 7H), 7.29 - 7.23 (m, 1H), 7.25 - 7.22 (s, 1H), 7.24 - 7.18 (m, 1H), 3.68 - 3.65 (s, 3H), 3.13 - 3.10 (s, 2H), 3.09 - 3.02 (m, 2H), 2.71 - 2.65 (m, 2H), 2.21 - 2.12 (m, 2H), 2.09 - 1.99 (m, 2H), 2.02 - 1.98 (s, 6H), 1.97 - 1.86 (m, 4H), 1.77 - 1.67 (m, 1H), 1.64 - 1.52 (m, 3H), 1.44 - 1.36 (td, 2H). 505.3
    SC_3110 cis-8-Dimethylamino-1-[2-(1-methoxy-cyclobutyl)-ethyl]-3-(2-methyl-pyrimidin-5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one INT-988 5-bromo2-methyl-pyrimidine SC_3103 1H NMR (600 MHz, DMSO) δ 8.94 - 8.90 (s, 2H), 7.41 - 7.34 (d, 4H), 7.32 - 7.24 (ddd, 1H), 3.76 - 3.72 (s, 2H), 3.15 - 3.08 (m, 5H), 2.72 - 2.65 (m, 2H), 2.57 - 2.52 (s, 3H), 2.25 - 2.16 (m, 2H), 2.11 - 2.02 (m, 2H), 2.03 - 1.99 (s, 6H), 1.99 - 1.86 (m, 4H), 1.78 - 1.68 (tq, 1H), 1.65 - 1.51 (m, 3H), 1.50 - 1.44 (d, 2H). 478.3
    SC_3111 cis-5-[1-[(1-Hydroxy-cyclobutyl)-methyl]-8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carbonitrile INT-799 5-bromo-2-cyanopyrimidine SC_3103 (step 1), SC_3099 (step 2) 1H NMR (600 MHz, DMSO) δ 9.24 - 9.20 (s, 2H), 7.53 - 7.48 (m, 2H), 7.37 - 7.31 (t, 2H), 7.25 - 7.19 (t, 1H), 3.93 - 3.89 (s, 2H), 3.42 - 3.36 (m, 2H), 2.35 - 2.26 (td, 2H), 2.18 - 2.10 (tt, 2H), 2.09 - 2.04 (s, 1H), 1.97 - 1.88 (m, 2H), 1.93 - 1.90 (s, 6H), 1.86 - 1.77 (td, 2H), 1.72 - 1.62 (s, 1H), 1.59 - 1.54 (d, 1H), 1.48 - 1.43 (d, 2H). 447.3
    SC_3113 cis-4-[1-[(1-Hydroxy-cyclobutyl)-methyl]-8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-3-methoxy-benzonitrile INT-976 1-bromo-4-cyano-2-methoxybenzene (step 1) SC_3112 1HNMR (DMSO-d6, 400 MHz), δ (ppm) =7.54 (s, 1H), 7.50 (d, 1H, J = 8.16 Hz), 7.46-7.39 (m, 3H), 7.30 (t, 2H, J = 7.48 Hz), 7.18 (t, 1H, J = 7.16 Hz), 5.59 (s, 1H), 3.85 (s, 3H), 3.73 (s, 2H), 3.30 (s, 2H, merged with DMSO-water), 2.32-2.08 (m, 4H), 1.91-1.87 (m, 7H), 1.68-1.47 (m, 6H). 475.3
    SC_3114 cis-4-[8-Ethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-3-methoxy-benzonitrile INT-1008 4-Bromo-3-methoxy-benzonitrile (step 1) SC_3112 (step 1, step 2) 1HNMR (DMSO-d6, 400 MHz), δ (ppm) = 7.54 (s, 1H), 7.51-7.45 (m, 3H), 7.40 (d, 1H, J = 8.24 Hz), 7.29 (t, 2H, J = 7.58 Hz), 7.17 (t, 1H, J = 7.12 (Hz), 5.60 (s, 1H), 3.85 (s, 3H), 3.73 (s, 2H), 3.21 (s, 2H, merged with DMSO-H2O), 2.32-2.27 (m, 2H), 2.08 (bs, 5H), 1.96-1.87 (m, 4H), 1.68-1.46 (m, 6H), 0.97 (t, 3H, J = 4.0 Hz). 489.1
    SC_3115 cis-2-[8-Ethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-benzonitrile INT-1008 2-bromo-benzonitrile (step 1) SC_3112 (step 1, step 2) 1HNMR (DMSO-d6, 400 MHz), δ (ppm) = 7.82 (d, 1H, J = 7.56 Hz), 7.71 (t, 1H, J = 6.98 Hz), 7.53-7.47 (m, 3H), 7.37-7.27 (m, 3H), 7.19-7.17 (m, 1H), 5.55 (s, 1H), 3.87 (s, 2H), 3.38 (s, 2H), 2.36-2.32 (m, 2H), 2.10 (bs, 4H), 1.94-1.86 (m. 4H), 1.75-1.48 (6H), 0.98 (bs, 3H). 458.9
    SC_3116 cis-5-[1-[(1-Hydroxy-cyclobutyl)-methyl]-8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-4-methoxy-pyrimidine-2-carbonitrile INT-799 5-bromo-4-methoxy-pyrimidine-2-carbonitrile (step 1) SC_3103 (step 1), SC_3099 (step 2) 1HNMR (DMSO-d6, 400 MHz, at 100 0C), δ (ppm) = 8.79 (s, 1H), 7.46 (d, 2H, J = 7.84 Hz), 7.32 (t, 2H, J = 7.12 Hz), 7.19 (t, 1H, J = 7.28 Hz), 5.09 (bs, 1H), 4.05 (s, 3H), 3.85 (s, 2H), 3.38 (s, 2H), 2.31-2.15 (m, 4H), 1.98 (m, 7H), 1.74-1.51 (m, 6H). 477.2
    SC_3117 cis-2-[8-Dimethylamino-1-(oxetan-3-yl-methyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-benzamide SC_3274 toluene-4-sulfonic acid oxetan-3-ylmethyl ester (step 1) SC_3105 (step 1), SC_3016 (step 2) 1HNMR (DMSO-d6, 400 MHz), δ (ppm) = 7.52 (s,1H), 7.43-7.33 (m, 6H), 7.30-7.17 (m, 4H), 4.63 (t, 2H, J = 6.9 Hz), 4.39 (t, 2H, J = 6.08 Hz), 3.64 (s, 2H), 3.38 (d, 2H, J = 7.32 Hz), 3.21-3.15 (m, 1H), 2.70-2.66 (m, 2H), 2.08-1.98 (m, 8H), 1.54-1.35 (m, 4H). 463.4
    SC_3118 cis-4-Methoxy-5-(8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-pyrimidine-2-carbonitrile INT-976 5-bromo-4-methoxy-pyrimidine-2-carbonitrile (step 1) SC_3103 (step 1), SC_3099 (step 2) 1HNMR (DMSO-d6, 400 MHz), δ (ppm) = 8.80 (s, 1H), 7.86 (bs, 1H), 7.43 (d, 2H, J = 7.84 Hz), 7.32 (t, 2H, J = 7.32 Hz), 7.21-7.18 (m, 1H), 4.02 (s, 3H), 3.83 (s, 2H), 2.07-2.00 (m, 3H), 1.90-1.74 (m, 7H), 1.48 (d, 2H, J = 13.8 Hz). 393.0
    SC_3119 cis-2-(8-Methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-benzamide INT-976 2-bromo-benzonitrile (step 1) SC_3103 (step 1), SC_3099 (step 2), SC_3016(step 3) 1HNMR (DMSO-d6, 400 MHz) δ 7.51 (bs, 1H), 7.43-7.37 (m, 4H), 7.33-2.29 (m, 3H, J = 8.28 Hz), 7.22-7.16 (m, 3H), 6.93 (bs, 1H), 3.64 (s, 2H), 2.03-1.97 (m, 2H), 1.86 (bs, 5H), 1.73-1.58 (m, 4H). 379.4
    SC_3121 cis-3-(2-Cyclopropyl-pyrimidin-5-yl)-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one INT-976 5-bromo-2-cyclopropyl-pyrimidine SC_3103 1H NMR (600 MHz, DMSO) δ 8.80 (s, 2H), 7.67 (s, 1H), 7.41 - 7.32 (m, 4H), 7.31 - 7.22 (ddt, 1H), 3.60 (s, 2H), 2.42 - 2.36 (m, 2H), 2.18 - 2.08 (m, 1H), 1.98 - 1.85 (m, 4H), 1.96 (s, 6H), 1.47 (s, 2H), 0.98 - 0.91 (m, 2H), 0.93 - 0.86 (m, 2H). 392.3
    SC_3122 cis-8-Dimethylamino-3-[4-methyl-6-(trifluoromethyl)-pyridin-3-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one INT-976 5-bromo-4-methyl-2-(trifluoromethyl)pyridine SC_3103 1H NMR (600 MHz, DMSO) δ 8.57 (s, 1H), 7.79 (s, 1H), 7.52 (s, 1H), 7.40 - 7.32 (m, 4H), 7.30 - 7.22 (tt, 1H), 3.61 (s, 2H), 2.39 - 2.30 (m, 5H), 1.96 (s, 6H), 2.00 - 1.91 (m, 2H), 1.84 (s, 2H), 1.57 - 1.53 (s, 2H). 433.2
    SC_3123 cis-8-Dimethylamino-3-(2-methylsulfonyl-phenyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one INT-976 1-bromo-2-methylsulfonyl-benzene SC_3103 1H NMR (600 MHz, DMSO) δ 7.98 - 7.92 (dd, 1H), 7.81 - 7.74 (td, 1H), 7.61 - 7.54 (td, 1H), 7.52 - 7.46 (m, 2H), 7.41 - 7.31 (m, 2H), 7.35 (s, 2H), 7.29 - 7.22 (tt, 1H), 3.49 (s, 2H), 3.25 (s, 3H), 2.37 (s, 2H), 1.99 - 1.96 (m, 1H), 1.98 - 1.94 (s, 6H), 1.95 - 1.91 (d, 1H), 1.83 - 1.79 (m, 2H), 1.58 - 1.55 (s, 2H). 428.2
    SC_3124 cis-8-Dimethylamino-8-phenyl-3-(2-piperazin-1-yl-pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one INT-989 Piperazine-2-one SC_3120 1H NMR (600 MHz, DMSO) δ 8.52 (s, 2H), 7.41 - 7.31 (m, 5H), 3.59 - 3.54 (m, 4H), 3.52 (s, 2H), 2.76 - 2.70 (m, 4H), 2.55 (s, 3H), 2.49 - 2.33 (m, 2H), 1.96 (s, 6H),1.93 - 1.83 (m, 4H), 1.51- 1.43 (s, 2H). 436.3
    SC_3125 trans-2-(8-Ethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-benzamide SC_3127 SC_3016 1HNMR (DMSO-d6, 400 MHz), δ (ppm) = 7.56- 7.20 (m, 12H), 3.60 (s, 2H), 2.08-1.92 (m, 6H), 1.69 (bs, 2H), 1.56 (bs, 2H), 0.93 (t, 3H). 393.1
    SC_3126 cis--2-(8-Ethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-benzamide SC_3128 SC_3016 1HNMR (DMSO-d6, 400 MHz), δ (ppm) = 7.51-2.38 (m, 5H), 7.32 -7.30 (m, 3H), 7.22-7.18 (m, 3H), 6.93 (s, 1H), 3.63 (s, 2H), 2.07-1.98 (m, 4H), 1.86-1.72 (m, 4H), 1.60-1.57 (m, 2H), 0.93 (t, 3H). 393.4
    SC_3127 cis-2-(8-Ethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-benzonitrile INT-1009 2-bromo-benzonitrile SC_3103 1HNMR (DMSO-d6, 400 MHz), δ (ppm) = 7.77 (d, 1H, J= 6.8 Hz), 7.69-7.65 (m, 1H), 7.51 (d, 1H, J= 8.4 Hz), 7.44 (d, 2H, J = 7.6 Hz), 7.39 (s, 1H), 7.34-7.28 (m, 3H), 7.17 (t, 1H, 7.2 Hz), 3.77 (s, 2H), 2.10-2.04 (m, 4H), 1.91-1.88 (m, 2H), 1.80-1.74 (m, 3H), 1.61-1.58 (m, 2H), 0.94 (t, 3H, J = 6.8 Hz). 375.1
    SC_3128 cis-2-(8-Ethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-benzonitrile INT-1008 2-bromo-benzonitrile SC_3103 1HNMR (DMSO-d6, 400 MHz), δ (ppm) = 7.89 (bs, 1H), 7.79 (d,1H, J = 7.6), 7.69 (t, 1H, J = 7.6 Hz), 7.54-7.50 (m, 3H), 7.36-7.30 (m, 3H), 7.18 (t, 1H, J = 7.2 Hz), 3.73 (s, 2H), 2.08-1.92 (m, 7H), 1.71 (bs, 2H), 1.59 (bs, 2H,), 0.93 (t, 3H, J = 6.4 Hz). 375.1
    SC_3131 cis-3-[5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-pyrimidin-2-yl]-benzamide SC_3129 SC_3016 1H NMR (600 MHz, DMSO) δ 9.11 (s, 2H), 8.79 (t, 1H), 8.43 (dt, 1H), 8.09 (s, 1H), 7.94 (dt, 1H), 7.84 (s, 1H), 7.56 (t, 1H), 7.41 - 7.35 (m, 4H), 7.28 (ddd, 1H), 3.72 (s, 2H), 2.00 - 1.84 (m, 2H), 1.98 (s, 6H), 1.53 (s, 2H). 471.3
    SC_3134 trans-4-(8-Ethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-3-methoxy-benzonitrile INT-1009 4-Bromo-3-methoxy-benzonitrile SC_3103 1HNMR (DMSO-d6, 400 MHz), δ (ppm) = 7.71 (bs, 1H), 7.56-7.49 (m, 4H), 7.37 (d, 1H, J = 6.6 Hz), 7.31 (t, 2H, J = 7.10 Hz), 7.19-7.17 (m, 1H), 3.87 (s, 3H), 3.62 (s, 2H), 2.06-1.90 (m, 7H), 1.69-1.53 (m, 4H), 0.92 (t, 3H, J = 6.70 Hz). 405.3
    SC_3135 cis-4-(8-Ethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-3-methoxy-benzonitrile INT-1008 4-Bromo-3-methoxy-benzonitrile SC_3103 1HNMR (DMSO-d6, 400 MHz), δ (ppm) = 7.52-7.50 (m, 2H), 7.44-7.43 (m, 2H), 736 (d, 1H, J = 8.04 Hz), 7.30-7.19 (m, 4H), 3.83 (s, 3H), 3.63 (s, 2H), 2.05-1.72 (m, 8H), 1.53-1.50 (m, 2H), 0.92 (t, 3H). 405.2
    SC_3136 cis-3-[2-(4-Acetyl-piperazin-1-yl)-pyrimidin-5-yl]-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3124 acetyl chloride SC_3130 478.3
    SC_3137 cis-8-Dimethylamino-8-phenyl-3-(2-pyridin-4-yl-pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one INT-989 pyridine-4-boronic acid SC_3129 1HNMR (600 MHz, DMSO) δ 9.16 (s, 2H), 8.70 (d, 1H), 8.18 (s, 1H), 7.91 (s, 1H), 7.42 - 7.35 (m, 4H), 7.28 (tt, 1H), 3.73 (s, 2H), 2.49 - 2.37 (m, 2H), 1.98 (s, 6H), 2.01 - 1.87 (m, 2H), 1.58 - 1.47 (m, 2H). 429.2
    SC_3138 cis-8-Dimethylamino-8-phenyl-3-(2-pyridin-3-yl-pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one INT-989 pyridine-3-boronic acid SC_3129 1HNMR (600 MHz, DMSO) δ 9.43 (dd, 1H), 9.13 (s, 2H), 8.65 (dd, 1H), 8.58 (dt,1H), 7.52 (ddd, 1H), 7.42 - 7.36 (m, 4H), 7.28 (ddd, 1H), 3.72 (s, 2H), 1.98 (s, 6H), 2.02 - 1.89 (m, 4H), 1.57 - 1.46 (m, 4H). 429.2
    SC_3139 cis-5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-N-(2-hydroxy-ethyl)-pyrimidine-2-carboxylic acid amide INT-991 2-aminoethanol SC_3133 1HNMR (600 MHz, DMSO) δ 9.08 (s, 2H), 8.59 (t, 1H), 7.94 (s, 1H), 7.43 - 7.30 (m, 5H), 7.30 - 7.21 (m, 1H), 3.72 (s, 2H), 3.51 (q, 2H), 2.49 - 2.37 (m, 2H), 2.00 - 1.90 (m, 10H), 1.89 - 1.74 (m, 2H), 1.57 - 1.48 (m, 2H), 1.38 - 1.32 (m, 1H). 439.3
    SC_3141 cis-8-Dimethylamino-3-[2-morpholin-4-yl-4-(trifluoromethyl)-pyrimidin-5-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one INT-976 4-[5-bromo-4-(trifluoromethyl)pyrimidin-2-yl]morpholine SC_3103 1HNMR (600 MHz, DMSO) δ 8.59 (d, 1H), 7.39 - 7.35 (m, 5H), 7.27 (d, 1H), 3.73 (t, 4H), 3.67 (q, 4H), 3.28 - 3.22 (m, 1H), 2.41 - 2.28 (m, 2H), 1.98 (s, 6H), 1.94 - 1.80 (m, 3H), 1.53 - 1.42 (m, 2H). 505.3
    SC_3142 cis-4-[5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-pyrimidin-2-yl] -benzonitrile INT-989 4-cyanophenylboronic acid SC_3129 1HNMR (600 MHz, DMSO) δ 9.15 (s, 2H), 8.49 - 8.43 (m, 2H), 7.99 - 7.92 (m, 2H), 7.89 (s, 1H), 7.38 (m, 4H), 7.28 (td, 1H), 3.73 (s, 2H), 2.48 - 2.35 (m, 1H), 2.03 - 1.90 (m, 10H), 1.55 - 1.48 (m,2H). 453.2
    SC_3143 cis-5-(8-Ethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-4-methoxy-pyrimidine-2-carbonitrile INT-1008 5-Bromo-4-methoxy-pyrimidine-2-carbonitrile SC_3103 (DMSO-d6, 400 MHz), δ (ppm) = 8.79 (s, 1H), 7.60 (s, 1H), 7.41 (d, 2H, J = 7.72 Hz), 7.28 (t, 2H, J = 7.54 Hz), 7.16 (t, 1H, J = 7.32 Hz), 3.97 (s, 3H), 3.72 (s, 2H), 2.02 (bs, 4H), 1.90-1.69 (m, 5H), 1.51-1.48 (m, 2H), 0.89 (t, 3H, J = 6.56 Hz). 407.2
    SC_3144 trans-5-(8-Ethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-4-methoxy-pyrimidine-2-carbonitrile INT-1009 5-Bromo-4-methoxy-pyrimidine-2-carbonitrile SC_3103 1HNMR (DMSO-d6, 400 MHz), δ (ppm) = 8.87 (s, 1H), 8.10 (bs, 1H), 7.50 (d, 2H, J = 7.52 Hz), 7.31 (t, 2H, J = 7.20 Hz), 7.18 (t, 1H, J = 6.88 Hz), 4.04 (s, 3H), 3.74 (s, 2H), 2.07-1.95 (m, 6H), 1.70-1.54 (m, 4H), 0.93 (t, 3H, J = 6.62 Hz). 407.3
    SC_3145 cis-8-Dimethylamino-3-[2-(morpholine-4-carbonyl)-pyrimidin-5-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one INT-991 morpholine SC_3133 1HNMR (600 MHz, DMSO) δ 9.04 (s, 2H), 7.88 (s, 1H), 7.42 - 7.30 (m, 5H), 7.30 - 7.22 (m, 1H), 3.75 - 3.58 (m, 6H), 3.51 (t, 2H), 3.20 (t, 2H), 2.50 - 2.33 (m, 2H), 1.99 - 1.90 (m, 8H), 1.89 - 1.74 (m, 2H), 1.54 - 1.44 (m, 2H). 478.3
    SC_3147 cis-8-Dimethylamino-3-[2-(methylsulfonyl-methyl)-phenyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one INT-976 1-bromo-2-(methylsulfonylmethyl)benzene SC_3103 1HNMR (600 MHz, DMSO) δ 7.47 (d, 1H), 7.42 - 7.31 (m, 6H), 7.30 - 7.22 (m, 3H), 4.50 (s, 2H), 3.56 (s, 2H), 2.88 (s, 3H), 2.42 - 2.28 (m, 2H), 2.07 (s, 2H), 1.98 - 1.90 (m, 8H), 1.89 - 1.69 (m, 2H), 1.61 - 1.48 (d, 2H). 442.2
    SC_3148 cis-8-Dimethylamino-3-(4-methyl-2-morpholin-4-yl-pyrimidin-5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one INT-992 morpholine SC_3120 1HNMR (600 MHz, DMSO) δ 8.14 (s, 1H), 7.40 - 7.32 (m, 4H), 7.26 (td, 1H), 7.21 (s, 1H), 3.69 - 3.60 (m, 8H), 3.38 (s, 2H), 2.41 - 2.27 (m, 2H), 2.20 (s, 3H), 1.97 (s, 6H), 1.95 - 1.76 (m, 4H), 1.54 - 1.45 (s, 2H). 451.3
    SC_3149 cis-8-Dimethylamino-3-[2-(1,1-dioxo-[1,4]thiazinan-4-yl)-pyrimidin-5-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one INT-989 thiomorpholine-1,1-dioxide hydrochloride SC_3120 1H NMR (600 MHz, DMSO) δ 8.63 (s, 2H), 7.50 (br s, 1H), 7.41 - 7.33 (m, 4H), 7.27 (td, 1H), 4.17 - 4.12 (m, 4H), 3.55 (s, 2H), 3.12 - 3.06 (m, 4H), 2.47 - 2.27 (m, 2H), 2.04 - 1.74 (m, 10H), 1.51 - 1.42 (m, 2H). 485.2
    SC_3150 cis-8-Dimethylamino-3-(4-fluoro-pyridin-3-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one INT-976 3-bromo-4-fluoro-pyridine SC_3103 1HNMR (600 MHz, DMSO) δ 8.70 (d, 1H), 8.36 (dd, 1H), 7.54 (s, 1H), 7.36 (td, 5H), 7.26 (s, 1H), 3.61 (s, 2H), 2.44 - 2.28 (m, 2H), 2.01 - 1.74 (m, 10H), 1.92 (d, 2H), 1.56 - 1.45 (m, 2H). 369.2
    SC_3151 cis-5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-N-(2-hydroxy-ethyl)-N-methyl-pyrimidine-2-carboxylic acid amide INT-991 2-(methylamino)ethanol SC_3133 1HNMR (600 MHz, DMSO) δ 9.03 (d, 2H), 7.86 (s, 1H), 7.40 - 7.23 (m, 5H), 3.69 (s, 2H), 3.61 (q, 1H), 3.50 (t, 1H), 3.45 (d, 1H), 3.17 (t, 1H), 3.01 and 2.83 (both s, together 3H, amide rotamers), 2.49 - 2.36 (m, 2H), 2.00 - 1.89 (m, 8H), 1.89 - 1.73 (m, 2H), 1.55 - 1.47 (m, 2H). 453.2
    SC_3152 cis-5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-2-morpholin-4-yl-isonicotinonitrile INT-976 5-bromo-2-morpholino-pyridine-4-carbonitrile SC_3103 1H NMR (600 MHz, DMSO) δ 8.24 (s, 1H), 7.67 - 7.30 (m, 5H), 7.29 (s, 1H), 3.70 - 3.65 (m, 4H), 3.51 - 3.44 (m, 4H), 2.37 - 2.22 (m, 2H), 2.10 - 1.87 (m, 10H), 1.53 - 1.31 (m, 2H). 461.3
    SC_3153 cis-4-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-benzamide SC_3272 SC_3016 1HNMR (600 MHz, DMSO) δ 7.79 (d, 2H), 7.62 (d, 2H), 7.41 - 7.34 (m, 4H), 7.27 (td, 1H), 7.13 - 7.09 (m, 1H), 3.62 (s, 2H), 2.46 - 2.35 (m, 2H), 1.97 (s, 6H), 1.93 - 1.76 (m, 4H), 1.51 - 1.45 (m, 2H). 393.2
    SC_3154 cis-8-Dimethylamino-3-(2-fluoro-4-methylsulfonyl-phenyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one INT-976 1-bromo-2-fluoro-4-methylsulfonyl-benzene SC_3103 1H NMR (600 MHz, DMSO) δ 7.89 - 7.83 (m, 1H), 7.76 (dd, 1H), 7.70 (dd, 1H), 7.40 - 7.32 (m, 5H), 7.29 - 7.23 (m, 1H), 3.69 (s, 2H), 3.23 (s, 3H), 2.43 - 2.30 (m, 2H), 1.96 (s, 6H), 1.94 - 1.88 (m, 2H), 1.53 - 1.47 (m, 2H). 446.2
    SC_3155 cis-4-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-3-fluoro-benzonitrile INT-976 4-bromo-3-fluoro-benzonitrile SC_3103 1H NMR (600 MHz, DMSO) δ 7.85 - 7.79 (m, 2H), 7.73 (s, 1H), 7.62 (dd, 1H), 7.40 - 7.31 (m, 4H), 7.26 (tt, 1H), 3.69 (s, 2H), 2.40 - 2.31 (m, 2H), 1.95 (s, 6H), 1.94 - 1.87 (m, 2H), 1.87 - 1.75 (m, 2H), 1.52 - 1.46 (m, 2H). 393.2
    SC_3156 cis-4-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-3,5-difluoro-benzonitrile INT-976 4-bromo-3,5-difluoro-benzonitrile SC_3103 1HNMR (600 MHz, DMSO) δ 7.85 (d, 2H), 7.61 (s, 1H), 7.39 - 7.31 (m, 4H), 7.25 (tt, 1H), 3.53 (s, 2H), 2.42 - 2.33 (m, 2H), 1.98 - 1.89 (m, 8H), 1.82 - 1.78 (m, 2H), 1.54 - 1.47 (m, 2H). 411.2
    SC_3157 cis-8-Dimethylamino-3-(2-methoxy-pyrimidin-5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one INT-989 methanol instead of n-butanol as a solvent SC_3120 1HNMR (600 MHz, DMSO) δ 8.76 (s, 2H), 7.41 - 7.33 (m, 5H), 7.27 (ddt, 1H), 3.86 (s, 3H), 3.60 (s, 2H), 2.47 - 2.30 (m, 2H), 2.01 - 1.74 (m, 10H), 1.52 - 1.45 (m, 2H). 382.2
    SC_3158 cis-3-[2-(Benzylamino)-pyrimidin-5-yl]-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one INT-989 benzylamine SC_3120 1H NMR (600 MHz, DMSO) δ 8.43 (s, 2H), 7.50 - 7.45 (m, 1H), 7.46 - 7.33 (m, 5H), 7.31 - 7.23 (m, 4H), 7.19 (tq, 1H), 4.46 (d, 2H), 4.02 (s, 1H), 3.50 (s, 2H), 2.41 - 2.31 (m, 2H), 1.97 (s, 6H), 1.88 (s, 2H), 1.49 - 1.41 (m, 2H). 457.3
    SC_3159 cis-8-Dimethylamino-3-[2-(4-fluorophenyl)-pyrimidin-5-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one INT-989 (4-fluorophenyl)boronic acid SC_3129 1HNMR (600 MHz, DMSO) δ 9.07 (s, 2H), 8.37 - 8.30 (m, 2H), 7.83 (s, 1H), 7.44 - 7.35 (m, 4H), 7.34 - 7.25 (m, 3H), 3.69 (s, 2H), 2.47 - 2.30 (m, 2H), 2.08 - 1.80 (m, 10H), 1.55 - 1.46 (m, 2H). 446.2
    SC_3160 trans-8-Benzyl-8-dimethylamino-3-(2-morpholin-4-yl-pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one INT-995 4-(5-bromopyrimidin-2-yl)morpholine SC_3103 1HNMR (600 MHz, DMSO) δ 8.57 (s, 2H), 7.60 (s, 1H), 7.27 (t, 2H), 7.22 - 7.15 (m, 3H), 3.68 - 3.62 (m, 4H), 3.64 - 3.57 (m, 4H), 3.49 (s, 2H), 2.66 (s, 2H), 2.22 (s, 6H), 1.80 - 1.70 (m, 4H), 1.51 - 1.43 (m, 4H). 451.3
    SC_3161 cis-8-Benzyl-8-dimethylamino-3-(2-morpholin-4-yl-pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one INT-994 4-(5-bromopyrimidin-2-yl)morpholine SC_3103 1H NMR (600 MHz, DMSO) δ 8.45 (s, 2H), 7.27 (t, 2H), 7.22 - 7.15 (m, 3H), 7.11 (s, 1H), 3.68 - 3.56 (m, 8H), 2.64 (s, 2H), 2.26 (s, 6H), 1.87 - 1.77 (m, 4H), 1.42 (d, 2H), 1.15 (dt, 2H). 451.3
    SC_3163 cis-4-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-3,5-difluoro-benzamide SC_3156 SC_3016 1H NMR (600 MHz, DMSO) δ 8.08 (s, 1H), 7.65 - 7.58 (m, 2H), 7.48 (br s, 1H), 7.39 - 7.31 (m, 4H), 7.28 - 7.22 (m, 1H), 3.49 (s, 2H), 2.40 - 2.32 (m, 2H), 1.96 (s, 6H), 1.95 - 1.90 (m, 2H), 1.87 - 1.77 (m, 2H), 1.54 - 1.49 (m, 2H). 429.2
    SC_3164 cis-4-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-3-fluoro-benzamide SC_3155 SC_3016 1H NMR (600 MHz, DMSO) δ 7.95 (s, 1H), 7.72 - 7.64 (m, 2H), 7.61 (t, 1H), 7.54 - 7.50 (m, 1H), 7.40 - 7.32 (m, 5H), 7.26 (tt, 1H), 3.62 (s, 2H), 2.41 - 2.31 (m, 2H), 1.96 (s, 6H), 1.93 - 1.88 (m, 2H), 1.86 - 1.75 (m, 2H), 1.53 - 1.45 (m, 2H). 411.2
    SC_3165 cis-8-Benzyl-8-dimethylamino-3-[2-(trifluoromethyl)-pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2-one INT-994 5-bromo-2-(trifluoromethyl)pyrimidine SC_3103 1HNMR (600 MHz, DMSO) δ 9.07 (s, 2H), 7.77 (s, 1H), 7.29 (t, 2H), 7.24 - 7.17 (m, 3H), 3.55 (s, 2H), 2.66 (s, 2H), 2.26 (s, 6H), 1.86 (dt, 4H), 1.44 (d, 2H), 1.25 - 1.17 (m, 2H). 434.2
    SC_3166 trans-8-Benzyl-8-dimethylamino-3-[2-(trifluoromethyl)-pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2-one INT-995 5-bromo-2-(trifluoromethyl)pyrimidine SC_3103 1HNMR (600 MHz, DMSO) δ 9.16 (s, 2H), 8.28 (s, 1H), 7.27 (t, 2H), 7.22 - 7.16 (m, 3H), 3.67 (s, 2H), 2.66 (s, 2H), 2.24 (s, 6H), 1.84 - 1.72 (m, 4H), 1.49 (q, 4H). 434.2
    SC_3167 cis-8-Dimethylamino-8-thiophen-2-yl-3-[2-(trifluoromethyl)-pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2-one INT-997 5-bromo-2-(trifluoromethyl)pyrimidine SC_3103 1HNMR (600 MHz, DMSO) δ 9.19 (d, 2H), 7.97 (s, 1H), 7.43 (t, 1H), 7.07 (dd, 1H), 6.97 (d, 1H), 3.78 (s, 2H), 2.40 - 2.27 (m, 2H), 2.04 (s, 6H), 1.96 (t, 2H), 1.90 - 1.79 (m, 2H), 1.60 - 1.52 (m, 2H). 426.1
    SC_3168 trans-8-Dimethylamino-8-thiophen-2-yl-3-[2-(trifluoromethyl)-pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2-one INT-998 5-bromo-2-(trifluoromethyl)pyrimidine SC_3103 1HNMR (600 MHz, DMSO) δ 9.20 (s, 2H), 8.00 (s, 1H), 7.45 (dd, 1H), 7.09 (dd, 1H), 7.02 - 6.97 (m, 1H), 3.81 (s, 2H), 2.12 (d, 4H), 2.03 (s, 6H), 1.85 (t, 2H), 1.62 - 1.54 (m, 2H). 426.1
    SC_3170 cis-8-Dimethylamino-8-phenyl-3-(2-piperidin-1-yl-pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one INT-989 piperidine SC_3120 1H NMR (DMSO-d6): δ 8.49 (s, 2H), 7.39-7.24 (m, 6H), 3.65-3.63 (m, 4H), 3.50 (s, 2H), 2.36-2.32 (m, 2H), 1.95-1.86 (m, 10H), 1.61-1.56 (m, 2H), 1.50-1.44 (m, 6H). 435.3
    SC_3171 cis-8-Dimethylamino-8-phenyl-3-(2-pyrrolidin-1-yl-pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one INT-989 pyrrolidine SC_3120 1H NMR (CDCl3): δ 8.43 (s, 2H), 7.41-7.38 (m, 2H), 7.32-7.30 (m, 3H), 5.05 (br s, 1H), 3.53 (t, 4H), 3.45 (s, 2H), 2.30-2.06 (m, 10H), 1.99-1.96 (m, 6H), 1.62-1.58 (m, 2H). 421.3
    SC_3172 cis-8-Dimethylamino-8-phenyl-3-(2-pyrimidin-5-yl-pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one INT-989 pyrimidin-5-ylboronic acid SC_3129 1H NMR (600 MHz, DMF) δ 9.56 (s, 2H), 9.27 (s, 1H), 9.17 (s, 2H), 8.35 (s, 1H), 7.89 (d, 2H), 7.63 (dq, 3H), 3.73 (s, 2H), 3.04 (d, 2H), 2.81 (s, 6H), 2.57 (td, 2H), 2.06 (d, 2H), 1.58 (td, 2H). 430.2
    SC_3174 trans-8-Benzyl-8-dimethylamino-3-[4-methyl-6-(trifluoromethyl)-pyridin-3-yl]-1,3-diazaspiro[4.5]decan-2-one INT-995 5-bromo-4-methyl-2-(trifluoromethyl)pyridine SC_3103 1H NMR (600 MHz, DMSO) δ 8.57 (s, 1H), 7.80 (s, 1H), 7.67 (s, 1H), 7.27 (t, 2H), 7.23 - 7.15 (m, 3H), 3.58 (d, 2H), 2.67 (s, 2H), 2.31 (s, 3H), 2.22 (d, 6H), 1.82 - 1.72 (m, 4H), 1.56 (dd, 2H), 1.48 (td, 2H). 447.2
    SC_3175 cis-5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-2-morpholin-4-yl-pyridine-4-carboxylic acid amide SC_3152 SC_3016 480.6
    SC_3176 cis-8-Dimethylamino-3-[2-(3,5-dimethyl-isoxazol-4-yl)-pyrimidin-5-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one INT-989 (3,5-dimethylisoxazol-4-yl)boronic acid SC_3129 1HNMR (600 MHz, DMSO) δ 9.05 (s, 2H), 7.80 (s, 1H), 7.43 - 7.34 (m, 4H), 7.28 (tt, 1H), 3.68 (s, 2H), 2.69 (s, 3H), 2.47 (s, 3H), 2.43 - 2.35 (m, 2H), 2.01 - 1.79 (m, 10H), 1.50 (s, 2H). 447.2
    SC_3177 cis-3 - [2-(Benzothiazol-6-yl)-pyrimidin-5-yl]-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one INT-989 1,3-benzothiazol-6-ylboronic acid SC_3129 1H NMR (600 MHz, DMSO) δ 9.46 (s, 1H), 9.12 (s, 2H), 9.07 (s, 1H), 8.49 (d, 1H), 8.16 (d, 1H), 7.84 (s, 1H), 7.39 (d, 4H), 7.29 (d, 1H), 3.73 (s, 2H), 2.42 (d, 2H), 1.97 (d, 10H), 1.54 (d, 2H). 485.2
    SC_3178 cis-8-Dimethylamino-3-[2-fluoro-4-(trifluoromethyl)-phenyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one INT-976 1-bromo-2-fluoro-4-(trifluoromethyl)benzene SC_3103 1H NMR (600 MHz, DMSO) δ 7.80 (t, 1H), 7.65 (dd, 1H), 7.53 (dd, 1H), 7.40 - 7.32 (m, 4H), 7.29 - 7.23 (m, 1H), 3.66 (s, 2H), 2.36 (s, 2H), 1.97 - 1.88 (m, 8H), 1.85 - 1.75 (m, 2H), 1.53 - 1.46 (m, 2H). 436.2
    SC_3179 cis-8-Dimethylamino-3-(6-morpholin-4-yl-pyridin-3-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one INT-976 4-(5-bromo-2-pyridyl)morpholine as SC_3097 step 2 1HNMR (600 MHz, DMSO) δ 8.20 (d, 1H), 7.89 (dd, 1H), 7.37 (p, 5H), 7.27 (d, 1H), 6.79 (d, 1H), 3.71 - 3.66 (m, 4H), 3.53 (s, 2H), 2.43 - 2.32 (m, 2H), 1.96 (s, 7H), 1.91 - 1.85 (m, 5H), 1.49 - 1.42 (m, 2H). 436.3
    SC_3180 cis-8-Dimethylamino-8-phenyl-3-(2-phenyl-thiazol-4-yl)-1,3-diazaspiro[4.5]decan-2-one INT-976 4-bromo-2-phenylthiazole SC_3103 1HNMR (DMSO-d6): δ 7.89-7.87 (m, 2H), 7.55 (br s, 1H), 7.43-7.35 (m, 8H), 7.29-7.26 (m, 1H), 3.82 (s, 2H), 2.45 (br m, 2H), 1.96-1.79 (m, 10H), 1.53-1.50 (m, 2H). 433.2
    SC_3181 cis-8-Dimethylamino-8-phenyl-3-[2-(tetrahydro-pyran-4-ylamino)-pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2-one INT-989 tetrahydro-2H-pyran-4-amine SC_3103 1H NMR (DMSO-d6): δ 8.42 (s, 2H), 7.39-7.35 (m, 5H), 7.27-7.24 (m, 1H), 6.83 (d, 1H), 3.84-3.79 (m, 3H), 3.50 (s, 2H), 3.38-3.35 (m, 2H), 2.36-2.32 (m, 2H), 1.94-1.77 (m, 12H), 1.50-1.40 (m, 4H). 451.3
    SC_3183 cis-8-Dimethylamino-8-phenyl-3-(4-phenyl-thiazol-2-yl)-1,3-diazaspiro[4.5]decan-2-one INT-976 2-bromo-4-phenylthiazole SC_3103 1H NMR (DMSO-d6): δ 8.09 (br s, 1H), 7.87 (d, 2H), 7.51 (s, 1H), 7.37-7.24 (m, 8H), 3.87 (s, 2H), 2.43 (m, 2H), 1.96-1.84 (m, 10H), 1.54 (m, 2H). 433.2
    SC_3184 cis-8-Dimethylamino-8-phenyl-3-[2-(1H-pyrrolo[2,3-b]pyridin-1-yl)-pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2-one INT-976 1H-pyrrolo[2,3-b]pyridine SC_3103 1H NMR (DMSO-d6): δ 9.07 (s, 2H), 8.35-8.33 (m, 1H), 8.10-8.04 (m, 2H), 7.83 (br s, 1H), 7.41-7.37 (m, 4H), 7.29-7.21 (m, 2H), 6.72-6.71 (d, 1H), 3.71 (s, 2H), 2.49 (m, 2H), 1.97 (m, 10H), 1.52 (m, 2H). 468.2
    SC_3185 cis-8-Dimethylamino-8-phenyl-3-[2-(3,4,5-trifluoro-phenyl)-pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2-one INT-989 (3,4,5-trifluorophenyl)boronic acid SC_3129 1HNMR (600 MHz, DMSO) δ 9.11 (s, 2H), 8.12 - 8.03 (m, 2H), 7.89 (s, 1H), 7.42 - 7.34 (m, 4H), 7.28 (dq, 1H), 3.71 (s, 2H), 2.48 - 2.35 (m, 2H), 1.99 - 1.79 (m, 10H), 1.58 - 1.47 (m, 2H). 481.2
    SC_3187 cis-8-Dimethylamino-3-m-tolyl-8-phenyl-1,3-diazaspiro[4.5]decan-2-one INT-976 1-bromo-3-methylbenzene SC_3186 363.2
    SC_3188 cis-8-Dimethylamino-8-phenyl-3-p-tolyl-1,3-diazaspiro[4.5]decan-2-one INT-976 1-bromo-4-methylbenzene SC_3186 363.2
    SC_3189 cis-8-Dimethylamino-8-phenyl-3-[4-(trifluoromethyl)-phenyl]-1,3-diazaspiro[4.5]decan-2-one INT-976 1-bromo-4-trifluoromethylbenzene SC_3186 417.2
    SC_3190 cis-8-Dimethylamino-8-phenyl-3-[3-(trifluoromethyloxy)-phenyl]-1,3-diazaspiro[4.5]decan-2-one INT-976 1-bromo-3-(trifluoromethoxy)benzene SC_3186 433.2
    SC_3191 cis-8-Dimethylamino-8-phenyl-3-[4-(trifluoromethyloxy)-phenyl]-1,3-diazaspiro[4.5]decan-2-one INT-976 1-bromo-4-(trifluoromethoxy)benzene SC_3186 433.2
    SC_3192 cis-2-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-benzoic acid methyl ester INT-976 methyl 2-bromobenzoate SC_3186 407.2
    SC_3193 cis-3-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-benzoic acid methyl ester INT-976 methyl 3-bromobenzoate SC_3186 407.2
    SC_3194 cis-4-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-benzoic acid methyl ester INT-976 methyl 4-bromobenzoate SC_3186 407.2
    SC_3195 cis-3-(1,3-Benzodioxol-5-yl)-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one INT-976 5-bromobenzo[d][1,3]dioxole SC_3186 393.2
    SC_3196 cis-8-Dimethylamino-8-phenyl-3-quinolin-5-yl-1,3-diazaspiro[4.5]decan-2-one INT-976 5-bromoquinoline SC_3186 400.2
    SC_3197 cis-3-(2,3-Dihydro-1H-indol-6-yl)-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one INT-976 6-bromoindoline SC_3186 390.2
    SC_3198 cis-5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-4-methyl-pyridine-2-carboxylic acid methyl ester INT-976 methyl 5-bromo-4-methylpicolinate SC_3186 422.2
    SC_3199 cis-8-Dimethylamino-3-(6-methoxy-4-methyl-pyridin-3-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one INT-976 5-bromo-2-methoxy-4-methylpyridine SC_3186 394.2
    SC_3200 cis-8-Dimethylamino-3-[2-methyl-5-(trifluoromethyl)-2H-pyrazol-3-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one INT-976 5-bromo-1-methyl-3-(trifluoromethyl)-1H-pyrazole SC_3186 421.2
    SC_3201 cis-8-Dimethylamino-3-(3-methoxy-pyridin-2-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one INT-976 2-bromo-3-methoxypyridine SC_3186 380.2
    SC_3202 cis-8-Dimethylamino-8-phenyl-3-[5-(trifluoromethyl)-pyridin-2-yl]-1,3-diazaspiro[4.5]decan-2-one INT-976 2-bromo-5-trifluoromethylpyridine SC_3186 418.2
    SC_3203 cis-5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-nicotinonitrile INT-976 3-bromo-5-cyanopyridine SC_3186 375.2
    SC_3204 cis-8-Dimethylamino-3-(3-methyl-pyridin-2-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one INT-976 2-bromo-3-methylpyridine SC_3186 364.2
    SC_3205 cis-8-Dimethylamino-3-(6-methoxy-pyridin-3-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one INT-976 5-bromo-2-methoxypyridine SC_3186 380.2
    SC_3206 cis-8-Dimethylamino-8-phenyl-3-[3-(trifluoromethyl)phenyl]-1,3-diazaspiro[4.5]decan-2-one INT-976 1-bromo-3-trifluoromethylbenzene SC_3186 417.2
    SC_3207 cis-3-(1,3-Benzodioxol-4-yl)-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one INT-976 4-bromobenzo[d][1,3]dioxole SC_3186 393.2
    SC_3209 cis-8-Dimethylamino-3-[2-(3,5-dimethyl-1H-pyrazol-1-yl)-pyrimidin-5-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one INT-976 3,5-dimethyl-1H-pyrazole SC_3103 1HNMR (DMSO-d6): δ 9.00 (s, 2H), 7.81 (br s, 1H), 7.38-7.27 (m, 5H), 6.07 (s, 1H), 3.69 (s, 2H), 2.45 (m, 5H), 2.17 (s, 3H), 1.96-1.91 (m, 10H), 1.51 (br m,2H). 446.2
    SC_3210 cis-8-Dimethylamino-3-[2-(3-hydroxy-piperidin-1-yl)-pyrimidin-5-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one INT-989 rac-piperidin-3-ol SC_3182 1H NMR (DMSO-d6): 8.48 (s, 2H), 7.39-7.35 (m, 5H), 7.27-7.24 (m, 1H), 4.82 (d, 1H), 4.39-4.36 (m, 1H), 4.24-4.21 (m, 1H), 3.51 (s, 2H), 3.41-3.36 (m, 1H), 2.92-2.87 (m, 1H), 2.77-2.72 (m, 1H), 2.42-2.32 (m, 2H), 2.00-1.66 (m, 12H), 1.46-1.39 (m, 2H), 1.34 (t, 2H). 451.2
    SC_3211 cis-8-Dimethylamino-3-[2-(3-hydroxy-piperidin-1-yl)-pyrimidin-5-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one INT-989 rac-piperidin-3-ol SC_3182 1H NMR (DMSO-d6): 8.48 (s, 2H), 7.35 (m, 5H), 7.25 (m, 1H), 4.82 (d, 1H), 4.39-4.37 (m, 1H), 4.24-4.21 (m, 1H), 3.51 (s, 2H), 3.40-3.39 (m, 1H), 2.90-2.87 (m, 1H), 2.77-2.72 (m, 1H), 2.37 (m, 2H), 2.00-1.66 (m, 12H), 1.45 (m, 2H), 1.34 (t, 2H). 451.3
    SC_3212 cis-8-Dimethylamino-3-[2-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-pyrimidin-5-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one INT-989 2-piperazin-1-ylethanol SC_3120 1H NMR (600 MHz, DMSO) δ 8.53 (s, 2H), 7.37 (p, 5H), 7.27 (d, 1H), 3.62 (t, 4H), 3.53 (q, 4H), 2.49 - 2.27 (m, 7H), 1.96 (s, 6H), 1.94 - 1.73 (m, 4H), 1.51 - 1.40 (m, 2H). 480.3
    SC_3213 cis-2- [4- [5 -(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-pyrimidin-2-yl]-piperazin-1-yl]-acetic acid SC_3146 INT-991 1H NMR (600 MHz, DMSO) δ 8.53 (s, 2H), 7.57 (s, 1H), 7.42 (d, 4H), 7.33 (d, 1H), 3.68 (t, 4H), 3.19 (s, 2H), 2.62 (t, 4H), 2.37 (d, 2H), 2.20 - 1.96 (m, 8H), 1.88 (t, 2H), 1.43 (t, 2H). 494.3
    SC_3214 cis-8-Dimethylamino-3-[2-(1-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-pyrimidin-5-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one INT-989 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydropyrrolo[2,3-b]pyridine SC_3208 1H NMR (600 MHz, DMSO + 2vol% TFA) δ 9.85 (s, 1H), 9.13 (s, 2H), 8.41 (d, 2H), 7.99 (s, 1H), 7.72 (s, 2H), 7.66 - 7.46 (m, 4H), 7.30 (s, 1H), 3.88 (s, 2H), 3.60 (s, 6H), 2.77 - 2.71 (m, 2H), 2.30 - 2.26 (m, 2H), 1.94 - 1.89 (m, 2H), 1.75 (s, 3H), 1.41 - 1.35 (m, 2H). 484.3
    SC_3215 cis-8-Benzyl-8-dimethylamino-3-[4-methyl-6-(trifluoromethyl)-pyridin-3-yl]-1,3-diazaspiro[4.5]decan-2-one INT-994 5-bromo-4-methyl-2-(trifluoromethyl)pyridine SC_3103 1H NMR (600 MHz, DMSO) δ 8.52 (s, 1H), 7.76 (s, 1H), 7.23 (dd, 2H), 7.19 - 7.11 (m, 4H), 2.62 (s, 2H), 2.27 (s, 6H), 2.25 (s, 3H), 1.86 (td, 2H), 1.80 (dt, 2H), 1.57 - 1.49 (m, 2H), 1.09 (td, 2H). 447.2
    SC_3216 trans-8-Dimethylamino-3-[4-methyl-6-(trifluoromethyl)-pyridin-3-yl]-8-thiophen-2-yl-1,3-diazaspiro[4.5]decan-2-one INT-998 5-bromo-4-methyl-2-(trifluoromethyl)pyridine SC_3103 1HNMR (600 MHz, DMSO) δ 8.61 (s, 1H), 7.83 (s, 1H), 7.53 - 7.49 (m, 1H), 7.45 (dd, 1H), 7.09 (dd, 1H), 6.99 (dd, 1H), 3.70 (s, 2H), 2.35 (s, 3H), 2.19 - 2.05 (m, 4H), 2.02 (s, 6H), 1.93 - 1.85 (m, 2H), 1.64 (dt, 2H). 439.2
    SC_3217 cis-8-Dimethylamino-3-[4-methyl-6-(trifluoromethyl)-pyridin-3-yl]-8-thiophen-2-yl-1,3-diazaspiro[4.5]decan-2-one INT-997 5-bromo-4-methyl-2-(trifluoromethyl)pyridine SC_3103 1H NMR (600 MHz, DMSO) δ 8.58 (s, 1H), 7.80 (s, 1H), 7.45 (s, 1H), 7.42 (dd, 1H), 7.05 (dd, 1H), 6.95 (dd, 1H), 3.67 (s, 2H), 2.33 (s, 3H), 2.32 - 2.25 (m, 2H), 2.04 (s, 6H), 2.00 - 1.92 (m, 2H), 1.89 - 1.76 (m, 2H), 1.62 (dt, 2H). 439.2
    SC_3218 cis-8-Dimethylamino-3-[2-(1,1-dioxo-[1,4]thiazinan-4-yl)-4-(trifluoromethyl)-pyrimidin-5-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one INT-976 4-[5-bromo-4-(trifluoromethyl)pyrimidin-2-yl]-1,4-thiazinane1,1-dioxide (prepared as SC_3097 step 1) SC_3103 1H NMR (600 MHz, DMSO) δ 8.65 (s, 1H), 7.42 (s, 1H), 7.41 - 7.31 (m, 5H), 7.25 (tt, 1H), 4.23 (t, 4H), 3.22 (t, 4H), 2.40 - 2.26 (m, 2H), 1.97 - 1.88 (m, 8H), 1.87 - 1.75 (m, 2H), 1.54 - 1.42 (m, 2H). 553.2
    SC_3219 cis-8-Dimethylamino-8-(1-methyl-1H-benzoimidazol-2-yl)-3-[2-(trifluoromethyl)-pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2-one INT-1000 5-bromo-2-(trifluoromethyl)pyrimidine SC_3103 1HNMR (600 MHz, DMSO) δ 9.14 (s, 2H), 8.65 (s, 1H), 7.63 (d, 1H), 7.51 (d, 1H), 7.25 (ddd, 1H), 7.19 (ddd, 1H), 4.02 (s, 3H), 3.61 (s, 2H), 2.26 (d, 2H), 2.18 (s, 6H), 2.16 - 2.09 (m, 2H), 1.87 (s, 2H), 1.78 (d, 2H). 474.2
    SC_3220 cis-8-Dimethylamino-8-(1-methyl-1H-benzoimidazol-2-yl)-3-[4-methyl-6-(trifluoromethyl)-pyridin-3-yl]-1,3-diazaspiro[4.5]decan-2-one INT-1000 5-bromo-4-methyl-2-(trifluoromethyl)pyridine SC_3103 1H NMR (600 MHz, DMSO) δ 8.56 (s, 1H), 8.10 (s, 1H), 7.80 (s, 1H), 7.60 (d, 1H), 7.50 (d, 1H), 7.23 (ddd, 1H), 7.17 (td, 1H), 4.02 (s, 3H), 3.50 (s, 2H), 2.34 - 2.25 (m, 5H), 2.19 - 2.09 (m, 8H), 1.90 - 1.74 (m, 4H). 487.3
    SC_3222 cis-3-[2-(Benzyl-methyl-amino)-pyrimidin-5-yl]-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one INT-976 N-benzyl-5-bromo-N-methylpyrimidin-2-amine SC_3103 1H NMR (DMSO-d6): δ 8.52 (s, 2H), 7.39-7.33 (m, 5H), 7.30-7.17 (m, 6H), 4.81 (s, 2H), 3.52 (s, 2H), 3.03 (s, 3H), 2.45-2.32 (m, 2H), 1.95-1.86 (m, 10H), 1.47-1.43 (m, 2H). 471.2
    SC_3223 cis-5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-N-[2-[2-[2-(2-methoxy-ethoxy)-ethoxy]-ethoxy]-ethyl]-pyrimidine-2-carboxylic acid amide INT-976 ethyl 5-bromopyrimidine-2-carboxylate (step 1), 2,5,8,11-tetraoxatridecan-13-amine (step 3) SC_3103 (step 1), INT-991 (step 2), SC_3133 (step 3) 1H NMR (DMSO-d6): δ 9.04 (s, 2H), 8.24-8.23 (m, 1H), 7.42-7.39 (m, 2H), 7.32-7.31 (m, 3H), 5.70 (s, 1H), 3.70-3.60 (m, 16H), 3.54-3.52 (m, 2H), 3.35 (s, 3H), 2.21-2.00 (m, 12H), 1.66-1.64 (m, 2H). 585.3
    SC_3225 cis-8-Dimethylamino-3-[2-[(2-hydroxy-ethyl)-methyl-amino]-pyrimidin-5-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one INT-989 2-(methylamino)ethanol SC_3182 1H NMR (DMSO-d6): δ 8.46 (s, 2H), 7.39-7.33 (m, 5H), 7.27-7.24 (m, 1H), 4.62 (t, 1H), 3.61-3.50 (m, 6H), 3.08 (s, 3H), 2.36-2.33 (m, 2H), 1.95-1.86 (m, 10H), 1.47-1.45 (m, 2H). 425.2
    SC_3226 cis-3-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-benzamide INT-976 5-bromo-4-methyl-2-(trifluoromethyl)pyridine SC_3103 (step 1), SC_3016 (step 2) 487.3
    SC_3227 cis-8-Dimethylamino-3-[3-fluoro-5-(trifluoromethyl)-pyridin-2-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one INT-976 2-bromo-3-fluoro-5-(trifluoromethyl)pyridine SC_3186 417.1
    SC_3228 cis-8-Dimethylamino-3-(5-methyl-pyrazin-2-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one INT-976 2-bromo-5-methylpyrazine SC_3186 459.1
    SC_3229 cis-8-Dimethylamino-3-(5-fluoro-pyrimidin-4-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one INT-976 4-bromo-5-fluoropyrimidine SC_3186 433.2
    SC_3230 cis-8-Dimethylamino-3-(5-fluoro-pyrimidin-2-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one INT-976 2-bromo-5-fluoropyrimidine SC_3186 458.1
    SC_3231 cis-8-Dimethylamino-8-phenyl-3-pyrazin-2-yl-1,3-diazaspiro[4.5]decan-2-one INT-976 2-bromopyrazine SC_3186 471.1
    SC_3232 cis-3-([2,1,3]Benzoxadiazol-5-yl)-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one INT-976 5-bromobenzo[c][1,2,5]-oxadiazole SC_3186 444.1
    SC_3233 cis-2-[2-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-phenoxy]-acetamide SC_3169 ammonium chloride SC_3133 1HNMR (600 MHz, DMSO) δ 7.73 (s, 1H), 7.40 - 7.32 (m, 4H), 7.31 (s, 1H), 7.26 (dd, 1H), 7.18 (td, 1H), 6.98 - 6.91 (m, 2H), 4.50 (s, 2H), 3.52 (s, 2H), 2.42 - 2.29 (m, 2H), 2.01 - 1.71 (m, 10H), 1.55 - 1.48 (m, 2H). 423.2
    SC_3234 cis-8-Dimethylamino-8-phenyl-3-(5-pyridin-4-yl-thiophen-2-yl)-1,3-diazaspiro[4.5]decan-2-one INT-976 4-(5 -bromothiophen-2-yl)pyridine SC_3103 1HNMR (DMSO-d6): δ 8.45-8.43 (d, 2H), 7.87 (br s, 1H), 7.54-7.53 (d, 1H), 7.49-7.48 (m, 2H), 7.38-7.27 (m, 5H), 6.35-6.34 (d, 2H), 3.64 (s, 2H), 2.42 (m, 2H), 1.96-1.90 (m, 10H), 1.51-1.49 (m, 2H). 433.2
    SC_3236 cis-8-Dimethylamino-3-(2-morpholin-4-yl-pyrimidin-4-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one INT-1002 morpholine SC_3120 1HNMR (600 MHz, DMSO) δ 8.07 (d, 1H), 7.93 (s, 1H), 7.37 (dt, 5H), 7.27 (t, 1H), 3.65 (s, 2H), 3.58 (s, 8H), 2.40 - 2.27 (m, 2H), 1.94 (s, 6H), 1.92 - 1.80 (m, 4H), 1.43 (d, 2H). 437.3
    SC_3237 cis-3-[2-(3,4-Difluoro-phenyl)-pyrimidin-5-yl]-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one INT-989 (3,4-difluorophenyl)boronic acid SC_3129 1HNMR (600 MHz, DMSO) δ 9.08 (s, 2H), 8.22 - 8.12 (m, 2H), 7.54 (dt, 1H), 7.41 - 7.37 (m, 4H), 7.29 (s, 1H), 3.70 (s, 2H), 2.06 - 1.75 (m, 12H), 1.50 (d, 2H). 463.2
    SC_3241 cis-2-[4-[5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-pyrimidin-2-yl]-piperazin-1-yl]-acetamide SC_3213 ammonium chloride SC_3133 1H NMR (600 MHz, DMSO) δ 8.53 (s, 2H), 7.38 (d, 5H), 7.27 (s, 1H), 7.23 (s, 1H), 7.11 (s, 1H), 3.67 (t, 4H), 3.54 - 3.50 (m, 2H), 2.89 (s, 2H), 2.47 (t, 4H), 2.39 - 2.35 (m, 2H), 1.96 (s, 7H), 1.93 - 1.82 (m, 3H), 1.48 - 1.44 (m, 2H). 493.3
    SC_3243 cis-8-Dimethylamino-3-[6-(4-methyl-piperazin-1-yl)-pyridin-3-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one INT-976 1-(5-bromo-2-pyridyl)-4-methyl-piperazine SC_3242 (step 2) 1HNMR (600 MHz, DMSO) δ 8.16 (d, 1H), 7.86 (dd, 1H), 7.41 - 7.33 (m, 4H), 7.32 (s, 1H), 7.27 (t, 1H), 6.78 (d, 1H), 3.51 (s, 2H), 2.55 - 2.45 (m, 4H), 2.42 - 2.27 (m, 6H), 2.21 (s, 3H), 1.96 (s, 6H), 1.93 - 1.73 (m, 4H), 1.46 (t, 2H). 449.3
    SC_3244 cis-8-Dimethylamino-3-[2-(1,1-dioxo-[1,4]thiazinan-4-yl)-4-methyl-pyrimidin-5-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one INT-976 4-(5-bromo-4-methyl-pyrimidin-2-yl)-1,4-thiazinane1,1-dioxide SC_3103 1H NMR (600 MHz, DMSO) δ 8.20 (s, 1H), 7.36 (h, 4H), 7.30 - 7.17 (m, 2H), 4.23 - 4.17 (m, 4H), 3.13 (t, 4H), 2.44 - 2.28 (m, 2H), 2.24 (s, 3H), 1.97 (s, 6H), 1.91 (d, 4H), 1.55 - 1.44 (m, 2H). 499.3
    SC_3245 cis-8-Dimethylamino-8-phenyl-3-[2-(trifluoromethyl)-pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2-one INT-976 5-bromo-2-(trifluoromethyl)-pyrimidine SC_3103 1HNMR (600 MHz, DMSO) δ 9.17 (s, 2H), 8.03 (s, 1H), 7.38 (s, 4H), 7.28 (tt, 1H), 3.73 (s, 2H), 2.49 - 2.35 (m, 2H), 1.97 (s, 6H), 1.97 - 1.92 (m, 2H), 1.90 - 1.73 (m, 2H), 1.55 - 1.49 (m, 2H). 419.2
    SC_3246 cis-2-[8-Dimethylamino-1-(3-methoxy-propyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-5-carbonitrile INT-979 2-chloropyrimidine-5-carbonitrile SC_3103 1HNMR (600 MHz, DMSO) δ 9.02 (s, 2H), 7.40 - 7.31 (m, 5H), 3.86 (s, 2H), 3.26 (s, 3H), 3.29 - 3.19 (m, 2H), 2.73 - 2.67 (m, 2H), 2.16 (td, 2H), 2.00 (s, 7H), 1.83 (dt, 2H), 1.50 - 1.40 (m, 5H). 449.3
    SC_3247 cis-8-Dimethylamino-3-[2-(4-methyl-piperazin-1-yl)-pyrimidin-5-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one INT-989 1-Methylpiperazin SC_3120 1HNMR (600 MHz, DMSO) δ 8.54 (s, 2H), 7.48 - 7.33 (m, 5H), 7.31 - 7.21 (m, 1H), 3.63 (dd, 4H), 2.45 - 2.29 (m, 6H), 2.20 (s, 3H), 1.96 (s, 6H), 1.94 - 1.78 (m, 4H), 1.51 - 1.42 (m, 2H). 450.3
    SC_3248 cis-8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-8-phenyl-3-[2-(trifluoromethyl)-pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2-one SC_3245 [1-[tert-butyl(dimethyl)silyl]-oxycyclobutyl]methyl 4-methylbenzenesulfonate INT-988 (step 1) 1HNMR (600 MHz, DMSO) δ 9.24 (s, 2H), 7.38 (d, 4H), 7.27 (p, 1H), 3.89 (s, 2H), 2.73 - 2.67 (m, 2H), 2.26 (ddd, 2H), 2.19 (tt, 2H), 2.08 (s, 1H), 2.00 (s, 6H), 1.92 (qd, 2H), 1.73 - 1.64 (m, 1H), 1.60 - 1.50 (m, 3H), 1.50 - 1.45 (m, 2H). 504.3
    SC_3249 cis-2-[1-(3-Methoxy-propyl)-8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-5-carbonitrile SC_3246 SC_3099 1H NMR (600 MHz, DMSO) δ 9.05 (s, 2H), 7.49 - 7.44 (m, 2H), 7.34 (t, 2H), 7.21 (t, 1H), 3.90 (s, 2H), 3.26 (s, 3H), 2.23 (td, 2H), 2.07 (s, 1H), 1.91 (d, 5H), 1.86 - 1.78 (m, 2H), 1.73 (tt, 2H), 1.42 (d, 2H). 435.3
    SC_3250 cis-8-Dimethylamino-8-phenyl-3-[6-(trifluoromethyl)-pyridin-3-yl]-1,3-diazaspiro[4.5]decan-2-one INT-976 5-bromo-2-(trifluoromethyl)pyridine SC_3103 1H NMR (600 MHz, DMSO) δ 8.88 (d, 1H), 8.24 (dd, 1H), 7.86 (s, 1H), 7.78 (d, 1H), 7.41 - 7.34 (m, 4H), 7.27 (t, 1H), 3.69 (s, 2H), 2.42 (s, 2H), 1.97 (s, 6H), 1.96 - 1.74 (m, 4H), 1.53 - 1.47 (m, 2H). 419.3
    SC_3251 cis-5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-pyridine-2-carbonitrile INT-976 5-bromopyridine-2-carbonitrile SC_3103 1H NMR (600 MHz, DMSO) δ 8.92 (d, 1H), 8.15 (dd, 1H), 7.95 (br s, 1H), 7.90 (d, 1H), 7.41 - 7.34 (m, 4H), 7.27 (t, 1H), 3.69 (s, 2H), 2.44 - 2.40 (m, 2H), 1.97 (s, 6H), 1.96 - 1.89 (m, 3H), 1.90 - 1.70 (m, 1H), 1.53 - 1.46 (m, 2H). 376.2
    SC_3252 cis-8-Dimethylamino-3-(2-morpholin-4-yl-pyrimidin-5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one INT-989 morpholine SC_3120 1H NMR (600 MHz, DMSO) δ 8.57 (s, 2H), 7.46 - 7.42 (m, 1H), 7.40 - 7.34 (m, 4H), 7.27 (td, 1H), 3.64 (dd, 4H), 3.59 (dd, 4H), 3.54 (s, 2H), 2.46 - 2.29 (m, 2H), 1.96 (s, 7H), 1.93 - 1.73 (m, 3H), 1.50 - 1.44 (m, 2H). 437.3
    SC_3253 cis-8-Dimethylamino-3-(2-methyl-pyrimidin-5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one INT-976 5-bromo-2-methyl-pyrimidine SC_3103 1H NMR (600 MHz, DMSO) δ 8.86 (s, 2H), 7.69 (s, 1H), 7.41 - 7.33 (m, 5H), 7.31 - 7.19 (m, 1H), 3.62 (s, 2H), 2.53 (s, 3H), 2.48 - 2.31 (m, 2H), 1.97 (s, 6H), 1.95 - 1.77 (m, 4H), 1.52 - 1.46 (m, 2H). 366.3
    SC_3254 cis-8-Dimethylamino-1-[(2-methoxyphenyl)-methyl]-3-(2-methyl-pyrimidin-5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3253 2-methoxybenzyl bromide SC_3105 1H NMR (DMSO-d6): δ 8.90 (s, 2H), 7.39-7.34 (m, 3H), 7.28-7.22 (m, 4H), 6.95-6.87 (m, 2H), 4.58 (s, 2H), 3.89 (s, 3H), 3.63 (s, 2H), 2.68-2.64 (m, 5H), 2.35-2.28 (m, 2H), 2.01(s, 6H), 1.49-1.43 (m, 4H). 486.2
    SC_3255 cis-1-[(1-Hydroxy-cyclobutyl)-methyl]-8-methylamino-8-phenyl-3-[2-(trifluoromethyl)-pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2-one SC_3248 SC_3099 1H NMR (600 MHz, DMSO) δ 9.26 (s, 2H), 7.51 (d, 2H), 7.34 (t, 2H), 7.22 (t, 1H), 3.92 (s, 2H), 3.41 (s, 1H), 2.31 (td, 2H), 2.15 (td, 2H), 2.07 (d, 1H), 1.93 (d, 7H), 1.83 (dt, 2H), 1.67 (t, 1H), 1.56 (q, 1H), 1.47 (d, 2H). 490.3
    SC_3256 cis-8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-3-(2-methyl-pyrimidin-5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3253 [1-[tert-butyl(dimethyl)silyl]-oxycyclobutyl]methyl 4-methylbenzenesulfonate INT-988 (step 1) 1H NMR (600 MHz, DMSO) δ 8.92 (s, 2H), 7.37 (d, 4H), 7.27 (td, 1H), 3.79 (s, 2H), 3.27 (s, 1H), 2.72 - 2.65 (m, 2H), 2.54 (s, 3H), 2.25 - 2.19 (m, 2H), 2.16 (tt, 2H), 2.07 (s, 2H), 2.00 (s, 6H), 1.95 - 1.86 (m, 2H), 1.67 (qd, 1H), 1.55 (td, 2H), 1.51 - 1.42 (m, 3H). 450.3
    SC_3257 cis-1-[(1-Hydroxy-cyclobutyl)-methyl]-8-methylamino-8-phenyl-3-pyrimidin-5-yl-1,3-diazaspiro[4.5]decan-2-one SC_3260 SC_3099 1H NMR (600 MHz, DMSO) δ 9.07 (s, 2H), 8.81 (s, 1H), 7.53 - 7.48 (m, 2H), 7.33 (t, 2H), 7.24 - 7.18 (m, 1H), 3.86 (s, 2H), 2.29 (td, 2H), 2.14 (tt, 2H), 2.07 (s, 1H), 1.96 - 1.87 (m, 8H), 1.82 (td, 2H), 1.71 - 1.62 (m, 1H), 1.54 (dp, 1H), 1.49 - 1.43 (m, 2H). 422.3
    SC_3258 cis-5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-4-methyl-pyridine-2-carbonitrile INT-976 5-bromo-4-methyl-pyridine-2-carbonitrile SC_3103 1H NMR (600 MHz, DMSO) δ 8.57 (s, 1H), 7.92 (s, 1H), 7.61 - 7.57 (m, 1H), 7.42 - 7.32 (m, 4H), 7.25 (tt, 1H), 3.63 (s, 2H), 2.38 (d, 2H), 2.28 (s, 3H), 2.00 - 1.90 (m, 9H), 1.90 - 1.72 (m, 1H), 1.59 - 1.49 (m, 2H). 390.2
    SC_3259 cis-8-Dimethylamino-3-(2-methyl-pyrimidin-5-yl)-8-phenyl-1-(pyridin-2-yl-methyl)-1,3-diazaspiro[4.5]decan-2-one SC_3253 2-(bromomethyl)pyridine SC_3105 1H NMR (DMSO-d6): δ 8.94 (s, 2H), 8.52-8.51 (m, 1H), 7.77-7.74 (m, 1H), 7.45-7.42 (d, 1H), 7.38-7.22 (m, 6H), 4.47 (s, 2H), 3.84 (s, 2H), 2.66-2.63 (m, 2H), 2.54 (s, 3H), 2.06-2.03 (m, 2H), 1.92(s, 6H), 1.57-1.42 (m, 4H). 457.2
    SC_3260 INT-976 5-bromopyrimidine SC_3103 1H NMR (600 MHz, DMSO) δ 8.98 (s, 2H), 8.76 (s, 1H), 7.78 (s, 1H), 7.41 - 7.34 (m, 4H), 7.31 - 7.24 (m, 1H), 3.65 (s, 2H), 2.49 - 2.34 (m, 2H), 1.97 (s, 6H), 1.95 - 1.76 (m, 4H), 1.50 (t, 2H). 352.2
    SC_3261 cis-8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-8-phenyl-3-pyrimidin-5-yl-1,3-diazaspiro[4.5]decan-2-one SC_3260 [1-[tert-butyl(dimethyl)silyl]-oxycyclobutyl]methyl 4-methylbenzenesulfonate INT-988 (step 1) 1H NMR (600 MHz, DMSO) δ 9.04 (s, 2H), 8.80 (s, 1H), 7.37 (d, 4H), 7.27 (p, 1H), 3.83 (s, 2H), 3.28 (s, 1H), 2.72 - 2.65 (m, 2H), 2.23 (td, 1H), 2.17 (tt, 1H), 2.07 (s, 2H), 2.00 (s, 6H), 1.91 (dt, 2H), 1.72 - 1.63 (m, 1H), 1.60 - 1.45 (m, 5H). 436.3
    SC_3262 cis-8-Amino-1-[(1-hydroxy-cyclobutyl)-methyl]-8-phenyl-3-[2-(trifluoromethyl)-pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2-one SC_3255 SC_3099 1H NMR (600 MHz, DMSO) δ 9.29 (s, 2H), 7.68 - 7.63 (m, 2H), 7.33 (t, 2H), 7.26-7.18 (m, 1H), 3.97 (s, 2H), 3.45 (s, 2H), 2.43 (td, 2H), 2.14 (tt, 2H), 1.99 (td, 2H), 1.96 - 1.90 (m, 2H), 1.71 - 1.54 (m, 4H), 1.52 - 1.47 (m, 2H). 476.2
    SC_3263 cis-8-Dimethylamino-3-(3-fluorophenyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one INT-976 1-bromo-3-fluoro-benzene SC_3103 1H NMR (600 MHz, DMSO) δ 7.58 - 7.50 (m, 2H), 7.41 - 7.33 (m, 4H), 7.33 - 7.23 (m, 3H), 6.77 - 6.71 (m, 1H), 3.58 (s, 2H), 2.48 - 2.31 (m, 2H), 1.97 (s, 6H), 1.92 - 1.80 (m, 4H), 1.47 (t, 2H). 368.2
    SC_3264 cis-8-Dimethylamino-3-(3-methylsulfonyl-phenyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one INT-976 1-bromo-3-methylsulfonylbenzene SC_3103 1H NMR (600 MHz, DMSO) δ 8.13 (t, 1H), 7.88 (d, 1H), 7.65 (s, 1H), 7.53 (t, 1H), 7.47 (dt, 1H), 7.41 - 7.35 (m, 4H), 7.28 (qd, 1H), 3.66 (s, 2H), 3.16 (s, 3H), 2.49 - 2.36 (m, 2H), 1.97 (s, 6H), 1.96 - 1.74 (m, 4H), 1.53 - 1.47 (m, 2H). 428.2
    SC_3265 cis-8-Dimethylamino-3-(4-methylsulfonyl-phenyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one INT-976 1-bromo-4-methylsulfonylbenzene SC_3103 1H NMR (600 MHz, DMSO) δ 7.83 - 7.70 (m, 5H), 7.41 - 7.34 (m, 4H), 7.27 (tt, J = 7.1, 1.9 Hz, 1H), 3.65 (s, 2H), 3.12 (s, 3H), 2.49 - 2.31 (m, 2H), 1.97 (s, 6H), 1.95 - 1.75 (m, 4H), 1.49 (t, J = 8.6 Hz, 2H). 428.2
    SC_3266 cis-8-Dimethylamino-8-phenyl-3-pyridazin-3-yl-1,3-diazaspiro[4.5]decan-2-one INT-976 3-bromopyridazine SC_3103 1H NMR (600 MHz, DMSO) δ 8.82 (dd, J = 4.6, 1.4 Hz, 1H), 8.45 (dd, J = 9.2, 1.4 Hz, 1H), 7.95 (br s, 1H), 7.55 (dd, J = 9.2, 4.5 Hz, 1H), 7.42 - 7.34 (m, 4H), 7.28 (t, J = 6.8 Hz, 1H), 3.83 (s, 2H), 2.47 - 2.29 (m, 1H), 1.97 (s, 10H), 1.54 - 1.48 (m, 2H). 352.2
    SC_3267 cis-3-Methoxy-4-(8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-benzonitrile INT-976 4-bromo-3-methoxy-benzonitrile (step 1) SC_3103 (for step 1), SC_3099 (for step 2) 1H NMR (DMSO-d6, 400 MHz), δ (ppm) = 7.50-7.50 (m, 2H), 7.42-7.31 (m, 5H), 7.18 (bs, 2H), 3.83 (s, 3H), 3.64 (s, 2H), 2.05-21.99 (m, 2H), 1.85 (bs, 5H), 1.70 (bs, 2H), 1.53-1.50 (m, 2H). 391.2
    SC_3268 cis-8-Dimethylamino-3-(2-fluorophenyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one INT-976 1-bromo-2-luorobenzene SC_3103 1H NMR (600 MHz, DMSO) δ 7.46 (td, J = 8.0, 1.6 Hz, 1H), 7.40 - 7.32 (m, 5H), 7.26 (td, J = 6.7, 3.3 Hz, 1H), 7.24 - 7.12 (m, 3H), 3.53 (s, 2H), 2.37 - 2.33 (m, 2H), 1.96 (s, 6H), 1.95 - 1.74 (m, 4H), 1.49 (t, J = 9.3 Hz, 2H). 368.2
    SC_3269 cis-8-Dimethylamino-8-phenyl-3-(2-phenyl-pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one INT-976 5-bromo-2-phenyl-pyrimidine SC_3103 1H NMR (600 MHz, DMSO) δ 9.07 (s, 2H), 8.34 - 8.28 (m, 2H), 7.82 (s, 1H), 7.52 - 7.42 (m, 4H), 7.39 (s, 1H), 7.38 (s, 3H), 7.28 (t, J = 4.8 Hz, 1H), 3.70 (s, 2H), 2.43 - 2.39 (m, 2H), 2.06 - 1.72 (m, 10H), 1.52 (d, J = 10.8 Hz, 2H). 428.3
    SC_3270 cis-8-Methylamino-1-(oxetan-3-yl-methyl)-8-phenyl-3-[2-(trifluoromethyl)-pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2-one SC_3245 oxetan-3-ylmethyl 4-methylbenzenesulfonate (step 2) SC_3099 (for step 1), SC_3105 (for step 2) 1H NMR (DMSO-d6): δ 9.24 (s, 2H), 7.49 (d, 2H), 7.34 (t, 2H), 7.21 (t, 1H), 4.66-4.62 (m, 2H), 4.44 (t, 2H), 3.87 (s, 2H), 3.55 (d, 2H), 3.28-3.23 (m, 1H), 2.36 (m, 1H), 2.20-2.14 (m, 2H), 1.95-1.91 (m, 5H), 1.84-1.77 (m, 2H), 1.43-1.40 (m, 2H). 476.2
    SC_3271 cis-1-(Cyclopropyl-methyl)-8-methylamino-8-phenyl-3-[2-(trifluoromethyl)-pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2-one SC_3245 (bromomethyl)-cyclopropane SC_3099 (for step 1), SC_3105 (for step 2) 1H NMR (DMSO-d6): δ 9.26 (s, 2H), 7.50 (d, 2H), 7.35 (t, 2H), 7.22 (t, 1H), 3.89 (s, 2H), 3.13 (d, 2H), 2.29-2.23 (m, 3H), 1.92-1.82 (m, 7H), 1.47-1.44 (m, 2H), 1.08-1.05 (m, 1H), 0.52-0.48 (m, 2H), 0.36-0.36-0.32 (m, 2H). 460.1
    SC_3272 cis-4-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-benzonitrile INT-976 4-bromobenzonitrile SC_3103 1H NMR (600 MHz, DMSO) δ 7.82 - 7.71 (m, 3H), 7.72 - 7.67 (m, 2H), 7.41 - 7.33 (m, 4H), 7.30 - 7.23 (m, 1H), 3.63 (s, 2H), 2.45 - 2.39 (m, 2H), 1.97 (s, 6H), 1.95 - 1.72 (m, 4H), 1.51 - 1.44 (m, 2H). 375.2
    SC_3273 cis-8-Dimethylamino-3-(4-fluorophenyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one INT-976 1-bromo-4-fluoro-benzene SC_3103 368.2
    SC_3274 cis-2-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-benzonitrile INT-976 2-bromobenzonitrile SC_3103 1H NMR (600 MHz, DMSO) δ 7.77 (dd, J = 7.5, 1.6 Hz, 1H), 7.66 (ddd, J = 8.3, 7.5, 1.6 Hz, 1H), 7.60 (s, 1H), 7.48 (dd, J = 8.3, 1.1 Hz, 1H), 7.39 - 7.34 (m, 4H), 7.32 (td, J = 7.5, 1.1 Hz, 1H), 7.26 (tt, J = 7.5, 1.6 Hz, 1H), 3.68 (s, 2H), 2.46 - 2.30 (m, 2H), 2.01 - 1.75 (m, 10H), 1.59 - 1.50 (m, 2H). 375.2
    SC_3276 cis-1-[(1-Hydroxy-cyclobutyl)-methyl]-8-methylamino-3-(2-methyl-pyrimidin-5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3256 SC_3099 1H NMR (600 MHz, DMSO) δ 8.94 (s, 2H), 7.53 - 7.47 (m, 2H), 7.39 - 7.30 (m, 2H), 7.24 - 7.17 (m, 1H), 3.83 (s, 2H), 3.54 - 3.36 (m, 2H), 2.56 (s, 3H), 2.28 (td, 2H), 2.18 - 2.09 (m, 2H), 1.97 - 1.86 (m, 7H), 1.81 (td, 2H), 1.71 - 1.61 (m, 1H), 1.59 - 1.47 (m, 1H), 1.49 - 1.42 (m, 2H). 436.3
    SC_3277 cis-8-Dimethylamino-3-[2-(morpholin-4-yl-methyl)-pyrimidin-5-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one INT-976 4-[(5-bromopyrimidin-2-yl)methyl]morpholine SC_3103 1H NMR (600 MHz, DMSO) δ 8.93 (s, 2H), 7.87 - 7.65 (m, 1H), 7.42 - 7.34 (m, 4H), 7.28 (dq, 1H), 3.66 - 3.62 (m, 2H), 3.61 (s, 2H), 3.54 (t, 4H), 2.43 (t, 4H), 1.98 (s, 6H), 1.96 - 1.74 (m, 4H), 1.52 - 1.46 (m, 2H).
    SC_3278 cis-8-Dimethylamino-3-[2-(methyl-tetrahydro-pyran-4-yl-amino)-pyrimidin-5-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one INT-989 N-methyltetrahydro-2H-pyran-4-amine SC_3120 1H NMR (DMSO-d6): δ 8.50 (s, 2H), 7.39-7.35 (m, 5H), 7.27-7.24 (m, 1H), 4.74-4.67 (m, 1H), 3.94-3.90 (m, 2H), 3.50 (s, 2H), 3.39 (t, 2H), 2.93 (s, 3H), 2.35 (m, 2H), 1.99-1.71 (m, 12H), 1.50-1.44 (m, 4H). 465.2
    SC_3279 cis-5-[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]-pyrimidine-2-carboxylic acid amide INT-990 (1-(tert-butyldimethylsilyloxy)cyclobutyl)methyl 4-methylbenzenesulfonate (step 1), 2,5,8,11-tetraoxatridecan-13-amine (step 2) SC_3105 (step 1), SC_3133 (step 2) 1H NMR (DMSO-d6): δ 9.12 (s, 2H), 8.63 (t, 1H), 7.36-7.33 (m, 4H), 7.26-7.23 (m, 1H), 5.25 (s, 1H), 3.85 (s, 2H), 3.52-3.34 (m, 16H), 3.35 (m, 2H), 3.19 (s, 3H), 2.69-2.66 (m, 2H), 2.25-2.13 (m, 4H), 1.97 (s, 6H), 1.92-1.87 (m, 2H), 1.57-1.44 (m, 6H). 669.4
    SC_3280 cis-1-(Cyclopropyl-methyl)-3-(2-fluoro-4-methylsulfonyl-phenyl)-8-methylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one INT-976 1-bromo-2-fluoro-4-(methylsulfonyl)benzene (step 1), (Bromomethyl)cyclopropane (step 2) SC_3103 (for step 1), SC_3105 (step 2), SC_3099 (step 3) 1H NMR (DMSO-d6): δ 7.86 (t, 1H), 7.81-7.77 (m, 1H), 7.73-7.70 (m, 1H), 7.45 (d, 2H), 7.31 (t, 2H), 7.19 (t, 1H), 3.85 (s, 2H), 3.24 (s, 3H), 3.09 (d, 2H), 2.29-2.22 (m, 3H), 1.93-1.90 (m, 5H), 1.74-1.68 (m, 2H), 1.49-1.46 (m, 2H), 1.04 (m, 1H), 0.51-0.46 (m, 2H), 0.34-0.30 (m, 2H). 486.2
    SC_3281 cis-2-[[5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-pyrimidin-2-yl] -methyl-amino]-acetamide INT-989 2-(methylamino)acetamide hydrochloride SC_3120 1H NMR (DMSO-d6): δ 8.48 (s, 2H), 7.39-7.35 (m, 5H), 7.27-7.25 (m, 2H), 6.89 (s, 1H), 4.08 (s, 2H), 3.51 (s, 2H), 3.07 (s, 3H), 2.36-2.33 (m, 2H), 1.94-1.86 (m, 10H), 1.45 (m, 2H). 438.2
    SC_3282 cis-2-[[5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-pyrimidin-2-yl]amino]-acetamide INT-976 tert-butyl (5-bromopyrimidin-2-yl)(cyanomethyl)carbamate (step 1) SC_3103 (for step 1), SC_3100 step 3 (for step 2) 1H NMR (DMSO-d6): δ 8.45 (s, 2H), 7.39-7.33 (m, 5H), 7.27-7.22 (m, 2H), 6.92 (s, 1H), 6.86 (t, 1H), 3.74 (d, 2H), 3.51 (s, 2H), 2.46-2.28 (m, 2H), 1.95-1.86 (m, 10H), 1.45 (m, 2H). 424.2
    SC_3283 cis-1-(Cyclopropyl-methyl)-8-methylamino-3-[4-methyl-6-(trifluoromethyl)-pyridin-3-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3284 SC_3099 1H NMR (DMSO-d6): δ 8.61 (s, 1H), 7.82 (s, 1H), 7.46-7.44 (m, 2H), 7.30 (t, 2H), 7.18 (t, 1H), 3.80 (s, 2H), 3.08 (d, 2H), 2.33-2.25 (m, 6H), 1.92-1.89 (m, 5H), 1.72 (t, 2H), 1.56-1.53 (m, 2H), 1.04 (m, 1H), 0.51-0.46 (m, 2H), 0.33-0.30 (m, 2H). 473.3
    SC_3284 cis-1-(Cyclopropyl-methyl)-8-dimethylamino-3-[4-methyl-6-(trifluoromethyl)-pyridin-3-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one INT-984 5-bromo-4-methyl-2-(trifluoromethyl)pyridine SC_3103 1H NMR (DMSO-d6): δ 8.59 (s, 1H), 7.82 (s, 1H), 7.35-7.34 (m, 4H), 7.27-7.23 (m, 1H), 3.75 (s, 2H), 3.06 (d, 2H), 2.71-2.68 (m, 2H), 2.33-2.24 (m, 5H), 2.00 (m, 6H), 1.59-1.56 (m, 2H), 1.46 (t, 2H), 1.02-0.99 (m, 1H), 0.53-0.48 (m, 2H), 0.33-0.30 (m, 2H). 487.3
    SC_3285 cis-N-[5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-pyrimidin-2-yl]-thiophene-2-carboxylic acid amide SC_3239 thiophene-2-carbonylchloride SC_3240 1H NMR (600 MHz, DMSO) δ 8.90 (s, 2H), 8.08 - 8.04 (m, 1H), 7.84 (dd, 1H), 7.71 (s, 1H), 7.38 (d, 5H), 7.27 (td, 1H), 7.19 (dd, 1H), 3.66 (s, 2H), 2.48 - 2.34 (m, 2H), 1.99 - 1.75 (m, 10H), 1.54 - 1.48 (m, 2H). 477.2
    SC_3286 cis-N-[5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-pyrimidin-2-yl]-benzamide SC_3239 benzoyl chloride SC_3240 1H NMR (600 MHz, DMSO) δ 10.84 (s, 1H), 8.91 (s, 2H), 7.98 - 7.93 (m, 2H), 7.62 - 7.55 (m, 1H), 7.50 (t, 2H), 7.39 (d, 4H), 7.28 (dt, 1H), 3.67 (s, 2H), 2.48 - 2.32 (m, 2H), 2.05 - 1.76 (m, 10H), 1.55 - 1.49 (m, 2H). 471.3
    SC_3287 cis-8-Dimethylamino-8-phenyl-3-(5 -phenyl-thiophen-2-yl)-1,3-diazaspiro[4.5]decan-2-one INT-976 2-bromo-5-phenylthiophene SC_3103 1H NMR (DMSO-d6): δ 7.80-7.70 (br s, 1H), 7.52 (d, 2H), 7.38-7.28 (m, 7H), 7.20-7.17 (m, 2H), 6.27 (d, 1H), 3.61 (s, 2H), 2.49 (m, 2H), 1.95-1.91 (m, 10H), 1.48 (m, 2H). 432.2
    SC_3288 cis-1-(Cyclopropyl-methyl)-8-dimethylamino-3-[2-(methylsulfonyl-methyl)-phenyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one INT-984 1-bromo-2-(methylsulfonylmethy1)benzene SC_3103 1H NMR (CDCl3): δ 7.49 (d, 1H), 7.41-7.22 (m, 8H), 4.45 (s, 2H), 3.64 (s, 2H), 3.15 (d, 2H), 2.79 (s, 3H), 2.71-2.67 (m, 2H), 2.37 (t, 2H), 2.06 (s, 6H), 1.67-1.64 (m, 2H), 1.55-1.44 (m, 2H), 1.10-1.06 (m, 1H), 0.57-0.52 (m, 2H), 0.39-0.35 (m, 2H). 496.3
    SC_3289 cis-1-(Cyclopropyl-methyl)-8-methylamino-3-[2-(methylsulfonyl-methyl)-phenyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3288 SC_3099 1H NMR (DMSO-d6): δ 7.49-7.37 (m, 5H), 7.32-7.30 (m, 3H), 7.19-7.15 (m, 1H), 4.49 (s, 2H), 3.71 (s, 2H), 3.05 (d, 2H), 2.87 (s, 3H), 2.26-2.20 (m, 3H), 1.91-1.87 (m, 5H), 1.71-1.56 (m, 4H), 1.03-1.01 (m, 1H), 0.49-0.45 (m, 2H), 0.31-0.28 (m, 2H). 482.3
    SC_3290 cis-8-Dimethylamino-8-(3-fluorophenyl)-3-[2-(methylsulfonyl-methyl)-phenyl]-1,3-diazaspiro[4.5]decan-2-one INT-1024 1-bromo-2-(methylsulfonylmethy 1)benzene SC_3103 1H NMR (600 MHz, DMSO) δ 7.46 (dd, 1H), 7.39 (td, 2H), 7.33 (dd, 1H), 7.31 - 7.21 (m, 1H), 7.18 (d, 1H), 7.15 (dd, 1H), 7.08 (td, 1H), 4.50 (s, 2H), 3.56 (s, 2H), 2.88 (s, 3H), 2.42 - 2.24 (m, 2H), 1.99 - 1.89 (m, 8H), 1.88 - 1.75 (m, 2H), 1.60 - 1.48 (m, 2H). 460.3
    SC_3291 cis-8-Dimethylamino-8-(4-fluorophenyl)-3-[2-(methylsulfonyl-methyl)-phenyl]-1,3-diazaspiro[4.5]decan-2-one INT-1025 1-bromo-2-(methylsulfonylmethy 1)benzene SC_3103 1H NMR (600 MHz, DMSO) δ 7.46 (dd, 1H), 7.43 - 7.34 (m, 3H), 7.33 (dd, 1H), 7.28 (td, 2H), 7.16 (t, 2H), 4.49 (s, 2H), 3.55 (s, 2H), 2.88 (s, 3H), 2.35 - 2.32 (m, 2H), 1.95 (s, 6H), 1.94 - 1.88 (m, 2H), 1.88 - 1.65 (m, 2H), 1.59 - 1.47 (m, 2H). 460.3
    SC_3294 cis-8-Dimethylamino-8-(3-fluorophenyl)-3-(4-methyl-2-morpholin-4-yl-pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one INT-1024 4-(5-bromo-4-methyl-pyrimidin-2-yl)morpholine SC_3103 1H NMR (600 MHz, DMSO) δ 8.13 (s, 1H), 7.40 (td, 1H), 7.22 - 7.11 (m, 4H), 7.08 (td, 1H), 3.69 - 3.60 (m, 8H), 2.34 - 2.31 (m, 2H), 2.20 (s, 3H), 1.96 (s, 6H), 1.96 - 1.70 (m, 4H), 1.56 - 1.43 (m, 2H). 469.3
    SC_3295 cis-3-[6-(4-Acetyl-piperazin-1-yl)-4-methyl-pyridin-3-yl]-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one INT-976 1-[4-(5-bromo-4-methyl-pyridin-2-yl)-piperazin-1-yl]-ethanone SC_3103 1HNMR (DMSO-d6, 400 MHz at 100 0C), δ (ppm) = 7.88 (s, 1H), 7.35-7.22 (m, 5H), 6.73 (s, 1H), 6.64 (s, 1H), 3.53-3.50 (m, 8H), 3.38 (s, 2H), 2.33-2.30 (m, 2H), 2.14 (s, 3H), 2.03-1.88 (m, 13H), 1.56-1.51 (m, 2H). 491.3
    SC_3296 cis-3-[2-(4-Acetyl-piperazin-1-yl)-4-methyl-pyrimidin-5-yl]-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one INT-976 1-[4-(5-bromo-4-methyl-pyrimidin-2-yl)-piperazin-1-yl]-ethanone SC_3103 1H-NMR (DMSO-d6, 400 MHz at 100 0C), δ (ppm) = 8.11 (s, 1H), 7.35-7.24 (m, 5H), 6.88 (s, 1H), 3.73 (bs, 4H), 3.52 (bs, 4H), 3.38 (s, 2H), 2.33 (bs, 2H), 2.22 (s, 3H), 2.03-1.87 (m, 13H), 1.56-1.53 (m, 2H). 492.3
    SC_3297 cis-8-Dimethylamino-3-(4-methyl-6-pyridin-4-yl-pyridin-3-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one INT-976 5-bromo-2-chloro-4-methyl-pyridine (step 1), 4-pyridinylboronic acid (step 2) SC_3103 (for step 1), SC_3129 (for step 2) 1H-NMR (DMSO-d6, 400 MHz at 100 0C), δ (ppm) = 8.65 (d, 2H, J = 5.92 Hz), 8.50 (s, 1H), 7.96 (d, 2H, J = 5.96 Hz), 7.91 (s, 1H), 7.36-7.23 (m, 5H), 7.07 (s, 1H), 3.57 (s, 2H), 2.38-2.33 (m, 5H), 2.04 (s, 6H), 2.00-1.88 (m, 4H), 1.61-1.57 (m, 2H). 442.3
    SC_3298 cis-3-[2-(4-Acetyl-piperazin-1-yl)-4-(trifluoromethyl)-pyrimidin-5-yl]-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one INT-976 1-[4-(5-bromo-4-trifluoromethyl-pyrimidin-2-yl)-piperazin-1-yl]-ethanone SC_3103 1H-NMR (DMSO-d6, 400 MHz at 100 0C), δ (ppm) = 8.52 (s, 1H), 7.35-7.22 (m, 5H), 7.07 (s, 1H), 3.79-3.78 (t, 4H, 5.08 Hz), 3.57 (t, 4H, 5.26 Hz), 3.39 (s, 2H), 2.36-2.32 (m, 2H), 2.04-1.85 (m, 13H), 1.54-1.50 (m, 2H). 546.3
    SC_3299 cis-8-Dimethylamino-3-[2-(3-oxo-piperazin-1-yl)-4-(trifluoromethyl)-pyrimidin-5-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one INT-976 4-(5-bromo-4-trifluoromethyl-pyrimidin-2-yl)-piperazin-2-one SC_3103 1H NMR (DMSO-d6, 400 MHz), δ (ppm) = 8.55 (s, 1H), 7.77 (bs, 1H), 7.35-7.23 (m, 5H), 7.09 (s, 1H), 4.20 (s, 2H), 3.92 (t, 2H, J = 5.04 Hz), 3.39 (s, 2H), 3.33 (bs, 2H), 2.36-2.33 (m, 2H), 2.03-1.85 (m, 10H), 1.54-1.39 (m, 2H). 518.2
    SC_3300 cis-8-Dimethylamino-3-isoquinolin-4-yl-8-phenyl-1,3-diazaspiro[4.5]decan-2-one INT-976 4-bromo-isoquinoline SC_3103 1HNMR (DMSO-d6, 400 MHz at 100 0C), δ (ppm) = 9.16 (s, 1H), 8.41 (s, 1H), 8.13 (d, 1H, J = 8.12 Hz), 7.91 (d, 1H, J = 8.64 Hz), 7.71 (t, 1H, J = 7.58 Hz), 7.67 (t, 1H, J = 7.46 Hz), 7.36-7.23 (m, 5H), 7.14 (s, 1H), 3.67 (s, 2H), 2.41-2.36 (m, 2H), 2.10-1.89 (m, 10H), 1.68-1.64 (m, 2H). 401.2
    SC_3301 cis-8-Dimethylamino-3-isoquinolin-5-yl-8-phenyl-1,3-diazaspiro[4.5]decan-2-one INT-976 5-bromo-isoquinoline SC_3103 1HNMR (DMSO-d6, 400 MHz at 100 0C), δ (ppm) = 9.29 (s, 1H), 8.48 (d, 1H, J = 5.92 Hz) 7.98-7.96 (m, 1H), 7.70-7.64 (m, 3H), 7.36-7.23 (m, 5H), 7.13 (s, 1H), 3.65 (s, 2H), 2.41-2.36 (m, 2H), 2.10-1.90 (m, 10H), 1.68-1.63 (m, 2H). 401.2
    SC_3302 cis-8-Dimethylamino-8-phenyl-3-(1H-pyrrolo [2,3-b]pyridin-4-yl)-1,3-diazaspiro[4.5]decan-2-one INT-976 4-bromo-1H-pyrrolo[2,3-b]pyridine SC_3103 1H NMR (600 MHz, DMSO) δ 11.42 (s, 1H), 7.99 (d, 1H), 7.66 (br s, 1H), 7.43 - 7.33 (m, 5H), 7.27 (t, 1H), 7.22 (t, 1H), 6.65 - 6.60 (m, 1H), 3.91 (s, 2H), 2.45 - 2.27 (m, 2H), 1.98 - 1.82 (m, 10H), 1.56 - 1.49 (m, 2H). 390.2
    SC_3303 cis-8-Dimethylamino-8-phenyl-3-(2-pyridin-4-yl-thiazol-4-yl)-1,3-diazaspiro[4.5]decan-2-one INT-976 4-bromo-2-(pyridin-4-yl)thiazole SC_3103 1H NMR (DMSO-d6): δ 8.62 (d, 2H), 7.82 (d, 2H), 7.61 (broad s, 1H), 7.54 (s, 1H), 7.40-7.37 (m, 4H), 7.29-7.27 (m, 1H), 3.84 (s, 2H), 2.49 (m, 2H), 1.96-1.79 (m, 10H), 1.51 (m, 2H). 434.1
    SC_3304 cis-8-[Methyl-(tetrahydro-furan-3-yl-methyl)-amino]-3-(2-morpholin-4-yl-pyrimidin-5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (enantiomer 1) INT-1026 4-(5-bromopyrimidin-2-yl)morpholine step 2 of SC_3097 (for synthesis), SC_3292 and SC_3293 (for separation of enantiomers) 1H NMR (DMSO-d6): δ 8.56 (s, 2H), 7.65 (broad s, 1H), 7.36-7.23 (m, 5H), 3.66-3.55 (m, 10H), 3.49 (s, 2H), 3.38 (m, 1H), 2.32-2.26 (m, 3H), 2.11-1.94 (m, 6H), 1.86-1.82 (m, 3H),1.50-1.41(m, 3H). 507.3
    SC_3305 cis-8-[Methyl-(tetrahydro-furan-3-yl-methyl)-amino]-3-(2-morpholin-4-yl-pyrimidin-5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (enantiomer 2) INT-1026 4-(5-bromopyrimidin-2-yl)morpholine step 2 of SC_3097 (for synthesis), SC_3292 and SC_3293 (for separation of enantiomers) 1H NMR (DMSO-d6): δ 8.56 (s, 2H), 7.66 (broad s, 1H), 7.35-7.24 (m, 5H), 3.63-3.49 (m, 12H), 3.31 (m, 1H), 2.27 (m, 3H), 2.11-1.84 (m, 10H), 1.42 (m, 3H). 507.2
    SC_3306 cis-3-[2-(Azetidin-1-yl)-pyrimidin-5-yl]-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one INT-976 2-azetidin-1-yl-5-bromo-pyrimidine step 2 of SC_3242 1HNMR (DMSO-d6, 400 MHz at 100 0C), δ (ppm) = 8.48 (s, 2H), 7.36-7.26 (m, 5H), 7.07 (s, 1H), 3.99 (t, 4H, J = 7.18 Hz), 3.50 (s, 2H), 2.35-2.26 (m, 4H), 2.03 (s, 6H), 1.95-1.91 (m, 2H), 1.52-1.50 (m, 2H). 407.2
    SC_3307 cis-3-[2-(3,3-Difluoro-azetidin-1-yl)-pyrimidin-5-yl]-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one INT-976 5-bromo-2-(3,3-difluoro-azetidin-1-yl)-pyrimidine step 2 of SC_3242 1HNMR (DMSO-d6, 400 MHz at 100 0C), δ (ppm) = 8.62 (s, 2H), 7.37-7.25 (m, 5H), 7.20 (s, 1H), 4.38 (t, 4H, J = 12.40 Hz), 3.55 (s, 2H), 2.36-233 (m, 2H), 2.03 (s, 6H) 1.97-1.89 (m, 4H), 1.53-1.51 (m, 2H). 443.2
    SC_3308 cis-8-Dimethylamino-3-[6-morpholin-4-yl-5-(trifluoromethyl)-pyridin-3-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one INT-976 4-(5-bromo-3-trifluoromethyl-pyridin-2-yl)-morpholine SC_3103 1HNMR (DMSO-d6, 400 MHz at 100 0C), δ (ppm) = 8.63 (s, 1H), 8.38 (s, 1H), 7.37-7.25 (m, 6H), 3.71 (bs, 4H), 3.65 (s, 2H), 3.03 (bs, 4H), 2.37-2.32 (m, 2H), 2.03 (s, 6H), 1.98-1.88 (m, 4H), 1.55-1.52 (m, 2H). 504.3
    SC_3309 cis-8-Methylamino-3-[6-morpholin-4-yl-5-(trifluoromethyl)-pyridin-3-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3308 SC_3099 1HNMR (DMSO-d6, 400 MHz at 100 0C), δ (ppm) = 8.68 (s, 1H), 8.42 (s, 1H), 7.48 (d, 2H, J = 8.12 Hz), 7.33 (t, 2H, J = 7.62 Hz), 7.20 (t, 1H, J = 7.38 Hz), 7.14 (s, 1H), 3.75-3.71 (m, 6H), 3.03 (t, 4H, J = 8.88 Hz), 2.08-2.02 (m, 2H), 1.95-1.79 (m, 8H), 1.58-1.55 (m, 2H). 490.4
    SC_3310 cis-8-Dimethylamino-8-phenyl-3-[5-(trifluoromethyloxy)-pyridin-2-yl]-1,3-diazaspiro[4.5]decan-2-one INT-976 2-bromo-5-(trifluoromethoxy)-pyridine SC_3103 1H NMR (600 MHz, DMSO) δ 8.32 - 8.26 (m, 2H), 7.86 - 7.82 (m, 1H), 7.79 (dd, 1H), 7.41 - 7.33 (m, 4H), 7.27 (t, 1H), 3.71 (s, 2H), 2.46 - 2.33 (m, 2H), 1.96 (s, 6H), 1.94 - 1.72 (m, 4H), 1.47 (t, 2H). 435.2
    SC_3311 cis-8-Dimethylamino-3-(5-methylsulfonyl-pyridin-2-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one INT-976 2-bromo-5-methylsulfonylpyridine SC_3103 1H NMR (600 MHz, DMSO) δ 8.66 (dd, 1H), 8.39 (dd, 1H), 8.14 (dd, 1H), 8.06 (s, 1H), 7.42 - 7.33 (m, 4H), 7.28 (t, 1H), 3.77 (s, 2H), 3.21 (s, 3H), 2.46 - 2.32 (m, 2H), 2.03 - 1.68 (m, 10H), 1.52 - 1.46 (m, 2H). 429.2
    SC_3312 cis-6-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-nicotinonitrile INT-976 6-bromopyridine-3-carbonitrile SC_3103 1H NMR (600 MHz, DMSO) δ 8.66 (d, 1H), 8.34 (d, 1H), 8.08 (dd, 1H), 7.41 - 7.33 (m, 4H), 7.28 (t, 1H), 3.74 (s, 2H), 2.46 - 2.30 (m, 2H), 1.96 (s, 6H), 1.94 - 1.73 (m, 4H), 1.51 - 1.44 (m, 2H). 376.2
    SC_3314 cis-8-Dimethylamino-3-[4-methyl-2-(3-oxo-piperazin-1-yl)-pyrimidin-5-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one INT-976 4-(5-bromo-4-methyl-pyrimidin-2-yl)-piperazin-2-one SC_3103 1HNMR (DMSO-d6, 400 MHz at 100oC), δ (ppm) = 8.14 (s, 1H), 7.65 (bs, 1H), 7.34-7.23 (m, 5H), 6.89 (s, 1H), 4.16 (s, 2H), 3.88 (bs, 2H), 3.39 (s, 2H), 3.29 (bs, 2H), 2.33 (bs, 2H), 2.24 (s, 3H), 2.03-1.87 (m, 10H), 1.53 (bs, 2H). 464.2
    SC_3315 cis-5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-pyridine-2-carboxylic acid amide SC_3312 SC_3016 1H NMR (600 MHz, DMSO) δ 8.80 (d, 1H), 8.10 (dd, 1H), 7.95 - 7.89 (m, 2H), 7.79 (s, 1H), 7.42 - 7.35 (m, 5H), 7.28 (s, 1H), 3.67 (s, 2H), 2.48 - 2.28 (m, 2H), 1.95 (d, 10H), 1.53 - 1.46 (m, 2H). 394.2
    SC_3316 cis-3-[4-(Azetidin-1-yl)-2-methyl-pyrimidin-5-yl]-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one INT-976 4-azetidin-1-yl-5-bromo-2-methyl-pyrimidine step 2 of SC_3242 1HNMR (DMSO-d6, 400 MHz at 100 0C), δ (ppm) = 7.85 (s, 1H), 7.34-7.23 (m, 5H), 6.93 (s, 1H), 4.11 (t, 4H, J = 7.40 Hz), 3.33 (s, 2H), 2.33-2.30 (m, 7H), 2.02 (s, 6H), 1.96-1.87 (m, 4H), 1.53-1.48 (m, 2H). 421.2
    SC_3317 cis-2-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-benzamide INT-976 2-bromobenzonitrile SC_3103 (step 1), SC_3016 (step 2) 1H NMR (600 MHz, DMSO) δ 7.50 (s, 1H), 7.42 (dd, 1H), 7.42 - 7.32 (m, 5H), 7.31 (d, 1H), 7.26 (t, 1H), 7.23 - 7.13 (m, 3H), 3.53 (s, 2H), 2.41 - 2.27 (m, 2H), 1.96 (s, 6H), 1.90 (t, 2H), 1.86 - 1.68 (m, 2H), 1.52 - 1.48 (m, 2H). 393.2
    SC_3318 cis-8-Dimethylamino-3-[2-(methylsulfonyl-methyl)-phenyl]-8-thiophen-2-yl-1,3-diazaspiro[4.5]decan-2-one INT-997 1-bromo-2-(methylsulfonylmethy 1)-benzene SC_3103 1H NMR (600 MHz, DMSO) δ 7.47 (dd, 1H), 7.43 - 7.36 (m, 2H), 7.34 (dd, 1H), 7.29 (ddd, 1H), 7.19 (s, 1H), 7.05 (ddd, 1H), 6.94 (d, 1H), 4.50 (s, 2H), 3.61 (s, 2H), 2.89 (s, 3H), 2.35 - 2.21 (m, 2H), 2.04 (s, 6H), 1.98 - 1.90 (m, 2H), 1.86 - 1.70 (m, 2H), 1.66 - 1.59 (m, 2H). 448.2
    SC_3320 cis-8-Dimethylamino-3-(4-methyl-2-morpholin-4-yl-pyrimidin-5-yl)-8-thiophen-2-yl-1,3-diazaspiro[4.5]decan-2-one INT-997 4-(5-bromo-4-methyl-pyrimidin-2-yl)morpholine SC_3319 1H NMR (600 MHz, DMSO) δ 8.15 (d, 1H), 7.41 (dt, 1H), 7.13 (s, 1H), 7.05 (ddd, 1H), 6.94 (dd, 1H), 3.71 - 3.60 (m, 8H), 3.44 (s, 2H), 2.32 - 2.24 (m, 2H), 2.21 (s, 3H), 2.04 (s, 6H), 1.98 - 1.88 (m, 2H), 1.87 - 1.75 (m, 2H), 1.62 - 1.54 (m, 2H). 457.2
    SC_3321 cis-8-Dimethylamino-3-(6-methylsulfonyl-pyridin-3-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one INT-976 5-bromo-2-methylsulfonylpyridine SC_3103 1H NMR (600 MHz, DMSO) δ 8.89 (d, J = 2.6 Hz, 1H), 8.28 (dd, J = 8.9, 2.6 Hz, 1H), 7.93 (d, 1H), 7.42 - 7.34 (m, 4H), 7.31 - 7.25 (m, 1H), 3.71 (s, 2H), 3.18 (s, 3H), 2.48 - 2.33 (m, 2H), 2.04 - 1.76 (m, 10H), 1.54-1.48 (m, 2H). 429.2
    SC_3322 cis-8-Dimethylamino-8-phenyl-3-(1H-pyrrolo [2,3-b]pyridin-5-yl)-1,3-diazaspiro[4.5]decan-2-one INT-976 tert-butyl 5-bromopyrrolo[2,3-b]pyridine-1-carboxylate (step 1) SC_3103 (for step 1), SC_3173 (for step 2) 1H NMR (600 MHz, DMSO) δ 11.45 (s, 1H), 8.38 (s, 1H), 8.00 (d, 1H), 7.85 - 7.81 (m, 1H), 7.70 - 7.66 (m, 2H), 7.57 - 7.53 (m, 3H), 7.41 (t, 1H), 6.35 (dd, 1H), 3.54 (s, 2H), 2.75 - 2.41 (m, 8H, overlapps with solvent residual peak), 2.30 - 2.26 (m, 2H), 1.89 (d, 2H), 1.41 - 1.37 (m, 2H). 390.2
    SC_3323 cis-N-[5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-pyrimidin-2-yl]-acetamide (enantiomer 1) SC_3239 acetyl chloride SC_3240 1H NMR (600 MHz, DMSO) δ 10.36 (s, 1H), 8.82 (s, 2H), 8.40 (s, rotamer), 7.67 (s, 1H), 7.44 - 7.31 (m, 4H), 7.27 (td, 1H), 3.62 (s, 2H), 2.46 - 2.30 (m, 2H), 2.11 (s, 3H), 2.08 (s, rotamer), 1.96 (s, 6H), 1.97 (s, rotamer), 1.95 - 1.75 (m, 4H), 1.52 - 1.47 (m, 2H). 409.2
    SC_3324 cis-3-[2-(4-Methyl-piperazin-1-yl)-pyrimidin-5-yl]-8-[methyl-(tetrahydro-furan-3-yl-methyl)-amino]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (enantiomer 2) INT-1026 5-bromo-2-(4-methylpiperazin-1-yl)pyrimidine step 2 of SC_3097 (for synthesis), SC_3292 and SC_3293 (for separation of enantiomers) 1H NMR (DMSO-d6): δ 8.52 (s, 2H), 7.64 (broad s, 1H), 7.36-7.23 (m, 5H), 3.66-3.55 (m, 7H), 3.48 (s, 2H), 3.37-3.36 (m, 1H), 2.33-2.13 (m, 11H), 2.01-1.82 (m, 9H), 1.50-1.41 (m, 3H). 518.3
    SC_3325 cis-3-[2-(4-Methyl-piperazin-1-yl)-pyrimidin-5-yl]-8-[methyl-(tetrahydro-furan-3-yl-methyl)-amino]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one INT-1026 5-bromo-2-(4-methylpiperazin-1-yl)pyrimidine step 2 of SC_3097 (for synthesis), SC_3292 and SC_3293 (for separation of enantiomers) 1H NMR (DMSO-d6): δ 8.52 (s, 2H), 7.64 (broad s, 1H), 7.36-7.24 (m, 5H), 3.66-3.55 (m, 7H), 3.48 (s, 2H), 3.36 (m, 1H), 2.34-2.13 (m, 10H), 2.01-1.83 (m, 10H), 1.50-1.41 (m, 3H). 518.3
    SC_3326 cis-8-Dimethylamino-3-(4,6-dimethyl-2-morpholin-4-yl-pyrimidin-5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one INT-976 4-(5-bromo-4,6-dimethyl-pyrimidin-2-yl)morpholine SC_3103 465.3
    SC_3327 cis-8-Dimethylamino-3-(2-morpholin-4-yl-pyrimidin-5-yl)-8-thiophen-2-yl-1,3-diazaspiro[4.5]decan-2-one INT-1027 morpholine SC_3120 1H NMR (600 MHz, DMSO) δ 8.58 (s, 2H), 7.43 (dd, 1H), 7.40 - 7.32 (m, 1H), 7.07 (dd, 1H), 6.96 (dd, 1H), 3.67 - 3.61 (m, 4H), 3.62 - 3.57 (m, 6H), 2.31 - 2.27 (m, 2H), 2.04 (s, 6H), 1.91 (t, 2H), 1.86 - 1.82 (m, 2H), 1.56 - 1.50 (m, 2H). 443.2
    SC_3328 cis-6-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-pyridine-3-carboxylic acid amide SC_3312 SC_3016 1H NMR (600 MHz, DMSO) δ 8.71 (d, J = 2.3 Hz, 1H), 8.24 (d, J = 8.9 Hz, 1H), 8.12 (dd, J = 9.0, 2.4 Hz, 1H), 7.95 (s, 1H), 7.86 (s, 1H), 7.36 (dq, J = 13.7, 6.6, 5.6 Hz, 5H), 7.27 (t, J = 7.2 Hz, 1H), 3.74 (s, 2H), 2.41 - 2.37 (m, 2H), 1.96 (s, 6H), 1.94 - 1.87 (m, 2H), 1.86 - 1.80 (m, 2H), 1.51 - 1.44 (m, 2H). 394.2
    SC_3329 cis-8-Dimethylamino-3-[2-methyl-5 -(trifluoromethyl)-2H-pyrazol-3-yl]-8-thiophen-2-yl-1,3-diazaspiro[4.5]decan-2-one INT-997 5-bromo-1-methyl-3-(trifluoromethyl)pyrazole SC_3319 1H NMR (600 MHz, DMSO) δ 7.66 - 7.63 (m, 1H), 7.42 (dd, 1H), 7.06 (dd, 1H), 6.95 (dd, 1H), 6.64 (s, 1H), 3.75 (s, 3H), 3.60 (s, 2H), 2.30 - 2.26 (m, 2H), 2.04 (s, 6H), 1.98 - 1.90 (m, 2H), 1.83 - 1.79 (m, 2H), 1.64 - 1.57 (m, 2H). 428.2
    SC_3330 cis-8-Dimethylamino-3-[2-[(2-hydroxy-ethyl)-methyl-amino]-pyrimidin-5-yl]-8-thiophen-2-yl-1,3-diazaspiro[4.5]decan-2-one INT-1027 2-(methylamino)ethanol SC_3120 1H NMR (600 MHz, DMSO) δ 8.48 (s, 2H), 7.43 (d, 1H), 7.30 (s, 1H), 7.07 (dd, 1H), 6.96 (d, 1H), 3.61 (dd, 2H), 3.58 - 3.51 (m, 4H), 3.09 (s, 3H), 2.34 - 2.22 (m, 2H), 2.04 (s, 6H), 1.96 - 1.76 (m, 4H), 1.56 - 1.50 (m, 2H). 431.2
    SC_3331 cis-8-Dimethylamino-3-[2-(2-oxo-1,3-dihydro-indol-4-yl)-pyrimidin-5-yl]-8-thiophen-2-yl-1,3-diazaspiro[4.5]decan-2-one INT-1027 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indolin-2-one SC_3208 1H NMR (600 MHz, DMSO) δ 10.46 (s, 1H), 9.12 (s, 2H), 7.87 (d, 1H), 7.47 - 7.42 (m, 1H), 7.31 (t, 1H), 7.08 (dd, 1H), 6.98 (dd, 1H), 6.92 (d, 1H), 3.83 (s, 2H), 3.77 (s, 2H), 2.35 - 2.30 (m, 2H), 2.05 (s, 6H), 1.96 (t, 2H), 1.88 (s, 2H), 1.60 - 1.54 (m, 2H). 489.2
    SC_3332 cis-8-Dimethylamino-3-[4-methyl-6-(3-oxo-piperazin-1-yl)-pyridin-3-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one INT-976 4-(5-bromo-4-methyl-pyridin-2-yl)-piperazin-2-one step 2 of SC_3097 1H-NMR (DMSO-d6, 400 MHz at 100oC), δ (ppm) = 7.89 (s, 1H), 7.62 (bs, 1H), 7.35-7.22 (m, 5H), 6.73 (s, 1H), 6.62 (s, 1H), 3.96 (s, 2H), 3.68 (t, 2H, J = 5.2 Hz), 3.39 (s, 2H), 3.30 (bs, 2H), 2.35-2.30 (m, 2H), 2.15 (s, 3H), 2.03-1.86 (m, 10H), 1.56-1.51 (m, 2H). 463.2
    SC_3333 cis-8-Dimethylamino-3-(4-methyl-6-pyridin-2-yl-pyridin-3-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one INT-976 5-bromo-2-chloro-4-methyl-pyridine (step 1), 2-tributylstannanyl-pyridine (step 2) SC_3103 (for step 1), SC_3162 (for step 2) 1H-NMR (DMSO-d6, 400 MHz at 100 0C), δ (ppm) = 8.64 (d, 1H, J = 4.0 Hz), 8.45 (s, 1H), 8.31 (d, 1H, J = 8.68 Hz), 8.22 (s, 1H), 7.88 (t, 1H, J = 7.04 Hz), 7.39-7.35 (m, 5H), 7.26-7.23 (m, 1H), 7.03 (s, 1H), 3.57 (s, 2H), 2.39-2.33 (m, 5H), 2.04 (s, 6H), 2.01-1.88 (m, 4H), 1.61-1.57 (m, 2H). 442.3
    SC_3334 cis-8-Dimethylamino-3-(4-methylsulfonyl-pyridin-3-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one INT-976 3-bromo-4-methylsulfanyl-pyridine (step 1) SC_3103 (for step 1), SC_3008 (for step 2) 1HNMR at 100oC (DMSO-d6, 400 MHz), δ (ppm) = 8.77-8.72 (m, 2H), 7.85-7.84 (m, 1H), 7.35-7.23 (m, 6H), 3.60 (s, 2H), 3.31 (s, 3H), 2.36 (bs, 2H), 2.03-1.82 (m, 10H), 1.60-1.58 (m, 2H). 429.3
    SC_3335 cis-3-(Benzothiazol-7-yl)-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one INT-976 7-bromo-benzothiazole SC_3103 407.1
    SC_3336 cis-8-Dimethylamino-8-(4-fluorophenyl)-3-(4-methyl-2-morpholin-4-yl-pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one INT-1025 4-(5-bromo-4-methyl-pyrimidin-2-yl)morpholine SC_3319 1H NMR (600 MHz, DMSO) δ 8.13 (s, 1H), 7.41 - 7.35 (m, 2H), 7.22 - 7.13 (m, 3H), 3.69 - 3.60 (m, 8H), 2.35 - 2.31 (m, 2H), 2.20 (s, 3H), 1.94 (s, 6H), 1.93 - 1.74 (m, 4H), 1.53 - 1.43 (m, 2H). 469.3
    SC_3337 cis-2-[8-Dimethylamino-3-[4-methyl-6-(trifluoromethyl)-pyridin-3-yl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl]-N,N-dimethyl-acetamide SC_3122 2-chloro-N,N-dimethyl-acetamide INT-988 (step 1) 1H NMR (600 MHz, DMSO) δ 8.59 (s, 1H), 7.82 (s, 1H), 7.37 - 7.32 (m, 4H), 7.25 (ddd, 1H), 4.00 (s, 2H), 3.80 (s, 2H), 3.07 (s, 3H), 2.87 (s, 3H), 2.71 - 2.64 (m, 2H), 2.55 (s, 3H), 2.34 (s, 3H), 2.03 (td, 2H), 1.98 (s, 6H), 1.67 - 1.58 (m, 2H), 1.49 - 1.40 (m, 2H). 518.3
    SC_3338 cis-8-Dimethylamino-3-[2-(2-methyl-1-oxo-2,3-dihydro-isoindol-4-yl)-pyrimidin-5-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one INT-989 2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-1-one SC_3208 1H NMR (600 MHz, DMSO) δ 9.57 (s, 1H), 9.08 (s, 2H), 8.52 (d, 1H), 8.43 (s, 1H), 7.77 (d, 1H), 7.72 (d, 2H), 7.63 (t, 1H), 7.59 (t, 2H), 7.55 (t, 1H), 4.86 (s, 2H), 3.59 (s, 2H), 3.13 (s, 3H), 2.72 (d, 2H), 2.61 (s, 6H), 2.25 (td, 2H), 1.91 (d, 2H), 1.43 - 1.35 (m, 2H). 497.3
    SC_3339 cis-2-[[5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-2-methyl-pyrimidin-4-yl]amino]-acetamide INT-976 (5-bromo-2-methyl-pyrimidin-4-ylamino)-acetonitrile (step 1) step 2 of SC_3242 (for step 1), SC_3016 (for step 2) 1HNMR at 100°C (DMSO-d6, 400 MHz), δ (ppm) = 7.93 (s, 1H), 7.36-7.22 (m, 5H), 7.12 (s, 1H), 6.91 (bs, 2H), 6.58 (bs, 1H), 3.94 (d, 2H), 3.46 (s, 2H), 2.35-2.32 (m, 5H), 2.03-1.97 (m, 8H), 1.91-1.84 (m, 2H), 1.61-1.56 (m, 2H). 438.4
    SC_3341 cis-8-Dimethylamino-3-[4-(methylsulfonyl-methyl)-pyridin-3-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one INT-976 3-bromo-4-methanesulfonylmethyl-pyridine step 2 of SC_3097 1HNMR at 100oC (DMSO-d6, 400 MHz), δ (ppm) = 8.53 (s, 1H), 8.43 (d, 1H, J = 4.88 Hz), 7.48 (d, 1H, J = 4.88 Hz), 7.36-7.23 (m, 5H), 7.15 (s, 1H), 4.55 (s, 2H), 3.64 (s, 2H), 2.95 (s, 3H), 2.38-2.33 (m, 2H), 2.04 (s, 6H), 1.99-1.83 (m, 4H), 1.62-1.57 (m, 2H). 443.4
    SC_3342 cis-8-Dimethylamino-3-[6-(4-methyl-3-oxo-piperazin-1-yl)-pyridin-3-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one INT-976 INT-976 4-(5-bromo-2-pyridyl)-1-methyl-piperazin-2-one SC_3242 (step 2) 1H NMR (600 MHz, CDCl3) δ 8.09 (d, 1H), 8.00 (dd, 1H), 7.45 - 7.39 (m, 2H), 7.37 - 7.28 (m, 3H), 6.61 (d, 1H), 5.71 (s, 1H), 4.04 (s, 2H), 3.87 - 3.82 (m, 2H), 3.51 (s, 2H), 3.45 (t, 2H), 3.03 (s, 3H), 2.32 - 2.02 (m, 10H), 2.02 - 1.94 (m, 2H), 1.64 - 1.53 (m, 2H). 463.3
    SC_3343 cis-8-Dimethylamino-3-(2,4-dimethyl-pyrimidin-5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one INT-976 5-bromo-2,4-dimethyl-pyrimidine SC_3103 1H NMR (600 MHz, DMSO) δ 8.46 (s, 1H), 7.45 - 7.33 (m, 5H), 7.28 - 7.24 (m, 1H), 3.51 (s, 2H), 2.54 (s, 3H), 2.41 - 2.28 (m, 5H), 2.03 - 1.77 (m, 10H), 1.56 - 1.49 (m, 2H). 380.3
    SC_3344 cis-8-Dimethylamino-3-[2-(1-oxo-2,3-dihydro-isoindol-4-yl)-pyrimidin-5-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; 2,2,2-trifluoro-acetic acid INT-989 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-1-one SC_3208 1H NMR (600 MHz, DMSO) δ 9.06 (s, 2H), 8.67 (s, 1H), 8.52 (d, 1H), 8.39 (s, 1H), 7.75 (dd, 3H), 7.66 - 7.51 (m, 4H), 4.75 (s, 2H), 3.58 (s, 2H), 3.18 (s, 2H), 2.75 (d, 2H), 2.60 (s, 6H), 2.27 (t, 2H), 1.91 (d, 2H), 1.39 (t, 2H). 483.3
    SC_3345 cis-8-Dimethylamino-3-[6-[(2-hydroxy-ethyl)-methyl-amino]-5-(trifluoromethyl)-pyridin-3-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one INT-976 2-[[5-bromo-3-(trifluoromethyl)-2-pyridyl]-methyl-amino] ethanol SC_3103 1H NMR (600 MHz, DMSO) δ 8.55 - 8.51 (m, 1H), 8.35 (d, 1H), 7.62 (s, 1H), 7.37 (td, 4H), 7.27 (td, 1H), 3.63 (s, 2H), 3.50 (td, 2H), 3.20 (t, 2H), 2.78 (s, 3H), 2.43 - 2.36 (m, 2H), 1.96 (s, 6H), 1.95 - 1.75 (m, 4H), 1.48 (t, 2H). 492.3
    SC_3346 cis-8-Dimethylamino-8-phenyl-3-[2-[4-(trifluoromethyl)-1H-[1,2,3]triazol-1-yl]-pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2-one INT-976 3,3,3-trifluoroprop-1-yne, 2-azido-5-bromo-pyrimidine SC_3313 1H NMR (600 MHz, DMSO) δ 9.56 (d, 1H), 9.16 (s, 2H), 7.99 (s, 1H), 7.42 - 7.35 (m, 4H), 7.31 - 7.25 (m, 1H), 3.75 (s, 2H), 2.49 - 2.34 (m, 2H), 2.05 - 1.75 (m, 10H), 1.60 - 1.47 (m, 2H). 487.3
    SC_3347 cis-8-Dimethylamino-3-[2-(4-isopropyl-1H-[1,2,3]triazol-1-yl)-pyrimidin-5-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one INT-976 3-methylbut-1-yne, 2-azido-5-bromo-pyrimidine SC_3313 1H NMR (600 MHz, DMSO) δ 9.10 (s, 2H), 8.50 (d, 1H), 7.91 (s, 1H), 7.42 - 7.35 (m, 5H), 7.28 (td, 1H), 3.73 (s, 2H), 3.08 (hept, 1H), 2.44 (s, 2H), 2.01 - 1.76 (m, 10H), 1.59 - 1.48 (m, 2H), 1.30 (d, 6H). 461.3
    SC_3348 cis-8-Dimethylamino-3-[6-(1,1-dioxo-[1,4]thiazinan-4-yl)-pyridin-3-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one INT-976 1,4-thiazinane 1,1-dioxide, 5-bromo-2-chloro-pyridine (step 1) SC_3242 1H NMR (600 MHz, DMSO) δ 8.23 (d, 1H), 7.93 (dd, 1H), 7.41 - 7.33 (m, 5H), 7.27 (t, 1H), 6.98 (d, 1H), 3.97 (t, 4H), 3.53 (s, 2H), 3.04 (t, 4H), 2.43 - 2.28 (m, 2H), 1.96 (s, 6H), 1.92 - 1.72 (m, 4H), 1.51 - 1.40 (m, 2H). 484.2
    SC_3349 cis-5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-2-morpholin-4-yl-nicotinonitrile INT-976 5-bromo-2-chloropyridine-3-carbonitrile, morpholine SC_3242 1H NMR (600 MHz, DMSO-d6) δ 8.66 (d, J = 2.9 Hz, 1H), 8.25 (d, J = 2.8 Hz, 1H), 7.60 (s, 1H), 7.41 - 7.33 (m, 4H), 7.30 - 7.24 (m, 1H), 3.74 - 3.69 (m, 4H), 3.60 (s, 2H), 2.48 - 2.29 (m, 2H), 1.96 (s, 6H), 1.94 - 1.68 (m, 4H), 1.52 - 1.41 (m, 2H). 461.3
    SC_3350 cis-8-Dimethylamino-3-(1-methylsulfonyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one INT-976 5-bromo-1-methylsulfonyl-pyrrolo[2,3-b]pyridine SC_3103 1H NMR (600 MHz, DMSO) δ 8.64 (d, 1H), 8.28 (d, 1H), 7.65 (dd, 1H), 7.57 (s, 1H), 7.38 (dd, 4H), 7.28 (dt, 1H), 6.72 (dd, 1H), 3.68 (s, 2H), 3.65 (s, 3H), 2.48 - 2.29 (m, 2H), 1.98 (s, 10H), 1.53 - 1.44 (m, 2H). 468.2
    SC_3351 cis-8-Dimethylamino-3-(1H-indol-4-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one INT-976 4-bromo-1-(toluene-4-sulfonyl)-1H-indole (step 1) SC_3357 1H-NMR (DMSO-d6, 400 MHz at 100 0C), δ (ppm) = 10.77 (bs, 1H), 7.37 (bs, 4H), 7.24-7.18 (m, 3H), 7.02-6.94 (m, 2H), 6.81 (bs, 1H), 6.41 (s, 1H), 3.66 (s, 2H), 2.36-2.33 (m, 2H), 2.05-1.96 (m, 10H), 1.60-156 (m, 2H). 389.3
    SC_3353 cis-8-Dimethylamino-3-[2-fluoro-4-(trifluoromethyloxy)-phenyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one INT-976 1-bromo-2-fluoro-4-(trifluoromethoxy)-benzene SC_3103 1H NMR (600 MHz, DMSO) δ 7.62 (t, 1H), 7.50 - 7.46 (m, 1H), 7.40 (dd, 1H), 7.38 - 7.31 (m, 4H), 7.25 (t, 1H), 7.21 (d, 1H), 3.57 (s, 2H), 2.38 (d, 2H), 1.97 - 1.88 (m, 8H), 1.84 - 1.79 (m, 2H), 1.53 - 1.46 (m, 2H). 452.2
    SC_3355 cis-8-Dimethylamino-3-(1-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one INT-976 4-bromo-1-methyl-pyrrolo[2,3-b]pyridine SC_3103 1H NMR (600 MHz, DMSO) δ 8.04 (d, 1H), 7.70 (s, 1H), 7.47 (d, 1H), 7.41 - 7.33 (m, 4H), 7.31 - 7.24 (m, 2H), 6.65 (d, 1H), 3.91 (s, 2H), 3.74 (s, 3H), 2.44 - 2.25 (m, 2H), 2.08 - 1.74 (m, 10H), 1.52 (t, 2H). 404.3
    SC_3356 cis-3-(1-Acetyl-1H-indol-4-yl)-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3351 acetyl chloride SC_3379 1H-NMR (DMSO-d6, 400 MHz at 100 0C), δ (ppm) = 8.12 (d, 1H, J = 8.28 Hz), 7.68 (d, 1H, J = 3.64 Hz), 7.36-7.22 (m, 6H), 7.16 (d, 1H, J = 7.80 Hz), 7.01 (s, 1H), 6.69 (d, 1H, J = 3.8 Hz), 3.66 (s, 2H), 2.62 (s, 3H), 2.38-2.33 (m, 2H), 2.05-1.92 (m, 10H), 1.61-1.56 (m, 2H). 431.2
    SC_3358 cis-6-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-5-methyl-nicotinonitrile INT-976 6-chloro-5-methyl-pyridine-3-carbonitrile SC_3103 1H NMR (600 MHz, DMSO) δ 8.64 (s, 1H), 8.12 (s, 1H), 7.76 (s, 1H), 7.39 - 7.34 (m, 4H), 7.27 (s, 1H), 3.71 (s, 2H), 2.43 - 2.15 (m, 5H), 2.11 - 1.70 (m, 10H), 1.52 (s, 2H). 390.2
    SC_3359 cis-6-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-5-fluoro-nicotinonitrile INT-976 6-chloro-5-fluoro-pyridine-3-carbonitrile SC_3103 1H NMR (600 MHz, DMSO) δ 8.64 (d, 1H), 8.30 (dd, 1H), 7.95 (s, 1H), 7.40 - 7.31 (m, 4H), 7.29 - 7.23 (m, 1H), 3.72 (s, 2H), 2.36 - 2.33 (m, 2H), 1.96 (s, 6H), 1.94 - 1.79 (m, 4H), 1.52 (t, 2H). 394.2
    SC_3361 cis-6-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-5-methyl-pyridine-3-carboxylic acid amide SC_3358 SC_3016 1H NMR (600 MHz, DMSO) δ 8.64 (d, 1H), 8.06 - 8.02 (m, 2H), 7.54 (s, 1H), 7.44 (s, 1H), 7.38 - 7.30 (m, 4H), 7.27 - 7.21 (m, 1H), 3.67 (s, 2H), 2.37 - 2.26 (m, 5H), 2.05 - 1.75 (m, 10H), 1.51 (t, 2H). 408.2
    SC_3362 cis-6-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-5-fluoro-pyridine-3-carboxylic acid amide SC_3359 SC_3016 1H NMR (600 MHz, DMSO) δ 8.65 - 8.61 (m, 1H), 8.13 (s, 1H), 8.04 (dd, 1H), 7.76 (s, 1H), 7.59 (s, 1H), 7.39 - 7.30 (m, 4H), 7.28 - 7.21 (m, 1H), 3.70 (s, 2H), 2.41 - 2.23 (m, 2H), 1.96 - 1.76 (m, 10H), 1.50 (t, 2H). 412.2
    SC_3363 cis-8-Dimethylamino-3-[4-methyl-6-(trifluoromethyl)-pyridin-3-yl]-8-m-tolyl-1,3-diazaspiro[4.5]decan-2-one INT-1038 5-bromo-4-methyl-2-(trifluoromethyl)pyridine SC_3319 1H NMR (600 MHz, DMSO) δ 8.56 (s, 1H), 7.80 (s, 1H), 7.52 (s, 1H), 7.24 (t, 1H), 7.17 - 7.11 (m, 2H), 7.06 (d, 1H), 3.60 (s, 2H), 2.39 - 2.25 (m, 8H), 2.01 - 1.78 (m, 10H), 1.58 - 1.48 (m, 2H). 447.2
    SC_3364 cis-3-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-isonicotinonitrile INT-976 3-bromopyridine-4-carbonitrile SC_3242 1H NMR (600 MHz, DMSO) δ 8.79 (s, 1H), 8.50 (d, 1H), 7.84 - 7.80 (m, 1H), 7.37 (td, 4H), 7.26 (td, 1H), 3.79 (s, 2H), 2.43 - 2.36 (m, 2H), 1.97 (s, 7H), 1.96 - 1.91 (m, 2H), 1.88 - 1.81 (m, 2H), 1.61 - 1.45 (m, 2H). 376.2
    SC_3365 cis-8-Dimethylamino-3-[3-fluoro-5-(2-oxo-1,3-dihydro-indol-4-yl)-pyridin-2-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one INT-1045 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indolin-2-one (step 2) SC_3354 1H NMR (600 MHz, DMSO) δ 10.51 (s, 1H), 8.39 (d, 1H), 7.96 (dd, 1H), 7.41 - 7.32 (m, 4H), 7.28 (dt, 2H), 7.08 (d, 1H), 6.88 (d, 1H), 3.71 (s, 2H), 3.67 (s, 2H), 2.44 - 2.22 (m, 2H), 1.98 - 1.87 (m, 11H), 1.58 - 1.46 (m, 2H). 500.2
    SC_3366 cis-8-Dimethylamino-3-[4-methyl-6-(trifluoromethyl)-pyridin-3-yl]-8-[3-(trifluoromethyloxy)-phenyl]-1,3-diazaspiro[4.5]decan-2-one INT-1039 5-bromo-4-methyl-2-(trifluoromethyl)pyridine SC_3319 1H NMR (600 MHz, DMSO) δ 8.55 (s, 1H), 7.79 (s, 1H), 7.51 (t, 2H), 7.38 (dd, 1H), 7.26 (d, 2H), 3.62 (s, 2H), 2.40 - 2.34 (m, 2H), 2.31 (s, 3H), 2.01 - 1.77 (m, 10H), 1.58 - 1.49 (m, 2H). 517.2
    SC_3367 cis-8-Dimethylamino-3-[4-methyl-6-(trifluoromethyl)-pyridin-3-yl]-8-[3-(trifluoromethyl)phenyl]-1,3-diazaspiro[4.5]decan-2-one INT-1040 5-bromo-4-methyl-2-(trifluoromethyl)pyridine SC_3319 1H NMR (600 MHz, DMSO) δ 8.55 (s, 1H), 7.79 (s, 1H), 7.69 - 7.56 (m, 5H), 7.52 (s, 1H), 3.61 (s, 2H), 2.44 - 2.36 (m, 2H), 2.31 (s, 3H), 2.02 - 1.80 (m, 10H), 1.60 - 1.47 (m, 2H). 501.2
    SC_3368 cis-8-Dimethylamino-8-(3-methoxyphenyl)-3-[4-methyl-6-(trifluoromethyl)-pyridin-3-yl]-1,3-diazaspiro[4.5]decan-2-one INT-1041 5-bromo-4-methyl-2-(trifluoromethyl)pyridine SC_3319 1H NMR (600 MHz, DMSO) δ 8.56 (s, 1H), 7.80 (s, 1H), 7.51 (s, 1H), 7.31 - 7.25 (m, 1H), 6.92 (dt, 1H), 6.87 - 6.82 (m, 2H), 3.75 (s, 3H), 3.61 (s, 2H), 2.35 - 2.30 (m, 5H), 1.98 (s, 7H), 1.96 - 1.90 (m, 2H), 1.88 - 1.80 (m, 2H), 1.60 - 1.49 (m, 2H). 463.2
    SC_3369 cis-8-(5-Chloro-thiophen-2-yl)-8-dimethylamino-3-[4-methyl-6-(trifluoromethyl)-pyridin-3-yl]-1,3-diazaspiro[4.5]decan-2-one INT-1042 5-bromo-4-methyl-2-(trifluoromethyl)pyridine SC_3319 1H NMR (600 MHz, DMSO) δ 8.56 (s, 1H), 7.79 (s, 1H), 7.39 (s, 1H), 7.04 - 7.00 (m, 1H), 6.80 (d, 1H), 3.64 (s, 2H), 2.31 (s, 3H), 2.22 - 2.15 (m, 2H), 2.04 (s, 6H), 1.95 - 1.87 (m, 2H), 1.83 - 1.77 (m, 2H), 1.63 - 1.57 (m, 2H). 473.1
    SC_3370 cis-8-Dimethylamino-8-(3-fluorophenyl)-3-[4-methyl-6-(trifluoromethyl)-pyridin-3-yl]-1,3-diazaspiro[4.5]decan-2-one INT-1024 5-bromo-4-methyl-2-(trifluoromethyl)pyridine SC_3319 1H NMR (600 MHz, DMSO) δ 8.56 (s, 1H), 7.80 (s, 1H), 7.51 (s, 1H), 7.41 (td, 1H), 7.21 - 7.12 (m, 2H), 7.12 - 7.06 (m, 1H), 3.61 (s, 2H), 2.38 - 2.30 (m, 5H), 1.97 (s, 6H), 1.96 - 1.90 (m, 2H), 1.90 - 1.73 (m, 2H), 1.61 - 1.45 (m, 2H). 451.2
    SC_3371 cis-8-Dimethylamino-3-(2-methylamino-pyrimidin-5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one INT-989 methylamine SC_3239 1H NMR (600 MHz, DMSO + TFA) δ 8.69 (s, 2H), 8.29 (s, 1H), 7.68 (d, 2H), 7.52 (dt, 3H), 2.90 (s, 3H), 2.68 (d, 2H), 2.59 (s, 6H), 2.24 (t, 2H), 1.86 (d, 2H), 1.39 - 1.31 (m, 2H) 381.2
    SC_3372 cis-8-(5-Chloro-thiophen-2-yl)-8-dimethylamino-3-(4-methyl-2-morpholin-4-yl-pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one INT-1042 4-(5-bromo-4-methyl-pyrimidin-2-yl)morpholine SC_3242 1H NMR (600 MHz, DMSO) δ 8.15 (d, 1H), 7.15 (s, 1H), 7.05 (d, 1H), 6.82 (d, 1H), 3.70 - 3.61 (m, 8H), 3.44 (s, 2H), 2.31 - 2.12 (m, 5H), 2.06 (s, 6H), 1.93 - 1.85 (m, 2H), 1.82 - 1.69 (m, 2H), 1.64 - 1.49 (m, 2H). 491.2
    SC_3373 cis-N-[5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-pyrimidin-2-yl]-N-methyl-cyclopropanecarboxylic acid amide SC_3371 Cyclopropancarbonyl chlorid SC_3240 1H NMR (600 MHz, DMSO) δ 8.97 (s, 2H), 7.83 - 7.73 (m, 1H), 7.41 - 7.34 (m, 4H), 7.30 - 7.24 (m, 1H), 3.66 (s, 2H), 3.27 (s, 3H), 2.47 - 2.29 (m, 2H), 1.99 - 1.87 (m, 10H), 1.49 (t, 2H), 0.88 - 0.80 (m, 2H), 0.70 (dt, 2H). 449.3
    SC_3374 cis-N-[5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-pyrimidin-2-yl]-N,2,5-trimethyl-2H-pyrazole-3-carboxylic acid amide SC_3371 2,5-dimethylpyrazole-3-carbonyl chloride SC_3240 1H NMR (600 MHz, DMSO) δ 8.83 (s, 2H), 7.77 (s, 1H), 7.41 - 7.32 (m, 4H), 7.27 (td, 1H), 5.48 (s, 1H), 3.80 (s, 3H), 3.61 (s, 2H), 3.40 (s, 3H), 2.46 - 2.31 (m, 2H), 1.96 (s, 3H), 1.96 (s, 6H), 1.94 - 1.74 (m, 5H), 1.52 - 1.42 (m, 2H). 503.3
    SC_3375 cis-3-[4,6-Bis(trifluoromethyl)-pyridin-3-yl]-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one INT-976 5-bromo-2,4-bis(trifluoromethyl)pyridine SC_3103 1H NMR (600 MHz, DMSO) δ 8.98 (s, 1H), 8.20 (s, 1H), 7.79 (s, 1H), 7.40 - 7.32 (m, 4H), 7.26 (td, 1H), 3.62 (s, 2H), 2.44 - 2.24 (m, 2H), 1.98 - 1.91 (m, 8H), 1.86 (s, 2H), 1.53 (t, 2H). 487.2
    SC_3376 cis-8-Dimethylamino-3-[2-[(2-hydroxy-ethyl)-methyl-amino]-quinazolin-6-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one INT-976 2-[(6-bromo-quinazolin-2-yl)-methyl-amino]-ethanol SC_3242 1HNMR at 100oC (DMSO-d6, 400 MHz), δ (ppm) = 8.99 (s, 1H), 8.28 (d, 1H, J = 9.24 Hz), 7.63 (s, 1H), 7.43-7.26 (m, 6H), 7.13 (s, 1H), 4.31 (bs, 1H), 3.78-3.76 (m, 2H), 3.66 (bs, 4H), 3.24 (s, 3H), 2.43-2.38 (m, 2H), 2.05-1.90 (m, 10H), 1.56-1.54 (m, 2H). 475.1
    SC_3377 cis-8-Dimethylamino-3-(2-morpholin-4-yl-quinazolin-6-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one INT-976 6-bromo-2-morpholin-4-yl-quinazoline SC_3242 1HNMR at 100oC (DMSO-d6, 400 MHz), δ (ppm) = 9.05 (s, 1H), 8.34 (d, 1H), 7.68 (s, 1H), 7.48 (d, 1H, J = 9.4 Hz), 7.38-7.27 (m, 5H), 7.18 (s, 1H), 3.81-3.67 (m, 10H), 2.40-2.38 (m, 2H), 2.05-1.90 (m, 10H), 1.57-1.54 (m, 2H). 487.2
    SC_3378 cis-8-[Methyl-(oxetan-3-yl-methyl)-amino]-8-phenyl-3-[2-(trifluoromethyl)-pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2-one INT-1047 2-trifluoromethyl-5-bromopyrimidine SC_3103 1H NMR (DMSO-d6): δ 9.21-9.15 (s, 2H), 8.19-8.18 (broad s, 1H), 7.41-7.34 (m, 4H), 7.27-7.25 (m, 1H), 4.58-4.56 (m, 2H), 4.18 (s, 1H), 3.69 (s, 2H), 3.05-2.99 (m, 1H), 2.41-2.36 (m, 4H), 1.91 (m, 7H), 1.47 (s, 2H). 476.2
    SC_3380 cis-8-Dimethylamino-8-phenyl-3-quinazolin-6-yl-1,3-diazaspiro[4.5]decan-2-one INT-976 6-bromo-quinazoline SC_3103 1HNMR at 100oC (DMSO-d6, 400 MHz), δ (ppm) = 9.35 (s,1H), 9.10 (s,1H), 8.65 (d, 1H, J = 9.04) 7.91-7.89 (m, 2H), 7.39-7.27 (m, 5H), 3.75 (s, 2H), 2.42-2.32 (m, 2H), 2.05 (s, 6H), 2.00-1.92 (m, 4H), 1.56 (bs, 2H). 402.2
    SC_3381 cis-5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-2-(2-oxo-1,3-dihydro-indol-4-yl)-isonicotinonitrile INT-976 5-bromo-2-chloro-pyridine-4-carbonitrile (step 1), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indolin-2-one (step 2) SC_3103 (for step 1), SC_3129 (for step 2) 1H NMR (600 MHz, DMSO) δ 8.88 (s, 1H), 8.24 (s, 1H), 7.85 (s, 1H), 7.52 - 7.46 (m, 1H), 7.41 - 7.29 (m, 6H), 7.27 (td, 1H), 6.92 (d, 1H), 3.84 (s, 2H), 3.78 (s, 2H), 2.48 - 2.30 (m, 2H), 1.99 - 1.93 (m, 8H), 1.92 - 1.74 (m, 2H), 1.58 - 1.54 (m, 2H). 507.3
    SC_3382 cis-N-[5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-pyrimidin-2-yl]-N-methyl-tetrahydro-pyran-4-carboxylic acid amide SC_3371 tetrahydropyran-4-carbonyl chloride SC_3240 1H NMR (600 MHz, DMSO) δ 8.97 (s, 2H), 7.80 (s, 1H), 7.42 - 7.34 (m, 4H), 7.31 - 7.25 (m, 1H), 3.79 (ddd, 2H), 3.67 (s, 2H), 3.25 (s, 2H), 3.17 (td, 2H), 3.04 - 2.96 (m, 1H), 2.49 - 2.34 (m, 2H), 1.97 (s, 6H), 1.95 - 1.74 (m, 4H), 1.68 - 1.53 (m, 4H), 1.54 - 1.48 (m, 2H). 493.3
    SC_3383 cis-N-[5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-pyrimidin-2-yl]-N,2,2-trimethyl-propionamide SC_3371 pivaloyl chloride SC_3240 1H NMR (600 MHz, DMSO) δ 8.98 (s, 2H), 7.42 - 7.34 (m, 4H), 7.30 - 7.26 (m, 1H), 3.69 (s, 2H), 3.14 (s, 3H), 2.46 - 2.41 (m, 2H), 1.99 - 1.87 (m, 10H), 1.54 - 1.45 (m, 2H), 0.97 (s, 9H). 465.3
    SC_3384 cis-8-Dimethylamino-3-[2-(1-methyl-2-oxo-1,3-dihydro-indol-4-yl)-pyrimidin-5-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one INT-989 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indolin-2-one SC_3208 1H NMR (600 MHz, CDCl3) δ 9.05 (s, 2H), 8.08 (d, 1H), 7.47 - 7.39 (m, 3H), 7.38 - 7.31 (m, 3H), 6.91 (d, 1H), 5.46 (s, 1H), 4.04 (s, 2H), 3.64 (s, 2H), 3.27 (s, 3H), 2.35 - 2.14 (m, 4H), 2.10 (s, 6H), 2.08 - 2.01 (m, 3H), 1.73 - 1.64 (m, 2H), 1.28 (s, 0H). 497.3
    SC_3385 cis-8-Dimethylamino-3-(2-morpholin-4-yl-1H-benzoimidazol-5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one INT-976 6-bromo-1-(tert-butylsilanyl-methoxymethyl)-2-morpholin-4-yl-1H-benzoimidazole (step 1) SC_3242 (for step 1), step 2 of SC_3352 (for step 2) 1HNMR at 100oC (DMSO-d6, 400 MHz), δ (ppm) = 10.94 (bs, 1H), 7.50 (bs, 1H), 7.39-7.27 (m, 5H), 7.06 (m, 2 H), 6.84 (bs, 1H), 3.72 (t, 4H, 4.56 Hz ), 3.55 (s, 2H), 3.45 (t, 4H, 4.56 Hz), 2.372.24 (m, 2H), 1.95-1.81 (m, 10H), 1.52-1.50 (m, 2H) 475.2
    SC_3386 cis-8-Dimethylamino-8-(3-fluoro-5-methyl-phenyl)-3-[4-methyl-6-(trifluoromethyl)-pyridin-3-yl]-1,3-diazaspiro[4.5]decan-2-one INT-1043 5-bromo-4-methyl-2-(trifluoromethyl)pyridine SC_3319 1H NMR (600 MHz, DMSO) δ 8.57 (s, 1H), 7.80 (s, 1H), 7.51 (s, 1H), 6.99 (s, 1H), 6.96 - 6.89 (m, 2H), 3.61 (s, 2H), 2.34 (s, 3H), 2.32 (s, 3H), 2.07 (s, 1H), 1.97 (s, 6H), 1.96 - 1.89 (m, 2H), 1.88 - 1.78 (m, 2H), 1.54 (d, 2H). 465.2
    SC_3387 cis-8-Dimethylamino-3-[6-(2-oxo-1,3-dihydro-indol-4-yl)-pyridin-3-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one INT-1048 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indolin-2-one SC_3129 1H NMR (600 MHz, DMSO) δ 8.83 (d, 1H), 8.11 (dd, 1H), 7.77 (d, 1H), 7.64 (s, 1H), 7.43 - 7.34 (m, 5H), 7.31 - 7.24 (m, 2H), 6.84 (d, 1H), 3.73 (s, 2H), 3.68 (s, 2H), 2.45 - 2.31 (m, 2H), 1.99 - 1.79 (m, 10H), 1.51 (t, 2H). 482.3
    SC_3389 cis-3-[6-(Azetidin-1-yl)-5-(trifluoromethyl)-pyridin-3-yl]-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one INT-976 5-bromo-2-chloro-3-(trifluoromethyl)pyridine (step 1), azetidine (step 2) SC_3103 (for step 1), SC_3120 (for step 2, 160 oC) 1H NMR (600 MHz, DMSO) δ 8.40 (d, 1H), 8.21 (d, 1H), 7.47 (s, 1H), 7.41 - 7.33 (m, 4H), 7.30 - 7.24 (m, 1H), 4.03 (t, 4H), 3.58 (s, 2H), 2.47 - 2.29 (m, 2H), 2.25 (p, 2H), 1.96 (s, 6H), 1.89 (s, 4H), 1.47 (t, 2H). 453.2
    SC_3390 cis-3-[1-(Cyclopropyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-isonicotinonitrile SC_3364 bromomethylcyclopropane INT-952 1H NMR (600 MHz, DMSO) δ 8.82 (s, 1H), 8.51 (dd, 1H), 7.81 (d, 1H), 7.40-7.33 (m, 4H), 7.29 - 7.23 (m, 1H), 3.93 (s, 2H), 3.10 (d, 2H), 2.76 - 2.70 (m, 2H), 2.29 (ddd, 2H), 2.02 (s, 6H), 1.58 (d, 2H), 1.52 - 1.44 (m, 2H), 1.01 (ddt, 1H), 0.55 - 0.49 (m, 2H), 0.37 - 0.31 (m, 2H). 430.3
    SC_3391 cis-3-[3,5-Bis(trifluoromethyl)-pyridin-2-yl]-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one INT-976 2-chloro-3,5-bis(trifluoromethyl)pyridine SC_3103 1H NMR (600 MHz, DMSO) δ 9.04 (d, 1H), 8.58 (d, 1H), 7.96 (s, 1H), 7.41 - 7.32 (m, 4H), 7.29 - 7.23 (m, 1H), 3.75 (s, 2H), 2.41 - 2.25 (m, 2H), 1.98 - 1.89 (m, 10H), 1.52 (t, 2H). 487.2
    SC_3392 cis-8-Dimethylamino-3-(5-fluoro-6-morpholin-4-yl-pyridin-3-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one INT-976 4-(5-bromo-3-fluoro-2-pyridyl)morpholine SC_3103 1H NMR (600 MHz, CDCl3) δ 8.13 (dd, 1H), 7.76 (d, 1H), 7.42 (t, 2H), 7.33 (dd, 3H), 5.84 (s, 1H), 3.84 (t, 4H), 3.52 (s, 2H), 3.37 (t, 4H), 2.29 - 2.12 (m, 4H), 2.08 (s, 6H), 2.01 - 1.94 (m, 2H), 1.60 (t, 2H). 454.3
    SC_3393 cis-8-(3-Chlorophenyl)-8-dimethylamino-3-[4-methyl-6-(trifluoromethyl)-pyridin-3-yl]-1,3-diazaspiro[4.5]decan-2-one INT-1044 5-bromo-4-methyl-2-(trifluoromethyl)pyridine SC_3319 1H NMR (600 MHz, DMSO) δ 8.57 (s, 1H), 7.80 (s, 1H), 7.55 - 7.49 (m, 1H), 7.43 - 7.37 (m, 1H), 7.38 - 7.29 (m, 3H), 3.61 (s, 2H), 2.40 - 2.24 (m, 5H), 1.99 - 1.90 (m, 8H), 1.90 - 1.76 (m, 2H), 1.60 - 1.47 (m, 2H). 467.2
    SC_3394 cis-8-Dimethylamino-3-[5-(2-oxo-1,3-dihydro-indol-4-yl)-pyridin-2-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one INT-1049 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indolin-2-one SC_3354 1H NMR (600 MHz, DMSO) δ 8.41 (d, 1H), 8.26 (d, 1H), 7.92 (dd, 1H), 7.75 (s, 1H), 7.41 - 7.32 (m, 5H), 7.30 - 7.23 (m, 2H), 7.01 (d, 1H), 6.83 (d, 1H), 3.75 (s, 2H), 3.61 (s, 2H), 2.46 - 2.30 (m, 2H), 1.96 (s, 6H), 1.94 - 1.88 (m, 2H), 1.86 - 1.82 (m, 2H), 1.48 (t, 2H). 482.3
    SC_3395 cis-8-Dimethylamino-8-phenyl-3-[5-(trifluoromethyl)-[1,3,4]thiadiazol-2-yl]-1,3-diazaspiro[4.5]decan-2-one INT-976 2-bromo-5-(trifluoromethyl)-1,3,4-thiadiazole SC_3103 1H NMR (600 MHz, DMSO) δ 8.69 (s, 1H), 7.42 - 7.34 (m, 4H), 7.28 (t, 1H), 3.89 (s, 2H), 2.45 - 2.31 (m, 2H), 2.07 - 1.88 (m, 8H), 1.88 - 1.84 (m, 2H), 1.60 - 1.53 (m, 2H). 426.2
    SC_3397 cis-8-Dimethylamino-3-[2-[(2-hydroxy-ethyl)-methyl-amino]-1H-benzoimidazol-5-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one INT-976 2-{[6-bromo-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazol-2-yl]-methyl-amino}-ethanol (step 1) SC_3242 (for step 1), step 2 of SC_3352 (for step 2) 1HNMR (DMSO-d6, 400 MHz at 100oC), δ (ppm) = 10.62 (bs, 1H), 7.48-7.24 (m, 6H), 7.01-6.91 (m, 2H,), 6.76 (s, 1H), 4.58 (bs, 1H), 3.66 (t, 2H, J = 5.62 Hz), 3.54-3.50 (m, 4H), 3.09 (s, 3H), 2.37-2.32 (m, 2H), 2.04 (s, 6H), 1.96-1.91 (m, 4H), 1.52-1.40 (m, 2H). 463.3
    SC_3398 cis-8-Dimethylamino-3-(5-methyl-6-morpholin-4-yl-pyridin-3-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one INT-976 4-(5-bromo-3-methyl-2-pyridyl)morpholine SC_3103 1H NMR (600 MHz, DMSO) δ 8.23 (s, 1H), 7.83 (s, 1H), 7.46 - 7.33 (m, 5H), 7.30 - 7.24 (m, 1H), 3.71 (t, 4H), 3.55 (s, 2H), 2.93 (t, 4H), 2.41 - 2.37 (m, 2H), 1.96 (s, 6H), 1.91 - 1.82 (m, 4H), 1.49 - 1.44 (m, 2H). 450.3
    SC_3399 cis-1-(Cyclopropyl-methyl)-8-dimethylamino-8-(3-fluorophenyl)-3-(5-methylsulfonyl-pyridin-2-yl)-1,3-diazaspiro[4.5]decan-2-one SC_3409 bromomethylcyclopropane SC_3105 1HNMR (DMSO-d6, 400 MHz), δ (ppm) = 8.68-8.68 (d, 1H, J = 2.32 Hz), 8.42-8.40 (d, 1H, J = 9.04 Hz), 8.18-8.15 (m, 1H), 7.44-7.38 (m, 1H), 7.20-7.08 (m, 3H), 3.90 (s, 2H), 3.22 (s, 3H), 3.11-3.10 (d, 2H, J = 6.68 Hz), 2.71-2.68 (d, 2H, J = 13.6 Hz), 2.27-2.21(m, 2H), 2.00 (s, 6H), 1.53-1.44 (m, 4H), 1.02-0.99 (m, 1H), 0.54-0.50 (m, 2H), 0.36-0.35 (m, 2H). 501.4
    SC_3400 cis-1-(Cyclopropyl-methyl)-8-(3-fluorophenyl)-8-methylamino-3-(5-methylsulfonyl-pyridin-2-yl)-1,3-diazaspiro[4.5]decan-2-one SC_3399 SC_3099 1HNMR (DMSO-d6, 400 MHz), δ (ppm) = 8.72-8.71 (d, 1H, J = 2.28 Hz), 8.42-8.40 (d, 1H, J = 9.04 Hz), 8.18-8.15 (m, 1H), 7.40-7.31 (m, 3H), 7.05-7.01 (m, 1H), 3.93 (s, 2H), 3.23 (s, 3H), 3.14-3.13 (d, 2H, J = 6.76 Hz), 2.42 (bs, 1H), 2.28-2.23(m, 2H), 1.96-1.88 (m, 5H), 1.79-1.73 (m, 2H), 1.44-1.41 (d, 2H, J = 12.2 Hz), 1.06-1.02 (m, 1H), 0.52-0.47 (m, 2H), 0.36-0.33 (m, 2H). 487.2
    SC_3401 cis-1-(Cyclobutyl-methyl)-8-(3-fluorophenyl)-8-methylamino-3-[2-(trifluoromethyl)-pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2-one SC_3404 bromomethylcyclobutane (step 1) SC_3105 (for step 1), SC_3099 (for step 2) 1HNMR at 100oC (DMSO-d6, 400 MHz), δ (ppm) = 9.23 (s, 2H), 7.38-7.26 (m, 3H), 7.00 (t, 1H, J = 8.1 Hz), 3.86 (s, 2H), 3.30-3.28 (d, 2H, J = 7.24 Hz), 2.68-2.65 (m, 1H), 2.27-2.16 (m, 3H), 2.06-1.78 (m, 13H), 1.46-1.43 (m, 2H). 492.1
    SC_3402 cis-1-(Cyclopropyl-methyl)-8-dimethylamino-8-(3-fluorophenyl)-3-[2-(trifluoromethyl)-pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2-one SC_3404 bromomethylcyclopropane SC_3105 1HNMR (DMSO-d6, 400 MHz), δ (ppm) = 9.21 (s, 2H), 7.45-7.39 (m, 1H), 7.22-7.18 (m, 2H), 7.14-7.09 (m, 1H), 3.84 (s, 2H), 3.09 (d, 2H, J = 6.4 Hz), 2.70 (d, 2H, J = 9.6 Hz), 2.32-2.21 (m, 2H), 2.01 (s, 6H), 1.59-1.46 (m, 4H), 1.01-1.00 (m, 1H), 0.54-0.49 (m, 2H), 0.35-0.33 (m, 2H). 492.0
    SC_3403 cis-1-(Cyclopropyl-methyl)-8-(3-fluorophenyl)-8-methylamino-3-[2-(trifluoromethyl)-pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2-one SC_3402 SC_3099 1HNMR (DMSO-d6, 400 MHz), δ (ppm) = 9.25 (s, 2H), 7.41-7.30 (m, 3H), 7.04 (t, 1H, J = 6.8 Hz), 3.89 (s, 2H), 3.12 (d, 2H, J = 6.8 Hz), 2.41 (bs, 1H), 2.27-2.22 (m, 2H), 1.93-1.78 (m, 7H), 1.46-1.43 (m, 2H), 1.08-1.03 (m, 1H),0.51-0.47 (m, 2H), 0.33-0.29 (m, 2H). 478.4
    SC_3404 cis-8-Dimethylamino-8-(3-fluorophenyl)-3-[2-(trifluoromethyl)-pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2-one INT-1024 2-trifluoromethyl-5-bromopyrimidine SC_3242 1HNMR at 100oC (DMSO-d6, 400 MHz), δ (ppm) = 9.15 (s, 2H), 7.75 (s, 1H), 7.44-7.38 (m, 1H), 7.21-7.04 (m, 3H), 3.73 (s, 2H), 2.38-2.37 (m, 2H), 2.05 (s, 6H), 2.01-1.85 (m, 4H), 1.57-1.53 (m, 2H). 437.9
    SC_3405 cis-1-(Cyclopropyl-methyl)-8-dimethylamino-8-(3-fluorophenyl)-3-[2-methyl-5-(trifluoromethyl)-2H-pyrazol-3-yl]-1,3-diazaspiro[4.5]decan-2-one SC_3319 bromomethylcyclopropane SC_3105 1HNMR at 100oC (DMSO-d6, 400 MHz), δ (ppm) = 7.39-7.36 (m, 1H), 7.19-7.05 (m, 3H), 6.56 (s, 1H), 3.78-3.67 (m, 5H), 3.10-3.08 (d, 2H, J = 6.12 Hz), 2.64-2.60 (d, 2H, J = 13.32 Hz), 2.37-2.26(m, 2H), 2.09 (s, 6H), 1.61-1.49 (m, 4H), 1.10-1.02 (m, 1H), 0.54-0.52 (m, 2H), 0.36-0.33 (m, 2H). 494.3
    SC_3406 cis-1-(Cyclopropyl-methyl)-8-(3-fluorophenyl)-8-methylamino-3-[2-methyl-5-(trifluoromethyl)-2H-pyrazol-3-yl]-1,3-diazaspiro[4.5]decan-2-one SC_3405 SC_3099 1HNMR at 100oC (DMSO-d6, 400 MHz), δ (ppm) = 7.39-7.24 (m, 3H), 6.99-6.96 (m, 1H), 6.58 (s, 1H), 3.78-3.71 (m, 5H), 3.11-3.10 (d, 2H, J = 5.40 Hz), 2.30-2.23(m, 2H), 1.99-1.92 (m, 5H), 1.79-1.72 (m, 2H), 1.58-1.56 (m, 2H), 1.10-1.00 (m, 1H), 0.54-0.52 (m, 2H), 0.36-0.33 (m, 2H). 480.0
    SC_3407 cis-8-Methylamino-3-(4-methyl-2-morpholin-4-yl-pyrimidin-5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3148 SC_3099 437.3
    SC_3408 cis-3-[5-(Azetidin-1-yl)-3-methyl-pyridin-2-yl]-8-dimethylamino-8-(3-fluorophenyl)-1,3-diazaspiro[4.5]decan-2-one INT-1024 5-(azetidin-1-yl)-2-chloro-3-methyl-pyridine SC_3103 1H NMR (600 MHz, DMSO) δ 7.44 - 7.36 (m, 2H), 7.20 - 7.05 (m, 4H), 6.69 (d, 1H), 3.82 (t, 4H), 3.51 (s, 2H), 2.36 - 2.26 (m, 4H), 2.15 (s, 3H), 1.96 (s, 6H), 1.94 - 1.76 (m, 4H), 1.49 (t, 2H). 438.3
    SC_3409 cis-8-Dimethylamino-8-(3-fluorophenyl)-3-(5-methylsulfonyl-pyridin-2-yl)-1,3-diazaspiro[4.5]decan-2-one INT-1024 2-bromo-5-methylsulfonyl-pyridine SC_3103 1H NMR (600 MHz, DMSO) δ 8.67 (dd, 1H),8.39 (dd, 1H), 8.14 (dd, 1H), 8.04 (s, 1H), 7.42 (td, 1H), 7.19 (d, 1H), 7.15 (dt, 1H), 7.11 (td, 1H), 3.78 (s, 2H), 3.21 (s, 3H), 2.41 - 2.37 (m, 2H), 1.97 (s, 6H), 1.94 -1.75 (m, 4H), 1.54 - 1.45 (m, 2H). 447.2
    SC_3410 cis-3-(6-(azetidin-1-yl)-4-fluoropyridin-3-yl)-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one INT-976 2-(azetidin-1-yl)-5-bromo-4-fluoropyridine SC_3103
    SC_3411 cis-3-(6-(azetidin-1-yl)pyridin-3-yl)-8-(dimethylamino)-8-(3-fluorophenyl)-1,3-diazaspiro[4.5]decan-2-one INT-1024 2-(azetidin-1-yl)-5-bromopyridine SC_3103
    SC_3412 cis-3-(1-(cyclopropanecarbonyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)-8-(dimethylamino)-8-(3-fluorophenyl)-1,3-diazaspiro[4.5]decan-2-one INT-1024 (5-bromo-3-(trifluoromethyl)-1H-pyrazol-1-yl)(cyclopropyl)methanone SC_3103
    SC_3413 cis-8-(dimethylamino)-8-(3-fluorophenyl)-3-(1-(2-hydroxyethyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)-1,3-diazaspiro[4.5]decan-2-one INT-1024 2-(5-bromo-3-(trifluoromethyl)-1H-pyrazol-1-yl)ethanol SC_3242
    SC_3414 cis-3-(1-(cyclopropylmethyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)-8-(dimethylamino)-8-(3-fluorophenyl)-1,3-diazaspiro[4.5]decan-2-one INT-1024 5-bromo-1-(cyclopropylmethyl)-3-(trifluoromethyl)-1H-pyrazole SC_3242 480.2
    SC_3415 cis-8-(dimethylamino)-8-(3-fluorophenyl)-3-(1-(methylsulfonyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)-1,3-diazaspiro[4.5]decan-2-one INT-1024 5-bromo-1-(methylsulfonyl)-3-(trifluoromethyl)-1H-pyrazole SC_3242
    SC_3416 cis-1-(cyclopropylmethyl)-8-(dimethylamino)-8-(3-fluorophenyl)-3-(1-(methylsulfonyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)-1,3-diazaspiro[4.5]decan-2-one SC_3415 bromomethylcyclopropane SC_3105
    SC_3417 cis-2-(5-(8-(dimethylamino)-8-(3-fluorophenyl)-2-oxo-1,3-diazaspiro[4.5]decan-3-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)-N,N-dimethylacetamide INT-1024 2-(5-bromo-3-(trifluoromethyl)-1H-pyrazol-1-yl)-N,N-dimethylacetamide SC_3242
    SC_3418 cis-2-(5-(1-(cyclopropylmethyl)-8-(dimethylamino)-8-(3-fluorophenyl)-2-oxo-1,3-diazaspiro[4.5]decan-3-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)-N,N-dimethylacetamide SC_3417 bromomethylcyclopropane SC_3105
    SC_3419 cis-8-(dimethylamino)-3-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one INT-976 5-bromo-1-methyl-1H-pyrrolo[2,3-b]pyridine SC_3103 404.3
    SC_3420 cis-8-(dimethylamino)-3-(3-fluoro-1H-pyrrolo[2,3-b]pyridin-5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one INT-976 5-bromo-3-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine (step 1) SC_3352 408.2
    SC_3421 cis-8-(dimethylamino)-8-phenyl-3-(1H-pyrrolo[2,3-c]pyridin-4-yl)-1,3-diazaspiro[4.5]decan-2-one INT-976 4-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-c]pyridine SC_3352 390.2
    SC_3422 cis-8-(dimethylamino)-8-phenyl-3-(2-(pyridazin-4-yl)pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one INT-989 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridazine SC_3354 430.2
    SC_3423 cis-8-(dimethylamino)-3-(2-(2-oxo-1,2-dihydropyridin-4-yl)pyrimidin-5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one INT-989 (2-oxo-1,2-dihydropyridin-4-yl)boronic acid SC_3354 445.2
    SC_3424 cis-8-(dimethylamino)-8-(3-fluorophenyl)-3-(1-methyl-3-(thiophen-2-yl)-1H-pyrazol-5-yl)-1,3-diazaspiro[4.5]decan-2-one INT-1024 3,5-dibromo-1-methyl-1H-pyrazole (step 1), thiophen-2-ylboronic acid (step 2) SC_3103 (for step 1), SC_3354 (for step 2)
    SC_3425 cis-8-(dimethylamino)-8-(3-fluorophenyl)-3-(1-methyl-3-morpholino-1H-pyrazol-5-yl)-1,3-diazaspiro[4.5]decan-2-one INT-1024 3,5-dibromo-1-methyl-1H-pyrazole (step 1), morpholine (step 2) SC_3103 (for step 1), SC_3103 (for step 2)
    SC_3426 cis-8-(dimethylamino)-8-phenyl-1-(2,2,2-trifluoroethyl)-3-(2-(trifluoromethyl)pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one INT-1068 2-trifluoromethyl-5-bromopyrimidine SC_3103 502.2
    SC_3427 cis-8-(dimethylamino)-8-phenyl-3-(2-(trifluoromethyl)pyrimidin-5-yl)-1-(3,3,3-trifluoropropyl)-1,3-diazaspiro[4.5]decan-2-one INT-1070 2-trifluoromethyl-5-bromopyrimidine SC_3103
    SC_3428 cis-3-(4-methyl-6-(trifluoromethyl)pyridin-3-yl)-8-(methylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3122 SC_3099
    SC_3429 cis-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-8-(methylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_3200 SC_3099
    SC_3430 cis-8-(dimethylamino)-8-(3-fluorophenyl)-3-(4-(methylsulfonyl)pyridin-3-yl)-1,3-diazaspiro[4.5]decan-2-one INT-1024 3-bromo-4-(methylsulfonyl)pyridine SC_3103
    SC_3431 cis-8-(dimethylamino)-3-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-8-(3-fluorophenyl)-1,3-diazaspiro[4.5]decan-2-one INT-1024 5-bromo-1-ethyl-3-(trifluoromethyl)-1H-pyrazole SC_3242
    SC_3432 cis-3-(1-cyclopropyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-8-(dimethylamino)-8-(3-fluorophenyl)-1,3-diazaspiro[4.5]decan-2-one INT-1024 5-bromo-1-cyclopropyl-3-(trifluoromethyl)-1H-pyrazole SC_3242
    SC_3433 cis-8-(dimethylamino)-8-(3-fluorophenyl)-3-(1-(oxetan-3-ylmethyl)-3 -(trifluoromethyl)-1H-pyrazol-5-yl)-1,3-diazaspiro[4.5]decan-2-one INT-1024 5-bromo-1-(oxetan-3-ylmethyl)-3-(trifluoromethyl)-1H-pyrazole SC_3242
    SC_3434 cis-8-(dimethylamino)-8-(3-fluorophenyl)-3-(1-(2-(methylsulfonyl)ethyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)-1,3-diazaspiro[4.5]decan-2-one INT-1024 5-bromo-1-(2-(methylsulfonyl)ethyl)-3-(trifluoromethyl)-1H-pyrazole SC_3242
    SC_3435 cis-8-(dimethylamino)-8-(3-fluorophenyl)-3-(4-methyl-2-(methylamino)pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one INT-1076 methylamine SC_3239
    SC_3436 cis-3 -(2-cyclopropoxy-4-methylpyrimidin-5-yl)-8-(dimethylamino)-8-(3-fluorophenyl)-1,3-diazaspiro[4.5]decan-2-one INT-1076 cyclopropanol SC_3224 440.3
    SC_3437 cis-N-(5-(8-(dimethylamino)-8-(3-fluorophenyl)-2-oxo-1,3-diazaspiro[4.5]decan-3-yl)-4-methylpyrimidin-2-yl)-N-methylcyclopropanecarboxamide INT-1024 N-(5-bromo-4-methylpyrimidin-2-yl)-N-methylcyclopropanecarboxamide SC_3103 481.3
    SC_3438 cis-N-(5-(8-(dimethylamino)-8-(3-fluorophenyl)-2-oxo-1,3-diazaspiro[4.5]decan-3-yl)-4-methylpyrimidin-2-yl)-N-methylpivalamide INT-1024 N-(5-bromo-4-methylpyrimidin-2-yl)-N-methylpivalamide SC_3103 497.3
    SC_3439 cis-3-(4-(azetidin-1-yl)-2-(trifluoromethyl)pyrimidin-5-yl)-8-(dimethylamino)-8-(3-fluorophenyl)-1,3-diazaspiro[4.5]decan-2-one INT-1077 azetidine SC_3120 493.2
    SC_3440 cis-8-(dimethylamino)-8-(3-fluorophenyl)-3-(4-(oxetan-3-ylmethoxy)-2-(trifluoromethyl)pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one INT-1077 oxetan-3-ylmethanol SC_3224 524.2
    SC_3441 cis-3-(2-cyclopropyl-4-(2,2,2-trifluoroethoxy)pyrimidin-5-yl)-8-(dimethylamino)-8-(3-fluorophenyl)-1,3-diazaspiro[4.5]decan-2-one INT-1078 2,2,2-trifluoroethanol SC_3224 508.2
    SC_3442 cis-3-(2-cyclopropyl-4-((2-hydroxyethyl)(methyl)amino)pyrimidin-5-yl)-8-(dimethylamino)-8-(3-fluorophenyl)-1,3-diazaspiro[4.5]decan-2-one INT-1078 2-(methylamino)ethanol SC_3120 483.3
  • Chemical Structures of all examples
    Figure US20230303573A1-20230928-C00476
    Figure US20230303573A1-20230928-C00477
    Figure US20230303573A1-20230928-C00478
    Figure US20230303573A1-20230928-C00479
    Figure US20230303573A1-20230928-C00480
    Figure US20230303573A1-20230928-C00481
    Figure US20230303573A1-20230928-C00482
    Figure US20230303573A1-20230928-C00483
    Figure US20230303573A1-20230928-C00484
    Figure US20230303573A1-20230928-C00485
    Figure US20230303573A1-20230928-C00486
    Figure US20230303573A1-20230928-C00487
    Figure US20230303573A1-20230928-C00488
    Figure US20230303573A1-20230928-C00489
    Figure US20230303573A1-20230928-C00490
    Figure US20230303573A1-20230928-C00491
    Figure US20230303573A1-20230928-C00492
    Figure US20230303573A1-20230928-C00493
    Figure US20230303573A1-20230928-C00494
    Figure US20230303573A1-20230928-C00495
    Figure US20230303573A1-20230928-C00496
    Figure US20230303573A1-20230928-C00497
    Figure US20230303573A1-20230928-C00498
    Figure US20230303573A1-20230928-C00499
    Figure US20230303573A1-20230928-C00500
    Figure US20230303573A1-20230928-C00501
    Figure US20230303573A1-20230928-C00502
    Figure US20230303573A1-20230928-C00503
    Figure US20230303573A1-20230928-C00504
    Figure US20230303573A1-20230928-C00505
    Figure US20230303573A1-20230928-C00506
    Figure US20230303573A1-20230928-C00507
    Figure US20230303573A1-20230928-C00508
    Figure US20230303573A1-20230928-C00509
    Figure US20230303573A1-20230928-C00510
    Figure US20230303573A1-20230928-C00511
    Figure US20230303573A1-20230928-C00512
    Figure US20230303573A1-20230928-C00513
    Figure US20230303573A1-20230928-C00514
    Figure US20230303573A1-20230928-C00515
    Figure US20230303573A1-20230928-C00516
    Figure US20230303573A1-20230928-C00517
    Figure US20230303573A1-20230928-C00518
    Figure US20230303573A1-20230928-C00519
    Figure US20230303573A1-20230928-C00520
    Figure US20230303573A1-20230928-C00521
    Figure US20230303573A1-20230928-C00522
    Figure US20230303573A1-20230928-C00523
    Figure US20230303573A1-20230928-C00524
    Figure US20230303573A1-20230928-C00525
    Figure US20230303573A1-20230928-C00526
    Figure US20230303573A1-20230928-C00527
    Figure US20230303573A1-20230928-C00528
    Figure US20230303573A1-20230928-C00529
    Figure US20230303573A1-20230928-C00530
    Figure US20230303573A1-20230928-C00531
    Figure US20230303573A1-20230928-C00532
    Figure US20230303573A1-20230928-C00533
    Figure US20230303573A1-20230928-C00534
    Figure US20230303573A1-20230928-C00535
    Figure US20230303573A1-20230928-C00536
    Figure US20230303573A1-20230928-C00537
    Figure US20230303573A1-20230928-C00538
    Figure US20230303573A1-20230928-C00539
    Figure US20230303573A1-20230928-C00540
    Figure US20230303573A1-20230928-C00541
    Figure US20230303573A1-20230928-C00542
    Figure US20230303573A1-20230928-C00543
    Figure US20230303573A1-20230928-C00544
    Figure US20230303573A1-20230928-C00545
    Figure US20230303573A1-20230928-C00546
    Figure US20230303573A1-20230928-C00547
    Figure US20230303573A1-20230928-C00548
    Figure US20230303573A1-20230928-C00549
    Figure US20230303573A1-20230928-C00550
    Figure US20230303573A1-20230928-C00551
    Figure US20230303573A1-20230928-C00552
    Figure US20230303573A1-20230928-C00553
    Figure US20230303573A1-20230928-C00554
    Figure US20230303573A1-20230928-C00555
    Figure US20230303573A1-20230928-C00556
    Figure US20230303573A1-20230928-C00557
    Figure US20230303573A1-20230928-C00558
    Figure US20230303573A1-20230928-C00559
    Figure US20230303573A1-20230928-C00560
    Figure US20230303573A1-20230928-C00561
    Figure US20230303573A1-20230928-C00562
    Figure US20230303573A1-20230928-C00563
    Figure US20230303573A1-20230928-C00564
    Figure US20230303573A1-20230928-C00565
    Figure US20230303573A1-20230928-C00566
    Figure US20230303573A1-20230928-C00567
    Figure US20230303573A1-20230928-C00568
    Figure US20230303573A1-20230928-C00569
    Figure US20230303573A1-20230928-C00570
    Figure US20230303573A1-20230928-C00571
    Figure US20230303573A1-20230928-C00572
    Figure US20230303573A1-20230928-C00573
    Figure US20230303573A1-20230928-C00574
    Figure US20230303573A1-20230928-C00575
    Figure US20230303573A1-20230928-C00576
    Figure US20230303573A1-20230928-C00577
    Figure US20230303573A1-20230928-C00578
    Figure US20230303573A1-20230928-C00579
    Figure US20230303573A1-20230928-C00580
    Figure US20230303573A1-20230928-C00581
    Figure US20230303573A1-20230928-C00582
    Figure US20230303573A1-20230928-C00583
    Figure US20230303573A1-20230928-C00584
    Figure US20230303573A1-20230928-C00585
    Figure US20230303573A1-20230928-C00586
    Figure US20230303573A1-20230928-C00587
    Figure US20230303573A1-20230928-C00588
    Figure US20230303573A1-20230928-C00589
    Figure US20230303573A1-20230928-C00590
    Figure US20230303573A1-20230928-C00591
    Figure US20230303573A1-20230928-C00592
    Figure US20230303573A1-20230928-C00593
    Figure US20230303573A1-20230928-C00594
    Figure US20230303573A1-20230928-C00595
    Figure US20230303573A1-20230928-C00596
    Figure US20230303573A1-20230928-C00597
    Figure US20230303573A1-20230928-C00598
    Figure US20230303573A1-20230928-C00599
    Figure US20230303573A1-20230928-C00600
    Figure US20230303573A1-20230928-C00601
    Figure US20230303573A1-20230928-C00602
    Figure US20230303573A1-20230928-C00603
    Figure US20230303573A1-20230928-C00604
    Figure US20230303573A1-20230928-C00605
    Figure US20230303573A1-20230928-C00606
    Figure US20230303573A1-20230928-C00607
    Figure US20230303573A1-20230928-C00608
    Figure US20230303573A1-20230928-C00609
    Figure US20230303573A1-20230928-C00610
    Figure US20230303573A1-20230928-C00611
    Figure US20230303573A1-20230928-C00612
    Figure US20230303573A1-20230928-C00613
    Figure US20230303573A1-20230928-C00614
    Figure US20230303573A1-20230928-C00615
    Figure US20230303573A1-20230928-C00616
    Figure US20230303573A1-20230928-C00617
    Figure US20230303573A1-20230928-C00618
    Figure US20230303573A1-20230928-C00619
    Figure US20230303573A1-20230928-C00620
    Figure US20230303573A1-20230928-C00621
    Figure US20230303573A1-20230928-C00622
    Figure US20230303573A1-20230928-C00623
    Figure US20230303573A1-20230928-C00624
    Figure US20230303573A1-20230928-C00625
    Figure US20230303573A1-20230928-C00626
    Figure US20230303573A1-20230928-C00627
    Figure US20230303573A1-20230928-C00628
    Figure US20230303573A1-20230928-C00629
    Figure US20230303573A1-20230928-C00630
    Figure US20230303573A1-20230928-C00631
    Figure US20230303573A1-20230928-C00632
    Figure US20230303573A1-20230928-C00633
    Figure US20230303573A1-20230928-C00634
    Figure US20230303573A1-20230928-C00635
    Figure US20230303573A1-20230928-C00636
    Figure US20230303573A1-20230928-C00637
    Figure US20230303573A1-20230928-C00638
    Figure US20230303573A1-20230928-C00639
    Figure US20230303573A1-20230928-C00640
    Figure US20230303573A1-20230928-C00641
    Figure US20230303573A1-20230928-C00642
    Figure US20230303573A1-20230928-C00643
    Figure US20230303573A1-20230928-C00644
    Figure US20230303573A1-20230928-C00645
    Figure US20230303573A1-20230928-C00646
    Figure US20230303573A1-20230928-C00647
    Figure US20230303573A1-20230928-C00648
    Figure US20230303573A1-20230928-C00649
    Figure US20230303573A1-20230928-C00650
    Figure US20230303573A1-20230928-C00651
    Figure US20230303573A1-20230928-C00652
    Figure US20230303573A1-20230928-C00653
    Figure US20230303573A1-20230928-C00654
    Figure US20230303573A1-20230928-C00655
    Figure US20230303573A1-20230928-C00656
    Figure US20230303573A1-20230928-C00657
    Figure US20230303573A1-20230928-C00658
    Figure US20230303573A1-20230928-C00659
    Figure US20230303573A1-20230928-C00660
    Figure US20230303573A1-20230928-C00661
    Figure US20230303573A1-20230928-C00662
    Figure US20230303573A1-20230928-C00663
    Figure US20230303573A1-20230928-C00664
    Figure US20230303573A1-20230928-C00665
    Figure US20230303573A1-20230928-C00666
    Figure US20230303573A1-20230928-C00667
    Figure US20230303573A1-20230928-C00668
    Figure US20230303573A1-20230928-C00669
    Figure US20230303573A1-20230928-C00670
    Figure US20230303573A1-20230928-C00671
    Figure US20230303573A1-20230928-C00672
    Figure US20230303573A1-20230928-C00673
    Figure US20230303573A1-20230928-C00674
    Figure US20230303573A1-20230928-C00675
    Figure US20230303573A1-20230928-C00676
    Figure US20230303573A1-20230928-C00677
    Figure US20230303573A1-20230928-C00678
    Figure US20230303573A1-20230928-C00679
    Figure US20230303573A1-20230928-C00680
    Figure US20230303573A1-20230928-C00681
    Figure US20230303573A1-20230928-C00682
    Figure US20230303573A1-20230928-C00683
    Figure US20230303573A1-20230928-C00684
    Figure US20230303573A1-20230928-C00685
    Figure US20230303573A1-20230928-C00686
    Figure US20230303573A1-20230928-C00687
    Figure US20230303573A1-20230928-C00688
    Figure US20230303573A1-20230928-C00689
    Figure US20230303573A1-20230928-C00690
    Figure US20230303573A1-20230928-C00691
    Figure US20230303573A1-20230928-C00692
    Figure US20230303573A1-20230928-C00693
    Figure US20230303573A1-20230928-C00694
    Figure US20230303573A1-20230928-C00695
    Figure US20230303573A1-20230928-C00696
    Figure US20230303573A1-20230928-C00697
    Figure US20230303573A1-20230928-C00698
    Figure US20230303573A1-20230928-C00699
    Figure US20230303573A1-20230928-C00700
    Figure US20230303573A1-20230928-C00701
    Figure US20230303573A1-20230928-C00702
    Figure US20230303573A1-20230928-C00703
    Figure US20230303573A1-20230928-C00704
    Figure US20230303573A1-20230928-C00705
    Figure US20230303573A1-20230928-C00706
    Figure US20230303573A1-20230928-C00707
    Figure US20230303573A1-20230928-C00708
    Figure US20230303573A1-20230928-C00709
    Figure US20230303573A1-20230928-C00710
    Figure US20230303573A1-20230928-C00711
    Figure US20230303573A1-20230928-C00712
    Figure US20230303573A1-20230928-C00713
    Figure US20230303573A1-20230928-C00714
    Figure US20230303573A1-20230928-C00715
    Figure US20230303573A1-20230928-C00716
    Figure US20230303573A1-20230928-C00717
    Figure US20230303573A1-20230928-C00718
    Figure US20230303573A1-20230928-C00719
    Figure US20230303573A1-20230928-C00720
    Figure US20230303573A1-20230928-C00721
    Figure US20230303573A1-20230928-C00722
    Figure US20230303573A1-20230928-C00723
    Figure US20230303573A1-20230928-C00724
    Figure US20230303573A1-20230928-C00725
    Figure US20230303573A1-20230928-C00726
    Figure US20230303573A1-20230928-C00727
    Figure US20230303573A1-20230928-C00728
    Figure US20230303573A1-20230928-C00729
    Figure US20230303573A1-20230928-C00730
    Figure US20230303573A1-20230928-C00731
    Figure US20230303573A1-20230928-C00732
    Figure US20230303573A1-20230928-C00733
    Figure US20230303573A1-20230928-C00734
    Figure US20230303573A1-20230928-C00735
    Figure US20230303573A1-20230928-C00736
    Figure US20230303573A1-20230928-C00737
    Figure US20230303573A1-20230928-C00738
    Figure US20230303573A1-20230928-C00739
    Figure US20230303573A1-20230928-C00740
    Figure US20230303573A1-20230928-C00741
    Figure US20230303573A1-20230928-C00742
    Figure US20230303573A1-20230928-C00743
    Figure US20230303573A1-20230928-C00744
    Figure US20230303573A1-20230928-C00745
    Figure US20230303573A1-20230928-C00746
    Figure US20230303573A1-20230928-C00747
    Figure US20230303573A1-20230928-C00748
    Figure US20230303573A1-20230928-C00749
    Figure US20230303573A1-20230928-C00750
    Figure US20230303573A1-20230928-C00751
    Figure US20230303573A1-20230928-C00752
    Figure US20230303573A1-20230928-C00753
    Figure US20230303573A1-20230928-C00754
    Figure US20230303573A1-20230928-C00755
    Figure US20230303573A1-20230928-C00756
    Figure US20230303573A1-20230928-C00757
    Figure US20230303573A1-20230928-C00758
    Figure US20230303573A1-20230928-C00759
    Figure US20230303573A1-20230928-C00760
    Figure US20230303573A1-20230928-C00761
    Figure US20230303573A1-20230928-C00762
    Figure US20230303573A1-20230928-C00763
    Figure US20230303573A1-20230928-C00764
    Figure US20230303573A1-20230928-C00765
    Figure US20230303573A1-20230928-C00766
    Figure US20230303573A1-20230928-C00767
    Figure US20230303573A1-20230928-C00768
    Figure US20230303573A1-20230928-C00769
    Figure US20230303573A1-20230928-C00770
    Figure US20230303573A1-20230928-C00771
    Figure US20230303573A1-20230928-C00772
    Figure US20230303573A1-20230928-C00773
    Figure US20230303573A1-20230928-C00774
    Figure US20230303573A1-20230928-C00775
    Figure US20230303573A1-20230928-C00776
    Figure US20230303573A1-20230928-C00777
    Figure US20230303573A1-20230928-C00778
    Figure US20230303573A1-20230928-C00779
    Figure US20230303573A1-20230928-C00780
    Figure US20230303573A1-20230928-C00781
    Figure US20230303573A1-20230928-C00782
    Figure US20230303573A1-20230928-C00783
    Figure US20230303573A1-20230928-C00784
    Figure US20230303573A1-20230928-C00785
    Figure US20230303573A1-20230928-C00786
    Figure US20230303573A1-20230928-C00787
    Figure US20230303573A1-20230928-C00788
    Figure US20230303573A1-20230928-C00789
    Figure US20230303573A1-20230928-C00790
    Figure US20230303573A1-20230928-C00791
    Figure US20230303573A1-20230928-C00792
    Figure US20230303573A1-20230928-C00793
    Figure US20230303573A1-20230928-C00794
    Figure US20230303573A1-20230928-C00795
    Figure US20230303573A1-20230928-C00796
    Figure US20230303573A1-20230928-C00797
    Figure US20230303573A1-20230928-C00798
    Figure US20230303573A1-20230928-C00799
    Figure US20230303573A1-20230928-C00800
    Figure US20230303573A1-20230928-C00801
    Figure US20230303573A1-20230928-C00802
    Figure US20230303573A1-20230928-C00803
    Figure US20230303573A1-20230928-C00804
    Figure US20230303573A1-20230928-C00805
    Figure US20230303573A1-20230928-C00806
    Figure US20230303573A1-20230928-C00807
    Figure US20230303573A1-20230928-C00808
    Figure US20230303573A1-20230928-C00809
    Figure US20230303573A1-20230928-C00810
    Figure US20230303573A1-20230928-C00811
    Figure US20230303573A1-20230928-C00812
    Figure US20230303573A1-20230928-C00813
    Figure US20230303573A1-20230928-C00814
    Figure US20230303573A1-20230928-C00815
    Figure US20230303573A1-20230928-C00816
    Figure US20230303573A1-20230928-C00817
    Figure US20230303573A1-20230928-C00818
    Figure US20230303573A1-20230928-C00819
    Figure US20230303573A1-20230928-C00820
    Figure US20230303573A1-20230928-C00821
    Figure US20230303573A1-20230928-C00822
    Figure US20230303573A1-20230928-C00823
    Figure US20230303573A1-20230928-C00824
    Figure US20230303573A1-20230928-C00825
    Figure US20230303573A1-20230928-C00826
    Figure US20230303573A1-20230928-C00827
    Figure US20230303573A1-20230928-C00828
    Figure US20230303573A1-20230928-C00829
    Figure US20230303573A1-20230928-C00830
    Figure US20230303573A1-20230928-C00831
    Figure US20230303573A1-20230928-C00832
    Figure US20230303573A1-20230928-C00833
    Figure US20230303573A1-20230928-C00834
    Figure US20230303573A1-20230928-C00835
    Figure US20230303573A1-20230928-C00836
    Figure US20230303573A1-20230928-C00837
    Figure US20230303573A1-20230928-C00838
    Figure US20230303573A1-20230928-C00839
    Figure US20230303573A1-20230928-C00840
    Figure US20230303573A1-20230928-C00841
    Figure US20230303573A1-20230928-C00842
    Figure US20230303573A1-20230928-C00843
    Figure US20230303573A1-20230928-C00844
    Figure US20230303573A1-20230928-C00845
    Figure US20230303573A1-20230928-C00846
    Figure US20230303573A1-20230928-C00847
    Figure US20230303573A1-20230928-C00848
    Figure US20230303573A1-20230928-C00849
    Figure US20230303573A1-20230928-C00850
    Figure US20230303573A1-20230928-C00851
    Figure US20230303573A1-20230928-C00852
    Figure US20230303573A1-20230928-C00853
    Figure US20230303573A1-20230928-C00854
    Figure US20230303573A1-20230928-C00855
    Figure US20230303573A1-20230928-C00856
    Figure US20230303573A1-20230928-C00857
    Figure US20230303573A1-20230928-C00858
    Figure US20230303573A1-20230928-C00859
    Figure US20230303573A1-20230928-C00860
    Figure US20230303573A1-20230928-C00861
    Figure US20230303573A1-20230928-C00862
    Figure US20230303573A1-20230928-C00863
    Figure US20230303573A1-20230928-C00864
    Figure US20230303573A1-20230928-C00865
    Figure US20230303573A1-20230928-C00866
    Figure US20230303573A1-20230928-C00867
    Figure US20230303573A1-20230928-C00868
    Figure US20230303573A1-20230928-C00869
    Figure US20230303573A1-20230928-C00870
    Figure US20230303573A1-20230928-C00871
    Figure US20230303573A1-20230928-C00872
    Figure US20230303573A1-20230928-C00873
    Figure US20230303573A1-20230928-C00874
    Figure US20230303573A1-20230928-C00875
    Figure US20230303573A1-20230928-C00876
    Figure US20230303573A1-20230928-C00877
    Figure US20230303573A1-20230928-C00878
    Figure US20230303573A1-20230928-C00879
    Figure US20230303573A1-20230928-C00880
    Figure US20230303573A1-20230928-C00881
    Figure US20230303573A1-20230928-C00882
    Figure US20230303573A1-20230928-C00883
    Figure US20230303573A1-20230928-C00884
    Figure US20230303573A1-20230928-C00885
    Figure US20230303573A1-20230928-C00886
    Figure US20230303573A1-20230928-C00887
    Figure US20230303573A1-20230928-C00888
    Figure US20230303573A1-20230928-C00889
    Figure US20230303573A1-20230928-C00890
    Figure US20230303573A1-20230928-C00891
    Figure US20230303573A1-20230928-C00892
    Figure US20230303573A1-20230928-C00893
    Figure US20230303573A1-20230928-C00894
    Figure US20230303573A1-20230928-C00895
    Figure US20230303573A1-20230928-C00896
    Figure US20230303573A1-20230928-C00897
    Figure US20230303573A1-20230928-C00898
    Figure US20230303573A1-20230928-C00899
    Figure US20230303573A1-20230928-C00900
    Figure US20230303573A1-20230928-C00901
    Figure US20230303573A1-20230928-C00902
    Figure US20230303573A1-20230928-C00903
    Figure US20230303573A1-20230928-C00904
    Figure US20230303573A1-20230928-C00905
    Figure US20230303573A1-20230928-C00906
    Figure US20230303573A1-20230928-C00907
    Figure US20230303573A1-20230928-C00908
    Figure US20230303573A1-20230928-C00909
    Figure US20230303573A1-20230928-C00910
    Figure US20230303573A1-20230928-C00911
    Figure US20230303573A1-20230928-C00912
    Figure US20230303573A1-20230928-C00913
    Figure US20230303573A1-20230928-C00914
    Figure US20230303573A1-20230928-C00915
    • 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. MA. USA). and either test compound in dilution series or 25 µM unlabelled 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. MA. 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 ß-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 unlabelled 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 ß-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 unlabelled 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 ß-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. 10mM 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. MA. USA). and either test compound in dilution series or 1 µM unlabelled 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. MA. 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 ß-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).
  • Example hNOP Ki [nM] or % inhibition at 1 µM hMOP Ki [nM] or % inhibition at 1 µM
    SC_3001 0.3 120
    SC_3002 1.3 250
    SC_3003 0.4 350
    SC_3004 19.5 515
    SC_3005 0.7 12
    SC_3006 1.1 46
    SC_3007 85.8 705
    SC_3008 0.6 23
    SC_3009 1.1 41
    SC_3010 2.7 18
    SC_3011 4.4 4.4
    SC_3012 2.2 120
    SC_3013 1.4 39
    SC_3014 0.8 29.5
    SC_3015 2.6 32.5
    SC_3016 4.2 45
    SC_3017 2 30
    SC_3018 5.2 101.5
    SC_3019 10.2 135
    SC_3020 10.8 290
    SC_3021 1.8 14.5
    SC_3022 0.4 37.2
    SC_3023 7.7 36
    SC_3024 1 145
    SC_3025 236.7 1530
    SC_3026 4.6 300
    SC_3027 5 136
    SC_3028 0.6 10.4
    SC_3029 1.8 7.3
    SC_3030 2.2 59
    SC_3031 4.1 45.5
    SC_3032 11 245
    SC_3033 107 38%@10µM
    SC_3034 12.2 730
    SC_3035 6.6 1055
    SC_3036 1.4 220
    SC_3037 33.5 775
    SC_3038 1 76
    SC_3039 13 380
    SC_3040 4 335
    SC_3041 0.9 79.5
    SC_3042 4.1 136.5
    SC_3043 70 655
    SC_3044 230 10920
    SC_3045 55.5 520
    SC_3046 13.9 63
    SC_3047 10.1 2105
    SC_3048 1 38.5
    SC_3049 25 940
    SC_3050 85 28
    SC_3051 3.6 170
    SC_3052 160 355
    SC_3053 73.5 1200
    SC_3054 16.5 29.5
    SC_3055 94.5 215
    SC_3056 9.8 49.5
    SC_3057 955 245
    SC_3058 5 7.8
    SC_3059 11.4 320
    SC_3060 3 65
    SC_3061 4.7 54.5
    SC_3063 0.7 38
    SC_3064 119 365
    SC_3065 6.2 1990
    SC_3066 2.2 96
    SC_3067 41.5 99.5
    SC_3068 5.9 50.5
    SC_3069 2.6 49
    SC_3070 2.8 12.5
    SC_3071 8.2 170
    SC_3072 5.9 235
    SC_3073 1 110
    SC_3074 1.6 55
    SC_3075 8.1 260
    SC_3076 0.6 35.3
    SC_3077 3.2 325
    SC_3078 0.6 77.5
    SC_3079 1.6 38.5
    SC_3080 1.6 90.5
    SC_3081 8 1320
    SC_3082 39 1110
    SC_3083 12 117.3
    SC_3084 1.8 22
    SC_3085 1.6 107
    SC_3086 1.1 43.5
    SC_3087 2.8 99
    SC_3088 3.1 770
    SC_3089 3.3 235
    SC_3090 1.3 67
    SC_3091 2.3 24
    SC_3092 2.2 330
    SC_3093 1.1 47
    SC_3094 5.4 45.5
    SC_3096 14 250
    SC_3097 17 18
    SC_3098 2 6
    SC_3099 13 19
    SC_3100 1 1
    SC_3101 1 3
    SC_3102 2 1
    SC_3103 7 1
    SC_3104 - -
    SC_3105 2 97
    SC_3106 8 165
    SC_3107 2 115
    SC_3108 5 26
    SC_3109 8 19
    SC_3110 6 20
    SC_3111 8 37
    SC_3112 36 120
    SC_3113 24 26
    SC_3114 245 460
    SC_3115 265 915
    SC_3116 6 170
    SC_3117 92 1380
    SC_3118 80 5%
    SC_3119 22% 10%
    SC_3120 26 4950
    SC_3121 44 30%
    SC_3122 21 32%
    SC_3123 82 2260
    SC_3124 5 1090
    SC 3125 3%@10µM 52%@10µM
    SC_3126 0% 0%
    SC_3127 0% 3945
    SC_3128 0% 1%
    SC_3129 6 2180
    SC_3130 13 4530
    SC_3131 4 3090
    SC_3132 540 6%
    SC_3133 19 6515
    SC_3134 3%@10µM 40%@10µM
    SC_3135 1% 1%
    SC_3136 16 5840
    SC_3137 5 4235
    SC_3138 28 7%
    SC_3139 59 1690
    SC_3140 119 2355
    SC_3141 34 7855
    SC_3142 9 3750
    SC_3143 0% 4%
    SC_3144 0% 3590
    SC_3145 46 1635
    SC_3146 18 7675
    SC_3147 27 3325
    SC_3148 14 4575
    SC_3149 18 6900
    SC_3150 105 16%
    SC_3151 115 3490
    SC_3152 24 4775
    SC_3153 77 2220
    SC_3154 17 3575
    SC_3155 34 3495
    SC_3156 45 6375
    SC_3157 35 5690
    SC_3158 19 2540
    SC_3159 13 19%
    SC_3160 4% 5730
    SC_3161 2% 13%
    SC_3162 5 1325
    SC_3163 28 2095
    SC_3164 30 880
    SC_3165 4% 17%
    SC_3166 3% 1640
    SC_3167 18 3745
    SC_3168 11 5
    SC_3169 635 3445
    SC_3170 7 3610
    SC_3171 15 2010
    SC_3172 130 7%
    SC_3173 10 2525
    SC_3174 3% 1265
    SC_3175 - -
    SC_3176 13 3740
    SC_3177 8 4630
    SC_3178 6 6700
    SC_3179 15 3950
    SC_3180 125 2250
    SC_3181 22 5490
    SC_3182 11 2990
    SC_3183 165 1415
    SC_3184 19 7645
    SC_3185 335 15%
    SC_3186 33 2210
    SC_3187 87 2240
    SC_3188 25 1060
    SC_3189 57 3470
    SC_3190 42 28%
    SC_3191 27 20%
    SC_3192 140 4270
    SC_3193 100 2480
    SC_3194 28 5120
    SC_3195 15 1240
    SC_3196 22 1595
    SC_3197 44 1680
    SC_3198 22 5885
    SC_3199 19 4020
    SC_3200 7 13%
    SC_3201 115 3885
    SC_3202 25 3210
    SC_3203 68 1225
    SC_3204 110 14%
    SC_3205 20 2465
    SC_3206 27 2445
    SC_3207 39 1505
    SC_3208 2 3285
    SC_3209 - -
    SC_3210 - -
    SC_3211 - -
    SC_3212 9 2005
    SC_3213 52 18%
    SC_3214 7 19%
    SC_3215 0% 14%
    SC_3216 11 14
    SC_3217 23 2155
    SC_3218 83 15%
    SC_3219 0% 1%
    SC_3220 10%@10µM 24%@10µM
    SC_3221 33 1935
    SC_3222 6 1910
    SC_3223 155 6150
    SC_3224 10 1695
    SC_3225 13 2520
    SC_3226 - -
    SC_3227 16 3785
    SC_3228 67 3135
    SC_3229 105 3625
    SC_3230 145 2485
    SC_3231 120 2420
    SC_3232 15 3475
    SC_3233 38 1390
    SC_3234 4 1350
    SC_3235 30 1095
    SC_3236 285 18%
    SC_3237 20 17%
    SC_3238 4 25%
    SC_3239 35 2410
    SC_3240 28 17%
    SC_3241 8 4610
    SC_3242 5 675
    SC_3243 6 695
    SC_3244 27 4265
    SC_3245 67 -
    SC_3246 11 1025
    SC_3247 16 1220
    SC_3248 4 41
    SC_3249 740 855
    SC_3250 52 -
    SC_3251 185 4550
    SC_3252 30 -
    SC_3253 205 -
    SC_3254 22 240
    SC_3255 23 150
    SC_3256 12 61
    SC_3257 150 240
    SC_3258 58 7125
    SC_3259 45 180
    SC_3260 570 nd
    SC_3261 10 63
    SC_3262 540 3060
    SC_3263 66 800
    SC_3264 145 130
    SC_3265 38 2405
    SC_3266 245 1055
    SC_3267 460 -
    SC_3268 41 1625
    SC_3269 13 5580
    SC_3270 305 31
    SC_3271 34 245
    SC_3272 115 4175
    SC_3273 - -
    SC_3274 63 1880
    SC_3275 155 124
    SC_3276 24 130
    SC_3277 37 13%
    SC_3278 12 7035
    SC_3279 17 78
    SC_3280 6 300
    SC_3281 19 2580
    SC_3282 37 3510
    SC_3283 12 1030
    SC_3284 5 305
    SC_3285 15 20%
    SC_3286 18 5895
    SC_3287 119 18%
    SC_3288 15 115
    SC_3289 84 430
    SC_3290 16 6605
    SC_3291 350 15%
    SC_3292 4% 0%
    SC_3293 3% 0%
    SC_3294 9 12%
    SC_3295 28 2975
    SC_3296 10 4530
    SC_3297 8 4270
    SC_3298 20 17%
    SC_3299 23 5705
    SC_3300 22 565
    SC_3301 33 2320
    SC_3302 31 1025
    SC_3303 450 21%
    SC_3304 9% 4%
    SC_3305 10% 0%
    SC_3306 9 4555
    SC_3307 13 5345
    SC_3308 2 2575
    SC_3309 17 6910
    SC_3310 7 23%
    SC_3311 14 27%
    SC_3312 23 1830
    SC_3313 10 2400
    SC_3314 9 4090
    SC_3315 14 5325
    SC_3316 255 5430
    SC_3317 56 6045
    SC_3318 35 1235
    SC_3319 4 15%
    SC_3320 11 1955
    SC_3321 13 5715
    SC_3322 12 1150
    SC_3323 27 5530
    SC_3324 12% 5%
    SC_3325 53%@10µM 20%@10µM
    SC_3326 - -
    SC_3327 17 3360
    SC_3328 31 3295
    SC_3329 13 4285
    SC_3330 14 1505
    SC_3331 2 5265
    SC_3332 19 2055
    SC_3333 5 1580
    SC_3334 17 4005
    SC_3335 30 2305
    SC_3336 240 13%
    SC_3337 10 1970
    SC_3338 36 7%
    SC_3339 10 6830
    SC_3340 150 5750
    SC_3341 15 3460
    SC_3342 21 3845
    SC_3343 27 16%
    SC_3344 1 13%
    SC_3345 4 1800
    SC_3346 12 2580
    SC_3347 15 4845
    SC_3348 25 4090
    SC_3349 8 3980
    SC_3350 7 1485
    SC_3351 20 2205
    SC_3352 37 2160
    SC_3353 53 15%
    SC_3354 2 23%
    SC_3355 52 4785
    SC_3356 9 4805
    SC_3357 13 555
    SC_3358 51 7020
    SC_3359 66 3520
    SC_3360 7 2870
    SC_3361 27 5095
    SC_3362 28 29%
    SC_3363 33 8%
    SC_3364 32 4685
    SC_3365 2 1655
    SC_3366 1285 14%
    SC_3367 1220 8%
    SC_3368 195 11%
    SC_3369 51 3105
    SC_3370 4 14%
    SC_3371 350 9%
    SC_3372 125 3535
    SC_3373 19 18%
    SC_3374 55 10%
    SC_3375 13 12%
    SC_3376 37 1720
    SC_3377 22 980
    SC_3379 11 635
    SC_3380 102 5415
    SC_3381 3 1235
    SC_3382 29 13%
    SC_3383 10 17%
    SC_3384 6 11%
    SC_3385 33 925
    SC_3386 14 0%
    SC_3387 2 1245
    SC_3388 29 185
    SC_3389 2 1970
    SC_3390 18 465
    SC_3391 53 10%
    SC_3392 7 4490
    SC_3393 88 13%
    SC_3394 6 735
    SC_3395 14 4990
    SC_3396 44 1730
    SC_3397 48 560
    SC_3398 9 5640
    SC_3399 5 45%
    SC_3400 8 635
    SC_3401 1 455
    SC_3402 7 3630
    SC_3403 9 1440
    SC_3404 10 5%
    SC_3405 12 925
    SC_3406 24 805
    SC_3407 77 13%
    SC_3408 7 18%
    SC_3409 11 25%
    • 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, MA). Membranes from CHO-K1 cells transfected with the human nociceptin/orphanin FQ peptide (hNOP) receptor (Art.-No. 93-0264C2, DiscoveRx Corporation, Freemont, CA) are also used. [35S]GTPγS (Art.-No. NEG030H; Lot-No. #0112, #0913, #1113 calibrated to 46.25 TBq/mmol) is available from PerkinElmer (Waltham, MA).
  • 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 ug 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, MA).
  • 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 [35]S]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 (30)

1. A compound according to general formula (I)
Figure US20230303573A1-20230928-C00916
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—;
R5 means
a 6-14-membered aryl moiety, unsubstituted, mono- or polysubstituted; or
a 5-14-membered heteroaryl moiety, unsubstituted, mono- or polysubstituted;
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, —C(═O)NH—(CH2CH2—O)1-30—CH3, —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, —CO2H, -C(=O)O-C1-C6-alkyl, —C(═O)NH2, -C(=O)NHC1-C6-alkyl, -C(=O)N(C1-C6-alkyl)2, -O-C1-C6-alkyl and -S(=O)2-C1-C6-alkyl;
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 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, mono-or polysubstituted; 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—; —(CH2)2—S(═O)2—(CH2)2— or —(CH2)2—NRB—(CH2)2—, wherein RB means —H, -C1-C6-alkyl, -C(=O)-C1-C6-alkyl, or -S(=O)2-C1-C6-alkyl, wherein said C1-C6-alkyl is 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, —CO2H, -C(=O)O-C1-C6-alkyl and -C(=O)NH2; and wherein said ring is 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, —OH, —NH2, -C1-C6-alkyl and -O-C1-C6-alkyl;
or a physiologically acceptable salt thereof.
2. The compound according to claim 1, wherein 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 -phenyl, unsubstituted, mono- or polysubstituted.
17. The compound according to claim 1, wherein R5 means a monocyclic 5-6-membered heteroaryl moiety, unsubstituted, mono- or polysubstituted.
18. The compound according to claim 1, wherein R5 means a bicyclic 9-10-membered heteroaryl moiety, unsubstituted, mono- or polysubstituted.
19. The compound according to claim 17, wherein R5 means -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, in each case unsubstituted, mono- or polysubstituted.
20. The compound according to claim 1, which has a structure according to any of general formulas (II-A) to (VIII-C):
Figure US20230303573A1-20230928-C00917
Figure US20230303573A1-20230928-C00918
Figure US20230303573A1-20230928-C00919
Figure US20230303573A1-20230928-C00920
Figure US20230303573A1-20230928-C00921
Figure US20230303573A1-20230928-C00922
Figure US20230303573A1-20230928-C00923
Figure US20230303573A1-20230928-C00924
Figure US20230303573A1-20230928-C00925
Figure US20230303573A1-20230928-C00926
Figure US20230303573A1-20230928-C00927
Figure US20230303573A1-20230928-C00928
Figure US20230303573A1-20230928-C00929
Figure US20230303573A1-20230928-C00930
Figure US20230303573A1-20230928-C00931
Figure US20230303573A1-20230928-C00932
Figure US20230303573A1-20230928-C00933
Figure US20230303573A1-20230928-C00934
Figure US20230303573A1-20230928-C00935
Figure US20230303573A1-20230928-C00936
Figure US20230303573A1-20230928-C00937
wherein in each case
R1, R2, R3, R4, and R5 are defined as in any of the preceding claims,
RC means —H, —OH, —F, —CN or -C1-C4-alkyl;
RD means —H or —F;
or a physiologically acceptable salt thereof.
21. The compound according to claim 1, wherein R5 is selected from the group consisting of:
Figure US20230303573A1-20230928-C00938
Figure US20230303573A1-20230928-C00939
Figure US20230303573A1-20230928-C00940
Figure US20230303573A1-20230928-C00941
Figure US20230303573A1-20230928-C00942
Figure US20230303573A1-20230928-C00943
Figure US20230303573A1-20230928-C00944
Figure US20230303573A1-20230928-C00945
Figure US20230303573A1-20230928-C00946
Figure US20230303573A1-20230928-C00947
Figure US20230303573A1-20230928-C00948
Figure US20230303573A1-20230928-C00949
Figure US20230303573A1-20230928-C00950
Figure US20230303573A1-20230928-C00951
Figure US20230303573A1-20230928-C00952
Figure US20230303573A1-20230928-C00953
Figure US20230303573A1-20230928-C00954
Figure US20230303573A1-20230928-C00955
Figure US20230303573A1-20230928-C00956
Figure US20230303573A1-20230928-C00957
Figure US20230303573A1-20230928-C00958
Figure US20230303573A1-20230928-C00959
Figure US20230303573A1-20230928-C00960
Figure US20230303573A1-20230928-C00961
Figure US20230303573A1-20230928-C00962
Figure US20230303573A1-20230928-C00963
Figure US20230303573A1-20230928-C00964
Figure US20230303573A1-20230928-C00965
Figure US20230303573A1-20230928-C00966
Figure US20230303573A1-20230928-C00967
Figure US20230303573A1-20230928-C00968
Figure US20230303573A1-20230928-C00969
Figure US20230303573A1-20230928-C00970
Figure US20230303573A1-20230928-C00971
Figure US20230303573A1-20230928-C00972
Figure US20230303573A1-20230928-C00973
Figure US20230303573A1-20230928-C00974
Figure US20230303573A1-20230928-C00975
Figure US20230303573A1-20230928-C00976
Figure US20230303573A1-20230928-C00977
Figure US20230303573A1-20230928-C00978
Figure US20230303573A1-20230928-C00979
Figure US20230303573A1-20230928-C00980
Figure US20230303573A1-20230928-C00981
Figure US20230303573A1-20230928-C00982
Figure US20230303573A1-20230928-C00983
Figure US20230303573A1-20230928-C00984
Figure US20230303573A1-20230928-C00985
Figure US20230303573A1-20230928-C00986
Figure US20230303573A1-20230928-C00987
Figure US20230303573A1-20230928-C00988
Figure US20230303573A1-20230928-C00989
Figure US20230303573A1-20230928-C00990
Figure US20230303573A1-20230928-C00991
Figure US20230303573A1-20230928-C00992
Figure US20230303573A1-20230928-C00993
Figure US20230303573A1-20230928-C00994
Figure US20230303573A1-20230928-C00995
Figure US20230303573A1-20230928-C00996
Figure US20230303573A1-20230928-C00997
Figure US20230303573A1-20230928-C00998
Figure US20230303573A1-20230928-C00999
Figure US20230303573A1-20230928-C01000
Figure US20230303573A1-20230928-C01001
Figure US20230303573A1-20230928-C01002
Figure US20230303573A1-20230928-C01003
Figure US20230303573A1-20230928-C01004
Figure US20230303573A1-20230928-C01005
Figure US20230303573A1-20230928-C01006
Figure US20230303573A1-20230928-C01007
Figure US20230303573A1-20230928-C01008
Figure US20230303573A1-20230928-C01009
Figure US20230303573A1-20230928-C01010
Figure US20230303573A1-20230928-C01011
Figure US20230303573A1-20230928-C01012
Figure US20230303573A1-20230928-C01013
Figure US20230303573A1-20230928-C01014
Figure US20230303573A1-20230928-C01015
Figure US20230303573A1-20230928-C01016
Figure US20230303573A1-20230928-C01017
Figure US20230303573A1-20230928-C01018
Figure US20230303573A1-20230928-C01019
Figure US20230303573A1-20230928-C01020
Figure US20230303573A1-20230928-C01021
Figure US20230303573A1-20230928-C01022
Figure US20230303573A1-20230928-C01023
Figure US20230303573A1-20230928-C01024
Figure US20230303573A1-20230928-C01025
Figure US20230303573A1-20230928-C01026
Figure US20230303573A1-20230928-C01027
Figure US20230303573A1-20230928-C01028
Figure US20230303573A1-20230928-C01029
Figure US20230303573A1-20230928-C01030
Figure US20230303573A1-20230928-C01031
Figure US20230303573A1-20230928-C01032
Figure US20230303573A1-20230928-C01033
Figure US20230303573A1-20230928-C01034
Figure US20230303573A1-20230928-C01035
Figure US20230303573A1-20230928-C01036
Figure US20230303573A1-20230928-C01037
Figure US20230303573A1-20230928-C01038
Figure US20230303573A1-20230928-C01039
Figure US20230303573A1-20230928-C01040
Figure US20230303573A1-20230928-C01041
Figure US20230303573A1-20230928-C01042
Figure US20230303573A1-20230928-C01043
Figure US20230303573A1-20230928-C01044
Figure US20230303573A1-20230928-C01045
Figure US20230303573A1-20230928-C01046
Figure US20230303573A1-20230928-C01047
Figure US20230303573A1-20230928-C01048
Figure US20230303573A1-20230928-C01049
Figure US20230303573A1-20230928-C01050
Figure US20230303573A1-20230928-C01051
Figure US20230303573A1-20230928-C01052
Figure US20230303573A1-20230928-C01053
Figure US20230303573A1-20230928-C01054
Figure US20230303573A1-20230928-C01055
Figure US20230303573A1-20230928-C01056
Figure US20230303573A1-20230928-C01057
Figure US20230303573A1-20230928-C01058
Figure US20230303573A1-20230928-C01059
Figure US20230303573A1-20230928-C01060
Figure US20230303573A1-20230928-C01061
Figure US20230303573A1-20230928-C01062
Figure US20230303573A1-20230928-C01063
Figure US20230303573A1-20230928-C01064
Figure US20230303573A1-20230928-C01065
Figure US20230303573A1-20230928-C01066
Figure US20230303573A1-20230928-C01067
Figure US20230303573A1-20230928-C01068
Figure US20230303573A1-20230928-C01069
Figure US20230303573A1-20230928-C01070
Figure US20230303573A1-20230928-C01071
Figure US20230303573A1-20230928-C01072
Figure US20230303573A1-20230928-C01073
Figure US20230303573A1-20230928-C01074
Figure US20230303573A1-20230928-C01075
Figure US20230303573A1-20230928-C01076
Figure US20230303573A1-20230928-C01077
Figure US20230303573A1-20230928-C01078
Figure US20230303573A1-20230928-C01079
Figure US20230303573A1-20230928-C01080
Figure US20230303573A1-20230928-C01081
Figure US20230303573A1-20230928-C01082
Figure US20230303573A1-20230928-C01083
Figure US20230303573A1-20230928-C01084
Figure US20230303573A1-20230928-C01085
Figure US20230303573A1-20230928-C01086
Figure US20230303573A1-20230928-C01087
Figure US20230303573A1-20230928-C01088
Figure US20230303573A1-20230928-C01089
Figure US20230303573A1-20230928-C01090
Figure US20230303573A1-20230928-C01091
Figure US20230303573A1-20230928-C01092
Figure US20230303573A1-20230928-C01093
Figure US20230303573A1-20230928-C01094
Figure US20230303573A1-20230928-C01095
Figure US20230303573A1-20230928-C01096
Figure US20230303573A1-20230928-C01097
Figure US20230303573A1-20230928-C01098
Figure US20230303573A1-20230928-C01099
Figure US20230303573A1-20230928-C01100
Figure US20230303573A1-20230928-C01101
Figure US20230303573A1-20230928-C01102
Figure US20230303573A1-20230928-C01103
Figure US20230303573A1-20230928-C01104
Figure US20230303573A1-20230928-C01105
Figure US20230303573A1-20230928-C01106
Figure US20230303573A1-20230928-C01107
Figure US20230303573A1-20230928-C01108
Figure US20230303573A1-20230928-C01109
Figure US20230303573A1-20230928-C01110
Figure US20230303573A1-20230928-C01111
Figure US20230303573A1-20230928-C01112
Figure US20230303573A1-20230928-C01113
Figure US20230303573A1-20230928-C01114
Figure US20230303573A1-20230928-C01115
Figure US20230303573A1-20230928-C01116
Figure US20230303573A1-20230928-C01117
Figure US20230303573A1-20230928-C01118
Figure US20230303573A1-20230928-C01119
Figure US20230303573A1-20230928-C01120
Figure US20230303573A1-20230928-C01121
Figure US20230303573A1-20230928-C01122
Figure US20230303573A1-20230928-C01123
Figure US20230303573A1-20230928-C01124
Figure US20230303573A1-20230928-C01125
Figure US20230303573A1-20230928-C01126
Figure US20230303573A1-20230928-C01127
Figure US20230303573A1-20230928-C01128
Figure US20230303573A1-20230928-C01129
Figure US20230303573A1-20230928-C01130
Figure US20230303573A1-20230928-C01131
Figure US20230303573A1-20230928-C01132
Figure US20230303573A1-20230928-C01133
Figure US20230303573A1-20230928-C01134
Figure US20230303573A1-20230928-C01135
Figure US20230303573A1-20230928-C01136
Figure US20230303573A1-20230928-C01137
Figure US20230303573A1-20230928-C01138
Figure US20230303573A1-20230928-C01139
Figure US20230303573A1-20230928-C01140
Figure US20230303573A1-20230928-C01141
Figure US20230303573A1-20230928-C01142
Figure US20230303573A1-20230928-C01143
Figure US20230303573A1-20230928-C01144
Figure US20230303573A1-20230928-C01145
Figure US20230303573A1-20230928-C01146
Figure US20230303573A1-20230928-C01147
Figure US20230303573A1-20230928-C01148
Figure US20230303573A1-20230928-C01149
Figure US20230303573A1-20230928-C01150
Figure US20230303573A1-20230928-C01151
Figure US20230303573A1-20230928-C01152
Figure US20230303573A1-20230928-C01153
Figure US20230303573A1-20230928-C01154
Figure US20230303573A1-20230928-C01155
Figure US20230303573A1-20230928-C01156
Figure US20230303573A1-20230928-C01157
Figure US20230303573A1-20230928-C01158
Figure US20230303573A1-20230928-C01159
Figure US20230303573A1-20230928-C01160
Figure US20230303573A1-20230928-C01161
Figure US20230303573A1-20230928-C01162
Figure US20230303573A1-20230928-C01163
Figure US20230303573A1-20230928-C01164
Figure US20230303573A1-20230928-C01165
Figure US20230303573A1-20230928-C01166
Figure US20230303573A1-20230928-C01167
Figure US20230303573A1-20230928-C01168
Figure US20230303573A1-20230928-C01169
Figure US20230303573A1-20230928-C01170
Figure US20230303573A1-20230928-C01171
Figure US20230303573A1-20230928-C01172
Figure US20230303573A1-20230928-C01173
Figure US20230303573A1-20230928-C01174
Figure US20230303573A1-20230928-C01175
Figure US20230303573A1-20230928-C01176
Figure US20230303573A1-20230928-C01177
Figure US20230303573A1-20230928-C01178
Figure US20230303573A1-20230928-C01179
Figure US20230303573A1-20230928-C01180
Figure US20230303573A1-20230928-C01181
Figure US20230303573A1-20230928-C01182
Figure US20230303573A1-20230928-C01183
Figure US20230303573A1-20230928-C01184
Figure US20230303573A1-20230928-C01185
Figure US20230303573A1-20230928-C01186
Figure US20230303573A1-20230928-C01187
Figure US20230303573A1-20230928-C01188
Figure US20230303573A1-20230928-C01189
Figure US20230303573A1-20230928-C01190
Figure US20230303573A1-20230928-C01191
Figure US20230303573A1-20230928-C01192
Figure US20230303573A1-20230928-C01193
Figure US20230303573A1-20230928-C01194
Figure US20230303573A1-20230928-C01195
Figure US20230303573A1-20230928-C01196
Figure US20230303573A1-20230928-C01197
Figure US20230303573A1-20230928-C01198
Figure US20230303573A1-20230928-C01199
Figure US20230303573A1-20230928-C01200
Figure US20230303573A1-20230928-C01201
Figure US20230303573A1-20230928-C01202
Figure US20230303573A1-20230928-C01203
Figure US20230303573A1-20230928-C01204
Figure US20230303573A1-20230928-C01205
Figure US20230303573A1-20230928-C01206
Figure US20230303573A1-20230928-C01207
Figure US20230303573A1-20230928-C01208
Figure US20230303573A1-20230928-C01209
Figure US20230303573A1-20230928-C01210
Figure US20230303573A1-20230928-C01211
Figure US20230303573A1-20230928-C01212
Figure US20230303573A1-20230928-C01213
Figure US20230303573A1-20230928-C01214
Figure US20230303573A1-20230928-C01215
Figure US20230303573A1-20230928-C01216
Figure US20230303573A1-20230928-C01217
Figure US20230303573A1-20230928-C01218
Figure US20230303573A1-20230928-C01219
Figure US20230303573A1-20230928-C01220
Figure US20230303573A1-20230928-C01221
Figure US20230303573A1-20230928-C01222
Figure US20230303573A1-20230928-C01223
Figure US20230303573A1-20230928-C01224
Figure US20230303573A1-20230928-C01225
Figure US20230303573A1-20230928-C01226
Figure US20230303573A1-20230928-C01227
Figure US20230303573A1-20230928-C01228
Figure US20230303573A1-20230928-C01229
Figure US20230303573A1-20230928-C01230
Figure US20230303573A1-20230928-C01231
Figure US20230303573A1-20230928-C01232
Figure US20230303573A1-20230928-C01233
Figure US20230303573A1-20230928-C01234
Figure US20230303573A1-20230928-C01235
Figure US20230303573A1-20230928-C01236
Figure US20230303573A1-20230928-C01237
Figure US20230303573A1-20230928-C01238
Figure US20230303573A1-20230928-C01239
Figure US20230303573A1-20230928-C01240
Figure US20230303573A1-20230928-C01241
Figure US20230303573A1-20230928-C01242
Figure US20230303573A1-20230928-C01243
Figure US20230303573A1-20230928-C01244
.
22. The compound according to claim 1, wherein
R1 means —H or —CH3;
R2 means -C1-C6-alkyl, linear or branched, saturated, unsubstituted; cyclopropyl connected through —CH2—; or tetrahydropyranyl connected through —CH2—;
R3 means -phenyl, benzyl, -thienyl or -pyridinyl, 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, —CN, —CH3, —CH2CH3, —CH2F, —CHF2, —CF3, —OCF3, —OH, —OCH3, —C(═O)NH2, C(═O)NHCH3, —C(═O)N(CH3)2, —NH2, —NHCH3, —N(CH3)2, —NHC(═O)CH3, —CH2OH, SOCH3 and SO2CH3; 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-C1-C4-alkyl, -C(=O)NH-C1-C6-alkyl, -C(=O)N(C1-C6-alkyl)2 or —C(═O)NRR′ wherein R and R′ together with the nitrogen atom to which they are attached form a ring and mean —(CH2)3-5—;
3-6-membered cycloalkyl, 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, and -O-C1-C4-alkyl, wherein said 3-6-membered cycloalkyl is connected through -C1-C6-alkylene;
3-6-membered heterocycloalkyl, 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, and -O-C1-C4-alkyl, wherein said 3-6-membered heterocycloalkyl is connected through -C1-C6-alkylene;
-phenyl, unsubstituted or monosubstituted with —OCH3; wherein said -phenyl isconnected through -C1-C6-alkylene-; or
-pyridyl, unsubstituted, mono- or polysubstituted; wherein said -pyridyl is connected through -C1-C6-alkylene-;
R5 means
-phenyl, -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, 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; -C1-C4-alkyl; -C1-C4-alkyl-OH; —CF3; -C1-C4-alkyl-CF3; -C1-C4-alkyl-C(=O)NH2; -C1-C4-alkyl-C(=O)NHC1-C6-alkyl; -C1-C4-alkyl-C(=O)N(C1-C6-alkyl)2;
-C1-C4-alkyl-S(=O)2-C1-C4-alkyl;
-C(=O)-C1-C4-alkyl; —C(═O)OH; -C(=O)O-C1-C4-alkyl; —C(═O)NH2; -C(=O)NHC1-C4-alkyl; -C(=O)N(C1-C4-alkyl)2; -C(=O)NH(C1-C4-alkyl-OH); -C(=O)N(C1-C4-alkyl)(C1-C4-alkyl-OH); —C(═O)NH—(CH2CH2O)1-30—CH3;
—NH2; -NHC1-C4-alkyl; -N(C1-C4-alkyl)2; -NHC1-C4-alkyl-OH; -NCH3C1-C4-alkyl-OH; -NH-C1-C4-alkyl-C(=O)NH2; -NCH3-C1-C4-alkyl-C(=O)NH2; -NHC(=O)-C1-C4-alkyl; -NCH3C(=O)-C1-C4-alkyl;
—OH; -O-C1-C4-alkyl; —OCF3; -O-C1-C4-alkyl-CO2H; -O-C1-C4-alkyl-C(=O)O-C1-C4-alkyl; -O-C1-C4-alkyl-CONH2;
-S-C1-C4-alkyl; -S(=O)C1-C4-alkyl; -S(=O)2C1-C4-alkyl; and -S(=O)2N(C1-C4-alkyl)2;
-3-12-membered cycloalkyl, saturated or unsaturated, unsubstituted, mono- or polysubstituted; wherein said 3-12-membered cycloalkyl is optionally connected through —CH2—, —O—, —NH—, —NCH3—, —NH—(CH2)1-3—, —NCH3(CH2)1-3—, —(C═O)—, —NHC(═O)—, —NCH3C(═O)—, —C(═O)NH—(CH2)1-3—, —C(═O)NCH3—(CH2)1-3—;
-3-12-membered heterocycloalkyl, saturated or unsaturated, unsubstituted, mono- or polysubstituted; wherein said 3-12-membered heterocycloalkyl is optionally connected through —CH2—, —O—, —NH—, —NCH3—, —NH—(CH2)1-3—, —NCH3(CH2)1-3—, —(C═O)—, —NHC(═O)—, —NCH3C(═O)—, —C(═O)NH—(CH2)1-3—, —C(═O)NCH3—(CH2)1-3—;
-6-14-membered aryl, unsubstituted, mono- or polysubstituted; wherein said 6-14-membered aryl is optionally connected through —CH2—, —O—, —NH—, —NCH3—, —NH—(CH2)1-3—, —NCH3(CH2)1-3—, —(C═O)—, —NHC(═O)—, —NCH3C(═O)—, —C(═O)NH—(CH2)1-3—, —C(═O)NCH3—(CH2)1-3—; or
-5-14-membered heteroaryl, unsubstituted, mono- or polysubstituted; wherein said 5-14-membered heteroaryl is optionally connected through —CH2—, —O—, —NH—, —NCH3—, —NH—(CH2)1-3—, —NCH3(CH2)1-3—, —(C═O)—, —NHC(═O)—, —NCH3C(═O)—, —C(═O)NH—(CH2)1-3—, —C(═O)NCH3—(CH2)1-3—;
and R11, R12, R13, R14, R15, R16, R17, R18, R19, and R20 mean —H.
23. The compound according to claim 1, which has a structure according to general formula (I′)
Figure US20230303573A1-20230928-C01245
wherein R1 to R5, R11 to R20 are defined as in claim 1,
or a physiologically acceptable salt thereof.
24. The compound according to claim 1, which has a structure according to general formula (IX) or (X)
Figure US20230303573A1-20230928-C01246
Figure US20230303573A1-20230928-C01247
wherein
R2 means —H or —CH3;
R3 means -phenyl or -3-fluorophenyl;
RC means —H or —OH;
RE means —H, —CH3, —F, —CF3, -cyclopropyl, -aziridinyl, —OH; -O-C1-C4-alkyl; —OCF3; -O-C1-C4-alkyl-CO2H; -O-C1-C4-alkyl-C(=O)O-C1-C4-alkyl; or -O-C1-C4-alkyl-CONH2;
RF means
—CF3, -cyclopropyl, —S(═O)2CH3,
—NH2; -NHC1-C4-alkyl; -N(C1-C4-alkyl)2; -NHC1-C4-alkyl-OH; -NCH3C1-C4-alkyl-OH; -NH-C1-C4-alkyl-C(=O)NH2; -NCH3-C1-C4-alkyl-C(=O)NH2; -NHC(=O)-C1-C4-alkyl; -NCH3C(=O)-C1-C4-alkyl;
-6-14-membered aryl, unsubstituted, mono- or polysubstituted; or -5-14-membered heteroaryl, unsubstituted, mono- or polysubstituted;
U means ═CH— or ═N—; and
V means ═CH- or ═N—;
or a physiologically acceptable salt thereof
.
25. The compound according to claim 1, which has a structure according to general formula (XI)
Figure US20230303573A1-20230928-C01248
wherein
R2 means —H or —CH3;
R3 means -phenyl or -3-fluorophenyl;
RH means
—CN; -C1-C4-alkyl; —CF3; -C1-C4-alkyl-C(=O)NH2; -C1-C4-alkyl-S(=O)2-C1-C4-alkyl; -C(=O)-C1-C4-alkyl; —C(═O)OH; -C(=O)O-C1-C4-alkyl; —C(═O)NH2; -C(=O)NHC1-C4-alkyl; -C(=O)N(C1-C4-alkyl)2; -C(=O)NH(C1-C4-alkyl-OH); -C(=O)N(C1-C4-alkyl)(C1-Ca-allcyl-OH); —C(═O)NH—(CH2CH2O)1-30—CH3;
-3-12-membered cycloalkyl, saturated or unsaturated, unsubstituted, mono- or polysubstituted; wherein said 3-12-membered cycloalkyl is optionally connected through —CH2—, —NH—, —NCH3—, —NH—(CH2)1-3—, —NCH3(CH2)1-3—, —(C═O)—, —NHC(═O)—, —NCH3C(═O)—, —C(═O)NH—(CH2)1-3—, —C(═O)NCH3—(CH2)1-3—; or
-3-12-membered heterocycloalkyl, saturated or unsaturated, unsubstituted, mono- or polysubstituted; 6-14-membered aryl, unsubstituted, mono- or polysubstituted; wherein said 3-12-membered heterocycloalkyl is optionally connected through —CH2—, —NH—, —NCH3—, —NH—(CH2)1-3—, —NCH3(CH2)1-3—, —(C═O)—, —NHC(═O)—, —NCH3C(═O)—, —C(═O)NH—(CH2)1-3—, —C(═O)NCH3—(CH2)1-3—;
RG means
—CF3, —S(═O)2CH3;
—NH2; -NHC1-C4-alkyl; -N(C1-C4-alkyl)2; -NHC1-C4-alkyl-OH; -NCH3C1-C4-alkyl-OH; -NH-C1-C4-alkyl-C(=O)NH2; -NCH3-C1-C4-alkyl-C(=O)NH2; -NHC(=O)-C1-C4-alkyl; -NCH3C(=O)-C1-C4-alkyl;
-3-12-membered cycloalkyl, saturated or unsaturated, unsubstituted, mono- or polysubstituted; wherein said 3-12-membered cycloalkyl is optionally connected through —CH2—, —NH—, —NCH3—, —NH—(CH2)1-3—, —NCH3(CH2)1-3—, —(C═O)—, —NHC(═O)—, —NCH3C(═O)—, —C(═O)NH—(CH2)1-3—, —C(═O)NCH3—(CH2)1-3—; or
-3-12-membered heterocycloalkyl, saturated or unsaturated, unsubstituted, mono- or polysubstituted; 6-14-membered aryl, unsubstituted, mono- or polysubstituted; wherein said 3-12-membered heterocycloalkyl is optionally connected through —CH2—, —NH—, —NCH3—, —NH—(CH2)1-3—, —NCH3(CH2)1-3—, —(C═O)—, —NHC(═O)—, —NCH3C(═O)—, —C(═O)NH—(CH2)1-3—, —C(═O)NCH3—(CH2)1-3—;
or a physiologically acceptable salt thereof.
26. The compound according to claim 1, which is selected from the group consisting of
cis-5-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carbonitrile;
cis-5-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-pyrazine-2-carbonitrile;
cis-5-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-4-methoxy-pyrimidine-2-carbonitrile;
cis-5-[8-Dimethylamino-1-(2-methoxy-ethyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carbonitrile;
cis-5-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carboxylic acid amide;
cis-5-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-2-methylsulfonyl-pyrimidine-4-carbonitrile;
cis-5-[1-(2-Methoxy-ethyl)-8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carbonitrile;
cis-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-5-methylsulfonyl-benzonitrile;
cis-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-benzamide;
cis-3-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-benzamide;
cis-5-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carboxylic acid amide;
cis-5-[1-(Cyclobutyl-methyl)-8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-4-methoxy-pyrimidine-2-carbonitrile;
cis-5-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carbonitrile;
cis-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-5-carbonitrile;
cis-8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-3-(2-methoxy-pyrimidin-5-yl)-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]-pyrimidine-5-carboxylic acid amide;
cis-4-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-methyl-benzamide;
cis-5-(8-Dimethylamino-2-oxo-8-phenyl-1-propyl-1,3-diazaspiro[4.5]decan-3-yl)-pyrimidine-2-carbonitrile;
cis-5-[8-Dimethylamino-1-(3-methoxy-propyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carbonitrile;
cis-5-[1-(Cyclopropyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carbonitrile;
cis-4-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-benzamide;
cis-1-(Cyclobutyl-methyl)-8-dimethylamino-8-phenyl-3-[2-(trifluoromethyl)-pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2-one;
cis-8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-3-(2-hydroxy-pyrimidin-5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
cis-5-[8-Dimethylamino-1-(2-methyl-propyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carbonitrile;
cis-5-[8-Dimethylamino-1-(2-hydroxy-ethyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carbonitrile;
cis-5-[1-(Cyclobutyl-methyl)-8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-4-methyl-pyridine-2-carbonitrile;
cis-1-(Cyclobutyl-methyl)-3-(5-methoxy-pyrazin-2-yl)-8-methylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
cis-4-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N,N-dimethyl-benzamide;
cis-4-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-ethyl-N-(2-hydroxy-ethyl)-benzamide;
cis-2-[1-(Cyclobutyl-methyl)-8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-5-methylsulfonyl-benzonitrile;
cis-1-(Cyclobutyl-methyl)-8-methylamino-3-[2-methylsulfonyl-4-(trifluoromethyl)-phenyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
cis-4-[1-(Cyclobutyl-methyl)-8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N,N-dimethyl-3-(trifluoromethyl)-benzenesulfonic acid amide;
cis-4-[1-(Cyclobutyl-methyl)-8-(ethyl-methyl-amino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl] -benzonitrile;
cis-1-(Cyclobutyl-methyl)-8-(ethyl-methyl-amino)-8-phenyl-3-[2-(trifluoromethyl)-pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2-one;
cis-5-[1-(Cyclobutyl-methyl)-8-(ethyl-methyl-amino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carbonitrile;
cis-5-[8-Dimethylamino-1-[(1-methyl-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carbonitrile;
cis-2-[3-(2-Cyano-pyrimidin-5-yl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl]-N,N-dimethyl-acetamide;
cis-1-(Cyclobutyl-methyl)-8-methylamino-8-phenyl-3-[2-(trifluoromethyl)-pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2-one;
cis-5-[8-Dimethylamino-8-(3-fluorophenyl)-1-(4-methoxy-butyl)-2-oxo-1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carbonitrile;
cis-5-[8-Dimethylamino-1-(3-methoxy-propyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-4-methoxy-pyrimidine-2-carbonitrile;
cis-5-[1-[(1-Cyano-cyclobutyl)-methyl]-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carbonitrile;
cis-N-(Cyclobutyl-methyl)-5-[1-(cyclobutyl-methyl)-8-dimethylamino-8-(3-fluorophenyl)-2-oxo-1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carboxylic acid amide;
cis-5-[1-(3-Methoxy-propyl)-8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carbonitrile;
cis-5-[8-Dimethylamino-8-(3-fluorophenyl)-1-methyl-2-oxo-1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carbonitrile;
cis-4-Methoxy-5-[1-(3-methoxy-propyl)-8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carbonitrile;
cis-4-[8-Dimethylamino-1-(2-methoxy-ethyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carbonitrile;
cis-5-[8-Dimethylamino-1-(2-methoxy-ethyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-4-methoxy-pyrimidine-2-carbonitrile;
cis-4-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carbonitrile;
cis-1-(Cyclobutyl-methyl)-8-dimethylamino-3-(6-methylsulfanyl-pyrimidin-4-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
cis-2-[3-(2-Cyano-pyrimidin-4-yl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl]-N,N-dimethyl-acetamide;
cis-6-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-4-carbonitrile;
cis-2-(8-Dimethylamino-2-oxo-3,8-diphenyl-1,3-diazaspiro[4.5]decan-1-yl)-N,N-dimethyl-acetamide;
cis-1-(Cyclobutyl-methyl)-8-dimethylamino-3,8-diphenyl-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]-pyrimidine-5-carbonitrile;
cis-8-Dimethylamino-1-(2-methoxy-ethyl)-3,8-diphenyl-1,3-diazaspiro[4.5]decan-2-one;
cis-5-[8-Dimethylamino-1-(2-methoxy-ethyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-4-methyl-pyridine-2-carbonitrile;
cis-N,N-Dimethyl-2-(8-methylamino-2-oxo-3,8-diphenyl-1,3-diazaspiro[4.5]decan-1-yl)-acetamide;
cis-5-[1-[(1-Cyano-cyclobutyl)-methyl]-8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carbonitrile;
cis-5-[1-[(1-Cyano-cyclobutyl)-methyl]-8-(ethyl-methyl-amino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carbonitrile;
CIS-4-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-benzonitrile;
cis-3-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-benzonitrile;
cis-5-[1-[(1-Cyano-cyclobutyl)-methyl]-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-pyridine-2-carbonitrile;
cis-2-[3-(2-Cyano-pyrimidin-5-yl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl]-N-propyl-acetamide;
cis-5-[1-(Cyclobutyl-methyl)-8-(ethyl-methyl-amino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-4-methoxy-pyrimidine-2-carbonitrile;
cis-4-[1-(Cyclobutyl-methyl)-8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-3-methoxy-benzonitrile;
cis-5-[8-Dimethylamino-1-(3-methoxy-propyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-6-methoxy-pyridine-2-carbonitrile;
cis-4-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-benzamide;
cis-5-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-pyridine-2-carbonitrile;
cis-5-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N-[(1-hydroxy-cyclobutyl)-methyl]-pyridine-2-carboxylic acid amide;
cis-2-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-benzonitrile;
cis-3-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-benzonitrile;
cis-1-(Cyclobutyl-methyl)-8-dimethylamino-8-phenyl-3-[2-(trifluoromethyl)-pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2-one;
cis-5-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-4-methyl-pyridine-2-carboxylic acid methyl ester;
cis-1-(Cyclobutyl-methyl)-8-dimethylamino-3-(5-methoxy-pyrazin-2-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
cis-1-(Cyclobutyl-methyl)-8-dimethylamino-3-(2-methoxy-pyrimidin-5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
cis-4-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-benzonitrile;
cis-5-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-4-methyl-pyridine-2-carbonitrile;
cis-1-(Cyclobutyl-methyl)-8-dimethylamino-3-(5-fluoro-pyrimidin-2-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
cis-4-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-3-methoxy-benzonitrile;
cis-4-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-benzoic acid methyl ester;
cis-1-(Cyclobutyl-methyl)-8-dimethylamino-8-phenyl-3-(2-pyrrolidin-1-yl-pyrimidin-4-yl)-1,3-diazaspiro[4.5]decan-2-one;
cis-1-(Cyclobutyl-methyl)-8-dimethylamino-8-phenyl-3-(5-pyridin-2-yl-thiophen-2-yl)-1,3-diazaspiro[4.5]decan-2-one;
cis-1-(Cyclobutyl-methyl)-8-dimethylamino-3-[2-methylsulfonyl-4-(trifluoromethyl)-phenyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
cis-1-(Cyclobutyl-methyl)-8-dimethylamino-8-phenyl-3-[6-(trifluoromethyl)-pyridin-3-yl]-1,3-diazaspiro[4.5]decan-2-one;
cis-1-(Cyclobutyl-methyl)-3-(2,4-dimethoxy-phenyl)-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]-4-methylsulfonyl-benzonitrile;
cis-5-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-2-fluoro-benzonitrile;
cis-4-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-N,N-dimethyl-3-(trifluoromethyl)-benzenesulfonic acid amide;
cis-2-[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-benzonitrile;
cis-1-(Cyclobutyl-methyl)-8-dimethylamino-3-(2-methyl-imidazo[1,2-a]pyrazin-6-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
cis-1-(Cyclobutyl-methyl)-8-dimethylamino-3-(4-methylsulfonyl-phenyl)-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]-5-methoxy-benzonitrile;
cis-1-(Cyclobutyl-methyl)-8-dimethylamino-3,8-diphenyl-1,3-diazaspiro[4.5]decan-2-one;
cis-1-(Cyclobutyl-methyl)-8-dimethylamino-8-phenyl-3-pyrazin-2-yl-1,3-diazaspiro[4.5]decan-2-one;
cis-8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-3-(2-morpholin-4-yl-pyrimidin-5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
cis-8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-3-[2-(4-methyl-piperazin-1-yl)-pyrimidin-5-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
cis-1-[(1-Hydroxy-cyclobutyl)-methyl]-8-methylamino-3-(2-morpholin-4-yl-pyrimidin-5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
cis-8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-8-phenyl-3-(2-piperazin-1-yl-pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one hydrochloride;
cis-1-[(1-Hydroxy-cyclobutyl)-methyl]-8-methylamino-3-[2-(4-methyl-piperazin-1-yl)-pyrimidin-5-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
cis-1-[(1-Hydroxy-cyclobutyl)-methyl]-8-methylamino-8-phenyl-3-(2-piperazin-1-yl-pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one dihydrochloride;
cis-1-(Cyclobutyl-methyl)-8-dimethylamino-3-[4-methyl-6-(trifluoromethyl)-pyridin-3-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
cis-1-(Cyclobutyl-methyl)-8-methylamino-3-[4-methyl-6-(trifluoromethyl)-pyridin-3-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
cis-1-(Cyclopropyl-methyl)-8-dimethylamino-3-(4-methylsulfonyl-phenyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one ;
cis-1-(Cyclopropyl-methyl)-8-methylamino-3-(4-methylsulfonyl-phenyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
cis-1-(Cyclopropyl-methyl)-8-dimethylamino-3-(2-fluoro-4-methylsulfonyl-phenyl)-8-phenyl-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]-benzamide; formic acid;
cis-2-[8-Dimethylamino-1-[2-(1-methoxy-cyclobutyl)-ethyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-benzamide;
cis-8-Dimethylamino-1-[2-(1-methoxy-cyclobutyl)-ethyl]-3-(2-methyl-pyrimidin-5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
cis-5-[1-[(1-Hydroxy-cyclobutyl)-methyl]-8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-2-carbonitrile;
cis-2-[1-[(1-Hydroxy-cyclobutyl)-methyl]-8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-benzonitrile;
cis-4-[1-[(1-Hydroxy-cyclobutyl)-methyl]-8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-3-methoxy-benzonitrile;
cis-4-[8-Ethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-3-methoxy-benzonitrile;
cis-2-[8-Ethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-benzonitrile;
cis-5-[1-[(1-Hydroxy-cyclobutyl)-methyl]-8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-4-methoxy-pyrimidine-2-carbonitrile;
cis-2-[8-Dimethylamino-1-(oxetan-3-yl-methyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-benzamide;
cis-4-Methoxy-5-(8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-pyrimidine-2-carbonitrile;
cis-2-(8-Methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-benzamide;
cis-8-Dimethylamino-3-[2-(3-oxo-piperazin-1-yl)-pyrimidin-5-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
cis-3-(2-Cyclopropyl-pyrimidin-5-yl)-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
cis-8-Dimethylamino-3-[4-methyl-6-(trifluoromethyl)-pyridin-3-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
cis-8-Dimethylamino-3-(2-methylsulfonyl-phenyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
cis-8-Dimethylamino-8-phenyl-3-(2-piperazin-1-yl-pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one;
trans-2-(8-Ethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-benzamide;
cis-2-(8-Ethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-benzamide;
cis-2-(8-Ethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-benzonitrile;
cis-2-(8-Ethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-benzonitrile;
cis-3-[5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-pyrimidin-2-yl]-benzonitrile;
cis-8-Dimethylamino-3-[2-(4-methylsulfonyl-piperazin-1-yl)-pyrimidin-5-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
cis-3-[5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-pyrimidin-2-yl]-benzamide
cis-8-[(Cyclopropyl-methyl)-methyl-amino]-8-phenyl-3-[2-(trifluoromethyl)-pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2-one;
cis-8-Dimethylamino-3-[2-(4-methyl-piperazine-1-carbonyl)-pyrimidin-5-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
trans-4-(8-Ethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-3-methoxy-benzonitrile;
cis-4-(8-Ethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-3-methoxy-benzonitrile;
cis-3-[2-(4-Acetyl-piperazin-1-yl)-pyrimidin-5-yl]-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
cis-8-Dimethylamino-8-phenyl-3-(2-pyridin-4-yl-pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one;
cis-8-Dimethylamino-8-phenyl-3-(2-pyridin-3-yl-pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one;
cis-5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-N-(2-hydroxy-ethyl)-pyrimidine-2-carboxylic acid amide;
cis-5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-pyrimidine-2-carboxylic acid amide;
cis-8-Dimethylamino-3-[2-morpholin-4-yl-4-(trifluoromethyl)-pyrimidin-5-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
cis-4-[5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-pyrimidin-2-yl]-benzonitrile;
cis-5-(8-Ethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-4-methoxy-pyrimidine-2-carbonitrile;
trans-5-(8-Ethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-4-methoxy-pyrimidine-2-carbonitrile;
cis-8-Dimethylamino-3-[2-(morpholine-4-carbonyl)-pyrimidin-5-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
cis-2-[4-[5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-pyrimidin-2-yl]-piperazin-1-yl]-acetic acid methyl ester;
cis-8-Dimethylamino-3-[2-(methylsulfonyl-methyl)-phenyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
cis-8-Dimethylamino-3-(4-methyl-2-morpholin-4-yl-pyrimidin-5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
cis-8-Dimethylamino-3-[2-(1,1-dioxo-[1,4]thiazinan-4-yl)-pyrimidin-5-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
cis-8-Dimethylamino-3-(4-fluoro-pyridin-3-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
cis-5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-N-(2-hydroxy-ethyl)-N-methyl-pyrimidine-2-carboxylic acid amide;
cis-5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-2-morpholin-4-yl-isonicotinonitrile;
cis-4-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-benzamide;
cis-8-Dimethylamino-3-(2-fluoro-4-methylsulfonyl-phenyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
cis-4-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-3-fluoro-benzonitrile;
cis-4-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-3,5-difluoro-benzonitrile;
cis-8-Dimethylamino-3-(2-methoxy-pyrimidin-5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
cis-3-[2-(Benzylamino)-pyrimidin-5-yl]-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
cis-8-Dimethylamino-3-[2-(4-fluorophenyl)-pyrimidin-5-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
trans-8-Benzyl-8-dimethylamino-3-(2-morpholin-4-yl-pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one;
cis-8-Benzyl-8-dimethylamino-3-(2-morpholin-4-yl-pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one;
cis-8-Dimethylamino-8-phenyl-3-(2-pyridin-2-yl-pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one;
cis-4-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-3,5-difluoro-benzamide;
cis-4-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-3-fluoro-benzamide;
cis-8-Benzyl-8-dimethylamino-3-[2-(trifluoromethyl)-pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2-one;
trans-8-Benzyl-8-dimethylamino-3-[2-(trifluoromethyl)-pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2-one;
cis-8-Dimethylamino-8-thiophen-2-yl-3-[2-(trifluoromethyl)-pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2-one;
trans-8-Dimethylamino-8-thiophen-2-yl-3-[2-(trifluoromethyl)-pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2-one;
cis-2-[2-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-phenoxy]-acetic acid;
cis-8-Dimethylamino-8-phenyl-3-(2-piperidin-1-yl-pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one;
cis-8-Dimethylamino-8-phenyl-3-(2-pyrrolidin-1-yl-pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one;
cis-8-Dimethylamino-8-phenyl-3-(2-pyrimidin-5-yl-pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one;
cis-8-Dimethylamino-8-phenyl-3-[2-(piperazine-1-carbonyl)-pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2-one;
trans-8-Benzyl-8-dimethylamino-3-[4-methyl-6-(trifluoromethyl)-pyridin-3-yl]-1,3-diazaspiro[4.5]decan-2-one;
cis-5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-2-morpholin-4-yl-pyridine-4-carboxylic acid amide;
cis-8-Dimethylamino-3-[2-(3,5-dimethyl-isoxazol-4-yl)-pyrimidin-5-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
cis-3-[2-(Benzothiazol-6-yl)-pyrimidin-5-yl]-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
cis-8-Dimethylamino-3-[2-fluoro-4-(trifluoromethyl)-phenyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
cis-8-Dimethylamino-3-(6-morpholin-4-yl-pyridin-3-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
cis-8-Dimethylamino-8-phenyl-3-(2-phenyl-thiazol-4-yl)-1,3-diazaspiro[4.5]decan-2-one;
cis-8-Dimethylamino-8-phenyl-3-[2-(tetrahydro-pyran-4-ylamino)-pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2-one;
cis-8-Dimethylamino-3-[2-(4-hydroxy-piperidin-1-yl)-pyrimidin-5-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
cis-8-Dimethylamino-8-phenyl-3-(4-phenyl-thiazol-2-yl)-1,3-diazaspiro[4.5]decan-2-one;
cis-8-Dimethylamino-8-phenyl-3-[2-(1H-pyrrolo[2,3-b]pyridin-1-yl)-pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2-one;
cis-8-Dimethylamino-8-phenyl-3-[2-(3,4,5-trifluoro-phenyl)-pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2-one;
cis-8-Dimethylamino-3-o-tolyl-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
cis-8-Dimethylamino-3-m-tolyl-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
cis-8-Dimethylamino-8-phenyl-3-p-tolyl-1,3-diazaspiro[4.5]decan-2-one;
cis-8-Dimethylamino-8-phenyl-3-[4-(trifluoromethyl)-phenyl]-1,3-diazaspiro[4.5]decan-2-one;
cis-8-Dimethylamino-8-phenyl-3-[3-(trifluoromethyloxy)-phenyl]-1,3-diazaspiro[4.5]decan-2-one;
cis-8-Dimethylamino-8-phenyl-3-[4-(trifluoromethyloxy)-phenyl]-1,3-diazaspiro[4.5]decan-2-one;
cis-2-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-benzoic acid methyl ester;
cis-3-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-benzoic acid methyl ester;
cis-4-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-benzoic acid methyl ester;
cis-3-(1,3-Benzodioxol-5-yl)-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
cis-8-Dimethylamino-8-phenyl-3-quinolin-5-yl-1,3-diazaspiro[4.5]decan-2-one;
cis-3-(2,3-Dihydro-1H-indol-6-yl)-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
cis-5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-4-methyl-pyridine-2-carboxylic acid methyl ester;
cis-8-Dimethylamino-3-(6-methoxy-4-methyl-pyridin-3-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
cis-8-Dimethylamino-3-[2-methyl-5-(trifluoromethyl)-2H-pyrazol-3-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
cis-8-Dimethylamino-3-(3-methoxy-pyridin-2-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
cis-8-Dimethylamino-8-phenyl-3-[5-(trifluoromethyl)-pyridin-2-yl]-1,3-diazaspiro[4.5]decan-2-one;
cis-5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-nicotinonitrile;
cis-8-Dimethylamino-3-(3-methyl-pyridin-2-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
cis-8-Dimethylamino-3-(6-methoxy-pyridin-3-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
cis-8-Dimethylamino-8-phenyl-3-[3-(trifluoromethyl)phenyl]-1,3-diazaspiro[4.5]decan-2-one;
cis-3-(1,3-Benzodioxol-4-yl)-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
cis-8-Dimethylamino-3-[2-(2-oxo-1,3-dihydro-indol-4-yl)-pyrimidin-5-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
cis-8-Dimethylamino-3-[2-(3,5-dimethyl-1H-pyrazol-1-yl)-pyrimidin-5-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
cis-8-Dimethylamino-3-[2-(3-hydroxy-piperidin-1-yl)-pyrimidin-5-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
cis-8-Dimethylamino-3-[2-(3-hydroxy-piperidin-1-yl)-pyrimidin-5-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
cis-8-Dimethylamino-3-[2-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-pyrimidin-5-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
cis-2-[4-[5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-pyrimidin-2-yl]-piperazin-1-yl]-acetic acid;
cis-8-Dimethylamino-3-[2-(1-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-pyrimidin-5-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
cis-8-Benzyl-8-dimethylamino-3-[4-methyl-6-(trifluoromethyl)-pyridin-3-yl]-1,3-diazaspiro[4.5]decan-2-one;
trans-8-Dimethylamino-3-[4-methyl-6-(trifluoromethyl)-pyridin-3-yl]-8-thiophen-2-yl-1,3-diazaspiro[4.5]decan-2-one;
cis-8-Dimethylamino-3-[4-methyl-6-(trifluoromethyl)-pyridin-3-yl]-8-thiophen-2-yl-1,3-diazaspiro[4.5]decan-2-one;
cis-8-Dimethylamino-3-[2-(1,1-dioxo-[1,4]thiazinan-4-yl)-4-(trifluoromethyl)-pyrimidin-5-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
cis-8-Dimethylamino-8-(1-methyl-1H-benzoimidazol-2-yl)-3-[2-(trifluoromethyl)-pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2-one;
cis-8-Dimethylamino-8-(1-methyl-1H-benzoimidazol-2-yl)-3-[4-methyl-6-(trifluoromethyl)-pyridin-3-yl]-1,3-diazaspiro[4.5]decan-2-one;
cis-8-Dimethylamino-3-[2-(2-hydroxy-ethylamino)-pyrimidin-5-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
cis-3-[2-(Benzyl-methyl-amino)-pyrimidin-5-yl]-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
cis-5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-N-[2-[2-[2-(2-methoxy-ethoxy)-ethoxy]-ethoxy]-ethyl]-pyrimidine-2-carboxylic acid amide;
cis-8-Dimethylamino-3-[2-(1H-indazol-1-yl)-pyrimidin-5-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
cis-8-Dimethylamino-3-[2-[(2-hydroxy-ethyl)-methyl-amino]-pyrimidin-5-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
cis-3-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-benzamide;
cis-8-Dimethylamino-3-[3-fluoro-5-(trifluoromethyl)-pyridin-2-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
cis-8-Dimethylamino-3-(5-methyl-pyrazin-2-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
cis-8-Dimethylamino-3-(5-fluoro-pyrimidin-4-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
cis-8-Dimethylamino-3-(5-fluoro-pyrimidin-2-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
cis-8-Dimethylamino-8-phenyl-3-pyrazin-2-yl-1,3-diazaspiro[4.5]decan-2-one;
cis-3-([2,1,3]Benzoxadiazol-5-yl)-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
cis-2-[2-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-phenoxy]-acetamide;
cis-8-Dimethylamino-8-phenyl-3-(5-pyridin-4-yl-thiophen-2-yl)-1,3-diazaspiro[4.5]decan-2-one;
cis-2-[2-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-phenoxy]-acetic acid methyl ester;
cis-8-Dimethylamino-3-(2-morpholin-4-yl-pyrimidin-4-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
cis-3-[2-(3,4-Difluoro-phenyl)-pyrimidin-5-yl]-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
cis-2-[5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-pyrimidin-2-yl]-benzonitrile;
cis-3-(2-Amino-pyrimidin-5-yl)-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
cis-N-[5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-pyrimidin-2-yl]-cyclopropanecarboxylic acid amide;
cis-2-[4-[5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-pyrimidin-2-yl]-piperazin-1-yl]-acetamide;
cis-8-Dimethylamino-8-phenyl-3-(6-piperazin-1-yl-pyridin-3-yl)-1,3-diazaspiro[4.5]decan-2-one;
cis-8-Dimethylamino-3-[6-(4-methyl-piperazin-1-yl)-pyridin-3-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
cis-8-Dimethylamino-3-[2-(1,1-dioxo-[1,4]thiazinan-4-yl)-4-methyl-pyrimidin-5-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
cis-8-Dimethylamino-8-phenyl-3-[2-(trifluoromethyl)-pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2-one;
cis-2-[8-Dimethylamino-1-(3-methoxy-propyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-5-carbonitrile;
cis-8-Dimethylamino-3-[2-(4-methyl-piperazin-1-yl)-pyrimidin-5-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
cis-8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-8-phenyl-3-[2-(trifluoromethyl)-pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2-one;
cis-2-[1-(3-Methoxy-propyl)-8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-pyrimidine-5-carbonitrile;
cis-8-Dimethylamino-8-phenyl-3-[6-(trifluoromethyl)-pyridin-3-yl]-1,3-diazaspiro[4.5]decan-2-one;
cis-5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-pyridine-2-carbonitrile;
cis-8-Dimethylamino-3-(2-morpholin-4-yl-pyrimidin-5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
cis-8-Dimethylamino-3-(2-methyl-pyrimidin-5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
cis-8-Dimethylamino-1-[(2-methoxyphenyl)-methyl]-3-(2-methyl-pyrimidin-5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
cis-1-[(1-Hydroxy-cyclobutyl)-methyl]-8-methylamino-8-phenyl-3-[2-(trifluoromethyl)-pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2-one;
cis-8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-3-(2-methyl-pyrimidin-5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
cis-1-[(1-Hydroxy-cyclobutyl)-methyl]-8-methylamino-8-phenyl-3-pyrimidin-5-yl-1,3-diazaspiro[4.5]decan-2-one;
cis-5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-4-methyl-pyridine-2-carbonitrile;
cis-8-Dimethylamino-3-(2-methyl-pyrimidin-5-yl)-8-phenyl-1-(pyridin-2-yl-methyl)-1,3-diazaspiro[4.5]decan-2-one;
cis-8-Dimethylamino-8-phenyl-3-pyrimidin-5-yl-1,3-diazaspiro[4.5]decan-2-one;
cis-8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-8-phenyl-3-pyrimidin-5-yl-1,3-diazaspiro[4.5]decan-2-one;
cis-8-Amino-1-[(1-hydroxy-cyclobutyl)-methyl]-8-phenyl-3-[2-(trifluoromethyl)-pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2-one;
cis-8-Dimethylamino-3-(3-fluorophenyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
cis-8-Dimethylamino-3-(3-methylsulfonyl-phenyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
cis-8-Dimethylamino-3-(4-methylsulfonyl-phenyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
cis-8-Dimethylamino-8-phenyl-3-pyridazin-3-yl-1,3-diazaspiro[4.5]decan-2-one;
cis-3-Methoxy-4-(8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-benzonitrile;
cis-8-Dimethylamino-3-(2-fluorophenyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
cis-8-Dimethylamino-8-phenyl-3-(2-phenyl-pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one;
cis-8-Methylamino-1-(oxetan-3-yl-methyl)-8-phenyl-3-[2-(trifluoromethyl)-pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2-one;
cis-1-(Cyclopropyl-methyl)-8-methylamino-8-phenyl-3-[2-(trifluoromethyl)-pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2-one;
cis-4-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-benzonitrile;
cis-8-Dimethylamino-3-(4-fluorophenyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
cis-2-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-benzonitrile;
cis-8-Ethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-8-phenyl-3-[2-(trifluoromethyl)-pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2-one;
cis-1-[(1-Hydroxy-cyclobutyl)-methyl]-8-methylamino-3-(2-methyl-pyrimidin-5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
cis-8-Dimethylamino-3-[2-(morpholin-4-yl-methyl)-pyrimidin-5-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
cis-8-Dimethylamino-3-[2-(methyl-tetrahydro-pyran-4-yl-amino)-pyrimidin-5-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
cis-5-[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]-pyrimidine-2-carboxylic acid amide;
cis-1-(Cyclopropyl-methyl)-3-(2-fluoro-4-methylsulfonyl-phenyl)-8-methylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
cis-2-[[5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-pyrimidin-2-yl]-methyl-amino]-acetamide;
cis-2-[[5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-pyrimidin-2-yl]amino]-acetamide;
cis-1-(Cyclopropyl-methyl)-8-methylamino-3-[4-methyl-6-(trifluoromethyl)-pyridin-3-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
cis-1-(Cyclopropyl-methyl)-8-dimethylamino-3-[4-methyl-6-(trifluoromethyl)-pyridin-3-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
cis-N-[5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-pyrimidin-2-yl]-thiophene-2-carboxylic acid amide;
cis-N-[5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-pyrimidin-2-yl]-benzamide;
cis-8-Dimethylamino-8-phenyl-3-(5-phenyl-thiophen-2-yl)-1,3-diazaspiro[4.5]decan-2-one;
cis-1-(Cyclopropyl-methyl)-8-dimethylamino-3-[2-(methylsulfonyl-methyl)-phenyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
cis-1-(Cyclopropyl-methyl)-8-methylamino-3-[2-(methylsulfonyl-methyl)-phenyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
cis-8-Dimethylamino-8-(3-fluorophenyl)-3-[2-(methylsulfonyl-methyl)-phenyl]-1,3-diazaspiro[4.5]decan-2-one;
cis-8-Dimethylamino-8-(4-fluorophenyl)-3-[2-(methylsulfonyl-methyl)-phenyl]-1,3-diazaspiro[4.5]decan-2-one;
cis-8-[Methyl-(tetrahydro-furan-3-yl-methyl)-amino]-8-phenyl-3-[2-(trifluoromethyl)-pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2-one (enantiomer 1);
cis-8-[Methyl-(tetrahydro-furan-3-yl-methyl)-amino]-8-phenyl-3-[2-(trifluoromethyl)-pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2-one (enantiomer 2);
cis-8-Dimethylamino-8-(3-fluorophenyl)-3-(4-methyl-2-morpholin-4-yl-pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one;
cis-3-[6-(4-Acetyl-piperazin-1-yl)-4-methyl-pyridin-3-yl]-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
cis-3-[2-(4-Acetyl-piperazin-1-yl)-4-methyl-pyrimidin-5-yl]-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
cis-8-Dimethylamino-3-(4-methyl-6-pyridin-4-yl-pyridin-3-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
cis-3-[2-(4-Acetyl-piperazin-1-yl)-4-(trifluoromethyl)-pyrimidin-5-yl]-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
cis-8-Dimethylamino-3-[2-(3-oxo-piperazin-1-yl)-4-(trifluoromethyl)-pyrimidin-5-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
cis-8-Dimethylamino-3-isoquinolin-4-yl-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
cis-8-Dimethylamino-3-isoquinolin-5-yl-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
cis-8-Dimethylamino-8-phenyl-3-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1,3-diazaspiro[4.5]decan-2-one;
cis-8-Dimethylamino-8-phenyl-3-(2-pyridin-4-yl-thiazol-4-yl)-1,3-diazaspiro[4.5]decan-2-one;
cis-8-[Methyl-(tetrahydro-furan-3-yl-methyl)-amino]-3-(2-morpholin-4-yl-pyrimidin-5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (enantiomer 1);
cis-8-[Methyl-(tetrahydro-furan-3-yl-methyl)-amino]-3-(2-morpholin-4-yl-pyrimidin-5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (enantiomer 2);
cis-3-[2-(Azetidin-1-yl)-pyrimidin-5-yl]-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
cis-3-[2-(3,3-Difluoro-azetidin-1-yl)-pyrimidin-5-yl]-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
cis-8-Dimethylamino-3-[6-morpholin-4-yl-5-(trifluoromethyl)-pyridin-3-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
cis-8-Methylamino-3-[6-morpholin-4-yl-5-(trifluoromethyl)-pyridin-3-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
cis-8-Dimethylamino-8-phenyl-3-[5-(trifluoromethyloxy)-pyridin-2-yl]-1,3-diazaspiro[4.5]decan-2-one;
cis-8-Dimethylamino-3-(5-methylsulfonyl-pyridin-2-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
cis-6-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-nicotinonitrile;
cis-3-[2-(4-Cyclopropyl-1H-[1,2,3]triazol-1-yl)-pyrimidin-5-yl]-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
cis-8-Dimethylamino-3-[4-methyl-2-(3-oxo-piperazin-1-yl)-pyrimidin-5-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
cis-5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-pyridine-2-carboxylic acid amide;
cis-3-[4-(Azetidin-1-yl)-2-methyl-pyrimidin-5-yl]-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
cis-2-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-benzamide;
cis-8-Dimethylamino-3-[2-(methylsulfonyl-methyl)-phenyl]-8-thiophen-2-yl-1,3-diazaspiro[4.5]decan-2-one;
cis-8-Dimethylamino-8-(3-fluorophenyl)-3-[2-methyl-5-(trifluoromethyl)-2H-pyrazol-3-yl]-1,3-diazaspiro[4.5]decan-2-one;
cis-8-Dimethylamino-3-(4-methyl-2-morpholin-4-yl-pyrimidin-5-yl)-8-thiophen-2-yl-1,3-diazaspiro[4.5]decan-2-one;
cis-8-Dimethylamino-3-(6-methylsulfonyl-pyridin-3-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
cis-8-Dimethylamino-8-phenyl-3-(1H-pyrrolo[2,3-b]pyridin-5-yl)-1,3-diazaspiro[4.5]decan-2-one;
cis-N-[5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-pyrimidin-2-yl]-acetamide;
cis-3-[2-(4-Methyl-piperazin-1-yl)-pyrimidin-5-yl]-8-[methyl-(tetrahydro-furan-3-yl-methyl)-amino]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (enantiomer 1);
cis-3-[2-(4-Methyl-piperazin-1-yl)-pyrimidin-5-yl]-8-[methyl-(tetrahydro-furan-3-yl-methyl)-amino]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (enantiomer 2);
cis-8-Dimethylamino-3-(4,6-dimethyl-2-morpholin-4-yl-pyrimidin-5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
cis-8-Dimethylamino-3-(2-morpholin-4-yl-pyrimidin-5-yl)-8-thiophen-2-yl-1,3-diazaspiro[4.5]decan-2-one;
cis-6-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-pyridine-3-carboxylic acid amide;
cis-8-Dimethylamino-3-[2-methyl-5-(trifluoromethyl)-2H-pyrazol-3-yl]-8-thiophen-2-yl-1,3-diazaspiro[4.5]decan-2-one;
cis-8-Dimethylamino-3-[2-[(2-hydroxy-ethyl)-methyl-amino]-pyrimidin-5-yl]-8-thiophen-2-yl-1,3-diazaspiro[4.5]decan-2-one;
cis-8-Dimethylamino-3-[2-(2-oxo-1,3-dihydro-indol-4-yl)-pyrimidin-5-yl]-8-thiophen-2-yl-1,3-diazaspiro[4.5]decan-2-one;
cis-8-Dimethylamino-3-[4-methyl-6-(3-oxo-piperazin-1-yl)-pyridin-3-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
cis-8-Dimethylamino-3-(4-methyl-6-pyridin-2-yl-pyridin-3-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
cis-8-Dimethylamino-3-(4-methylsulfonyl-pyridin-3-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
cis-3-(Benzothiazol-7-yl)-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
cis-8-Dimethylamino-8-(4-fluorophenyl)-3-(4-methyl-2-morpholin-4-yl-pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one;
cis-2-[8-Dimethylamino-3-[4-methyl-6-(trifluoromethyl)-pyridin-3-yl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl]-N,N-dimethyl-acetamide;
cis-8-Dimethylamino-3-[2-(2-methyl-1-oxo-2,3-dihydro-isoindol-4-yl)-pyrimidin-5-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
cis-2-[[5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-2-methyl-pyrimidin-4-yl]amino]-acetamide;
cis-2-[3-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-pyridin-4-yl]-acetamide;
cis-8-Dimethylamino-3-[4-(methylsulfonyl-methyl)-pyridin-3-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
cis-8-Dimethylamino-3-[6-(4-methyl-3-oxo-piperazin-1-yl)-pyridin-3-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
cis-8-Dimethylamino-3-(2,4-dimethyl-pyrimidin-5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
cis-8-Dimethylamino-3-[2-(1-oxo-2,3-dihydro-isoindol-4-yl)-pyrimidin-5-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one; 2,2,2-trifluoro-acetic acid;
cis-8-Dimethylamino-3-[6-[(2-hydroxy-ethyl)-methyl-amino]-5-(trifluoromethyl)-pyridin-3-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
cis-8-Dimethylamino-8-phenyl-3-[2-[4-(trifluoromethyl)-1H-[1,2,3]triazol-1-yl]-pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2-one;
cis-8-Dimethylamino-3-[2-(4-isopropyl-1H-[1,2,3]triazol-1-yl)-pyrimidin-5-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
cis-8-Dimethylamino-3-[6-(1,1-dioxo-[1,4]thiazinan-4-yl)-pyridin-3-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
cis-5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-2-morpholin-4-yl-nicotinonitrile;
cis-8-Dimethylamino-3-(1-methylsulfonyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
cis-8-Dimethylamino-3-(1H-indol-4-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
cis-8-Dimethylamino-3-(2-hydroxy-benzooxazol-7-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
cis-8-Dimethylamino-3-[2-fluoro-4-(trifluoromethyloxy)-phenyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
cis-4-[5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-pyrimidin-2-yl]-benzamide; 2,2,2-trifluoro-acetic acid;
cis-8-Dimethylamino-3-(1-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
cis-3-(1-Acetyl-1H-indol-4-yl)-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
cis-8-Dimethylamino-3-(1H-indol-3-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
cis-6-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-5-methyl-nicotinonitrile;
cis-6-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-5-fluoro-nicotinonitrile;
cis-8-Dimethylamino-3-[4-methyl-6-(trifluoromethyl)-pyridin-3-yl]-1-(2-oxo-2-pyrrolidin-1-yl-ethyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
cis-6-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-5-methyl-pyridine-3-carboxylic acid amide;
cis-6-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-5-fluoro-pyridine-3-carboxylic acid amide;
cis-8-Dimethylamino-3-[4-methyl-6-(trifluoromethyl)-pyridin-3-yl]-8-m-tolyl-1,3-diazaspiro[4.5]decan-2-one;
cis-3-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-isonicotinonitrile;
cis-8-Dimethylamino-3-[3-fluoro-5-(2-oxo-1,3-dihydro-indol-4-yl)-pyridin-2-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
cis-8-Dimethylamino-3-[4-methyl-6-(trifluoromethyl)-pyridin-3-yl]-8-[3-(trifluoromethyloxy)-phenyl]-1,3-diazaspiro[4.5]decan-2-one;
cis-8-Dimethylamino-3-[4-methyl-6-(trifluoromethyl)-pyridin-3-yl]-8-[3-(trifluoromethyl)phenyl]-1,3-diazaspiro[4.5]decan-2-one;
cis-8-Dimethylamino-8-(3-methoxyphenyl)-3-[4-methyl-6-(trifluoromethyl)-pyridin-3-yl]-1,3-diazaspiro[4.5]decan-2-one;
cis-8-(5-Chloro-thiophen-2-yl)-8-dimethylamino-3-[4-methyl-6-(trifluoromethyl)-pyridin-3-yl]-1,3-diazaspiro[4.5]decan-2-one;
cis-8-Dimethylamino-8-(3-fluorophenyl)-3-[4-methyl-6-(trifluoromethyl)-pyridin-3-yl]-1,3-diazaspiro[4.5]decan-2-one;
cis-8-Dimethylamino-3-(2-methylamino-pyrimidin-5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
cis-8-(5-Chloro-thiophen-2-yl)-8-dimethylamino-3-(4-methyl-2-morpholin-4-yl-pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one;
cis-N-[5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-pyrimidin-2-yl]-N-methyl-cyclopropanecarboxylic acid amide;
cis-N-[5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-pyrimidin-2-yl]-N,2,5-trimethyl-2H-pyrazole-3-carboxylic acid amide;
cis-3-[4,6-Bis(trifluoromethyl)-pyridin-3-yl]-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
cis-8-Dimethylamino-3-[2-[(2-hydroxy-ethyl)-methyl-amino]-quinazolin-6-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
cis-8-Dimethylamino-3-(2-morpholin-4-yl-quinazolin-6-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
cis-8-[Methyl-(oxetan-3-yl-methyl)-amino]-8-phenyl-3-[2-(trifluoromethyl)-pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2-one;
cis-3-(1-Acetyl-1H-indol-3-yl)-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
cis-8-Dimethylamino-8-phenyl-3-quinazolin-6-yl-1,3-diazaspiro[4.5]decan-2-one;
cis-5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-2-(2-oxo-1,3-dihydro-indol-4-yl)-isonicotinonitrile;
cis-N-[5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-pyrimidin-2-yl]-N-methyl-tetrahydro-pyran-4-carboxylic acid amide;
cis-N-[5-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-pyrimidin-2-yl]-N,2,2-trimethyl-propionamide;
cis-8-Dimethylamino-3-[2-(1-methyl-2-oxo-1,3-dihydro-indol-4-yl)-pyrimidin-5-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
cis-8-Dimethylamino-3-(2-morpholin-4-yl-1H-benzoimidazol-5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
cis-8-Dimethylamino-8-(3-fluoro-5-methyl-phenyl)-3-[4-methyl-6-(trifluoromethyl)-pyridin-3-yl]-1,3-diazaspiro[4.5]decan-2-one;
cis-8-Dimethylamino-3-[6-(2-oxo-1,3-dihydro-indol-4-yl)-pyridin-3-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
cis-8-Dimethylamino-8-(3-hydroxyphenyl)-3-[4-methyl-6-(trifluoromethyl)-pyridin-3-yl]-1,3-diazaspiro[4.5]decan-2-one;
cis-3-[6-(Azetidin-1-yl)-5-(trifluoromethyl)-pyridin-3-yl]-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
cis-3-[1-(Cyclopropyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-isonicotinonitrile;
cis-3-[3,5-Bis(trifluoromethyl)-pyridin-2-yl]-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one
cis-8-Dimethylamino-3-(5-fluoro-6-morpholin-4-yl-pyridin-3-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
cis-8-(3-Chlorophenyl)-8-dimethylamino-3-[4-methyl-6-(trifluoromethyl)-pyridin-3-yl]-1,3-diazaspiro[4.5]decan-2-one;
cis-8-Dimethylamino-3-[5-(2-oxo-1,3-dihydro-indol-4-yl)-pyridin-2-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
cis-8-Dimethylamino-8-phenyl-3-[5-(trifluoromethyl)-[1,3,4]thiadiazol-2-yl]-1,3-diazaspiro[4.5]decan-2-one;
cis-8-Dimethylamino-3-(2-oxo-1,3-dihydro-indol-4-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
cis-8-Dimethylamino-3-[2-[(2-hydroxy-ethyl)-methyl-amino]-1H-benzoimidazol-5-yl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
cis-8-Dimethylamino-3-(5-methyl-6-morpholin-4-yl-pyridin-3-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
cis-1-(Cyclopropyl-methyl)-8-dimethylamino-8-(3-fluorophenyl)-3-(5-methylsulfonyl-pyridin-2-yl)-1,3-diazaspiro[4.5]decan-2-one;
cis-1-(Cyclopropyl-methyl)-8-(3-fluorophenyl)-8-methylamino-3-(5-methylsulfonyl-pyridin-2-yl)-1,3-diazaspiro[4.5]decan-2-one;
cis-1-(Cyclobutyl-methyl)-8-(3-fluorophenyl)-8-methylamino-3-[2-(trifluoromethyl)-pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2-one;
cis-1-(Cyclopropyl-methyl)-8-dimethylamino-8-(3-fluorophenyl)-3-[2-(trifluoromethyl)-pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2-one;
cis-1-(Cyclopropyl-methyl)-8-(3-fluorophenyl)-8-methylamino-3-[2-(trifluoromethyl)-pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2-one;
cis-8-Dimethylamino-8-(3-fluorophenyl)-3-[2-(trifluoromethyl)-pyrimidin-5-yl]-1,3-diazaspiro[4.5]decan-2-one;
cis-1-(Cyclopropyl-methyl)-8-dimethylamino-8-(3-fluorophenyl)-3-[2-methyl-5-(trifluoromethyl)-2H-pyrazol-3-yl]-1,3-diazaspiro[4.5]decan-2-one
cis-1-(Cyclopropyl-methyl)-8-(3-fluorophenyl)-8-methylamino-3-[2-methyl-5-(trifluoromethyl)-2H-pyrazol-3-yl]-1,3-diazaspiro[4.5]decan-2-one;
cis-8-Methylamino-3-(4-methyl-2-morpholin-4-yl-pyrimidin-5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
cis-3-[5-(Azetidin-1-yl)-3-methyl-pyridin-2-yl]-8-dimethylamino-8-(3-fluorophenyl)-1,3-diazaspiro[4.5]decan-2-one;
cis-8-Dimethylamino-8-(3-fluorophenyl)-3-(5-methylsulfonyl-pyridin-2-yl)-1,3-diazaspiro[4.5]decan-2-one;
cis-3-(6-(azetidin-1-yl)-4-fluoropyridin-3-yl)-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
cis-3-(6-(azetidin-1-yl)pyridin-3-yl)-8-(dimethylamino)-8-(3-fluorophenyl)-1,3-diazaspiro[4.5]decan-2-one;
cis-3-(1-(cyclopropanecarbonyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)-8-(dimethylamino)-8-(3-fluorophenyl)-1,3-diazaspiro[4.5]decan-2-one;
cis-8-(dimethylamino)-8-(3-fluorophenyl)-3-(1-(2-hydroxyethyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)-1,3-diazaspiro[4.5]decan-2-one;
cis-3-(1-(cyclopropylmethyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)-8-(dimethylamino)-8-(3-fluorophenyl)-1,3-diazaspiro[4.5]decan-2-one;
cis-8-(dimethylamino)-8-(3-fluorophenyl)-3-(1-(methylsulfonyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)-1,3-diazaspiro[4.5]decan-2-one;
cis-1-(cyclopropylmethyl)-8-(dimethylamino)-8-(3-fluorophenyl)-3-(1-(methylsulfonyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)-1,3-diazaspiro[4.5]decan-2-one;
cis-2-(5-(8-(dimethylamino)-8-(3-fluorophenyl)-2-oxo-1,3-diazaspiro[4.5]decan-3-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)-N,N-dimethylacetamide;
cis-2-(5-(1-(cyclopropylmethyl)-8-(dimethylamino)-8-(3-fluorophenyl)-2-oxo-1,3-diazaspiro[4.5]decan-3-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)-N,N-dimethylacetamide;
cis-8-(dimethylamino)-3-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
cis-8-(dimethylamino)-3-(3-fluoro-1H-pyrrolo[2,3-b]pyridin-5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
cis-8-(dimethylamino)-8-phenyl-3-(1H-pyrrolo[2,3-c]pyridin-4-yl)-1,3-diazaspiro[4.5]decan-2-one;
cis-8-(dimethylamino)-8-phenyl-3-(2-(pyridazin-4-yl)pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one;
cis-8-(dimethylamino)-3-(2-(2-oxo-1,2-dihydropyridin-4-yl)pyrimidin-5-yl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
cis-8-(dimethylamino)-8-(3-fluorophenyl)-3-(1-methyl-3-(thiophen-2-yl)-1H-pyrazol-5-yl)-1,3-diazaspiro[4.5]decan-2-one;
cis-8-(dimethylamino)-8-(3-fluorophenyl)-3-(1-methyl-3-morpholino-1H-pyrazol-5-yl)-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;
cis-3-(4-methyl-6-(trifluoromethyl)pyridin-3-yl)-8-(methylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
cis-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-8-(methylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;
cis-8-(dimethylamino)-8-(3-fluorophenyl)-3-(4-(methylsulfonyl)pyridin-3-yl)-1,3-diazaspiro[4.5]decan-2-one;
cis-8-(dimethylamino)-3-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-8-(3-fluorophenyl)-1,3-diazaspiro[4.5]decan-2-one;
cis-3-(1-cyclopropyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-8-(dimethylamino)-8-(3-fluorophenyl)-1,3-diazaspiro[4.5]decan-2-one;
cis-8-(dimethylamino)-8-(3-fluorophenyl)-3-(1-(oxetan-3-ylmethyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)-1,3-diazaspiro[4.5]decan-2-one;
cis-8-(dimethylamino)-8-(3-fluorophenyl)-3-(1-(2-(methylsulfonyl)ethyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)-1,3-diazaspiro[4.5]decan-2-one;
cis-8-(dimethylamino)-8-(3-fluorophenyl)-3-(4-methyl-2-(methylamino)pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one;
cis-3-(2-cyclopropoxy-4-methylpyrimidin-5-yl)-8-(dimethylamino)-8-(3-fluorophenyl)-1,3-diazaspiro[4.5]decan-2-one;
cis-N-(5-(8-(dimethylamino)-8-(3-fluorophenyl)-2-oxo-1,3-diazaspiro[4.5]decan-3-yl)-4-methylpyrimidin-2-yl)-N-methylcyclopropanecarboxamide;
cis-N-(5-(8-(dimethylamino)-8-(3-fluorophenyl)-2-oxo-1,3-diazaspiro[4.5]decan-3-yl)-4-methylpyrimidin-2-yl)-N-methylpivalamide;
cis-3-(4-(azetidin-1-yl)-2-(trifluoromethyl)pyrimidin-5-yl)-8-(dimethylamino)-8-(3-fluorophenyl)-1,3-diazaspiro[4.5]decan-2-one;
cis-8-(dimethylamino)-8-(3-fluorophenyl)-3-(4-(oxetan-3-ylmethoxy)-2-(trifluoromethyl)pyrimidin-5-yl)-1,3-diazaspiro[4.5]decan-2-one;
cis-3-(2-cyclopropyl-4-(2,2,2-trifluoroethoxy)pyrimidin-5-yl)-8-(dimethylamino)-8-(3-fluorophenyl)-1,3-diazaspiro[4.5]decan-2-one;
cis-3-(2-cyclopropyl-4-((2-hydroxyethyl)(methyl)amino)pyrimidin-5-yl)-8-(dimethylamino)-8-(3-fluorophenyl)-1,3-diazaspiro[4.5]decan-2-one
and the physiologically acceptable salts thereof.
27. The compound according to claim 1 adapted for use in the treatment of pain.
28. A medicament comprising a compound according to claim 1.
29. A method of treating pain, said method comprising administering to a patient in need thereof an effective amount therefor of at leas one compond according to claim 1.
30. 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.
US17/986,207 2016-01-13 2022-11-14 3-((Hetero-)Aryl)-8-Amino-2-Oxo-1,3-Diaza-Spiro-[4.5]-Decane Derivatives Pending US20230303573A1 (en)

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