WO2015066371A1 - SPIRO-OXADIAZOLINE COMPOUNDS AS AGONISTS OF α-7-NICOTINIC ACETYLCHOLINE RECEPTORS - Google Patents

SPIRO-OXADIAZOLINE COMPOUNDS AS AGONISTS OF α-7-NICOTINIC ACETYLCHOLINE RECEPTORS Download PDF

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WO2015066371A1
WO2015066371A1 PCT/US2014/063242 US2014063242W WO2015066371A1 WO 2015066371 A1 WO2015066371 A1 WO 2015066371A1 US 2014063242 W US2014063242 W US 2014063242W WO 2015066371 A1 WO2015066371 A1 WO 2015066371A1
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azaspiro
oxadiazole
bicyclo
octane
thiophen
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PCT/US2014/063242
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French (fr)
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Duane A. Burnett
Matthew Gregory Bursavich
Andrew J. Mcriner
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Forum Pharmaceuticals, Inc.
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Publication of WO2015066371A1 publication Critical patent/WO2015066371A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D453/00—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/10—Spiro-condensed systems

Definitions

  • the present invention relates to novel spiro-oxadiazoline compounds that are suitable as agonists or partial agonists of a7-nAChR, and pharmaceutical compositions of the same, methods of preparing these compounds and compositions, and the use of these compounds and compositions in methods of maintaining, treating and/or improving cognitive function.
  • acetylcholine esterase inhibitors may ameliorate the cognitive deficits in patients with cognitive disease.
  • the most widely used acetylcholine esterase inhibitor is donepezil hydrochloride (Aricept ® ).
  • Nicotinic acetylcholine receptors form a large family of ion channels which are activated by the messenger acetylcholine which is produced in the body (Galzi and Changeux, Neuropharmacol. 1995, 34, 563-582).
  • a functional nAChR consists of five subunits which may be different (certain combinations of al -9 and ⁇ 1-4, ⁇ , ⁇ , ⁇ subunits) or identical (a7-9). This leads to the formation of a diversity of subtypes which differ in the distribution in the muscles, the nervous system and other organs (McGehee and Role, Annu. Rev. Physiol. 1995, 57, 521-546).
  • nAChR Activation of nAChR leads to influx of cations into the cell and to stimulation of nerve cells or muscle cells. Selective activation of individual nAChR subtypes restricts this stimulation to the cell types which have a corresponding subtype and is thus able to avoid unwanted side effects such as, for example, stimulation of nAChR in the muscles.
  • Clinical experiments with nicotine and experiments in various animal models indicate that central nicotinic acetylcholine receptors are involved in learning and memory processes (e.g. Rezvani and Levin, Biol. Psychiatry 2001 , 49, 258-267).
  • Nicotinic acetylcholine receptors of the alpha7 subtype have a particularly high concentration in regions of the brain which are important for learning and memory, such as the hippocampus and the cerebral cortex (Seguela et al., J. Neurosci. 1993, 13, 596-604).
  • the a7 nAChR has a particularly high permeability for calcium ions, increases glutamatergic neurotransmission, influences the growth of axons and, in this way, modulates neuronal plasticity (Broide and Leslie, Mol. Neurobiol. 1999, 20, 1-16).
  • WO 2003/055878 describes a variety of agonists of the alpha7 nAChR said to be useful for improving cognition.
  • WO 2003/055878 suggests that certain agonists of the alpha7 nAChR are useful for improving perception, concentration, learning or memory, especially after cognitive impairments like those occurring for example in situations/diseases/syndromes such as mild cognitive impairment, age-associated learning and memory impairments, age-associated memory loss, Alzheimer's disease, schizophrenia and certain other cognitive disorders.
  • An aspect of the invention provides a spiro-oxadiazoline compound represented by Formula (I), (Ila), or (lib):
  • R independently represents -H; a C r C 6 -alkyl radical; a C 3 -C 6 - cycloalkyl radical; a (3-6 membered)-heterocycloalkyl radical; an aryl radical; or a heteroaryl radical; wherein the Ci-C6-alkyl radical, the (3-6 membered)-heterocycloalkyl radical, the aryl radical, and the heteroaryl radical may be substituted with up to 4 radical substituents comprising: -D, -F, -CI, -Br, -I, -CN, -N0 2, -OR 2 , -(CH 2 ) m OR 2 , - N(R 2 )(R 3 ), -(CH 2 ) m N(R 2 )(R 3 ), -S0 2 (CH 2 ) m R 2 , -(CO)(CH 2 ) m R 2 , -(CO)(CH 2 )
  • R 2 and R independently represent -H; a branched or unbranched Q-Ce-alkyl radical; C 3 -C 6 -cycloalkyl radical; or the N(R 2 )(R 3 ) moiety forms a cycle, wherein R 2 and R 3 taken together represent a C 2 -C6-alkyl di- radical or a (3-6 membered)-heteroalkyl di-radical;
  • n independently represents an integer from 0 to 6;
  • n independently represents an integer from 1 to 6;
  • W represents a moiety represented by ring system M-I, M-II, M-III, M- rv, M-V,
  • Z Z 2 , Z 3 , Z 4 , and Z independently represent N or CR ; with the proviso that no more than two of Z Z 2 , Z 3 , Z 4 , and Z 5 are N;
  • R 4 independently represents -H; -D; -F; -CI; -Br; -I; -CN; -NO2; - OR 5 ; -(CH 2 ) m OR 5 ; -N(R 5 )(R 6 ); -(CH 2 ) m N(R 5 )(R 6 ); -S0 2 (CH 2 ) m R 5 ; - (CO)(CH 2 ) m R 5 ; -(CO)N(R 5 )(R 6 ); -OCF 3 ; a C r C 6 -alkyl radical; a C,- C 6 -hydroxyalkyl radical, a Ci-C 6 -haloalkyl radical; a C 3 -C6- cycloalkyl radical; a (3-6 membered)-heterocycloalkyl radical; an aryl radical; or a heteroaryl radical; wherein the C r C 6 -alkyI radical,
  • R 5 and R 6 independently represent -H; a branched or unbranched Ci-C 6 -alkyl radical; a C 3 -C6-cycloalkyl radical; or the N(R 5 )(R 6 ) moiety forms a cycle, wherein R 5 and R 6 taken together represent a C 2 -C 6 -alkyl di- radical or a (3-6 membered)-heteroalkyl di-radical; independently represent N or CR 7 ; with the proviso that no more than two of Z 6 , Z 7 , Z 8 , and Z 9 are N;
  • R 12 and R 13 independently represent -H; a branched or unbranched CpCe-alkyl radical; a C 3 -C 6 -cycloalkyl radical; or the N(R I 2 )(R 13 ) moiety forms a cycle, wherein R 12 and R 13 taken together represent a C 2 -C 6 -alkyl di- radical or a (3-6 membered)-heteroalkyl di-radical;
  • X 2 independently represents N or C
  • a 5 , A 6 , and A 7 independently represent N; NR 14 ; N(CH 2 ) m R 14 ; O; S; or CR 15 ; with the proviso that only one A 5 , A 6 , and A 7 is NR 14 , O, or S; with the further proviso that when X 2 is N, then A 5 , A 6 , and A 7 independently represent N or CR 15 ;
  • R' 4 independently represents -H; -D; -(CH 2 ) m OR 16 ; -(CH 2 ) m N(R 16 )(R 17 );
  • Ci-C 6 -alkyl radical, the (3-6 membered)-heterocycloalkyl radical, the aryl radical, and the heteroaryl radical may be substituted with up to 4 radical substituents comprising: -D, -F, -CI, -Br, -I, -CN, -N0 2, -
  • R 15 independently represents -H; -D; -F; -CI; -Br; -I; -CN; -N0 2 ; -
  • Ci-C 6 - alkyl radical independently represents -H; -D; -F; -CI; -Br; -I; -CN; -N0 2 ; - OR 19 ; -(CH 2 ) m OR 19 ; -N(R ,9 )(R 20 ); - ⁇ CH 2 ) m N(R ,9 )(R 20 ); - S0 2 (CH 2 ) m R 19 ; -(CO)(CH 2 ) m R 19 ; -(CO)N(R 19 )(R 20 ); -OCF 3 ; a C,-C 6 - alkyl radical; a Ci-C 6 -hydroxyalkyl radical, a d-C 6 -haloalkyl radical; a C 3 -C 6 -cycloalkyl radical; a (3-6 membered)-heterocycloalkyl radical; an aryl radical; or a heteroaryl radical; where
  • An aspect of the invention relates to a method comprising administering to a patient in need thereof an effective dose of a spiro-oxadiazoline compound represented by Formula (I), Formula (Ila), or Formula (lib), or a pharmaceutically acceptable salt thereof.
  • Another aspect of the invention provides a method of treating a patient in need thereof, comprising: administering to the patient an effective dose of a spifo-oxadiazoline compound represented by Formula (I), Formula (Ila), or Formula (lib), or a pharmaceutically acceptable salt thereof.
  • Another aspect of the invention provides a method of maintaining, treating, curing and/or improving at least one cognitive function in a patient in need thereof, comprising:
  • Another aspect of the invention provides a method of maintaining, treating, curing and/or improving at least one cognitive function in a patient in need thereof, comprising:
  • a pharmaceutical composition comprising an effective dose of a spiro- oxadiazoline compound represented by Formula (I), Formula (Ha), or Formula (lib), or a pharmaceutically acceptable salt thereof.
  • Another aspect of the invention provides a method of treating a patient in need thereof, comprising: administering to the patient diagnosed as having a cognitive impairment an effective dose of a pharmaceutical composition comprising a spiro-oxadiazoline compound represented by Formula (I), Formula (Ila), or Formula (lib), or a pharmaceutically acceptable salt thereof.
  • a pharmaceutical composition comprising a spiro-oxadiazoline compound represented by Formula (I), Formula (Ila), or Formula (lib), or a pharmaceutically acceptable salt thereof.
  • Another aspect of the invention provides a method of treating a patient in need thereof, comprising: administering to the patient, for example, a patient diagnosed with having a cognitive impairment, Limited Cognitive Impairment, Mild Cognitive Impairment, Alzheimer's disease, and/or schizophrenia, a spiro-oxadiazoline compound represented by Formula (I), Formula (Ila), or Formula (lib), or a pharmaceutically acceptable salt thereof such that the patient may derive a benefit therefrom.
  • Another aspect of the invention provides a method of treating one or more symptoms associated with a cognitive impairment, comprising administering to a patient an effective dose of a spiro-oxadiazoline compound represented by Formula (I), Formula (Ila), or Formula (lib), or a pharmaceutically acceptable salt thereof, wherein the patient suffers from, or has been diagnosed as having, a cognitive impairment.
  • Another aspect of the invention provides a method of improving cognition in a patient suffering from a cognitive impairment, such as a cognitive impairment associated with either schizophrenia or Alzheimer's disease, for example mild Alzheimer's disease, moderate
  • Alzheimer's disease severe Alzheimer's disease, or mild-to-moderate Alzheimer's disease, comprising administering an effective dose of a spiro-oxadiazoline compound represented by Formula (I), Formula (Ila), or Formula (lib), or a pharmaceutically acceptable salt thereof.
  • a spiro-oxadiazoline compound represented by Formula (I), Formula (Ila), or Formula (lib), or a pharmaceutically acceptable salt thereof.
  • Another aspect of the invention provides a method of treating a patient suffering from, diagnosed with having, or suffers from one or more symptoms associated with, a cognitive impairment, for example, Alzheimer's disease, dementia of an Alzheimer's type, MCI, LCI, or schizophrenia, comprising: administering to the patient a pharmaceutical composition comprising an effective dose of a spiro-oxadiazoline compound represented by Formula (I), Formula (Ila), or Formula (lib), or a pharmaceutically acceptable salt thereof.
  • a spiro-oxadiazoline compound represented by Formula (I), Formula (Ila), or Formula (lib)
  • the method of treating a patient suffering from, diagnosed with having, or suffers from one or more symptoms associated with, a cognitive impairment may provide said patient at least one of the following: (i) treats, minimizes progression of, prevents the deterioration of, or reduces the rate of detioraration of, one or more symptoms associated with the cognitive impairment; (ii) treats the cognitive impairment; (iii) improves cognition in said cognitively impaired patient; (iv) improves one or more behavioral symptoms associated with the cognitive impairment; (v) provides a pro-cognitive effect; (vi) provides a pro-cognitive effect, exclusive of attention, in at least one of the following: visual motor, learning, delayed memory, or executive function, or (vii) provides a positive effect on clinical function in said cognitively impaired patient.
  • Another aspect of the invention provides a method of treating a patient previously treated, or currently being treated, with an AChEI, that is suffering from, or has been diagnosed with having, a cognitive impairment, for example, Alzheimer's disease, dementia of an
  • Alzheimer's type, MCI, LCI, or schizophrenia comprising: administering to the patient a pharmaceutical composition comprising an effective dose of a spiro-oxadiazoline compound represented by Formula (I), Formula (Ila), or Formula (lib), or a pharmaceutically acceptable salt thereof, wherein the method improves one or more symptoms associated with the cognitive impairment in the previously, or currently, AChEI treated patient.
  • a pharmaceutical composition comprising an effective dose of a spiro-oxadiazoline compound represented by Formula (I), Formula (Ila), or Formula (lib), or a pharmaceutically acceptable salt thereof, wherein the method improves one or more symptoms associated with the cognitive impairment in the previously, or currently, AChEI treated patient.
  • Another aspect of the invention provides a method of treating a patient suffering from, or diagnosed with having a cognitive impairment, comprising: administering to the patient a pharmaceutical composition comprising an effective dose of a spiro-oxadiazoline compound represented by Formula (I), Formula (Ila), or Formula (lib), or a pharmaceutically acceptable salt thereof, wherein the method provides a positive effect on cognition or a positive effect on clinical function in said cognitively impaired patient, and wherein said patient has been previously treated or is currently being treated with an AChEI.
  • Another aspect of the invention provides a method of improving cognition in a patient diagnosed as having a probable cognitive disease, comprising: administering to the patient an effective dose of a pharmaceutical composition comprising a spiro-oxadiazoline compound represented by Formula (I), Formula (Ila), or Formula (lib), or a pharmaceutically acceptable salt thereof.
  • a pharmaceutical composition comprising a spiro-oxadiazoline compound represented by Formula (I), Formula (Ila), or Formula (lib), or a pharmaceutically acceptable salt thereof.
  • Another aspect of the invention provides a method of improving or substantially improving one or more symptoms in a cognitve disease patient, comprising: administering to the patient an effective dose of a compound represented by Formula (I), Formula (Ila), or Formula (lib), or a pharmaceutically acceptable salt thereof.
  • Another aspect of the invention provides a method of slowing the rate of deterioration of at least one symptom in a cognitve disease patient, comprising: administering to the patient the pharmaceutical composition comprising a spiro-oxadiazoline compound represented by Formula (I), Formula (Ila), or Formula (lib), or a pharmaceutically acceptable salt thereof.
  • Another aspect of the invention provides a method of treating one or more symptoms associated with a cognitive disease in a patient suffering therefrom, comprising: administering to the patient an effective dose of a pharmaceutical composition comprising a spiro-oxadiazoline compound represented by Formula (I), Formula (Ila), or Formula (lib), or a pharmaceutically acceptable salt thereof.
  • a pharmaceutical composition comprising a spiro-oxadiazoline compound represented by Formula (I), Formula (Ila), or Formula (lib), or a pharmaceutically acceptable salt thereof.
  • Another aspect provides a method of minimizing or substantially halting the rate of progression of one or more cognitive diseases in a patient suffering from a cognitive disease, comprising: administering to the patient an effective dose of a pharmaceutical composition comprising a spiro-oxadiazoline compound represented by Formula (I), Formula (Ila), or Formula (lib), or a pharmaceutically acceptable salt thereof.
  • a pharmaceutical composition comprising a spiro-oxadiazoline compound represented by Formula (I), Formula (Ila), or Formula (lib), or a pharmaceutically acceptable salt thereof.
  • Another aspect of the invention provides a method of substantially stopping or reversing progression of one or more cognitive diseases, in a patient suffering therefrom, comprising: administering to the patient an effective dose of a pharmaceutical composition comprising a spiro-oxadiazoline compound represented by Formula (I), Formula (Ila), or Formula (lib), or a pharmaceutically acceptable salt thereof.
  • a pharmaceutical composition comprising a spiro-oxadiazoline compound represented by Formula (I), Formula (Ila), or Formula (lib), or a pharmaceutically acceptable salt thereof.
  • Another aspect of the invention provides a method of treating dementia, comprising: administering to a patient in need thereof an effective amount of a spiro-oxadiazoline compound represented by Formula (I), Formula (Ila), or Formula (lib), or a pharmaceutically acceptable salt thereof, wherein said effective amount is administered in an effective dose.
  • a spiro-oxadiazoline compound represented by Formula (I), Formula (Ila), or Formula (lib) or a pharmaceutically acceptable salt thereof, wherein said effective amount is administered in an effective dose.
  • Another aspect of the invention provides a method of treating dementia, comprising: administering to a patient in need thereof an effective amount of a spiro-oxadiazoline compound represented by Formula (I), Formula (Ha), or Formula (lib), or a pharmaceutically acceptable salt thereof.
  • Another aspect of the invention provides a method of treating dementia, comprising: administering to a patient in need thereof an effective amount of a spiro-oxadiazoline compound represented by Formula (I), Formula (Ila), or Formula (lib), or a pharmaceutically acceptable salt thereof, wherein the spiro-oxadiazoline compound represented by Formula (I), Formula (Ila), or Formula (lib), or a pharmaceutically acceptable salt thereof, is administered in the form of a pharmaceutical composition comprising at least one pharmaceutically acceptable carrier, excipient or diluent.
  • Another aspect of the invention provides a method of treating dementia, comprising: administering to a patient in need thereof an effective amount of a spiro-oxadiazoline compound represented by Formula (I), Formula (Ila), or Formula (lib), or a pharmaceutically acceptable salt thereof, wherein the pharmaceutical composition is in the form of a tablet.
  • Another aspect of the invention provides a method of treating a patient having a cognitive disease and being administered an acetylcholine esterase inhibitor, comprising:
  • a pharmaceutical composition comprising a spiro- oxadiazoline compound represented by Formula (I), Formula (Ila), or Formula (lib), or a pharmaceutically acceptable salt thereof, wherein the treatment comprises halting the
  • Figure 1 Illustrates results of Novel Object Recognition Task in male Wistar rats.
  • An embodiment of the present invention provides a spiro-oxadiazoline compound represented by Formula (I), (Ila), or (lib):
  • R independently represents -H; a Ci-Cg-alkyl radical; a C3-C6- cycloalkyl radical; a (3-6 membered)-heterocycloalkyl radical; an aryl radical; or a heteroaryl radical; wherein the Ci-C6-alkyl radical, the (3-6 membered)-heterocycloalkyl radical, the aryl radical, and the heteroaryl radical may be substituted with up to 4 radical substituents comprising: -D, -F, -CI, -Br, -I, -CN, -N0 2 .
  • R 2 and R 3 independently represent -H; a branched or unbranched Ci-Ci-alkyl radical; C 3 -C 6 -cycloalkyl radical; or the N(R 2 )(R 3 ) moiety forms a cycle, wherein R 2 and R 3 taken together represent a C 2 -C6-alkyl di- radical or a (3-6 membered)-heteroalkyl di-radical;
  • n independently represents an integer from 0 to 6;
  • n independently represents an integer from 1 to 6;
  • W represents a moiety represented by ring system M-I, M-II, M-III, M-
  • Z Z 2 , Z Z 4 , and Z 5 independently represent N or CR 4 ; with the proviso that no more than two Z 2 , Z 3 , Z 4 , and Z 5 are N;
  • R 4 independently represents -H; -D; -F; -CI; -Br; -I; -CN; -N0 2 ; - OR 5 ; -(CH 2 ) m OR 5 ; -N(R 5 )(R 6 ); -(CH 2 ) m N(R 5 )(R 6 ); -S0 2 (CH 2 ) m R 5 ; - (CO)(CH 2 ) m R 5 ; -(CO)N(R 5 )(R 6 ); -OCF 3 ; a C,-C 6 -alkyl radical; a C,- C 6 -hydroxyalkyl radical, a C C6-haloalkyl radical; a C3-C6- cycloalkyl radical; a (3-6 membered)-heterocycloalkyl radical; an aryl radical; or a heteroaryl radical; wherein the Ci-C 6 -alkyl radical, the (
  • R 5 and R 6 independently represent -H; a branched or unbranched
  • R 5 and R 6 taken together represent a C 2 -C 6 -alkyl di- radical or a (3-6 membered)-heteroalkyl di-radical;
  • Z 5 , Z 7 , Z 8 , and Z 9 independently represent N or CR 7 ; with the proviso that no more than two of Z 6 , Z 7 , Z s , and Z 9 are N;
  • R 7 independently represents -H; -D; -F; -CI; -Br; -I; -CN; -N0 2 ; -
  • R 8 and R 9 independently represent -H; a branched or unbranched Ci-C6-alkyl radical; a C 3 -C 6 -cycloalkyl radical; or the N(R 8 )(R 9 ) moiety forms a cycle, wherein R 8 and R 9 taken together represent a C 2 -C 6 -alkyl di- radical or a (3-6 membered)-heteroalkyl di-radical;
  • X 1 independently represents N or C
  • a 1 , A 2 , A 3 and A 4 independently represent N; NR 10 ; N(CH 2 ) m R 10 ; O; S; or CR 11 ; with the proviso that only one A 1 , A 2 , A 3 and A 4 is NR 10 , O, or S; with the further proviso that when X 1 is present and is N, then A 1 , A 2 , and A 3 independently represent N or CR 1 1 ;
  • R 10 independently represents -H; -D; -(CH 2 ) m OR 12 ; -(CH 2 ) m N(R ,2 )(R 13 );
  • R 1 ' independently represents -H; -D; -F; -CI; -Br; -I; -CN; -N0 2 ; -
  • R 12 and R 13 independently represent -H; a branched or unbranched Ci-C 6 -alkyl radical; a C 3 -C 6 -cycloalkyl radical; or the N(R 12 )(R 13 ) moiety forms a cycle, wherein R 12 and R 13 taken together represent a C 2 -C6-alkyl di- radical or a (3-6 membered)-heteroalkyl di-radical;
  • X 2 independently represents N or C
  • a 5 , A 6 , and A 7 independently represent N; NR 14 ; N(CH 2 ) m R 14 ; O; S; or CR 15 ; with the proviso that only one A 5 , A 6 , and A 7 is NR 14 , O, or S; with the further proviso that when X 2 is N, then A 5 , A 6 , and A 7 independently represent N or CR 15 ;
  • R 14 independently represents -H; -D; - ⁇ CH 2 ) m OR 16 ; -(CH 2 ) m N(R , 6 )(R 17 );
  • Ci-C 6 -alkyl radical, the (3-6 membered)-heterocycloalkyl radical, the aryl radical, and the heteroaryl radical may be substituted with up to 4 radical substituents comprising: -D, -F, -CI, -Br, -I, -CN, -N0 2, -OR 16
  • R 16 and R 17 independently represent -H; a branched or unbranched Ci-C6-alkyl radical; a C3-C6-cycloalkyl radical; or the N(R ,6 )(R 17 ) moiety forms a cycle, wherein R 16 and R 17 taken together represent a C 2 -C6-alkyl di- radical or a (3-6 membered)-heteroalkyl di-radical;
  • G', G 2 , G 3 , and G 4 independently represent C(R 18 )(R 18 ); C(R ,9 )(R 20 ); -NH; -
  • R 18 independently represents -H; -D; -F; -CI; -Br; -I; -CN; -N0 2 ; -
  • the spiro-oxadiazoline compound represented by Formula (I), (Ila), or (lib) may comprise the W representing the moiety represented by the ring system M- I.
  • the spiro-oxadiazoline compound represented by Formula (I), (Ila), or (lib) may comprise the W representing the moiety represented by the ring system M-I, wherein, for example, the Z 1 represents N, and Z 2 , Z 3 , Z 4 , and Z 5 each independently represent CR 4 ; Z 2 represents N, and Z Z 3 , Z 4 , and Z 5 each independently represent CR 4 ; Z 3 represents N, and Z Z 2 , Z 4 , and Z 5 each independently represent CR 4 ; Z 1 and Z 2 each represent N, and Z 3 , Z 4 , and Z 5 each independently represent CR 4 ; Z 1 and Z 3 each represent N, and Z 2 , Z 4 , and Z 5 each independently represent CR 4 ; Z 1 and Z 3 each represent N, and Z 2 , Z 4 ,
  • the spiro-oxadiazoline compound represented by Formula (I), (Ila), or (lib) may comprise the W representing the moiety represented by the ring system M- I, wherein at least one Z 2 , Z 3 , Z 4 , and Z 5 , represent CR 4 with said R 4 representing - D; -F; -CI; -Br; -I; -CN; -N0 2 ; -OR 5 ; -(CH 2 ) m OR 5 ; -N(R 5 )(R 6 ); -(CH 2 ) m N(R 5 )(R 6 ); - S0 2 (CH 2 ) m R 5 ; -(CO)(CH 2 ) m R 5 ; -(CO)N(R 5 )(R 6 ); -OCF 3 ; a C,-C 6 -alkyl radical; a C,-C 6 - hydroxyalkyl radical, a
  • the spiro-oxadiazoline compound represented by Formula (I), (Ila), or (lib) may comprise the W representing the moiety represented by the ring system M- I, wherein at least one or two of Z Z 2 , Z 3 , Z 4 , and Z 5 , represent CR 4 with said R 4 representing -F; -CI; -Br; -I; or -CN.
  • the spiro-oxadiazoline compound represented by Formula (I), (Ila), or (lib) may comprise the W representing the moiety represented by the ring system M- I, wherein at least one or two of Z 1 , Z 2 , Z 3 , Z 4 , and Z 5 , represent CR 4 with said R 4 representing an aryl radical or a heteroaryl radical; wherein the aryl radical and the heteroaryl radical may be substituted with up to 4 radical substituents comprising: -D, -F, -CI, -Br, -I, -CN, -N0 2i -OR 5 , -(CH 2 ) m OR 5 , -N(R 5 )(R 6 ), -(CH 2 ) m N(R 5 )(R 6 ), -S0 2 (CH 2 ) m R 5 , -(CO)(CH 2 ) m R 5 , -(CO)N(R
  • the spiro-oxadiazoline compound represented by Formula (I), (Ila), or (lib) may comprise the W representing the moiety represented by the ring system M-I, wherein Z 1 and Z 5 represent CR 4 , and Z 2 , Z 3 , and Z 4 , represent CR 4 or N with the proviso that no more than two of Z 2 , Z 3 , and Z 4 , represent N, with said R 4 representing -D; -F; - CI; -Br; -I; -CN; -N0 2 ; -OR 5 ; -(CH 2 ) m OR 5 ; -N(R 5 )(R 6 ); -(CH 2 ) m N(R 5 )(R 6 ); -S0 2 (CH 2 ) m R 5 ; - (CO)(CH 2 ) m R 5 ; - ⁇ CO)N(R 5 )(R 6 );
  • the spiro-oxadiazoline compound represented by Formula (I), (Ila), or (lib) may comprise the W representing the moiety represented by the ring system M- I, wherein Z 1 and Z 5 represent CR 4 , and Z 2 , Z 3 , and Z 4 , represent CR 4 or N with the proviso that no more than two of Z 2 , Z 3 , and Z 4 , represent N, with said R 4 representing -F; -CI; -Br; -I; or - CN.
  • the spiro-oxadiazoline compound represented by Formula (I), (Ila), or (lib) may comprise the W representing the moiety represented by the ring system M-
  • Z 1 and Z 5 represent CR 4 , and Z 2 , Z 3 , and Z 4 , represent CR 4 or N with the proviso that no more than two of Z 2 , Z 3 , and Z 4 , represent N, with said R 4 representing an aryl radical or a heteroaryl radical; wherein the aryl radical and the heteroaryl radical may be substituted with up to 4 radical substituents comprising: -D, -F, -CI, -Br, -I, -CN, -N0 2, -OR 5 , -(CH 2 ) m OR 5 , - N(R 5 )(R 6 ), -(CH 2 ) m N(R 5 )(R 6 ), -S0 2 (CH 2 ) m R 5 , -(CO)(CH 2 ) m R 5 , -(CO)N(R 5 )(R 6 ), -OCF 3 , a branched or unbranched C
  • the spiro-oxadiazoline compound represented by Formula (I), (Ila), or (lib) may comprise the W representing the moiety represented by the ring system M-
  • the spiro-oxadiazoline compound represented by Formula (I), (Ila), or (lib) may comprise the W representing the moiety represented by the ring system M-II, wherein X 1 represents C.
  • the spiro-oxadiazoline compound represented by Formula (I), (Ila), or (lib) may comprise the W representing the moiety represented by the ring system M-II, wherein M-II represents a moiety represented by one of the following:
  • the spiro-oxadiazoline compound represented by Formula (I), (Ila), or (lib) may comprise the W representing the moiety represented by the ring system M-II, wherein either Z 6 or Z 7 represents CR 7 with said R 7 representing the bond directly attaching the W moiety with the oxadiazoline moiety, or wherein either Z 8 or Z 9 represents CR 7 with said R 7 representing the bond directly attaching the W moiety with the oxadiazoline moiety.
  • the spiro-oxadiazoline compound represented by Formula (I), (Ha), or (lib) may comprise the W representing the moiety represented by the ring system M-II with X 1 representing C, wherein M-II represents a moiety represented by:
  • a 1 and A 2 independently represent N or CR 11
  • a 3 independently represents NR 10 , O, or S
  • Z , Z , Z , and Z represent CR , with one of said R of Z , Z , Z , and Z representing the bond directly attaching the W moiety with the oxadiazoline moiety.
  • the spiro-oxadiazoline compound represented by Formula (I), (Ila), or (lib) may comprise the W representing the moiety represented by the ring system M-II with X 1 representing C, said R 7 of Z 7 or Z 8 represents the bond directly attaching the W moiety with the oxadiazoline moiety.
  • a 1 and A 2 independently represent N or CR 1 1 , preferably CR 1 1 , A 3 independently represents NR 10 , O, or S, preferably O or S, and Z 6 , Z 7 , Z 8 , and Z 9 represent CR 7 , wherein R u preferably independently represents -H;-F; -CI; -Br; -I; -CN; -OR 12 ; -(CH 2 ) m OR 12 ; -OCF 3 ; a Ci-C 6 -alkyl radical; a Ci-Q-haloalkyl radical, preferably -CF 3 ; or a C 3 -C 6 -cycloalkyl radical, and R 11 more preferably independently represents -H;-F; -CI; -Br; -I; -CN; -OCF 3 ; a C]-C 6 -alkyl radical; or -CF 3 .
  • the spiro-oxadiazoline compound represented by Formula (I), (Ila), or (lib) may comprise the W representing the moiety represented by the ring system M- II, wherein X 1 represents N.
  • the spiro-oxadiazoline compound represented by Formula (I), (Ila), or (lib) may comprise the W representing the moiety represented by the ring system M-II, wherein M-II represents a moiety represented by one of the following:
  • the spiro- oxadiazoline compound represented by Formula (I), (Ila), or (lib) may comprise the W representing the moiety represented by the ring system M-II, wherein, for example, A 1 independently represents CR 11 , and A 2 and A 3 independently represents N or CR 1 1 ; A 2 independently represents CR 11 , and A 1 and A 3 independently represents N or CR 1 1 ; A 3 independently represents CR 10 , and A 1 and A 2 independently represents N or CR 1 ' ; or each of A 1 , A 2 , and A 3 , represents N.
  • the spiro-oxadiazoline compound represented by Formula (I), (Ila), or (lib) may comprise the W representing the moiety represented by the ring system M-II, wherein either Z 6 or Z 7 represents CR 7 with said R 7 representing the bond directly attaching the W moiety with the oxadiazoline moiety, or wherein either Z 8 or Z 9 represents CR 7 with said R 7 representing the bond directly attaching the W moiety with the oxadiazoline moiety.
  • the spiro-oxadiazoline compound represented by Formula (I), (Ila), or (lib) may comprise the W representing the moiety represented by the ring system M-II with X 1 representing N, wherein M-II represents a moiety represented by:
  • a 1 , A 2 , and A 3 independently represent N or CR 1 1 , and Z 6 , Z 7 , Z 8 , and Z 9 represent CR 7 , with one of said R 7 of Z 6 , Z 7 , Z 8 , and Z 9 representing the bond directly attaching the W moiety with the oxadiazoline moiety.
  • a 1 independently represents CR 1 1 , and A 2 and A 3 independently represents N or CR 1 1 ;
  • a 2 independently represents CR 1 1 , and A 1 and A 3 independently represents N or CR 1 1 ;
  • a 3 independently represents CR 10 , and A 1 and A 2 independently represents N or CR 11 ; or each of A 1 , A 2 , and A 3 , represents N.
  • said R 7 of Z 6 or Z 9 represents the bond directly attaching the W moiety with the oxadiazoline moiety.
  • said R 7 of Z 7 or Z 8 represents the bond directly attaching the W moiety with the oxadiazoline moiety.
  • the spiro-oxadiazoline compound represented by Formula (I), (Ila), or (lib) may comprise the W representing the moiety represented by the ring system M- III.
  • the spiro-oxadiazoline compound represented by Formula (I), (Ila), or (lib) may comprise the W representing the moiety represented by the ring system M-III, wherein M-III represents a moiety represented by one of the following ring systems:
  • the spiro-oxadiazoline compound represented by Formula (I), (Ila), or (lib) may comprise the W representing the moiety represented by the ring system M- III, wh
  • the spiro-oxadiazoline compound represented by Formula (I), (Ila), or (lib) may comprise the W representing the moiety represented by the ring system M- III, wh
  • the spiro-oxadiazoline compound represented by Formula (I), (Ila), or (lib) may comprise the W representing the moiety represented by the ring system M- owing:
  • the spiro-oxadiazoline compound represented by Formula (I), (Ila), or (lib) may comprise the W representing the moiety represented by the ring system M- IV.
  • the spiro-oxadiazoline compound represented by Formula (I), (Ila), or (lib) may comprise the W representing the moiety represented by the ring system M- rV, wherein X 2 represents C.
  • the spiro-oxadiazoline compound represented by Formula (I), (Ila), or (lib), comprising W representing the moiety represented by the ring system M-IV may comprise a moiety represented by one of the following:
  • a 7 represents NR. 14 ; O; or S, preferably A 7 represents S; and A 5 represents N or CR 15 , preferably A 5 represents CR 15 , wherein R 15 preferably represents -H.
  • the spiro-oxadiazoline compound represented by Formula (I), (Ila), or (lib), comprising W representing the moiety represented by the ring system M-IV may comprise a moiety represented by one of the following:
  • a 5 represents NR 14 ; O; or S.
  • the spiro-oxadiazoline compound represented by Formula (I), (Ila), or (lib) may comprise the W representing the moiety represented by the ring system M-IV, wherein X 2 represents C, and may comprise a moiety represented by one of the following:
  • a 5 represents CR 15 ; and A 7 represents S.
  • the spiro-oxadiazoline compound represented by Formula (I), (lla), or (lib) may comprise the W representing the moiety represented by the ring system M-IV, wherein X 2 represents C, and may comprise a moiety represented by one of the following:
  • a 5 represents NR. 14 , O, or S, preferably S;
  • a 6 represents CR 15 ; and
  • Z 4 represents CR 4 .
  • the spiro-oxadiazoline compound represented by Formula (I), (Ha), or (lib) may comprise the W representing the moiety represented by the ring system M- rv, wherein X 2 represents N.
  • the spiro-oxadiazoline compound represented by Formula (I), (Ha), or (lib), comprising W representing the moiety represented by the ring system M-IV may comprise a moiety represented by one of the following:
  • the spiro-oxadiazoline compound represented by Formula (I), (lla), or (lib) may comprise the W representing the moiety represented by the ring system M-IV, wherein X 2 represents N, and may comprise a moiety represented by one of the following: wherein A 5 represents N or CR 15 ; A 6 represents CR 15 ; and Z 4 represents CR 4 .
  • the spiro-oxadiazoline compound represented by Formula (I), (Ila), or (lib) may comprise the W representing the moiety represented by the ring system M-
  • a 5 and A 7 represents CR 15 .
  • the spiro-oxadiazoline compound represented by Formula (I), (Ila), or (lib) may comprise the W representing the moiety represented by the ring system M- rV, wherein 2 represents N, and may comprise a moiety represented by one of the following:
  • a 6 represents CR 15 ; and Z' represents CR 4 .
  • the spiro-oxadiazoline compound represented by Formula (I), (Ila), or (lib) may comprise the W representing the moiety represented by the ring system M- V.
  • the spiro-oxadiazoline compound represented by Formula (I), (Ila), or (lib), comprising W representing the moiety represented by the ring system M-V may comprise a moiety represented by one of the following:
  • the spiro-oxadiazoline compound represented by Formula (I), (Ila), or (lib), comprising W representing the moiety represented by the ring system M-V may comprise a moiety represented by one of the following:
  • Z 6 , Z 7 , Z 8 , and Z 9 represent CR 7 , with one of said R 7 of Z 6 , Z 7 , Z 8 , and Z 9 representing the bond directly attaching the W moiety with the oxadiazoline moiety.
  • the spiro-oxadiazoline compound represented by Formula (I), (Ha), or (lib), comprising W representing the moiety represented by the ring system M-V, wherein said R 7 of Z 8 represents the bond directly attaching the W moiety with the oxadiazoline moi
  • the spiro-oxadiazoline compound represented by Formula (I), (Ha), or (lib) may comprise the W representing the moiety represented by the ring system M- VI.
  • the spiro-oxadiazoline compound represented by Formula (I), (Ila), or (lib), comprising W representing the moiety represented by the ring system M-VI may comprise a moiety represented by one of the following:
  • the spiro-oxadiazoline compound represented by Formula (I), (Ila), or (lib), comprising W representing the moiety represented by the ring system M-VI, wherein Z 6 , Z 7 , Z 8 , and Z 9 represent CR 7 , with one of said R 7 of Z 6 , Z 7 , Z 8 , and Z 9 representing the bond directly attaching the W moiety with the oxadiazoline moiety.
  • the spiro-oxadiazoline compound represented by Formula (I), (Ila), or (lib) may comprise the W representing a moiety represented by any one of ring systems M-IIa, M-IIb, or M-IVa:
  • a 1 and A 2 independently represent N or CR 11 , preferably CR 1 1
  • a 3 independently represents NR 10 , O, or S, preferably O or S
  • Z 6 , Z 7 , Z 8 , and Z 9 represent CR 7
  • R 1 1 preferably independently represents -H; -F; -CI; -Br; -I; -CN; -OR 12 ; -(CH 2 ) m OR 12 ; -OCF 3 ; a C r C 6 -alkyl radical; a C]-C 6 -haloalkyl radical, preferably -CF 3 ; or a C 3 -C 6 -cycloalkyl radical
  • R n more preferably independently represents -H;-F; -CI; -Br; -I; -CN; -OCF3; a C]-C 6 -alkyl radical; or -CF 3
  • R n more preferably independently represents -H;-F;
  • a 5 represents N or CR 15 , preferably A 5 represents CR 15 , wherein R 15 preferably represents -H; and A 7 represents NR 14 ; O; or S, preferably A 7 represents S; and
  • Z 1 , Z 2 , Z 3 , and Z 4 independently represent N or CR 4 ; with the proviso that no more than two of Z 1 , Z 2 , Z 3 , and Z 4 are N; preferably wherein Z Z 2 , Z 3 , and Z 4 independently represent CR 4 ; and preferably wherein R 4 independently represents -H; -D; -F; -CI; -Br; -I; -CN; -N0 2 ;- OCF 3 ; a C r C6-alkyl radical; a C C6-haloalkyl radical; or a C 3 -C 6 -cycloalkyl radical.
  • the spiro-oxadiazoline compound represented may be represented by Formula (I):
  • the spiro-oxadiazoline compound represented may be represented by Formula (Ila):
  • the spiro-oxadiazoline compound represented may be represented by Formula (lib): Formula (lib)
  • the spiro-oxadiazoline compound represented by Formula (I), (Ila), or (lib) may comprise R 1 representing -H, and n is 0-3.
  • the spiro-oxadiazoline compound represented by Formula (I), (Ila), or (lib) may comprise R 1 representing a (3-6 membered)-heterocycloalkyl radical; an aryl radical; or a heteroaryl radical; and wherein n is 0-3.
  • the spiro-oxadiazoline compound represented by Formula (I), (Ila), or (lib) may comprise racemic mixture of enantiomers, a mixture of diastereomers, a mixture of geometric isomes, a single enantiomer, a single diastereomer, or a single geometric isomer of the compound, or a pharmaceutically acceptable salt thereof.
  • the spiro-oxadiazoline compound represented by Formula (I), (Ila), or (lib) may comprise a mixture of tautomers, substantially a single tautomer form, or a single tautomer form, such as a tautomer contained within R 1 or contained within W, for example, a tautomer may be contained within a W containing a heteroaryl ring nitrogen adjacent to a heteroaryl ring carbon substituted with a hydroxyl group.
  • specific examples of the spiro-oxadiazoline compound represented by Formula (I), (Ila), or (lib), according to the present invention may include, collectively or individually, those listed below, and pharmaceutically acceptable salts thereof:
  • (+/-)-3 isoquinolin-3-yl)-4H- -azaspiro[[l,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane];
  • the specific examples of the spiro-oxadiazoline compound represented by Formula (I), (Ila), or (lib), according to the present invention may include, collectively or individually, those listed below, and pharmaceutically acceptable salts thereof:
  • the spiro-oxadiazoline compound represented by Formula (I), (Ila), or (lib), and pharmaceutically acceptable salts thereof may comprise the W representing a moiety represented by any one of ring systems M-IIa, M-IIb, or M-IVa:
  • a 1 and A 2 independently represent N or CR 1 1 ;
  • a 3 independently represents NR 10 , O, or S; and
  • Z 6 , Z 7 , Z 8 , and Z 9 represent CR 7 ;
  • a 5 represents N or CR 15 ; and A 7 represents NR 14 ; O; or S; and
  • Z Z 2 , Z 3 , and Z 4 independently represent N or CR 4 ; with the proviso that no more than two of Z', Z 2 , Z 3 , and Z 4 are N;
  • the specific examples of the spiro-oxadiazoline compound represented by Formula (I), (Ha), or (lib), and pharmaceutically acceptable salts thereof may comprise the W representing a moiety represented by the ring system M-IIa, M-IIb, or M-rVa, wherein the compound may include, collectively or individually, a racemic mixture or geometric mixture of any of those listed below, and pharmaceutically acceptable salts thereof:
  • the specific examples of the spiro-oxadiazoline compound represented by Formula (I), (Ila), or (lib), and pharmaceutically acceptable salts thereof may comprise the W representing a moiety represented by the ring system M-IIa, M-IIb, or M-IVa, wherein the compound may include, collectively or individually, a single enantiomer, diastereomer, or geometric isomer, of any of those listed below, and pharmaceutically acceptable salts thereof:
  • the specific examples of the spiro-oxadiazoline compound represented by Formula (I), (Ila), or (lib), and pharmaceutically acceptable salts thereof may comprise the W representing a moiety represented by the ring system M-IIa:
  • a 1 and A 2 independently represent N or CR", preferably CR H
  • a 3 independently represents NR 10 , O, or S, preferably O or S
  • Z 6 , Z 8 , and Z 9 represent CR 7
  • R" preferably independently represents -H; -F; -CI; -Br; -I; -CN; -OR 12 ; -(CHs ⁇ OR 1 ; -OCF 3 ; a Ci-C 6 -alkyl radical; a C)-C 6 -haloalkyl radical, preferably -CF 3 ; or a C 3 -C 6 -cycloalkyl radical
  • R 1 ' more preferably independently represents -H;-F; -CI; -Br; -I; -CN; -OCF 3 ; a Ci-C 6 -alkyl radical; or -CF 3 ;
  • the specific examples of the spiro-oxadiazoline compound represented by Formula (I), (Ila), or (lib), and pharmaceutically acceptable salts thereof may comprise the W representing a moiety represented by the ring system M-IIa, wherein the compound may include, collectively or individually, a racemic mixture of any of those listed below, and pharmaceutically acceptable salts thereof:
  • the specific examples of the spiro-oxadiazoline compound represented by Formula (I), (Ila), or (lib), and pharmaceutically acceptable salts thereof may comprise the W representing a moiety represented by the ring system M-IIa, wherein the compound may include, collectively or individually, a single enantiomer of any of those listed below, and pharmaceutically acceptable salts thereof:
  • the specific examples of the spiro-oxadiazoline compound represented by Formula (I), (Ila), or (lib), and pharmaceutically acceptable salts thereof may comprise the W representing a moiety represented by the ring system M-IIa, wherein the compound may include, collectively or individually, a single enantiomer of any of those listed below, and pharmaceutically acceptable salts thereof:
  • the specific examples of the spiro-oxadiazoline compound represented by Formula (I), (Ila), or (lib), and pharmaceutically acceptable salts thereof may comprise the W representing a moiety represented by the ring system M-IIa, wherein the compound may include, collectively or individually, a single enantiomer of any of those listed below, and pharmaceutically acceptable salts thereof:
  • the specific examples of the spiro-oxadiazoline compound represented by Formula (I), (Ila), or (lib), and pharmaceutically acceptable salts thereof may comprise the W representing a moiety represented by the ring system M-IIb:
  • a 1 and A 2 independently represent N or CR 11 , preferably CR n
  • a 3 independently represents NR 10 , O, or S, preferably O or S
  • Z 6 , Z 7 , and Z 9 represent CR 7
  • R 1 1 preferably independently represents -H; -F; -CI; -Br; -I; -CN; -OR 12 ; - ⁇ CH 2 ) m OR 12 ; -OCF 3 ; a C r C 6 -alkyl radical; a Ci-C 6 -haloalkyl radical, preferably -CF 3 ; or a C 3 -C 6 -cycloalkyl radical, and R u more preferably independently represents -H;-F; -CI; -Br; -I; -CN; -OCF 3 ; a d-C 6 -alkyl radical; or -CF 3 ;
  • the specific examples of the spiro-oxadiazoline compound represented by Formula (I), (Ha), or (lib), and pharmaceutically acceptable salts thereof may comprise the W representing a moiety represented by the ring system M-IIb, wherein the compound may include, collectively or individually, a racemic mixture of any of those listed below, and pharmaceutically acceptable salts thereof:
  • the specific examples of the spiro-oxadiazoline compound represented by Formula (I), (Ila), or (lib), and pharmaceutically acceptable salts thereof may comprise the W representing a moiety represented by the ring system M-IIb, wherein the compound may include, collectively or individually, a single enantiomer of any of those listed below, and pharmaceutically acceptable salts thereof:
  • the specific examples of the spiro-oxadiazoline compound represented by Formula (I), (Ila), or (lib), and pharmaceutically acceptable salts thereof may comprise the W representing a moiety represented by the ring system M-IIb, wherein the compound may include, collectively or individually, a single enantiomer of any of those listed below, and pharmaceutically acceptable salts thereof:
  • the specific examples of the spiro-oxadiazoline compound represented by Formula (I), (Ila), or (lib), and pharmaceutically acceptable salts thereof may comprise the W representing a moiety represented by the ring system M-IIb, wherein the compound may include, collectively or individually, a single enantiomer of any of those listed below, and pharmaceutically acceptable salts thereof:
  • the specific examples of the spiro-oxadiazoline compound represented by Formula (I), (Ila), or (lib), and pharmaceutically acceptable salts thereof may comprise the W representing a moiety represented by the ring system M-IVa:
  • a 5 represents N or CR 15 , preferably A 5 represents CR 15 , wherein R 15 preferably represents -H; and A 7 represents NR 14 ; O; or S, preferably A 7 represents S; and
  • Z 1 , Z 2 , Z 3 , and Z 4 independently represent N or CR 4 ; with the proviso that no more than two of Z 1 , Z 2 , Z 3 , and Z 4 are N; preferably wherein Z', Z 2 , Z 3 , and Z 4 independently represent
  • R 4 independently represents -H; -D; -F; -CI; -Br; -I; -CN; -N0 2 ;-
  • the specific examples of the spiro-oxadiazoline compound represented by Formula (I), (Ila), or (lib), and pharmaceutically acceptable salts thereof may comprise the W representing a moiety represented by the ring system M-IVa, wherein the compound may include a geometric mixture, or a single enantiomer or diastereomer, of any of those listed below, and pharmaceutically acceptable salts thereof:
  • the specific examples of the spiro-oxadiazoline compound represented by Formula (I), (Ila), or (lib), and pharmaceutically acceptable salts thereof may comprise the W representing a moiety represented by the ring system M-IVa, wherein the compound may include a geometric mixture, or a single enantiomer or diastereomer, of any of those listed below, and pharmaceutically acceptable salts thereof:
  • treating includes the generally accepted meaning which encompasses improving, modifying, decreasing, prohibiting, preventing, restraining, minimizing, slowing, halting, stopping, curing, and/or reversing a symptom associated with a disease and/or a disease.
  • Treatment may include both therapeutic and prophylactic administration.
  • treatment of a cognitive impairment, in a patient diagnosed as having a cognitive impairment may include, but is not limited to, curing the cognitive impairment, preventing the deterioration of one or more symptoms associated with the cognitive impairment; improving cognition in a patient suffering from the cognitive impairment, slowing the progression of the cognitive impairment and/or modifying the cognitive impairment.
  • the term "cognitive impairment,” unless otherwise specified, includes at least one of the following: Limited Cognitive Impairment (LCI), Mild Cognitive Impairment (MCI), Alzheimer's disease (or dementia of an Alzheimer's-type) or a particular stage of Alzheimer's disease, inclusive of pre-Alzheimer's disease, early Alzheimer's disease, mild Alzheimer's disease, moderate Alzheimer's disease, severe Alzheimer's disease, pre-Alzheimer's- to-mild Alzheimer's disease, mild-to-moderate Alzheimer's disease, moderate-to-severe
  • LCI Limited Cognitive Impairment
  • MCI Mild Cognitive Impairment
  • Alzheimer's disease or dementia of an Alzheimer's-type
  • a particular stage of Alzheimer's disease inclusive of pre-Alzheimer's disease, early Alzheimer's disease, mild Alzheimer's disease, moderate Alzheimer's disease, severe Alzheimer's disease, pre-Alzheimer's- to-mild Alzheimer's disease, mild-to-moderate Alzheimer's disease
  • Alzheimer's disease schizophrenia (for example, paranoid type schizophrenia, disorganized type schizophrenia, catatonic type schizophrenia, undifferentiated type schizophrenia),
  • schizophreniform disorder schizoaffective disorder, delusional disorder, positive symptoms of schizophrenia, negative symptoms of schizophrenia, or schizophrenia with dementia.
  • Alzheimer's disease may include, unless otherwise specified, any of the sub- diagnostic categories used to characterize the type or degree of cognitive impairment in a patient for treatment purposes.
  • a commonly referenced diagnostic scale for characterizing the degree of cognitive impairment for a patient with Alzheimer's disease includes the 3-stage Alzheimer Disease Model.
  • the 3-stages consist of: mild stage (also referred to as “early Alzheimer's disease” or “mild Alzheimer's disease” or “early stage Alzheimer's disease” or “mild dementia of an Alzheimer's-type”), moderate stage (also referred to as “middle Alzheimer's disease” or “moderate Alzheimer's disease” or “middle stage Alzheimer's disease” or “moderate dementia of an Alzheimer's-type”), and severe stage (also referred to as "late Alzheimer's disease” or “severe Alzheimer's disease” or “late stage Alzheimer's disease” or “severe dementia of an Alzheimer's- type”).
  • mild stage also referred to as "early Alzheimer's disease” or “mild Alzheimer's disease” or “early stage Alzheimer's disease” or “mild dementia of an Alzheimer's-type
  • moderate stage also referred to as “middle Alzheimer's disease” or “moderate Alzheimer's disease” or “middle stage Alzheimer's disease” or “moderate dementia of an
  • Alzheimer's disease they may be diagnosed as having pre-Alzheimer's disease. It is also not uncommon for treatment purposes to characterize stages together, such as pre-Alzheimer's disease-to-mild stage Alzheimer's disease, mild-to-moderate Alzheimer's disease, or moderate-to- severe Alzheimer's disease.
  • Another useful diagnostic scale that is used in characterizing the degree of cognitive impairment for a patient having Alzheimer's disease is the Seven Stage Alzheimer's Disease Model (sometimes known as the "Seven Stage Global Deterioration Scale” or the "Reisberg Scale”).
  • This diagnostic scale divides the progression of the cognitive disorder associated with Alzheimer's disease as follows: Stage 1 -no Alzheimer's disease (generally characterized by absence of impairment, no impairment, or normal function), Stage 2-pre- Alzheimer's disease (generally characterized by minimal impairment, normal forgetfulness, or very mild cognitive decline), Stage 3-early-stage Alzheimer's disease (generally characterized by a noticeable cognitive decline, early confusional/mild cognitive impairment, or mild cognitive decline), Stage 4-early-stage/mild Alzheimer's disease (also referred to as late confusional/mild Alzheimer's, and generally characterized by moderate cognitive decline), Stage 5-middle- stage/moderate Alzheimer's (also referred to as early dementia moderate Alzheimer's disease and generally characterized by moderately severe cognitive decline), Stage 6-middle
  • dementia/moderately severe Alzheimer's disease also referred to as middle-stage/moderate to late-stage/severe Alzheimer's disease and generally characterized by severe cognitive decline
  • Stage 7-late-stage/severe Alzheimer's disease also referred to as severe dementia or failure- to-thrive, and generally characterized by very severe cognitive decline. It is also not uncommon for treatment purposes to characterize stages together, such as pre-Alzheimer's disease-to-mild stage Alzheimer's disease, mild-to-moderate Alzheimer's disease, or moderate-to-severe
  • Alzheimer's disease includes all of the above named diagnostic catagories or disease characterizations. It is also not uncommon for a physician to categorize any one or more of the above noted states of Alzheimer's disease as being probable, for example, probable mild-to-moderate Alzheimer's disease or probable severe Alzheimer's disease, when their diagnosis does not include, for example a physical biopsy or other definitive analysis.
  • Mild Cognitive Impairment is considered by some to be an intermediate stage between normal aging and the onset of Alzheimer's disease.
  • MCI may be characterized by persistent forgetfulness, but may lack some or many of the more debilitating symptoms of Alzheimer's disease.
  • Another set of criteria that may characterize a patient as having mild cognitive impairment suitable for treatment includes a patient that meets the following: 1) memory complaints corroborated by an informant, 2) objective memory impairment for age and education, 3) normal general cognitive function, 4) intact activities of daily living, and 5) the patient does not meet criteria for dementia.
  • a patient characterized as having mild cognitive impairment may not yet have a clinical cognitive deficit.
  • Mild cognitive impairment may also be distinguished from senile dementia in that mild cognitive impairment involves a more persistent and troublesome problem of memory loss for the age of the patient. On the clinical diagnostic scale, mild cognitive impairment is followed, in increased severity, by Alzheimer's disease.
  • Limited Cognitive Impairment describes a cognitive impairment (i.e., symptoms or conditions), which precedes mild cognitive impairment on a clinical diagnostic scale, and includes any chronic or temporary impairment in cognition, learning or memory that prevents or reduces the ability of a patient from achieving their individual potential in these areas.
  • LCIs may include minor impairments to memory associated with focus and concentration (e.g., accuracy and speed of learning and recalling information), working memory (e.g., used in decision making and problem solving), cognition, focus, mental quickness, and mental clarity.
  • stereoisomer refers to a molecule capable of existing in more than one spatial atomic arrangement for a given atomic connectivity (e.g., enantiomers, meso compounds, and diastereomers). As used herein, the term “stereoisomer” means either or both enantiomers and diastereomers.
  • the spiro-oxadiazoline compounds represented by Formula (Ila) are assigned the configurational assignment of "(lr,3R,4s,5S,7s).” and compounds represented by Formula (lib) are assigned the configurational assignment of "(l r,3R,4r,5S,7s).”
  • the drawn structural configuration shall govern.
  • the spiro-oxadiazoline compounds of the present invention represented by Formula (I), Formula (Ila), or Formula (lib), or a pharmaceutically acceptable salt thereof, may contain one or more stereogenic centers. Accordingly, compounds of this invention can exist as either individual stereoisomers or mixtures of two or more stereoisomers. A compound of the present invention will include both mixtures (e.g., racemic mixtures) and also individual respective stereoisomers that are substantially free from another possible stereoisomer.
  • mixtures e.g., racemic mixtures
  • individual respective stereoisomers that are substantially free from another possible stereoisomer.
  • substantially free of other stereoisomers means less than 25% of other stereoisomers, less than 10% of other stereoisomers, less than 5% of other stereoisomers, less than 2% of other stereoisomers, or less than "X"% of other stereoisomers (wherein X is a number between 0 and 100, inclusive) are present.
  • the spiro-oxadiazoline compounds represented by Formula (Ha) and Formula (lib) may be synthesized separately or together (after which the individual geometric isomers may be separated by chromatographic methods from the mixture of the geometric isomers).
  • the mixtures of the geometric isomers may also be separated through fractional crystallization of salts of amines contained in the spiro-oxadiazoline compounds represented by Formula (I) or Formula (lib), for example, when combined with enantiomerically pure carboxylic acids.
  • the spiro-oxadiazoline compounds of the present invention represented by Formula (I), Formula (Ila), or Formula (lib), or a pharmaceutically acceptable salt thereof, may contain one or more tautomeric forms. Accordingly, compounds of this invention can exist as either individual tautomers or mixtures of tautomeric forms. A compound of the present invention will include both mixtures (e.g., mixtures of tautomeric forms) and also individual respective tautomers that are substantially free from another possible tautomer.
  • the spiro-oxadiazoline compounds of the present invention represented by Formula (I), Formula (Ila), or Formula (lib), or a pharmaceutically acceptable salt thereof, may contain one or more geometric isomers. Accordingly, compounds of this invention can exist as either geometric isomers or mixtures of geometric isomers. A compound of the present invention will include both mixtures (e.g., mixtures of geometric isomers) and also individual respective geometric isomers that are substantially free from another possible geometric isomer.
  • haloalkyl refers to an alky group having from 1 to 5 halogen substituents independently selected from -F, -CI, -Br, and -I.
  • a haloalkyl may represent a -CF 3 group, a -CCI3 group, a -CH 2 CF 3 group, or a -CF 2 CF 3 group.
  • heteroaryl refers to an aromatic ring system comprising at least one or more hetero- ring atoms, such as two, three, four, or five hetero- ring atoms, independently selected from N, O, and S.
  • Suitable heteroaryl groups may include a single ring, for example, thienyl, pyridyl, thiazolyl, pyrazinyl, pyrimidyl, imidazolyl, furanyl, isothiazolyl, pyrazolyl, triazolyl, tetrazolyl, isoxazolyl, oxazolyl, pyrrolyl, pydridazinyl, triazinyl, oxadiazolyl, and furazanyl.
  • Sutiable heteroaryl groups may include a fused ring system, for example, a six-six fused ring system, a six-five fused ring system, or a five-six fused ring system, such as benzothienyl, quinolyl, benzofuranyl, benzothiazolyl, benzisothiazolyl, benzisoxazolyl, benzimidazolyl, indolyl, benzoxazolyl, isoquinolinyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, isoindolyl, purinyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, quinazolinyl, quinoxalinyl, naphthridinyl, and furopyridinyl.
  • a fused ring system for example, a six-six fused ring system, a six
  • Suitable "heterocycloalkyl” groups include those having at least one or more hetero- ring atoms, such as two or three hetero- ring atoms, independently selected from -0-, -S-, -S(0) 2 -, -N(H)-, and -N(CH 2 ) m R 18 -.
  • Suitable heterocycloalkyl groups may include, for example, tetrahydrofurano, tetrahydropyrano, morpholino, pyrrolidino, piperidino, piperazino, azetidino, azetidinono, oxindolo, oxetano, dihydroimidazolo, and pyrrolidinono.
  • the pharmaceutically acceptable salt of the spiro-oxadiazoline compounds represented by Formula (I), Formula (Ila), or Formula (lib), according to the present invention may be acid addition salts with inorganic or organic acids.
  • these salts include acid addition salts with, for instance, mineral acids such as hydrochloric acid, hydrobromic acid, hydriodic acid, sulfuric acid, nitric acid or phosphoric acid; organic acids, for example carboxylic acids or sulfonic acids, such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, benzoic acid, p-toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, isethionic acid, glucuronic acid, gluconic acid, methanesulfonic acid or ethan
  • the spiro-oxadiazoline compound represented by Formula (I), Formula (Ila), or Formula (lib), or a pharmaceutically acceptable salt thereof may be synthesized by a variety of methods.
  • the following schemes represent typical examples of such preparation methods:
  • racemic mixture of N-protected oxadiazoline compound (+/-) (iv) is then chirally separated into N- protected oxadiazoline compound (R)-(iv) and (S)-(iv), and each stereoisomer is then separately deprotected to form oxadiazoline compound (R)-(v) and (S)-(v).
  • ketone (i) quinuclidin-3-one or ketone (iii) (1-aza- adamantan-4-one) is condensed with an amine to form an imine (ii) or (iv), respectively, which is then utilized in one or more of reaction schemes 3-6 in the preparation of oxadiazoline compounds of the present invention.
  • a pharmaceutical composition may comprise a spiro- oxadiazoline compound represented by Formula (I), (Ila), or (lib), or a pharmaceutically acceptable salt thereof.
  • the spiro-oxadiazoline compounds represented by Formula (I), Formula (Ila), or Formula (lib), or a pharmaceutically acceptable salt thereof are suitable for use as medicaments for the treatment and/or prophylaxis of diseases in humans and/or animals.
  • the invention relates to a method comprising administering to a patient in need thereof an effective dose of a spiro-oxadiazoline compound represented by Formula (I), Formula (Ila), or Formula (lib), or a pharmaceutically acceptable salt thereof.
  • the spiro-oxadiazoline compounds represented by Formula (I), Formula (Ila), or Formula (lib), or a pharmaceutically acceptable salt thereof act as ligands, in particular as a7-nAChR agonists.
  • a method of treating a patient in need thereof comprising administering a spiro-oxadiazoline compound represented by Formula (I), (Ila), or (lib), or a pharmaceutically acceptable salt thereof.
  • a method of treating a patient in need thereof comprising administering a pharmaceutical composition comprising a spiro- oxadiazoline compound represented by Formula (I), (Ila), or (lib), or a pharmaceutically acceptable salt thereof.
  • the patient may suffer from a cognitive impairment or suffers from one or more symptoms associated with a cognitive impairment, such as Limited Cognitive Impairment (LCI), Mild Cognitive Impairment (MCI), Alzheimer's disease, dementia of an Alzheimer's-type, schizophrenia, schizophreniform disorder, schizoaffective disorder, delusional disorder, positive symptoms of schizophrenia, negative symptoms of schizophrenia, or schizophrenia with dementia.
  • LCI Limited Cognitive Impairment
  • MCI Mild Cognitive Impairment
  • Alzheimer's disease dementia of an Alzheimer's-type
  • schizophrenia schizophreniform disorder
  • schizoaffective disorder schizoaffective disorder
  • delusional disorder positive symptoms of schizophrenia, negative symptoms of schizophrenia, or schizophrenia with dementia.
  • the spiro-oxadiazoline compounds represented by Formula (I), Formula (Ila), or Formula (lib), or a pharmaceutically acceptable salt thereof can, because of their pharmacological properties, be employed alone or in combination with other active ingredients for the treatment and/or prevention of cognitive impairments, for example,
  • the spiro-oxadiazoline compounds represented by Formula (I), Formula (Ila), or Formula (lib), or a pharmaceutically acceptable salt thereof are particularly suitable for improving cognition, providing procognitive effects, improving perception, improving concentration, improving learning or memory, improving one or more aspects of cognition, e.g., one or more of: executive function, memory (e.g., working memory), social cognition, visual learning, verbal learning and speed of processing, especially after or associated with cognitive impairments like those occurring for example in situations/diseases/syndromes such as mild cognitive impairment, age-associated learning and memory impairments, age-associated memory loss, vascular dementia,
  • craniocerebral trauma stroke, dementia occurring after strokes (post-stroke dementia), posttraumatic brain syndrome, general concentration impairments, concentration impairments in children with learning and memory problems, attention deficit hyperactivity disorder, Alzheimer's disease, Lewy body dementia, dementia with degeneration of the frontal lobes, including Pick's syndrome, Parkinson's disease, dyskinesias associated with dopamine agonist therapy in
  • Parkinson's Disease progressive nuclear palsy, dementia with corticobasal degeneration, amyotrophic lateral sclerosis (ALS), Huntington's disease, multiple sclerosis, thalamic degeneration, Creutzfeld-Jakob dementia, HIV dementia, schizophrenia (e.g., paranoid type, disorganized type, catatonic type, and undifferentiated type), schizophreniform disorder, schizoaffective disorder, delusional disorder, positive symptoms of schizophrenia, negative symptoms of schizophrenia, schizophrenia with dementia, Korsakoff s psychosis, depression, anxiety, mood and affective disorders, traumatic brain injury, withdrawal symptoms associated with smoking cessation and dependent drug cessation, Gilles de la Tourette's Syndrome, age- related macular degeneration, glaucoma, neurodegeneration associated with glaucoma, treatment (including amelioration, prevention or delay of progression) of sleep disorders (e.g., narcolepsy, excessive daytime sleepiness, nocturnal sleep disruption and/or cataplexy), treatment (including
  • the spiro-oxadiazoline compounds represented by Formula (I), Formula (Ila), or Formula (lib), or a pharmaceutically acceptable salt thereof can be employed alone or in combination with other active ingredients for the prophylaxis and treatment of acute and/or chronic pain (for a classification, see “Classification of Chronic Pain, Descriptions of Chronic Pain Syndromes and Definitions of Pain Terms", 2nd edition, Meskey and Begduk, editors; IASP Press, Seattle, 1994), especially for the treatment of cancer-induced pain and chronic neuropathic pain like, for example, that associated with diabetic neuropathy, postherpetic neuralgia, peripheral nerve damage, central pain (for example as a consequence of cerebral ischaemia) and trigeminal neuralgia, and other chronic pain such as, for example, lumbago, backache (low back pain) or rheumatic pain.
  • these active ingredients are also suitable for the therapy of primary acute pain of any origin and of secondary states of pain resulting therefrom, and for the therapy of states
  • the invention relates to a method comprising administering to a patient in need thereof an effective dose of a spiro-oxadiazoline compound represented by Formula (I), Formula (Ha), or Formula (lib), or a pharmaceutically acceptable salt thereof.
  • a spiro-oxadiazoline compound represented by Formula (I), Formula (Ha), or Formula (lib) or a pharmaceutically acceptable salt thereof.
  • one or more symptoms associated with a cognitive impairment and/or the cognitive impairment may be treated and/or improved by administering to a patient in need thereof, an effective dose of a spiro-oxadiazoline compound represented by Formula (I), Formula (Ila), or Formula (lib), or a pharmaceutically acceptable salt thereof.
  • a certain embodiment of the present invention provides a method of improving one or more cognitive symptoms, improving one or more behavioral symptoms, or both, associated with a cognitive impairment, comprising: administering to a patient in need thereof a
  • composition comprising an effective dose of a spiro-oxadiazoline compound represented by Formula (I), Formula (Ila), or Formula (lib), or a pharmaceutically acceptable salt thereof.
  • the method provides a pro-cognitive effect in a patient suffering from, or diagnosed as having, a cognitive disease or dementia, comprising: administering to a patient in need thereof, a pharmaceutical composition comprising an effective dose of a spiro-oxadiazoline compound represented by Formula (I), Formula (Ila), or Formula (lib), or a pharmaceutically acceptable salt thereof, wherein the method provides at least one of the following: visual motor, learning, delayed memory, or executive function; for example provides a pro-cognitive effect, exclusive of attention, in said patient; for example provides a pro- cognitive effect in at least one of the following: visual motor, learning, delayed memory, or executive function.
  • a certain embodiment of the present invention provides a method of treating a patient with a cognitive disease, comprising: administering to the patient a daily dose of a pharmaceutical composition comprising a spiro-oxadiazoline compound represented by Formula (I), Formula (Ila), or Formula (lib), or a pharmaceutically acceptable salt thereof.
  • the method provides a pro-cognitive effect in a patient suffering from, or diagnosed as having, schizophrenia, for example, paranoid type schizophrenia, disorganized type schizophrenia, catatonic type schizophrenia,
  • undifferentiated type schizophrenia, schizophreniform disorder, schizoaffective disorder, delusional disorder, positive symptoms of schizophrenia, negative symptoms of schizophrenia, or schizophrenia with dementia comprising: administering to a patient in need thereof, a pharmaceutical composition comprising an effective dose of a spiro-oxadiazoline compound represented by Formula (I), Formula (Ha), or Formula (lib), or a pharmaceutically acceptable salt thereof, wherein the method provides at least one of the following: visual motor, learning, delayed memory, or executive function; for example provides a pro-cognitive effect, exclusive of attention, in said patient; for example provides a pro-cognitive effect in at least one of the following: visual motor, learning, delayed memory, or executive function.
  • a pharmaceutical composition comprising an effective dose of a spiro-oxadiazoline compound represented by Formula (I), Formula (Ha), or Formula (lib), or a pharmaceutically acceptable salt thereof, wherein the method provides at least one of the following: visual motor, learning, delayed memory, or executive function; for
  • any one of the above-noted embodiments includes the daily dose as an initial daily dose.
  • any one of the above-noted embodiments includes improving cognition of the patient.
  • any one of the above-noted embodiments includes treating a symptom associated with a cognitive disease.
  • any one of the above-noted embodiments includes improving a symptom associated with a cognitive disease.
  • any one of the above-noted embodiments includes preventing progression of a cognitive disease.
  • any one of the above-noted embodiments includes the patient has been diagnosed as having a cognitive disease.
  • any one of the above-noted embodiments includes treating a symptom associated with Alzheimer's disease.
  • any one of the above-noted embodiments includes improving a symptom associated with Alzheimer's disease.
  • any one of the above-noted embodiments includes preventing progression of Alzheimer's disease.
  • any one of the above-noted embodiments includes the patient has been diagnosed as having mild-to-moderate Alzheimer's disease.
  • any one of the above-noted embodiments includes treating a symptom associated with schizophrenia.
  • any one of the above-noted embodiments includes improving a symptom associated with schizophrenia.
  • any one of the above-noted embodiments includes preventing progression of schizophrenia.
  • any one of the above-noted embodiments includes the patient has been diagnosed as having schizophrenia.
  • any one of the above-noted embodiments includes treating a symptom associated with positive symptoms of schizophrenia.
  • any one of the above-noted embodiments includes improving a symptom associated with positive symptoms of schizophrenia.
  • any one of the above-noted embodiments includes preventing progression of positive symptoms of schizophrenia.
  • any one of the above-noted embodiments includes the patient has been diagnosed as having positive symptoms of schizophrenia.
  • any one of the above-noted embodiments includes treating a symptom associated with negative symptoms of schizophrenia.
  • any one of the above-noted embodiments includes improving a symptom associated with negative symptoms of schizophrenia.
  • any one of the above-noted embodiments includes preventing progression of negative symptoms of schizophrenia.
  • any one of the above-noted embodiments includes the patient has been diagnosed as having negative symptoms of schizophrenia.
  • any one of the above-noted embodiments includes treating a symptom associated with schizophrenia with dementia.
  • any one of the above-noted embodiments includes improving a symptom associated with schizophrenia with dementia.
  • any one of the above-noted embodiments includes preventing progression of schizophrenia with dementia.
  • any one of the above-noted embodiments includes the patient has been diagnosed as having schizophrenia with dementia.
  • any one of the above-noted embodiments includes the patient has been diagnosed as having a disease associated with chronic inflammation, including atherosclerosis, rheumatoid arthritis and inflammatory bowel diseases.
  • any one of the above-noted embodiments includes the pharmaceutical composition is in the form of a tablet.
  • the invention also includes pharmaceutical preparations which, besides inert, nontoxic, pharmaceutically suitable excipients, adjuvants and carriers, contain one or more spiro-oxadiazoline compounds represented by Formula (I), Formula (Ha), or Formula (lib), or a pharmaceutically acceptable salt thereof, or consist of one or more spiro- oxadiazoline compounds represented by Formula (I), Formula (Ha), or Formula (lib), or a pharmaceutically acceptable salt thereof, and processes for producing these preparations.
  • pharmaceutical preparations which, besides inert, nontoxic, pharmaceutically suitable excipients, adjuvants and carriers, contain one or more spiro-oxadiazoline compounds represented by Formula (I), Formula (Ha), or Formula (lib), or a pharmaceutically acceptable salt thereof, or consist of one or more spiro- oxadiazoline compounds represented by Formula (I), Formula (Ha), or Formula (lib), or a pharmaceutically acceptable salt thereof, and processes for producing these preparations.
  • a spiro-oxadiazoline compound represented by Formula (I), Formula (Ila), or Formula (lib), or a pharmaceutically acceptable salt thereof may be formulated for administration in solid or liquid form.
  • a spiro-oxadiazoline compound represented by Formula (I), Formula (Ila), or Formula (lib), or a pharmaceutically acceptable salt thereof may be formulated for administration in a capsule, a tablet, or a powder form.
  • a spiro-oxadiazoline compound represented by Formula (I), Formula (Ila), or Formula (lib), or a pharmaceutically acceptable salt thereof may be formulated alone or as part of a pharmaceutical composition, suitable for oral administration, such as in a capsule or tablet, intravenous administration, parenteral administration, topical administration, or transdermal administration, such as in a patch, to a patient in need thereof.
  • a spiro-oxadiazoline compound represented by Formula (I), Formula (Ha), or Formula (lib), or a pharmaceutically acceptable salt thereof may be administered as a pharmaceutical composition, for example, in the presence of carriers, adjuvants, excipients, diluents, fillers, buffers, stabilizers, preservatives, lubricants, and the like, for example, administered as a pharmaceutical composition (e.g., formulation) comprising at least a spiro- oxadiazoline compound represented by Formula (I), Formula (Ila), or Formula (lib), or a pharmaceutically acceptable salt thereof, together with one or more pharmaceutically acceptable carriers, adjuvants, excipients, diluents, or other materials well known to those skilled in the art.
  • a pharmaceutical composition e.g., formulation
  • the term "pharmaceutically acceptable”, unless otherwise specified, includes the generally accepted meaning which encompasses combinations, compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for consumption by humans without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • Suitable pharmaceutically acceptable carriers, adjuvants, excipients, and diluents can include, but are not limited to, lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum, acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water syrup, methyl cellulose, methyl and propyl
  • compositions of this invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat.
  • ion exchangers alumina, aluminum stearate, lecithin
  • serum proteins such as human serum albumin
  • buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate,
  • the formulations can additionally include, but are not limited to, pharmaceutically acceptable lubricating agents, glidants, wetting agents, emulsifying and suspending agents, preserving agents, sweetening agents, and/or flavoring agents.
  • the pharmaceutical compositions of the present invention may be formulated so as to provide quick release, immediate release, sustained release, or delayed release of a spiro-oxadiazoline compound represented by Formula (I), Formula (Ila), or Formula (lib), or a pharmaceutically acceptable salt thereof, after administration to the patient by employing procedures well-known in the art.
  • Another embodiment of the invention further comprises methods of making
  • composition comprising admixing at least a spiro-oxadiazoline compound represented by Formula (I), Formula (Ila), or Formula (lib), or a pharmaceutically acceptable salt thereof, together with one or more pharmaceutically acceptable carriers, excipients, buffers, adjuvants, stabilizers, or other materials.
  • the spiro-oxadiazoline compounds represented by Formula (I), Formula (Ila), or Formula (lib), or a pharmaceutically acceptable salt thereof are to be present in these preparations in a concentration of from 0.1 to 99.5% by weight, preferably from 0.5 to 95% by weight, of the complete mixture.
  • the pharmaceutical preparations may also contain other active pharmaceutical ingredients.
  • the novel active ingredients can be converted in a known manner into conventional formulations such as tablets, coated tablets, pills, granules, aerosols, syrups, emulsions, suspensions and solutions, using inert, nontoxic, pharmaceutically suitable excipients or solvents.
  • the therapeutically active compound should in each case be present in a concentration of about 0.5 to 90% by weight of the entire mixture, i.e., in amounts which are sufficient to reach the stated dose range.
  • the formulations are produced, for example, by extending the active ingredients with solvents and/or excipients, where appropriate with use of emulsifiers and/or dispersants, it being possible for example when water is used as diluent where appropriate to use organic solvents as auxiliary solvents.
  • administration may take place in a conventional way, for example, orally, transdermally or parenterally, especially perlingually or intravenously.
  • administration may also take place by inhalation through the mouth or nose, for example, with the aid of a spray, or topically via the skin.
  • the spiro-oxadiazoline compounds represented by Formula (I), Formula (Ila), or Formula (lib), or a pharmaceutically acceptable salt thereof may be administered in amounts of about 0.01 to 10 mg/kg, on oral administration, for example, about 0.05 to 5 mg/kg, of body weight to achieve effective results.
  • LCMS Conditions A (“LCMS (AT): Instrument: LCMS-A, Mobile phase A: 4L H 2 0 ⁇ 1.5 mL TFA Mobile phase B: 4L ACN ⁇ 0.75 mL TFA, Method name: 10-80AB_4MIN_2W, Flow Rate: 0.8 mL/min., Gradient: 10%-80%; Column: Boston Green ODS 2.1 *30 mm, 3 ⁇ , Column temperature: 50 °C; Wavelength: 220 nm & 254 nm.
  • LCMS Conditions B (BY'): Instrument: LCMS-B, Mobile phase A: 4L H 2 0 ⁇ 1.5 ml TFA Mobile phase B: 4L ACN ⁇ 0.75 mL TFA, Method name: 5-95AB_R_2W, Flow Rate: 1.5 mL/min., Gradient: 5%-95%; Column: Chromolith Flash RP-18e 25-2 mm, Column temperature: 50 °C; Wavelength: 220 nm & 254 nm.
  • LCMS Conditions C LCMS (CV'V Instrument: LCMS-C, Mobile phase A: 4L H 2 0 ⁇ 1.5 mL TFA, Mobile phase B: 4L ACN ⁇ 0.75 mL TFA, Method name: 5-95AB_R_4MIN_2W Flow Rate: 1.5 mL/min., Method name: 5-95CD_4.5MI _2W, Flow Rate: 0.8 mL/min., Gradient: 5%-95%; Column: Chromolith Flash RP-18e 25-2 mm, Column temperature 50 °C; Wavelength: 220 nm & 254 nm.
  • LCMS Conditions D LCMS (DV'V Instrument: LCMS-C, Mobile phase A: 4L H 2 0 ⁇ 1.5 mL TFA, Mobile phase B: 4L ACN ⁇ 0.75 mL TFA, Method name: 5-95AB_R_4MIN_2W, Flow Rate: 0.8 mL/min., Gradient: 5%-95%; Column: Chromolith Flash RP-18e 25-2 mm, Column temperature: 50 °C; Wavelength: 220 nm & 254 nm.
  • LCMS (EV) Instrument: LCMS-C, Mobile phase A:4L H 2 0 ⁇ 1.5 ml TFA, Mobile phase B:4L ACN ⁇ 0.75 mL TFA, Method name: 5-95AB R Flow Rate: 1.5 mL/min., Gradient: 5%-95%; Column: Chromolith Flash RP-18e 25-2 mm, Column temperature: 50 °C; Wavelength: 220 nm & 254 nm.
  • LCMS Conditions F LCMS ( ⁇ T): Instrument: LCMS-D, Mobile phase A: 4L H 2 0 ⁇ 2 ml NH 3 H 2 0, Mobile phase B: Acetonitrile, Method name: 5-95CD_2MIN_ 2W, Flow Rate: 1 .2 mL/min., Gradient: 5%-95%, Column: XBrige Shield RP-18 2.1 *50 mm, 5 ⁇ , Column temperature: 30 °C; Wavelength: 220 nm & 254 nm.
  • LCMS Conditions G LCMS (GV : Instrument: LCMS-D, Mobile phase A: 4L H 2 0 ⁇ 2 mL NH 3 H 2 0, Mobile phase B: Acetonitrile, Method name: 10-80CD_4MI _POS, Flow Rate: 0.8 mL/min., Gradient: 10%-80%; Column: XBridge C-1 8 2.1 *50 mm, 5 ⁇ , Column temperature: 40 °C; Wavelength: 220 nm & 254 nm.
  • LCMS (HT) Instrument: LCMS-E, Mobile phase A: 4L H 2 0 ⁇ 1 .5 mL TFA, Mobile phase B: 4L ACN ⁇ 0.75 mL TFA, Method name: 10-80AB_4MIN_2W, Flow Rate: 0.8 mL/min., Gradient: 10%-80%; Column: Xtimate C-18, 2.1 *30 mm, 3 ⁇ , Column temperature: 50 °C; Wavelength: 220 nm & 254 nm.
  • LCMS Conditions I Instrument: LCMS-E, Mobile phase A: 4L H 2 0 ⁇ 2 mL NH 3 H 2 0, Mobile phase B: Acetonitrile Method name:0-60CD_4.5MI _2W, Flow Rate: 0.8 ml/min., Gradient: 0%-60%; Column:XBrige Shield RP-18 2.1 *50 mm, 5 ⁇ , Column temperature 50 °C; Wavelength: 220 nm & 254 nm.
  • LCMS (J) Instrument: LCMS-D, Mobile phase A: 4L H 2 0 ⁇ 2mL NH 3 H 2 0
  • Mobile phase B Acetonitrile Method name: 10-80CD_2MIN_POS_2W, Flow Rate: 1.2ml/min., Gradient: 10%-80%; Column: Xbridge C-18 2.1 *50 mm, 5 ⁇ , Column temperature: 40 °C; Wavelength: 220 nm & 254 nm.
  • Example 6B benzorblthiazole-2-carb a ldehyde oxime (B-106)
  • Example 33B - thieno[2,3-blpyridine-2-carbaldehyde oxime (B-133) [00267] To a solution of compound B-132 (3.4 g, 21 mmol) in anhydrous ethanol (50 mL) was added hydroxylamine hydrochloride (4.4 g, 63 mmol) and potassium carbonate (8.7 g, 63 mmol) at room temperature. The reaction mixture was stirred at room temperature overnight. On completion, the mixture was filtered and washed with ethanol.

Abstract

The present invention relates to novel spiro-oxadiazoline compounds that are suitable as agonists or partial agonists of a7-nAChR, and pharmaceutical compositions of the same, methods of preparing these compounds and compositions, and the use of these compounds and compositions in methods of maintaining, treating and/or improving cognitive function. In particular, methods of administering a spiro-oxadiazoline cx7-nAChR agonist or partial agonist, to a patient in need thereof, for example a patient with a cognitive deficiency and/or a desire to enhance cognitive function, that may derive a benefit therefrom.

Description

SPIRO-OXADIAZOLINE COMPOUNDS AS AGONISTS OF
0C7-NICOTINIC ACETYLCHOLINE RECEPTORS
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application claims the benefit of U.S. Provisional Application No. 61/962,098, filed October 31 , 2013, which, in its entirety, is incorporated herein by reference.
FIELD OF THE INVENTION
[0002] The present invention relates to novel spiro-oxadiazoline compounds that are suitable as agonists or partial agonists of a7-nAChR, and pharmaceutical compositions of the same, methods of preparing these compounds and compositions, and the use of these compounds and compositions in methods of maintaining, treating and/or improving cognitive function. In particular, methods of administering a spiro-oxadiazoline a7-nAChR agonist or partial agonist, to a patient in need thereof, for example a patient with a cognitive deficiency and/or a desire to enhance cognitive function, that may derive a benefit therefrom.
BACKGROUND OF THE INVENTION
[0003] The prevalence of cognitive disease, for example dementia in North America, is approximately 6 to 10% of the population, with Alzheimer's disease accounting for a substantial portion of these cases. Many forms of cognitive disease represent a steadily growing medical and social problem of our aging societies around the World. Some believe the main pathological features may relate to intraneuronal neurofibrillary tangles, formation of amyloid beta plaques and/or neurodegeneration of mainly cholinergic and, in later stages, also serotonergic, noradrenergic, and other neurons, resulting in deficiencies of acetylcholine and other
neurotransmitters. Some theories suggest that the gradual development of an acetylcholine signaling deficiency may be responsible for the early clinical manifestations of cognitive disease. Consequently, some believe that compounds that improve cholinergic functioning, such as acetylcholine esterase inhibitors may ameliorate the cognitive deficits in patients with cognitive disease. The most widely used acetylcholine esterase inhibitor is donepezil hydrochloride (Aricept®).
[0004] Nicotinic acetylcholine receptors (nAChR) form a large family of ion channels which are activated by the messenger acetylcholine which is produced in the body (Galzi and Changeux, Neuropharmacol. 1995, 34, 563-582). A functional nAChR consists of five subunits which may be different (certain combinations of al -9 and β1-4,γ,δ,ε subunits) or identical (a7-9). This leads to the formation of a diversity of subtypes which differ in the distribution in the muscles, the nervous system and other organs (McGehee and Role, Annu. Rev. Physiol. 1995, 57, 521-546). Activation of nAChR leads to influx of cations into the cell and to stimulation of nerve cells or muscle cells. Selective activation of individual nAChR subtypes restricts this stimulation to the cell types which have a corresponding subtype and is thus able to avoid unwanted side effects such as, for example, stimulation of nAChR in the muscles. Clinical experiments with nicotine and experiments in various animal models indicate that central nicotinic acetylcholine receptors are involved in learning and memory processes (e.g. Rezvani and Levin, Biol. Psychiatry 2001 , 49, 258-267). Nicotinic acetylcholine receptors of the alpha7 subtype (a7 nAChR) have a particularly high concentration in regions of the brain which are important for learning and memory, such as the hippocampus and the cerebral cortex (Seguela et al., J. Neurosci. 1993, 13, 596-604). The a7 nAChR has a particularly high permeability for calcium ions, increases glutamatergic neurotransmission, influences the growth of axons and, in this way, modulates neuronal plasticity (Broide and Leslie, Mol. Neurobiol. 1999, 20, 1-16).
[0005] WO 2003/055878 describes a variety of agonists of the alpha7 nAChR said to be useful for improving cognition. WO 2003/055878 suggests that certain agonists of the alpha7 nAChR are useful for improving perception, concentration, learning or memory, especially after cognitive impairments like those occurring for example in situations/diseases/syndromes such as mild cognitive impairment, age-associated learning and memory impairments, age-associated memory loss, Alzheimer's disease, schizophrenia and certain other cognitive disorders.
BRIEF SUMMARY OF THE INVENTION
[0006] An aspect of the invention provides a spiro-oxadiazoline compound represented by Formula (I), (Ila), or (lib):
Formula (lib)
Figure imgf000003_0001
wherein:
R independently represents -H; a CrC6-alkyl radical; a C3-C6- cycloalkyl radical; a (3-6 membered)-heterocycloalkyl radical; an aryl radical; or a heteroaryl radical; wherein the Ci-C6-alkyl radical, the (3-6 membered)-heterocycloalkyl radical, the aryl radical, and the heteroaryl radical may be substituted with up to 4 radical substituents comprising: -D, -F, -CI, -Br, -I, -CN, -N02, -OR2, -(CH2)mOR2, - N(R2)(R3), -(CH2)mN(R2)(R3), -S02(CH2)mR2, -(CO)(CH2)mR2, -
(CO)N(R2)(R3), -OCF3, a branched or unbranched CrC6-alkyl radical, a C3-C6-cycloalkyl radical, a Ci-C6-hydroxyalkyl radical, or a C] -C6-haloalkyl radical;
R2 and R independently represent -H; a branched or unbranched Q-Ce-alkyl radical; C3-C6-cycloalkyl radical; or the N(R2)(R3) moiety forms a cycle, wherein R2 and R3 taken together represent a C2-C6-alkyl di- radical or a (3-6 membered)-heteroalkyl di-radical;
n independently represents an integer from 0 to 6;
m independently represents an integer from 1 to 6;
W represents a moiety represented by ring system M-I, M-II, M-III, M- rv, M-V,
Figure imgf000004_0001
Z Z2, Z3, Z4, and Z independently represent N or CR ; with the proviso that no more than two of Z Z2, Z3, Z4, and Z5 are N;
R4 independently represents -H; -D; -F; -CI; -Br; -I; -CN; -NO2; - OR5; -(CH2)mOR5; -N(R5)(R6); -(CH2)mN(R5)(R6); -S02(CH2)mR5; - (CO)(CH2)mR5; -(CO)N(R5)(R6); -OCF3; a CrC6-alkyl radical; a C,- C6-hydroxyalkyl radical, a Ci-C6-haloalkyl radical; a C3-C6- cycloalkyl radical; a (3-6 membered)-heterocycloalkyl radical; an aryl radical; or a heteroaryl radical; wherein the CrC6-alkyI radical, the (3-6 membered)-heterocycloalkyl radical, the aryl radical, and the heteroaryl radical may be substituted with up to 4 radical substituents comprising: -D, -F, -CI, -Br, -I, -CN, -N02, -OR5, -(CH2)mOR5, - N(R5)(R6), -(CH2)mN(R5)(R6), -S02(CH2)mR5, -(CO)(CH2)mR5, - (CO)N(R5)(R6), -OCF3, a branched or unbranched C,-C6-alkyl radical, a C3-C6-cycloalkyl radical, a C]-C6-hydroxyalkyl radical, or a Ci-C6-haloalkyl radical;
R5 and R6 independently represent -H; a branched or unbranched Ci-C6-alkyl radical; a C3-C6-cycloalkyl radical; or the N(R5)(R6) moiety forms a cycle, wherein R5 and R6 taken together represent a C2-C6-alkyl di- radical or a (3-6 membered)-heteroalkyl di-radical; independently represent N or CR7; with the proviso that no more than two of Z6, Z7, Z8, and Z9 are N;
independently represents -H; -D; -F; -CI; -Br; -I; -CN; -NO2; - OR8; -(CH2)mOR8; -N(R8)(R9); -(CH2)mN(R8)(R9); -S02(CH2)mR8; - (CO)(CH2)mR8; -(CO)N(R8)(R9); -OCF3; a C,-C6-alkyl radical; a C,- C6-hydroxyalkyl radical, a d-C6-haloalkyl radical; a C3-C6- cycloalkyl radical; a (3-6 membered)-heterocycloalkyl radical; an aryl radical; a heteroaryl radical; or the bond directly attaching the W moiety with the oxadiazoline moiety; wherein the Ci-C6-alkyl radical, the (3-6 membered)-heterocycloalkyl radical, the aryl radical, and the heteroaryl radical may be substituted with up to 4 radical substituents comprising: -D, -F, -CI, -Br, -I, -CN, -N02, -OR8, -(CH2)mOR8, - N(R8)(R9), -(CH2)raN(R8)(R9), -S02(CH2)mR8, -(CO)(CH2)mR8, - (CO)N(R8)(R9), -OCF3, a branched or unbranched C,-C6-alkyl radical, a C3-C6-cycloalkyl radical, a C|-C6-hydroxyalkyl radical, or a Ci-C6-haloalkyl radical;
independently represent -H; a branched or unbranched Ci-C6-alkyl radical; a C3-C6-cycloalkyl radical; or the N(R8)(R9) moiety forms a cycle, wherein R8 and R9 taken together represent a C2-C6-alkyl di- radical or a (3-6 membered)-heteroalkyl di-radical;
independently represents N or C;
independently represent N; NR10; N(CH2)mR10; O; S; or CR1 1; with the proviso that only one A1, A2, A3 and A4 is NR10, O, or S; with the further proviso that when X1 is present and is N, then A1, A2, and A3 independently represent N or CR1 1;
independently represents -H; -D; -(CH2)mOR12; -(CH2)mN(R12)(R13); -S02(CH2)mR12; -(CO)(CH2)mR12; -(CO)N(R1 )(R13); a C,-C6-alkyl radical; a C]-C6-hydroxyalkyl radical, a C C6-haloalkyl radical; a C3- C6-cycloalkyl radical; a (3-6 membered)-heterocycloalkyl radical; an aryl radical; or a heteroaryl radical; wherein the Ci-C6-alkyl radical, the (3-6 membered)-heterocycloalkyl radical, the aryl radical, and the heteroaryl radical may be substituted with up to 4 radical substituents comprising: -D, -F, -CI, -Br, -I, -CN, -N02, -OR12, -<CH2)mOR12, -N(R12)(R13), -(CH2)mN(R, 2)(R13), -S02(CH2)mR12, -(CO)(CH2)mR13, -(CO)N(R12)(R13), -OCF3, a branched or unbranched C,-C6-alkyl radical, a C3-C6-cycloalkyl radical, a C|-C6-hydroxyalkyl radical, or a Ci-C6-haloalkyl radical; R11 independently represents -H; -D; -F; -CI; -Br; -I; -CN; -N02; -
OR12; -(CH2)mOR12; -N(R12)(R13); -(CH2)mN(R12)(R13); - S02(CH2)mR12; -(CO)(CH2)raR12; -(CO)N(R12)(R13); -OCF3; a C,-C6- alkyl radical; a Ci-C6-hydroxyalkyl radical; a Ci-C6-haloalkyl radical; a C3-C6-cycloalkyl radical; a (3-6 membered)-heterocycloalkyl radical; an aryl radical; or a heteroaryl radical; wherein the CrC6- alkyl radical, the (3-6 membered)-heterocycloalkyl radical, the aryl radical, and the heteroaryl radical may be substituted with up to 4 radical substituents comprising: -D; -F; -CI; -Br; -I; -CN; -N02; - OR12; -(CH2)mOR12; -N(R,2)(R13); -(CH2)mN(R,2)(R,3); - S02(CH2)mR12; -(CO)(CH2)mR12; -(CO)N(R12)(R13); -OCF3; a branched or unbranched C C6-alkyl radical, a C3-C6-cycloalkyl radical, a Ci-C6-hydroxyalkyl radical, or a Ci-C6-haloalkyl radical;
R12 and R13 independently represent -H; a branched or unbranched CpCe-alkyl radical; a C3-C6-cycloalkyl radical; or the N(RI 2)(R13) moiety forms a cycle, wherein R12 and R13 taken together represent a C2-C6-alkyl di- radical or a (3-6 membered)-heteroalkyl di-radical;
X2 independently represents N or C;
A5, A6, and A7 independently represent N; NR14; N(CH2)mR14; O; S; or CR15; with the proviso that only one A5, A6, and A7 is NR14, O, or S; with the further proviso that when X2 is N, then A5, A6, and A7 independently represent N or CR15;
R'4 independently represents -H; -D; -(CH2)mOR16; -(CH2)mN(R16)(R17);
-S02(CH2)mR16; -iCO)(CH2)mR16; -(CO)N(Rl6)(R17); a C,-C6-alkyl radical; a C]-C6-hydroxyalkyl radical, a Ci-C6-haloalkyl radical; a C3- C6-cycloalkyl radical; a (3-6 membered)-heterocycloalkyl radical; an aryl radical; a heteroaryl radical; or the bond directly attaching the W moiety with the oxadiazoline moiety; wherein the Ci-C6-alkyl radical, the (3-6 membered)-heterocycloalkyl radical, the aryl radical, and the heteroaryl radical may be substituted with up to 4 radical substituents comprising: -D, -F, -CI, -Br, -I, -CN, -N02, -OR16, -(CH2)mOR16, -N(R16)(R17), -(CH2)mN(R16)(R17), -S02(CH2)mR16, -(CO)(CH2)mR16, -(CO)N(R16)(R17), -OCF3, a branched or unbranched C,-C6-alkyl radical, a C3-C6-cycloalkyl radical, a Ci-C6-hydroxyalkyl radical, or a C C6-haloalkyl;
R15 independently represents -H; -D; -F; -CI; -Br; -I; -CN; -N02; -
OR16; -(CH2)mOR16; -N(R16)(R17); -(CH2)mN(R16)(R17); - S02(CH2)mR'6; -(CO)(CH2)mR16; -(CO)N(R,6)(R, 7); -OCF3; a C,-C6- alkyl radical; a Ci-C6-hydroxyalkyl radical; a Ci-C6-haloalkyl radical a C3-C6-cycloalkyl radical; a (3-6 membered)-heterocycloalkyl radical; an aryl radical; a heteroaryl radical; or the bond directly attaching the W moiety with the oxadiazoline moiety; wherein the Ci-C6-alkyl radical, the (3-6 membered)-heterocycloalkyl radical, the aryl radical, and the heteroaryl radical may be substituted with up to 4 radical substituents comprising: -D; -F; -CI; -Br; -I; -CN; -N02; -OR16; -(CH2)mOR16; -N(RI6)(R17); -(CH2)mN(R16)(R17); - S02(CH2)mR16; -(CO)(CH2)mR16; -(CO)N(R,6)(R17); -OCF3; a branched or unbranched Ci-C6-alkyl radical, a C3-C6-cycloalkyl radical, a CrC6-hydroxyalkyl radical, or a Ci-C6-haloalkyl radical; independently represent -H; a branched or unbranched Ci-C6-alkyl radical; a C3-C6-cycloalkyl radical; or the N(R16)(R'7) moiety forms a cycle, wherein R16 and R17 taken together represent a C2-C6-alkyl di- radical or a (3-6 membered)-heteroalkyl di-radical;
independently represent C(R18)(R18); C(R19)(R20); -NH; - N(CH2)mR18; O; S; S02; or (C=0); with the proviso that no more than two of G1, G2, G3, and G4 represent -NH; -N(CH2)mR18, O; S; S02; or (C=0);
independently represents -H; -D; -F; -CI; -Br; -I; -CN; -N02; - OR19; -(CH2)mOR19; -N(R,9)(R20); -<CH2)mN(R,9)(R20); - S02(CH2)mR19; -(CO)(CH2)mR19; -(CO)N(R19)(R20); -OCF3; a C,-C6- alkyl radical; a Ci-C6-hydroxyalkyl radical, a d-C6-haloalkyl radical; a C3-C6-cycloalkyl radical; a (3-6 membered)-heterocycloalkyl radical; an aryl radical; or a heteroaryl radical; wherein the Ci-C6- alkyl radical, the (3-6 membered)-heterocycloalkyl radical, the aryl radical, and the heteroaryl radical may be substituted with up to 4 radical substituents comprising: -D, -F, -CI, -Br, -I, -CN, -N02i - OR19, -(CH2)mOR19, -N(R, 9)(R20), -(CH2)mN(R19)(R20), - S02(CH2)mR19, -(CO)(CH2)mR19, -(CO)N(R, 9)(R20), -OCF3, a branched or unbranched CrC6-alkyl radical, a C -C6-cycloalkyl radical, a CrC6-hydroxyalkyl radical, or a C]-C6-haloalkyl radical; and
independently represent -H; a branched or unbranched Ci-C6-alkyl radical; a C3-C6-cycloalkyl radical; or the N(R19)(R20) moiety forms a cycle, wherein R19 and R20 taken together represent a C2-C6-alkyl di- radical or a (3-6 membered)-heteroalkyl di-radical; or the C(R19)(R20) moiety forms a cycle, wherein R19 and R20 taken together represent a C2-C6-alkyl di-radical or a (3-6 membered)-heteroalkyl di-radical; or a pharmaceutically acceptable salt thereof.
[0007] An aspect of the invention relates to a method comprising administering to a patient in need thereof an effective dose of a spiro-oxadiazoline compound represented by Formula (I), Formula (Ila), or Formula (lib), or a pharmaceutically acceptable salt thereof.
[0008] Another aspect of the invention provides a method of treating a patient in need thereof, comprising: administering to the patient an effective dose of a spifo-oxadiazoline compound represented by Formula (I), Formula (Ila), or Formula (lib), or a pharmaceutically acceptable salt thereof.
[0009] Another aspect of the invention provides a method of maintaining, treating, curing and/or improving at least one cognitive function in a patient in need thereof, comprising:
administering to the patient an effective dose of a spiro-oxadiazoline compound represented by Formula (I), Formula (Ila), or Formula (lib), or a pharmaceutically acceptable salt thereof.
[0010] Another aspect of the invention provides a method of maintaining, treating, curing and/or improving at least one cognitive function in a patient in need thereof, comprising:
administering to the patient a pharmaceutical composition comprising an effective dose of a spiro- oxadiazoline compound represented by Formula (I), Formula (Ha), or Formula (lib), or a pharmaceutically acceptable salt thereof.
[0011] Another aspect of the invention provides a method of treating a patient in need thereof, comprising: administering to the patient diagnosed as having a cognitive impairment an effective dose of a pharmaceutical composition comprising a spiro-oxadiazoline compound represented by Formula (I), Formula (Ila), or Formula (lib), or a pharmaceutically acceptable salt thereof.
[0012] Another aspect of the invention provides a method of treating a patient in need thereof, comprising: administering to the patient, for example, a patient diagnosed with having a cognitive impairment, Limited Cognitive Impairment, Mild Cognitive Impairment, Alzheimer's disease, and/or schizophrenia, a spiro-oxadiazoline compound represented by Formula (I), Formula (Ila), or Formula (lib), or a pharmaceutically acceptable salt thereof such that the patient may derive a benefit therefrom.
[0013] Another aspect of the invention provides a method of treating one or more symptoms associated with a cognitive impairment, comprising administering to a patient an effective dose of a spiro-oxadiazoline compound represented by Formula (I), Formula (Ila), or Formula (lib), or a pharmaceutically acceptable salt thereof, wherein the patient suffers from, or has been diagnosed as having, a cognitive impairment. [0014] Another aspect of the invention provides a method of improving cognition in a patient suffering from a cognitive impairment, such as a cognitive impairment associated with either schizophrenia or Alzheimer's disease, for example mild Alzheimer's disease, moderate
Alzheimer's disease, severe Alzheimer's disease, or mild-to-moderate Alzheimer's disease, comprising administering an effective dose of a spiro-oxadiazoline compound represented by Formula (I), Formula (Ila), or Formula (lib), or a pharmaceutically acceptable salt thereof.
[0015] Another aspect of the invention provides a method of treating a patient suffering from, diagnosed with having, or suffers from one or more symptoms associated with, a cognitive impairment, for example, Alzheimer's disease, dementia of an Alzheimer's type, MCI, LCI, or schizophrenia, comprising: administering to the patient a pharmaceutical composition comprising an effective dose of a spiro-oxadiazoline compound represented by Formula (I), Formula (Ila), or Formula (lib), or a pharmaceutically acceptable salt thereof. For example, the method of treating a patient suffering from, diagnosed with having, or suffers from one or more symptoms associated with, a cognitive impairment, may provide said patient at least one of the following: (i) treats, minimizes progression of, prevents the deterioration of, or reduces the rate of detioraration of, one or more symptoms associated with the cognitive impairment; (ii) treats the cognitive impairment; (iii) improves cognition in said cognitively impaired patient; (iv) improves one or more behavioral symptoms associated with the cognitive impairment; (v) provides a pro-cognitive effect; (vi) provides a pro-cognitive effect, exclusive of attention, in at least one of the following: visual motor, learning, delayed memory, or executive function, or (vii) provides a positive effect on clinical function in said cognitively impaired patient.
[0016] Another aspect of the invention provides a method of treating a patient previously treated, or currently being treated, with an AChEI, that is suffering from, or has been diagnosed with having, a cognitive impairment, for example, Alzheimer's disease, dementia of an
Alzheimer's type, MCI, LCI, or schizophrenia, comprising: administering to the patient a pharmaceutical composition comprising an effective dose of a spiro-oxadiazoline compound represented by Formula (I), Formula (Ila), or Formula (lib), or a pharmaceutically acceptable salt thereof, wherein the method improves one or more symptoms associated with the cognitive impairment in the previously, or currently, AChEI treated patient.
[0017] Another aspect of the invention provides a method of treating a patient suffering from, or diagnosed with having a cognitive impairment, comprising: administering to the patient a pharmaceutical composition comprising an effective dose of a spiro-oxadiazoline compound represented by Formula (I), Formula (Ila), or Formula (lib), or a pharmaceutically acceptable salt thereof, wherein the method provides a positive effect on cognition or a positive effect on clinical function in said cognitively impaired patient, and wherein said patient has been previously treated or is currently being treated with an AChEI. [0018] Another aspect of the invention provides a method of improving cognition in a patient diagnosed as having a probable cognitive disease, comprising: administering to the patient an effective dose of a pharmaceutical composition comprising a spiro-oxadiazoline compound represented by Formula (I), Formula (Ila), or Formula (lib), or a pharmaceutically acceptable salt thereof.
[0019] Another aspect of the invention provides a method of improving or substantially improving one or more symptoms in a cognitve disease patient, comprising: administering to the patient an effective dose of a compound represented by Formula (I), Formula (Ila), or Formula (lib), or a pharmaceutically acceptable salt thereof.
[0020] Another aspect of the invention provides a method of slowing the rate of deterioration of at least one symptom in a cognitve disease patient, comprising: administering to the patient the pharmaceutical composition comprising a spiro-oxadiazoline compound represented by Formula (I), Formula (Ila), or Formula (lib), or a pharmaceutically acceptable salt thereof.
[0021] Another aspect of the invention provides a method of treating one or more symptoms associated with a cognitive disease in a patient suffering therefrom, comprising: administering to the patient an effective dose of a pharmaceutical composition comprising a spiro-oxadiazoline compound represented by Formula (I), Formula (Ila), or Formula (lib), or a pharmaceutically acceptable salt thereof.
[0022] Another aspect provides a method of minimizing or substantially halting the rate of progression of one or more cognitive diseases in a patient suffering from a cognitive disease, comprising: administering to the patient an effective dose of a pharmaceutical composition comprising a spiro-oxadiazoline compound represented by Formula (I), Formula (Ila), or Formula (lib), or a pharmaceutically acceptable salt thereof.
[0023] Another aspect of the invention provides a method of substantially stopping or reversing progression of one or more cognitive diseases, in a patient suffering therefrom, comprising: administering to the patient an effective dose of a pharmaceutical composition comprising a spiro-oxadiazoline compound represented by Formula (I), Formula (Ila), or Formula (lib), or a pharmaceutically acceptable salt thereof.
[0024] Another aspect of the invention provides a method of treating dementia, comprising: administering to a patient in need thereof an effective amount of a spiro-oxadiazoline compound represented by Formula (I), Formula (Ila), or Formula (lib), or a pharmaceutically acceptable salt thereof, wherein said effective amount is administered in an effective dose.
[0025] Another aspect of the invention provides a method of treating dementia, comprising: administering to a patient in need thereof an effective amount of a spiro-oxadiazoline compound represented by Formula (I), Formula (Ha), or Formula (lib), or a pharmaceutically acceptable salt thereof. [0026] Another aspect of the invention provides a method of treating dementia, comprising: administering to a patient in need thereof an effective amount of a spiro-oxadiazoline compound represented by Formula (I), Formula (Ila), or Formula (lib), or a pharmaceutically acceptable salt thereof, wherein the spiro-oxadiazoline compound represented by Formula (I), Formula (Ila), or Formula (lib), or a pharmaceutically acceptable salt thereof, is administered in the form of a pharmaceutical composition comprising at least one pharmaceutically acceptable carrier, excipient or diluent.
[0027] Another aspect of the invention provides a method of treating dementia, comprising: administering to a patient in need thereof an effective amount of a spiro-oxadiazoline compound represented by Formula (I), Formula (Ila), or Formula (lib), or a pharmaceutically acceptable salt thereof, wherein the pharmaceutical composition is in the form of a tablet.
[0028] Another aspect of the invention provides a method of treating a patient having a cognitive disease and being administered an acetylcholine esterase inhibitor, comprising:
administering to the patient an effective dose of a pharmaceutical composition comprising a spiro- oxadiazoline compound represented by Formula (I), Formula (Ila), or Formula (lib), or a pharmaceutically acceptable salt thereof, wherein the treatment comprises halting the
administration of the acetylcholine esterase inhibitor prior to treating with the spiro-oxadiazoline compound represented by Formula (I), Formula (Ila), or Formula (lib), or a pharmaceutically acceptable salt thereof.
BRIEF DESCRIPTION OF THE DRAWINGS
[0029] Figure 1: Illustrates results of Novel Object Recognition Task in male Wistar rats.
DETAILED DESCREPTION OF THE INVENTION
[0030] An embodiment of the present invention provides a spiro-oxadiazoline compound represented by Formula (I), (Ila), or (lib):
Formula (lib)
Figure imgf000011_0001
wherein:
R independently represents -H; a Ci-Cg-alkyl radical; a C3-C6- cycloalkyl radical; a (3-6 membered)-heterocycloalkyl radical; an aryl radical; or a heteroaryl radical; wherein the Ci-C6-alkyl radical, the (3-6 membered)-heterocycloalkyl radical, the aryl radical, and the heteroaryl radical may be substituted with up to 4 radical substituents comprising: -D, -F, -CI, -Br, -I, -CN, -N02. -OR2, -(CH2)mOR2, - N(R2)(R3), -(CH2)mN(R2)(R3), -S02(CH2)mR2, -(CO)(CH2)mR2, - (CO)N(R2)(R3), -OCF3, a branched or unbranched C,-C6-alkyl radical, a C3-C6-cycloalkyl radical, a Ci-C6-hydroxyalkyl radical, or a Ci-C6-haloalkyl radical;
R2 and R3 independently represent -H; a branched or unbranched Ci-Ci-alkyl radical; C3-C6-cycloalkyl radical; or the N(R2)(R3) moiety forms a cycle, wherein R2 and R3 taken together represent a C2-C6-alkyl di- radical or a (3-6 membered)-heteroalkyl di-radical;
n independently represents an integer from 0 to 6;
m independently represents an integer from 1 to 6;
W represents a moiety represented by ring system M-I, M-II, M-III, M-
Figure imgf000012_0001
Z Z2, Z Z4, and Z5 independently represent N or CR4; with the proviso that no more than two
Figure imgf000012_0002
Z2, Z3, Z4, and Z5 are N;
R4 independently represents -H; -D; -F; -CI; -Br; -I; -CN; -N02; - OR5; -(CH2)mOR5; -N(R5)(R6); -(CH2)mN(R5)(R6); -S02(CH2)mR5; - (CO)(CH2)mR5; -(CO)N(R5)(R6); -OCF3; a C,-C6-alkyl radical; a C,- C6-hydroxyalkyl radical, a C C6-haloalkyl radical; a C3-C6- cycloalkyl radical; a (3-6 membered)-heterocycloalkyl radical; an aryl radical; or a heteroaryl radical; wherein the Ci-C6-alkyl radical, the (3-6 membered)-heterocycloalkyl radical, the aryl radical, and the heteroaryl radical may be substituted with up to 4 radical substituents comprising: -D, -F, -CI, -Br, -I, -CN, -N02, -OR5, -(CH2)mOR5, - N(R5)(R6), -(CH2)mN(R5)(R6), -S02(CH2)mR5, -(CO)(CH2)mR5, - (CO)N(R5)(R6), -OCF3, a branched or unbranched C,-C6-alkyl radical, a C3-C6-cycloalkyl radical, a Ci-C6-hydroxyalkyl radical, or a C|-C6-haloalkyl radical;
R5 and R6 independently represent -H; a branched or unbranched
Figure imgf000012_0003
radical; a C3-C6-cycloalkyl radical; or the N(R5)(R6) moiety forms a cycle, wherein R5 and R6 taken together represent a C2-C6-alkyl di- radical or a (3-6 membered)-heteroalkyl di-radical;
Z5, Z7, Z8, and Z9 independently represent N or CR7; with the proviso that no more than two of Z6, Z7, Zs, and Z9 are N;
R7 independently represents -H; -D; -F; -CI; -Br; -I; -CN; -N02; -
OR8; -(CH2)mOR8; -N(R8)(R9); -(CH2)mN(R8)(R9); -S02(CH2)mR8; - (CO)(CH2)mR8; -(CO)N(R8)(R9); -OCF3; a C,-C6-alky] radical; a C,- C6-hydroxyalkyl radical, a Ci-C6-haloalkyl radical; a C3-C6- cycloalkyl radical; a (3-6 membered)-heterocycloalkyl radical; an aryl radical; a heteroaryl radical; or the bond directly attaching the W moiety with the oxadiazoline moiety; wherein the Ci-C6-alkyl radical, the (3-6 membered)-heterocycloalkyl radical, the aryl radical, and the heteroaryl radical may be substituted with up to 4 radical substituents comprising: -D, -F, -CI, -Br, -I, -CN, -N02, -OR8, -(CH2)mOR8, - N(R8)(R9), -<CH2)mN(R8)(R9), -S02(CH2)mR8, -(CO)(CH2)mR8, - (CO)N(R8)(R9), -OCF3, a branched or unbranched CrC6-alkyl radical, a C3-C6-cycloalkyl radical, a C]-C6-hydroxyalkyl radical, or a Ci-C6-haloalkyl radical;
R8 and R9 independently represent -H; a branched or unbranched Ci-C6-alkyl radical; a C3-C6-cycloalkyl radical; or the N(R8)(R9) moiety forms a cycle, wherein R8 and R9 taken together represent a C2-C6-alkyl di- radical or a (3-6 membered)-heteroalkyl di-radical;
X1 independently represents N or C;
A1, A2, A3 and A4 independently represent N; NR10; N(CH2)mR10; O; S; or CR11; with the proviso that only one A1, A2, A3 and A4 is NR10, O, or S; with the further proviso that when X1 is present and is N, then A1, A2, and A3 independently represent N or CR1 1;
R10 independently represents -H; -D; -(CH2)mOR12; -(CH2)mN(R,2)(R13);
-S02(CH2)mR12; -(CO)(CH2)mR12; -<CO)N(R12)(R13); a C,-C6-alkyl radical; a Ci-C6-hydroxyalkyl radical, a C]-C6-haloalkyl radical; a C3- C6-cycloalkyl radical; a (3-6 membered)-heterocycloalkyl radical; an aryl radical; or a heteroaryl radical; wherein the CrC6-alkyl radical, the (3-6 membered)-heterocycloalkyl radical, the aryl radical, and the heteroaryl radical may be substituted with up to 4 radical substituents comprising: -D, -F, -CI, -Br, -I, -CN, -N02, -OR12, -(CH2)mOR12, -N(R1 )(R13), -<CH2)mN(R12)(R13), -S02(CH2)mR12, -(CO)(CH2)mR13, -<CO)N(R12)(R13), -OCF3, a branched or unbranched C,-C6-alkyl radical, a C3-C6-cycloalkyl radical, a Ci-C6-hydroxyalkyl radical, or a C] -C6-haloalkyl radical;
R1 ' independently represents -H; -D; -F; -CI; -Br; -I; -CN; -N02; -
OR12; -(CH2)mOR12; -N(R12)(R13); -(CH2)raN(R1 )(R13); - S02(CH2)mR12; -(CO)(CH2)mR,2 ; -(CO)N(R, )(R13); -OCF3; a C,-C6- alkyl radical; a Ci-C6-hydroxyalkyl radical; a C]-C6-haloalkyl radical; a C3-Q-cycloalkyl radical; a (3-6 membered)-heterocycloalkyl radical; an aryl radical; or a heteroaryl radical; wherein the Ci-Ce- alkyl radical, the (3-6 membered)-heterocycIoalkyl radical, the aryl radical, and the heteroaryl radical may be substituted with up to 4 radical substituents comprising: -D; -F; -CI; -Br; -I; -CN; -N02; - OR12; -(CH2)mOR12; -N(R,2)(R13); -(CH2)mN(R,2)(R13); - S02(CH2)mR12; -(CO)(CH2)mR'2; -<CO)N(R,2)(R13); -OCF3; a branched or unbranched C]-C6-alkyl radical, a C3-C6-cycloalkyl radical, a Ci-C6-hydroxyalkyl radical, or a Ci-C6-haloalkyl radical;
R12 and R13 independently represent -H; a branched or unbranched Ci-C6-alkyl radical; a C3-C6-cycloalkyl radical; or the N(R12)(R13) moiety forms a cycle, wherein R12 and R13 taken together represent a C2-C6-alkyl di- radical or a (3-6 membered)-heteroalkyl di-radical;
X2 independently represents N or C;
A5, A6, and A7 independently represent N; NR14; N(CH2)mR14; O; S; or CR15; with the proviso that only one A5, A6, and A7 is NR14, O, or S; with the further proviso that when X2 is N, then A5, A6, and A7 independently represent N or CR15;
R14 independently represents -H; -D; -<CH2)mOR16; -(CH2)mN(R, 6)(R17);
-S02(CH2)mR16; -(CO)(CH2)mR16; -(CO)N(R16)(R17); a C,-C6-alkyl radical; a C,-C6-hydroxyalkyl radical, a Ci-C6-haloalkyl radical; a C3- C6-cycloalkyl radical; a (3-6 membered)-heterocycloalkyl radical; an aryl radical; a heteroaryl radical; or the bond directly attaching the W moiety with the oxadiazoline moiety; wherein the Ci-C6-alkyl radical, the (3-6 membered)-heterocycloalkyl radical, the aryl radical, and the heteroaryl radical may be substituted with up to 4 radical substituents comprising: -D, -F, -CI, -Br, -I, -CN, -N02, -OR16, -(CH2)mOR16, -N(R16)(R17), -(CH2)mN(R16)(R17), -S02(CH2)mR16, -(CO)(CH2)mR16, -(CO)N(R16)(R17), -OCF3, a branched or unbranched C,-C6-alkyl radical, a C3-C6-cycloalkyl radical, a CrC6-hydroxyalkyl radical, or a C-C6-haloalkyl; R15 independently represents -H; -D; -F; -CI; -Br; -I; -CN; -N02; -
OR16; -(CH2)mOR16; -N(R16)(R17); -(CH2)mN(R16)(R17); - S02(CH2)mR16; -(CO)(CH2)raR16; -(CO)N(R16)(R17); -OCF3; a C,-C6- alkyl radical; a Ci-Ci-hydroxyalkyl radical; a C] -C6-haloalkyl radical; a C3-C6-cycloalkyl radical; a (3-6 membered)-heterocycloalkyl radical; an aryl radical; a heteroaryl radical; or the bond directly attaching the W moiety with the oxadiazoline moiety; wherein the Ci-C6-alkyl radical, the (3-6 membered)-heterocycloalkyl radical, the aryl radical, and the heteroaryl radical may be substituted with up to 4 radical substituents comprising: -D; -F; -CI; -Br; -I; -CN; -N02; -OR16; -(CH2)mOR16; -N(R, 6)(R17); -(CH2)mN(R, 6)(R17); - S02(CH2)mR16; -(CO)(CH2)mR16; -(CO)N(R16)(R17); -OCF3; a branched or unbranched CrC6-alkyI radical, a C3-C6-cycloalkyl radical, a Ci-C6-hydroxyalkyl radical, or a CrC6-haloalkyl radical;
R16 and R17 independently represent -H; a branched or unbranched Ci-C6-alkyl radical; a C3-C6-cycloalkyl radical; or the N(R,6)(R17) moiety forms a cycle, wherein R16 and R17 taken together represent a C2-C6-alkyl di- radical or a (3-6 membered)-heteroalkyl di-radical;
G', G2, G3, and G4 independently represent C(R18)(R18); C(R,9)(R20); -NH; -
N(CH2)mR18; O; S; S02; or (C=0); with the proviso that no more than two of G\ G2, G3, and G4 represent -NH; -N(CH2)mR18, O; S; S02; or (C=0);
R18 independently represents -H; -D; -F; -CI; -Br; -I; -CN; -N02; -
OR19; -(CH2)mOR19; -N(R19)(R20); -(CH2)mN(R19)(R20); - S02(CH2)mR'9; -(CO)(CH2)mR19; -(CO)N(R] )(R20); -OCF3; a C,-C6- alkyl radical; a Ci-C6-hydroxyalkyl radical, a Ci-C6-haloalkyl radical; a C3-C6-cycloalkyl radical; a (3-6 membered)-heterocycloalkyl radical; an aryl radical; or a heteroaryl radical; wherein the Ci-C6- alkyl radical, the (3-6 membered)-heterocycloalkyl radical, the aryl radical, and the heteroaryl radical may be substituted with up to 4 radical substituents comprising: -D, -F, -CI, -Br, -I, -CN, -N02j - OR19, -(CH2)mOR'9, -N(R, 9)(R20), -(CH2)mN(R,9)(R20), - S02(CH2)mR19, -(CO)(CH2)mR19, -(CO)N(R19)(R20), -OCF3, a branched or unbranched CrC6-alkyl radical, a C3-C6-cycloalkyl radical, a CrC6-hydroxyalkyl radical, or a CrC6-haloalkyl radical; and R19 and R20 independently represent -H; a branched or unbranched Ci-C6-alkyl radical; a C3-C6-cycloalkyI radical; or the N(R19)(R20) moiety forms a cycle, wherein R19 and R20 taken together represent a C2-C6-alkyl di- radical or a (3-6 membered)-heteroalkyl di-radical; or the C(R19)(R20) moiety forms a cycle, wherein R19 and R20 taken together represent a C2-C6-alkyl di-radical or a (3-6 membered)-heteroalkyl di-radical; or a pharmaceutically acceptable salt thereof.
[0031] In certain embodiments, the spiro-oxadiazoline compound represented by Formula (I), (Ila), or (lib), may comprise the W representing the moiety represented by the ring system M- I. In certain embodiments, the spiro-oxadiazoline compound represented by Formula (I), (Ila), or (lib), may comprise the W representing the moiety represented by the ring system M-I, wherein, for example, the Z1 represents N, and Z2, Z3, Z4, and Z5 each independently represent CR4; Z2 represents N, and Z Z3, Z4, and Z5 each independently represent CR4; Z3 represents N, and Z Z2, Z4, and Z5 each independently represent CR4; Z1 and Z2 each represent N, and Z3, Z4, and Z5 each independently represent CR4; Z1 and Z3 each represent N, and Z2, Z4, and Z5 each independently represent CR4; Z1 and Z4 each represent N, and Z2, Z3, and Z5 each independently represent CR4; Z1 and Z5 each represent N, and Z2, Z3, and Z4 each independently represent CR4; Z2 and Z3 each represent N, and Z1, Z4, and Z5 each independently represent CR4; or Z2 and Z4 each represent N, and Z', Z3, and Z5 each independently represent CR4.
[0032] In certain embodiments, the spiro-oxadiazoline compound represented by Formula (I), (Ila), or (lib), may comprise the W representing the moiety represented by the ring system M- I, wherein at least one
Figure imgf000016_0001
Z2, Z3, Z4, and Z5, represent CR4 with said R4 representing - D; -F; -CI; -Br; -I; -CN; -N02; -OR5; -(CH2)mOR5; -N(R5)(R6); -(CH2)mN(R5)(R6); - S02(CH2)mR5; -(CO)(CH2)mR5; -(CO)N(R5)(R6); -OCF3; a C,-C6-alkyl radical; a C,-C6- hydroxyalkyl radical, a C]-C6-haloalkyl radical; a C3-C6-cycloalkyl radical; or a (3-6 membered)- heterocycloalkyl radical; wherein the CrQ-alkyl radical and the (3-6 membered)- heterocycloalkyl radical, may be substituted with up to 4 radical substituents comprising: -D, -F, -CI, -Br, -I, -CN, -N02, -OR5, -(CH2)mOR5, -N(R5)(R6), -(CH2)mN(R5)(R6), -S02(CH2)mR5, - (CO)(CH2)mR5, -(CO)N(R5)(R6), -OCF3, a branched or unbranched C,-C6-alkyl radical, a C3-C6- cycloalkyl radical, a Ci-C6-hydroxyalkyl radical, or a Ci-C6-haloalkyl radical.
[0033] In certain embodiments, the spiro-oxadiazoline compound represented by Formula (I), (Ila), or (lib), may comprise the W representing the moiety represented by the ring system M- I, wherein at least one or two of Z Z2, Z3, Z4, and Z5, represent CR4 with said R4 representing -F; -CI; -Br; -I; or -CN.
[0034] In certain embodiments, the spiro-oxadiazoline compound represented by Formula (I), (Ila), or (lib), may comprise the W representing the moiety represented by the ring system M- I, wherein at least one or two of Z1, Z2, Z3, Z4, and Z5, represent CR4 with said R4 representing an aryl radical or a heteroaryl radical; wherein the aryl radical and the heteroaryl radical may be substituted with up to 4 radical substituents comprising: -D, -F, -CI, -Br, -I, -CN, -N02i -OR5, -(CH2)mOR5, -N(R5)(R6), -(CH2)mN(R5)(R6), -S02(CH2)mR5, -(CO)(CH2)mR5, -(CO)N(R5)(R6), -OCF3) a branched or unbranched Ci-C6-alkyl radical, a C3-C6-cycloalkyl radical, a Cj-C6- hydroxyalkyl radical, or a Ci-C6-haloalkyl radical.
[0035] For example, in certain embodiments, the spiro-oxadiazoline compound represented by Formula (I), (Ila), or (lib), may comprise the W representing the moiety represented by the ring system M-I, wherein Z1 and Z5 represent CR4, and Z2, Z3, and Z4, represent CR4 or N with the proviso that no more than two of Z2, Z3, and Z4, represent N, with said R4 representing -D; -F; - CI; -Br; -I; -CN; -N02; -OR5; -(CH2)mOR5; -N(R5)(R6); -(CH2)mN(R5)(R6); -S02(CH2)mR5; - (CO)(CH2)mR5; -<CO)N(R5)(R6); -OCF3; a C,-C6-alkyl radical; a C,-C6-hydroxyalkyl radical, a C] -C6-haloalkyl radical; a C3-C6-cycloalkyl radical; or a (3-6 membered)-heterocycloalkyl radical; wherein the Ci-C6-alkyl radical and the (3-6 membered)-heterocycloalkyl radical, may be substituted with up to 4 radical substituents comprising: -D, -F, -CI, -Br, -I, -CN, -N02_ -OR5, -(CH2)mOR5, -N(R5)(R6), -(CH2)mN(R5)(R6), -S02(CH2)mR5, -(CO)(CH2)mR5, -(CO)N(R5)(R6), -OCF3, a branched or unbranched C]-C6-alkyl radical, a C3-C6-cycloalkyl radical, a CrC6- hydroxyalkyl radical, or a Ci-C6-haloalkyl radical.
[0036] In certain embodiments, the spiro-oxadiazoline compound represented by Formula (I), (Ila), or (lib), may comprise the W representing the moiety represented by the ring system M- I, wherein Z1 and Z5 represent CR4, and Z2, Z3, and Z4, represent CR4 or N with the proviso that no more than two of Z2, Z3, and Z4, represent N, with said R4 representing -F; -CI; -Br; -I; or - CN.
[0037] In certain embodiments, the spiro-oxadiazoline compound represented by Formula (I), (Ila), or (lib), may comprise the W representing the moiety represented by the ring system M-
I, wherein Z1 and Z5 represent CR4, and Z2, Z3, and Z4, represent CR4 or N with the proviso that no more than two of Z2, Z3, and Z4, represent N, with said R4 representing an aryl radical or a heteroaryl radical; wherein the aryl radical and the heteroaryl radical may be substituted with up to 4 radical substituents comprising: -D, -F, -CI, -Br, -I, -CN, -N02, -OR5, -(CH2)mOR5, - N(R5)(R6), -(CH2)mN(R5)(R6), -S02(CH2)mR5, -(CO)(CH2)mR5, -(CO)N(R5)(R6), -OCF3, a branched or unbranched CrC6-alkyl radical, a C3-C6-cycloalkyl radical, a Ci-C6-hydroxyalkyl radical, or a Ci-C6-haloalkyl radical.
[0038] In certain embodiments, the spiro-oxadiazoline compound represented by Formula (I), (Ila), or (lib), may comprise the W representing the moiety represented by the ring system M-
II. In certain embodiments, the spiro-oxadiazoline compound represented by Formula (I), (Ila), or (lib), may comprise the W representing the moiety represented by the ring system M-II, wherein X1 represents C. For example, the spiro-oxadiazoline compound represented by Formula (I), (Ila), or (lib), may comprise the W representing the moiety represented by the ring system M-II, wherein M-II represents a moiety represented by one of the following:
Figure imgf000018_0001
wherein A1 and A2 independently represent N or CRn, and A3 independently represents NR10, O, or S. In certain embodiments, the spiro-oxadiazoline compound represented by Formula (I), (Ila), or (lib), may comprise the W representing the moiety represented by the ring system M-II, wherein either Z6 or Z7 represents CR7 with said R7 representing the bond directly attaching the W moiety with the oxadiazoline moiety, or wherein either Z8 or Z9 represents CR7 with said R7 representing the bond directly attaching the W moiety with the oxadiazoline moiety.
[0039] For example, in certain embodiments, the spiro-oxadiazoline compound represented by Formula (I), (Ha), or (lib), may comprise the W representing the moiety represented by the ring system M-II with X1 representing C, wherein M-II represents a moiety represented by:
Figure imgf000018_0002
wherein A1 and A2 independently represent N or CR11, A3 independently represents NR10, O, or S, and Z , Z , Z , and Z represent CR , with one of said R of Z , Z , Z , and Z representing the bond directly attaching the W moiety with the oxadiazoline moiety.
[0040] In certain embodiments, for example, the spiro-oxadiazoline compound represented by Formula (I), (Ila), or (lib), may comprise the W representing the moiety represented by the ring system M-II with X1 representing C, said R7 of Z7 or Z8 represents the bond directly attaching the W moiety with the oxadiazoline moiety.
Figure imgf000018_0003
wherein A1 and A2 independently represent N or CR1 1, preferably CR1 1, A3 independently represents NR10, O, or S, preferably O or S, and Z6, Z7, Z8, and Z9 represent CR7, wherein Ru preferably independently represents -H;-F; -CI; -Br; -I; -CN; -OR12; -(CH2)mOR12; -OCF3; a Ci-C6-alkyl radical; a Ci-Q-haloalkyl radical, preferably -CF3; or a C3-C6-cycloalkyl radical, and R11 more preferably independently represents -H;-F; -CI; -Br; -I; -CN; -OCF3; a C]-C6-alkyl radical; or -CF3.
[0041] In certain embodiments, the spiro-oxadiazoline compound represented by Formula (I), (Ila), or (lib), may comprise the W representing the moiety represented by the ring system M- II, wherein X1 represents N. In certain embodiments, the spiro-oxadiazoline compound represented by Formula (I), (Ila), or (lib), may comprise the W representing the moiety represented by the ring system M-II, wherein M-II represents a moiety represented by one of the following:
Figure imgf000019_0001
wherein A1, A2, and A3, independently represent N or CRn . In certain embodiments, the spiro- oxadiazoline compound represented by Formula (I), (Ila), or (lib), may comprise the W representing the moiety represented by the ring system M-II, wherein, for example, A1 independently represents CR11, and A2 and A3 independently represents N or CR1 1 ; A2 independently represents CR11, and A1 and A3 independently represents N or CR1 1 ; A3 independently represents CR10, and A1 and A2 independently represents N or CR1 ' ; or each of A1, A2, and A3, represents N. In certain embodiments, the spiro-oxadiazoline compound represented by Formula (I), (Ila), or (lib), may comprise the W representing the moiety represented by the ring system M-II, wherein either Z6 or Z7 represents CR7 with said R7 representing the bond directly attaching the W moiety with the oxadiazoline moiety, or wherein either Z8 or Z9 represents CR7 with said R7 representing the bond directly attaching the W moiety with the oxadiazoline moiety.
[0042] For example, in certain embodiments, the spiro-oxadiazoline compound represented by Formula (I), (Ila), or (lib), may comprise the W representing the moiety represented by the ring system M-II with X1 representing N, wherein M-II represents a moiety represented by:
Figure imgf000019_0002
wherein A1, A2, and A3, independently represent N or CR1 1, and Z6, Z7, Z8, and Z9 represent CR7, with one of said R7 of Z6, Z7, Z8, and Z9 representing the bond directly attaching the W moiety with the oxadiazoline moiety. For example, in certain embodiments, A1 independently represents CR1 1, and A2 and A3 independently represents N or CR1 1; A2 independently represents CR1 1, and A1 and A3 independently represents N or CR1 1; A3 independently represents CR10, and A1 and A2 independently represents N or CR11; or each of A1, A2, and A3, represents N. In certain embodiments, said R7 of Z6 or Z9 represents the bond directly attaching the W moiety with the oxadiazoline moiety. In certain embodiments, said R7 of Z7 or Z8 represents the bond directly attaching the W moiety with the oxadiazoline moiety.
[0043] In certain embodiments, the spiro-oxadiazoline compound represented by Formula (I), (Ila), or (lib), may comprise the W representing the moiety represented by the ring system M- III. In certain embodiments, the spiro-oxadiazoline compound represented by Formula (I), (Ila), or (lib), may comprise the W representing the moiety represented by the ring system M-III, wherein M-III represents a moiety represented by one of the following ring systems:
Figure imgf000020_0001
[0044] In certain embodiments, the spiro-oxadiazoline compound represented by Formula (I), (Ila), or (lib), may comprise the W representing the moiety represented by the ring system M- III, wh
Figure imgf000020_0002
[0045] In certain embodiments, the spiro-oxadiazoline compound represented by Formula (I), (Ila), or (lib), may comprise the W representing the moiety represented by the ring system M- III, wh
Figure imgf000020_0003
[0046] For example, in certain embodiments, the spiro-oxadiazoline compound represented by Formula (I), (Ila), or (lib), may comprise the W representing the moiety represented by the ring system M- owing:
Figure imgf000021_0001
[0047] In certain embodiments, the spiro-oxadiazoline compound represented by Formula (I), (Ila), or (lib), may comprise the W representing the moiety represented by the ring system M- IV.
[0048] In certain embodiments, the spiro-oxadiazoline compound represented by Formula (I), (Ila), or (lib), may comprise the W representing the moiety represented by the ring system M- rV, wherein X2 represents C. For example, the spiro-oxadiazoline compound represented by Formula (I), (Ila), or (lib), comprising W representing the moiety represented by the ring system M-IV, may comprise a moiety represented by one of the following:
Figure imgf000021_0002
wherein A7 represents NR.14; O; or S, preferably A7 represents S; and A5 represents N or CR15, preferably A5 represents CR15, wherein R15 preferably represents -H.
[0049] In certain embodiments, for example, the spiro-oxadiazoline compound represented by Formula (I), (Ila), or (lib), comprising W representing the moiety represented by the ring system M-IV, may comprise a moiety represented by one of the following:
Figure imgf000021_0003
wherein A5 represents NR14; O; or S.
[0050] For example, in certain embodiments, the spiro-oxadiazoline compound represented by Formula (I), (Ila), or (lib), may comprise the W representing the moiety represented by the ring system M-IV, wherein X2 represents C, and may comprise a moiety represented by one of the following:
Figure imgf000022_0001
wherein A5 represents CR15; and A7 represents S.
[0051] In certain embodiments, for example, the spiro-oxadiazoline compound represented by Formula (I), (lla), or (lib), may comprise the W representing the moiety represented by the ring system M-IV, wherein X2 represents C, and may comprise a moiety represented by one of the following:
Figure imgf000022_0002
wherein A5 represents NR.14, O, or S, preferably S; A6 represents CR15; and Z4 represents CR4.
[0052] In certain embodiments, the spiro-oxadiazoline compound represented by Formula (I), (Ha), or (lib), may comprise the W representing the moiety represented by the ring system M- rv, wherein X2 represents N.
[0053] In certain embodiments, for example, the spiro-oxadiazoline compound represented by Formula (I), (Ha), or (lib), comprising W representing the moiety represented by the ring system M-IV, may comprise a moiety represented by one of the following:
Figure imgf000022_0003
[0054] For example, in certain embodiments, the spiro-oxadiazoline compound represented by Formula (I), (lla), or (lib), may comprise the W representing the moiety represented by the ring system M-IV, wherein X2 represents N, and may comprise a moiety represented by one of the following:
Figure imgf000022_0004
wherein A5 represents N or CR15; A6 represents CR15; and Z4 represents CR4.
[0055] In certain embodiments, the spiro-oxadiazoline compound represented by Formula (I), (Ila), or (lib), may comprise the W representing the moiety represented by the ring system M-
Figure imgf000023_0001
wherein A5 and A7 represents CR15.
[0056] In certain embodiments, the spiro-oxadiazoline compound represented by Formula (I), (Ila), or (lib), may comprise the W representing the moiety represented by the ring system M- rV, wherein 2 represents N, and may comprise a moiety represented by one of the following:
Figure imgf000023_0002
wherein A6 represents CR15; and Z' represents CR4.
[0057] In certain embodiments, the spiro-oxadiazoline compound represented by Formula (I), (Ila), or (lib), may comprise the W representing the moiety represented by the ring system M- V.
[0058] In certain embodiments, for example, the spiro-oxadiazoline compound represented by Formula (I), (Ila), or (lib), comprising W representing the moiety represented by the ring system M-V, may comprise a moiety represented by one of the following:
Figure imgf000023_0003
[0059] For example, in certain embodiments, the spiro-oxadiazoline compound represented by Formula (I), (Ila), or (lib), comprising W representing the moiety represented by the ring system M-V, may comprise a moiety represented by one of the following:
Figure imgf000024_0001
wherein Z6, Z7, Z8, and Z9 represent CR7, with one of said R7 of Z6, Z7, Z8, and Z9 representing the bond directly attaching the W moiety with the oxadiazoline moiety.
[0060] In certain embodiments, the spiro-oxadiazoline compound represented by Formula (I), (Ha), or (lib), comprising W representing the moiety represented by the ring system M-V, wherein said R7 of Z7 represents the bond directly attaching the W moiety with the oxadiazoline moiety, and may comprise a moiety represented by one of the following:
Figure imgf000024_0002
[0061] In certain embodiments, the spiro-oxadiazoline compound represented by Formula (I), (Ha), or (lib), comprising W representing the moiety represented by the ring system M-V, wherein said R7 of Z8 represents the bond directly attaching the W moiety with the oxadiazoline moi
Figure imgf000024_0003
[0062] In certain embodiments, the spiro-oxadiazoline compound represented by Formula (I), (Ha), or (lib), may comprise the W representing the moiety represented by the ring system M- VI. [0063] In certain embodiments, for example, the spiro-oxadiazoline compound represented by Formula (I), (Ila), or (lib), comprising W representing the moiety represented by the ring system M-VI, may comprise a moiety represented by one of the following:
Figure imgf000025_0001
[0064] For example, in certain embodiments, the spiro-oxadiazoline compound represented by Formula (I), (Ila), or (lib), comprising W representing the moiety represented by the ring system M-VI, wherein Z6, Z7, Z8, and Z9 represent CR7, with one of said R7 of Z6, Z7, Z8, and Z9 representing the bond directly attaching the W moiety with the oxadiazoline moiety.
[0065] In certain embodiments, the spiro-oxadiazoline compound represented by Formula (I), (Ila), or (lib), comprising W representing the moiety represented by the ring system M-VI, wherein said R7 of Z7 represents the bond directly attaching the W moiety with the oxadiazoline moiety, and may comprise a moiety represented by one of the following:
Figure imgf000025_0002
[0066] In certain embodiments, the spiro-oxadiazoline compound represented by Formula (I), (Ila), or (lib), comprising W representing the moiety represented by the ring system M-VI, wherein said R7 of Z8 represents the bond directly attaching the W moiety with the oxadiazoline moiety, and may comprise a moiety represented by one of the following:
Figure imgf000025_0003
[0067] In certain embodiments, for example, the spiro-oxadiazoline compound represented by Formula (I), (Ila), or (lib), may comprise the W representing a moiety represented by any one of ring systems M-IIa, M-IIb, or M-IVa:
Figure imgf000025_0004
wherein A1 and A2 independently represent N or CR11, preferably CR1 1, A3 independently represents NR10, O, or S, preferably O or S, and Z6, Z7, Z8, and Z9 represent CR7, wherein R1 1 preferably independently represents -H; -F; -CI; -Br; -I; -CN; -OR12; -(CH2)mOR12; -OCF3; a CrC6-alkyl radical; a C]-C6-haloalkyl radical, preferably -CF3; or a C3-C6-cycloalkyl radical, and Rn more preferably independently represents -H;-F; -CI; -Br; -I; -CN; -OCF3; a C]-C6-alkyl radical; or -CF3;
wherein A5 represents N or CR15, preferably A5 represents CR15, wherein R15 preferably represents -H; and A7 represents NR14; O; or S, preferably A7 represents S; and
wherein Z1, Z2, Z3, and Z4 independently represent N or CR4; with the proviso that no more than two of Z1, Z2, Z3, and Z4 are N; preferably wherein Z Z2, Z3, and Z4 independently represent CR4; and preferably wherein R4 independently represents -H; -D; -F; -CI; -Br; -I; -CN; -N02;- OCF3; a CrC6-alkyl radical; a C C6-haloalkyl radical; or a C3-C6-cycloalkyl radical.
[0068] In certain embodiments, the spiro-oxadiazoline compound represented may be represented by Formula (I):
Formula (I)
Figure imgf000026_0001
[0069] In certain embodiments, the spiro-oxadiazoline compound represented may be represented by Formula (Ila):
Formula (Ila)
Figure imgf000026_0002
[0070] In certain embodiments, the spiro-oxadiazoline compound represented may be represented by Formula (lib): Formula (lib)
Figure imgf000026_0003
[0071] In certain embodiments, the spiro-oxadiazoline compound represented by Formula (I), (Ila), or (lib), may comprise R1 representing -H, and n is 0-3.
[0072] In certain embodiments, the spiro-oxadiazoline compound represented by Formula (I), (Ila), or (lib), may comprise R1 representing a (3-6 membered)-heterocycloalkyl radical; an aryl radical; or a heteroaryl radical; and wherein n is 0-3.
[0073] In certain embodiments, the spiro-oxadiazoline compound represented by Formula (I), (Ila), or (lib), may comprise racemic mixture of enantiomers, a mixture of diastereomers, a mixture of geometric isomes, a single enantiomer, a single diastereomer, or a single geometric isomer of the compound, or a pharmaceutically acceptable salt thereof. In certain embodiments, the spiro-oxadiazoline compound represented by Formula (I), (Ila), or (lib), may comprise a mixture of tautomers, substantially a single tautomer form, or a single tautomer form, such as a tautomer contained within R1 or contained within W, for example, a tautomer may be contained within a W containing a heteroaryl ring nitrogen adjacent to a heteroaryl ring carbon substituted with a hydroxyl group.
[0074] In certain embodiments, specific examples of the spiro-oxadiazoline compound represented by Formula (I), (Ila), or (lib), according to the present invention, may include, collectively or individually, those listed below, and pharmaceutically acceptable salts thereof:
(+/-)-3-phenyl-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane];
(+/-)-3-(4-chlorophenyl)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane];
(+/-)-3-(benzo[b]thiophen-2-yl)-4H-l'-azaspiro[[l,2,4]oxadiazol-5,3'- bicyclo[2.2.2]octane];
(+/-)-3-(benzofuran-2-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane];
(+/-)-3-(l H-indol-2-yl)-4H- l '-azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane];
(+/-)-3-(7-fluorobenzo[b]thiophen-2-yl)-4H- -azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(+/-)-3-(7-chlorobenzo[b]thiophen-2-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(+/-)-3-(7-bromobenzo[b]thiophen-2-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(+/-)-3-(7-fluorobenzofuran-2-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(+/-)-3-(benzo[b]thiophen-5-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(+/-)-3-(2-methyl-l,2,3,4-tetrahydroisoquinolin-6-yl)-4H-l '-aza-spiro[[l ,2,4]oxadiazole- 5 ,3 '-bicyclo[2.2.2]octane] ;
(+/-)-3 -(5 -fluorobenzo [b]thiophen-2-yl)-4H- 1 '-azaspiro [[ 1 ,2,4] oxadiazole-5 ,3 '- bicyclo[2.2.2]octane];
(+/-)-3-(benzo[b]thiazol-2-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(+/-)-3 -(benzo [b]thiophen-3 -yl)-4H- 1 '-azaspiro[[ 1 ,2,4]oxadiazole-5 ,3 '- bicyclo[2.2.2]octane];
(+/-)-3 l -methyl-l ,2,3,4 etrahydroquinolin-6-yl)-4H-l'-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(+/-)-3-(4-chlorophenyl)-4-phenyl-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane]; (+/-)-3-(benzo[b]thiophen-2-yl)-4-phenyl-4H-l '-azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(+/-)-4-benzyl-3 -(4-chlorophenyl)-4H- 1 '-azaspiro[[ 1 ,2,4]oxadiazole-5,3 '- bicyclo[2.2.2]octane];
(+/-)-3-(benzo[b]thiophen-2-yl)-4-benzyl-4H-l'-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(+/-)-3-(benzo[b]thiophen-2-yl)-4-isopropyl-4H-l'-azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(+/-)-3-(benzo[b]thiophen-2-yl)-4-isobutyl-4H-l'-azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(+/-)-3-(benzo[b]thiophen-2-yl)-4-((tetrahydro-2H-pyran-4-yl)methyl)-4H-l '- azaspiro[[l,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane];
(+/-)-3-(benzo[b]thiophen-2-yl)-4-(pyridin-3-ylmethyI)-4H-l'-azaspiro[[l ,2,4]oxadiazole- 5,3'-bicyclo[2.2.2]octane];
(+/-)-3-(benzo[b]thiophen-2-yl)-4-ethyl-4H-l'-azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(+/-)-3-(benzo[b]thiophen-2-yl)-4-(2,2>2-trifluoroethyl)-4H-l'-azaspiro[[l ,2,4]oxadiazole- 5,3'-bicyclo[2.2.2]octane];
(+/-)-3-(4-chlorophenyl)-4-methyl-4H-l'-azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(+/-)-3-(benzo[b]thiophen-2-yl)-4-methyl-4H-r-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(+/-)-3 -(benzofuran-2-y l)-4-methy 1-4H- 1 '-azaspiro[ [ 1 ,2,4]oxadiazole-5 ,3 '- bicyclo[2.2.2]octane];
(+/-)-3-(7-chlorobenzo[b]thiophen-2-yl)-4-methyl-4H- -azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane] ;
(+/-)-3-(lH-indoI-2-yl)-4-methyl-4H-l '-azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(+/-)-3-(7-fluorobenzofuran-2-yl)-4-methyl-4H-l '-azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(+/-)-3-(7-fluorobenzo[b]thiophen-2-y])-4-methyl-4H-l '-azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(+/-)-3 -(benzo[b]thiazol-2-yl)-4-methy 1-4H- 1 '-azaspiro [[ 1 ,2,4] oxadiazole-5 ,3 '- bicyclo[2.2.2]octane];
(+/-)-3-(6-methoxybenzo[b]thiazol-2-yl)-4-methyl-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane]; (+/-)-3 -(5 -fluorobenzo [b]thiophen-2-y l)-4-methy 1-4H- 1 '-azaspiro [[ 1 ,2,4]oxadiazole-5 ,3 '- bicyclo[2.2.2]octane];
(+/-)-2-(4-methyl-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3,-bicyclo[2.2.2]octan]-3- yl)benzo[b]thiophene-7-carbonitrile;
(+/-)-3-(7-bromobenzo[b]thiophen-2-yl)-4-methyl-4H- -azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(+/-)-3-(benzo[b]thiophen-5-yl)-4-methyl-4H-l'-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(+/-)-3-(isoquinolin-3-yl)-4-methyl-4H- -azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(+/-)-4-methyl-3-(l -methyl-l ,2,3,4-tetrahydroquinolin-6-yl)-4H-r- azaspiro[[l,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane];
(+/-)-4-methyl-3-(2-methyl-l ,2,3,4-tetrahydroisoquinolin-6-yl)-4H-l'- azaspiro[[l,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane];
(+/-)-2-(4H-l'-azaspiro[[l,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octan]-3- yl)benzo[b]thiophene-7-carbonitrile;
(+/-)-3-(isoquinolin-3-yl)-4H-r-azaspiro[[l,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane];
(+/-)-3-(5-phenyl-l,3,4-oxadiazol-2-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazoIe-5,3'- bicyclo[2.2.2]octane];
(+/-)-3-(l ,2,3>4-tetrahydroquinolin-6-yl)-4H-l'-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(+/-)-3-(6-methoxybenzo[d]thiazol-2-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(+/-)-3-(5,6,7,8-tetrahydroisoquinolin-3-yl)-4H-l '-azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(+/-)-3-(thieno[2,3-b]pyridin-2-yl)-4H-l '-azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2 ,2]octane] ;
(+/-)-3-(thieno[3,2-b]pyridin-2-yl 4H-l'-azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(+/-)-3-(pyrazolo[l ,5-a]pyridin-2-yl)-4H- -azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(+/-)-3 -(6-fluorobenzo [b]thiophen-2-y 1)-4H- 1 '-azaspiro[ [ 1 ,2,4] oxadiazole-5 ,3 '- bicyclo[2.2.2]octane];
(+/-)-3-( 1 -methyl- 1 H-indol-2-yl)-4H- 1 '-azaspiro[[ 1 ,2,4]oxadiazole-5,3 '- bicyclo[2.2.2]octane];
(+/-)-3-(l -methyl-lH-benzo[d]imidazol-2-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane]; (+/-)-3-(6-fluorobenzofuran-2-yl)-4H-r-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2 ,2]octane] ;
(+/-)-3-(5-fluorobenzofuran-2-yl)-4H- -azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(+/-)-3-(4-fluorobenzofuran-2-yl)-4H- -azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(+/-)-3 -(3 -fluorobenzofuran-2-yl)-4H- 1 '-azaspiro[[ 1 ,2,4]oxadiazole-5,3 '- bicyclo[2.2.2]octane];
(+/-)-3 -(5 ,7-difluorobenzofitran-2-yl)-4H~ 1 '-azaspiro [[ 1 ,2,4]oxadiazole-5 ,3 '- bicyclo[2.2.2]octane] ;
(+/-)-3-(pyrimidin-2-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2 .2]octane];
(+/-)-3-benzyl-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane];
(+/-)-3-([l , l ,-biphenyl]-4-yl)-4H-l ,-azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane];
(+/-)-4-rnethyl-3-(5,6,7,8-tetrahydroisoquinolin-3-yl)-4H-l '-azaspiro[[l,2,4]oxadiazole- 5,3'-bicyclo[2.2.2]octane];
(+/-)-4-methyl-3-(5-phenyl-l,3,4-oxadiazol-2-yl)-4H-r-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(+/-)-4-methyl-3-(l,2,3,44etrahydroquinolin-6-yl)-4H-r-azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(+/-)-4-methyl-3-(l,2,3,4 etrahydroisoquinolin-6-yl)-4H-r-azaspiro[[l ,2,4]oxadiazole- 5,3'-bicyclo[2.2.2]octane];
(+/-)-2-(4H-l'-azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octan]-3- yl)benzo[b]thiophene-7-carbonitrile;
(+/-)-3 isoquinolin-3-yl)-4H- -azaspiro[[l,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane];
(+/-)-3-(5-phenyl-l ,3,4-oxadiazol-2-yl)-4H-l'-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(+/-)-(R)-3-(6-methoxybenzo[d]thiazol-2-yl)-4H-l '-azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(+/-)-3-(thieno[2,3-b]pyridin-2-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2] octane];
(+/-)-3<thieno[3,2-b]pyridin-2-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2 .2] octane];
(+/-)-3-(pyrazolo[l ,5-a]pyridin-2-yl)-4H- -azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(+/-)-3-(6-fluorobenzo[b]thiophen-2-yl)-4H-l'-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane]; (+/-)-3-(l -methyl- 1 H-indol-2-yl)-4H- 1 '-azaspiro[[l ,2,4]oxadiazole-5 ,3'- bicyclo[2.2.2]octane];
(+/-)-3 -( 1 -methyl- 1 H-benzo [d] imidazol-2-yl)-4H- 1 '-azaspiro[ [ 1 ,2,4]oxadiazole-5 ,3 '- bicyclo[2.2.2]octane];
(+/-)-3-(6-fluorobenzofuran-2-yl)-4H-r-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(+/-)-3-(5-fluorobenzofuran-2-yl)-4H- -azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(+/-)-3-(4-fluorobenzofuran-2-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(+/-)-3 -(5,7-d ifluorobenzofiiran-2-yl)-4H- 1 '-azaspiro [[ 1 ,2,4] oxad iazole-5 ,3 '- bicyclo[2.2.2]octane];
(+/-)-3-([l ,l '-biphenyl]-4-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane];
(+/-)-4-methyl-3-(l,2,3,4-tetrahydroquinolin-6-yl)-4H-r-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(+/-)-2-(4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octan]-3- yl)benzo[b]thiophene-7-carboxamide;
(+/-)-3-(quinolin-3-yl)-4H-l'-azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane];
(+/-)-3-(benzofuran-5-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane];
(+/-)-3-(l H-indol-5-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane];
(+/-)-3-(benzo[d]thiazol-6-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazo!e-5,3'- bicyclo[2.2.2]octane];
(+/-)-3-(quinolin-6-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane];
(+/-)-3-(benzo[d]thiazol-5-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(+/-)-3-(benzofuran-6-yl)-4H- -azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane];
(+/-)-3-(benzo[b]thiophen-6-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(+/-)-3-(4-fluorophenyl)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane];
(+/-)-3-(3,4-dichlorophenyl)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane];
(+/-)-3-(3-chlorobenzo[b]thiophen-2-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(+/-)-3-(4-(4-fluorophenoxy)phenyl)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(+/-)-3-(l H-indol-6-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane];
(+/-)-3-(3-(trifluoromethyl)benzofuran-5-yl)-4H- -azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane]; (+/-)-3-(2-(trifluoromethyl)benzofuran-5-yl)-4H-r-azaspiro[[l ,2,4]oxadiazole-5,3'- bicycIo[2.2.2]octane];
(+/-)-3-(3-(trifluoromethyl)benzo[b]thiophen-6-yl)-4H-r-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(+/-)-3 -(3 -fluorobenzofuran-5-y 1)-4H- 1 '-azaspiro[[ 1 ,2,4] oxadiazole-5 ,3 '- bicyclo[2.2.2]octane];
(+/-)-3-(pyrimidin-5-yI)-4H-l '-azaspiro[[l,2,4]oxadiazoIe-5,3'-bicyclo[2.2.2]octane];
(+/-)-3-(2-fluorobenzofuran-5-yl)-4H- -azaspiro[[l ,2,4]oxadiazole-5!3'- bicyclo[2.2.2]octane];
(+/-)-3-(2-(trifluoromethyl)benzo[b]thiophen-6-yl)-4H-l'-azaspiro[[l,2,4]oxadiazoIe-5,3'- bicyclo[2.2.2]octane];
(+/-)-3-(2-fluorobenzo[b]thiophen-6-yl)-4H- -azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(+/-)-3-(3-fluorobenzo[b]thiophen-6-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazoIe-5,3'- bicyclo[2.2.2]octane];
(+/-)-3-(thieno[3,2-b]pyridin-6-yl)-4H-l '-azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(+/-)-3-(pyrazolo[l ,5-a]pyridin-5-yl)-4H-r-azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(+/-)-3-(furo[2,3-b]pyridin-5-yl)-4H-l '-azaspiro[[l,2,4]oxadiazole-5,3'- bicyc lo [2.2.2] octane] ;
(+/-)-3-(3,4-dihydro-2H-benzo[b][l ,4]oxazin-5-yl)-4H-l '-azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(+/ -7 4H '-azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octan]-3-yl)indolin-2-one;
(+/-)-3-(imidazo[l ,2-a]pyridin-6-yl)-4H-l'-azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(+/-)-3-(pyrrolo[l,2-b]pyridazin-6-yl)-4H-l '-azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(+/-)-3-(3-methylbenzofuran-5-yI)-4H-l'-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(+/-)-3-(3-methylbenzo[b]thiophen-5-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazoIe-5,3'- bicyclo[2.2.2]octane];
(+/-)-3-(3-methylbenzofuran-6-yl)-4H-l '-azaspiro[[l,2,4]oxadiazole-5,3'-bicyclo[2.2.2] octane];
(+/-)-3-(3-methylbenzo[b]thiophen-6-yl)-4H-l'-azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane]; (+/-)-3-(5,6,7,8-tetrahydroisoquinolin-3-yl)-4H-l'-azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(+/-)-4-methyl-3-(2-methyl-l ,2,3,4-tetrahydroisoquinolin-6-yl)-4H-l'- azaspiro[[ 1 ,2,4]oxadiazole-5 ,3 '-bicyclo[2.2.2]octane] ;
(+/-)-3-(quinolin-7-yl)-4H-l'-azaspiro[[l,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane];
(+/-)-3-(l-methyl-lH-indol-6-yl)-4H-l '-azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane;
(+/-)-3-(imidazo[l ,5-a]pyridin-7-yl)-4H- -azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(+/-)-3 -(3 ,4-dihydro-2H-benzo[b] [ 1 ,4] oxazin-5 -y l)-4-methy 1-4H- 1 '- azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane];
(+/-)-3-(pyrrolo[l ,2-a]pyrirnidin-7-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(R)-3-phenyl-4H-r-azaspiro[[l,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane];
(S)-3-phenyl-4H-r-azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane];
(R)-3-(4-chlorophenyl)-4H-l '-azaspiro[[l,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane];
(S)-3-(4-chlorophenyl)-4H- l '-azaspiro[[l,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane];
(R)-3-(benzo[b]thiophen-2-yl)-4H-l'-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(S)-3-(benzo[b]thiophen-2-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(R)-3-(benzofuran-2-yl)-4H- -azaspiro[[l,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane];
(S)-3 -(benzofuran-2-yl)-4H- 1 '-azaspiro[[ 1 ,2,4]oxadiazole-5 ,3 '-bicyclo [2.2.2]octane] ;
(R)-3-(lH-indol-2-yl)-4H-l'-azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane];
(S)-3-(lH-indol-2-yl)-4H-l'-azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane];
(R)-3-(7-fluorobenzo[b]thiophen-2-yl)-4H-l'-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(S)-3-(7-fluorobenzo[b]thiophen-2-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(R)-3-(7-chlorobenzo[b]thiophen-2-yl)-4H-l'-azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(S)-3-(7-chlorobenzo[b]thiophen-2-yl)-4H-r-azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(R)-3-(7-bromobenzo[b]thiophen-2-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'- bicycIo[2.2.2]octane];
(S)-3-(7-bromobenzo[b]thiophen-2-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane]; (R)-3-(7-fluorobenzofuran-2-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo [2.2.2] octane] ;
(S)-3-(7-fluorobenzofuran-2-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(R)-3-(benzo[b]thiophen-5-yl)-4H-l '-azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(S)-3-(benzo[b]thiophen-5-yl)-4H-r-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(R)-3 -(2-methyl- 1 ,2,3 ,4-tetrahydroisoquinolin-6-yl)-4H- 1 '-azaspiro[[ 1 ,2,4] oxadiazole- 5,3'-bicyclo[2.2.2]octane];
(S)-3-(2-methyl-l ,2,3,4-tetrahydroisoquinolin-6-yl)-4H- -azaspiro[[l ,2,4]oxadiazole- 5,3'-bicyclo[2.2.2]octane];
(lr,3R,^,5S,7s)-3'-(4-chlorophenyl)-4'H-l-azaspiro[adamantane-4,5'-[l ,2,4]oxadiazole];
(lr,3R,^r,5S,75)-3'-(4-chlorophenyl)-4'H-l-azaspiro[adamantane-4,5'-[l ,2,4]oxadiazole];
(l r,3R,45,5S,75)-3'-(benzo[b]thiophen-2-yl)-4'H-l -azaspiro[adamantane-4,5'- [l ,2,4]oxadiazole];
(lr,3R,^,5S,7>s)-3'-(benzo[b]thiophen-2-yl)-4'H-l -azaspiro[adamantane-4,5'- [l ,2,4]oxadiazole];
(l ,3R,^,5S,75)-3'-(7-chlorobenzo[b]thiophen-2-yl)-4'H-l -azaspiro[adamantane-4,5'- [l ,2,4]oxadiazole];
(l r,3R, r,5S,75)-3'-(7-chlorobenzo[b]thiophen-2-yl)-4'H-l -azaspiro[adamantane-4,5'- [l ,2,4]oxadiazole];
(lr,3R,45,5S,75)-3'-(7-fluorobenzo[b]thiophen-2-yl)-4'H-l -azaspiro[adamantane-4,5'- [l,2,4]oxadiazole];
(lr,3R, r,5S,75)-3'-(7-fluorobenzo[b]thiophen-2-yl)-4'H-l -azaspiro[adamantane-4,5'- [l ,2,4]oxadiazole];
(l r,3R,45,5S,7s)-3'-(benzofuran-2-yl)-4'H-l -azaspiro[adamantane-4,5'-[l ,2,4]oxadiazole];
(lr,3R,^r,5S,75)-3'-(benzofuran-2-yl)-4'H-l -azaspiro[adamantane-4,5'-[l ,2,4]oxadiazole];
(R)-3-(5-fluorobenzo[b]thiophen-2-yl)-4H- 1 '-azaspiro[[ 1 ,2,4]oxadiazole-5 ,3 '- bicyclo[2.2.2]octane];
(S)-3-(5-fluorobenzo[b]thiophen-2-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(R)-3-(benzo[b]thiazol-2-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane]; (S)-3-(benzo[b]thiazol-2-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane.]; (R)-3-(benzo[b]thiophen-3-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane]; (S)-3-(benzo[b]thiophen-3-yl)-4H-l '-azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(R)-3-(l-methyl-l ,2,3,4-tetrahydroquinolin-6-yl)-4H-l'-azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(S)-3 -( 1 -methyl- 1 ,2,3 ,4-tetrahydroquinolin-6-yl)-4H- 1 '-azaspiro[[ 1 ,2,4]oxadiazole-5 ,3 '- bicyclo[2.2.2]octane];
(R)-3-(4-chlorophenyl)-4-phenyl-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(S)-3-(4-chlorophenyl)-4-phenyl-4H-r-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(R)-3-(benzo[b]thiophen-2-yl)-4-phenyl-4H-l '-azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(S)-3-(benzo[b]thiophen-2-yl)-4-phenyl-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2] octane] ;
(R)-4-benzyl-3-(4-chlorophenyl)-4H-l'-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(S)-4-benzyl-3-(4-chlorophenyl)-4H- -azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(R)-3-(benzo[b]thiophen-2-yl)-4-benzyl-4H-l '-azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(S)-3-(benzo[b]thiophen-2-yl)-4-benzyl-4H-r-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(R)-3-(benzo[b]thiophen-2-yl)-4-isopropyl-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(S)-3-(benzo[b]thiophen-2-yl)-4-isopropyl-4H-l'-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(R)-3-(benzo[b]thiophen-2-yl)-4-isobutyl-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2] octane] ;
(S)-3-(benzo[b]thiophen-2-yl)-4-isobutyl-4H-l'-azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(R)-3 -(benzo[b]thiophen-2-yl)-4-((tetrahydro-2H-pyran-4-yl)methyl)-4H- 1 '- azaspiro[[l,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane];
(S)-3-(benzo[b]thiophen-2-yl)-4-((tetrahydro-2H-pyran-4-yl)methyl)-4H-l '- azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane];
(R)-3-(benzo[b]thiophen-2-yl)-4-(pyridin-3-ylmethyl)-4H- -azaspiro[[l,2,4]oxadiazole- 5,3'-bicyclo[2.2.2]octane]; (S)-3-(benzo[b]thiophen-2-yl)-4-(pyridin-3-ylmethyl)-4H-l '-azaspiro[[l,2,4]oxadiazole- 5,3'-bicycIo[2.2.2]octane];
(R)-3-(benzo[b]thiophen-2-yl)-4-ethyl-4H-l'-azaspiro[[l>2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(S)-3-(benzo[b]thiophen-2-yl)-4-ethyl-4H-l'-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(R)-3-(benzo[b]thiophen-2-yl)-4-(2,2,2-trifluoroethyl)-4H-l'-azaspiro[[l,2,4]oxadiazole- 5,3'-bicyclo[2.2.2]octane];
(S)-3-(benzo[b]thiophen-2-yl)-4-(2,2,2-trifluoroethyl)-4H-l'-azaspiro[[l ,2,4]oxadiazole- 5,3'-bicyclo[2.2.2]octane];
(R)-3-(4-chlorophenyl)-4-methyl-4H-l '-azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane] ;
(S)-3-(4-chlorophenyl)-4-methyl-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(R)-3-(benzo[b]thiophen-2-yl)-4-methyl-4H-l'-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(S)-3-(benzo[b]thiophen-2-yl)-4-methyl-4H-r-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(R)-3-(benzofuran-2-yl)-4-methyl-4H-r-azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(S)-3-(benzofuran-2-yl)-4-methyl-4H-l'-azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(R)-3-(7-chlorobenzo[b]thiophen-2-yl)-4-methyl-4H-l'-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(S)-3-(7-chlorobenzo[b]thiophen-2-yl)-4-methyl-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(R)-3-( 1 H-indol-2-yl)-4-methyl-4H- 1 '-azaspiro[[ 1 ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(S)-3-(l H-indol-2-yl)-4-methyl-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(R)-3-(7-fluorobenzofuran-2-yl)-4-methyl-4H- -azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(S)-3-(7-fluorobenzofuran-2-yl)-4-methyl-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(R)-3-(7-fluorobenzo[b]thiophen-2-yl)-4-methyl-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2] octane] ; (S)-3-(7-fluorobenzo[b]thiophen-2-yl)-4-methyl-4H-r-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(R)-3-(benzo[b]thiazol-2-yl)-4-methyl-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(S)-3-(benzo[b]thiazol-2-yl)-4-methyl-4H-l'-azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(R)-3-(6-methoxybenzo[b]thiazol-2-yl)-4-methyl-4H- -azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(S)-3-(6-methoxybenzo[b]thiazol-2-yl)-4-methyl-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane] ;
(R)-3-(5-fluorobenzo[b]thiophen-2-yl)-4-methyl-4H-r-azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(S)-3-(5-fluorobenzo[b]thiophen-2-yl)-4-methyl-4H- -azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(R)-2-(4-methyl-4H-l'-azaspiro[[l,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octan]-3- y l)benzo [b]thiophene-7-carbonitri le;
(S)-2-(4-methyl-4H-l'-azaspiro[[l,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octan]-3- yl)benzo[b]thiophene-7-carbonitrile;
(R)-3-(7-bromobenzo[b]thiophen-2-yl)-4-methyl-4H- -azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(S)-3-(7-bromobenzo[b]thiophen-2-yl)-4-methyl-4H-r-azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(R)-3-(benzo[b]thiophen-5-yl)-4-methyl-4H-l'-azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(S)-3-(benzo[b]thiophen-5-yl)-4-methyl-4H-r-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(R)-3-(isoquinolin-3-yl)-4-methyl-4H-r-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(S)-3-(isoquinolin-3-yl)-4-methyl-4H-l'-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(R)-4-methy l-3-( 1 -methyl- 1 ,2,3 ,4-tetrahydroquinolin-6-yl)-4H- 1 '- azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane];
(S)-4-methyl-3-(l-methyl-l ,2,354-tetrahydroquinolin-6-yl)-4H-l'- azaspiro[[l,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane];
(R)-4-methyl-3-(2-methyl- 1 ,2,3,4-tetrahydroisoquinolin-6-yl)-4H-l '- azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane]; (S)-4-methyl-3 -(2-methy 1- 1 ,2,3 ,4-tetrahydroisoquinolin-6-yl)-4H- 1 '- azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane];
( 1 r,3R,4s,5 S, Zs)-3 '-(4-chlorophenyl)-4'-methyl-4'H- 1 -azaspiro[adamantane-4,5'- [l ,2,4]oxadiazole];
(l r,3R,4r,5S,7s)-3'-(4-chlorophenyl)-4'-methyl-4'H-l -azaspiro[adamantane-4,5'- [l ,2,4]oxadiazole];
(l ,3R, 5,5S,75')-3,-(benzo[b]thiophen-2-yl)-4'-methyl-4'H-l -azaspiro[adamantane-4,5'- [ l ,2,4]oxadiazole];
(l ^R^ .SS^^' benzo^thiophen^-ylH'-methyl^'H-l -azaspiroCadamantane^^'- [l ,2,4]oxadiazole];
(lr,3R,^,5S,75)-3'-(benzofuran-2-yl)-4'-methyl-4'H-l -azaspiro[adamantane-4,5'- [l ,2,4]oxadiazole];
(lr,3R, r,5S,7i)-3'-(benzofuran-2-yl)-4'-methyl-4'H-l -azaspiro[adamantane-4,5'- [l ,2,4]oxadiazole];
( 1 r,3 R,4s,5 S, 7s)-3 '-(7-chlorobenzo [b]thiophen-2-yl)-4'-methyl-4'H- 1 - azaspiro[adamantane-4,5 '- [ 1 ,2,4] oxadiazole] ;
(lr,3R,^r,5S,7_;)-3'-(7-chlorobenzo[b]thiophen-2-yl)-4'-methyl-4'H-l - azaspiro[adamantane-4,5'-[l ,2,4]oxadiazole];
(R)-2-(4H- -azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octan]-3- yl)benzo[b]thiophene-7-carbonitrile;(S)-2-(4H- -azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2] octan] -3 -yl)benzo [b]thiophene-7-carbonitrile;
(R)-3-(isoquinolin-3-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane];
(S)-3-(isoquinolin-3-yl)-4H-l'-azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane];
(R)-3-(5-phenyl-l ,3,4-oxadiazol-2-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(S)-3-(5-phenyl-l ,3,4-oxadiazol-2-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(R)-3-(l,2,3,4-tetrahydroquinolin-6-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(S)-3-( 1 ,2,3 ,4-tetrahydroquinolin-6-yl)-4H- 1 '-azaspiro[[ 1 ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(R)-3-(6-methoxybenzo[d]thiazol-2-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(S)-3-(6-methoxybenzo[d]thiazol-2-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(R)-3-(5,6,7,8-tetrahydroisoquinolin-3-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane]; (S)-3-(5,6,7,8-tetrahydroisoquinolin-3-yl)-4H-l '-azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(R)-3-(thieno[2,3-b]pyridin-2-yl)-4H- -azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(S)-3-(thieno[2,3-b]pyridin-2-yl)-4H-l'-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(R)-3-(thieno[3,2-b]pyridin-2-yl)-4H-l'-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(S)-3-(thieno[3,2-b]pyridin-2-yl)-4H-l'-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(R)-3-(pyrazolo[l ,5-a]pyridin-2-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(S)-3-(pyrazolo[l,5-a]pyridin-2-yl)-4H-l '-azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(R)-3-(6-fluorobenzo[b]thiophen-2-yl)-4H-l '-azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(S)-3-(6-fluorobenzo[b]thiophen-2-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(R)-3-(l-methyl-lH-indol-2-yl)-4H-l*-azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(S)-3-(l-methyl-l H-indol-2-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(R)-3-(l -methyl-lH-benzo[d]imidazol-2-yl)-4H-l'-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(S)-3 l -methyl-lH-benzo[d]imidazol-2-yl)-4H-l '-azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(R)-3-(6-fluorobenzofuran-2-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(S)-3-(6-fluorobenzofuran-2-yl)-4H-V-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(R)-3 -(5 -fluorobenzofuran-2-y 1)-4H- 1 '-azaspiro[[ 1 ,2,4] oxadiazole-5 ,3 '- bicyclo[2.2.2]octane];
(S)-3-(5-fluorobenzofuran-2-yl)-4H-r-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(R)-3-(4-fluorobenzofuran-2-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2] octane] ; (S)-3-(4-fluorobenzofuran-2-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(R)-3 -(3 -fluorobenzofuran-2-yl)-4H- 1 '-azaspiro[ [ 1 ,2,4]oxadiazole-5 ,3 '- bicyclo[2.2.2]octane];
(S)-3 -(3 -fluorobenzofuran-2-y 1)-4H- 1 '-azaspiro[[ 1 ,2,4] oxadiazole-5 ,3 '- bicyclo[2.2.2]octane];
(R)-3-(5,7-difluorobenzofuran-2-yl)-4H-r-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(S)-3-(5,7-difluorobenzofuran-2-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(R)-3 -(pyrimidin-2-yl)-4H- 1 '-azaspiro [[ 1 ,2,4]oxadiazole-5 ,3 '-bicyclo [2.2.2]octane] ;
(S)-3-(pyrimidin-2-yl)-4H- -azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane];
(R)-3 -benzy 1-4H- 1 '-azaspiro[[ 1 ,2,4] oxadiazole-5 ,3'-bicyclo[2.2.2] octane] ;
(S)-3-benzyl-4H- -azaspiro[[l,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane];
(R)-3-([l , r-biphenyl]-4-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane];
(S)-3-([l ,l '-biphenyl]-4-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane];
(R)-4-methyl-3-(5,6,7,8-tetrahydroisoquinolin-3-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole- 5,3'-bicyclo[2.2.2]octane];
(S)-4-methyl-3-(5,6,7,8-tetrahydroisoquinolin-3-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole- 5,3'-bicyclo[2.2.2]octane];
(R)-4-methyl-3-(5-phenyl-l,3,4-oxadiazol-2-yl)-4H-l '-azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(S)-4-methyl-3-(5-phenyl-l ,3,4-oxadiazol-2-yl)-4H- -azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(R)-4-methyl-3-(l ,2,3,4-tetrahydroquinolin-6-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(S)-4-methyl-3-(l ,2,3,4-tetrahydroquinolin-6-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(R)-4-methyl-3-(l ,2,3,4-tetrahydroisoquinolin-6-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole- 5,3'-bicyclo[2.2.2]octane];
(S)-4-methyl-3-(l ,2,3,4-tetrahydroisoquinolin-6-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole- 5,3'-bicyclo[2.2.2]octane];
(lr,3R,^,5S,7i)-3'-(6-fluorobenzo[b]thiophen-2-yl)-4'H-l -azaspiro[adamantane-4,5'- [l ,2,4]oxadiazole];
( 1 r,3R,4r,5 S, 7s)-3 '-(6-fluorobenzo[b]thiophen-2-yl)-4'H- 1 -azaspiro[adamantane-4,5'- [l ,2,4]oxadiazole]; (lr,3R,^,5S,75)-3'-(5-fluorobenzo[b]thiophen-2-yl)-4'H-l-azaspiro[adamantane-4,5'- [l,2,4]oxadiazole];
(lr,3R,4r,5S,75)-3'-(5-fluorobenzo[b]thiophen-2-yl)-4'H-l-azaspiro[adamantane-4,5'- [l,2,4]oxadiazole];
( 1 r,3R,4s,5S, 7s)-3'-(benzo[d]thiazol-2-yl)-4'H- 1 -azaspiro[adamantane-4,5'- [l,2,4]oxadiazole];
(lr,3R,^r,5S,75)-3'-(benzo[d]thiazol-2-yl)-4'H-l-azaspiro[adamantane-4,5'- [l,2,4]oxadiazole];
(lr,3R,^s,5S,7i)-3'-(benzo[b]thiophen-5-yl)-4'H-l-azaspiro[adamantane-4,5'- [l,2,4]oxadiazole];
(lr,3R,^,5S,75)-3'-(benzo[b]thiophen-5-yl)-4'H-l-azaspiro[adamantane-4,5'- [l,2,4]oxadiazole];
(lr,3R,^i,5S,75)-3'-(5,6,7,8 etrahydroisoquinolin-3-yl)-4'H-l-azaspiro[adamantane-4,5'- [l,2,4]oxadiazole];
(l ,3R,4 ,5S,75)-3'-(5,6,7,8-tetrahydroisoquinolin-3-yl)-4'H-l-azaspiro[adamantane-4,5'- [l,2,4]oxadiazole];
(lr,3R,^j,5S,7_;)-3'-(thiazol-2-yl)-4'H-l-azaspiro[adamantane-4,5'-[l,2,4]oxadiazole]; (l ,3R,¥r,5S,75)-3'-(thiazol-2-yl)-4'H-l-azaspiro[adamantane-4)5'-[l,2,4]oxadiazole]; (lr,3R,4s,5S,7i)-3' l-methyl-lH-imidazol-2-yl)-4'H-l-azaspiro[adamantane-4,5'- [l,2,4]oxadiazole];
(lr,3R,^r,5S,7i)-3Hl-methyl H-imidazol-2-yI)-4'H-l-azaspiro[adamantane-4,5'- [l,2,4]oxadiazole];
(R)-2-(4H-l'-azaspiro[[l,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octan]-3- yl)benzo[b]thiophene-7-carbonitrile;
(S)-2-(4H-r-azaspiro[[l,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octan]-3- yl)benzo[b]thiophene-7-carbonitrile;
(R)-3-(isoquinolin-3-yl)-4H-l'-azaspiro[[l,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane];
(S)-3-(isoquinolin-3-yl)-4H-l'-azaspiro[[l,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane];
(R)-3-(5-phenyl-l)3,4-oxadiazol-2-yl)-4H-l'-azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(S)-3-(5-phenyl-l,3,4-oxadiazol-2-yl)-4H-r-azaspiro[[l,2,4]oxadiazole-5,3- bicyclo[2.2.2]octane];
(R)-3-(6-methoxybenzo[d]thiazo]-2-yl)-4H- -azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(S)-3-(6-methoxybenzo[d]thiazol-2-yl)-4H-l'-azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane]; (R)-3-(thieno[2,3-b]pyridin-2-yl)-4H-l'-azaspiro[[l,2,4]oxadiazole-5,3'-bicyclo[2.2.2] octane];
(S)-3-(thieno[2,3-b]pyridin-2-yl)-4H-l'-azaspiro[[l )2,4]oxadiazole-5,3,-bicyclo[2.2.2] octane];
(R)-3-(thieno[3,2-b]pyridin-2-yl)-4H-l'-azaspiro[[l,2,4]oxadiazole-5,3'-bicyclo[2.2.2] octane];
(S)-3-(thieno[3,2-b]pyridin-2-yl)-4H-l'-azaspiro[[l,2,4]oxadiazole-5,3'-bicyclo[2.2.2] octane];
(R)-3-(pyrazolo[l ,5-a]pyridin-2-yl)-4H- -azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(S)-3-(pyrazolo[l ,5-a]pyridin-2-yl)-4H- -azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(R)-3-(6-fluorobenzo[b]thiophen-2-yl)-4H-l'-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(S)-3-(6-fluorobenzo[b]thiophen-2-yl)-4H-l'-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(R)-3-(l-methyl-lH-indol-2-yl)-4H-l'-azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(S)-3-( 1 -methyl- 1 H-indol-2-yl)-4H- 1 '-azaspiro[[ 1 ,2,4]oxadiazole-5,3 '- bicyclo[2.2.2]octane];
(R)-3-(l-methyl-lH-benzo[d]imidazol-2-yl)-4H-r-azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(S)-3-(l-methyl-lH-benzo[d]imidazol-2-yl)-4H-r-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(R)-3-(6-fluorobenzofuran-2-yl)-4H-l'-azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(S)-3-(6-fIuorobenzofuran-2-yI)-4H-l '-azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(R)-3-(5-fluorobenzofuran-2-yl)-4H-l'-azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(S)-3-(5-fluorobenzofuran-2-yl)-4H-l'-azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(R)-3 -(4-fluorobenzofuran-2-y 1)-4H- 1 '-azaspiro[ [ 1 ,2,4] oxadiazole-5 ,3 '- bicyclo[2.2.2]octane];
(S)-3-(4-fluorobenzofuran-2-yl)-4H-r-azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane]; (R)-3-(5,7-difluorobenzofuran-2-yl)-4H-r-azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(S)-3-(5,7-difluorobenzofuran-2-yl)-4H-r-azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(R)-3-([l ,l '-biphenyl]-4-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane];
(S)-3 [l ,l'-biphenyl]-4-yl)-4H-r-azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane];
(R)-4-methyl-3-(l ,2,3,4-tetrahydroquinolin-6-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(S)-4-methyl-3-(l ,2,3,4-tetrahydroquinolin-6-yl)-4H-r-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(l r,3R,4s,5S,7s)-3'-(6-fluorobenzo[b]thiophen-2-yl)-4'H-l -azaspiro[adamantane-4,5'- [l ,2,4]oxadiazole];
(l r,3R,4r,5S,7s)-3'-(6-fluorobenzo[b]thiophen-2-yl)-4'H-l -azaspiro[adamantane-4,5'- [l ,2,4]oxadiazole];
(lr,3R,4s,5S,7s)-3'-(5-fluorobenzo[b]thiophen-2-yl)-4'H-l -azaspiro[adamantane-4,5'- [l ,2,4]oxadiazole];
(l r,3R,4r,5S,7s)-3'-(5-fluorobenzo[b]thiophen-2-yl)-4'H-l -azaspiro[adamantane-4)5l- [l ,2,4]oxadiazole];
(l r,3R,4s,5S,7s)-3'-(benzo[b]thiophen-5-yl)-4'H-l -azaspiro[adamantane-4,5'- [l ,2,4]oxadiazole];
(l r,3R,4r,5S,7s)-3'-(benzo[b]thiophen-5-yl)-4'H-l -azaspiro[adamantane-4,5'- [l ,2,4]oxadiazole];
(lr,3R,4s,5S,7s)-3'-(5,6,7,8-tetrahydroisoquinolin-3-yl)-4'H-l -azaspiro[adamantine-4,5'- [l ,2,4]oxadiazole];
(l r,3R,4r,5S,7s) '-(5,6,7,8-tetrahydroisoquinolin-3-yl)-4'H-l -azaspiro[adamantine-4,5'- [l ,2,4]oxadiazole];
(R)-2-(4H-l'-azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octan]-3- yl)benzo[b]thiophene-7-carboxamide;
(S)-2-(4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octan]-3- yl)benzo[b]thiophene-7-carboxamide;
(R)-3-(quinolin-3-yl)-4H-l'-azaspiro[[l ,2)4]oxadiazole-5,3'-bicyclo[2.2.2]octane];
(S)-3-(quinolin-3-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane];
(R)-3-(benzofuran-5-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane];
(S)-3-(benzofuran-5-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane];
(R)-3-(lH-indol-5-yl)-4H-l'-azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane];
(S^ lH-indol-S-ylHH-l'-azaspirofCl ^^oxadiazole-S^'-bicycloP^^Joctane];
(R)-3-(benzo[d]thiazol-6-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane]; (S)-3-(benzo[d]thiazol-6-yl)-4H-r-azaspiro[[l,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane];
(R)-3-(quinolin-6-yl)-4H-r-azaspiro[[l,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane];
(S)-3-(quinolin-6-yl)-4H-l '-azaspiro[[l,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane];
(R)-3-(benzo[d]thiazol-5-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane];
(S)-3-(benzo[d]thiazol-5-yl)-4H-l'-azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane];
(R)-3-(benzofuran-6-yl)-4H-l '-azaspiro[[l,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane];
(S)-3-(benzofuran-6-yl)-4H-l'-azaspiro[[l,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane];
(R)-3-(benzo[b]thiophen-6-yl)-4H-l'-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(S)-3-(benzo[b]thiophen-6-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(R)-3-(4-fluorophenyl)-4H-l'-azaspiro[[l,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane];
(S)-3-(4-fluorophenyl)-4H-l'-azaspiro[[l,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane];
(R)-3-(3,4-dichlorophenyl)-4H-l '-azaspiro[[l,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane];
(S)-3-(3,4-dichlorophenyl)-4H-l '-azaspiro[[l,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane];
(R)-3-(3-chlorobenzo[b]thiophen-2-yl)-4H-l'-azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(S)-3-(3-chlorobenzo[b]thiophen-2-yl)-4H-l'-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(R)-3-(4-(4-fluorophenoxy)phenyl)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(S)-3 -(4-(4-fluorophenoxy)phenyl)-4H- 1 '-azaspiro[[ 1 ,2,4]oxadiazole-5,3 '- bicyclo[2.2.2]octane];
(R)-3-(l H-indol-6-yl)-4H-l '-azaspiro[[l,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane];
(S)-3-(l H-indol-6-yl)-4H-l '-azaspiro[[l,2,4]oxadiazole-5,3'-bicyc]o[2.2.2]octane];
(l r,3R,4s,5S,7s)-3'-(benzofuran-5-yl)-4'H-l-azaspiro[adamantane-4,5'-[l,2,4]oxadiazole];
(lr,3R,4r,5S,7s)-3'-(benzofuran-5-yl)-4'H-l -azaspiro[adamantane-4,5'-[l ,2,4]oxadiazole];
(l r,3R,4s,5S,7s)-3'-(benzo[b]thiophen-6-yl)-4'H-l-azaspiro[adamantane-4,5'- [l ,2,4]oxadiazole];
( 1 r,3 R,4r,5 S,7s)-3 '-(benzo[b]thiophen-6-yl)-4'H- 1 -azaspiro[adamantane-4,5'- [l,2,4]oxadiazole];
(R)-3-(3-(trifluoromethyl)benzofuran-5-yl)-4H-l '-azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(S)-3-(3-(trifluoromethyl)benzofuran-5-yl)-4H- -azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(R)-3-(2-(trifluoromethyl)benzofuran-5-yl)-4H- -azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane]; (S)-3-(2-(trifluoromethyl)benzofuran-5-yl)-4H- -azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(R)-3-(3-(trifluoromethyl)benzo[b]thiophen-6-yl)-4H-r-azaspiro[[ l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(S)-3-(3-(trifluoromethyl)benzo[b]thiophen-6-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(lr,3R,4s,5S,7s)-3'-(benzofuran-6-yl)-4'H-l -azaspiro[adamantane-4,5'-[l ,2,4]oxadiazole];
(l r,3R,4r,5S,7s)-3'-(benzofuran-6-yl)-4'H-l-azaspiro[adamantane-4,5'-[l,2,4]oxadiazole];
(R)-3-(3-fluorobenzofuran-5-yl)-4H-r-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(S)-3-(3-fluorobenzofuran-5-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(R)-3-(pyrimidin-5-yl)-4H- -azaspiro[[l,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane];
(S)-3-(pyrimidin-5-yl)-4H-l'-azaspiro[[l,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane];
(R)-3-(2-fluorobenzofuran-5-yl)-4H-r-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(S)-3-(2-fluorobenzofuran-5-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(R)-3-(2-(trifluoromethyl)benzo[b]thiophen-6-yl)-4H- -azaspiro[[l ,2,4]oxadiazoIe-5,3'- bicyclo[2.2.2]octane];
(S)-3-(2-(trifluoromethyl)benzo[b]thiophen-6-yl)-4H-l'-azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(R)-3-(2-fluorobenzo[b]thiophen-6-yl)-4H-l '-azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(S)-3-(2-fluorobenzo[b]thiophen-6-yl)-4H- -azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(R)-3-(3-fluorobenzo[b]thiophen-6-yl)-4H-l'-azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(S)-3-(3-fluorobenzo[b]thiophen-6-yl)-4H- -azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(R)-3-(thieno[3,2-b]pyridin-6-yl)-4H-l'-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(S)-3-(thieno[3,2-b]pyridin-6-yl)-4H-r-azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(R)-3-(pyrazolo[l,5-a]pyridin-5-yl)-4H- -azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane]; (S)-3-(pyrazolo[l ,5-a]pyridin-5-yl)-4H- -azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(R)-3-(furo[2,3-b]pyridin-5-yI)-4H-l'-azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(S)-3-(furo[2,3-b]pyridin-5-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2] octane] ;
(R)-3-(3,4-dihydro-2H-benzo[b][l,4]oxazin-5-yl)-4H-l'-azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(S)-3 -(3 ,4-dihydro-2H-benzo[b] [ 1 ,4]oxazin-5 -y 1)-4H- 1 '-azaspiro [[ 1 ,2,4] oxadiazole-5 ,3 '- bicyclo[2.2.2]octane];
(R)-7-(4H- -azaspiro[[l,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octan]-3-yl)indolin-2-one;
(S)-7-(4H- -azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octan]-3-yl)indolin-2-one;
(R)-3-(imidazo[l,2-a]pyridin-6-yl)-4H- -azaspiro[[l,2,4]oxadiazole-5,3'- bicyc lo[2.2.2]octane] ;
(S)-3-(imidazo[l,2-a]pyridin-6-yl)-4H-r-azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(R)-3-(pyrrolo[l,2-b]pyridazin-6-yl)-4H-l '-azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(S)-3-(pyrrolo[l ,2-b]pyridazin-6-yl)-4H-l'-azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(R)-3 -(3 -methy lbenzofuran-5 -y 1)-4H- 1 '-azaspiro [[ 1 ,2,4]oxadiazole-5 ,3 '- bicyclo[2.2.2]octane];
(S)-3-(3-methylbenzofuran-5-yl)-4H- -azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(R)-3-(3-rnethylbenzo[b]thiophen-5-yl)-4H-r-azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(S)-3-(3-methylbenzo[b]thiophen-5-yl)-4H-l '-azaspiro[[l,2,4]oxadiazole-5,3'- b icycl o [2.2.2] octane] ;
(R)-3-(3-methylbenzofuran-6-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2] octane];
(S)-3-(3-methylbenzofuran-6-yl)-4H-l'-azaspiro[[l,2,4]oxadiazole-5,3'-bicyclo[2.2.2] octane];
(R)-3-(3-methylbenzo[b]thiophen-6-yl)-4H-l'-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(S)-3 -(3 -methy lbenzo[b]thiophen-6-yl)-4H- 1 '-azaspiro[[ 1 ,2,4] oxadiazole-5 ,3 '- bicyclo[2.2.2]octane]; (R)-3-(5,6,7,8-tetrahydroisoquinolin-3-yl)-4H-l '-azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(S)-3-(5,6,7,8-tetrahydroisoquinolin-3-yl)-4H-r-azaspiro[[l ,2,4]oxadiazole-5,3'- b icyclo [2.2.2] octane] ;
(R)-4-methyl-3 -(2-methy 1- 1 ,2,3 ,4-tetrahydroisoquinolin-6-y 1)-4H- 1 '- azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane];
(S)-4-methy 1-3 -(2-methyl- 1 ,2,3 ,4-tetrahydroisoquinolin-6-yl)-4H- 1 '- azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane];
(R)-3-(quinolin-7-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane];
(S)-3-(quinolin-7-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane];
(R)-3-(l-methyl-l H-indol-6-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane;
(S)-3-( 1 -methyl- 1 H-indol-6-yl)-4H- 1 '-azaspiro[[ 1 ,2,4]oxadiazole-5,3 '- bicyclo[2.2.2]octane;
(R)-3-(imidazo[l ,5-a]pyridin-7-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(S)-3-(imidazo[l ,5-a]pyridin-7-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(R)-3-(3,4-dihydro-2H-benzo[b][l ,4]oxazin-5-yl)-4-methyl-4H-l '- azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane];
(S)-3 -(3 ,4-dihydro-2H-benzo[b] [ 1 ,4]oxazin-5-yl)-4-methyl-4H- 1 '- azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane];
(R)-3-(pyrrolo[l ,2-a]pyrimidin-7-yl)-4H- -azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane]; and
(S)-3 -(pyrrolo[ 1 ,2-a]pyrimidin-7-yl)-4H- 1 '-azaspiro[[ 1 ,2,4]oxadiazole-5,3 '- bicyclo[2.2.2]octane];
Figure imgf000047_0001
Figure imgf000048_0001
Figure imgf000049_0001
[0075] In certain embodiments, the specific examples of the spiro-oxadiazoline compound represented by Formula (I), (Ila), or (lib), according to the present invention, may include, collectively or individually, those listed below, and pharmaceutically acceptable salts thereof:
(+/-)-3-(benzo[b]thiophen-5-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyc lo [2.2.2] octane] ;
(+/-)-3-(benzofuran-5-yl)-4H-l '-azaspiro[[l,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane];
(+/-)-3-(benzo[b]thiophen-6-yl)-4H-l'-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(+/-)-3-(3-(trifluoromethyl)benzofuran-5-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(+/-)-3-(3-fluorobenzofuran-5-yl)-4H-r-azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(+/-)-3-(2-fluorobenzofuran-5-yl)-4H-l '-azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane]; (+/-)-3-(3-fluorobenzo[b]thiophen-6-yl)-4H- -azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(R)-3-(benzo[b]thiophen-5-yl)-4H-l '-azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(S)-3-(benzo[b]thiophen-5-yl)-4H-l'-azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(l r^R^s^SJsVS'-CbenzoCbJthiophen^-y ^'H-l-azaspirotadamantane^^'- [l,2,4]oxadiazoIe];
(l r,3R,4r,5S,7s)-3'-(benzo[b]thiophen-2-yl)-4'H-l-azaspiro[adamantane-4,5'- [l,2,4]oxadiazole];
(R)-3-(benzofuran-5-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'-bicycIo[2.2.2]octane];
(S)-3-(benzofuran-5-yl)-4H-l'-azaspiro[[l,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane];
(R)-3-(benzo[b]thiophen-6-yl)-4H-l '-azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(S)-3-(benzo[b]thiophen-6-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(R)-3-(3-(trifluoromethyl)benzofuran-5-yl)-4H-l '-azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(S)-3-(3-(trifluoromethyl)benzofuran-5-yl)-4H- -azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(R)-3-(3-fluorobenzofuran-5-yl)-4H- -azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(S)-3-(3-fluorobenzofuran-5-yl)-4H- -azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(R)-3-(2-fluorobenzofuran-5-yl)-4H- -azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(S)-3-(2-fluorobenzofuran-5-yl)-4H- -azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(R)-3-(3-fluorobenzo[b]thiophen-6-yl)-4H-l '-azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane]; and
(S)-3-(3-fluorobenzo[b]thiophen-6-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane].
[0076] In certain embodiments, for example, the spiro-oxadiazoline compound represented by Formula (I), (Ila), or (lib), and pharmaceutically acceptable salts thereof, may comprise the W representing a moiety represented by any one of ring systems M-IIa, M-IIb, or M-IVa:
Figure imgf000051_0001
wherein A1 and A2 independently represent N or CR1 1; A3 independently represents NR10, O, or S; and Z6, Z7, Z8, and Z9 represent CR7;
wherein A5 represents N or CR15; and A7 represents NR14; O; or S; and
wherein Z Z2, Z3, and Z4 independently represent N or CR4; with the proviso that no more than two of Z', Z2, Z3, and Z4 are N;
and may include, collectively or individually, a racemic mixture, a geometric mixture, or a single enantiomer, diastereomer, or geometric isomer, of any of those listed below, and pharmaceutically acceptable salts thereof:
3-(benzo[b]thiophen-5-yl)-4H-l'-azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane];
3-(benzofuran-5-yl)-4H-l '-azaspiro[[l,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane];
3-(benzo[b]thiophen-6-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane];
3-(3-(trifluoromethyl)benzofuran-5-yl)-4H- -azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
3-(3-fluorobenzofuran-5-yl)-4H-l'-azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane];
3-(2-fluorobenzofuran-5-yl)-4H-l'-azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane];
3-(3-fluorobenzo[b]thiophen-6-yl)-4H- -azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
3-(benzo[b]thiophen-5-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane];
3-(benzo[b]thiophen-5-yl)-4H-l '-azaspiro[[l,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane];
(l r,3R,4s,5S,7s)-3'-(benzo[b]thiophen-2-yl)-4'H-l -azaspiro[adamantane-4,5'- [l ,2,4]oxadiazole]; and
(l r,3R,4r,5S,7s)-3'-(benzo[b]thiophen-2-yl)-4'H-l -azaspiro[adamantane-4,5'- [l ,2,4]oxadiazole].
[0077] For example, in certain embodiments, the specific examples of the spiro-oxadiazoline compound represented by Formula (I), (Ha), or (lib), and pharmaceutically acceptable salts thereof, may comprise the W representing a moiety represented by the ring system M-IIa, M-IIb, or M-rVa, wherein the compound may include, collectively or individually, a racemic mixture or geometric mixture of any of those listed below, and pharmaceutically acceptable salts thereof:
(+/-)-3-(benzo[b]thiophen-5-yl)-4H-l'-azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(+/-)-3 -(benzofuran-5 -yl)-4H- 1 '-azaspiro[[ 1 ,2,4]oxadiazole-5 ,3 '-bicyclo[2.2.2] octane] ;
(+/-)-3-(benzo[b]thiophen-6-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane]; (+/-)-3 -(3 -(trifluoromethyl)benzofuran-5-y 1)-4H- 1 '-azaspiro [[ 1 ,2,4] oxadiazole-5 ,3 '- bicyclo[2.2.2]octane];
(+/-)-3-(3-fluorobenzofuran-5-yl)-4H-l'-azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(+/-)-3-(2-fluorobenzofuran-5-yl)-4H- -azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(+/-)-3-(3-fluorobenzo[b]thiophen-6-yl)-4H- -azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(R)-3 -(benzo [b]thiophen-5 -yl)-4H- 1 '-azaspiro [[ 1 ,2,4] oxadiazole-5 ,3 '- bicyclo[2.2.2]octane];
(S)-3-(benzo[b]thiophen-5-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(lr,3R,4s,5S,7s)-3'-(benzo[b]thiophen-2-yl)-4'H-l-azaspiro[adamantane-4,5'- [l,2,4]oxadiazole]; and
(lr,3R,4r,5S,7s)-3'-(benzo[b]thiophen-2-yl)-4'H-l-azaspiro[adamantane-4,5'- [l ,2,4]oxadiazole].
[0078] For example, in certain embodiments, the specific examples of the spiro-oxadiazoline compound represented by Formula (I), (Ila), or (lib), and pharmaceutically acceptable salts thereof, may comprise the W representing a moiety represented by the ring system M-IIa, M-IIb, or M-IVa, wherein the compound may include, collectively or individually, a single enantiomer, diastereomer, or geometric isomer, of any of those listed below, and pharmaceutically acceptable salts thereof:
(R)-3 -(benzo [b]thiophen-5 -yl)-4H- 1 '-azaspiro [[ 1 ,2,4]oxad iazole-5 ,3 '- bicyclo[2.2.2]octane];
(S)-3-(benzo[b]thiophen-5-yl)-4H-l'-azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
( 1 r,3R,4s,5 S,7s)-3 '-(benzo[b]thiophen-2-yl)-4'H- 1 -azaspiro[adamantane-4,5'- [l ,2,4]oxadiazole];
(lr,3R,4r,5S,7s)-3'-(benzo[b]thiophen-2-yl)-4'H-l -azaspiro[adamantane-4,5'- [l ,2,4]oxadiazole];
(R)-3 -(benzofuran-5-yl)-4H- 1 '-azaspiro[[ 1 ,2,4]oxadiazole-5 ,3 '-bicyclo [2.2.2] octane] ;
(S)-3-(benzofuran-5-yl)-4H-l'-azaspiro[[l,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane];
(R)-3 -(benzo [b]thiophen-6-y 1)-4H- 1 '-azaspiro[[ 1 ,2,4] oxadiazole-5 ,3 '- bicyclo[2.2.2]octane];
(S)-3-(benzo[b]thiophen-6-yl)-4H-l'-azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane]; (R)-3-(3-(trifluoromethyl)benzofuran-5-yl)-4H- -azaspiro[[l ,2,4]oxadiazole-5,3'- b icyclo[2.2.2] octane] ;
(S)-3-(3-(trifluoromethyl)benzofuran-5-yl)-4H-r-azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(R)-3 -(3 -fluorobenzofuran-5-yl)-4H- 1 '-azaspiro[[ 1 ,2,4]oxadiazole-5 ,3 '- bicyclo[2.2.2]octane];
(S)-3 -(3 -fluorobenzofuran-5 -yl)-4H- 1 '-azaspiro[[ 1 ,2,4]oxadiazole-5 ,3 '- bicyclo[2.2.2]octane];
(R)-3-(2-fluorobenzofuran-5-yl)-4H- -azaspiro[[l ,2,4]oxadiazole-5,3'- b icyc lo [2.2.2] octane] ;
(S)-3-(2-fluorobenzofuran-5-yl)-4H- -azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(R)-3 -(3 -fluorobenzo [b]thiophen-6-yl)-4H- 1 '-azaspiro[[ 1 ,2,4] oxadiazole-5 ,3 '- bicyclo[2.2.2]octane]; and
(S)-3 -(3 -fluorobenzo[b]thiophen-6-y 1)-4H- 1 '-azaspiro[[ 1 ,2,4] oxadiazole-5 ,3 '- bicyclo[2.2.2]octane].
[0079] In certain embodiments, for example, the specific examples of the spiro-oxadiazoline compound represented by Formula (I), (Ila), or (lib), and pharmaceutically acceptable salts thereof, may comprise the W representing a moiety represented by the ring system M-IIa:
Figure imgf000053_0001
wherein A1 and A2 independently represent N or CR", preferably CRH, A3 independently represents NR10, O, or S, preferably O or S, and Z6, Z8, and Z9 represent CR7, wherein R" preferably independently represents -H; -F; -CI; -Br; -I; -CN; -OR12; -(CHs^OR1 ; -OCF3; a Ci-C6-alkyl radical; a C)-C6-haloalkyl radical, preferably -CF3; or a C3-C6-cycloalkyl radical, and R1 ' more preferably independently represents -H;-F; -CI; -Br; -I; -CN; -OCF3; a Ci-C6-alkyl radical; or -CF3;
and may include, collectively or individually, a racemic mixture or a single enantiomer of any of those listed below, and pharmaceutically acceptable salts thereof:
3-(benzo[b]thiophen-5-yl)-4H-l'-azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane];
3-(benzofuran-5-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane];
3-(3-(trifluoromethyl)benzofuran-5-yl)-4H- -azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
3-(3-fluorobenzofuran-5-yl)-4H- -azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane]; and 3-(2-fluorobenzofuran-5-yl)-4H- -azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane].
[0080] For example, in certain embodiments, the specific examples of the spiro-oxadiazoline compound represented by Formula (I), (Ila), or (lib), and pharmaceutically acceptable salts thereof, may comprise the W representing a moiety represented by the ring system M-IIa, wherein the compound may include, collectively or individually, a racemic mixture of any of those listed below, and pharmaceutically acceptable salts thereof:
(+/-)-3-(benzo[b]thiophen-5-yl)-4H-l'-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(+/-)-3-(benzofuran-5-yl)-4H-l'-azaspiro[[l,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane];
(+/-)-3-(3-(trifluoromethyl)benzofuran-5-yl)-4H- -azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(+/-)-3 -(3 -fluorobenzofuran-5 -y 1)-4H- 1 '-azaspiro[[ 1 ,2,4] oxadiazole-5 ,3 '- bicyclo[2.2.2]octane];and
(+/-)-3-(2-fluorobenzofuran-5-yl)-4H-l'-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane].
[0081] For example, in certain embodiments, the specific examples of the spiro-oxadiazoline compound represented by Formula (I), (Ila), or (lib), and pharmaceutically acceptable salts thereof, may comprise the W representing a moiety represented by the ring system M-IIa, wherein the compound may include, collectively or individually, a single enantiomer of any of those listed below, and pharmaceutically acceptable salts thereof:
(R)-3-(benzo[b]thiophen-5-yl)-4H-l '-azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(S)-3-(benzo[b]thiophen-5-yl)-4H-l'-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(R)-3-(benzofuran-5-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane];
(S)-3-(benzofuran-5-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane];
(R)-3-(3-(trifluoromethyl)benzofuran-5-yl)-4H- -azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(S)-3-(3-(trifluoromethyl)benzofuran-5-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(R)-3-(3-fluorobenzofuran-5-yl)-4H-l '-azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(S)-3-(3-fluorobenzofuran-5-yl)-4H-l '-azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(R)-3-(2-fluorobenzofuran-5-yl)-4H-l'-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane]; and (S)-3-(2-fluorobenzofuran-5-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane].
[0082] For example, in certain embodiments, the specific examples of the spiro-oxadiazoline compound represented by Formula (I), (Ila), or (lib), and pharmaceutically acceptable salts thereof, may comprise the W representing a moiety represented by the ring system M-IIa, wherein the compound may include, collectively or individually, a single enantiomer of any of those listed below, and pharmaceutically acceptable salts thereof:
(R)-3-(benzo[b]thiophen-5-yl)-4H-r-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(R)-3-(benzofuran-5-yl)-4H-l'-azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane];
(R)-3-(3-(trifluoromethyl)benzofuran-5-yl)-4H- -azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(R)-3-(3-fluorobenzofuran-5-yl)-4H- -azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane]; and
(R)-3-(2-fluorobenzofuran-5-yl)-4H-l '-azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane].
[0083] For example, in certain embodiments, the specific examples of the spiro-oxadiazoline compound represented by Formula (I), (Ila), or (lib), and pharmaceutically acceptable salts thereof, may comprise the W representing a moiety represented by the ring system M-IIa, wherein the compound may include, collectively or individually, a single enantiomer of any of those listed below, and pharmaceutically acceptable salts thereof:
(S)-3-(benzo[b]thiophen-5-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyc!o[2.2.2]octane];
(S)-3-(benzofuran-5-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane];
(S)-3-(3-(trifluoromethyl)benzofuran-5-yl)-4H-l '-azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(S)-3-(3-fluorobenzofuran-5-yl)-4H- -azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane]; and
(S)-3-(2-fluorobenzofuran-5-yl)-4H-r-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane].
[0084] In certain embodiments, for example, the specific examples of the spiro-oxadiazoline compound represented by Formula (I), (Ila), or (lib), and pharmaceutically acceptable salts thereof, may comprise the W representing a moiety represented by the ring system M-IIb:
M-IIb
Figure imgf000055_0001
wherein A1 and A2 independently represent N or CR11, preferably CRn, A3 independently represents NR10, O, or S, preferably O or S, and Z6, Z7, and Z9 represent CR7, wherein R1 1 preferably independently represents -H; -F; -CI; -Br; -I; -CN; -OR12; -<CH2)mOR12; -OCF3; a CrC6-alkyl radical; a Ci-C6-haloalkyl radical, preferably -CF3; or a C3-C6-cycloalkyl radical, and Ru more preferably independently represents -H;-F; -CI; -Br; -I; -CN; -OCF3; a d-C6-alkyl radical; or -CF3;
and may include, collectively or individually, a racemic mixture or a single enantiomer of any of those listed below, and pharmaceutically acceptable salts thereof:
3-(benzo[b]thiophen-6-yl)-4H-l '-azaspiro[[l,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane]; and
3-(3-fIuorobenzo[b]thiophen-6-yl)-4H-r-azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane].
[0085] For example, in certain embodiments, the specific examples of the spiro-oxadiazoline compound represented by Formula (I), (Ha), or (lib), and pharmaceutically acceptable salts thereof, may comprise the W representing a moiety represented by the ring system M-IIb, wherein the compound may include, collectively or individually, a racemic mixture of any of those listed below, and pharmaceutically acceptable salts thereof:
(+/-)-3-(benzo[b]thiophen-6-yl)-4H-l'-azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane]; and
(+/-)-3-(3-fluorobenzo[b]thiophen-6-yl)-4H-l '-azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane].
[0086] For example, in certain embodiments, the specific examples of the spiro-oxadiazoline compound represented by Formula (I), (Ila), or (lib), and pharmaceutically acceptable salts thereof, may comprise the W representing a moiety represented by the ring system M-IIb, wherein the compound may include, collectively or individually, a single enantiomer of any of those listed below, and pharmaceutically acceptable salts thereof:
(R)-3 -(benzo[b]thiophen-6-yl)-4H- 1 '-azaspiro[[ 1 ,2,4]oxadiazole-5,3 '- bicyclo[2.2.2]octane];
(S)-3-(benzo[b]thiophen-6-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(R)-3-(3-fluorobenzo[b]thiophen-6-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane]; and
(S)-3-(3-fluorobenzo[b]thiophen-6-yl)-4H-r-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane].
[0087] For example, in certain embodiments, the specific examples of the spiro-oxadiazoline compound represented by Formula (I), (Ila), or (lib), and pharmaceutically acceptable salts thereof, may comprise the W representing a moiety represented by the ring system M-IIb, wherein the compound may include, collectively or individually, a single enantiomer of any of those listed below, and pharmaceutically acceptable salts thereof:
(R)-3-(benzo[b]thiophen-6-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane]; and
(R)-3-(3-fluorobenzo[b]thiophen-6-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane].
[0088] For example, in certain embodiments, the specific examples of the spiro-oxadiazoline compound represented by Formula (I), (Ila), or (lib), and pharmaceutically acceptable salts thereof, may comprise the W representing a moiety represented by the ring system M-IIb, wherein the compound may include, collectively or individually, a single enantiomer of any of those listed below, and pharmaceutically acceptable salts thereof:
(S)-3-(benzo[b]thiophen-6-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane]; and
(S)-3-(3-fluorobenzo[b]thiophen-6-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane].
[0089] In certain embodiments, for example, the specific examples of the spiro-oxadiazoline compound represented by Formula (I), (Ila), or (lib), and pharmaceutically acceptable salts thereof, may comprise the W representing a moiety represented by the ring system M-IVa:
M-IVa
Figure imgf000057_0001
wherein A5 represents N or CR15, preferably A5 represents CR15, wherein R15 preferably represents -H; and A7 represents NR14; O; or S, preferably A7 represents S; and
wherein Z1, Z2, Z3, and Z4 independently represent N or CR4; with the proviso that no more than two of Z1, Z2, Z3, and Z4 are N; preferably wherein Z', Z2, Z3, and Z4 independently represent
CR4; and preferably wherein R4 independently represents -H; -D; -F; -CI; -Br; -I; -CN; -N02;-
OCF3; a CrC6-alkyl radical; a Ci-C6-haloalkyl radical; or a C3-C6-cycloalkyl radical.
and may include, collectively or individually, a racemic mixture, a geometric mixture, or a single enantiomer or diastereomer, of any of those listed below, and pharmaceutically acceptable salts thereof:
(l r,3R,4s,5S,7s)-3'-(benzo[b]thiophen-2-yl)-4'H-l -azaspiro[adamantane-4,5'- [l ,2,4]oxadiazole]; and
(l r,3R,4r,5S,7s)-3'-(benzo[b]thiophen-2-yl)-4'H-l -azaspiro[adamantane-4,5'- [l ,2,4]oxadiazole].
[0090] For example, in certain embodiments, the specific examples of the spiro-oxadiazoline compound represented by Formula (I), (Ila), or (lib), and pharmaceutically acceptable salts thereof, may comprise the W representing a moiety represented by the ring system M-IVa, wherein the compound may include a geometric mixture, or a single enantiomer or diastereomer, of any of those listed below, and pharmaceutically acceptable salts thereof:
( 1 r,3R,4s,5 S,7s)-3 '-(benzo[b]thiophen-2-yl)-4'H- 1 -azaspiro[adamantane-4,5'- [l ,2,4]oxadiazole].
[0091] For example, in certain embodiments, the specific examples of the spiro-oxadiazoline compound represented by Formula (I), (Ila), or (lib), and pharmaceutically acceptable salts thereof, may comprise the W representing a moiety represented by the ring system M-IVa, wherein the compound may include a geometric mixture, or a single enantiomer or diastereomer, of any of those listed below, and pharmaceutically acceptable salts thereof:
(l r,3R,4r,5S,7s)-3'-(benzo[b]thiophen-2-yl)-4'H-l -azaspiro[adamantane-4,5'- [l ,2,4]oxadiazole].
[0092] As used herein, the term "treating" (or "treat" or "treatment"), unless otherwise specified, includes the generally accepted meaning which encompasses improving, modifying, decreasing, prohibiting, preventing, restraining, minimizing, slowing, halting, stopping, curing, and/or reversing a symptom associated with a disease and/or a disease. Treatment may include both therapeutic and prophylactic administration. For example, treatment of a cognitive impairment, in a patient diagnosed as having a cognitive impairment, may include, but is not limited to, curing the cognitive impairment, preventing the deterioration of one or more symptoms associated with the cognitive impairment; improving cognition in a patient suffering from the cognitive impairment, slowing the progression of the cognitive impairment and/or modifying the cognitive impairment.
[0093] As used herein, the term "cognitive impairment," unless otherwise specified, includes at least one of the following: Limited Cognitive Impairment (LCI), Mild Cognitive Impairment (MCI), Alzheimer's disease (or dementia of an Alzheimer's-type) or a particular stage of Alzheimer's disease, inclusive of pre-Alzheimer's disease, early Alzheimer's disease, mild Alzheimer's disease, moderate Alzheimer's disease, severe Alzheimer's disease, pre-Alzheimer's- to-mild Alzheimer's disease, mild-to-moderate Alzheimer's disease, moderate-to-severe
Alzheimer's disease, schizophrenia (for example, paranoid type schizophrenia, disorganized type schizophrenia, catatonic type schizophrenia, undifferentiated type schizophrenia),
schizophreniform disorder, schizoaffective disorder, delusional disorder, positive symptoms of schizophrenia, negative symptoms of schizophrenia, or schizophrenia with dementia.
[0094] Alzheimer's disease may include, unless otherwise specified, any of the sub- diagnostic categories used to characterize the type or degree of cognitive impairment in a patient for treatment purposes. A commonly referenced diagnostic scale for characterizing the degree of cognitive impairment for a patient with Alzheimer's disease includes the 3-stage Alzheimer Disease Model. The 3-stages consist of: mild stage (also referred to as "early Alzheimer's disease" or "mild Alzheimer's disease" or "early stage Alzheimer's disease" or "mild dementia of an Alzheimer's-type"), moderate stage (also referred to as "middle Alzheimer's disease" or "moderate Alzheimer's disease" or "middle stage Alzheimer's disease" or "moderate dementia of an Alzheimer's-type"), and severe stage (also referred to as "late Alzheimer's disease" or "severe Alzheimer's disease" or "late stage Alzheimer's disease" or "severe dementia of an Alzheimer's- type"). For patients with a condition that has not progressed to the point of mild stage
Alzheimer's disease, they may be diagnosed as having pre-Alzheimer's disease. It is also not uncommon for treatment purposes to characterize stages together, such as pre-Alzheimer's disease-to-mild stage Alzheimer's disease, mild-to-moderate Alzheimer's disease, or moderate-to- severe Alzheimer's disease. Another useful diagnostic scale that is used in characterizing the degree of cognitive impairment for a patient having Alzheimer's disease is the Seven Stage Alzheimer's Disease Model (sometimes known as the "Seven Stage Global Deterioration Scale" or the "Reisberg Scale"). This diagnostic scale divides the progression of the cognitive disorder associated with Alzheimer's disease as follows: Stage 1 -no Alzheimer's disease (generally characterized by absence of impairment, no impairment, or normal function), Stage 2-pre- Alzheimer's disease (generally characterized by minimal impairment, normal forgetfulness, or very mild cognitive decline), Stage 3-early-stage Alzheimer's disease (generally characterized by a noticeable cognitive decline, early confusional/mild cognitive impairment, or mild cognitive decline), Stage 4-early-stage/mild Alzheimer's disease (also referred to as late confusional/mild Alzheimer's, and generally characterized by moderate cognitive decline), Stage 5-middle- stage/moderate Alzheimer's (also referred to as early dementia moderate Alzheimer's disease and generally characterized by moderately severe cognitive decline), Stage 6-middle
dementia/moderately severe Alzheimer's disease (also referred to as middle-stage/moderate to late-stage/severe Alzheimer's disease and generally characterized by severe cognitive decline), and Stage 7-late-stage/severe Alzheimer's disease (also referred to as severe dementia or failure- to-thrive, and generally characterized by very severe cognitive decline). It is also not uncommon for treatment purposes to characterize stages together, such as pre-Alzheimer's disease-to-mild stage Alzheimer's disease, mild-to-moderate Alzheimer's disease, or moderate-to-severe
Alzheimer's disease. As used herein, unless otherwise specified, Alzheimer's disease includes all of the above named diagnostic catagories or disease characterizations. It is also not uncommon for a physician to categorize any one or more of the above noted states of Alzheimer's disease as being probable, for example, probable mild-to-moderate Alzheimer's disease or probable severe Alzheimer's disease, when their diagnosis does not include, for example a physical biopsy or other definitive analysis.
[0095] Mild Cognitive Impairment (MCI) is considered by some to be an intermediate stage between normal aging and the onset of Alzheimer's disease. For example, MCI may be characterized by persistent forgetfulness, but may lack some or many of the more debilitating symptoms of Alzheimer's disease. Another set of criteria that may characterize a patient as having mild cognitive impairment suitable for treatment includes a patient that meets the following: 1) memory complaints corroborated by an informant, 2) objective memory impairment for age and education, 3) normal general cognitive function, 4) intact activities of daily living, and 5) the patient does not meet criteria for dementia. In general, a patient characterized as having mild cognitive impairment may not yet have a clinical cognitive deficit. Mild cognitive impairment may also be distinguished from senile dementia in that mild cognitive impairment involves a more persistent and troublesome problem of memory loss for the age of the patient. On the clinical diagnostic scale, mild cognitive impairment is followed, in increased severity, by Alzheimer's disease.
[0096] Limited Cognitive Impairment (LCI) describes a cognitive impairment (i.e., symptoms or conditions), which precedes mild cognitive impairment on a clinical diagnostic scale, and includes any chronic or temporary impairment in cognition, learning or memory that prevents or reduces the ability of a patient from achieving their individual potential in these areas. For example, LCIs may include minor impairments to memory associated with focus and concentration (e.g., accuracy and speed of learning and recalling information), working memory (e.g., used in decision making and problem solving), cognition, focus, mental quickness, and mental clarity.
[0097] The term "stereoisomer" refers to a molecule capable of existing in more than one spatial atomic arrangement for a given atomic connectivity (e.g., enantiomers, meso compounds, and diastereomers). As used herein, the term "stereoisomer" means either or both enantiomers and diastereomers.
[0098] The following annotated Formula (Ila) and Formula (lib) structures are provided to assist i oiety:
Formula (lib)
Figure imgf000060_0001
For example, the spiro-oxadiazoline compounds represented by Formula (Ila) are assigned the configurational assignment of "(lr,3R,4s,5S,7s)." and compounds represented by Formula (lib) are assigned the configurational assignment of "(l r,3R,4r,5S,7s)." To the extent there is any conflict between the compound name and the drawn structural configuration, herein, the drawn structural configuration shall govern.
[0099] The spiro-oxadiazoline compounds of the present invention represented by Formula (I), Formula (Ila), or Formula (lib), or a pharmaceutically acceptable salt thereof, may contain one or more stereogenic centers. Accordingly, compounds of this invention can exist as either individual stereoisomers or mixtures of two or more stereoisomers. A compound of the present invention will include both mixtures (e.g., racemic mixtures) and also individual respective stereoisomers that are substantially free from another possible stereoisomer. The term
"substantially free of other stereoisomers" as used herein means less than 25% of other stereoisomers, less than 10% of other stereoisomers, less than 5% of other stereoisomers, less than 2% of other stereoisomers, or less than "X"% of other stereoisomers (wherein X is a number between 0 and 100, inclusive) are present.
[00100] The spiro-oxadiazoline compounds represented by Formula (Ha) and Formula (lib) may be synthesized separately or together (after which the individual geometric isomers may be separated by chromatographic methods from the mixture of the geometric isomers). The mixtures of the geometric isomers may also be separated through fractional crystallization of salts of amines contained in the spiro-oxadiazoline compounds represented by Formula (I) or Formula (lib), for example, when combined with enantiomerically pure carboxylic acids.
[00101] The spiro-oxadiazoline compounds of the present invention represented by Formula (I), Formula (Ila), or Formula (lib), or a pharmaceutically acceptable salt thereof, may contain one or more tautomeric forms. Accordingly, compounds of this invention can exist as either individual tautomers or mixtures of tautomeric forms. A compound of the present invention will include both mixtures (e.g., mixtures of tautomeric forms) and also individual respective tautomers that are substantially free from another possible tautomer.
[00102] The spiro-oxadiazoline compounds of the present invention represented by Formula (I), Formula (Ila), or Formula (lib), or a pharmaceutically acceptable salt thereof, may contain one or more geometric isomers. Accordingly, compounds of this invention can exist as either geometric isomers or mixtures of geometric isomers. A compound of the present invention will include both mixtures (e.g., mixtures of geometric isomers) and also individual respective geometric isomers that are substantially free from another possible geometric isomer.
[00103] The term "haloalkyl" refers to an alky group having from 1 to 5 halogen substituents independently selected from -F, -CI, -Br, and -I. For example, a haloalkyl may represent a -CF3 group, a -CCI3 group, a -CH2CF3 group, or a -CF2CF3 group.
[00104] The term "heteroaryl" refers to an aromatic ring system comprising at least one or more hetero- ring atoms, such as two, three, four, or five hetero- ring atoms, independently selected from N, O, and S. Suitable heteroaryl groups may include a single ring, for example, thienyl, pyridyl, thiazolyl, pyrazinyl, pyrimidyl, imidazolyl, furanyl, isothiazolyl, pyrazolyl, triazolyl, tetrazolyl, isoxazolyl, oxazolyl, pyrrolyl, pydridazinyl, triazinyl, oxadiazolyl, and furazanyl. Sutiable heteroaryl groups may include a fused ring system, for example, a six-six fused ring system, a six-five fused ring system, or a five-six fused ring system, such as benzothienyl, quinolyl, benzofuranyl, benzothiazolyl, benzisothiazolyl, benzisoxazolyl, benzimidazolyl, indolyl, benzoxazolyl, isoquinolinyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, isoindolyl, purinyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, quinazolinyl, quinoxalinyl, naphthridinyl, and furopyridinyl.
[00105] Suitable "heterocycloalkyl" groups include those having at least one or more hetero- ring atoms, such as two or three hetero- ring atoms, independently selected from -0-, -S-, -S(0)2-, -N(H)-, and -N(CH2)mR18-. Suitable heterocycloalkyl groups may include, for example, tetrahydrofurano, tetrahydropyrano, morpholino, pyrrolidino, piperidino, piperazino, azetidino, azetidinono, oxindolo, oxetano, dihydroimidazolo, and pyrrolidinono.
[00106] The pharmaceutically acceptable salt of the spiro-oxadiazoline compounds represented by Formula (I), Formula (Ila), or Formula (lib), according to the present invention may be acid addition salts with inorganic or organic acids. Specific examples of these salts include acid addition salts with, for instance, mineral acids such as hydrochloric acid, hydrobromic acid, hydriodic acid, sulfuric acid, nitric acid or phosphoric acid; organic acids, for example carboxylic acids or sulfonic acids, such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, benzoic acid, p-toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, isethionic acid, glucuronic acid, gluconic acid, methanesulfonic acid or ethanesulfonic acid; or acidic amino acids such as aspartic acid or glutamic acid.
[00107] The spiro-oxadiazoline compound represented by Formula (I), Formula (Ila), or Formula (lib), or a pharmaceutically acceptable salt thereof, may be synthesized by a variety of methods. The following schemes represent typical examples of such preparation methods:
Reaction Scheme 1:
Figure imgf000062_0001
(+/-) (iii)
[00108] In Reaction Scheme 1 , the nitrile group of (i) is reacted with hydroxylamine to form a hydroxyamidine (ii). The resulting hydroxyamidine (ii) is then condensed with quinuclidin-3-one via a [3+2] cycloaddition to form a racemic mixture of an oxadiazoline compound (+/-) (iii).
Figure imgf000062_0002
(iii) (iv) [00109] In Reaction Scheme 2, the nitrile group of (i) is reacted with hydroxylamine to form a hydroxyamidine (ii). The resulting hydroxyamidine (ii) is then condensed with 1 -aza-adamantan- 4-one via a [3+2] cycloaddition to form a mixture of geometric isomers of an oxadiazoline compound (iii) and (iv).
Reaction Sche
Figure imgf000063_0001
(0 (ϋ) (+/-) (iv)
[00110] In Reaction Scheme 3, the aldehyde group of (i) is reacted with hydroxylamine to form an oxime (ii). The resulting oxime (ii) is then reacted with an imine (iii) (prepared from quinuclidin-3-one in accordance with reaction scheme 7) via a [3+2] cycloaddition to form a racemic mixture of an oxadiazoline compound (+/-) (iv).
Reaction Scheme 4:
Figure imgf000063_0002
[00111] In Reaction Scheme 4, the aldehyde group of (i) is reacted with hydroxylamine to form an oxime (ii). The resulting oxime (ii) is then reacted with an imine (iii) (prepared from 1 - aza-adamantan-4-one in accordance with reaction scheme 7) via a [3+2] cycloaddition to form a mixture of geometric isomers of an oxadiazoline compound (iv) and (v).
Reaction Scheme 5:
Figure imgf000063_0003
(') (ϋ) (+/-) (W)
Figure imgf000064_0001
(S)-(iv) (S)-(v)
[00112] In Reaction Scheme 5, the aldehyde group of (i) is reacted with hydroxylamine to form an oxime (ii). The resulting oxime (ii) is then reacted with an N-protected imine (iii) (prepared from quinuclidin-3-one in accordance with reaction scheme 7) via a [3+2] cycloaddition to form a racemic mixture of an N-protected oxadiazoline compound (+/-) (iv). The racemic mixture of N-protected oxadiazoline compound (+/-) (iv) is then chirally separated into N- protected oxadiazoline compound (R)-(iv) and (S)-(iv), and each stereoisomer is then separately deprotected to form oxadiazoline compound (R)-(v) and (S)-(v).
Reaction Scheme 6:
Figure imgf000064_0002
TFA TFA
Figure imgf000064_0003
(vi) (vii)
[00113] In Reaction Scheme 6, the aldehyde group of (i) is reacted with hydroxylamine to form an oxime (ii). The resulting oxime (ii) is then reacted with an N-protected imine (iii) (prepared from 1 -aza-adamantan-4-one in accordance with reaction scheme 7) via a [3+2] cycloaddition to form a mixture of geometric isomers of an N-protected oxadiazoline compound (iv) and (v). The mixture of geometric isomers (iv) and (v) are then separated and each geometric isomer is then separately deprotected to form the single geometric isomer oxadiazoline compounds (vi) and (vii). Reaction Scheme 7 - Synthesis of intermediates:
Figure imgf000065_0001
(i) (iii) (iv)
[00114] In Reaction Scheme 7, ketone (i) (quinuclidin-3-one) or ketone (iii) (1-aza- adamantan-4-one) is condensed with an amine to form an imine (ii) or (iv), respectively, which is then utilized in one or more of reaction schemes 3-6 in the preparation of oxadiazoline compounds of the present invention.
[00115] In certain embodiments, a pharmaceutical composition may comprise a spiro- oxadiazoline compound represented by Formula (I), (Ila), or (lib), or a pharmaceutically acceptable salt thereof.
[00116] In certain embodiments, the spiro-oxadiazoline compounds represented by Formula (I), Formula (Ila), or Formula (lib), or a pharmaceutically acceptable salt thereof, are suitable for use as medicaments for the treatment and/or prophylaxis of diseases in humans and/or animals.
[00117] In certain embodiments, the invention relates to a method comprising administering to a patient in need thereof an effective dose of a spiro-oxadiazoline compound represented by Formula (I), Formula (Ila), or Formula (lib), or a pharmaceutically acceptable salt thereof.
[00118] In certain embodiments, the spiro-oxadiazoline compounds represented by Formula (I), Formula (Ila), or Formula (lib), or a pharmaceutically acceptable salt thereof, act as ligands, in particular as a7-nAChR agonists.
[00119] In certain embodiments, a method of treating a patient in need thereof, comprising administering a spiro-oxadiazoline compound represented by Formula (I), (Ila), or (lib), or a pharmaceutically acceptable salt thereof. In certain embodiments, a method of treating a patient in need thereof, comprising administering a pharmaceutical composition comprising a spiro- oxadiazoline compound represented by Formula (I), (Ila), or (lib), or a pharmaceutically acceptable salt thereof. For example, the patient may suffer from a cognitive impairment or suffers from one or more symptoms associated with a cognitive impairment, such as Limited Cognitive Impairment (LCI), Mild Cognitive Impairment (MCI), Alzheimer's disease, dementia of an Alzheimer's-type, schizophrenia, schizophreniform disorder, schizoaffective disorder, delusional disorder, positive symptoms of schizophrenia, negative symptoms of schizophrenia, or schizophrenia with dementia.
[00120] In certain embodiments, the spiro-oxadiazoline compounds represented by Formula (I), Formula (Ila), or Formula (lib), or a pharmaceutically acceptable salt thereof, can, because of their pharmacological properties, be employed alone or in combination with other active ingredients for the treatment and/or prevention of cognitive impairments, for example,
Alzheimer's disease or schizophrenia. Because of their selective effect as a7-nAChR agonists, the spiro-oxadiazoline compounds represented by Formula (I), Formula (Ila), or Formula (lib), or a pharmaceutically acceptable salt thereof, are particularly suitable for improving cognition, providing procognitive effects, improving perception, improving concentration, improving learning or memory, improving one or more aspects of cognition, e.g., one or more of: executive function, memory (e.g., working memory), social cognition, visual learning, verbal learning and speed of processing, especially after or associated with cognitive impairments like those occurring for example in situations/diseases/syndromes such as mild cognitive impairment, age-associated learning and memory impairments, age-associated memory loss, vascular dementia,
craniocerebral trauma, stroke, dementia occurring after strokes (post-stroke dementia), posttraumatic brain syndrome, general concentration impairments, concentration impairments in children with learning and memory problems, attention deficit hyperactivity disorder, Alzheimer's disease, Lewy body dementia, dementia with degeneration of the frontal lobes, including Pick's syndrome, Parkinson's disease, dyskinesias associated with dopamine agonist therapy in
Parkinson's Disease, progressive nuclear palsy, dementia with corticobasal degeneration, amyotrophic lateral sclerosis (ALS), Huntington's disease, multiple sclerosis, thalamic degeneration, Creutzfeld-Jakob dementia, HIV dementia, schizophrenia (e.g., paranoid type, disorganized type, catatonic type, and undifferentiated type), schizophreniform disorder, schizoaffective disorder, delusional disorder, positive symptoms of schizophrenia, negative symptoms of schizophrenia, schizophrenia with dementia, Korsakoff s psychosis, depression, anxiety, mood and affective disorders, traumatic brain injury, withdrawal symptoms associated with smoking cessation and dependent drug cessation, Gilles de la Tourette's Syndrome, age- related macular degeneration, glaucoma, neurodegeneration associated with glaucoma, treatment (including amelioration, prevention or delay of progression) of sleep disorders (e.g., narcolepsy, excessive daytime sleepiness, nocturnal sleep disruption and/or cataplexy), treatment (including amelioration, prevention or delay) of progression of fatigue, or use for facilitation of emergence from general anesthesia.
[00121] In certain embodiments, the spiro-oxadiazoline compounds represented by Formula (I), Formula (Ila), or Formula (lib), or a pharmaceutically acceptable salt thereof, can be employed alone or in combination with other active ingredients for the prophylaxis and treatment of acute and/or chronic pain (for a classification, see "Classification of Chronic Pain, Descriptions of Chronic Pain Syndromes and Definitions of Pain Terms", 2nd edition, Meskey and Begduk, editors; IASP Press, Seattle, 1994), especially for the treatment of cancer-induced pain and chronic neuropathic pain like, for example, that associated with diabetic neuropathy, postherpetic neuralgia, peripheral nerve damage, central pain (for example as a consequence of cerebral ischaemia) and trigeminal neuralgia, and other chronic pain such as, for example, lumbago, backache (low back pain) or rheumatic pain. In addition, these active ingredients are also suitable for the therapy of primary acute pain of any origin and of secondary states of pain resulting therefrom, and for the therapy of states of pain which were formerly acute and have become chronic.
[00122] In certain embodiments, the invention relates to a method comprising administering to a patient in need thereof an effective dose of a spiro-oxadiazoline compound represented by Formula (I), Formula (Ha), or Formula (lib), or a pharmaceutically acceptable salt thereof. For example, one or more symptoms associated with a cognitive impairment and/or the cognitive impairment may be treated and/or improved by administering to a patient in need thereof, an effective dose of a spiro-oxadiazoline compound represented by Formula (I), Formula (Ila), or Formula (lib), or a pharmaceutically acceptable salt thereof.
[00123] A certain embodiment of the present invention provides a method of improving one or more cognitive symptoms, improving one or more behavioral symptoms, or both, associated with a cognitive impairment, comprising: administering to a patient in need thereof a
pharmaceutical composition comprising an effective dose of a spiro-oxadiazoline compound represented by Formula (I), Formula (Ila), or Formula (lib), or a pharmaceutically acceptable salt thereof.
[00124] In a certain embodiment of the present invention, the method provides a pro-cognitive effect in a patient suffering from, or diagnosed as having, a cognitive disease or dementia, comprising: administering to a patient in need thereof, a pharmaceutical composition comprising an effective dose of a spiro-oxadiazoline compound represented by Formula (I), Formula (Ila), or Formula (lib), or a pharmaceutically acceptable salt thereof, wherein the method provides at least one of the following: visual motor, learning, delayed memory, or executive function; for example provides a pro-cognitive effect, exclusive of attention, in said patient; for example provides a pro- cognitive effect in at least one of the following: visual motor, learning, delayed memory, or executive function.
[00125] A certain embodiment of the present invention provides a method of treating a patient with a cognitive disease, comprising: administering to the patient a daily dose of a pharmaceutical composition comprising a spiro-oxadiazoline compound represented by Formula (I), Formula (Ila), or Formula (lib), or a pharmaceutically acceptable salt thereof.
[00126] In a certain embodiment of the present invention, the method provides a pro-cognitive effect in a patient suffering from, or diagnosed as having, schizophrenia, for example, paranoid type schizophrenia, disorganized type schizophrenia, catatonic type schizophrenia,
undifferentiated type schizophrenia, schizophreniform disorder, schizoaffective disorder, delusional disorder, positive symptoms of schizophrenia, negative symptoms of schizophrenia, or schizophrenia with dementia, comprising: administering to a patient in need thereof, a pharmaceutical composition comprising an effective dose of a spiro-oxadiazoline compound represented by Formula (I), Formula (Ha), or Formula (lib), or a pharmaceutically acceptable salt thereof, wherein the method provides at least one of the following: visual motor, learning, delayed memory, or executive function; for example provides a pro-cognitive effect, exclusive of attention, in said patient; for example provides a pro-cognitive effect in at least one of the following: visual motor, learning, delayed memory, or executive function.
[00127] In an embodiment of the present invention, any one of the above-noted embodiments, includes the daily dose as an initial daily dose.
[00128] In an embodiment of the present invention, any one of the above-noted embodiments, includes improving cognition of the patient.
[00129] In an embodiment of the present invention, any one of the above-noted embodiments, includes treating a symptom associated with a cognitive disease.
[00130] In an embodiment of the present invention, any one of the above-noted embodiments, includes improving a symptom associated with a cognitive disease.
[00131] In an embodiment of the present invention, any one of the above-noted embodiments, includes preventing progression of a cognitive disease.
[00132] In an embodiment of the present invention, any one of the above-noted embodiments, includes the patient has been diagnosed as having a cognitive disease.
[00133] In an embodiment of the present invention, any one of the above-noted embodiments, includes treating a symptom associated with Alzheimer's disease.
[00134] In an embodiment of the present invention, any one of the above-noted embodiments, includes improving a symptom associated with Alzheimer's disease.
[00135] In an embodiment of the present invention, any one of the above-noted embodiments, includes preventing progression of Alzheimer's disease.
[00136] In an embodiment of the present invention, any one of the above-noted embodiments, includes the patient has been diagnosed as having mild-to-moderate Alzheimer's disease.
[00137] In an embodiment of the present invention, any one of the above-noted embodiments, includes treating a symptom associated with schizophrenia.
[00138] In an embodiment of the present invention, any one of the above-noted embodiments, includes improving a symptom associated with schizophrenia.
[00139] In an embodiment of the present invention, any one of the above-noted embodiments, includes preventing progression of schizophrenia.
[00140] In an embodiment of the present invention, any one of the above-noted embodiments, includes the patient has been diagnosed as having schizophrenia.
[00141] In an embodiment of the present invention, any one of the above-noted embodiments, includes treating a symptom associated with positive symptoms of schizophrenia.
[00142] In an embodiment of the present invention, any one of the above-noted embodiments, includes improving a symptom associated with positive symptoms of schizophrenia.
[00143] In an embodiment of the present invention, any one of the above-noted embodiments, includes preventing progression of positive symptoms of schizophrenia. [00144] In an embodiment of the present invention, any one of the above-noted embodiments, includes the patient has been diagnosed as having positive symptoms of schizophrenia.
[00145] In an embodiment of the present invention, any one of the above-noted embodiments, includes treating a symptom associated with negative symptoms of schizophrenia.
[00146] In an embodiment of the present invention, any one of the above-noted embodiments, includes improving a symptom associated with negative symptoms of schizophrenia.
[00147] In an embodiment of the present invention, any one of the above-noted embodiments, includes preventing progression of negative symptoms of schizophrenia.
[00148] In an embodiment of the present invention, any one of the above-noted embodiments, includes the patient has been diagnosed as having negative symptoms of schizophrenia.
[00149] In an embodiment of the present invention, any one of the above-noted embodiments, includes treating a symptom associated with schizophrenia with dementia.
[00150] In an embodiment of the present invention, any one of the above-noted embodiments, includes improving a symptom associated with schizophrenia with dementia.
[00151] In an embodiment of the present invention, any one of the above-noted embodiments, includes preventing progression of schizophrenia with dementia.
[00152] In an embodiment of the present invention, any one of the above-noted embodiments, includes the patient has been diagnosed as having schizophrenia with dementia.
[00153] In an embodiment of the present invention, any one of the above-noted embodiments, includes the patient has been diagnosed as having a disease associated with chronic inflammation, including atherosclerosis, rheumatoid arthritis and inflammatory bowel diseases.
[00154] In an embodiment of the present invention, any one of the above-noted embodiments, includes the pharmaceutical composition is in the form of a tablet.
[00155] Pharmaceutical Compositions
[00156] In certain embodiments, the invention also includes pharmaceutical preparations which, besides inert, nontoxic, pharmaceutically suitable excipients, adjuvants and carriers, contain one or more spiro-oxadiazoline compounds represented by Formula (I), Formula (Ha), or Formula (lib), or a pharmaceutically acceptable salt thereof, or consist of one or more spiro- oxadiazoline compounds represented by Formula (I), Formula (Ha), or Formula (lib), or a pharmaceutically acceptable salt thereof, and processes for producing these preparations.
[00157] A spiro-oxadiazoline compound represented by Formula (I), Formula (Ila), or Formula (lib), or a pharmaceutically acceptable salt thereof, may be formulated for administration in solid or liquid form. For example, a spiro-oxadiazoline compound represented by Formula (I), Formula (Ila), or Formula (lib), or a pharmaceutically acceptable salt thereof, may be formulated for administration in a capsule, a tablet, or a powder form. For example, a spiro-oxadiazoline compound represented by Formula (I), Formula (Ila), or Formula (lib), or a pharmaceutically acceptable salt thereof, may be formulated alone or as part of a pharmaceutical composition, suitable for oral administration, such as in a capsule or tablet, intravenous administration, parenteral administration, topical administration, or transdermal administration, such as in a patch, to a patient in need thereof.
[00158] A spiro-oxadiazoline compound represented by Formula (I), Formula (Ha), or Formula (lib), or a pharmaceutically acceptable salt thereof, may be administered as a pharmaceutical composition, for example, in the presence of carriers, adjuvants, excipients, diluents, fillers, buffers, stabilizers, preservatives, lubricants, and the like, for example, administered as a pharmaceutical composition (e.g., formulation) comprising at least a spiro- oxadiazoline compound represented by Formula (I), Formula (Ila), or Formula (lib), or a pharmaceutically acceptable salt thereof, together with one or more pharmaceutically acceptable carriers, adjuvants, excipients, diluents, or other materials well known to those skilled in the art. As used herein, the term "pharmaceutically acceptable", unless otherwise specified, includes the generally accepted meaning which encompasses combinations, compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for consumption by humans without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
[00159] Suitable pharmaceutically acceptable carriers, adjuvants, excipients, and diluents, can include, but are not limited to, lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum, acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water syrup, methyl cellulose, methyl and propyl
hydroxybenzoates, talc, magnesium stearate, and mineral oil. Pharmaceutically acceptable carriers, adjuvants and vehicles that may be used in the pharmaceutical compositions of this invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat.
[00160] The formulations can additionally include, but are not limited to, pharmaceutically acceptable lubricating agents, glidants, wetting agents, emulsifying and suspending agents, preserving agents, sweetening agents, and/or flavoring agents. The pharmaceutical compositions of the present invention may be formulated so as to provide quick release, immediate release, sustained release, or delayed release of a spiro-oxadiazoline compound represented by Formula (I), Formula (Ila), or Formula (lib), or a pharmaceutically acceptable salt thereof, after administration to the patient by employing procedures well-known in the art. [00161] Another embodiment of the invention further comprises methods of making
Pharmaceutical Composition, comprising admixing at least a spiro-oxadiazoline compound represented by Formula (I), Formula (Ila), or Formula (lib), or a pharmaceutically acceptable salt thereof, together with one or more pharmaceutically acceptable carriers, excipients, buffers, adjuvants, stabilizers, or other materials.
[00162] In certain embodiments, the spiro-oxadiazoline compounds represented by Formula (I), Formula (Ila), or Formula (lib), or a pharmaceutically acceptable salt thereof, are to be present in these preparations in a concentration of from 0.1 to 99.5% by weight, preferably from 0.5 to 95% by weight, of the complete mixture. Besides the spiro-oxadiazoline compounds represented by Formula (I), Formula (Ila), or Formula (lib), or a pharmaceutically acceptable salt thereof, the pharmaceutical preparations may also contain other active pharmaceutical ingredients.
[00163] In certain embodiments, the novel active ingredients can be converted in a known manner into conventional formulations such as tablets, coated tablets, pills, granules, aerosols, syrups, emulsions, suspensions and solutions, using inert, nontoxic, pharmaceutically suitable excipients or solvents. In these cases, the therapeutically active compound should in each case be present in a concentration of about 0.5 to 90% by weight of the entire mixture, i.e., in amounts which are sufficient to reach the stated dose range.
[00164] In certain embodiments, the formulations are produced, for example, by extending the active ingredients with solvents and/or excipients, where appropriate with use of emulsifiers and/or dispersants, it being possible for example when water is used as diluent where appropriate to use organic solvents as auxiliary solvents.
[00165] In certain embodiments, administration may take place in a conventional way, for example, orally, transdermally or parenterally, especially perlingually or intravenously. In certain embodiments, administration may also take place by inhalation through the mouth or nose, for example, with the aid of a spray, or topically via the skin.
[00166] In certain embodiments, the spiro-oxadiazoline compounds represented by Formula (I), Formula (Ila), or Formula (lib), or a pharmaceutically acceptable salt thereof, may be administered in amounts of about 0.01 to 10 mg/kg, on oral administration, for example, about 0.05 to 5 mg/kg, of body weight to achieve effective results. [00167] EXAMPLES
[00168] Analytical instrument model:
Table 1
Figure imgf000072_0001
[00169] LCMS Conditions A ("LCMS (AT): Instrument: LCMS-A, Mobile phase A: 4L H20 \ 1.5 mL TFA Mobile phase B: 4L ACN \ 0.75 mL TFA, Method name: 10-80AB_4MIN_2W, Flow Rate: 0.8 mL/min., Gradient: 10%-80%; Column: Boston Green ODS 2.1 *30 mm, 3 μπι, Column temperature: 50 °C; Wavelength: 220 nm & 254 nm.
[00170] LCMS Conditions B ("LCMS (BY'): Instrument: LCMS-B, Mobile phase A: 4L H20 \ 1.5 ml TFA Mobile phase B: 4L ACN \ 0.75 mL TFA, Method name: 5-95AB_R_2W, Flow Rate: 1.5 mL/min., Gradient: 5%-95%; Column: Chromolith Flash RP-18e 25-2 mm, Column temperature: 50 °C; Wavelength: 220 nm & 254 nm.
[00171] LCMS Conditions C ("LCMS (CV'V Instrument: LCMS-C, Mobile phase A: 4L H20 \ 1.5 mL TFA, Mobile phase B: 4L ACN \ 0.75 mL TFA, Method name: 5-95AB_R_4MIN_2W Flow Rate: 1.5 mL/min., Method name: 5-95CD_4.5MI _2W, Flow Rate: 0.8 mL/min., Gradient: 5%-95%; Column: Chromolith Flash RP-18e 25-2 mm, Column temperature 50 °C; Wavelength: 220 nm & 254 nm.
[00172] LCMS Conditions D ("LCMS (DV'V Instrument: LCMS-C, Mobile phase A: 4L H20 \ 1.5 mL TFA, Mobile phase B: 4L ACN \ 0.75 mL TFA, Method name: 5-95AB_R_4MIN_2W, Flow Rate: 0.8 mL/min., Gradient: 5%-95%; Column: Chromolith Flash RP-18e 25-2 mm, Column temperature: 50 °C; Wavelength: 220 nm & 254 nm.
[00173] LCMS Conditions E ("LCMS (EV): Instrument: LCMS-C, Mobile phase A:4L H20 \ 1.5 ml TFA, Mobile phase B:4L ACN\0.75 mL TFA, Method name: 5-95AB R Flow Rate: 1.5 mL/min., Gradient: 5%-95%; Column: Chromolith Flash RP-18e 25-2 mm, Column temperature: 50 °C; Wavelength: 220 nm & 254 nm.
[00174] LCMS Conditions F ("LCMS (¥T): Instrument: LCMS-D, Mobile phase A: 4L H20 \ 2 ml NH3H20, Mobile phase B: Acetonitrile, Method name: 5-95CD_2MIN_ 2W, Flow Rate: 1 .2 mL/min., Gradient: 5%-95%, Column: XBrige Shield RP-18 2.1 *50 mm, 5 μπι, Column temperature: 30 °C; Wavelength: 220 nm & 254 nm. [00175] LCMS Conditions G ("LCMS (GV : Instrument: LCMS-D, Mobile phase A: 4L H20 \ 2 mL NH3H20, Mobile phase B: Acetonitrile, Method name: 10-80CD_4MI _POS, Flow Rate: 0.8 mL/min., Gradient: 10%-80%; Column: XBridge C-1 8 2.1 *50 mm, 5μιη, Column temperature: 40 °C; Wavelength: 220 nm & 254 nm.
[00176] LCMS Conditions H ("LCMS (HT): Instrument: LCMS-E, Mobile phase A: 4L H20 \ 1 .5 mL TFA, Mobile phase B: 4L ACN \ 0.75 mL TFA, Method name: 10-80AB_4MIN_2W, Flow Rate: 0.8 mL/min., Gradient: 10%-80%; Column: Xtimate C-18, 2.1 *30 mm, 3 μιη, Column temperature: 50 °C; Wavelength: 220 nm & 254 nm.
[00177] LCMS Conditions I ("LCMS (1)"): Instrument: LCMS-E, Mobile phase A: 4L H20 \ 2 mL NH3H20, Mobile phase B: Acetonitrile Method name:0-60CD_4.5MI _2W, Flow Rate: 0.8 ml/min., Gradient: 0%-60%; Column:XBrige Shield RP-18 2.1 *50 mm, 5μηι, Column temperature 50 °C; Wavelength: 220 nm & 254 nm.
[00178] LCMS Conditions J ("LCMS (J)"): Instrument: LCMS-D, Mobile phase A: 4L H20 \ 2mL NH3H20 Mobile phase B: Acetonitrile Method name: 10-80CD_2MIN_POS_2W, Flow Rate: 1.2ml/min., Gradient: 10%-80%; Column: Xbridge C-18 2.1 *50 mm, 5 μιη, Column temperature: 40 °C; Wavelength: 220 nm & 254 nm.
[00179] cSFC Analytical Conditions: Instrument: Agilent Technologies 1290 Infinity, Column temperature: 35 °C (unless otherwise stated), back pressure: 120 bar (unless otherwise stated), and wavelength: 220 nm.
[00180] Example 1A - -hydroxybenzimidamide (A-101)
Figure imgf000073_0001
[00181] To a solution of benzonitrile (5.00 g, 0.048 mol) and hydroxylamine hydrochloride (10.00 g, 0.144 mol) in anhydrous methanol (40 mL) was added potassium carbonate (20.00 g, 0.144 mol) at room temperature. The mixture was stirred at room temperature overnight. On completion, the mixture was filtered and washed with methanol. The filtrate was concentrated under reduced pressure to give compound A-101 (4.5 g, 69% yield) as a white solid.
[00182] Example 2 - 4-chloro-N-hvdroxybenzimidamide (A-102)
Figure imgf000073_0002
[00183] To a solution of 4-chlorobenzonitrile (4 g, 0.029 mol) and hydroxylamine
hydrochloride (5.9 g, 0.087 mmol) in anhydrous methanol (50 mL) was added potassium carbonate (12 g, 0.087 mol) at room temperature and the mixture was stirred at room temperature for 4 hours. On completion, the mixture was filtered and washed with methanol. The filtrate was concentrated under reduced pressure to give compound A-102 (4.8 g, 94% yield) as a white solid
[00184]
Figure imgf000074_0001
[00185] [0009] A solution of benzo[b]thiophene-2-carbonitrile (4g, 0.025 mol), potassium carbonate (10.35g, 0.075mol) and hydroxylamine hydrochloride (5.18 g, 0.075 mol) in methanol (80 mL) was stirred at room temperature for 5 hours. On completion, the solution was filtered and the filtrate was concentrated. The resulting residue was purified by column chromatography [petroleum ether/ethyl acetate=2: l ] to give compound A-103 (4g, 83%) as a yellow solid. LCMS: (ES+) m/z (M+H)+ = 193.1 , retention time (tR) = 1.065.
[00186]
Figure imgf000074_0002
[00187] To a solution of benzofuran-2-carbonitrile (1 g, 6.99 mmol) and hydroxylamine hydrochloride (1.46 g, 21.0 mmol) in anhydrous MeOH (20 mL) was added potassium carbonate (2.90 g, 21.0 mmol) at room temperature and the reaction was stirred at room temperature overnight. On completion, the mixture was filtered and washed with methanol. The filtrate was concentrated under reduced pressure to give compound A-104 (1.1 g, 89% yield) as a white solid. LCMS: (ES+) m/z (M+H)+ = 176.9, tR=1.044.
[00188]
Figure imgf000074_0003
[00189] To a solution of l H-indole-2-carbonitrile (4 g, 0.028 mol) and hydroxylamine hydrochloride (5.87 g, 0.085 mol) in anhydrous methanol (80 mL) was added potassium carbonate (1 1.66 g, 0.085 mol) at room temperature. The mixture was stirred at room temperature overnight. On completion, the mixture was filtered and washed with methanol. The filtrate was concentrated under reduced pressure to give compound A-105 (4.0 g, 81% yield) as a white solid. The crude was used for next step without any purification. LCMS: (ES+) m/z (M+H)+ = 176.1 , tR=0.568.
[00190] Example 6A - 7-fluoro-N-hvdroxybenzo[b1thiophene-2-carboximidamide (A-106)
Figure imgf000075_0001
[00191] To a solution of 7-fluorobenzo[b]thiophene-2-carbonitrile (0.50 g, 2.8 mmol) and hydroxylamine hydrochloride (0.58 g, 8.4 mmol) in anhydrous methanol (10 mL) was added potassium carbonate (1.16 g, 8.4 mmol) at room temperature. The mixture was stirred at room temperature overnight. On completion, the mixture was filtered and washed with methanol. The filtrate was concentrated under reduced pressure to give compound A-106 (0.5 g, 85% yield) as a white solid. LCMS: (ES+) m/z (M+H)+ = 21 1.1, tR=0.636.
[00192] Example 7A - 7-chloro-N-hvdroxybenzo b]thiophene-2-carboximidamide (A-107)
Figure imgf000075_0002
[00193] To a solution of 7-chlorobenzo[b]thiophene-2-carbonitrile (0.5 g, 2.6 mmol) and hydroxylamine hydrochloride (0.54 g, 7.8 mmol) in anhydrous MeOH (10 mL) was added potassium carbonate (1.08 g, 7.8 mmol) at room temperature. The mixture was stirred for 5 hours at room temperature. On completion, the mixture was filtered and washed with methanol. The filtrate was concentrated under reduced pressure to give compound A-107 (0.52 g, 89% yield) as a yellow solid. LCMS: (ES+) m/z (M+H)+ = 21 1.9, tR=1.195.
[00194] Example 8A - 7-bromo-N-hvdroxybenzo blthiophene-2-carboximidamide (A-108)
Figure imgf000075_0003
[00195] To a solution of 7-bromobenzo[b]thiophene-2-carbonitrile (1.55 g, 0.0065 mol) and hydroxylamine hydrochloride (1.36 g, 0.020 mol) in anhydrous methanol (60 mL) was added potassium carbonate (2.71 g, 0.020 mol) at room temperature. The mixture was stirred at room temperature overnight. On completion, the mixture was filtered and washed with methanol. The filtrate was concentrated under reduced pressure to give compound A-108 (1.8 g, 100% yield) as a white solid. LCMS: (ES+) m/z (M+H)+ = 271.0, tR=0.612.
[00196]
Figure imgf000076_0001
[00197] To a solution of 7-fluorobenzofuran-2-carbonitrile (0.9 g, 5.6 mmol) and
hydroxylamine hydrochloride (1.17 g, 17 mmol) in anhydrous methanol (40 mL) was added potassium carbonate (2.31 g, 17 mmol) at room temperature. The mixture was stirred at room temperature overnight. On completion, the mixture was filtered and washed with methanol. The filtrate was concentrated under reduced pressure to give compound A-109 (1.1 g, 100% yield) as a white solid. The crude was used for next step without any purification. LCMS: (ES+) m/z (M+H)+ = 195.0, tR=0.996.
[00198] Example 10A - N'-hvdroxybenzo[b]thiophene-5-carboximidarnide (A-110)
Figure imgf000076_0002
[00199] A solution of 5-bromobenzo[b]thiophene (2.2 g, 13.8 mmol), hydroxylamine hydrochloride (2.88 g, 41.4 mmol) and potassium carbonate (5.72 g, 41.4 mmol) in ethyl alcohol (50 mL) was heated at reflux for 3 hours. The reaction was monitored by TLC. On completion, the resulting mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (100 mL) and was washed with water and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was recrystallized with ethyl alcohol to give compound A-110 (2.0 g, 68%) as a pale yellow solid. This material was used for next step without further purification.
[00200] Example 11A - N-hydroxy-2-methyl-L2,3,4-tetrahvdroisoquinoline-6- carboximidamide (A-lll)
Figure imgf000076_0003
[00201] A solution of 2-methyl-l ,2,3,4-tetrahydroisoquinoline-6-carbonitrile (0.7 g, 4.07 mmol), potassium carbonate (1.68 g, 12.21 mmol) and hydroxylamine hydrochloride (0.84 g, 12.21 mmol) in methanol (20 mL) was stirred at room temperature for 24 hours. On completion, a filtration was performed. The filtrate was concentrated in vacuo to give compound A-111 (0.8 g, 94% yield) as a white solid. This material was used for next step without further purification. LCMS: (ES+) m/z (M+H)+ = 206.0, tR=0.625.
[00202] Example IB - 4-chlorobenzaldehyde oxime (B-101
Figure imgf000077_0001
B-101
[00203] To a mixture of 4-chlorobenzaldehyde (25.0 g, 0.179 mol) and hydroxylamine hydrochloride (26.0 g, 0.375 mol) in ethanol/water (5: 1 , 200 mL) was added sodium hydroxide (15.7 g, 0.394 mol) at room temperature. The mixture was stirred at room temperature overnight. On completion, a filtration was performed. The filtrate was concentrated and purified by chromatography on silica gel [petroleum ether/ethyl acetate=15: l] to give compound B-101 (16.0 g, 58% yield) as a white solid.
[00204] Example 2B - benzorblthiophene-2-carbaldehyde oxime (B-102)
Figure imgf000077_0002
B-102
[00205] To a mixture of benzo[b]thiophene-2-carbaldehyde (12 g, 0.074 mol) and hydroxylamine hydrochloride (15.32 g, 0.222 mol) in anhydrous methanol (250 mL) was added potassium carbonate (30.64 g, 0.222 mol) at room temperature. The mixture was stirred at room temperature for 4 hours. On completion, the mixture was filtered and purified by column chromatography [petroleum ether/ethyl acetate=20: l] to give compound B-102 (1 1.8 g, 90% yield) as a white solid. LCMS: (ES+) m/z (M+H)+ = 178.1 , tR=1.218.
[00206] Example 3B - benzorblthiophene-3-carbaldehyde oxime (B-103)
0
Figure imgf000077_0003
[00207] To a mixture of benzo[b]thiophene-3-carbaldehyde (10 g, 0.06 mol) and
hydroxylamine hydrochloride (6.4 g, 0.09 mol) in anhydrous methyl alcohol (100 mL) was added potassium carbonate (12.4 g, 0.09 mol) at room temperature. The mixture was stirred at room temperature overnight. On completion, a filtration was performed and the residue was purified by silica gel chromatography eluting with petroleum ethenethyl acetate = 10: 1 to give compound B- 103 (7.0 g, 66% yield) as a white solid. LCMS: (ES+) m/z (M+H)+ = 178.1 , tR=0.725.
[00208]
Figure imgf000078_0001
[00209] To a solution of benzofuran-2-carbaldehyde (3.0 g, 20.5 mmol) and hydroxylamine hydrochloride (2.1 g, 30.8 mmol) in dichloromethane was added triethylamine (3.1 g, 30.8 mmol) slowly at 0 °C. The reaction mixture was allowed to stir at room temperature for 3 hours. Once complete by TLC analysis the reaction mixture was washed with water (2 x 20 mL) and brine before being dried over anhydrous sodium sulfate. After concentration, the crude product was purified by column chromatography [petroleum ether/ethyl acetate=15: l] to afford compound B- 104 (3.0 g, 91% yield) as a yellow solid. LCMS: (ES+) m/z (M+H)+ = 162.2, tR=0.605 and 0.653.
[00210] Exam - l H-indole-2-carbaldehvde oxime (B-105
Figure imgf000078_0002
B-105
[00211] A mixture of lH-indole-2-carbaldehyde (2 g, 13.8 mmol), hydroxylamine hydrochloride (1.44 g, 20.7 mmol) and sodium hydroxide (0.83 g, 20.7 mmol) in 50%
ethanol/water (30 mL) was stirred at room temperature for 2 hours. On completion, the mixture was concentrated to remove most of ethanol and then extracted with dichloromethane. The organic layer was concentrated and purified by column chromatography [petroleum ether/ethyl acetate=2: l] to give compound B-105 (1.9 g, 86% yield) as a white solid. LCMS: (ES+) m/z (M+H)+ =161.1 , tR=l .060.
[00212] Example 6B - benzorblthiazole-2-carbaldehyde oxime (B-106)
Figure imgf000078_0003
[00213] To a mixture of benzo[b]thiazole-2-carbaldehyde (2.0 g, 12.3 mmol) and
hydroxylamine hydrochloride (1.3 g, 18.5 mmol) in ethanohwater (9: 1 , 20 mL) was added sodium hydroxide (1.0 g, 24.6 mmol) at room temperature. The mixture was stirred at room temperature for 4 h. On completion, two isomers were observed on TLC. After concentration, the mixture was extracted with dichloromethane (10 mL x 2). The combined organic layers were washed with water, brine and then dried over sodium sulfate. After concentration the two spots was separated by silica chromatography (petroleum ether / ethyl acetate = 10 : 1). The higher running spot was isolated to give compound B-106 as a white solid (1.5 g, 78 % yield) and was used for next step. LCMS: (ES+) m/z (M+H)+ = 178.9, tR=0.852.
[00214] Example 7B - isoquinoline-3-carbaldehvde oxime (B-107)
Figure imgf000079_0001
B-107
[00215] To a mixture of isoquinoline-3-carbaldehyde (1.8 g, 1 1.5 mmol) and hydroxylamine hydrochloride (1.2 g, 17.0 mmol) in ethanol/water (5: 1 , 20 mL) was added sodium hydroxide (0.7 g, 17.0 mmol) at room temperature. The mixture was stirred at room temperature overnight. On completion, the mixture was filtered, the organic layers were concentrated and the resulting residue was purified by chromatography on silica gel [dichloromethane/methanol=80: l] to give compound B-107 (1.4 g, 70% yield) as a yellow solid. LCMS: (ES+) m/z (M+H)+ =173.1 , tR=0.621.
[00216] Example 8B - 7-fluorobenzo[blthiophene-2-carbaldehyde oxime (B-108)
Figure imgf000079_0002
[00217] A mixture of 7-fluorobenzo[b]thiophene-2-carbaldehyde (4.2 g, 23.33 mmol), hydroxylamine hydrochloride (2.42 g, 35 mmol) and sodium hydroxide (1.4 g, 35 mmol) in 50% ethanol/water (30 mL) was allowed to stir at room temperature for 3 hours. On completion, the reaction was concentrated to remove most of ethanol and then extracted with dichloromethane. The organic layer was concentrated and purified by column chromatography [petroleum ether/ethyl acetate=15: l] to give compound B-108 (3.8 g, 84% yield) as a white solid. LCMS: (ES+) m/z (M+H)+ = 196.1 , tR=0.751 and 0.765.
[00218] Example 9B - 7-chlorobenzorblthiophene-2-carbaldehyde oxime (B-109)
Figure imgf000079_0003
B-109
[00219] To a solution of 7-chlorobenzo[b]thiophene-2-carbaldehyde (5.2 g, 26.5mmol), hydroxylamine hydrochloride (2.7 g, 39.8 mmol) in dichloromethane (50 mL) was added triethylamine (4.1 g, 39.8 mmol) slowly at room temperature. The reaction was allowed to stir at room temperature for 3 hours. On completion the reaction mixture was washed with water (20 mL x 2) and, after concentration, the crude product was purified by column chromatography
[petroleum ether/ethyl acetate=15: l] to give the less polar oxime isomer, compound B-109 (2.6 g, 46%), as a yellow solid. LCMS: (ES+) m/z (M+H)+ = 212.0, tR=0.916.
[00220] Example 10B - 7-bromobenzo[b]thiophene-2-carbaldehyde (B-110)
Figure imgf000080_0001
B-110
[00221] A solution of 7-bromobenzo[b]thiophene (6 g, 28.6 mmol) in tetrahydrofuran (60 mL) was cooled to -60 °C. Lithium diisopropylamide (2M in THF, 43 mL, 86 mmol) was added dropwise and stirred at -60 °C for 1 hour. Then N,N-dimethylformamide (6.3 g, 85.8 mmol) was added and stirred at -60 °C for 2 hours. TLC showed the reaction was completed. The reaction was quenched by water and extracted with dichloromethane (30 mL x 3). The combined organic phases were washed with brine, dried over sodium sulfate and concentrated in vacuum. The residue was purified by silica gel column chromatography [petroleum ether/ethyl acetate=15: l ] to afford compound B-110 (5.2 g, 76% yield) as yellow solid. GCMS: M= 241 .9, tR= 10.655.
[00222] Example 11B - 2-formylbenzorblthiophene-7-carbonitrile (B-lll)
Figure imgf000080_0002
B-110 B-111
[00223] A mixture of compound B-110 (500 mg, 2.08 mmol) and copper (I) cyanide (222 mg, 2.5 mmol) in l -methylpyrrolidin-2-one (5 mL) was heated by microwave at 200 °C for 1 hour. The reaction mixture was diluted with dichloromethane (30 mL). The organic solution was washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuum. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate =3: 1) to give compound B-l ll (300 mg, 77% yield) as yellow solid. Ή-NMR (DMSO-c¾ 400 MHz): δ 10.21
(s, IH), 8.60 (s, IH), 8.50-8.48 (d, J=8.4 Hz, IH), 8.20-8.1 8 (d, J=7.2 Hz, IH), 7.74-7.70 (t, J=8.0
Hz, IH).
[00224] Example 12B - 2-(("hvdroxyimino)methyl)benzo blthiophene-7-carbonitrile (B-112)
Figure imgf000080_0003
B-111 B-112
[00225] A solution of compound B-lll (100 mg, 0.53 mmol), hydroxylamine hydrochloride (33 mg, 0.48 mmol) and triethylamine (107 mg, 1.06 mmol) in dichloromethane (5 mL) was stirred at room temperature for 3 hours. On completion, the reaction was diluted with
dichloromethane (30 mL). The organic solution was washed with brine, dried over sodium sulfate and concentrated in vacuum. The residue was purified by silica gel-chromatography [petroleum ether/ethyl acetate=10: l ] to isolate the less polar oxime isomer, compound B-112 (30 mg, 28% yield), as yellow solid. LCMS: (ES+) m/z (M+H)+ =203.1 , tR=0.703.
[00226] Example 13B - 7-bromobenzorb]thiophene-2-carbaldehyde oxime (B-113)
Figure imgf000081_0001
B-110 B-113
[00227] A solution of compound B-110 (3.41 g, 14.3 mmol), hydroxylamine hydrochloride (1.48 g, 21.4 mmol) and triethylamine (2.16 g, 21.4 mmol) in dichloromethane (5 mL) was stirred at room temperature for 3 hours. On completion, the mixture was diluted with dichloromethane (60 mL). The organic solution was washed with brine, dried over sodium sulfate and concentrated in vacuum. The residue was purified by silica gel-chromatography with eluent (petroleum ether: ethyl acetate =3 : 1 ) to isolate the less polar oxime isomer of compound B-113 (1.5 g, 41 % yield) as a yellow solid. LCMS: (ES+) m/z (M+H)+ =257.9, tR=0.878.
[00228] Example 14B - 5-fluorobenzorb1thiophene-2-carbaldehyde oxime (B-114)
Figure imgf000081_0002
[00229] A mixture of 5-fluorobenzo[b]thiophene-2-carbaldehyde (4.6 g, 25.56 mmol), hydroxylamine hydrochloride (2.65 g, 38.33 mmol) and sodium hydroxide (1.53 g, 38.33 mmol) in ethanol/water (50%, 60 mL) was stirred at room temperature for 4 hours. The solution was concentrated to remove most of ethanol and extracted with dichloromethane. The organic layer was concentrated in vacuo and purified by column chromatography [petroleum ether/ethyl acetate=15: l ] to give compound B-114 (4.1 g, 82% yield) as a yellow solid. LCMS: (ES+) m/z (M+H)+ = 196.1 , tR=0.730 and 0.744.
[00230] Example 15B - benzorblthiophene-5-carbaldehyde oxime (B-115)
Figure imgf000081_0003
B-115
[00231] A solution of benzo[b]thiophene-5-carbaldehyde (420 mg, 2.6 mmol), hydroxylamine hydrochloride (268 mg, 3.9 mmol) and triethylamine (394 mg, 3.9 mmol) in dichloromethane (10 mL) was stirred at room temperature for 3 hours. On completion, the reaction mixture was extracted with ethyl acetate (20 mL x 3). The combined organic phases were washed with brine, dried over sodium sulfate and concentrated to give compound B-115 (400 mg, 41 % yield) as a yellow solid. The crude product was used in next step without further purification. LCMS: (ES+) m/z (M+H)+ =178.1 , tR=0.721 .
[00232] Example 16B - ethyl 7-fluorobenzofuran-2-carboxylate (B-116)
Figure imgf000082_0001
B-116
[00233] To a solution of 3-fIuoro-2-hydroxybenzaldehyde (19.8 g, 87.9 mmol) and potassium carbonate (14.4 g, 105 mmol) in N,N-dimethylformamide (80 mL) was added ethyl-2- bromoacetate (17.4 g, 105 mmol) via syringe. The resulting mixture was heated to 1 10 °C for 3 hours. TLC showed the starting material was completely consumed. The reaction solution was cooled to room temperature and a filtration was performed. The filtrate was evaporated under reduced pressure. The residue was dissolved in water, and extracted with ethyl acetate (100 mL x 2). The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluted with petroleum ether/ethyl acetate (10: 1) to give compound B-116 (13.0 g, 70%) as a yellow solid. LCMS: (ES+) m/z (M+H)+ =209.1 , tR=0.94.
[00234] Example - (7-fluorobenzofuran-2-vnmethanol (B-117)
Figure imgf000082_0002
B-116 B-117
[00235] A solution of compound B-116 (4.2 g, 20.0 mmol) was added dropwise via addition funnel to a mixture of lithium aluminum hydride (0.76 g, 20.0 mmol) in anhydrous
tetrahydrofuran (60 mL) at room temperature under an atmosphere of nitrogen. The reaction mixture was heated at reflux for 3 hours. TLC showed the starting material was completely consumed. After the reaction temperature was cooled to room temperature, saturated aqueous potassium carbonate (100 mL) was added. The mixture was extracted with ethyl acetate (100 mL x 3), dried over sodium sulfate, filtered and evaporated under reduced pressure. The crude product was purified by silica gel chromatography [petroleum ether/ethyl acetate=8: l ] to give compound B-117 (2.6 g, 68%) as a white solid. LCMS: (ES+) m/z (M+H)+ =149.1 , tR=0.807.
[00236] Example 18B - 7-fluorobenzofuran-2-carbaldehvde (B-118)
Figure imgf000083_0001
B-117 B-118
[00237] To a solution of compound B-117 (2.6 g, 16 mmol) in anhydrous dichloromethane (50 mL) was added manganese dioxide (7.0 g, 80 mmol). The reaction mixture was stirred at room temperature for 24 hours. The slurry was filtered. The filtrate was evaporated under reduced pressure to give compound B-118 (1.6 g, 61%) as a yellow solid.
[00238] Example 19B - 7-fluorobenzofuran-2-carbaldehyde oxime (B-119)
Figure imgf000083_0002
B-118 B.119
[00239] A solution of compound B-118 (0.5 g, 3.0 mmol), hydroxylamine hydrochloride (0.31 g, 4.5 mmol) and a 1 : 1 mixture of sodium hydroxide (0.1 8 g, 4.5 mmol) in ethyl alcohol/water (1 : 1 , 14 mL) was stirred at ambient temperature for 2 hours. TLC showed the reaction was completed. The reaction was added water (10 mL), and extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with water and brine, dried over sodium sulfate and concentrated under reduced pressure to give compound B-119 (0.4 g, 74%) as a white solid. LCMS: (ES+) m/z (M+H)+ =180.1, tR=0.694.
[00240] Example 20B - 2-bromo-6-methoxybenzorblthiazole (B-120)
Figure imgf000083_0003
[00241] To a solution of copper bromide (7.4 g, 0.0336 mol) and polyethylene glycol (14 g) in acetonitrile (150 mL) was added isoamyl nitrite (4.9 g, 0.042 mol) portionwise at room temperature. A solution of 6-methoxybenzo[b]thiazol-2-amine (5 g, 0.028 mol) in acetonitrile (100 mL) was then added dropwise to the mixture under nitrogen over a period of 10 minutes. The mixture was then stirred at 65 °C for 3 hours. After being cooled to room temperature, the mixture was poured into a 20% aq. hydrochloric acid solution (200 mL) and organics were extracted with dichloromethane (3 x 50 mL). The organic layers were washed with water and brine, dried over anhydrous sodium sulfate and evaporated in vacuo. The residue was purified by column chromatography [petroleum ether/ethyl acetate=15: l] to give compound B-120 (5.3 g, 78% yield) as a white solid. LCMS: (ES+) m/z (M+H)+ =244.0, tR=0.820.
[00242] Example 21B - 6-methoxybenzo|"blthiazole-2-carbaldehvde (B-121)
Figure imgf000084_0001
B-120 B-121
[00243] To a solution of compound B-120 (4.5 g, 0.0185 mol) in anhydrous tetrahydrofuran (40 mL) was added n-butyl lithium (2.5M in hexanes, 9.6 mL, 0.024 mol) dropwise at -78 °C. The resulting solution was stirred at -78 °C for 0.5 h. Anhydrous N,N-dimethylformarnide (5.4 g, 0.074 mol) was then added dropwise at -78 °C and the reaction was stirred at this temperature for an hour. The reaction was warmed to -40 °C and stirred for 0.5 hour. On completion, the mixture was quenched by ammonium chloride solution at -40 °C and organics were extracted with dichloromethane (3 x 50 mL). The organic layers were washed with water and brine, dried over anhydrous sodium sulfate and concentrated in vacuum to give compound B-121 (3.5 g, 100% yield) as a yellow solid. The crude product was used for next step directly. LCMS: (ES+) m/z (M+H)+ =194.0, tR=0.739.
[00244] Example 22B - 6-methoxybenzorblthiazole-2-carbaldehyde oxime (B-122)
Figure imgf000084_0002
B-121 B-122
[00245] A solution of compound B-121 (3.5 g, 0.0185 mol), hydroxylamine hydrochloride (2.7 g, 0.038 mol) and sodium hydroxide (1.6 g, 0.04 mol) in ethanol/water (1 : 1 , 60 mL) was stirred at room temperature for 3 hours. On completion the mixture was concentrated and organics were extracted by ethyl acetate (3 x 50 mL). The combined organics were concentrated in vacuo and the resulting residue was purified by column chromatography [petroleum ether/ethyl acetate=5: l] to give compound B-122 (1 .5 g, 40% yield) as a white solid. LCMS: (ES+) m/z (M+H)+ =209.0, tR=0.827.
[00246] Exampl - 1 -methyl- 1 , 2,3, 4-tetrahvdroquinoline-6-carbaldehyde oxime (B-123)
Figure imgf000084_0003
[00247] To a solution of 1 -methyl- 1 ,2,3, 4-tetrahydroquinoline-6-carbaldehyde (4.5 g, 25.7 mmol) and hydroxylamine hydrochloride (2.66 g, 38.6 mmol) in anhydrous dichloromethane (50 mL) was added triethylamine (3.89 g, 38.6 mmol) at room temperature. The mixture was stirred at room temperature for 16 hours. On completion, the mixture was concentrated and organics were extracted into ethyl acetate (3 x 50 mL). The combined organics were washed with water and brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography [petroleum ether/ethyl acetate = 1.5: 1] to give compound B- 123 (2.5 g, 51% yield) as a yellow solid: LCMS: (ES+) m/z (M+H)+ = 191.3, tR=0.568.
[00248] Exampl - 6-bromo-2-methyl-l ,2,3,4-tetrahydroisoquinoline (B-124)
Figure imgf000085_0001
B-124
[00249] To a solution of 6-bromo-l ,2,3,4-tetrahydroisoquinoline (5.0 g, 23.6 mmol) and formaldehyde (1.4 g, 47.2 mmol) in methanol (100 mL) was added sodium cyanoborohydride (5.9 g, 94.4 mmol). The mixture was stirred at room temperature overnight. On completion, the reaction mixture was poured into water (20 mL). Organics were then extracted with ethyl acetate (3 x 30 mL) and the combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting residue was purified by a silica chromatography [petroleum ether/ethyl acetate = 1 : 1.5] to give compound B-124 (6.3 g, crude) as a yellow oil: LCMS: (ES+) m/z (M+H)+ = 226.0, tR=1.408.
[00250] Exam - 2-methyl- 1 ,2,3, 4-tetrahydroisoquinoline-6-carbaldehyde (B-125)
Figure imgf000085_0002
B-124 B-125
[00251] To a mixture of compound B-124 (3.2 g, 0.014 mol) and N,N-dimethylformamide (1.3 g, 0.017 mol) in anhydrous tetrahydrofuran (50 mL) was added tert-butyllithium (1.3M in pentane, 16.8 mL, 0.042 mol) at -78 °C. The mixture was stirred at -78 °C for 3 hours. On completion, the reaction mixture was poured into water (10 mL). The organic layer was separated, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give compound B-125 (2.8 g, crude) as a white solid. LCMS: (ES+) m/z (M+H)+ = 176.1 , tR=1.171.
[00252] Example 26B - 2-methyl-l,2,3,4-tetrahvdroisoquinoline-6-carbaldehyde oxime (B- 126)
Figure imgf000085_0003
B-125 B-126 [00253] To a mixture of compound B-125 (2.8 g, 15.9 mmol) and hydroxylamine hydrochloride (3.3 g, 47.7 mmol) in anhydrous ethanol (80 mL) was added potassium carbonate (6.6 g, 47.7 mmol). The mixture was stirred at room temperature for 4 hours. After the reaction was complete, the mixture was filtered, concentrated and the resulting resiude was purified by silica gel chromatography eluting with 2: 1 petroleum ethenethyl acetate to give compound B-126 (1.0 g, 33% yield) as a yellow solid: LCMS: (ES+) m/z (M+H)+ = 191.1 , tR=1.014.
[00254] Example 27B - N'-(2-chloroacetyl)benzohvdrazide (B-127)
Figure imgf000086_0001
B-127
[00255] To a solution of benzohydrazide (30 g, 0.22 mol) and triethylamine (26 g, 0.26 mol) in tetrahydrofuran (400 mL) was added 2-chloroacetyl chloride (29 g, 0.26 mol) dropwise at 0 °C . The resulting mixture was stirred at this temperature for 4 hours. On completion, the reaction was quenched with water (200 mL) and extracted with dichloromethane (3 x 300 mL). The combined organic layers were concentrated to give B-127 (28.0 g, 60%> yield), which was used for the next step without further purification. LCMS: (ES+) m/z (M+H)+ = 213.2, tR=0.212.
[00256] Example 28B - 2-(chloromethyl)-5-phenyl-L3.4-oxadiazole (B-128)
Figure imgf000086_0002
B-127 B-128
[00257] B-127 (30 g, 0.14 mol) was added to POCl3 (200 mL) slowly at room temperature over a course of 0.5 hour. The resulting mixture was stirred at 100 °C for 12 hours. On completion, the reaction was cooled to room temperature and poured into ice-water slowly. The resulting mixture was extracted with dichloromethane (3 x 300 mL). The combined organic layers were concentrated and purified by silica gel chromatography [petroleum ether : ethyl acetate= 10: 1 ] to give B-128 (3.2 g, 1 1 % yield) as a yellow solid. LCMS: (ES+) m/z (M+H)+ = 195.2, tR=0.654.
[00258] Example 29B - N-hydroxy-5-phenyl-L3,4-oxadiazole-2-carbimidoyl chloride (B-
129
Figure imgf000086_0003
B-128 B-129
[00259] To a solution of B-128 (4.4 g, 22 mmol) in 4N HCI/dioxane (50 mL) was added isoamyl nitrite (2.6 g, 22 mmol) at room temperature and then the mixture solution was stirred at 50 °C for 12 hours. On completion, the reaction mixture was concentrated and purified by silica gel chromatography [petroleum ether : ethyl acetate= 12: 1] to give B-129 (0.90 g, 18% yield) as a white solid. LCMS: (ES+) m/z (M+H)+ = 224.0, tR=0.514.
[00260] Exam le 30B - methyl thienor2,3-blpyridine-2-carboxylate (B-130)
Figure imgf000087_0001
B-130
[00261] To a mixture of 2-chloronicotinaldehyde (10 g, 71 mmol) and methyl 2- mercaptoacetate (7.6 g, 71 mmol) in anhydrous N, N-dimethylformamide (100 mL) was added anhydrous triethylamine (14 g, 0.14 mol). The mixture was stirred at 100 °C for 3 hours. On completion, the solution was concentrated in vacuo and purified by silica gel column
chromatography [petroleum ether : ethyl acetate = 10: 1 ] to give B-130 (10 g, 72% yield) as a white solid. LCMS: (ES+) m/z (M+H)+ = 194.1 , tR=0.671.
[00262] Exa - methyl thieno 2,3-blpyridin-2-ylmethanol (B-131)
Figure imgf000087_0002
B-130 B-131
[00263] To a mixture of compound B-130 (10 g, 52 mmol) in anhydrous tetrahydrofuran (100 mL) was added lithium aluminum hydride (4.0 g, 0.10 mol) at 0 °C. The mixture was stirred at 0 °C for 4 h. On completion, the solution was quenched with water (5 mL) at 0 °C and filtered. The filtrate was concentrated in vacuo to give compound B-131 (7.0 g, 82% yield) as a yellow solid. LCMS: (ES+) m/z (M+H)+ = 166.2, tR=0.249.
[00264] Example 32B - thieno[2,3-blpyridine-2-carbaldehvde (B-132)
Figure imgf000087_0003
[00265] To a solution of compound B-131 (4.0 g, 24 mmol) in dichloromethane (40 mL) was added manganese dioxide (21 g, 24 mmol) at room temperature. The mixture was stirred at room temperature overnight. On completion, the mixture was filtered, and the filtrate was concentrated in vacuo to give compound B-132 (3.4 g, 85% yield) as a yellow solid. LCMS: (ES+) m/z (M+H)+ = 164.1, tR=0.537.
[00266] Example 33B - thieno[2,3-blpyridine-2-carbaldehyde oxime (B-133)
Figure imgf000087_0004
[00267] To a solution of compound B-132 (3.4 g, 21 mmol) in anhydrous ethanol (50 mL) was added hydroxylamine hydrochloride (4.4 g, 63 mmol) and potassium carbonate (8.7 g, 63 mmol) at room temperature. The reaction mixture was stirred at room temperature overnight. On completion, the mixture was filtered and washed with ethanol. The filtrate was concentrated in vacuo and purified by silica gel column chromatography [petroleum ether : ethyl acetate = 20: 1 ] to give compound B-133 (3.0 g, 81 % yield) as a yellow solid. LCMS: (ES+) m/z (M+H)+ = 1 79.1 , tR=0.543.
[00268] Example 34B - Methyl thieno[3,2-b]pyridine-2-carboxylate (B-134)
Figure imgf000088_0001
B-134
[00269] To a mixture of 3-fluoropicolinaldehyde (20 g, 0.16 mol) and methyl 2- mercaptoacetate (17 g, 0.16 mol) in N,N-dimethylformamide (200 mL) was added triethylamine (32 g, 0.32 mol) at room temperature. The mixture was stirred at 100 °C for 4 hours. On completion, the reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (3 x 200 mL). The combined organic layers were washed with brine (2 χ 200 mL), dried over anhydrous sodium sulfate, concentrated in vacuo and purified by silica gel column
chromatography [petroleum ether: ethyl acetate = 10: 1 ] to give compound B-134 (20 g, 65% yield) as a yellow solid.
[00270] Exam - Thieno[3.2-b1pyridin-2-ylmethanol (B-135)
Figure imgf000088_0002
B-134 B-135
[00271] To a mixture of compound B-134 (4.7 g, 24 mmol) in anhydrous tetrahydrofuran (50 mL) was added DIBAL-H (48 mL, 1 M in hexane) dropwise at -78 °C under nitrogen atmosphere. The mixture was stirred at -78 °C for 2 hours. TLC showed the reaction was completed. The reaction was quenched with water (50 mL) at 0 °C and filtered, and the filtrate was extracted with dichloromethane (3 χ 100 mL). The combined organic layers were concentrated in vacuo to give compound B-135 (2.7 g, 68% yield) as a brown solid.
[00272] Example - Thienor3.2-blpyridine-2-carbaldehvde (B-136
Figure imgf000088_0003
B-135 B-136
[00273] To a mixture of compound B-135 (2.7 g, 16 mmol) in anhydrous dichloromethane (20 mL) was added manganese dioxide (14 g, 0.16 mol) at room temperature. The mixture was stirred at room temperature for 16 hours. On completion, a filtration was performed, and the filtrate was concentrated in vacuo to give compound B-136 (2.3 g, 87% yield) as a brown solid.
[00274] Example 37B - Thienor3.2-blpyridine-2-carbaldehvde oxime (B-137)
Figure imgf000089_0001
B-136 B-137
[00275] To a solution of compound B-136 (2.3 g, 14 mmol) in 50% ethanol/water (20 mL) was added hydroxylamine hydrochloride (2.0 g, 28 mmol) and potassium carbonate (3.9 g, 28 mmol) at room temperature. The mixture was stirred at room temperature overnight. On completion, the reaction was filtered, and the filtrate was concentrated and purified by silica gel column chromatography [petroleum ether: ethyl acetate = 20: 1 ] to give compound B-137 (2.3 g, 93% yield) as a yellow solid.
[00276] Example 38 - pyridin-l-ium-l -ylamide (B-138)
Figure imgf000089_0002
B-138
[00277] To a mixture of (aminooxy)diphenylphosphine oxide (60 g, 0.26 mol) in H20 (600 mL) was added pyridine (20 g, 0.26 mmol) at room temperature. The mixture was stirred at 80 °C for 16 hours. On completion, the reaction mixture was concentrated to give compound B-138 (85 g, crude) as a white solid. The crude was used in the next step without further purification.
[00278] Example 39B - dimethyl pyrazolo[L5-a1pyridine-2,3-dicarboxylate (B-139)
Figure imgf000089_0003
B-138
B-139
[00279] To a mixture of compound B-138 (80 g, 0.85 mol) in N,N-dimethyl formamide (800 mL) was added potassium carbonate (180 g, 1.3 mol) and dimethyl but-2-ynedioate (140 g, 1.0 mol) at room temperature. The mixture was stirred for 16 hours. On completion, the reaction mixture was poured into water and some precipitates formed. The precipitates were collected by filtration and dried in vacuo to give compound B-139 (30 g, 15% yield) as a white solid.
[00280] Example 40B - pyrazolon ,5-a1pyridine-2.3-dicarboxylic acid (B-140)
Figure imgf000090_0001
B-139 B-140
[00281] To a mixture of compound B-139 (28 g, 0.12 mmol) in tetrahydrofuran (150 mL) and H20 (150 mL) was added lithium hydroxide (14 g, 0.60 mmol) at room temperature. The mixture was stirred for 16 hours. On completion, the reaction mixture was acidified with 4N hydrochloric acid. The solid was collected by filtration and dried in vacuo to give compound B-140 (21 g, 85% yield) as a white solid.
[00282] Exampl - pyrazolori -a1pyridine-2-carboxyl (B-141-)
Figure imgf000090_0002
B-140 B-141
[00283] To a mixture of compound B-140 (20 g, 97 mmol) in dioxane (100 mL) was added 12 N hydrochloric acid (100 mL) at room temperature. The mixture was stirred at reflux for 12 hours. On completion, the reaction mixture was concentrated and neutralized with saturated aqueous sodium bicarbonate. The precipitates were collected by filtration and dried in vacuo to give compound B-141 (13 g, 83% yield) as a white solid.
[00284] Example 42B - pyrazolo[L5-a1pyridin-2-ylmethanol (B-142)
Figure imgf000090_0003
B-141 B-142
[00285] To a mixture of compound B-141 (8.0 g, 49 mmol) in anhydrous tetrahydrofuran (80 mL) was added DIBAL-H (98 mL, 1 M in hexane) dropwise at -78 °C. The mixture was stirred at -78 °C for 2 hours until TLC showed the reaction was complete. The reaction was quenched with 50 mL of aqueous saturated ammonium chloride solution at 0 °C and filtered, and the filtrate was concentrated in vacuo to give compound B-142 (5.7 g, crude) as a brown oil. The crude product was used for the next step without any further purification.
[00286] Example 43B - pyrazolo l ,5-a1pyridine-2-carbaldehvde (B-143)
Figure imgf000091_0001
B-143
[00287] To a mixture of compound B-142 (5.0 g, 34 mmol) in anhydrous dichloromethane (20 mL) was added manganese dioxide (30 g, 0.34 mol) at room temperature/The mixture was stirred at room temperature for 16 hours until TLC showed the reaction was completed. The reaction was filtered, and the filtrate was concentrated to give compound B-143 (4.5 g, 91% yield) as a brown oil.
[00288] Example 44 - yrazolof l ,5-a1pyridine-2-carbal oxime (B-144)
Figure imgf000091_0002
[00289] To a solution of compound B-143 (2.3 g, 16 mmol) in 50% ethanol/water (20 mL) was added hydroxylamine hydrochloride (2.2 g, 32 mmol) and potassium carbonate (4.3 g, 32 mmol) at room temperature. The mixture was stirred at room temperature overnight. On completion, the reaction mixture was concentrated and purified by silica gel column
chromatography [petroleum ether: ethyl acetate = 20: 1] to give compound B-144 (2.1 g, 83% yield) as a yellow solid.
[00290] Example 45B - Methyl 6-fluorobenzorb]thiophene-2-carboxylate (B-145)
Figure imgf000091_0003
100 °C, 4 h B-145
[00291] To a mixture of 2,4-difluorobenzaldehyde (20 g, 0.14 mol) and methyl 2- mercaptoacetate (18 g, 0.17 mol) in anhydrous N,N-dimethylformamide (200 mL) was added triethylamine (28 g, 0.28 mol) at room temperature. The mixture was stirred at 100 °C for 4 hours. On completion, the reaction mixture was diluted with water (200 mL) and extracted with ethyl acetate (3 χ 200 mL). The combined organic layers were washed with brine (2 χ 200 mL), dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography [petroleum ether: ethyl acetate = 10: 1] to give compound B-145 (20 g, 69% yield) as a white solid.
[00292] Example 46B - (6-fluorobenzorblthiophen-2-vn methanol (B-146) S LiAIH4 F^^i^ Q OH
~ C02Me ► |[ — '
7 THF, 0 °C, 2 h
B-145 B-146
[00293] To a mixture of compound B-145 (7.0 g, 33 mmol) in anhydrous tetrahydrofuran (70 mL) was added lithium aluminum hydride (1.2 g, 33 mmol) portionwise at 0 °C. The resulting mixture was stirred at 0 °C for 3 hours. On completion, the reaction was quenched with water (2 mL) at 0 °C and filtered, and the filtrate was extracted with dichloromethane (3 x 100 mL). The combined organic layers were concentrated in vacuo to give compound B-146 (5.8 g, 83% yield) as a brown solid.
[00294] Example 47B - (6-fluorobenzorblthiophene-2-carbaldehyde (B-147)
Figure imgf000092_0001
B-146 B-147
[00295] To a solution of compound B-146 (5.8 g, 32 mmol) in anhydrous dichloromethane (100 mL) was added manganese dioxide (28 g, 0.32 mol). The mixture was stirred at room temperature for 16 hours until TLC showed the reaction was complete. The reaction was filtered, and the filtrate was concentrated in vacuo to give compound B-147 (4.9 g, 85% yield) as a brown solid.
[00296] Example 48B - (6-fluorobenzo blthiophene-2-carbaldehyde oxime (B-148)
Figure imgf000092_0002
B-147 B-148
[00297] To a mixture of compound B-147 (3.2 g, 18 mmol) and hydroxylamine
hydrochloride (2.5 g, 35 mmol) in 50% ethanol/water (30 mL) was added potassium carbonate
(5.6 g, 40 mmol) at room temperature. The mixture was stirred at room temperature overnight. On completion, two isomers showed on TLC. These two spots were separated by silica gel column chromatography [petroleum ether: ethyl acetate = 20: 1] to give the upper spot compound B-148
(2.8 g, 80% yield) as a yellow solid. LCMS: (ES+) m/z (M+H)+ = 196.1 , tR=0.763.
[00298]
Figure imgf000092_0003
B-149
[00299] To a mixture of 1 -methyl- l H-indole-2-carbaldehyde (5.0 g, 31 mmol) and hydroxylamine hydrochloride (6.5 g, 94 mmol) in ethanol (20 mL) was added sodium hydroxide (3.8 g, 94 mmol) at room temperature. The mixture was stirred at room temperature for 8 hours. On completion, the reaction was filtered, and the filtrate was concentrated in vacuo to give compound B-149 (3.5 g, 64% yield) as a yellow solid.
[00300] Example SOB - l-methyl-l H-benzo[d]imidazole-2-carbaldehyde oxime (B-150)
Figure imgf000093_0001
B-150
[00301] To a mixture of l-methyl-l H-benzo[d]imidazole-2-carbaldehyde (2.0 g, 13 mmol) and hydroxylamine hydrochloride (1.3 g, 19 mmol) in ethanol (20 mL) was added sodium hydroxide (0.8 g, 19 mmol. The mixture was stirred at room temperature for 8 hours. On completion, the reaction was filtered, and the filtrate was concentrated in vacuo to give
compound B-150 (2.0 g, 91% yield) as a yellow solid. LCMS: (ES+) mix (M+H)+ = 176.1 , tR=0.946.
[00302] Example 51B - ethyl 6-fluorobenzofuran-2-carboxylate (B-151)
Figure imgf000093_0002
B-151
[00303] To a mixture of 4-fluoro-6-hydroxybenzaldehyde (10 g, 71 mmol) and ethyl 2- bromoacetate (14 g, 86 mmol) in NN-dimethylformamide (100 mL) was added potassium carbonate (20 g, 0.14 mol) at room temperature. The mixture was stirred at 120 °C for 2 hours. On completion, the reaction mixture was quenched with water and extracted with dichloromethane (3 x 100 mL). The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give compound B-151 (10 g, 68% yield) as a yellow solid. LCMS: (ES+) m/z (M+H)+ = 209.1 , tR= 0.856.
[00304] Example 52B - (6-fluorobenzofuran-2-vnmethanol (B-152
Figure imgf000093_0003
[00305] To a solution of compound B-151 (10 g, 48 mmol) in tetrahydrofuran (100 mL) was added diisobutylaluminum hydride (106 mmol) dropwise at -60 °C. The mixture was stirred at - 60 °C for 2 hours. On completion, the reaction mixture was quenched with water carefully and extracted with dichloromethane (3 x 200 mL). The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give crude compound B-152 (5.0 g, 63% yield) as a colorless oil. LCMS: (ES+) m/z (M+H)+ = 149.0, tR= 0.875.
[00306] Example 53B - 6-fluorobenzofuran-2-carbaldehyde (B-153)
Figure imgf000094_0001
[00307] A mixture of compound B-152 (5.0 g, 30 mmol) and manganese dioxide (26 g, 0.30 mol) in dichloromethane (50 mL) was stirred at room temperature for 12 hours. On completion, the mixture was filtered, and the filtrate was concentrated in vacuo to give crude compound B- 153 (4.0 g, 80% yield) as a yellow solid. LCMS: (ES+) m/z (M+H)+ = 165.1 , tR= 0.695.
[00308] Example 54B - 6-fluorobenzofuran-2-carbaldehyde oxime (B-154)
Figure imgf000094_0002
[00309] To a mixture of compound B-153 (4.0 g, 24 mmol) and hydroxylamine
hydrochloride (2.5 g, 37 mmol) in anhydrous dichloromethane (40 mL) was added triethylamine (3.7 g, 37 mmol) at room temperature. The mixture was stirred at room temperature overnight. On completion, the reaction mixture was quenched with water and extracted with dichloromethane (3 x 40 mL). The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, concentrated in vacuo and purified by silica gel chromatography [petroleum ether: ethyl acetate = 8: 1] to give compound B-154 (2.6 g, 60% yield) as a white solid. LCMS: (ES+) m/z (M+H)+ = 180.2, tR= 0.692.
[00310] Example 55B - ethyl 5-fluorobenzofuran-2-carboxylate (B-155)
Figure imgf000094_0003
B-155
[00311] A solution of 5-fluoro-2-hydroxybenzaldehyde (10 g, 71 mmol), ethyl 2- bromoacetate (14 g, 86 mmol) and potassium carbonate (20 g, 0.14 mol) in N, N- dimethylformamide (100 mL) was stirred at 120 °C for 2 hours. On completion, the reaction mixture was quenched with 50 mL of water and extracted with dichloromethane (3 χ 50 mL). The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, concentrated in vacuo and purified by silica gel chromatography [petroleum ether: ethyl acetate = 10: 1] to give compound B-155 (6.0 g, 41% yield) as a yellow solid.
[00312] Example 5 - (5-fluorobenzofuran-2-yl)methanol (B-156)
Figure imgf000095_0001
B-155 B-156
[00313] To a solution of compound B-155 (6.0 g, 29 mmol) in tetrahydrofuran (60 mL) at - 60 °C was added dropwise diisobutylaluminium hydride (64 mL, 64 mmol). The resulting solution was stirred at -60 °C for 2 hours until TLC showed the reaction was complete. The reaction was quenched with saturated aqueous citric acid solution (50 mL) and extracted with dichloromethane (3 χ 50 mL). The combined organic phases were washed with brine, dried over sodium sulfate and concentrated in vacuo to give compound B-156 (4.0 g, 83% yield) as a white solid.
[00314] Example 57B - 5-fluorobenzofuran-2-carbaldehvde (B-157)
Figure imgf000095_0002
B-156 B-157
[00315] A mixture of compound B-156 (4.0 g, 24 mmol) and manganese dioxide (21 g, 0.24 mol) in dichloromethane (100 mL) was stirred at reflux overnight until TLC showed the reaction was complete. The mixture was filtered, and the filtrate was concentrated in vacuo and purified by silica gel chromatography [petroleum ether: ethyl acetate = 10: 1] to give compound B-157 (2.5 g, 64% yield) as a brown solid.
[00316] Example 58 - 5-fluorobenzofuran-2-carbaldehyde oxime (B-158)
Figure imgf000095_0003
B-157 B-158 [00317] A solution of compound B-157 (1.5 g, 9.0 mmol), hydroxylamine hydrochloride (0.95 g, 13 mmol) and triethylamine (1.8 g, 18 mmol) in dichloromethane (20 mL) was stirred at room temperature for 3 hours until TLC showed the reaction was complete. The reaction was diluted with dichloromethane (20 mL), washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography [petroleum ether: ethyl acetate = 8: 1] to give compound B-158 (1.2 g, 75% yeild) as a yellow solid. LCMS: (ES+) m/z (M+H)+ = 180.1 , tR=0.715 & 0.752.
[00318] Example 59B - ethyl 4-fluorobenzofuran-2-carbox late (B-159^
Figure imgf000096_0001
[00319] To a mixture of 2-fluoro-6-hydroxybenzaldehyde (10 g, 71 mmol) and ethyl 2- bromoacetate (14 g, 86 mmol) and in anhydrous N,N-dimethylformamide (100 mL) was added potassium carbonate (20 g, 0.14 mol) at room temperature. The mixture was stirred at 120 °C for 2 hours. On completion, the reaction mixture was quenched with 50 mL of water and extracted with dichloromethane (3 x 50 mL). The combined organic phases were washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography [petroleum ether: ethyl acetate = 10: 1] to give compound B-159 (10 g, 68% yield) as a yellow solid.
[00320] Exam - (4-fluorobenzofuran-2-vnmetha -160)
Figure imgf000096_0002
B-159 B-160
[00321] A solution of compound B-159 (10 g, 48 mmol) in anhydrous tetrahydrofuran (100 mL) was cooled to - 60 °C. Diisobutylaluminium hydride (1 10 mL, 0.1 1 mol) was added dropwise at this temperature, and the resulting solution was stirred at - 60 °C for 2 hours. The reaction was quenched with saturated citric acid solution (50 mL) and organics were extracted with dichloromethane (3 χ 50 mL). The combined organic phases were washed with brine, dried over sodium sulfate and concentrated in vacuo to give compound B-160 (7.6 g, 95% yield) as white solid.
[00322] Example 61B - 4-fluorobenzofuran-2-carbaldehvde (B-161
Figure imgf000097_0001
B-160 B-161
[00323] A mixture of compound B-160 (7.6 g, 46 mmol) and manganese dioxide (40 g, 0.46 mol) in dicloromethane (100 mL) was stirred at reflux overnight. On completion, the reaction mixture was filtered, and the filtrate was concentrated in vacuo and purified by silica gel chromatography [petroleum ether: ethyl acetate = 10: 1] to give compound B-161 (5.0 g, 66% yield) as a brown solid.
[00324] Exam - 4-fluorobenzofuran-2-carbaldehyde oxime (B-162)
Figure imgf000097_0002
B-161 B-162
[00325] A solution of compound B-161 (3.8 g, 23 mmol), hydroxylamine hydrochloride (2.4 g, 34 mmol) and triethylamine (4.6 g, 46 mmol) in dichloromethane (30 mL) was stirred at room temperature for 3 hours. On completion, the reaction was diluted with dichloromethane (30 mL). The organic solution was washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography [petroleum ether: ethyl acetate = 8: 1 ] to give compound B-162 (3.5 g, 85% yield) as a yellow solid. LCMS: (ES+) m/z (M+H)+ = 180.1 , tR=0.714 & 0.749.
[00326] Example - 3.5-difluoro-2-hydroxybenzaldehvde (B-163)
Figure imgf000097_0003
B-163
[00327] Phosphorus oxychloride (12 g, 77 mmol) was added dropwise to anhydrous dimethyl formamide (8.4 g, 0.12 mol) at 0 °C under nitrogen with stirring. The mixture was stirred at this temperature for 30 minutes, and 2,4-difluorophenol (5.0 g, 39 mmol) in N N-dimethyl formamide (50mL) was added dropwise. The reaction mixture was stirred at room temperature for 5 hours. On completion, the reaction mixture was quenched slowly with water and extracted with ethyl acetate (3 x 150 mL). The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give compound B-163 (5.5 g, 90% yield) as a yellow oil.
[00328] Example 64B - 5J-difluorobenzofuran-2-carboxylate (B-164)
Figure imgf000098_0001
[00329] To a mixture of compound B-163 (5.0 g, 32 mmol) and ethyl 2-bromoacetate (6.3 g, 38 mmol) in N N-dimethylformamide (100 mL) was added potassium carbonate (8.7 g, 63 mmol) at room temperature. The mixture was stirred at 120 °C for 2 hours. On completion, the reaction mixture was quenched with water and organics were extracted with dichloromethane (3 100 mL). The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give compound B-164 (5.5 g, 77% yield) as a yellow solid. LCMS: (ES+) m/z (M+H)+ = 227.1 , tR= 0.856.
[00330] Exampl - (5,7-difluorobenzofuran-2-yl)methanol (B-165)
Figure imgf000098_0002
B-164 B-165
[00331] To a solution of compound B-164 (5.0 g, 22 mmol) in tetrahydrofuran (50 mL) was added diisobutylaluminum hydride (49 mmol) dropwise at -60 °C. The mixture was stirred at this temperature for 2 hours. On completion, the reaction mixture was quenched carefully with water and extracted with dichloromethane (3 x 100 mL). The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give crude compound B-165 (3.0 g, 74% yield) as a colorless oil. LCMS: (ES+) m/z (M+H)+ = 167.1 , tR= 0.673.
[00332] Example 66 - 5,7-difluorobenzofuran-2-carbaldehyde (B-166)
Figure imgf000098_0003
B-165 B-166
[00333] A mixture of compound B-165 (3.0 g, 16 mmol) and manganese dioxide (14.2 g, 0.16 mol) in dichloromethane (30 mL) was stirred at room temperature for 12 hours. On completion, the mixture was filtered, and the filtrate concentrated in vacuo to give crude
compound B-166 (2.0 g, 67% yield) as a yellow solid.
[00334] Example 67B - 5 J-difluorobenzofuran-2-carbaldehyde oxime (B-167)
Figure imgf000099_0001
[00335] To a mixture of compound B-166 (1 .0 g, 5.5 mmol) and hydroxylamine
hydrochloride (0.57 g, 8.3 mmol) in anhydrous dichloromethane (10 mL) was added triethylamine (0.83 g, 8.3 mmol) at room temperature. The mixture was stirred at this temperature overnight. On completion, the reaction mixture was quenched with water and extracted with dichloromethane (3 x 20 mL). The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, concentrated in vacuo and purified by silica gel chromatography [petroleum ether: ethyl acetate = 8: 1] to give compound B-167 (0.60 g, 55% yield) as a white solid. LCMS: (ES+) m/z (M+H)+ = 198.1 , tR= 0.771.
[00336] Exam le 68B - 2-phenylacetaldehvde oxime (B-168)
Figure imgf000099_0002
[00337] To a mixture of [l ,l'-biphenyl]-4-carbaldehyde (5.0 g, 27 mmol) and hydroxylamine hydrochloride (2.8 g, 41 mmol) in ethanol (25 mL) and water (25 mL) was added sodium hydroxide (1.6 g, 41 mmol) slowly at 0 °C. The mixture was allowed to warm to room temperature and was stirred at this temperature overnight. On completion, the mixture was concentrated to remove most of ethanol and extracted with dichloromethane (3 x 50 mL). The combined organic layers were washed with brine (3 χ 50 mL), dried over anhydrous sodium sulfate, concentrated in vacuo and purified by silica gel chromatography [petroleum ether: ethyl acetate = 10: 1] to give compound B-168 (3.0 g, 56% yield) as a white solid. LCMS: (ES+) m/z (M+H)+ = 198.1 , tR=0.821.
[00338] Example 69B - l -(2.4-dimethoxybenzylVl,2 ,4-tetrahvdroquinoline (B-169)
Figure imgf000099_0003
MeOH, 0 °C~rt, overnight
[00339] To a mixture of 1 ,2,3,4-tetrahydroquinoline (10 g, 75 mmol) and 2,4- dimethoxybenzaldehyde (15 g, 90 mmol) in anhydrous methanol (150 mL) was added one drop of acetic acid as catalyst at room temperature. After stirring at 0 °C for half an hour, sodium cyanoborohydride (14 g, 0.23 mol) was added to the reaction portionwise at 0 °C. The resulting mixture was stirred overnight at room temperature. On completion, the reaction mixture was quenched with water and extracted with ethyl acetate (3 x 500 mL). The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, concentrated in vacuo and purified by silica gel chromatography [petroleum ether: ethyl acetate = 20: 1] to give
compound B-169 (20 g, 94% yield) as a yellow oil.
[00340] Example 70B - l-(2,4-dimethoxybenzylVl ,2,3,4-tetrahydroquinoline-6-
Figure imgf000100_0001
[00341] Phosphorus oxychloride (1 1 g, 70 mmol) was added dropwise to anhydrous NN- dimethyl formamide (7.7 g, 0.1 1 mol) at 0 °C, and the mixture was stirred in an ice bath for 30 minutes. Compound B-169 (10 g, 35 mmol) in NN-dimethylformamide (100 mL) was added dropwise. The resulting mixture was stirred at room temperature for 5 hours. On completion, the reaction mixture was quenched with water carefully and extracted with ethyl acetate (3 x 500 mL). The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give crude compound B-170 (10 g, 91 % yield) as a green oil.
[00342] - 1,2,3, 4-tetrahydroquinoline-6-carbaldehyde (B-171)
Figure imgf000100_0002
[00343] To compound B-170 (10 g, 32 mmol) was added 10% trifluoroacetic
acid/dichloromethane (100 mL), and the reaction was stirred at room temperature for 2 hours. On completion, the reaction mixture was quenched with water and extracted with dichloromethane (3 x 200 mL). The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give crude compound B-171 (4.0 g, 77% yield) as a brown oil. LCMS: (ES+) m z (M+H)+ = 162.3, tR= 0.612.
[00344] Example 72B - tert-butyl 6-formyl-3,4-dihydroquinoline-l (2H)-carboxylate (B-172)
Figure imgf000101_0001
B-171
[00345] To a mixture of compound B-171 (4.0 g, 25 mmol) and di-tert-butyl dicarbonate (6.5 g, 30 mmol) in dichloromethane (40 mL) was added NN-diisopropylethylamine (3.9 g, 30 mmol) and 4-dimethylaminopyridine (0.31 g, 2.5 mmol) at room temperature. The mixture was stirred at 50 °C overnight. On completion, the reaction mixture was cooled to room temperature, quenched with water and extracted with dichloromethane (3 x 100 mL). The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, concentrated in vacuo and purified by silica gel chromatography [petroleum ether: ethyl acetate = 10: 1 ] to give compound B-172 (5.0 g, 76% yield) as a yellow oil. LCMS: (ES+) m/z (M+H)+ = 262.2, tR= 0.890.
[00346] Example 73B - tert-butyl 6-((hvdroxyimino)methyl)-3,4-dihydroquinoline-l (2H)- carboxylate (B-173)
Figure imgf000101_0002
B-172 B-173
[00347] To a mixture of compound B-172 (5.0 g, 19 mmol) and hydroxylamine
hydrochloride (2.0 g, 29 mmol) in anhydrous dichloromethane (50 mL) was added triethylamine (2.9 g, 29 mmol) at room temperature. The mixture was stirred at room temperature overnight. On completion, the reaction mixture was quenched with water and extracted with dichloromethane (3 x 100 mL). The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, concentrated in vacuo and purified by silica gel chromatography [petroleum ether: ethyl acetate = 2: 1] to give compound B-173 (3.5 g, 66% yield) as a yellow solid. LCMS: (ES+) m/z (M+H)+ = 277.3, tR= 0.864.
[00348] Example 74B - CpCofCOVdmfiiVl (dmfu=dimethyl fumarate) (B-174)
Figure imgf000101_0003
B-174
[00349] A mixture of dicarbonylcyclopentadienylcobalt (10 g, 55 mmol) and dimethyl fumarate (7.9 g, 55 mmol) in anhydrous toluene (200 mL) was reflux under visible light irradiation for 3 hours. On completion, the reaction mixture was concentrated in vacuo and purified by silica gel column chromatography [petroleum ether : ethyl acetate = 15: 1 ] to give compound B-174 (7.0 g, 43% yield) as a deep red solid.
[00350] Example 75B - ethyl 5,6,7,8-tetrahvdroisoquinoline-3-carboxylate (B-175) NC 0
Figure imgf000102_0001
B-1 5
[00351] A mixture of 1 ,7-octadiyne (20 g, 0.19 mol), ethyl carbonocyanidate (23 g, 0.23 mol) and B-174 (5.6 g, 19 mmol, 0.1 eq) in anhydrous toluene (600 mL) were heated at reflux under visible light irradiation for 16 hours. On completion, the reaction mixture was concentrated in vacuo and purified by silica gel column chromatography [petroleum ether: ethyl acetate = 10: 1] to give compound B-175 (4.2 g, 1 1% yield) as a yellow solid.
[00352] Examp - (5,6,7,8-tetrahydroisoquinolin-3- (B-176)
Figure imgf000102_0002
[00353] To a mixture of compound B-175 (4.7 g, 23 mmol) in anhydrous tetrahydrofuran (100 mL) was added lithium aluminum (1.1 g, 27 mmol) portionwise at 0 °C. The resulting mixture was stirred at 0 °C for 2 hours. On completion, the reaction was quenched with water (2 mL) at 0 °C and filtered, and the filtrate was concentrated to give compound B-176 (2.8 g, 74% yield) as a yellow solid.
[00354] Example - 5,6 J,8-tetrahvdroisoquinoline-3-carbaldehyde (B-177)
Figure imgf000102_0003
[00355] To a mixture of compound B-176 (3.7 g, 23 mmol) in anhydrous dichloromethane (100 mL) was added manganese dioxide (20 g, 0.23 mol) slowly at room temperature. The mixture was stirred at room temperature for 16 hours. On completion, the reation was filtered, and the filtrate was concentrated to give compound B-177 (2.8 g, 69% yield) as a yellow solid.
[00356] Example 78B - 5,6 ,8-tetrahydroisoquinoline-3-carbaldehyde oxime (B-178)
Figure imgf000102_0004
[00357] To a mixture of compound B-177 (2.3 g, 14 mmol) and hydroxylamine
hydrochloride (1.5 g, 22 mmol) in ethanol (40 mL) was added potassium carbonate (0.86 g, 22 mmol) at room temperature. The mixture was stirred at room temperature for 4 hours. On completion, the mixture was concentrated and purified by silica gel column chromatography [petroleum ether: ethyl acetate = 3 : 1] to give compound B-178 (1.8 g, 72% yield) as a white solid. LCMS: (ES+) m/z (M+H)+ = 177.1 , tR=1.093.
[00358] Example 79B - Ouinoline-3-carbaldehvde oxime (B-179^
Figure imgf000103_0001
B-179
[00359] To a solution of quinoline-3-carbaldehyde (5.0 g, 32 mmol) and hydroxylamine hydrochloride (4.4 g, 64 mmol) in anhydrous methanol (50 mL) was added potassium carbonate (8.8 g, 64 mmol) at room temperature. The mixture was stirred at room temperature overnight. On completion, the reaction was filtered, and the resulting filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography [petroleum ether: ethyl acetate = 10: 1 ] to give compound B-179 (4.3 g, 78% yield) as a white solid.
[00360] Example 80B - benzofuran-5-carbaldehvde oxime (B-180)
Figure imgf000103_0002
[00361] A solution of benzofuran-5-carbaldehyde (3.0 g, 21 mmol), hydroxylamine hydrochloride (2.1 g, 31 mmol) and triethylamine (3.1 g, 31 mmol) in dichloromethane (50 mL) was stirred at room temperature for 3 hours. On completion, the mixture was concentrated and purified by silica gel chromatography [petroleum ether: ethyl acetate = 3 : 1 ] to give compound B- 180 (3.0 g, 91% yield) as a white solid.
[00362] Example 81B - lH-indole-5-carbaldehvde oxim -18n
Figure imgf000103_0003
B-181
[00363] To a mixture of lH-indoIe-5-carbaldehyde (2.2 g, 15 mmol) and hydroxylamine hydrochloride (1.6 g, 23 mmol) in ethanol (50 mL) was added sodium hydroxide (0.90 g, 23 mmol) at room temperature. The mixture was stirred at room temperature overnight. On completion, the mixture was filtered, and the filtrate was concentrated in vacuo to give
compound B-181 (1 .4 g, 58% yield) as a white solid. LCMS: (ES+) m/z (M+H)+ = 161.1 , tR=0.955.
[00364] Exa - Methyl benzordlthiazole-6-carboxylate (B-182)
Figure imgf000103_0004
B-182 [00365] To a mixture of benzo[d]thiazole-6-carboxylic acid (10 g, 56 mmol) in anhydrous methanol (100 mL) was added thionyl chloride (21 g, 0.18 mol) slowly at room temperature. The mixture was heated to 60 °C and stirred under nitrogen for 2 hours. On completion, the mixture was concentrated in vacuo. The residue was diluted with water (100 mL) and extracted with dichloromethane (3 100 mL). The combined organic layers were concentrated in vacuo give compound B-182 (8.5 g, 79% yield) as a brown solid.
[00366] Example 83B - Benzordlthiazol-6-ylmethanol (B-183)
Me02
Figure imgf000104_0001
B-182 B-183
[00367] To a mixture of compound B-182 (5.0 g, 26 mmol) in anhydrous tetrahydrofuran (50 mL) was added DIBAL-H (50 mL, 1 .0 M in hexane) dropwise at -78 °C. The mixture was stirred at -78 °C for 2 hours. On completion, the reaction was quenched with water (50 mL) at 0 °C and filtered, and the resulting filtrate was extracted with dichloromethane (3 x 100 mL). The combined organic layers were concentrated in vacuo to give compound B-183 (3.5 g, 81% yield) as a yellow oil.
[00368] Example - Benzordlthiazole-6-carbaldehyd -184)
Figure imgf000104_0002
B-183 B-184
[00369] To a mixture of compound B-183 (3.5 g, 21 mmol) in anhydrous dichloromethane (20 mL) was added manganese dioxide (14 g, 0.21 mol) at room temperature. The mixture was stirred at room temperature for 16 hours. On completion, the reaction was filtered, and the filtrate was concentrated in vacuo to give compound B-184 (3.0 g, 88% yield) as a yellow solid.
[00370] Example 85B - Benzo[d"|thiazole-6-carbaldehyde oxime (B-185)
Figure imgf000104_0003
B-184 B-185
[00371] To a mixture of compound B-184 (2.5 g, 15 mmol) in 50% ethanol/water (20 mL) was added hydroxylamine hydrochloride (2.1 g, 30 mmol) and potassium carbonate (4.2 g, 30 mmol) at room temperature. The mixture was stirred at room temperature overnight. On completion, the reaction was filtered, and the resulting filtrate was concentrated in vacuo and purified by silica gel column chromatography [petroleum ether : ethyl acetate = 20: 1] to give compound B-185 (2.3 g, 84% yield) as a white solid.
[00372] Example 86B - quinoline-6-carbaldehyde oxime (B-186)
Figure imgf000105_0001
B-186
[00373] To a mixture of quinoline-6-carbaldehyde (3.0 g, 19 mmol) and hydroxylamine hydrochloride (2.6 g, 38 mmol) in dichloromethane (30 mL) was added triethylamine (3.8 g, 38 mmol) slowly at 0 °C. The mixture was allowed to warm to room temperature and stirred overnight. On completion, the mixture was diluted with water (20 mL) and extracted with dichloromethane (3 χ 50 mL). The combined organic layers were washed with brine (3 x 50 mL), dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography [petroleum ether : ethyl acetate = 10: 1 ], and the upper of the two major spots was collected to give compound B-186 (1.3 g, 38% yield) as a white solid.
[00374] Exa - Methyl benzordlthiazole-5-carboxylate (B-187)
Figure imgf000105_0002
B-187
[00375] To a mixture of benzo[d]thiazole-5-carboxylic acid (10 g, 56 mmol) in anhydrous methanol (100 mL) was added thionyl chloride (21 g, 0.18 mol) slowly at room temperature. The mixture was heated at 60 °C and stirred under nitrogen for 2 hours. On completion, the mixture was concentrated in vacuo. The residue was diluted with water (100 mL) and extracted with dichloromethane (3 χ 100 mL). The combined organic layers were concentrated in vacuo to give compound B-187 (8.2 g, 76% yield) as a brown solid.
[00376] Exa - Benzordlthiazol-5-ylmethanol (B-188)
Figure imgf000105_0003
B-187 B-188
[00377] To a mixture of compound B-187 (5.0 g, 26 mmol) in anhydrous tetrahydrofuran (50 mL) was added DIBAL-H (50 mL, 1 M in hexane) dropwise at -78 °C. The mixture was stirred at -78 °C for 2 hours. On completion, the reaction was quenched with water (50 mL) at 0 °C and filtered, and the filtrate was extracted with dichloromethane (3 x 100 mL). The combined organic layers were concentrated in vacuo to give compound B-188 (2.8 g, 65% yield) as a yellow oil.
[00378] Examp - Benzordlthiazole-5-carbaldehvde (Έ-189")
Figure imgf000105_0004
B-188 B-189
[00379] To a mixture of compound B-188 (2.8 g, 17 mmol) in anhydrous dichloromethane (20 mL) was added manganese dioxide (14 g, 0.16 mol) at room temperature. The mixture was stirred at room temperature for 16 hours. On completion, the reaction was filtered, and the filtrate was concentrated in vacuo to give compound B-189 (2.5 g, 93% yield) as a yellow solid.
[00380] Example 90B - Benzordlthiazole-5-carbaldehyde oxime CB-190^
Figure imgf000106_0001
B-189 B-190
[00381] To a mixture of compound B-189 (2.5 g, 15 mmol) in 50% ethanol/water (20 mL) was added hydroxylamine hydrochloride (2.1 g, 30 mmol) and potassium carbonate (4.2 g, 30 mmol) at room temperature. The mixture was stirred at room temperature overnight. On completion, the reaction was filtered, and the filtrate was concentrated in vacuo and purified by silica gel column chromatography [petroleum ether : ethyl acetate = 20: 1] to give compound B- 190 (2.1 g, 78% yield) as a white solid.
[00382] Example 91B - l-bromo-3-(2.2-diethoxyeth
Figure imgf000106_0002
B-191
[00383] To a mixture of 3-bromophenol (50 g, 0.29 mol) and 2-bromo-l , l -diethoxyethane (57 g, 0.29 mol) in N,N-dimethylformamide (500 mL) was added potassium carbonate (80 g, 0.58 mol) at room temperature. The mixture was then stirred at 100 °C overnight. On completion, the reaction mixture was diluted with water (200 mL) and extracted with ethyl acetate (3 χ 500 mL). The combined organic layers were washed with brine (2 x 500 mL), dried over anhydrous sodium sulfate and concentrated in vacuo to give compound B-191 (60 g, 76% yield) as a brown oil.
[00384] Example 92B - 6-bromobenzofuran (B-192)
Figure imgf000106_0003
B-191 B-192 B-193
[00385] To a solution of compound B-191 (50 g, 0.18 mol) in toluene (500 mL) was added polyphosphoric acid (20 g) at room temperature. The mixture was heated to reflux for 3 hours. On completion, the reaction mixture was diluted with hot water (200 mL) and extracted with dichloromethane (3 x 500 mL). The combined organic layers were washed with brine (2 x 500 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by silica gel column chromatography [petroleum ether: ethyl acetate = 20: 1 ] to give a mixture of compound B-192 and compound B-193 (1 1 g, 29% yield) as yellow oil. [00386] Example 93B - Benzofuran-6-carbaIdehvde (B-194)
Figure imgf000107_0001
B-192 B-193 B-194 B-195
[00387] To a mixture of compound B-192 and compound B-193 (10 g, 50 mmol) in anhydrous tetrahydrofuran (100 mL) was added n-BuLi (20 mL, 50 mmol, 2.5 M in hexhane) dropwise at -78 °C. Anhydrous N,N-dimethylformamide (8.8 g, 0.10 mol) was added slowly at - 78 °C. The mixture was stirred at -78 °C for 2 hours. On completion, the reaction was quenched with water (100 mL) at -78 °C. The reaction was filtered, and the resulting filtrate was extracted with dichloromethane (3 x 200 mL), washed with brine (2 χ 200 mL), dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography [petroleum ether: ethyl acetate = 100: 1] to give compound B-194 (2.5 g, 34% yield) as a yellow oil.
[00388] Example 94B - Benzofuran-6-carbaldehvde oxime (B-196
Figure imgf000107_0002
B-194 B-196
[00389] To a mixture of compound B-194 (2.0 g, 14 mmol) in 50% ethanol/water (20 mL) was added hydroxylamine hydrochloride (1.9 g, 24 mmol) and potassium carbonate (3.8 g, 24 mmol) at room temperature. The mixture was stirred overnight. On completion, the reaction was filtered, and the filtrate was concentrated in vacuo and purified by silica gel column
chromatography [petroleum ether : ethyl acetate = 20: 1 ] to give compound B-196 (1.1 g, 41 % yield) as a yellow solid.
[00390] Example 95B - (3-bromophenylY2.2-diethoxyethvnsulfane (B-197)
Figure imgf000107_0003
B-197
[00391] To a mixture of 3-bromobenzenethiol (39 g, 0.21 mol) and 2-bromo-l ,l - diethoxy ethane (45 g, 0.23 mol) in N N-dimethylformamide (400 mL) was added potassium carbonate (31 g, 0.23 mol) at room temperature. The mixture was stirred at room temperature for 2 hours. On completion, the reaction mixture was quenched with water and extracted with ethyl acetate (3 x 250 mL). The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give compound B-197 (50 g, 94% yield) as a yellow oil.
[00392] Example 96B - 6-bromobenzorblthiophene (B-198)
Figure imgf000108_0001
B-197 B-198
[00393] A solution of compound B-197 (50 g, 0.16 mol) in 1 ,2-dichloroethane (500 mL) was added dropwise to a mixture of polyphosphoric acid (100 g) in 1 ,2-dichloroethane (500 mL) at reflux. The mixture was stirred at reflux for 3 hours. On completion, the reaction mixture was cooled to room temperature and quenched with water (200 mL). The resulting mixture was extracted with dichloromethane (3 x 50 mL). The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, concentrated in vacuo and purified by silica gel chromatography [petroleum ether: ethyl acetate = 20: 1 ] to give compound B-198 (25 g, 72% yield) as a colorless oil. LCMS: (ES+) m/z (M+H)+ = 215.1 , tR= 0.945.
[00394] Example - benzorblthiophene-6-carbonitrile
Figure imgf000108_0002
B-198 B-199
[00395] A mixture of compound B-198 (4.0 g, 0.019 mol) and cuprous cyanide (2.5 g, 28 mmol) in l-methylpyrrolidin-2-one (20 mL) was stirred at 200 °C for 1 hour under microwave irradiation (150 W, 100 psi). On completion, the mixture was filtered, and the filtrate was diluted with dichloromethane (60 mL). This solution was washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give crude compound B-199 (2.6 g, 87% yield) as a yellow solid. LCMS: (ES+) m/z (M+H)+ = 160.1, tR= 0.795.
[00396] Example 9 - benzorblthiophene-6-carboxy )
Figure imgf000108_0003
B-199
[00397] A mixture of compound B-199 (2.6 g, 16 mmol) in 4N hydrochloric acid (30 mL) was stirred at 100 °C for 5 hours. On completion, the reaction mixture was cooled to 0 °C, and the solid was collected by filtration. The residue was dried in vacuo to give compound B-200 (2.4 g, 83% yield) as a yellow solid.
[00398] Exampl - benzorblthiophen-6-ylmethanol (B-201)
Figure imgf000108_0004
[00399] To a solution of compound B-200 (2.4 g, 13 mmol) in tetrahydrofuran (20 mL) was added borane tetrahydrofuran complex (40 mL, 40 mmol) dropwise at 0 °C. The mixture was allowed to gradually warm to room temperature and was stirred for a total of 3 hours. On completion, the reaction mixture was quenched carefully with methanol and concentrated in vacuo to give crude compound B-201 (2.0 g, 90% yield) as a colorless oil. LCMS: (ES+) m/z (M+H)+ = 147.2, tR= 0.637.
[00400] Example 100 - benzorblthiophene-6-carbald (B-202)
Figure imgf000109_0001
[00401] A mixture of compound B-201 (2.0 g, 12 mmol) and manganese dioxide (1 1 g, 0.12 mol) in dichloromethane (40 mL) was stirred at room temperature for 12 hours. On completion, the mixture was filtered, and the resulting filtrate was concentrated in vacuo to give crude compound B-202 (1.5 g, 76% yield) as a colorless oil. LCMS: (ES+) m/z (M+H)+ - 163.2, tR= 0.721 .
[00402] Example 10 - benzorblthiophene-6-carbald oxime (B-203)
Figure imgf000109_0002
[00403] To a mixture of compound B-202 (1 .0 g, 6.2 mmol) and hydroxylamine
hydrochloride (0.64 g, 9.3 mmol) in anhydrous dichloromethane (10 mL) was added triethylamine (0.94 g, 9.3 mmol) at room temperature. The mixture was stirred overnight. On completion, the reaction mixture was quenched with water and extracted with dichloromethane (3 x 40 mL). The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, concentrated in vacuo and purified by silica gel chromatography [petroleum ether: ethyl acetate = 1 : 1 ] to give compound B-203 (0.90 g, 82% yield) as a yellow solid. LCMS: (ES+) m/z (M+H)+ = 178.2, tR= 0.704.
[00404] Example 102B - 4-fluorobenzaldehvde oxime (B-204)
Figure imgf000109_0003
B-204
[00405] To a solution of 4-fluorobenzaldehyde (7.0 g, 56 mmol) and hydroxylamine hydrochloride (7.8 g, 0.1 1 mol) in anhydrous methanol (70 mL) was added potassium carbonate (15 g, 0.1 1 mol) at room temperature. The mixture was stirred at this temperature overnight. On completion, the reaction was filtered, and the filtrate was concentrated and purified by silica gel column chromatography [petroleum ether: ethyl acetate = 20: 1 ] to give compound B-204 (2.7 g, 35% yield) as a white solid.
[00406] Example 103B - 3.4-dichlorobenzaldehvde oxime (Β-205Ί
Figure imgf000110_0001
B-205
[00407] To a mixture of 3,4-dichlorobenzaldehyde (1.5 g, 8.6 mmol) and hydroxylamine hydrochloride (0.90 g, 13 mmol) in ethanol (30 mL) was added sodium hydroxide (0.50 g, 13 mmol) at room temperature. The mixture was stirred at room temperature overnight. On completion, the mixture was filtered, and the filtrate was concentrated in vacuo to give
compound B-205 (1.1 g, 68% yield) as a white solid. Ή-NMR (DMSO-d6, 400 MHz): δ 1 1.56 (s, 1H), 8.16 (s, 1H), 7.81 (s, 1H), 7.67-7.65 (d, J=8.4 Hz, 1H), 7.60-7.58 (dd, J,=8 Hz, J2=1.2 Hz, 1 H);
[00408] Example 104B - 3-chlorobenzorb]thiophene-2-carbaldehyde oxime (B-206)
Figure imgf000110_0002
[00409] To a solution of 3-chlorobenzo[b]thiophene-2-carbaldehyde (5.0 g, 25 mmol) and hydroxylamine hydrochloride (3.5 g, 50 mmol) in anhydrous methanol (50 mL) was added potassium carbonate (7.0 g, 50 mmol) at room temperature. The mixture was stirred at room temperature overnight. On completion, the reaction was filtered, and the filtrate was concentrated in vacuo and purified by silica gel column chromatography [petroleum ether: ethyl acetate = 20: 1 ] to give compound B-206 (3.5 g, 67% yield) as a yellow solid.
[00410] Example 105B - 4-(4-fluorophenoxy)benzaldehyde oxime (B-207)
Figure imgf000110_0003
B-207
[00411] To a solution of 4-(4-fluorophenoxy)benzaldehyde (2.0 g, 9.3 mmol) and
hydroxylamine hydrochloride (1.3 g, 18 mmol) in anhydrous methanol (20 mL) was added potassium carbonate (2.5 g, 18 mmol) at room temperature. The mixture was stirred at room temperature overnight. On completion, the reaction was filtered, and the resulting filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography [petroleum ether: ethyl acetate = 50: 1] to give compound B-207 (1.5 g, 71% yield) as a white solid.
[00412] Example 106B - l H-indole-6-carbaldehvde oxime (B-208
Figure imgf000111_0001
[00413] To a mixture of 1 H-indole-6-carbaldehyde (2.0 g, 14 mmol) and hydroxylamine hydrochloride (1.4 g, 21 mmol) in anhydrous dichloromethane (20 mL) was added triethylamine (2.1 g, 21 mmol) at room temperature. The reaction mixture was stirred at this temperature overnight. On completion, the reaction mixture was quenched with water and extracted with dichloromethane (3 x 20 mL). The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography [dichloromethane: methanol = 10: 1] to give compound B-208 (1.7 g, 77% yield) as a yellow solid. LCMS: (ES+) m/z (M+H)+ = 161.1 , tR= 1 .017.
[00414] - 5-bromo-3-(trifluoromethyl)-2.3-dihvdrobenzofuran-2-ol (B-209)
Figure imgf000111_0002
[00415] A mixture of 2,2,2-trifluoroethanamine hydrochloride (65 g, 0.48 mol) and sodium nitrite (40 g, 0.58 mol) were dissolved in dichloromethane (2.1 L) and water (70 mL) and stirred for 1 hour in an ice bath under nitrogen. The yellow mixture was then cooled to -78 °C and stirred at this temperature for 10 minutes. 5-bromo-2-hydroxybenzaldehyde (32 g, 0.16 mol) and BF3 Et20 (35 mL, 0.32 mol) were added. The mixture was stirred at -78 °C for 3 hours. On completion, the mixture was allowed to warm to room temperature before being quenched with methanol (40 mL). Aqueous saturated sodium bicarbonate was added, and the resulting solution was extracted with dichloromethane (3 x 500 mL). The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, concentrated in vacuo and purified by silica gel chromatography [petroleum ether: ethyl acetate = 5: 1] to give compound B-209 (10 g, 22% yield) as a white solid.
[00416] Example - 5-bromo-3-(trifluoromethyl)benzofuran (B-210)
Figure imgf000111_0003
B-209 B-210
[00417] TA solution of compound B-209 (10 g, 0.71 mmol) in phosphoric acid (50 mL) was heated to 120 °C and stirred for 18 h with a Dean-Stark trap. On completion, the mixture was diluted with water (40 mL) and extracted with dichloromethane (3 χ 50 mL). The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, concentrated in vacuo and purified by silica gel chromatography (petroleum ether: ethyl acetate = 50: 1) to give compound B-210 (2.3 g, 24% yield) as a yellow solid.
[00418] Example 109B - 3-(trifluoromethyl)benzofuran-5-carbaldehyde (B-211)
Figure imgf000112_0001
B-210 B-211
[00419] To a solution of compound B-210 (2.3 g, 8.7 mmol) in anhydrous tetrahydrofuran (20 mL) was added n-butyllithium (4 mL, 10 mmol, 2.5 M in hexane) dropwise at -78 °C. The resulting solution was stirred at -78 °C for 0.5 hour. Then anhydrous NN-dimethylformamide (3.1 g, 43 mmol) was added dropwise at -78 °C. The reaction was stirred at this temperature for 1 hour, then warmed to -40 °C and stirred at this temperature for a further 0.5 hours. On completion, the mixture was quenched with aqueous saturated ammonium chloride solution (50 mL) at -40 °C, allowed to warm to room temperature and organics were extracted with dichloromethane (3 χ 70 mL). The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give compound B-211 (0.63 g, 34% yield) as a yellow solid.
[00420] Example HOB - 3-(trifluoromethyl)benzofuran-5-carbaldehvde oxime (B-212)
Figure imgf000112_0002
[00421] A solution of compound B-211 (0.33 g, 1.4 mmol), hydroxylamine hydrochloride (0.20 g, 2.9 mmol) and triethylamine (0.29 g, 2.9 mmol) in dichloromethane (10 mL) was stirred at room temperature for 3 hours. On completion, the mixture was concentrated and purified by silica gel chromatography [petroleum ether: ethyl acetate = 3: 1] to give compound B-212 (0.21 g, 59% yield) as a white solid.
[00422] Example 111B - 4-bromo-2-(2-chloro-3, 3, 3-trifluoroprop-l -en-l-yl) phenyl acetate (B-213
Figure imgf000112_0003
[00423] Zinc powder (8.1 g, 0.13 mol) and acetic anhydride (7.7 g, 75 mmol) were added to a solution of 5-bromo-2-hydroxybenzaldehyde (5.0 g, 25 mmol) in N,N-dimethylformamide (100 mL) in an argon atmosphere at room temperature. Then l ,l ,l-trichloro-2,2,2-trifluoroethane (14 g, 75 mmol) was added dropwise to this system over 10 minutes with vigorous stirring. The reaction was monitored by TLC. On completion, the reaction mixture was treated with saturated ammonium chloride solution (100 mL) and extracted with dichloromethane (3 χ 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, concentrated in vacuo and purified by silica gel chromatography [petroleum ether: ethyl acetate = 10: 1 ] to give compound B-213 (5.0 g, 58% yield) as yellow oil. LCMS: (ES+) m/z (M+H)+ = 344.9, tR=0.979.
[00424] Exampl - 5-bromo-2-(trifluoromethyl)benzofuran (B-214)
Figure imgf000113_0001
B-213 B-214
[00425] Potassium tert-butoxide (0.49 g, 4.4 mmol) was added to a solution of compound B- 213 (0.50 g, 1.5 mmol) in N,N-dimethylformamide (10 mL) at room temperature. After addition, the reaction was stirred at room temperature for 1 hour. On completion, the reaction was quenched with 10 mL of water and then extracted with dichloromethane (3 χ 20 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, concentrated in vacuo and purified by silica gel chromatography [petroleum ether: ethyl acetate = 20: 1] to give compound B-214 (0.20 g, 52% yield) as a yellow solid. GCMS: M=265.9, tR= 4.384.
[00426] Example - 2-(trifluoromethyl) benzofuran-5-carbaldehyde (B-215)
Figure imgf000113_0002
B-214 B-215
[00427] To a solution of compound B-214 (0.20 g, 0.76 mmol) in diethyl ether (10 mL) was added tert-butyllithium (1.5 mL, 1.3 M in n-hexane) dropwise at -90 °C. After addition, the resulting solution was stirred at this temperature for 25 minutes. Anhydrous N,N- dimethylformamide (0.22 g, 3.0 mmol) was added, and the reaction was stirred at -70 °C for 1 h. The reaction was monitored by TLC. On completion, the reaction mixture was quenched with water (5 mL) and extracted with dichloromethane (3 χ 20 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, concentrated in vacuo and purified by silica gel chromatography [petroleum ether: ethyl acetate = 20: 1] to give compound B-215 (0.10 g, 61 % yield) as a yellow solid. 1H-NMR (CDC13, 400 MHz): 510.12 (s, 1H), 8.26 (s, 1 H), 8.06- 8.04 (d, J=7.6 Hz, 1H), 7.75-7.73 (d, J=8.4 Hz, 1H), 7.34 (s, 1H).
[00428] Example 114B - 2-(trifluoromethyl) benzofuran-5-carbaldehyde oxime (B-216)
Figure imgf000114_0001
B-215 B-216
[00429] To a mixture of compound B-215 (0.36 g, 1.7 mmol) and hydroxylamine hydrochloride (0.17 g, 2.5 mmol) in anhydrous methanol (5 mL) was added potassium carbonate (0.35 g, 2.5 mmol). The mixture was stirred at room temperature for 3 hours. On completion, the reaction was filtered, and the filtrate was concentrated in vacuo and purified by silica gel chromatography [petroleum ether: ethyl acetate = 3: 1] to give compound B-216 (0.36 g, 94% yield) as a white solid. LCMS: (ES+) m/z (M+H)+ = 230.0, tR= 0.819 & 0.835.
[00430] Example 115B - l-(4-bromo-2-fluorophenvn-2.2.2-trifluoroethanol (B-217)
Figure imgf000114_0002
B-217
[00431] To a mixture of 4-bromo-2-fluorobenzaldehyde (25 g, 0.12 mol) and
trimethyl(trifluoromethyl)silane (21 g, 0.15 mol) in tetrahydrofuran (150 mL) was added tetrabutylammonium fluoride (3.2 g, 12 mmol) at 0 °C. The reaction mixture was warmed to room temperature, stirred at this temperature for 4 hours, and then concentrated in vacuo. The crude product was dissolved in dichloromethane (100 mL), and 1 N hydrochloric acid (100 mL) was added. The resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was extracted with ethyl acetate (3 χ 100 mL). The combined organic layers were then washed with water and brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography [petroleum ether: ethyl acetate = 20: 1] to give compound B-217 (27 g, 79% yield) as a yellow oil. LCMS: (ES+) m/z (M+H)+ = 272.9, tR = 0.827.
[00432] Example 116B - l-(4-bromo-2-fluorophenyl)-2,2,2-trifluoroethanone (B-218)
Figure imgf000115_0001
B-217 B-218
[00433] To a solution of compound B-217 (25 g, 92 mmol) in dichloromethane (500 mL) was added sodium bicarbonate (31 g, 0.37 mol), followed by Dess-Martin reagent ( 141 g, 0.33 mol). The resulting slurry was stirred at room temperature for 12 hours. On completion, the reaction mixture was quenched by addition of isopropanol (100 mL) and concentrated in vacuo. The residue was partitioned between ethyl acetate (500 mL) and saturated aqueous solution of sodium sulfite (250 mL). The organic layer was separated, washed with water and brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography [petroleum ether: ethyl acetate = 20: 1 ] to give compound B-218 (18 g, 74% yield) as a yellow oil. LCMS: (ES+) m/z (M+H)+ = 270.9, tR = 0.739.
[00434] Example 117B - methyl 6-bromo-3-(trifluoromethyQbenzorb]thiophene-2- carboxylate (B-219)
Figure imgf000115_0002
B-218 B-219
[00435] A solution of compound B-218 (22 g, 87 mmol), triethylamine (1 1 g, 0.1 1 mol) and methyl mercaptoacetate (9.5 g, 89 mmol) in dimethylsulfoxide (200 mL) was stirred at 80 °C for 18 hours. On completion, the reaction solution was cooled to room temperature, diluted with water (500 mL) and extracted with ethyl acetate (3 x 200 mL). The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography [petroleum ether: ethyl acetate = 50: 1] to give compound B-219 (17 g, 60% yield) as a white solid. 'H MR (CD3C1, 400 MHz): 6 8.04 (s, 2H), 8.04 - 7.98 (t, J=7.2 Hz, 1 H), 7.63 - 7.61 (m, 1 H), 4.00 (s, 3H).
[00436] Example 118B - 6-bromo-3-(trifluoromethyl)benzo[b]thiophene-2-carboxylic acid
(B-220)
Figure imgf000115_0003
[00437] To a solution of compound B-219 (15 g, 44 mmol) in a mixture of tetrahydrofuran (190 mL) and water (10 mL) was added lithium hydroxide hydrate (5.6 g, 0.13 mol). The resulting mixture was stirred at room temperature for 16 hours and then concentrated in vacuo. The residue was diluted with water (50 mL) and washed with ethyl acetate (2 x50 mL). The aqueous solution was acidified with 2 N hydrochloric acid. The resulting precipitate was collected by filtration and dried in vacuo to give compound B-220 (13 g, 91% yield) as a white solid. 'HNMR (CD3CI, 400 MHz): δ 8.42 (s, 1 H), 7.88 - 7.86 (d, J=8.8 Hz, 1 H), 7.69 - 7.67 (d, J=8.8 Hz, 1H).
[00438] - 6-bromo-3-arifluoromethyl)benzorb1thiophene 03-221)
Figure imgf000116_0001
B-220 B-221
[00439] A solution of compound B-220 (10 g, 31 mmol) and l,8-diazabicyclo[5.4.0]undec-7- ene (25 g, 0.16 mol) in N, N-dimethylacetamide (80 mL) was stirred at 180 °C for 1 hour. On completion, the reaction mixture was poured into 1 Ν hydrochloric acid (100 mL) and extracted with ethyl acetate (3 χ 100 mL). The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography [petroleum ether: ethyl acetate = 20: 1 ] to give compound B-221 (6.0 g, 70% yield) as a white solid. 'HNMR (CD3C1, 400 MHz): δ 8.06 - 8.05 (d, 3=1.2 Hz, 1H), 7.90 (s, 1 H), 7.82 - 7.80 (d, J=8.4 Hz, 1H), 7.61 - 7.59 (d, J=8.4 Hz, 1H).
[00440] - 3-(trifluoromethyl)benzorblthiophene-6-carbaldehyde (B-222)
Figure imgf000116_0002
B-221 B-222
[00441] To a solution of compound B-221 (1.0 g, 3.6 mmol) in dry diethyl ether (20 mL) was added dropwise tert-butyllithium (4.1 mL, 5.3 mmol, 1.3 M in hexane) at -100 °C under nitrogen. The reaction was stirred at this temperature for 15 minutes. Then N, N-dimethylformamide (1.0 g, 14 mmol) was added dropwise at -100 °C, and the resulting mixture was stirred at this temperature for another 15 minutes. On completion, the reaction was quenched with water (10 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography [petroleum ether: ethyl acetate = 10: 1 ] to give compound B-222 (0.70 g, 84% yield) as a yellow solid. 'HNMR (DMSO-i/6, 400 MHz): δ 10.13 (s, 1 H), 8.88 (s, 1 H), 8.80 (s, 1H), 8.07 - 8.01 (m, 1 H).
[00442] Example 121B - 3-(trifluoromethyl)benzorblthiophene-6-carbaldehydeoxime (B- 223)
Figure imgf000117_0001
B-222
[00443] To a mixture of compound B-222 (0.60 g, 2.6 mmol) and hydroxylamine hydrochloride (0.36 g, 5.2 mmol) in dichloromethane (15 mL) was added triethylamine (0.52 g, 5.2 mmol). The resulting mixture was stirred at room temperature for 4 hours. On completion, the reaction mixture was diluted with dichloromethane and filtered. The filtrate was concentrated in vacuo and purified by silica gel chromatography [petroleum ether: ethyl acetate = 8: 1 ] to give compound B-223 (0.49 g, 76% yield) as a white solid. LCMS: (ES+) m/z (M+H)+ = 246.1 , tR = 0.824.
[00444] Example 122B - (2R, 3 SV2 -dibromo-2.3-dihvdrobenzofuran-5-carbaldehvde (B- 224]
Figure imgf000117_0002
B-224
[00445] A solution of benzofuran-5-carbaldehyde (0.50 g, 3.4 mmol) in chloroform (20 mL) was cooled to -10 °C. To this solution was added a solution of liquid bromine (0.83 g, 5.3 mmol) in chloroform (5 mL). The reaction mixture turned dark and was allowed to warm to room temperature over 1 hour. On completion, the solvent and remaining bromine were evaporated under reduced pressure. The residue was purified by silica gel chromatography [petroleum ether: ethyl acetate = 3 : 1 ] to give racemate B-224 (0.50 g, 50% yield) as a yellow solid. LCMS: (ES+) m/z (M+H)+ = 306.9, tR=0.984.
[00446] Example - 2. 3-difluoro-2.3-dihvdrobenzofuran-5-carbaldehvde (B-225
Figure imgf000117_0003
B-224 B-225
[00447] To a solution of racemate B-224 (1 .0 g, 3.3 mmol) in toluene (9 mL) and acetonitrile (1 mL) at 0 °C in the dark was added silver fluoride (3.3 g, 26 mmol). The solution was allowed to warm to room temperature and stirred overnight. On completion, water (20 mL) was added, and the resulting mixture was extracted with dichloromethane (3 χ 30 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography [petroleum ether: ethyl acetate = 1 Oi l- to give compound B-225 (0.20 g, 52% yield) as a yellow solid. LCMS: (ES+) m/z (M+H)+ = 185.0, tR=0.702.
[00448] Example 124B - 3-fluorobenzofuran-5-carbaldehyde (B-226)
Figure imgf000118_0001
B-225
[00449] A solution of compound B-225 (0.20 g, 1.1 mmol) and l ,8-diazabicyclo[5.4.0]undec- 7-ene (0.83 g, 5.4 mmol) in dimethylsulfoxide (5 mL) was stirred at 100 °C for 2 days. On completion, the reaction was quenched with water (10 mL) and extracted with dichloromethane (3 x 30 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography
[petroleum ether: ethyl acetate = 10: 1] to give compound B-226 (0.10 g, 56% yield) as a yellow solid. GCMS: M= 164, tR= 4.809.
[00450] Example 125B - 3-fluorobenzofuran-5-carbaldehyde oxime (B-227)
Figure imgf000118_0002
[00451] To a mixture of compound B-226 (0.15 g, 0.90 mmol) and hydroxylamine hydrochloride (94 mg, 1.4 mmol) in anhydrous ethanol (5 mL) was added potassium carbonate (0.25 g, 1.8 mmol) at room temperature. The mixture was stirred at room temperature for 3 hours. On completion, the reaction was filtered, and the filtrate was concentrated. The residue was purified by silica gel chromatography [petroleum ether: ethyl acetate = 3: 1 ] to give compound B-227 (0.12 g, 94% yield) as a white solid. LCMS: (ES+) m/z (M+H)+ = 180.1 , tR= O.f
[00452] Example 126B - pyrimidine-5-carbaldehyde oxime (B-228)
Figure imgf000118_0003
[00453] To a mixture of pyrimidine-5-carbaldehyde (0.50 g, 4.6 mmol) and hydroxylamine hydrochloride (0.97 g, 14 mmol) in ethanol (10 mL) was added sodium hydroxide (0.56 g, 14 mmol). The mixture was stirred at room temperature overnight. On completion, the mixture was filtered, and the filtrate was concentrated in vacuo and purified by silica gel chromatography (Petroleum ether: Ethyl acetate = 1 : 1 ) to give compound B-228 (0.40 g, 70% yield) as a white solid.
[00454] Example 127B - 2-fluorobenzofuran-5-carbaldehydeoxime (B-229)
Figure imgf000119_0001
[00455] To a solution of 2-fluorobenzofuran-5-carbaldehyde (1.0 g, 6.1 mmol) and hydroxylamine hydrochloride (0.90 g, 12 mmol) in dichloromethane (20 mL) was added triethylamine (1.2 g, 12 mmol). The resulting mixture was stirred at room temperature for 4 hours. On completion, the reaction suspension was diluted with dichloromethane and filtered. The filtrate was concentrated in vacuo and purified by silica gel chromatography [petroleum ether: ethyl acetate = 5: 1] to give compound B-229 (1.0 g, 92% yield) as a white solid. LCMS: (ES+) m/z (M+H)+ = 180.1 , tR = 0.713.
[00456] Example 128B - (6-bromobenzorblthiophen-2-yl)boronic acid (B-230)
Figure imgf000119_0002
B-230
[00457] To a mixture of 6-bromobenzo[b]thiophene (1.0 g, 4.7 mmol) in anhydrous tetrahydrofuran (10 mL) was added LDA (2.8 mL, 2.0 M in THF) dropwise at -70 °C. The mixture was stirred at this temperature for 1 hour. Then triisopropyl borate (1.1 g, 5.6 mmol) was added at -70 °C, and the reaction stirred at this temperature for 2 hours. Sulfuric acid (0.92 g, 9.4 mmol) was added slowly, and the reaction stirred at room temperature for another 2 hours. On completion, the reaction mixture were diluted with water (10 mL) and extracted with
dichloromethane (3 x20 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, concentrated in vacuo and purified by silica gel column
chromatography [petroleum ether: ethyl acetate = 5: 1] to give B-230 (0.8 g, 67% yield) as a yellow solid.
[00458] Example 129B - 6-bromo-2-(trifluoromethyl)benzo[blthiophene (B-231)
Figure imgf000119_0003
[00459] To a mixture of compound B-230 (1 .2 g, 4.7 mmol), sodium
trifluoromethanesulfinate (2.2 g, 14 mmol) and copper(I) chloride (0.46 g, 4.7 mmol) in methanol/dichloromethane/water (5:5:4, 28 mL) was added tert-butyl hydroperoxide (2.2 g, 24 mmol) slowly at room temperature. The resulting mixture was stirred at room temperature for 16 hours. On completion, the reaction was quenched with sodium sulfite and concentrated to remove most of the organic solvent. The reaction mixture was diluted with water (10 mL) and extracted with dichloromethane (3 x20 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, concentrated in vacuo and purified by silica gel column chromatography [petroleum ether: ethyl acetate = 15: 1] to give B-231 (0.60 g, 48% yield) as a yellow solid.
[00460] Exampl - 2-(trifluoromethyl)benzo[blthiophene-6-carbaldehvde (B-232)
Figure imgf000120_0001
[00461] To a mixture of compound B-231 (0.15 g, 0.54 mmol) in anhydrous ether (10 mL) was added t-BuLi (1.0 mL, 1.3 M in n-hexane) slowly at -100 °C. The mixture was stirred at -100 °C for about 20 minutes. Then N, N-dimethylformamide (0.19 g, 2.2 mmol) was added slowly at - 100 °C. The mixture solution was stirred for another hour. On completion, the reaction was quenched with water (2 mL) and extracted with ethyl acetate (3 x 10 mL). The combined organic layers were concentrated and purified by silica gel chromatography [petroleum ether: ethyl acetate = 5: 1] to give B-232 (40 mg, 28% yield) as a yellow oil. LCMS: (ES+) m/z (M+H)+ = 231.1 , tR= 1.208.
[00462] Example 131B - 2-(trifluoromethyl)benzo[blthiophene-6-carbaldehyde oxime (B- 233)
Figure imgf000120_0002
B-232 B-233
[00463] To a mixture of compound B-232 (70 mg, 0.30 mmol) and hydroxylamine hydrochloride (31 mg, 0.45 mmol) in ethanol (5 mL) was added potassium carbonate (18 mg, 0.45 mmol). The mixture was stirred at room temperature for about 2 hours. On completion, the resulting mixture was concentrated and purified by silica gel chromatography [petroleum ether: ethyl acetate = 3: 1 ] to give B-233 (30 mg, 41 % yield) as a white solid.
[00464] Example 132B - 6-bromo-2-fluorobenzofb1thiophene (B-234)
Figure imgf000121_0001
B-234
[00465] To a solution of diisopropylamine (9.5 g, 94 mmol) in dry tetrahydrofuran (100 mL) was added n-BuLi (34mL, 2.5M in n-hexane) dropwise at -65 °C during which the temperature was not allowed to exceed -55 °C. The mixture was stirred at -30 °C for 30 minutes and then re- cooled to -65 °C. 6-bromobenzo[b]thiophene (8.0 g, 38 mmol) was added in one portion, and the reation was stirred at -50 °C for 1 hour and then cooled to -65 °C. A solution of N-fluoro-N- (phenylsulfonyl)benzenesulfonamide (12 g, 38 mmol) in dry tetrahydrofuran (20 mL) was added dropwise at -65 °C. The reaction temperature was allowed to rise slowly to room temperature, and the reaction was stirred at this temperature for 4 hours, at which time GCMS analysis showed about 30% desired product. The reaction was quenched with water (50 mL) and extracted with ethyl acetate (3 x 100 mL). The combined organic layers were concentrated and purified by silica gel chromatography [petroleum ether] to give B-234 (2.2 g, 25% yield) as a white solid.
[00466] Example - 2-fluorobenzorblthiophene-6-carbaldehvde ΓΒ-235
Figure imgf000121_0002
B-234 B-235
[00467] To a mixture of compound B-234 (1.0 g, 4.3 mmol) in anhydrous ether (20 mL) was added t-BuLi (8.3 mL, 1.3M in n-hexane) slowly at -100 °C. The mixture was stirred at -100 °C for 20 minutes. Then NN-dimethylformamide (1.5 g, 17 mmol) was added dropwise and stirred at this temperature for another 2 hour. On completion, the reaction was quenched with water (10 mL) and extracted with ethyl acetate (3x30 mL). The combined organic layers were concentrated and purified by silica gel chromatography [petroleum ether: ethyl acetate = 5: 1 ] to give B-235 (0.25 g, 32% yield) as a yellow oil.
[00468]
Figure imgf000121_0003
B-235 B-236
[00469] To a mixture of compound B-235 (1.0 g, 5.5 mmol) and hydroxylamine
hydrochloride (0.57 g, 8.3 mmol) in ethanol (20 mL) was added potassium carbonate (0.33 g, 8.3 mmol). The mixture was stirred at room temperature for 2 hours. On completion, the resulting mixture was concentrated and purified by silica gel chromatography [petroleum ether: ethyl acetate = 3 : 1 ] to give B-236 (0.80 g, 73% yield) as a white solid.
[00470] - 6-bromo-3-fluorobenzo[b]thiophene-2-carboxylic acid (B-237)
Figure imgf000122_0001
B-237
[00471] To a solution of anhydrous diisopropylamine (4.0 g, 40 mmol) in anhydrous tetrahydrofuran (60 mL) under nitrogen at -78 °C was added n-butyllithium (16 mL, 2.5 N in hexane, 40 mmol) dropwise over 30 minutes. The resulting solution was stirred at -78 °C for 1 hour. Then a solution of 6-bromobenzothiophene -2-carboxylic acid (2.0 g, 7.8 mmol) in anhydrous tetrahydrofuran (15 mL) was added dropwise to the mixture over a period of 40 minutes. The resulting mixture was stirred at -78 °C for 1 hour. Then a solution of N- fluorobenzenesulfonimide (6.5 g, 21 mmol) in anhydrous tetrahydrofuran (20 mL) was added dropwise at -78 °C over a period of 30 minutes. The reaction solution was warmed to room temperature and stirred at this temperature for 12 hours. On completion, the mixture was quenched with water at 0 °C and extracted with dichloromethane (3 χ 50 mL). The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography [dichloromethane: methanol = 10: 1 ] to give compound B-237 (1 .5 g, 70% yield) as a white solid. LCMS: (ES+) m/z (M+H)+ = 274.9, tR = 0.81 1.
[00472] Ex - 6-bromo-3-fluorobenzorblthiophene (B-238)
Figure imgf000122_0002
[00473] A mixture of compound B-237 (3.3 g, 12 mmol) and l ,8-diazabicyclo[5.4.0]undec-7- ene [l ,2-a]azepine (7.3 g, 48 mmol) in N,N-dimethylacetamide (30 mL) was stirred at 1 80 °C for 2 hours. On completion, the mixture was poured into IN hydrochloric acid and extracted with ethyl acetate (3 χ 40 mL). The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, concentrated in vacuo and purified by silica gel chromatography [petroleum ether: ethyl acetate = 100: 1 ] to give compound B-238 (1 .3 g, 47% yield) as a yellow solid. GCMS: M = 231.9, tR = 8.552.
[00474] Example 137B - 3-fluorobenzorb1thiophene-6-carbaldehyde (B-239)
Figure imgf000123_0001
[00475] To a solution of compound B-238 (1.8 g, 7.8 mmol) in anhydrous diethyl ether (15 mL) was added tert-butyllithium (6.5 mL, 1.3 N in hexane, 8.6 mmol) dropwise at -100 °C. The resulting solution was stirred at -100 °C for 15 minutes. Then anhydrous N,N-dimethylformamide (2.3 g, 31 mmol) was added dropwise at -100 °C, and the reaction was stirred at this temperature for 1 hour. On completion, the mixture was quenched with saturated ammonium chloride aqueous (20 mL) and extracted with dichloromethane (3 x 40 mL). The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, concentrated in vacuo and purified by silica gel chromatography [petroleum ether : ethyl acetate = 4: 1] to give compound B-239 (1.3 g, 93% yield) as a yellow solid. GCMS: M = 179.9, tR = 6.183.
[00476] Exa - 3-fluorobenzo[blthiophene-6-carbaldehyde oxime (B-240)
Figure imgf000123_0002
[00477] A solution of compound B-239 (1.6 g, 8.9 mmol), hydroxylamine hydrochloride
(0.74 g, 1 1 mmol) and triethylamine (1.8 g, 18 mmol) in dichloromethane (30 mL) was stirred at room temperature for 3 hours. On completion, the reaction was filtered, and the filtrate was concentrated. The residue was purified by silica gel chromatography [petroleum ether: ethyl acetate = 4 : 1 ] to give compound B-240 (0.75 g, 43% yield) as a yellow solid. LCMS: (ES+) m/z
(M+H)+ = 196.1 , tR = 0.752.
[00478] Example 139B - N-ithiophen-3-yl)acetamide (B-241)
Figure imgf000123_0003
B-241
[00479] 3-Aminothiophene (1.1 g, 1 1 mmol) was dissolved in acetic anhydride (20 mL), and the mixture was stirred at room temperature for 3 hours. Water (50 mL) was added, and the mixture was stirred for a further 30 minutes. Sodium hydroxide (4M aq., 150 mL) was added until pH > 9 was attained. The mixture was extracted with dichloromethane (3 x 100 mL), the combined organic extracts were washed with brine (30 mL), dried over sodium sulfate and evaporated. The residue was recrystallized using dichloromethane/petroleum ether, to give compound B-241 (1.0 g, 65% yield) as a white crystalline solid; Ή-NMR (CDC13, 400 MHz): δ 7.57-7.57 (d, J=2.0 Hz, 1H), 7.25-7.23 (dd, J=5.2 Hz, J=3.6 Hz, 1 H), 7.02-7.00 (m, 1H), 2.18 (s, 3H).
[00480] Example 140B - 5-chlorothieno[3,2-b1pyridine-6-carbaldehyde (B-242)
Figure imgf000124_0001
[00481] Phosphorus oxychloride (23 g, 0.15 mol) was added dropwise to anhydrous N,N- dimethylformamide (4.7 g, 64 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for a period of 30 minutes, and then compound B-241 (3.0 g, 21 mmol) was added. The mixture was stirred at room temperature for 15 minutes and then heated at reflux overnight, cooled, and poured into ice with vigorous stirring. The solution was neutralized with aqueous sodium hydroxide with ice cooling and extracted with dichloromethane (3 x 50 mL). The combined organic layers were concentrated and purified by silica gel chromatography [petroleum ether: ethyl acetate = 3: 1 ] to afford compound B-242 (1.0 g, 24% yield) as a yellow solid. LCMS: (ES+) m/z (M+H)+ = 198.1 , tR=0.653.
[00482] Example 14 - thienor3,2-b1pyridine-6-carba (B-243)
Figure imgf000124_0002
[00483] A suspension of compound B-242 (1.0 g, 5.1 mmol), magnesium oxide (82 mg, 2.0 mmol) and Pd/C (10%, 0.52 g) in 50 mL of ethanol was stirred at room temperature under hydrogen atmosphere for 12 hours. On completion, the reaction mixture was filtered, and the filtrate was concentrated and purified by silica gel chromatography [petroleum ether: ethyl acetate = 2: 1] to give compound B-243 (0.50 g, 61% yield) as a yellow solid. LCMS: (ES+) m/z (M+H)+ = 164.1 , tR=0.137.
[00484] Example 142B - thienor3,2-blpyridine-6-carbaldehvde oxime (B-244)
Figure imgf000124_0003
B-243 B-244
[00485] To a mixture of compound B-243 (0.50 g, 3.1 mmol) and hydroxylamine hydrochloride (0.32 g, 4.6 mmol) in anhydrous ethanol (10 mL) was added potassium carbonate (0.64 g, 4.7 mmol). The reaction mixture was stirred at room temperature for 3 hours. On completion, the reaction was filtered, and the filtrate was concentrated and purified by silica gel chromatography [petroleum ether: ethyl acetate = 3: 1] to give compound B-244 (0.50 g, 92% yield) as a white solid. LCMS: (ES+) m/z (M+H)+ = 179.1 , tR=0.1 15.
[00486] Example 143B - l-amino-3-(hydroxymethyl)pyridinium 2.4,6- trimethylbenzenesulfonate (B-245)
Figure imgf000125_0001
B-245
[00487] Perchloric acid (20 mL) was added to the solution of ethyl N- (mesitylsulfonyl)oxyacetimidate (34 g, 0.12 mol) in tetrahydrofuran (200 mL), and the mixture was stirred at room temperature under nitrogen for 2 hours. The reaction mixture was poured into a water/ice mixture (200 mL), and the precipitate was collected by filtration, washed with ice- water and dried in vacuo. The solid was added to a solution of 4-pyridinylmethanol (1 1 g, 0.10 mmol) in dichloromethane (250 mL), and the mixture was stirred under nitrogen at room temperature for 12 hours. The mixture was diluted with diethyl ether (150 mL), and the solid was collected to give B-245 (31 g, crude) which was used directly.
[00488] Example 144B - 5-bromo-3-(trifluoromethyl)benzofuran (B-246)
Figure imgf000125_0002
[00489] To a solution of B-245 (12 g, crude) in N,N-dimethyl formamide ( 100 mL) was added methyl acrylate (6.0 g, 71 mmol) and potassium carbonate (19 g, 0.14 mol). The mixture was stirred at room temperature for 18 hours under nitrogen. On completion, the reaction mixture was diluted with ethyl acetate (200 mL), washed with water (3 x 100 mL), 0.1 M hydrochloric acid (200 mL) and brine (200 mL), dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography (dichloromethane: methanol = 100: 1-10: 1 ) to give compound B-246 (2.0 g, 27% yield) as a yellow solid. LCMS: ( ES+ ) m/z (M+H)+ = 207.1 , tR = 1.281.
[00490] Example 145B - pyrazolori ,5-a1pyridin-5-ylmethanol (B-247)
Figure imgf000126_0001
[00491] A mixture of compound B-246 (2.0 g, 9.7 mmol) in 40% hydrobromic acid (20 mL) was heated to 120 °C and stirred for 12 hours. On completion, the mixture was concentrated, neutralized with sodium carbonate, and extracted with dichloromethane (3 χ 50 mL). The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, concentrated in vacuo and purified by silica gel chromatography (dichloromethane: methanol = 100: 1-10: 1 ) to give compound B-247 (1.0 g, 69% yield) as a yellow solid. LCMS: (ES+ ) m/z (M+H)+ = 149.0, tR = 1.146.
[00492] Example 146B - pyrazolon ,5-a1pyridine-5-carbaldehyde (B-248)
Figure imgf000126_0002
[00493] To a solution of compound B-247 (1 .0 g, 6.7 mmol) in dichloromethane (10 mL) was added manganese dioxide (5.9 g, 67 mmol). The mixture was stirred at room temperature for 20 hours. On completion, the mixture was filtered, and the resulting filtrate was concentrated to give compound B-248 (0.70 g, 71 % yield) as a white solid. LCMS: (ES+) m/z (M+H)+ = 147.0, tR = 0.837.
[00494] Example 147B - pyrazolo[l,5-a]pyridine-5-carbaldehyde oxime (B-249)
Figure imgf000126_0003
[00495] A solution of compound B-248 (0.70 g, 4.8 mmol), hydroxylamine hydrochloride (0.5 g, 7.2 mmol) and triethylamine (0.73 g, 7.2 mmol) in dichloromethane (10 mL) was stirred at room temperature for 3 hours. On completion, the mixture was diluted with water (20 mL) and extracted with dichloromethane (3 χ 50 mL). The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, concentrated in vacuo and purified by silica gel chromatography [dichloromethane: methanol = 20: 1 ] to give compound B-249 (0.60 g, 78% yield) as a white solid. LCMS: ( ES+ ) m/z (M+H)+ = 162.0, tR = 1 .418.
[00496] Example 148B - ethyl 6-oxo-L6-dihydropyridine-3-carboxylate (B-250)
Figure imgf000127_0001
B-250
[00497] A solution of 6-oxo-l ,6-dihydropyridine-3-carboxylic acid (10 g, 72 mmol) in thionyl chloride (20 mL) was heated at reflux for 1 hr. The reaction mixture was cooled to room temperature and concentrated in vacuo. The residue was treated with ethanol (100 mL), and the solid was collected by filtration, washed with ether (2 x 100 mL) and dried to give compound B- 250 (1 1 g, 92% yield) as a white solid. LCMS: (ES+) m/z (M+H)+ = 168.0, tR= 0.122.
[00498] Exampl - ethyl 5-iodo-6-oxo-l ,6-dihvdropyridine-3-carboxylate (B-251)
Figure imgf000127_0002
[00499] To a solution of compound B-250 (5.0 g, 30 mmol) in methanol (120 mL) was added portionwise N-iodosuccinimide (10 g, 45 mmol). The resulting solution was stirred at 50 °C for 24 hours. On completion, the reaction mixture was concentrated, and the residue was diluted with water (100 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by silica gel chromatography [petroleum ether: ethyl acetate = 3: 1] to give
compound B-251 (6.0 g, 68% yield) as a yellow solid. LCMS: (ES+) m/z (M+H)+ = 293.9, tR= 0.639.
[00500] Example 150B - ethyl 6-oxo-5-((trimethylsilyl)ethvnyl)-L6-dihvdropyridine-3- carboxylate (B-252)
Figure imgf000127_0003
[00501] To a solution of compound B-251 (12 g, 40 mmol) in tetrahydrofuran (93 mL) and chloroform (185 mL) under an atmosphere of argon were added trimethylsilylacetylene (4.7 g, 48 mmol), dichlorobis-(triphenylphosphine)palladium(U) (0.84 g, 1.2 mmol), copper iodide (0.1 1 g, 0.60 mmol) and triethylamine (12 g, 0.12 mol). The resulting mixture was stirred at 50 °C for 20 hours. The mixture was cooled to room temperature and diluted with ethyl acetate (100 mL). The resulting solution was washed with 10% aqueous citric acid, brine, and saturated aqueous sodium bicarbonate, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography [petroleum ether: ethyl acetate = 10: 1] to give compound B-252 (6.0 g, 57% yield) as a white solid. LCMS: (ES+) m/z (M+H)+ = 264.1 , tR= 1.679.
[00502] Example 151B - ethyl furor2,3-blpyridine-5-carboxylate (B-253)
Figure imgf000128_0001
[00503] To a solution of compound B-252 (2.6 g, 9.9 mmol) in ethanol (50 mL) were added copper iodide (95 mg, 0.50 mmol) and triethylamine (150 mL). The reaction solution was stirred at 70 °C for 12 hours. On completion, the reaction mixture was quenched with water (20 mL) and extracted with dichloromethane (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography [petroleum ether: ethyl acetate = 5: 1] to give compound B-253 (0.65 g, 34% yield) as a white solid. LCMS: (ES+) m/z (M+H)+ = 192.1 , tR = 1 .193.
[00504] Exa - furor2.3-b1pyridin-5- lmethanol B-254
Figure imgf000128_0002
B-253 B-254
[00505] To a mixture of lithium aluminum hydride (70 mg, 1.8 mmol) in tetrahydrofuran (10 mL) was added a solution of compound B-253 (0.10 g, 0.52 mmol) in tetrahydrofuran (5 mL) dropwise at 0 °C. The resulting mixture was stirred at this temperature for 2 hours. On completion, the mixture was quenched with water (5 mL), treated with tartaric acid and extracted with ethyl acetate (3 10 mL). The combined organics were concentrated and purified by prep- TLC to give compound B-254 (35 mg, 45% yield) as a yellow solid. LCMS: (ES+) m/z (M+H)+ = 150.1 , tR= 0.103.
[00506] Example 153B - furor2.3-blpyridine-5-carbaldehvde ΓΒ-2551
Figure imgf000128_0003
B-254 B_255
[00507] A mixture of compound B-254 (0.30 g, 2.0 mmol) and manganese dioxide (1.8 g, 20 mmol) in dichloromethane (10 mL) was stirred at 25 °C overnight. On completion, the reaction was filtered, and the filtrate was concentrated in vacuo and purified by silica gel chromatography [petroleum ether: ethyl acetate = 5: 1] to give compound B-255 (0.25 g, 85% yeild) as a brown solid. LCMS: (ES+) m/z (M+H)+ = 148.0, tR= 0.687. [00508] Example 154B - furor2J-blpyridine-5-carbaldehvde oxime (B-256)
Figure imgf000129_0001
B-255 B-256
[00509] A solution of compound B-255 (20 mg, 0.14 mmol), hydroxylamine hydrochloride (19 mg, 0.27 mmol) and triethylamine (41 mg, 0.41 mmol) in dichloromethane (5 mL) was stirred at room temperature for 3 hrs. On completion, the reaction solution was diluted with
dichloromethane (30 mL), washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography [petroleum ether: ethyl acetate = 5: 1 ] to give compound B-256 (20 mg, 91 % yeild) as a yellow solid. LCMS: (ES+) m/z (M+H)+ = 163.0, tR= 0.809.
[00510] Example 155B - methyl 2-amino-3-hydroxybenzoate (B-257)
Figure imgf000129_0002
[00511] To a solution of 2-amino-3-hydroxybenzoic acid (10 g, 65 mmol) in anhydrous methanol (300 mL) was added thionyl chloride (16 g, 0.13 mol) dropwise at room temperature.
The solution was heated to reflux for 2 hours. On completion, the resulting solution was concentrated in vacuo to give compound B-257 (10 g, crude) as a red solid.
[00512] Example 156B - methyl 3-oxo-3, 4-dihvdro-2H-benzorb][L4]oxazine-5-carboxylate
(B-258)
Figure imgf000129_0003
[00513] To a mixture of compound B-257 (7.0 g, 42 mmol) and triethylamine (13 g, 0.13 mol) in acetonitrile (70 mL) was added 2-chloroacetyl chloride (4.7 g, 42 mmol) dropwise at 0 °C. The reaction was allowed to warm to room temperature and was stirred at this temperature for 6 hours. On completion, the reaction mixture was concentrated in vacuo and purified by silica gel chromatography [petroleum ether: ethyl acetate = 5: 1] to give compound B-258 (7.0 g, 81 % yield) as a brown solid.
[00514] Example 157B - (3. 4-dihvdro-2H-benzorbllT .41oxazin-5-vnmethanol (B-259
Figure imgf000130_0001
[00515] To a solution of compound B-258 (7.0 g, 34 mmol) in tetrahydrofuran (70 mL) was added lithium aluminum hydride (2.6 g, 68 mmol) portionwise at 0 °C under nitrogen. The reaction was allowed to warm to room temperature and was stirred at this temperature for 16 hours. On completion, the reaction was quenched with water (7 mL) and 10% sodium hydroxide solution (7 mL) at 0 °C. The mixture was filtered, and the filter cake was washed with ethyl acetate (3 χ 50 mL). The combined filtrate was concentrated in vacuo and purified by silica gel chromatography [petroleum ether: ethyl acetate = 5: 1] to give compound B-259 (4.0 g, 70% yield) as a yellow oil.
[00516] Example 158B - (4-(4-methoxybenzyl)-3, 4-dihydro-2H-benzorbl[l ,4]oxazin-5- vnmethanol (
Figure imgf000130_0002
[00517] To a mixture of compound B-259 (4.0 g, 24 mmol), potassium carbonate (6.6 g, 48 mmol) and potassium iodide (0.40 g, 2.4 mmol) in N, N-dimethylformamide (40 mL) was added l-(chloromethyl)-4-methoxybenzene (4.5 g, 29 mmol) at room temperature. The mixture was then stirred at 60 °C for 2 hours. On completion, the reaction solution was concentrated in vacuo and purified by silica gel chromatography [petroleum ether: ethyl acetate = 5: 1] to give compound B- 260 (5.5 g, 80% yield) as a yellow oil
[00518] Example 159B - 4-(4-methoxybenzylV3. 4-dihvdro-2H-benzorb1IT ,41oxazine-5- carbaldehyde ( -261)
Figure imgf000130_0003
[00519] To a solution of compound B-260 (5.0 g, 18 mmol) in dichloromethane (50 mL) was added manganese dioxide (16 g, 0.18 mol) at room temperature. The mixture was stirred at this temperature overnight. On completion, the solution was filtered, and the resulting filtrate was concentrated in vacuo to give compound B-261 (4.5 g, 90% yield) as a yellow oil, which was used for next step without further purification. [00520] Example 160B - 4-(4-methoxybenzyl)-3,4-dihydro-2H-benzorbirL41oxazine-5- carbaldehyde oxime (B-262)
Figure imgf000131_0001
[00521] To a mixture of compound B-261 (3.0 g, 1 1 mmol) and hydroxylamine
hydrochloride (1.5 g, 22 mmol) in 50% ethanol/water (30 mL) was added potassium carbonate (3.0 g, 22 mmol). The reaction was stirred at room temperature overnight. On completion, the mixture was concentrated to remove most of the ethanol and extracted with dichloromethane (3 χ 50 mL). The combined organic layers was washed with brine (3 χ 50 mL), dried over anhydrous sodium sulfate, concentrated in vacuo and purified by silica gel chromatography [petroleum ether: ethyl acetate = 5: 1] to give compound B-262 (2.8 g, 88% yield) as a yellow solid.
[00522] Exam - 7-vinylind (B-263)
Figure imgf000131_0002
dioxane, reflux, overnight
B-263
[00523] To a mixture of 7-bromoindolin-2-one (10 g, 48 mmol) and sodium carbonate (10 g, 96 mmol) in 1,4-dioxane (100 mL) was added 4,4,5, 5-tetramethyl-2-vinyl-l ,3,2-dioxaborolane (7.3 g, 48 mmol) and Pd(PPh4)3 (2.5 g, 2.4 mmol) at room temperature. The mixture was heated to reflux and stirred under nitrogen overnight. On completion, the mixture was diluted with water (100 mL) and extracted with dichloromethane (3 x 200 mL). The combined organic layers were washed with brine (2 χ 200 mL), dried over anhydrous sodium sulfate, concentrated in vacuo and purified by silica gel column chromatography [petroleum ether: ethyl acetate = 6: 1 ] to give compound B-263 (6.8 g, 90% yield) as a yellow solid.
[00524] Example 162B - 2-oxoindoline-7-carbaldehvde (B-264)
Figure imgf000131_0003
B-263 B-264
[00525] Ozone was bubbled into a solution of compound B-263 (2.2 g, 14 mmol) in dichloromethane (20 mL) at -78 °C for 30 minutes. On completion, excess O3 was purged from the reaction with nitrogen and dimethylsulfide (30 mL) was added. The reaction mixture was concentrated in vacuo and purified by silica gel chromatography [petroleum ether: ethyl acetate : 6: 1] to give compound B-264 (1.0 g, 46% yield) as a yellow solid.
[00526] Example 163B - 2-oxoindoline-7-carbaldehyde oxime (B-265)
Figure imgf000132_0001
B-264 B-265
[00527] To a mixture of compound B-264 (2.1 g, 13 mmol) in 50% ethanol water (20 mL) was added hydroxylamine hydrochloride (0.90 g, 26 mmol) and potassium carbonate (1.7 g, 26 mmol) at room temperature. The mixture was stirred at room temperature overnight. On completion, the reaction was filtered, and the resulting filtrate was concentrated in vacuo and purified by silica gel chromatography [petroleum ether: ethyl acetate = 20: 1] to give compound B-265 (1.0 g, 46% yield) as a yellow solid.
[00528] Ex - imidazori ,2-a1pyridine-6-carboxylic acid (B-266)
Figure imgf000132_0002
B-266
[00529] To a solution of ethyl imidazo[l ,2-a]pyridine-6-carboxylate (6.0 g, 36 mmol) in tetrahydrofuran (30 mL) and water (30 mL) was added lithium hydroxide hydrate (2.7 g, 63 mmol). The reaction mixture was stirred at 25 °C for 2 hours. On completion, the mixture was acidified with 36% hydrochloric acid. The solid was collected, washed with water and dried in vacuo to give compound B-266 (4.0 g, 78% yield) as a yellow solid.
[00530]
Figure imgf000132_0003
B-267
[00531] To a solution of compound B-266 (4.3 g, 27 mmol) in anhydrous tetrahydrofuran (25 mL) was added borane dimethyl sulfide complex (5.8 mL, 10 N in dimethyl sulfide, 58 mmol) dropwise at 0 °C. The resulting solution was stirred at 0 °C for 0.5 hour, then heated to 80 °C and stirred at this temperature for 3 hours. On completion, the mixture was quenched with methanol (10 mL) at 0 °C, concentrated in vacuo and purified by silica gel chromatography
[dichloromethane: methanol = 10: 1] to give compound B-267 (1.0 g, 26% yield) as a white solid. LCMS: (ES+) m/z (M+H)+ = 149.1 , tR = 0.279.
[00532] Example 166B - imidazori .2-a]pyridine-6-carbaldehvde (B-268)
Figure imgf000133_0001
HO^ />¾^ii y DCM, rt, overnight
B-267 B-268
[00533] To a solution of compound B-267 (1 .0 g, 7.4 mmol) in anhydrous dichloromethane (50 mL) was added manganese dioxide (6.5 g, 74 mmol). The mixture was stirred at room temperature for 16 hours. On completion, the reaction was filtered, and the filtrate
was concentrated in vacuo to give compound B-268 (0.30 g, 28% yield) as a yellow solid.
LCMS: (ES+) m/z (M+H)+ = 147.1 , tR = 0.329.
[00534] Example 167B - (6E)-imidazof L2-alpyridine-6-carbaldehyde oxime (B-269)
Figure imgf000133_0002
B-268 B-269
[00535] A solution of compound B-268 (0.30 g, 2.1 mmol), hydroxylamine hydrochloride (0.17 g, 2.5 mmol) and triethylamine (0.42 g, 4.1 mmol) in dichloromethane (15 mL) was stirred at room temperature for 4 hours. On completion, the reaction was filtered, and the resulting filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography
[dichloromethane: methanol = 10: 1 ] to give compound B-269 (0.30 g, 90% yield) as a yellow solid. LCMS: (ES+) m/z (M+H)+ = 162.1 , tR = 0.379.
[00536] Example 16 - l-(2-methoxy-2-oxoethyl)pyridazin-l-ium bromide (B-270)
.
Figure imgf000133_0003
[00537] A mixture of pyridazine (5.0 g, 62 mmol) and methyl bromoacetate (1 1 g, 69 mmol) in ethyl acetate (100 mL) was refluxed for 3 hours. On completion, the reaction mixture was cooled to room temperature. The solid was collected by filtration, washed with ethyl acetate (3 x 30 mL) and dried in vacuo to give compound B-270 (1 1 g, 76% yield) as a brown solid.
[00538] - trimethyl pyrrolo[l ,2-b]pyridazine-5, -tric-arboxylate (B-271)
Figure imgf000133_0004
[00539] To a mixture of compound B-270 (5.0 g, 21 mmol), dimethyl acetylenedicarboxylate (3.4 g, 24 mmol) and triethylamine (2.4 g, 24 mmol) in toluene (100 mL) was added manganese dioxide (7.5 g, 86 mmol). The resulting mixture was stirred at 80 °C under oxygen (balloon) for 16 hours. On completion, the reaction mixture was filtered, and the filtrate was concentrated. The residue was purified by silica gel chromatography [petroleum ether: ethyl acetate = 3:2] to give compound B-271 (3.5 g, 56% yield) as a yellow solid.
[00540] Example 170B - pyrroloil,2-b1pyridazine-5,6 J-tricarboxylic acid (B-272)
Figure imgf000134_0001
[00541] To a solution of compound B-271 (3.2 g, 1 1 mmol) in tetrahydrofuran (15 mL) and water (15 mL) was added potassium hydroxide (6.1 g, 0.1 1 mol). The reaction mixture was refluxed for 4 hours. On completion, the mixture was acidified with 36% hydrochloric acid. The solid was collected, washed with water and dried in vacuo to give compound B-272 (2.2 g, 80% yield) as a yellow solid.
[00542] Example 171B - pyrrolon ,2-b1pyridazine-6-carboxylic acid (B-273)
Figure imgf000134_0002
B-272 B-273
[00543] A mixture of compound B-272 (3.0 g, 12 mmol) in 36% hydrochloric acid (30 mL) was refluxed for 4 hours. On completion, the reaction mixture was cooled to room temperature. The solid was collected by filtration and washed with water to give compound Β· 273 (1.2 g, 62% yield) as a green solid.
[00544] Example 172B - pyrrolori .2-blpyridazin-6-ylmethanol (B-274)
Figure imgf000134_0003
B-273 B-274
[00545] To a suspension of lithium aluminum hydride (0.61 g, 16 mmol) in tetrahydrofuran (20 mL) was added dropwise compound B-273 (1.3 g, 8.0 mmol) in tetrahydrofuran (20 mL) at 0 °C. The reaction mixture was stirred at 25 °C for 1 hour. On completion, the reaction was quenched carefully with water and extracted with ethyl acetate (3 χ 30 mL). The combined organic phases were washed with brine, dried over anhydrous sodium sulfate and concentrated to give compound B-274 (0.50 g, 42% yield) as a brown solid.
[00546] Example 173B - pyrrolo[T,2-b1pyridazine-6-carbaldehvde Β-275
Figure imgf000135_0001
[00547] To a solution of compound B-274 (0.60 g, 4.0 mmol) in dichloromethane (10 mL) was added Dess-Martin periodate (1.7 g, 4.0 mmol). The reaction mixture was stirred at room temparature for 2 hours. On completion, the mixture was quenched with saturated sodium bicarbonate solution and extracted with dichloromethane (3 χ 20 mL). The combined organics were washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography [petroleum ether: ethyl acetate = 3: 1] to give compound B-275 (0.31 g, 52% yield) as a yellow solid.
[00548] Example 174B - pyrrolon ,2-blpyridazine-6-carbaldehyde oxime (B-276)
Figure imgf000135_0002
[00549] To a solution of compound B-275 (0.25 g, 1.7 mmol) and hydroxylamine hydrochloride (0.24 g, 3.4 mmol) in dichloromethane (5 mL) was added triethylamine (0.35 g, 3.4 mmol) at room temperature. The reaction mixture was stirred at room temperature for 4 hours. On completion, the reaction was filtered, and the filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography [dichloromethane: ethyl acetate = 3 : 1] to give compound B-276 (0.25 g, 91% yield) as a yellow solid.
[00550] Exa - 3-methylbenzofuran-5-carbaldeh de (B-277)
Figure imgf000135_0003
B-277
[00551] To a mixture of magnesium (0.79 g, 33 mmol) and 1 ,2-dibromoethane (0.82 g, 4.4 mmol) in tetrahydrofuran (50 mL) was added 5-bromo-3-methylbenzofuran (4.6 g, 22 mmol) under nitrogen. The mixture was heated at reflux for about 2 hours. The reaction was then cooled to -40 °C, and anhydrous N N-dimethylformamide (6.4 g, 88 mmol) was added slowly. The reaction was allowed to warm to room temperature and was stirred for 2 hours. On completion, the reaction was quenched with water (20 mL) at 0 °C and organics were extracted with ethyl acetate (3 ^40 mL). The combined organic layers were washed with brine (2 x 20 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by silica gel chromatography [petroleum ether: ethyl acetate = 15: 1] to give B-277 (1.2 g, 34% yield) as a yellow solid.
[00552] Example 176B - 3-methylbenzofuran-5-carbaldehyde oxime (B-278)
Figure imgf000136_0001
[00553] To a mixture of compound B-277 (1.2 g, 7.5 mmol) and hydroxylamine
hydrochloride (0.78 g, 1 1 mmol) in ethanol (20 mL) was added potassium carbonate (0.45 g, 1 1 mmol). The mixture was stirred at room temperature for about 2 hours. On completion, the reaction was filtered, and the resulting filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography [petroleum ether: ethyl acetate = 10: 1] to give B-278 (1.3 g, 91% yield) as a white solid.
[00554] Example 177B - 3-methylbenzorblthiophene-5-carbald
1. g, BrCH2CH2Br, THF, reflux, 2 h
Figure imgf000136_0002
2. DMF, -40 °C~rt, overnight
B-279
[00555] To a solution of 1 ,2-dibromoethane (0.25 g, 1.3 mmol) in anhydrous tetrahydrofuran (30 mL) was added magnesium (0.47 g, 20 mmol) at room temperature. After stirring for 10 minutes, 5-bromo-3-methylbenzo[b]thiophene (3.0 g, 13 mmol) was added. The mixture was heated at reflux for 2 hours, then cooled to -40 °C, and anhydrous NN-dimethylformamide (4.6 g, 52 mmol) was added. The reaction was allowed to warm to room temperature and was stirred overnight. On completion, the reaction was quenched with water (100 mL) at 0 °C and extracted with ethyl acetate (3 x200 mL). The combined organic layers were washed with brine (2 x 200 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by silica gel column chromatography [petroleum ether: ethyl acetate = 10: 1] to give compound B-279 (1.2 g, 46% yield) as a white solid.
[00556] E - 3-methylbenzorb1thiophene-5-ca oxime (B-280)
Figure imgf000136_0003
[00557] To a solution of compound B-279 (1.2 g, 6.8 mmol) and hydroxylamine
hydrochloride (0.98 g, 14 mmol) in anhydrous methanol (10 mL) was added potassium carbonate (1.9 g, 14 mmol) at room temperature. The mixture was stirred at room temperature overnight. On completion, the reaction was filtered, and the resulting filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography [petroleum ether: ethyl acetate = 10: 1] to give compound B-280 (0.90 g, 65% yield) as a yellow solid.
[00558 - ethyl 6-bromo-3-methylbenzofuran- -carboxylate (B-281)
Figure imgf000137_0001
B-281
[00559] To a solution of l-(4-bromo-2-hydroxy-phenyl)ethanone (22 g, 0.10 mol) in N,N- dimethylformamide (200 mL) was added cesium carbonate (83 g, 0.26 mol) at room
temperature. The reaction solution turned yellow and was stirred at room temperature for 30 min. Then ethyl 2-bromoacetate (21 g, 0.12 mol) was added slowly over 30 min., and stirring was continued for 12 hours. On completion, the reaction mixture was quenched with water and extracted with dichloromethane (3 x 200 mL). The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give crude compound B-281 (12 g, 42% yield) as a white solid. LCMS: (ES+) m/z (M+H)+ = 283.0, tR= 0.960.
[00560] Example 180B - 6-bromo-3-methylbenzofuran-2-carboxylic acid (B-282)
Figure imgf000137_0002
B-281 B-282
[00561] To a solution of compound B-281 (12 g, 42 mmol) in methanol (150 mL) and water (50 mL) was added lithium hydroxide (3.1 g, 0.13 mol). The reaction mixture was stirred at room temperature for 12 hours. On completion, the reaction was concentrated in vacuo to remove methanol, and the residue was dissolved in water (100 mL). Hydrochloric acid (IN) was added to the resulting mixture to adjust the pH to about 3-4. The solid was then collected by filtration and dried in vacuo to give compound B-282 (8.0 g, 74%) as a white solid. LCMS: (ES+) m/z (M+H)+ = 254.9, tR= 1.183.
[00562]
Figure imgf000137_0003
B-282 B-283
[00563] To a solution of compound B-282 (2.2 g, 8.7 mmol) in dimethylsulfoxide (20 mL) was added silver carbonate (0.12 g, 0.44 mmol) and one drop of acetic acid. The resulting mixture was stirred at 180 °C for 2 hours. On completion, the reaction mixture was cooled to room temperature, quenched with water and extracted with dichloromethane (3 x 20 mL). The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, concentrated in vacuo and purified by silica gel chromatography [petroleum ether: ethyl acetate = 10: 1 ] to give compound B-283 (1.2 g, 67% yield) as a yellow oil.
[00564]
Figure imgf000138_0001
B-283 THF, H20, reflux, 16hrs B-284
[00565] To a mixture of compound B-283 (1.0 g, 4.7 mmol), potassium vinyltrifluoroborate (0.63 g, 4.7 mmol) and palladium acetate (17 mg, 0.094 mmol) in tetrahydrofuran (18 mL) and water (2 mL) was added cesium carbonate (4.6 g, 14 mmol) at room temperature. The resulting mixture was heated at reflux overnight. On completion, the mixture was filtered, and the filtrate was extracted with water and ethyl acetate (3 x 40 mL). The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, concentrated in vacuo and purified by silica gel chromatography [petroleum ether: ethyl acetate = 1 :0] to give crude compound B-284 (0.60 g, 81 % yield) as a colorless oil.
[00566] E - 3-methylbenzofuran-6-carbaldehyde (B-285)
Figure imgf000138_0002
B-284 B-285
[00567] To a mixture of compound B-284 (0.38 g, 2.4 mmol), sodium periodate (1.0 g, 4.8 mmol) and N-methyl morpholine-n-oxide (0.84 g, 7.2 mmol) in tetrahydrofuran (10 mL) and water (5 mL) was added osmium tetroxide (61 mg, 0.24 mmol). The resulting mixture was stirred at room temperature for 1 hour. On completion, the mixture was quenched with water and extracted with ethyl acetate (3 x 10 mL). The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, concentrated in vacuo and purified by silica gel chromatography [petroleum ether: ethyl acetate = 20: 1] to give crude compound B-285 (0.30 g, 78% yield) as a yellow solid. LCMS: (ES+) m/z (M+H)+ = 161.1 , tR= 0.742.
[00568] Example 184B - 3-rnethylbenzofuran-6-carbaldehvde oxime (B-286)
Figure imgf000138_0003
[00569] To a mixture of compound B-285 (0.30 g, 1.9 mmol) and hydroxylamine hydrochloride (0.19 g, 2.8 mmol) in anhydrous dichloromethane (10 mL) was added triethylamine (0.38 g, 3.7 mmol) at room temperature. The mixture was stirred at room temperature overnight. On completion, the reaction mixture was quenched with water and extracted with
dichloromethane (3 x 10 mL). The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, concentrated in vacuo and purified by silica gel chromatography [petroleum ether: ethyl acetate = 30: 1 ] to give compound B-286 (0.30 g, 91% yield) as a yellow solid. LCMS: (ES+) m/z (M+H)+ = 176.1 , tR= 0.730.
[00570] Example 185B - (3-bromophenyl)(2,2-dirnethoxypropynsulfane (B-287)
Figure imgf000139_0001
B-287
[00571] To a mixture of 3-bromobenzenethiol (8.7 g, 46 mmol) and l -bromo-2,2- dimethoxypropane (8.4 g, 46 mmol) in NN-dimethylformamide (50 mL) was added potassium carbonate (9.5 g, 69 mmol) at room temperature. The mixture was stirred at 80 °C overnight. On completion, the reaction mixture was quenched with water and extracted with ethyl acetate (3 x 100 mL). The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give crude compound B-287 (13 g, 97% yield) as a colorless oil.
[00572] Example 186B - 6-bromo-3-methylbenzo[b1thiophene & 4-bromo-3- methylbenzorblthiophene (B-288 and B-289)
Figure imgf000139_0002
[00573] To a mixture of polyphosphoric acid (130 g) in chlorobenzene (100 mL) at reflux was added compound B-287 (13 g, 45 mmol) in chlorobenzene (130 mL). The mixture was heated at reflux for 5 hours. On completion, the reaction was cooled to room temperature, quenched with water (200 mL) and organics were extracted with dichloromethane (3 x 200 mL). The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, concentrated in vacuo and purified by silica gel chromatography [petroleum ether: ethyl acetate = 1 :0] to give compounds B-288 and B-289 (8 g, 79% yield) as a colorless oil.
[00574] Example 187B - 3-methyl-6-vinylbenzorb1thiophene & 3-methyl-4- vinylbenzo[b1thiophene (B-290 and B-291)
Figure imgf000139_0003
B-291 [00575] To a mixture of compounds B-288 and B-289 (2.0 g, 8.8 mmol), triphenylphosphine (0.14 g, O.53mmol), potassium vinyltrifluoroborate (1.2 g, 8.8 mmol) and palladium chloride (31 mg, 0.18 mmol) in tetrahydrofuran (18 mL) and water (2 mL) was added cesium carbonate (8.6 g, 26 mmol) at room temperature. The resulting mixture was stirred at reflux overnight. On completion, the mixture was filtered, and the filtrate was diluted with water and extracted with ethyl acetate (3 χ 40 mL). The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, concentrated in vacuo and purified by silica gel chromatography [petroleum ether: ethyl acetate = 1 :0] to give crude compounds B-290 and B-291 (1.5 g, 98% yield) as a colorless oil. GCMS: (ES+) m/z (M)+ = 174.0, tR= 9.207.
[00576] Example 188B - 3-rnethylbenzo[blthiophene-6-carbaldehvde & 3- methylbenzorblthiophene-4-carbaldehvde (B-292 and B-293)
Figure imgf000140_0001
[00577] To a mixture of compounds B-290 and B-291 (1 .5 g, 8.6 mmol), sodium periodate (3.6 g, 17 mmol) and N-methyl morpholine-N-oxide (3.0 g, 26 mmol) in tetrahydrofuran (10 mL) and water (5 mL) was added osmium tetroxide (22 mg, 0.086 mmol). The resulting mixture was stirred at room temperature for 1 hour. On completion, the mixture was filtered, and the filtrate was extracted with water and ethyl acetate (3 x 20 mL). The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, concentrated in vacuo and purified by silica gel chromatography [petroleum ether: ethyl acetate = 50: 1 ] to give crude compounds B-292 and B-293 (1.1 g, 72% yield) as a yellow solid. LCMS: (ES+) m/z (M+H)+ = 177.0, tR= 1.043.
[00578] Example 189B - 3-methylbenzorblthiophene-6-carbaldehvde oxime & 3- methylbenzorblthiophene- -carbaldeh de oxime (B-294 and B-295)
Figure imgf000140_0002
[00579] To a mixture of compounds B-292 and B-293 (1 .1 g, 6.3 mmol) and hydroxylamine hydrochloride (0.87 g, 13 mmol) in anhydrous dichloromethane (10 mL) was added triethylamine (1.3 g, 13 mmol) at room temperature. The mixture was stirred at room temperature overnight. On completion, the reaction was quenched with water and extracted with dichloromethane (3 χ 20 mL). The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, concentrated in vacuo and purified by silica gel chromatography [petroleum ether: ethyl acetate = 30: 1] to give compounds B-294 and B-295 (0.90 g, 76% yield) as a white solid. LCMS: (ES+) m/z (M+H)+ = 192.0, tR= 0.982.
[00580] Example 1C - N-(quinuclidin-3-ylidene)methanamine (C-101)
Figure imgf000141_0001
C-101
[00581] A solution of 3-quinuclidinone hydrochloride (5.0 g, 31.0 mmol) in 30%
methylamine/methanol (15 mL) was stirred at 60 °C for 6 h in a sealed tube. The reaction mixture was then filtered and the resulting filtrate was concentrated under reduced pressure to give compound C-101 (2.5 g, 58%) as yellow solid.
[00582] Example 2C - -(quinuclidin-3-ylidene)ethanamine (C-102)
Figure imgf000141_0002
C-102
[00583] A mixture of quinuclidin-3-one hydrochloride (10.0 g, 0.062 mol) and ethylamine (3.3 g, 0.074 mol) in ethanol (80 mL) was stirred at 90 °C in a sealed tube overnight. The mixture was concentrated under reduced pressure to give compound C-102 (10.1 g, crude) as a brown oil. LCMS: (ES+) m/z (M+H)+ =153.2, tR=0.336.
[00584] Example 3C - N-(quinuclidin-3-ylidene)propan-2-amine (C-103)
Figure imgf000141_0003
C-103
[00585] A mixture of quinuclidin-3-one (5.0 gs 0.04 mol) and propan-2-amine (4.7 g, 0.08 mol) in ethanol (60 mL) was stirred at 90 °C in a sealed tube overnight. The residue was concentrated under reduced pressure to give compound C-103 (5.5 g, 83% yield) as a brown oil. LCMS: (ES+) m/z (M+H)+ =167.2, tR=0.844.
[00586] Example 4 - 2-methyl-N-(quinuclidin-3-ylidene)propan-l -amine (C-104)
Figure imgf000141_0004
C-104 [00587] To a mixture of quinuclidin-3-one (5 g, 0.04 mol) in ethanol (40 mL) was added 2- methylpropan-1 -amine (5.84 g, 0.08 mol) at room temperature. The mixture was stirred at 70 °C in a sealed tube overnight. The residue was concentrated under reduced pressure to give
compound C-104 (3 g, crude) as a brown oil. LCMS: (ES+) m/z (M+H)+ =181.2, tR=0.975.
[00588] Example 5C - 2.2.2-trifluoro-N-(quinuclidin-3-ylidene ethanamine (C-105)
Figure imgf000142_0001
C-105
[00589] To a mixture of quinuclidin-3-one (4 g, 0.032 mo!) in ethanol (40 mL) was added 2,2,2-trifluoroethanamine (2.53 g, 0.0256 mol). The mixture was stirred at 90 °C in a sealed tube overnight. The residue was concentrated under reduced pressure to give compound C-105 (4 g, crude) as a brown oil. LCMS: (ES+) m/z (M+H)+ =207.1 , tR=0.628.
[00590] Example 6C - N-(quinuclidin-3-ylidene)-l -(tetrahvdro-2H-pyran-4-yl)methanamine (C-106)
Figure imgf000142_0002
[00591] A mixture of quinuclidin-3-one (5.0 g, 0.04 mol) and (tetrahydro-2H-pyran-4- yl)methanamine (9.2 g, 0.08 mol) in ethanol (60 mL) was stirred at 90 °C in a sealed tube overnight. The reaction mixture was concentrated under reduced pressure to give compound C- 106 (8.88 g, crude) as a brown oil. LCMS: (ES+) m/z (M+H)+ =223.2, tR=0.837.
[00592] Example 7C - l -phenyl-N-(quinuclidin-3-ylidene)methanamine (C-107)
Figure imgf000142_0003
C-107
[00593] A mixture of quinuclidin-3-one (20 g, 0.16 mol) and benzylamine (17 g, 0.16 mol) in toluene (80 mL) was stirred at refluxing overnight. The residue was concentrated and purified by silica gel chromatography (dichloromethane: methanol = 50: 1) to give compound C-107 (18.0 g, 18% yield) as a brown oil.
[00594] Example 8C - l -C2.4-dimethoxyphenyl)-N-rquinuclidin-3-ylidene)methanamine (C- 108
Figure imgf000143_0001
C-108
[00595] A mixture of quinuclidin-3-one (10 g, 0.08 mol) and (2,4- dimethoxyphenyl)methanamine (13.3 g, 0.08 mol) in toluene (80 mL) was heated at reflux overnight. The residue was concentrated and the resulting residue was purified by silica gel chromatography (dichloromethane: methanol = 10: 1) to give compound C-108 (10.0 g, 45% yield) as a brown oil; LCMS; (ES+) m/z (M+H)+ =275.2, tR=1.033.
[00596] Example 9 - l -(pyridin-3-yl)-N-(quinuclidin-3-ylidene)methanamine (C-109)
Figure imgf000143_0002
C-109
[00597] A mixture of quinuclidin-3-one (4.0 g, 0.032 mol) and pyridin-3-ylmethanamine (3.5 g, 0.032 mol) in ethanol (30 mL) was stirred at 90 °C in a sealed tube overnight. The residue was concentrated in vacuum to give compound C-109 (6.0 g, crude) as a brown oil. The crude product was used for the next step without further purification. LCMS: (ES+) m/z (M+H)+ =216.2, tR=0.843.
[00598] Example - N-(quinuclidin-3-ylidene)aniline (C-110)
Figure imgf000143_0003
C-110
[00599] A mixture of quinuclidin-3-one (20 g, 0.16 mol) and aniline (15 g, 0.16 mol) in toluene (80 mL) was heated at refluxing overnight. The residue was concentrated and purified by silica gel chromatography (dichloromethane: methanol = 50: 1) to give compound C-110 (10.0 g, 45% yield) as a brown oil. LCMS: (ES+) m/z (M+H)+ =201.1 , tR=l .468.
[00600] Example 11 - N-(l-azaadamantan-4-ylidene)methanamine (C-lll)
Figure imgf000143_0004
C-111 [00601] A solution of 1 -azaadamantan-4-one (500 mg, 3.3 mmol) in 30% methylamine/methyl alcohol solution (10 ml) was heated to 100 °C in sealed tube and stirred for 14 hours. The solvent was concentrated under reduced pressure to provide compound C-111 as a colorless oil (500 mg, 92% yield).
[00602] Example 12C - N- -azaadamantan-4-ylidene)-l-(2,4- dimethoxyphenvDmethanamine (C-112)
Figure imgf000144_0001
[00603] A mixture of 1 -azaadamantan-4-one (2 g, 13.24 mmol), (2,4- dimethoxyphenyl)methanamine (1.77 g, 10.59 mmol), and 4A molecular sieves, in dry ethanol (30 mL) was stirred at 100 °C in a sealed tube for 6 hours. The residue was filtrated and the filtrate was concentrated and purified by silica gel chromatography (dichloromethane: methanol = 50: 1) to give compound C-112 (10.0 g, 45% yield) as a yellow oil.
[00604] Example 13C - l-(4-methoxyphenyl)-N-(quinuclidin-3-ylidene)methanamine (C- 113)
Figure imgf000144_0002
C-113
[00605] A mixture of quinuclidin-3-one (12.5 g, 0.1 mol) and (4- methoxyphenyl)methanamine (13.72 g, 0.1 mol) in toluene (80 mL) was stirred at refluxing overnight. The residue was concentrated and purified by silica gel chromatography
(dichloromethane: methanol = 30: 1 ) to give compound C-113 (13 g, 53% yield) as a brown oil
[00606] Example 1 - (+/-)-3-phenyl-4H-l '-azaspirorri .2,41oxadiazole-5,3'- bicyclo[2.2.2]octane1 (1)
re ux, overn g
Figure imgf000144_0003
A-101 1
[00607] To a mixture of compound A-101 (0.40 g, 0.003 mol) and quinuclidin-3-one hydrochloride (1.90 g, 0.012 mol) in anhydrous toluene (5 mL) was added imidazole (0.83 g, 0.012 mol) at room temperature. The mixture was heated at reflux overnight. On completion, the mixture was concentrated in vacuo and the resulting residue was purified by prep-HPLC
[Instrument: Shimadzu pump LC-20A; Column: GEMINI 250*50 mm, particle size: 10 μιη; Mobile phase: 20-54 % ACN in H20 (Add 1 % NH3.H20, v/v)] to afford racemate 1 (0.04 g, 5% yield), a mixture of (R)-l -(4-methoxyphenyl)-N-(quinuclidin-3-ylidene)methanamine and (S)-l- (4-methoxyphenyl)-N-(quinuclidin-3-ylidene)methanamine, as a yellow solid: LCMS (I): 2.73 min., 244.1 m/z (M+l ); Ή-NMR (CD3OD, 400 MHz): δ 7.59-7.57 (m, 2H), 7.37-7.32 (m, 3H), 3.04-2.98 (m, 2H), 2.75-2.72 (m, 4H), 2.05-1.82 (m, 3H), 1.65-1.45 (m, 2H).
[00608] Example 2 - (+/-V3-(4-chlorophenyl)-4H-l '-azaspirorn ,2.41oxadiazole-5.3'- bicyclo[2.2.21octanel (2)
I
Figure imgf000145_0001
A-102 2
[00609] To a mixture of compound A-102 (1 .1 g, 6.47 mmol) and quinuclidin-3-one hydrochloride (2.08 g, 12.94 mmol) in anhydrous toluene (20 mL) was added imidazole (0.8 g, 1 1.65 mmol) at room temperature. The mixture was heated at reflux overnight. On completion, the mixture was concentrated in vacuo and the resulting residue was purified by prep-HPLC
[Instrument: Shimadzu pump LC-20A; Column: GEMINI 250*50 mm, particle size: 10 μπι; Mobile phase: 20-54 % acetonitrile in H20 (Add 1 % NH3.H20, v/v)] to afford racemate 2 (0.3 g, 17% yield), a mixture of (R)-3-(4-chlorophenyl)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane] and (S)-3-(4-chlorophenyl)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane], as a yellow solid.
[00610] Chiral Separation:
[00611] A solution of racemate 2 (100 mg, 0.36 mmol) in MeOH (5 ml) was separated by SFC (Instrument: SFC 80; Column: Chiralpak AD-H 250x25 mm I.D., 10 μηι; Mobile phase: 35 ethanol (0.01 %NH3 H20) in C02) at room temperature. To each collected fraction was quickly added 0.2 N HCl EtOH until pH=5 was attained. This solution was then concentrated at room temperature to give 30 mg compound 3-(4-chIorophenyl)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane]-enantiomerl hydrochloride and 30 mg compound 3-(4-chlorophenyl)-4H- l '-azaspiro[[l,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane]-enantiomer2 hydrochloride, each containing residual NH4CI. The two compounds were then further individually purified by prep- HPLC [Instrument: GX-E; Column: Agella Venusil ASB CI 8 150 * 21.2 mm * 5 μπι; Mobile phase: 18-48 % acetonitrile in H20 (add 0.5% HCl, v/v)] to remove NH4C1. The eluent from each prep-HPLC run was concentrated at room temperature and subjected to lyophilization to give: 3-(4-chlorophenyl)-4H- -azaspiro[[l,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane]- enantiomerl hydrochloride (compound 2a) (7.1 mg, 7% yield) as a yellow solid: cSFC analytical tR: 2.54 min., purity: 93.0%; LCMS (I): 2.34 min., 278.0 m/z (M+l); Ή-NMR (CD3OD, 400 MHz): δ 7.73-7.71 (d, J=8.4, 2H), 7.52-7.50 (d, J=8.8, 2H), 3.76-3.72 (m, 1H), 3.60-3.42 (m, 1H), 3.39-3.37 (m, 4H), 2.39-2.38 (m, 2H), 2.26-2.24 (m, 1H), 2.1 1-2.10 (m, 1 H), 2.01-2.00 (m, 1H), and
3-(4-chlorophenyl)-4H-l '-azaspiro[[l,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane]- enantiomer2 hydrochloride (compound 2b) (14.8 mg, 15% yield) as a yellow solid: cSFC analytical tR: 3.61 min., purity: 95.6%; LCMS (I): 2.32 min., 278.0 m/z (M+l); 'H-NMR (CD3OD, 400 MHz): δ 7.76-7.74 (d, J=8.8, 2H), 7.53-7.51 (d, J=8.4, 2H), 3.76-3.72 (m, 1 H), 3.66-3.62 (m, 1H), 3.44-3.35 (m, 4H), 2.40-2.30 (m, 3H), 2.14-2.02 (m, 2H);
cSFC analytical conditions: Column: Chiralpak AD-H 250 x 4.6 mm, I.D., 5 μηι; Mobile phase: 40% ethanol (0.05% diethyl amine ("DEA") in C02; Flow rate: 2.4 mL/min.; Back pressure: 120 bar; Column temperature: 40 °C.
[00612] Example 3 - (+/-)-3-(benzorblthiophen-2-vn-4H-l '-azaspirorrL2,41oxadiazol-5.3'- bicyclo|"2.2.2]octanel
Figure imgf000146_0001
A-103 3
[00613] To a mixture of compound A-103 (2.1 g, 0.01 1 mol) and quinuclidin-3-one hydrochloride (3.52 g, 0.022 mol) in anhydrous toluene (40 mL) was added imidazole (1.35 g, 0.020 mol) at room temperature. The mixture was heated at reflux overnight. On completion, the mixture was concentrated in vacuo and the resulting residue was purified by prep-HPLC
[Instrument: Shimadzu pump LC-20A; Column: GEMINI 250*50 mm, particle size: 10 μιτι; Mobile phase: 30-54 % Acetonitrile in H20 (add 1% NH3.H20, v/v)] to afford racemate 3 (0.45 g, 12% yield), a mixture of (R)-3-(benzo[b]thiophen-2-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazol-5,3'- bicyclo[2.2.2]octane] and (S)-3-(benzo[b]thiophen-2-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazol-5,3'- bicyclo[2.2.2]octane], as a yellow solid.
[00614] Chiral Separation:
[00615] A solution of racemate 3 (450 mg, 1.5 mmol) in MeOH (5 ml) was separated by SFC (Instrument: SFC 80; Column: Chiralpak AD-H 250x25 mm I.D., 10 μιη; Mobile phase: 40% ethanol (0.01% NH3 H20) in C02 at room temperature. To each collected fraction was quickly added 0.2 N HCl/EtOH until pH=5 was attained. Each solution was then concentrated at room temperature to give 3-(benzo[b]thiophen-2-yl)-4H-l '-azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane]-enantiomerl hydrochloride (300 mg) and 3-(benzo[b]thiophen-2-yl)-4H-l '- azaspiro[[l,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane]-enantiomer2 hydrochloride (300 mg) (containing NH4CI). The two compounds were then further individually purified by prep-HPLC [Instrument: GX-E; Column: Agella Venusil ASB C 18 150*21 .2 mm*5 μπι; Mobile phase: 1 8-48% acetonitrile in H20 (add 0.5% HCl, v/v)] to remove NH4C1. The eluent from each prep-HPLC run was concentrated at room temperature and subjected to lyophilization to give:
3-(benzo[b]thiophen-2-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane]- enantiomer-1 hydrochloride (compound 3a) (164.9 mg, 36% yield) as a yellow solid: cSFC analytical tR: 0.99 min., purity: 96.9%; LCMS (E): 1 .78 min., 300.1 m/z (M+l ); Ή-NMR
(CD3OD, 400 MHz): δ 7.93-7.90 (m, 2H), 7.84 (s, I H), 7.49-7.43 (m, 2H), 3.80-3.76 (m, I H), 3.68-3.64 (m, I H), 3.49-3.37 (m, 4H), 2.45-2.40 (m, 2H), 2.34-2.30 (m, I H), 2.17-2.14 (m, I H) , 2.06-2.00 (m, I H); Optical Rotation (a): +0.036; C (g/l OOml): 0.0366 (in acetone); Optical Rotatory Power: +39.3 (sample of 9.15 mg in 10 mL, length = 1 dm, Na lamp 589 nm, temperature: 25 °C), and
3-(benzo [b] thiophen-2-yl)-4H-l'-azaspiro [[1 ,2,4] oxadiazole-5,3'-bicyclo[2.2.2]octane]- enantiomer-2 hydrochloride (compound 3b) (145.8 mg, 32% yield) as a yellow solid: cSFC analytical tR: 1 .42 min, purity: 91.3%; LCMS (E): 1.57 min, 300.1 m/z (M+l ); Ή-NMR
(CD3OD, 400 MHz): δ 7.94-7.90 (m, 2H), 7.82 (s, I H), 7.49-7.43 (m, 2H), 3.80-3.77 (m, I H), 3.66-3.62 (m, I H), 3.49-3.40 (m, 4H), 2.45-2.40 (m, 2H), 2.32-2.29 (m, I H), 2.1 8-2.15 (m, I H), 2.06-2.00 (m, I H); Optical Rotation (a): -0.031 ; C (g/l OOml): 0.0394 (in acetone); Optical Rotatory Power: -3 1 .5 (sample of 9.84 mg in 1 0 mL, length = 1 dm, Na lamp 589 nm, temperature: 25 °C);
cSFC analytical conditions: Column: Chiralpak AD-3 100 x 4.6 mm, I.D, 3 μιη; Mobile phase: 40% ethanol (0.05% DEA) in C02; Flow rate: 3.0 mL/min.
[00616] Example 4 - (+/-V3-(benzofuran-2-ylV4H-l '-azaspirorn .2,41oxadiazole-5.3'- bicvclor2.2.21octanel
Figure imgf000147_0001
A-104
[00617] To a mixture of compound A-104 (1 .1 g, 6.25 mmol) and quinuclidin-3-one hydrochloride (2.01 g, 12.5 mmol) in anhydrous toluene (20 mL) was added imidazole (0.77 g, 1 1.25 mmol) at room temperature. The mixture was heated at reflux overnight. On completion, the mixture was concentrated in vacuo and the resulting residue was purified by prep-HPLC
[Instrument: Shimadzu pump LC-20A; Column: GEMINI 250*50 mm, particle size: 10 μπι;
Mobile phase: 20-54% acetonitrile in H20 (add 1% NH3 H20, v/v)] to afford racemate 4 (0.4 g, 22% yield), a mixture of (R)-3-(benzofuran-2-yl)-4H-l'-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane] and (S)-3-(benzofuran-2-yl)-4H-l'-azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane], as a yellow solid.
[00618] Chiral Separation:
[00619] A solution of racemate 4 (200 mg, 0.71 mmol) in MeOH (5 ml) was separated by SFC (Instrument: SFC 80. Column: Chiralpak AD-H 250x25 mm I.D., 10 μηι, Mobile phase: 40% methanol (0.01% NH3 H20) in C02) at room temperature. To each collected fraction was quickly added 0.2 N HCl/EtOH until pH=5 was attained. Each solution was then concentrated at room temperature to give 3-(benzofuran-2-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2] octane]-enantiomerl hydrochloride (40 mg) and 3-(benzofuran-2-yl)-4H-l '- azaspiro[[l,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane]-enantiomer2 hydrochloride (40 mg) (containing NH4CI). The two compounds were then further individually purified by prep-HPLC [Instrument: GX-E; Column: Agella Venusil ASB CI 8 150*21.2 mm*5 μηι; Mobile phase: 18-48% acetonitrile in H20 (add 0.5% HC1, v/v)] to remove NH4C1. The eluent from each prep-HPLC run was concentrated at room temperature and subjected to lyophilization to give:
3-(benzofuran-2-yl)-4H-r-azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane]- enantiomerl hydrochloride (compound 4a) (10.4 mg, 5% yield) as a yellow solid: cSFC analytical tR: 1.92 min., purity: 97.8%; LCMS (E): 0.66 min„ 284.1 m/z (M+l); Ή-NMR
(CD3OD, 400 MHz): δ 7.72-7.70 (d, J=8.0, IH), 7.58-7.56 (d, J=8.4, I H), 7.46-7.42 (t, J=7.6, I H), 7.38 (s, IH), 7.35-7.31 (t, J=7.6, IH), 3.78-3.75 (m, I H), 3.65-3.62 (m, IH), 3.44-3.39 (m, 4H), 2.42-2.40 (m, 2H), 2.27-2.13 (m, I H), 2.12-2.01 (m, 2H), and
3-(benzofuran-2-yl)-4H-l'-azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane]- enantiomer2 hydrochloride (compound 4b) (14.9 mg, 8% yield) as a white solid: cSFC analytical tR: 3.31 min., purity: 98.0%; LCMS (E): 0.66 min., 284.1 m/z (M+l ); Ή-NMR (CD3OD, 400 MHz): 57.73-7.71 (d, J=8.0, I H), 7.59-7.56 (d, J=8.4, I H), 7.46-7.43 (t, J=7.2, I H), 7.38 (s, I H), 7.35-7.31 (t, 3=1.2, IH), 3.79-3.75 (m, IH), 3.65-3.61 (m, I H), 3.44-3.39 (m, 4H), 2.43-2.40 (m, 3H), 2.15-2.02 (m, 2H);
cSFC analytical conditions: Column: Chiralpak AD-3 150 x 4.6 mm, I.D., 3 μιη; Mobile phase: 40% ethanol (0.05% DEA) in C02; Flow rate: 2.5 mL/min.; Back pressure: 120 bar; Column temperature: 40 °C.
[00620] Example 5 - f+/-V3-f lH-indol-2-vn-4H-l '-azaspirorn ,2,41oxadiazole-5.3'-bicvclo [2.2.2]octane] (5)
Figure imgf000149_0001
A-105
[00621] To a mixture of compound A-105 (4.0 g, 0.023 mol) and quinuclidin-3-one hydrochloride (7.36 g, 0.046 mol) in anhydrous toluene (40 mL) was added imidazole (2.8 g, 0.041 mol) at room temperature. The mixture was heated at reflux overnight. On completion, the mixture was concentrated in vacuo and the resulting residue was purified by prep-HPLC
[Instrument: Shimadzu pump LC-20A; Column: GEMINI 250*50 mm, particle size: 10 μιη;
Mobile phase: 5-30% acetonitrile in H20 (add 1 % TFA, v/v)] to afford racemate 5 (0.4 g, 6% yield), a mixture of TFA salts of (R)-3-(l H-indol-2-yl)-4H- -azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo [2.2.2]octane] and (S)-3-(lH-indol-2-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo [2.2.2]octane], as a white solid.
[00622] Chiral Separation:
[00623] A solution of racemate 5 (200 mg, 0.707 mmol) in methanol (5 mL) was separated by SFC (Instrument: SFC 80, Column: Chiralpak OD-H 250x25 mm I.D., 10 μπι, Mobile phase: 45% ethanol (0.01 % NH3 H20) in C02) at room temperature. To each collected fraction was quickly added 0.2 N HCl/EtOH until pH=5 was attained. Each solution was then concentrated at room temperature to give 3-(lH-indol-2-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane]-enantiomerl hydrochloride (150 mg) and 3-(l H-indol-2-yl)-4H-l '- azaspiro[[l,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane]-enantiomer2 hydrochloride (150 mg) (containing ammonium chloride). The crude compounds were then further purified by prep-HPLC [Instrument: GX-E; Column: Agella Venusil ASB CI 8 150*21.2 mm*5 μπι; Mobile phase: 1 8-48% acetonitrile in H20 (add 0.5% HC1, v/v)] to remove ammonium chloride. The eluent from each prep-HPLC run was concentrated at room temperature and subjected to lyophilization to give:
3-(l H-indol-2-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane]- enantiomerl hydrochloride (compound 5a) (27.0 mg, 14% yield) as a yellow solid: cSFC analytical tR: 3.19 min, purity: 98.5%; LCMS (E): 1.60 min., 283.1 m/z (M+l ); Ή-NMR
(CD3OD, 400 MHz): δ 7.62-7.60 (d, J=8.0 Hz, 1 H), 7.44-7.42 (d, J=8.0 Hz, 1 H), 7.25-7.22 (t, J=7.2 Hz, 1H), 7.10-7.06 (t, J=7.2 Hz, 1H), 6.95 (s, 1H), 3.78-3.74 (m, 1 H), 3.63-3.59 (m, 1 H), 3.48-3.37 (m, 4H), 2.49-2.39 (m, 2H), 2.33-2.29 (m, 1 H), 2.18-2.12 (m, 1 H) , 2.07-2.01 (m, 1 H), and
3-(l H-indol-2-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane]- enantiomer2 hydrochloride (compound 5b) (27.4 mg, 14% yield) as a black solid: cSFC analytical tR: 3.97 min, purity: 97.7%; LCMS (E): 0.71 min., 283.1 m/z (M+l ); Ή-NMR (CDjOD, 400 MHz): δ 7.60-7.58 (d, J=8.0 Hz, 1 H), 7.42-7.40 (d, J=8.0 Hz, 1 H), 7.23-7.19 (t, J=8.0 Hz, 1H), 7.08-7.04 (t, J=8.0 Hz, 1H), 6.94 (s, 1Η),3.76-3.72 (m, 1H), 3.63-3.59 (m, 1 H), 3.43-3.31 (m, 4H), 2.43-2.38 (m, 2H), 2.31-2.26 (m, 1H), 2.14-2.10 (m, 1H), 2.05-1.99 (m, 1 H); cSFC analytical conditions: Column: Chiralpak OD-3 100 x 4.6 mm, I.D., 3 μπι; Mobile phase: 40% ethanol (0.05% DEA) in C02; Flow rate: 3.0 mL/min.
[00624] Example 6 - (+/-V3-(7-fluorobenzorb1thiophen-2-vn-4H-l'-azaspirorn .2.41
Figure imgf000150_0001
A-106
[00625] To a mixture of compound A-106 (0.50 g, 2.37 mmol) and quinuclidin-3-one hydrochloride (0.59 g, 4.74 mmol) in anhydrous toluene (10 mL) was added imidazole (0.29 g, 4.27 mmol) at room temperature. The mixture was heated at reflux overnight. On completion, the mixture was concentrated in vacuo and the resulting residue was purified by prep-HPLC
[Instrument: Shimadzu pump LC-20A; Column: GEMINI 250*50 mm, particle size: 10 μ ι; Mobile phase: 25-55% acetonitrile in H20 (add 1% NH3 H20, v/v)] to afford racemate 6 (0.1 g, 13% yield), a mixture of (R)-3-(7-fluorobenzo[b]thiophen-2-yl)-4H-l '-azaspiro[[l ,2,4] oxadiazole-5,3'-bicyclo[2.2.2]octane] and (S)-3-(7-fluorobenzo[b]thiophen-2-yl)-4H-l '- azaspiro[[l ,2,4] oxadiazole-5,3'-bicyclo[2.2.2]octane], as a yellow solid.
[00626] Chiral Separation:
[00627] A solution of racemate 6 (120 mg, 0.4 mmol) in methanol (2 ml) was separated by SFC (Instrument: SFC 80; Column: Chiralpak OD-H 250x25 mm I.D., 5 μπι; Mobile phase: A for C02 and B for EtOH with 0.01 % NH3 H20) at room temperature. To each collected fraction was quickly added 0.2 N HCl/EtOH until pH=5 was attained. Each solution was then concentrated at room temperature to give3-(7-fluorobenzo[b]thiophen-2-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole- 5,3'-bicyclo[2.2.2]octane]-enantiomerl hydrochloride (60 mg) and 3-(7-fluorobenzo[b]thiophen- 2-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane]-enantiomer2 hydrochloride (50 mg) (containing NH4CI). Each crude compound was further purified by prep-HPLC [Instrument: GX-E; Column: Agella Venusil ASB CI 8 150*21.2 mm*5 μιη; Mobile phase: 18-48% acetonitrile in H20 (add 0.5% HC1, v/v)] to remove ammonium chloride. The eluent from each prep-HPLC was concentrated at room temperature and then subjected to lyophilization to give: 3-(7-fluorobenzo[b]thiophen-2-yl)-4H-r-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane-enantiomerl hydrochloride (compound 6a) (29.6 mg, 25% yield) as a yellow solid: cSFC analytical tR: 5.07 min., purity: 98.5%; LCMS (C): 1.80 min., 318.1 m/z (M+l); Ή-NMR (CD3OD, 400 MHz): δ 7.96 (d, J = 3.6 Hz, IH), 7.77 (d, J = 7.6 Hz, IH), 7.49- 7.43 (m, IH), 7.24-7.20 (m, IH), 3.79-3.71 (m, 2H), 3.47-3.32 (m, 4H), 2.44-2.35 (m, 3H), 2.16-
2.04 (m, 2H), and
3-(7-fluorobenzo[b]thiophen-2-yl)-4H-r-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane]-enantiomer2 hydrochloride (compound 6b) (22.4 mg, 19% yield) as a white solid: cSFC analytical tR: 5.77 min, purity: 97.5%; LCMS (C): 1.80 min, 318.1 m/z (M+l); Ή-NMR (CD3OD, 400 MHz): δ 7.97 (d, J = 3.6 Hz, IH), 7.77 (d, J = 7.6 Hz, IH), 7.49- 7.43 (m, IH), 7.24-7.20 (m, IH), 3.79-3.75 (m, 2H), 3.47-3.44 (m, 4H), 2.43-2.38 (m, 3H), 2.09-
2.05 (m, 2H);
cSFC analytical conditions: Column: Chiralpak OD-3 150 x 4.6 mm, I.D, 3 μπι; Mobile phase: 40% ethanol (0.05% DEA) in C02; Flow rate: 2.4 mL/min.; Back pressure: 120 bar; Column temperature: 40 °C.
[00628] Example 7 - C+/-V3-(,7-chlorobenzorblthiophen-2-vn-4H-l l-
Figure imgf000151_0001
A-107
[00629] To a mixture of compound A-107 (0.52 g, 2.3 mmol) and quinuclidin-3-one hydrochloride (1.04 g, 6.9 mmol) in anhydrous toluene (10 mL) was added imidazole (0.47 g, 6.9 mmol) at room temperature. The mixture was heated at reflux overnight. On completion, the mixture was concentrated in vacuo and the resulting residue was purified by prep-HPLC
[Instrument: Gilson-281 ; Column: Phenomenex Gemini CI 8 150*30 mm*5 μπι; Mobile phase: 50%-80% acetonitrile in H20 (0.05% ammonia v/v)] to afford racemate 7 (0.16 g, 21% yield), a mixture of (R)-3-(7-chlorobenzo[b]thiophen-2-yl)-4H-l'-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane] and (S)-3-(7-chlorobenzo[b]thiophen-2-yl)-4H-l '- azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane], as a yellow solid.
[00630] Chiral Separation:
[00631] A solution of racemate 7 (150 mg, 0.48 mmol) in MeOH (5 ml) was separated by SFC (Instrument: SFC 80; Column: Chiralpak AD-H 250x25 mm I.D, 10 μπι; Mobile phase: A for C02 and B for EtOH with 0.01% NH3 H20) at room temperature. To each collected fraction was quickly added 0.2 N HCl/EtOH until pH=5 was attained. Each solution was then concentrated at room temperature to give 3-(7-chlorobenzo[b]thiophen-2-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole- 5,3'-bicyclo[2.2.2]octane]-enantiomerl hydrochloride (70 mg) and 3-(7-chlorobenzo[b]thiophen- 2-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane]-enantiomer2 hydrochloride (75 mg) (containing NHjCl). The two compounds were then further individually purified by prep- HPLC [Instrument: GX-E; Column: Agella Venusil ASB CI 8 150*21.2 mm*5 μπι; Mobile phase: 18-48% acetonitrile in H20 (add 0.5% HC1, v/v)] to remove NH4C1. The eluent from each prep- HPLC run was concentrated at room temperature and subjected to lyophilization to give:
3-(7-chlorobenzo[b]thiophen-2-yl)-4H-r-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane]-enantiomerl hydrochloride (compound 7a) (10.4 mg, 14% yield) as a white solid: cSFC analytical tR: 1.80 min, purity: 97.0%; LCMS (B): 0.64 min., 334.2 m/z (M+l); Ή-NMR (CD3OD, 400 MHz): δ 7.89-7.87 (m, 2H), 7.53-7.45 (m, 2H), 3.82-3.78 (m, I H), 3.66-3.62 (m, I H), 3.49-3.37 (m, 4H), 2.46-2.43 (m, 2H), 2.31 -2.26 (m, I H), 2.20-2.15 (m, I H) , 2.08-2.03 (m, l H), and
3-(7-chlorobenzo[b]thiophen-2-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane]-enantiomer2 hydrochloride (compound 7b) (17.3 mg, 23% yield) as a white solid: cSFC analytical tR: 2.50 min., purity: 88.6%; LCMS (E): 1.94 min., 334.0 m/z (M+l); Ή-NMR (CD3OD, 400 MHz): δ 7.89-7.87 (m, 2H), 7.53-7.45 (m, 2H), 3.82-3.78 (m, I H), 3.67-3.63 (m, I H), 3.49-3.37 (m, 4H), 2.46-2.40 (m, 2H), 2.31 -2.26 (m, I H), 2.20-2.14 (m, IH), 2.09-2.00 (m, I H);
cSFC analytical conditions: Column: Chiralpak AD-H 250 x 4.6 mm, I.D., 5 μπι; Mobile phase: 40% ethanol (0.05% DEA) in C02; Flow rate: 2.4 mL/min.
[00632] Example 8 - (+/-)-3-(7-bromobenzo[b]thiophen-2-yl)-4H-l '-azaspiro
[[h2,4]oxadiazol -5,3'-bicyclo[2.2.2]octane] (8)
Figure imgf000152_0001
A-108 8
[00633] To a mixture of compound A-108 (1.0 g, 0.0037 mol) and quinuclidin-3-one hydrochloride (1.8 g, 0.01 1 mol) in anhydrous toluene (60 mL) was added imidazole (0.68 g, 0.010 mol) at room temperature. The mixture was heated at reflux overnight. After the reaction was complete, the mixture was concentrated and purified by prep-HPLC [Instrument: GX-E; Column: Agella Venusil ASB C18 150*21.2 mm, particle size: 5 μπι; Mobile phase: 27-57% acetonitrile in H20 (add 1% NH3 H20, v/v)] to afford racemate 8 (0.74 g, 50% yield), a mixture of (R)-3-(7-bromobenzo[b]thiophen-2-yl)-4H-l '-azaspiro [[1 ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane] and (S)-3-(7-bromobenzo[b]thiophen-2-yl)-4H-l '-azaspiro
[[l,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane], as a yellow solid.
[00634] Chiral Separation:
[00635] A solution of racemate 8 (0.14 g) in methanol (5 ml) was separated by SFC
(Instrument: SFC 80; Column: Chiralpak AD-H 250x25 mm I.D., 10 μπι; Mobile phase: 40% ethanol (0.01% NH3 H20) in C02) at room temperature. To each collected fraction was quickly added 0.2 N HCl/EtOH until pH=5 was attained. Each solution was then concentrated at room temperature to give 3-(7-bromobenzo[b]thiophen-2-yl)-4H-l '-azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane]-enantiomerl hydrochloride (50 mg) and 3-(7-bromobenzo[b]thiophen-2-yl)- 4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane]-enantiomer2 hydrochloride (250 mg) (containing ammonium chloride). Each crude product was further purified by prep-HPLC
[Instrument: GX-E; Column: Agella Venusil ASB C18 150*21.2 mm*5 μηι; Mobile phase: 18-48% acetonitrile in ¾0 (add 0.5% HCl, v/v)] to remove ammonium chloride. The eluents from prep- HPLC run were each concentrated at room temperature and subjected to lyophilization to give:
3 -(7-bromobenzo[b]thiophen-2-y 1)-4H- 1 '-azaspiro[ [ 1 ,2,4] oxadiazole-5 ,3 '- bicyclo[2.2.2]octane]-enantiomerl hydrochloride (compound 8a) (5.5 mg, 4 % yield) as a yellow solid: cSFC analytical tR: 4.61 min., purity: 97.6%; LCMS (E): 1.95 min., 378.0 m/z (M+1); Ή- NMR (CD3OD, 400 MHz): δ 7.95-7.91 (m, 2H), 7.66-7.64 (d, J = 7.6 Hz, 1 H), 7.41 -7.37 (t, J = 8.0 Hz, 1 H), 3.81 -3.78 (d, J = 14.0 Hz, 1 H), 3.68-3.64 (d, J = 15.6 Hz, 1 H), 3.45-3.37 (m, 4H), 2.45-2.30 (m, 3H), 2.18-2.13 (m, 1 H), 2.06-2.03 (m, 1 H), and
3-(7-bromobenzo[b]thiophen-2-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane]-enantiomer2 hydrochloride (compound 8b) (5 mg, 4 % yield) as a yellow solid: cSFC analytical tR: 5.07 min., purity: 96.9%; LCMS (E): 1.94 min., 378.0 m/z (M+1); Ή- NMR (CD3OD, 400 MHz): δ 7.94-7.91 (m, 2H), 7.67-7.65 (d, J = 7.6 Hz, 1H), 7.41-7.38 (t, J = 8.0 Hz, 1 H), 3.81-3.78 (dd, Jl = 12.4 Hz, J2= 2.0 Hz, 1H), 3.67-3.62 (dd, Jl = 12.4 Hz, J2= 2.4 Hz, 1H), 3.46-3.39 (m, 4H), 2.45-2.40 (m, 2H), 2.32-2.28 (m, 1 H), 2.18-2.14 (m, 1 H), 2.06-2.03 (m, 1H);
cSFC analytical conditions: Column: Chiralpak OD-3 150 x 4.6 mm, I.D., 3 μπι; Mobile phase: 5% to 40% ethanol (0.05% DEA) in C02; Flow rate: 2.8 mL/min.
[00636] Example 9 - (+/-)-3-f7-fluorobenzofuran-2-vn-4H-l '-azaspirorn .2.41 oxadiazole- 5.3'-bicvclor2.2.21octanel (9)
Figure imgf000154_0001
A-109 9
[00637] To a mixture of compound A-109 (1.0 g, 0.0052 mol) and quinuclidin-3-one hydrochloride (2.5 g, 0.016 mol) in anhydrous toluene (60 mL) was added imidazole (0.98 g, 0.014 mol) at room temperature. The mixture was heated at reflux overnight. On completion, the mixture was concentrated in vacuo and the resulting residue was purified by prep-HPLC
[Instrument: Shimadzu pump LC-20A; Column: GEMINI 150*21.2 mm, particle size: 5 μηι; Mobile phase: B 18-48% acetonitrile in H20 (add 0.75% HCl, v/v) ] to afford racemate 9 (0.72 g, 50% yield), a mixture of HCl salts of (R)-3-(7-fluorobenzofuran-2-yl)-4H-l '-azaspiro[[l,2,4] oxadiazole-5,3'-bicyclo[2.2.2]octane] and (S)-3-(7-fluorobenzofuran-2-yl)-4H-l'-azaspiro[[ 1 ,2,4] oxadiazole-5,3'-bicyclo[2.2.2]octane], as a yellow solid.
[00638] Chiral Separation:
[00639] A solution of racemate 9 (720 mg, 2.4 mmol) in methanol (5 mL) was separated by SFC (Instrument: SFC 80; Column: Chiralpak OD-H 250x25 mm I.D., 5 μηι; Mobile phase: 20% ethanol (0.01% NH3 H20) in C02) at room temperature. To each collected fraction was quickly added 0.2 N HCl/EtOH until pH=5 was attained. Each solution was then concentrated at room temperature to give 3-(7-fluorobenzofuran-2-yl)-4H-l'-azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane]-enantiomerl hydrochloride (30 mg) and 3-(7-fluorobenzofuran-2-yl)-4H-l'- azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane]-enantiomer2 hydrochloride (50 mg) (containing ammonium chloride). Each crude compound was further purified by prep-HPLC
[Instrument: GX-E; Column: Agella Venusil ASB CI 8 150*21.2 mm*5 μπι; Mobile phase: 18-48% acetonitrile in H20 (add 0.5% HCl, v/v)] to remove ammonium chloride. The eluent from each prep-HPLC run was concentrated at room temperature and then subjected to lyophilization to give:
3-(7-fluorobenzofuran-2-yl)-4H-l '-azaspiro[[l,2,4] oxadiazole-5,3'-bicyclo[2.2.2]octane]- enantiomerl hydrochloride (compound 9a) (5 mg, 1% yield) as a yellow solid: cSFC analytical tR: 2.972 min., purity: 87.1%; LCMS (E): 1.734 min., 302.1 m/z (M+l ); Ή-NMR (CD3OD, 400 MHz): δ 7.56-7.54 (d, J=8.0 Hz, IH), 7.46 (s, IH), 7.33-7.32 (d, I H), 7.27-7.23 (m, IH), 3.81 - 3.77 (d, J=14.0 Hz, IH), 3.64-3.61 (d, J=14.0 Hz, IH), 3.42-3.36 (m, 4H), 2.45 (m, 2H), 2.28 (m, I H), 2.15 (m, I H) , 2.05-2.03 (m, IH), and
3-(7-fluorobenzofuran-2-yl)-4H-l'-azaspiro[[ 1 ,2,4] oxadiazole-5,3'-bicyclo[2.2.2]octane]- enantiomer2 hydrochloride (compound 9b) (7.8 mg, 2% yield) as a yellow solid: cSFC analytical tR: 3.165 min., purity: 88.0%; LCMS (E): 1.744 min., 302.1 m/z (M+1 ); Ή-NMR (CD3OD, 400 MHz): δ 7.56-7.54 (d, J=8.0 Hz, 1H), 7.46-7.45 (d, J=2.8 Hz, 1H), 7.35-7.31 (m, 1H), 7.30-7.22 (m, 1 H), 3.81-3.77 (dd, Jl=14.4 Hz, J2=2.0 Ηζ,Ι Η), 3.64-3.60 (dd, Jl=14.0 Hz, J2=2.0 Hz, 1 H), 3.45-3.39 (m, 4H), 2.45-2.42 (m, 2H), 2.29-2.27 (m, 1 H), 2.17-2.13 (m, 1 H) , 2.05-2.03 (m, 1 H); cSFC analytical conditions: Column: Chiralpak OD-3 150 x 4.6 mm, I.D., 3 μιη; Mobile phase: 5% to 40% ethanol (0.05% DEA) in C02; Flow rate: 2.8 mL/min.
[00640] Example 10 - (+/-)-3-(benzorblthiophen-5-yl)-4H-l '-azaspirorn,2.41oxadiazole-5,3'-
Figure imgf000155_0001
A-110 10
[00641] To a solution of compound A-110 (1.5 g, 7.8 mmol) in toluene (50 mL) were added 3-quinucIidinone hydrochloride (3.8 g, 23.4 mmol) and imidazole (1.6 g, 23.4 mmol). The resulting mixture was heated at reflux for 8 hours. On completion, the mixture was concentrated in vacuo and the resulting residue was purified by prep-HPLC [Instrument: Shimadzu pump LC- 20A; Column: GEMINI 250*50 mm, particle size: 10 μπι; Mobile phase: 17-47% acetonitrile in H20 (add 1% NH3 H20, v/v)] to give racemate 10 (0.3 g, 13%), a mixture of (R)-3- (benzo[b]thiophen-5-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane] and (S)-3- (benzo[b]thiophen-5-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane], as a pale yellow solid.
[00642] Chiral Separation:
A solution of racemate 10 (300 mg, 1.0 mmol) in methanol (20 ml) was separated by SFC (Instrument: SFC 80; Column: Chiralpak AD-H 250x25 mm I.D., 10 μηι; Mobile phase: 60% methanol (0.01% NH3 H20) in C02) at room temperature and the resulting two collected solutions were concentrated at room temperature. To each was added 0.1 N HCl and each was subjected to lyophilization to give:
3-(benzo[b]thiophen-5-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane]- enenatiomerl hydrochloride (compound 10a) (20.0 mg, 7% yield) as a yellow solid: cSFC analytical tR: 1.314 min., purity: 97.3%; LCMS (E): 0.631 min., 300.1 m/z (M+1 ); Ή-NMR (CD3OD, 400 MHz): δ 8.22 (s, 1 H), 8.01-7.99 (d, J=8.4 Hz, 1H), 7.71 - 7.69 (m, 2H), 7.48-7.46 (d, J=5.6 Hz, 1H), 3.79 - 3.58 (m, 2H), 3.52 - 3.35 (m, 4H), 2.50 - 2.24 (m, 3H), 2.19 - 1.95 (m, 2H), and 3-(benzo[b]thiophen-5-yl)-4H-l '-azaspiro[[l,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane]- enantiomer2 hydrochloride (compound 10b) (38.0 mg, 13% yield) as a yellow solid: cSFC analytical tR: 3.131 min, purity: 98.3%; LCMS (E): 0.633 min., 300.1 m/z (M+l); Ή-NMR (CD3OD, 400 MHz): δ 8.22 (s, 1H), 8.00 (d, J=8.4 Hz, 1H), 7.74 - 7.66 (m, 2H), 7.47 (d, J=5.6 Hz, 1H), 3.79 - 3.58 (m, 2H), 3.52 - 3.35 (m, 4H), 2.50 - 2.24 (m, 3H), 2.19 - 1.95 (m, 2H);
cSFC analytical conditions: Column: Chiralpak AD-H 250 x 4.6 mm, I.D., 5 μπι; Mobile phase: 40% methanol (0.05% DEA) in C02; Flow rate: 3.0 mL/min.; Back pressure: 120 bar.
[00643] Example 11 - (+/-)-3-(2-methyl-1.2.3.4-tetrahvdroisoquinolin-6-vn-4H-l '-aza- spiro [l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane1 (11)
Figure imgf000156_0001
A-111 11
[00644] A mixture of compound A-lll (0.4 g, 1.95 mmol), quinuclidin-3-one hydrochloride (0.94 g, 5.85 mmol) and imidazole (0.37 g, 5.46 mmol) in toluene (30 ml) was heated at reflux for about 24 hours. LCMS showed 30% starting material remained. Then the mixture solution was concentrated to remove most of toluene and purified by column chromatography and prep-HPLC [Instrument: HPLC B; Column: Phenomenex Gemini CI 8 150x30 mm 5 μηι; Mobile phase: 25%-50% acetonitrile in H20 (0.05% ammonia v/v)] to give racemate 11 (75 mg, 12% yield), a mixture of (R)-3-(2-methyl-l ,2,3,4-tetrahydroisoquinolin-6-yl)-4H-l '-aza- spiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane] and (S)-3-(2-methyl-l ,2,3,4- tetrahydroisoquinolin-6-yl)-4H-l '-aza-spiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane], as a white solid.
[00645] Chiral Separation:
[00646] A solution of racemate 11 (30 mg) in methanol (5 ml) was separated by SFC (Instrument: SFC-80-A; Column: Chiralpak OD-H 250x25 mm I.D., 10 μιη; Mobile phase: A for CO2 and B for ethanol with 0.01% NH3 H 0) at room temperature. To each collected fraction was quickly added 0.2 N HCl EtOH until pH=5 was attained. Each solution was then concentrated at room temperature to give 3-(2-methyl- 1 ,2,3 , 4-tetrahydroisoquinolin-6-y 1)-4Η-Γ- azaspiro[[l,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane]-enantiomerl hydrochloride (30 mg) and 3- (2-methyl-l ,2,3,4-tetrahydroisoquinolin-6-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane]-enantiomer2 hydrochloride (30 mg) (containing ammonium chloride). The crude compounds were each then purified by prep-HPLC [Instrument: GX-E; Column: Agella Venusil ASB CI 8 150x21.2 mmx5 μπι; Mobile phase: 14%-44% acetonitrile in H20 (0.05% HCl v/v)] to remove ammonium chloride. The eluents from prep-HPLC run were concentrated at room temperature and subjected to lyophilization to give:
3-(2-methyl-l,2,3,4-tetrahydroisoquinolin-6-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane]-enantiomerl hydrochloride (compound 11a) (6.1 mg, 20% yield) as a yellow solid: cSFC analytical tR: 2.78 min., purity: 94.3%; LCMS (F): 1.27 min., 313.2 m/z (M+l); 1H-NMR (CD30D, 400 MHz): δ 7.70-7.68 (m, 2H), 7.36-7.34 (d, J=8.0 Hz, IH), 4.67- 4.63 (d, J=15.6 Hz, I H,), 4.43-4.39 (d, J=16.0 Hz, I H), 3.81 (s, IH), 3.75-3.64 (m, 2H), 3.50-3.38 (m, 6H), 3.26-3.22 (m, 2H), 3.10 (s, 3H), 2.39-2.23(m, 3H), 2.12-2.01 (m, 2H), and
3-(2-methyl-l ,2,3,4-tetrahydroisoquinolin-6-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane]-enantiomer2 hydrochloride (compound lib) (6.3 mg, 21 % yield) as a yellow solid: cSFC analytical tR: 3.32 min., purity: 94.8%; LCMS (F): 1.31 min., 313.2 m/z (M+l); Ή-NMR (CD3OD, 400 MHz): δ 7.71-7.68 (m, 2H), 7.36-7.34 (d, J=8.0 Hz, I H,), 4.67- 4.63 (d, J=16.0 Hz, IH,), 4.44-4.40 (d, J=16.0 Hz, I H), 3.83-3.81 (m, I H), 3.67 (s, 2H), 3.51 -3.43 (m, 6H), 3.25-3.21 (m, IH), 3.10 (s, 3H,), 2.43(m, 3H), 2.13-2.01 (m, 2H);
cSFC analytical conditions: Column: Chiralpak OD-3 100 x 4.6 mm, I.D., 3 μιτι; Mobile phase: 40% ethanol (0.05% DEA) in C02; Flow rate: 3.0 mL/min.
[00647] Example 12 - (lr,3R,^,5S,7^)-3'-(4-chlorophenyl)-4'H-l -azaspiro[adamantane-4,5'- n,2,41oxadiazolel hydrochloride (12 and (,lA3R.^.5S.7^-3'-(4-chlorophenyl)-4'H-l - azaspiro[adamantane-4,5'-ri,2,41oxadiazolel hydrochloride (13)
Figure imgf000157_0001
[00648] To a mixture of compound A-102 (0.8 g, 4.7 mmol) and l -aza-adamantan-4-one (2.13 g, 14.1 mmol) in anhydrous toluene (8 mL) was added titanium tetrachloride (1 drop, cat.) slowly at room temperature. The resulting mixture was then heated at 150 °C in a microwave for 6 hours. Three identical batches of this reaction were run and the resulting residues combined for workup. The mixture of the three reactions was concentrated and the resulting residue was purified by column chromatography [dichloromethane/methanol/30% ammonia water=80: 1 :0.1], and then by prep-TLC [dichloromethane/methanol=20: l ] to give compound (lr,3R,4s,5S,7s)-3'- (4-chlorophenyl)-4'H-l -azaspiro[adamantane-4,5'-[l ,2,4]oxadiazole] (crude) and compound (lr,3R, r,5S, 75)-3'-(4-chlorophenyl)-4'H-l -azaspiro[adamantane-4,5'-[l ,2,4]oxadiazole] (crude). The crude products were further purified by prep-HPLC [Instrument: GX-C; Column:
Phenomenex Gemini CI 8 150x30 mmx5 μηι; Mobile phase: 45%-75% acetonitrile in H20 (0.05% ammonia v/v)]. Each of the resulting solutions were concentrated to give (lr,3R,4s,5S,7s)-3'-(4- chlorophenyl)-4'H-l -azaspiro[adamantane-4,5'-[l ,2,4]oxadiazole] and (lr,3R,4r,5S, 7s)-3'-(4- chlorophenyl)-4'H-l-azaspiro[adamantane-4,5'-[l ,2,4]oxadiazole], respectively, as free bases. To each free base was then added 0.2mol/L aqueous hydrochloric acid (5 mL) and each resulting solution was subjected to lyophilization to give:
(lr,3R,^5,5S, 75)-3'-(4-chlorophenyl)-4'H-l -azaspiro[adamantane-4,5'-[l ,2,4]oxadiazole] hydrochloride (compound 12) (62.8mg, 2% yield) as a white solid: LCMS (E): 1.78 min., 304.1 m/z (M+2); Ή-NMR (CD3OD, 400 MHz): δ 7.81-7.79 (d, J = 8.4 Hz, 2H), 7.52-7.50 (d, J = 8.4 Hz, 2H), 3.83-3.80 (d, J = 12.4 Hz, 2H), 3.71 -3.67 (m, J = 12.8 Hz, 2H), 3.59 (s, 2H), 2.36 (s, 4H), 2.20 (s, 1H), 2.1 1 -2.08 (m, 2H), and
(lr,3R,^r,5S, 75)-3'-(4-chlorophenyl)-4'H-l -azaspiro[adamantane-4,5'-[l ,2,4]oxadiazole] hydrochloride (compound 13) (16.4mg, 0.4% yield) as a yellow solid: LCMS (E): 1.65 min., 304.1 m/z (M+3); Ή-NMR (CD3OD, 400 MHz): δ 7.82-7.80 (d, J = 8.8 Hz, 2H), 7.51 -7.49 (d, J = 8.4 Hz, 2H), 3.77-3.74 (d, J = 12.0 Hz, 2H), 3.63-3.60 (m, 4H), 2.37-2.31 (m, 4H), 2.24-2.18 (m, 3H).
[00649] Example 13 - nrJR.^.SS.Z^'-rbenzorblthiophen^-vn^'H-l - azaspiroradamantane-4,5'-ri ,2,41oxadiazole] hydrochloride (14) and (l rJR^SS^Zs S1-
Figure imgf000158_0001
[00650] To a mixture of compound A-103 (0.8 g, 4.17 mmol) and 1 -aza-adamantan-4-one (1.89 g, 12.5 mmol) in toluene (5 ml) was added titanium tetrachloride (cat.) slowly at room temperature. The resulting mixture was then heated at 150 °C in a microwave for 6 hours. The reaction was concentrated and the resulting residue was purified by column chromatography [dichloromethane/methanol/30% ammonia water = 80: 1 :0.1] and prep-TLC
[dichloromethane/methanol = 20: 1] to give crude (l/%3R,4s,5S,7s)-3'-(benzo[b]thiophen-2-yl)- 4'H-l -azaspiro[adamantane-4,5'-[l ,2,4]oxadiazole] and (lr,3R,47%5S,7s)-3'-(benzo[b]thiophen-2- yl)-4'H-l -azaspiro[adamantane-4,5'-[l ,2,4]oxadiazole]. Each crude product was further purified by prep-HPLC [Instrument: GX-E; Column: Agella Venusil ASB C18 150x21 .2 mmx5 μπι; Mobile phase: 20%-50% acetonitrile in H20 (0.05% HC1 v/v)] to give:
(lr,3R,^5,5S, 75)-3'-(benzo[b]thiophen-2-yl)-4'H-l -azaspiro[adamantane-4,5'- [l ,2,4]oxadiazole] hydrochloride (compound 14) (31.8 mg, 2%) as a white solid: LCMS (F): 1.51 min., 326.1 m/z (M+l ); Ή-NMR (CD3OD, 400 MHz): δ 7.94 -7.89 (m, 2H), 7.85 (s, 2H), 7.47- 7.44(m, 2H), 3.80-3.71 (m, 4H), 3.61 (s, 2H), 2.40-2.37 (m, 4H), 2.21 (s, IH), 2.12-2.09 (m, 2H), and
(lr,3R,^r,5S,7i)-3'-(benzo[b]thiophen-2-yl)-4'H-l -azaspiro[adamantane-4,5'- [l,2,4]oxadiazole] hydrochloride (compound 15) (40 mg, 3%) as a white solid: LCMS (F): 1.64 min., 326.2 m/z (M+1 ); 1 H-NMR (CD3OD, 400 MHz): δ 7.93-7.89 (m, 3H), 7.49-7.44 (m, 2H), 3.82-3.79 (m, 2H), 3.63-3.60 (m, 4H), 2.41 (s, 2H), 2.32-2.20 (m, 5H).
[00651] Example 14 - (lr.3R,^.5S,7^-3l-(7-chlorobenzorblthiophen-2-ylV4lH-l - azaspiro[adamantane-4,5'-|"l ,2,4]oxadiazole1 hydrochloride (16) and (lr,3R,^r,5S,7^)-3'-(7- chlorobenzo blthiophen-2-yl)-4'H-l -azaspiro adamantane-4,S'- l ,2,4]oxadiazolel hydrochloride
Figure imgf000159_0001
[00652] To a mixture of compound A-107 (0.4 g, 1.77 mmol) and 1 -aza-adamantan-4-one (0.8 g, 5.31 mmol) in toluene (5 mL) was added titanium tetrachloride (cat.) slowly at room temperature. The resulting mixture was then heated at 150 °C in a microwave for 7 hours. The reaction was concentrated and the resulting residue was purified by column chromatography [dichloromethane/methanol/30% ammonia water = 80: 1 :0.1] and prep-TLC (two times)
[dichloromethane/methanol = 20: 1] to give the free base of (lr,3R,4s,5S,7s)-3'-(7- chlorobenzo[b]thiophen-2-yl)-4'H-l -azaspiro[adamantane-4,5'-[l ,2,4]oxadiazole] and
( 1 r,3 R,4r, 5 S, 7s)-3 '-(7-chlorobenzo[b]thiophen-2-y 1)-4'H- 1 -azaspiro[adamantane-4,5 '- [l ,2,4]oxadiazole]. The free bases were dissolved in deionized water and adjusted to pH=3~5 by 0.2mol/L aqueous hydrochloric acid, respectively. The two solutions were each subjected to lyophilization, respectively, to give:
(l r,3R,^,5S,75)-3'-(7-chlorobenzo[b]thiophen-2-yl)-4'H-l -azaspiro[adamantane-4,5'- [l ,2,4]oxadiazole] hydrochloride (compound 16) (10.6 mg, 2% yield) as a yellow solid: LCMS (E): 1.94 min., 360.0 m/z (M+1 ); 1 H-NMR (CD3OD, 400 MHz): δ 7.94 (s, I H), 7.88-7.87 (d, I H, J=7.6), 7.52-7.45 (m, 2H), 3.82-3.71 (m, 4H), 3.61 (m, 2H), 2.41 -2.36 (m, 4H), 2.22 (s, I H), 2.13- 2.10 (m, 2H), and
(l ,3R,^ ,5S,7l$)-3'-(7-chlorobenzo[b]thiophen-2-yl)-4'H-l -azaspiro[adamantane-4,5'- [l ,2,4]oxadiazole] hydrochloride (compound 17) (5.0 mg, 1 % yield) as a white solid: LCMS (E): 1.9 min., 360.1 m/z (M+1 ); 1 H-NMR (CD3OD, 400 MHz): δ 7.94 (s, IH), 7.89-7.87 (d, 2H; J=7.2), 7.53-7.45 (m, 2H), 3.83-3.80 (m, 2H), 3.63-3.60 (m, 4H), 2.42 (s, 2H), 2.31 -2.20 (m, 5H). [00653] Example 15 - (l 3R.^.5S, 7^)-4l-(2,4-dimethoxybenzylV3'-(7- fluorobenzo[b]thiophen-2-yl)-4'H-l -azaspiro[adamantane-4,5'-[l ,2,4]oxadiazole] (18) and (I r.3 R r.5 S.7JV4'-( 2.4-dimethoxybenzyl V3 '-(7-fluorobenzo rblthiophen-2-vn-4'H- 1 - azaspiro[adamantane-4,5'-n ,2,4]oxadiazole] (19)
Figure imgf000160_0001
B-108 18 19
[00654] To a mixture of compound B-108 (0.5 g, 2.56 mmol) and compound C-112 (0.92 g, 3.07 mmol) in dichloromethane ( 10 mL) was added sodium hypochlorite (0.38g, 5.12mmol) slowly at 0 °C. The mixture was stirred at room temperature for 4 hours. On completion, the reaction was quenched with sodium sulfite solution and extracted with dichloromethane. The organic layer was concentrated and purified by column chromatography
[dichloromethane/methanol = 70: 1 ] and prep-HPLC [Instrument: HPLC-A Column: Phenomenex
Gemini C I 8 150x30 mmx5 μπι; Mobile phase: 20%-50% acetonitrile in H20 (0.05% TFA v/v)] to give a mixture of compounds 18 and 19 (0.25 g, 20%) as a yellow solid.
[00655] Example 16 - (l rJR.^.5S.7jV3'-(7-fluoroben2orb1thiophen-2-ylV4'H-l - azaspiro[adamantane-4,5'-|T ,2,4]oxadiazole] hydrochloride (20) and (l^,3R,^5S,7 ,)-3'-(7- fluorobenzo[b1thiophen-2-yl)-4'H-l -azaspiroradamantane-4,5'- l ,2,41oxadiazolel hydrochloride
Figure imgf000160_0002
18 19
[00656] The mixture of compounds 18 and 19 (0.25, 0.51 mmol) in 10% trifluoroacetic acid/dichloromethane (1 0 mL) was stirred at room temperature for 4 hours. The resulting solution was concentrated in vacuo and the resulting residue was purified by prep-HPLC [Instrument: GX- E; Column: Agella Venusil ASB CI 8 150x21.2 mmx5 μπι; Mobile phase: 28%-36% acetonitrile in H20 (0.05% HCI v/v)] to give:
( l r,3R,4s,5S, 75)-3'-(7-fluorobenzo[b]thiophen-2-yl)-4'H-l -azaspiro[adamantane-4,5'- [l ,2,4]oxadiazole] hydrochloride (compound 20) ( 17.8mg, 9%) as a yellow solid: LCMS (B): 0.7 min, 344.1 m/z (M+l ); Ή-NMR (CD3OD, 400 MHz): δ 7.91 -7.90 (d, J = 3.6 Hz, 1 H), 7.76-7.74 (d, J = 8.0 Hz, 1H), 7.49-7.46 (m, 1H), 7.26-7.21 (m, 1H), 3.80-3.71 (m, 4H), 3.61 (s, 2H), 2.41- 2.37 (m, 4H), 2.22 (s, 1H), 2.13-2.09 (m, 2H), and
(lr,3R,^r,5S, 75)-3'-(7-fIuorobenzo[b]thiophen-2-yl)-4'H-l-azaspiro[adamantane-4,5'- [l ,2,4]oxadiazole] hydrochloride (compound 21) (23.8 mg, 12%) as a white solid: LCMS (B): 0.68 min., 344.2 m/z (M+l); Ή-NMR (CD3OD, 400 MHz): δ 7.95-7.94 (d, J = 3.6 Hz, 1 H), 7.76- 7.74 (d, J = 8.0 Hz, 1 H), 7.50-7.45 (m, 1H), 7.25-7.21 (m, 1 H), 3.82-3.79 (m, 2H,), 3.63-3.60 (m, 4H), 2.42 (s, 2H), 2.32-2.20 (m, 5H).
[00657] Example 17 - (l r,3R,^,5S,7^)-3'-(benzofuran-2-yl)-4'-(2,4-dimethoxybenzyl)-4'H-l - azaspiro adamantane-4,5'- l ,2,4]oxadiazolel (22) and (l r,3R,^5S,7^)-3'-(benzofuran-2-yl)-4'- (2,4-dimethoxybenzyl)-4'H-l -azaspiro adamantane-4,5'-[l ,2,41oxadiazole] (23)
Figure imgf000161_0001
[00658] To a mixture of compound B-104 (1.0 g, 6.2 mmol) and compound C-112 (2.2 g, 7.44 mmol) was added sodium hypochlorite (0.93 g, 12.4 mmol) slowly at 0 °C. The mixture was stirred at room temperature for about 4 hours before the reaction was quenched with sodium sulfite solution and organics were extracted with dichloromethane (3 x 50 raL). The combined organic layers were concentrated and purified by column chromatography [dichloromethane/ methanol = 70: 1] to give a mixture of compounds 22 and 23 (0.2 g, 7%) as a yellow solid.
[00659] Example 18 - dr.3R.^.5S.7 V3'-(benzofuran-2-yl)-4'H-l -azaspiroradamantane-4,5'- r i .2,41oxadiazolel hydrochloride (24 and q^R.^.SS^^'-ibenzofuran^-yl' 'H-l - azaspiro[adamantane-4,5'-[l ,2,4]oxadiazole1 hydrochloride (25)
Figure imgf000161_0002
[00660] The mixture of compounds 22 and 23 (0.2 g, 0.6 mmol) in 10% trifluoroacetic acid/dichloromethane (2ml) was stirred at room temperature for 4 hours. The resulting solution was concentrated in vacuo and the resulting residue was purified by prep-HPLC [Instrument: Gilson-281 ; Column: Phenomenex Gemini CI 8 150x30 mmx5 μιη; Mobile phase: 20%-50% acetonitrile in H20 (0.05% HCl v/v)] to give:
( 1 r,3R,4s,5 S, Zs)-3 '-(benzofuran-2-yI)-4'H- 1 -azaspiro[adamantane-4,5'-[ 1 ,2,4]oxadiazole] hydrochloride (compound 24) (27.2mg, 18%) as a white solid: LCMS (E): 1.33 min., 310.1 m/z (M+l); Ή-NMR (CD3OD, 400 MHz): δ 7.74-7.72 (d, J = 8.0 Hz, 1 H), 7.60-7.58 (d, J = 8.4 Hz, 1H), 7.47-7.43 (m, 2H), 7.36-7.32 (t, J = 7.6 Hz, 1 H), 3.85-3.81 (d, J = 12.8 Hz, 2H), 3.73-3.70 (d, J = 12.8 Hz, 2H), 3.60 (s, 2H), 2.41-2.36 (m, 4H), 2.21 (s, 1H) , 2.13-2.10 (m, 2H), and
(l^,3R,¥r,5S,7j)-3'-(benzofuran-2-yl)-4'H-l-azaspiro[adamantane-4,5'-[l,2,4]oxadiazole] hydrochloride (compound 25) (28.1 mg, 19%) as a white solid: LCMS (E): 1.3 min., 310.1 m/z (M+l); Ή-NMR (CD3OD, 400 MHz): δ 7.74-7.72 (d, J = 8.0 Hz, 1H), 7.60-7.58 (m, J = 8.4 Hz, 1H), 7.47-7.43 (m, 2H), 7.36-7.33(t, J = 7.2 Hz, 1 H), 3.82-3.79 (m, 2H), 3.63-3.60 (m, 4H), 2.41 (s, 2H), 2.31 -2.20 (m, 5H).
[00661] Example 19 - (+/-)-4-(2,4-dimethoxybenzvn-3-(5-fluorobenzorblthiophen-2-vn-4H- r-azaspiroin ,2,41oxadiazole-5,3'-bicyclo|"2.2.2]octane] (26)
Figure imgf000162_0001
B-114 26
[00662] To a mixture of compound B-l 14 (1 g, 5.1 mmol) and compound C-108 (1 .67 g, 6.1 mmol) in dichloromethane (30 mL) was added sodium hypochlorite (0.76 g, 10.2 mmol) at 0 °C. The reaction was then stirred at room temperature for 4 hours before being quenched with sodium sulfite. Organics were extracted with dichloromethane (3 x 50 mL) dried over sodium sulfate and concentrated in vacuo. The resulting residue was then purified by prep-HPLC [Instrument: GX-E; Column: Agella Venusil ASB CI 8 150x21.2 mmx5 μηι; Mobile phase: 18%-48% acetonitrile in H20 (0.05% HCl v/v)] to give racemate 26 (0.28 g, 12% yield) as a white solid. Racemate 26 is a mixture of (R)-4-(2,4-dtmethoxybenzyl)-3-(5-fluorobenzo[b]thiophen-2-yl)-4H- - azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane] (when deprotected provides (R)-3-(5- fluorobenzo[b]thiophen-2-yl)-4H-r-azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane]}1 and (S)-4-(2,4-dimethoxybenzy l)-3 -(5 -fluorobenzo [b]thiophen-2-yl)-4H- 1 '- azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane] (when deprotected provides (S)-3-(5- fluorobenzo[b]thiophen-2-yl)-4H- -azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane]).
[00663] Chiral Separation: [00664] A solution of racemate 26 (0.28 g, 0.6 mmol) was separated by SFC (Instrument: SFC 80; Column: Chiralpak AD-H 250x25 mm I.D., 10 μηι; Mobile phase: 65% ethanol (0.01 % NH3 H20) in CO2) at room temperature. The solution was concentrated under reduced pressure at room temperature to give:
4-(2,4-dimethoxybenzyl)-3-(5-fluorobenzo[b]thiophen-2-yl)-4H-r- azaspiro[[l,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane]-enantiomerl (compound 26a) (0.08 g, 29% yield) as a white solid, and
4-(2,4-dimethoxybenzyl)-3-(5-fluorobenzo[b]thiophen-2-yl)-4H- - azaspiro[[l,2,4]oxadiazole-5,3'-bi-cyclo[2.2.2]octane]-enantiomer2 (compound 26b) (0.08 g, 29% yield) as a white solid.
[00665] Example 20 - 3-(5-fluorobenzo b1thiophen-2-yl)-4H-r-azaspiro ri ,2,41oxadiazole- 5,3'-bicyclo[2.2.2]octane] hydrochloride-enantiomerl (27a)
[00666] To a solution of compound 26a (80 mg, 0.1 mmol) was added 5% trifluoroacetic acid/dichloromethane (2 mL). The reaction was stirred at 0 °C for 2 hours before addition of deionized water and 0.5% aqueous hydrochloric acid (10ml). The resulting solution was concentrated in vacuo at room temperature and then subjected to lyophilization to give 3-(5- fluorobenzo[b]thiophen-2-yl)-4H-l '-azaspiro[[l,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane]- enantiomerl hydrochloride (compound 27a) (40 mg, 67% yield) as a yellow solid: cSFC analytical tR: 2.08 min, purity: 100.0%; LCMS (B): 0.65 min., 318.2 m/z (M+l); Ή-NMR (CD3OD, 400 MHz): δ 7.90-7.87 (m, 1 H), 7.75 (s, 1H), 7.65-7.62 (dd, Jl=9.6 Hz, J2=2.4 Hz, 1 H), 7.31-7.25 (m, 1H), 3.81 -3.77 (dd, Jl=14.0 Hz, J2=2.0 Hz, 1 H), 3.65-3.61 (dd, Jl=14.4 Hz, J2=2.4 Hz, 1 H), 3.48-3.39 (m, H=4), 2.45-2.39 (m, 2H), 2.31-2.27 (m, 1 H), 2.18-2.15 (m,l H), 2.06-2.00 (m, 1H);
cSFC analytical conditions: Column: Chiralcel OJ-3 250 x 4.6 mm, I.D., 5 μπι; Mobile phase: 5% to 40% ethanol (0.05% DEA) in C02; Flow rate: 3.0 mL/min.
[00667] Example 21 - 3-("5-fluorobenzo b1thiophen-2-yl)-4H-r-azaspiro[[l,2,41oxadiazole- 5,3'-bicyclo|"2,2.2]octanel hydrochloride-enantiomer2 (27b)
[00668] To a solution of compound 26b (80 mg, 0.1 mmol) was added 5% trifluoroacetic acid of dichloromethane (2 mL) . The mixture solution was stirred at 0 °C for 2 hours. The organic layer was added deionized water and 0.5% aqueous hydrochloric acid (10ml). The solution was concentrated under reduced pressure at room temperature and then dried in freezed drying to give 3-(5-fluorobenzo[b]thiophen-2-yl)-4H-l'-azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane]-enantiomer2 hydrochloride (compound 27b) (52.3 mg, 87% yield) as a yellow solid: cSFC analytical tR: 2.79 min, purity: 98.0%; LCMS (B): 0.65 min., 318.2 m/z (M+l); Ή-NMR (CD3OD, 400 MHz): δ 7.95-7.92 (m, 1H), 7.77 (s, 1H), 7.65-7.62 (dd, Jl=9.6 Hz, J2=2.4 Hz, 1H), 7.31-7.26 (m, 1H), 3.82-3.77 (dd, Jl=14.4 Hz, J2=2.4 Hz, 1H), 3.64-3.60 (dd, Jl=14.4 Hz, J2=2.4 Hz, 1H), 3.84-3.38 (m, H=4), 2.447 (m, H=2), 2.29-2.27 (m, 1 H), 2.19- 2.15 (m, 1H), 2.06-2.03 (m, 1 H);
cSFC analytical conditions: Column: Chiralcel OJ-3 250 x 4.6 mm, I.D., 5 μιη; Mobile phase: 5% to 40% ethanol (0.05% DEA) in C02; Flow rate: 3.0 mL/min.
[00669] Example 22 - (+/-)-3-(benzorb1thiazol-2-vn-4-(2.4-dimethoxybenzvn-4H-l '- azaspiro[[1.2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane] (28)
Figure imgf000164_0001
28
[00670] To a mixture of compound B-106 (1.45 g, 8.14 mmol) and compound C-108 (2.68 g, 9.77 mmol) in dichloromethane (15 mL) was carefully added (dropwise) sodium hypochlorite (2.4 g, 32.6 mmol) at 0 °C. The reaction was stirred at room temperature for 3 hours before being filtered. The resulting filtrate was concentrated in vacuo and the residue purified by prep-HPLC [Instrument: Shimadzu pump LC-20A; Column: Phenomenex Gemini CI 8 150*30 mm, particle size: 5 μιη; Mobile phase: 40-70% acetonitrile in H20 (add 1% NH3 H20, v/v)] to give racemate 28 (70 mg, 2.0%) as a yellow solid. Racemate 28 is a mixture of (R)-3-(benzo[b]thiazol-2-yl)-4- (2,4-dimethoxybenzyl)-4H-r-azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane] (when deprotected provides (R)-3-(benzo[d]thiazol-2-yl)-4H-l'-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane])1 and (S)-3-(benzo[b]thiazol-2-yl)-4-(2,4-dimethoxybenzyl)-4H-l '- azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane] (when deprotected provides (S)-3- (benzo[d]thiazol-2-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane]).
[00671] Chiral Separation:
[00672] A solution of racemate 28 (70 mg, 0.16 mmol) was separated by SFC (Instrument: SFC 80; Column: Chiralpak AD-H 250x25 mm I.D., 10 μιη; Mobile phase: 60% ethanol (0.01% NH3 H20) in C02) at room temperature. The solution was concentrated under reduced pressure at room temperature to give:
3-(benzo[b]thiazol-2-yl)-4-(2,4-dimethoxybenzyl)-4H-r-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane]-enantiomerl (compound 28a) (25 g, 36% yield), and
3-(benzo[b]thiazol-2-yl)-4-(2,4-dimethoxybenzyl)-4H-l'-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane]-enantiomer2 (compound 28b) (30g, 43%) as a yellow solid.
[00673] Example 23 - 3-(benzorblthiazol-2-yl)-4H-l l-azaspirorn .2.41oxadiazole-5Jl- bicyclo[2.2,2]octane] enantiomerl trifluoroacetate (29a) [00674] To compound 28a (25 mg, 0.056 mmol) was added 5% trifluoroacetic
acid/dichloromethane (10 mL) and the mixture was stirred at 0 °C for 2h. The reaction was concentrated under reduced pressure at 0 °C to give 3-(benzo[b]thiazol-2-yl)-4H-l '- azaspiro[[l,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane]-enantiomerl trifluoroacetate (compound 29a) (13 mg, 80%) as a yellow solid: cSFC analytical tR: 1.04 min., purity: 91.8%; LCMS (E): 1.20 min., 301.1 m/z (M+l); Ή-NMR (CD3OD, 400 MHz): δ 8.12-8.06 (m, 2Η), 7.63-7.54 (m, 2Η), 3.83-3.79 (m, I H), 3.66-3.62 (m, I H), 3.45-3.33 (m, 4Η), 2.48-2.44 (m, 2H), 2.30-2.28 (m, I H), 2.16-2.13 (m, I H), 2.05-2.04 (m, IH);
cSFC analytical conditions: Column: Chiralpak AD-3 100 x 4.6 mm, I.D., 3 μηι; Mobile phase: 40% ethanol (0.05% DEA) in C02; Flow rate: 3.0 mL/min.
[00675] Example 24 - 3-(benzorblthiazol-2-yl)-4H-l '-azaspirorri .2,41oxadiazole-5.3'- bicyclo[2.2.2]octane1 enantiomer2 trifluoroacetate (29b)
[00676] To compound 28b (20 mg, 0.044 mmol) was added 5% trifluoroacetic
acid/dichloromethane (3 mL) . The mixture was stirred at 0 °C for 2h. The reaction was concentrated under reduced pressure at 0 °C to give 3-(benzo[b]thiazol-2-yl)-4H-l '- azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane]-enantiomer2 trifluoroacetate (compound 29b) (12 mg, 91 %) as a white solid: cSFC analytical tR: 1.74 min., purity: 89.0%; LCMS (E): 1.27 min., 301.0 m/z (M+l ); Ή-NMR (CD3OD, 400 MHz): δ 8.13-8.08 (m, 2H), 7.64-7.55 (m, 2H), 3.84-3.80(m, I H), 3.66-3.65 (m, I H), 3.42-3.33 (m, 4H), 2.48-2.44 (m, 2H), 2.31-2.28 (m, IH), 2.15-2.14 (m, I H), 2.06-2.04 (m, IH);
cSFC analytical conditions: Column: Chiralpak AD-3 100 x 4.6 mm, I.D., 3 μπι; Mobile phase: 40% ethanol (0.05% DEA) in C02; Flow rate: 3.0 mL/min.
[00677] Example 25 - (+/-)-3-(benzorblthiophen-3-yl)-4-(2.4-dimethoxybenzyl')-4H-l '- azaspiro[[l ,2,4]oxadiazole-5,,3'-bicvclo[2.2.2]octanel (30)
Figure imgf000165_0001
30
[00678] To a mixture of compound B-103 (6 g, 0.033 mol) and compound C-108 (8.05 g, 0.029 mol) in dichloromethane (50 mL) was added 10% aqueous sodium hypochlorite (68 g, 0.092 mol) dropwise at 0 °C. The reaction was allowed to warm to room temperature and was stirred at this temperature. On completion, the reaction was filtered and the resulting filtrate was concentrated and purified by prep-HPLC [Instrument: Shimadzu pump LC-20A; Column:
GEMINI 200*50 mm, particle size: 10 μιη; Mobile phase: 55-66.7% acetonitrile in H20 (add 0.5% NH3.H20, v/v)] to give racemate 30 (4.2 g, 41% yield) as a white solid. Racemate 30 is a mixture of (R)-3-(benzo[b]thiophen-3-yl)-4-(2,4-dimethoxybenzyl)-4H-l '- azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane] (when deprotected provides (R)-3- (benzo[b]thiophen-3-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane]il and (S)-3- (benzo[b]thiophen-3 -yl)-4-(2,4-dimethoxybenzyl)-4H- 1 '-azaspiro[[ 1 ,2,4]oxadiazole-5,3 '- bicyclo[2.2.2]octane] (when deprotected provides (S)-3-(benzo[b]thiophen-3-yl)-4H-l '- azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane]).
[00679] Chiral Separation:
[00680] A solution of racemate 30 (0.8 g, 1.78 mmol) in 10 ml of ethanol was separated by SFC (Instrument: SFC 80; Column: Chiralpak AD-H 250 25 mm I.D., 10 μιη; Mobile phase: 60% ethanol (0.01% NH3.H2O) in CO2) at room temperature. The solution was concentrated under reduced pressure at room temperature to give:
3-(benzo[b]thiophen-3-yl)-4-(2,4-dimethoxybenzyl)-4H-l '-azaspiro[[l ,2,4]oxadiazole- 5,3'-bicyclo[2.2.2]octane]-enantiomerl (compound 30a) (0.12 g, 15% yield), and
3-(benzo[b]thiophen-3-yl)-4-(2,4-dimethoxybenzyl)-4H-l'-azaspiro[[l ,2,4]oxadiazole- 5,3'-bicyclo[2.2.2]octane]-enantiomer2 (compound 30b) (0.3 g, 38% yield) as yellow solid.
[00681] Example 26 - 3-(benzo[blthiophen-3-yl')-4H-l l-azaspirorn ,2,41oxadiazole-5.3l- bicyclo[2,2.2"|octane"|-enantiomerl hydrochloride (31a)
[00682] To compound 30a (120 mg, 0.27 mmol) was added 10% trifluoroacetic
acid/dichloromethane (20 ml) and the reaction was stirred at 0 °C for 2 hours. On completion, the reaction was filtered and the resulting filtrate was concentrated and purified by prep-HPLC
[Instrument: Shimadzu pump LC-20A; Column: Phenomenex Gemini CI 8 150x30 mm, particle size: 5 μηι; Mobile phase: 42-72% acetonitrile in H20 (add 0.5% HC1, v/v)]. The product was then subjected to lyophilization to give 3-(benzo[b]thiophen-3-yl)-4H-l '- azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane]-enantiomerl hydrochloride (compound 31a) (40.7 mg, 50% yield ) as yellow solid: cSFC analytical tR: 4.89 min., purity: 97.5%; LCMS (G): 2.41 min., 300.1 m/z (M+1); Ή-NMR (CD3OD, 400 MHz): δ 8.44-8.42 (d, J=8.4 Ηζ,Ι Η), 8.09 (s, 1H), 7.97-7.94 (d, J=8.8 Hz, 2H), 7.49-7.43 (m, 2H), 3.26-3.22 (d, J=15.6 Ηζ,Ι Η), 3.15-3.1 1 (d, J=14.8 Hz, 1 H), 2.93-2.87 (m, 4H), 2.23-2.12 (m, 2H), 2.05-2.03 (m, 1 H) , 1.80-1.66 (m, 1 H); cSFC analytical conditions: Column: Chiracel IC 250 x 4.6 mm, I.D., 5 μιη; Mobile phase: 50% isopropanol (0.05% DEA) in CO2; Flow rate: 2.4 mL/min.; Back pressure: 120 bar.
[00683] Example 27 - 3-(benzorblthiophen-3-vn-4H-l '-azaspirorri ,2,41oxadiazole-5.3'- bicyclo|"2.2.21octane1-enantiomer2 hydrochloride (31b")
[00684] To compound 30b (120 mg, 0.27 mmol) was added 10% trifluoroacetic
acid/dichloromethane (20 ml) and the reaction was stirred at 0 °C for 2 hours. On completion, the reaction was filtered and the resulting filtrate was concentrated and purified by prep-HPLC
[Instrument: Shimadzu pump LC-20A; Column: Phenomenex Gemini CI 8 150χ30 mm, particle size: 5 μηι; Mobile phase: 42-72% acetonitrile in H20 (add 0.5% HC1, v/v)]. The product was then subjected to lyophilization to give 3-(benzo[b]thiophen-3-yl)-4H-l '- azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane]-enantiomer2 hydrochloride (compound 31b) (42.6 mg, 53% yield) as yellow solid: cSFC analytical tR: 5.80 min., purity: 93.3%; LCMS (G): 2.41 min., 300.1 m/z (M+l); Ή-NMR (CD3OD, 400 MHz): δ 8.44-8.42 (d, J=8.4 Hz, IH), 8.09 (s, IH), 7.97-7.94 (d, J=8.8 Hz, 2H), 7.49-7.42 (m, 2H), 3.26-3.22 (d, J=14.8 Hz, IH), 3.15-3.1 1 (m, I H), 2.93-2.87 (m, 4H), 2.23-2.12 (m, 2H), 2.06-2.03 (m, IH) , 1.80-1.66 (m, 2H);
cSFC analytical conditions: Column: Chiracel IC 250 x 4.6 mm, I.D., 5 μπι; Mobile phase: 50% isopropanol (0.05% DEA) in CO2; Flow rate: 2.4 mL/min.; Back pressure: 120 bar.
[00685] Example 28 - (+/-)-3-(l-methyl-1.2.3.4-tetrahvdroquinolin-6-yl)-4H-l '- azaspiro[[l,2,41oxadiazole-5,3'-bicyclo 2.2.21octane1 (32)
Figure imgf000167_0001
[00686] To a mixture of compound B-123 (0.64 g, 2.6 mmol) and compound C-113 (0.5 g, 2.6 mmol) in dichloromethane (20 mL) was added sodium hypochlorite (0.19 g, 2.63 mmol) at 0 °C. The mixture was stirred at room temperature overnight. This solution was quenched with sodium sulfite solution and organics were extracted with dichloromethane (3 x 50 mL). The combined organics were concentrated and purified by column chromatography
[dichloromethane/methanol = 50: 1] to give racemate 32 (0.38 g, 33% yield) as a yellow solid. LCMS: (ES+) m/z (M+H)+ = 433.2, tR=0.922.
[00687] A solution of racemate 32 (0.8g, 1.8mmol) in 4M hydrochloric acid/dioxane (20mL) was stirred at room temperature for 16 hours before being heated at 50 °C for another 4 hours. On completion, the reaction was concentrated and the resulting residue was purified by prep-HPLC [Instrument: GX-C; Column: Phenomenex Gemini CI 8 150x30 mmx5 μιη; Mobile phase: 40%- 70% acetonitrile in H20 (0.05% ammonia v/v)] to give (+/-)-3 -(1 -methyl- 1 ,2,3, 4- tetrahydroquinolin-6-yl)-4H- -azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane]
hydrochloride (racemate 33) (65 mg, 12% yield), a mixture of (R)-3-(l -methyl- 1 ,2,3, 4- tetrahydroquinolin-6-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane] and (S)-3- (l -methyl-l ,2,3,4-tetrahydroquinolin-6-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane], as yellow solid. LCMS: (ES+) m/z (M+H)+ =313.2, tR=1.308.
[00688] Chiral Separation:
[00689] A solution of racemate 33 (40 mg) in methanol (5 mL) was separated by SFC (Instrument: SFC-80-A; Column: Chiralpak AD-H 250x25 mm I.D., 10 μηι; Mobile phase: 40% MeOH in C02 with 0.01% NH3 H20) at room temperature. To each collected fraction was quickly added 0.2 N HCl/EtOH until pH=5 was attained. Each solution was then concentrated at room temperature to give 3-(l -methyl- 1 ,2,3, 4-tetrahydroquinolin-6-yl)-4H- Γ- azaspiro[[l,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane]-enantiomerl hydrochloride (50 mg) and 3- (1 -methyl- l ,2,3,4-tetrahydroquinolin-6-yl)-4H-r-azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane]-enantiomer2 hydrochloride (30 mg) (containing ammonium chloride). The crude compounds were individually further purified by prep-HPLC [Instrument: GX-E; Column: Agella Venusil ASB C18 150x21.2 mmx5 μιη; Mobile phase: 14%-44% acetonitrile in H20 (0.05% HC1 v/v)] to remove ammonium chloride. The eluents from prep-HPLC were concentrated at room temperature and subjected to lyophilization to give
3-( 1 -methyl-1 ,2,3,4-tetrahydroquinolin-6-yl)-4H-l'-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane]-enantiomerl hydrochloride (compound 33a) (16.2 mg, 41 % yield) as a yellow solid: cSFC analytical tR: 1.03 min., purity: 92.9%; LCMS (F): 1.34 min., 313.2 m/z (M+l); Ή-NMR (CD3OD, 400 MHz): δ 7.46-7.44 (m, I H), 7.35 (s, I H), 6.79-6.77 (d, J=8.8 HZ, IH), 3.74-3.70 (m, I H), 3.58-3.54 (m, I H), 3.42-3.99 (m, 6H), 3.03 (s, 3H), 2.84-2.81 (m, 2H), 2.41-2.39 (m, 2H), 2.28-2.26(m, IH), 2.14-1.97(m, 4H), and
3-(l -methyl-1 , 2,3,4-tetrahydroquinolin-6-yl)-4H- -azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane]-enantiomer2 hydrochloride (compound 33b) (7.8 mg, 20% yield) as a yellow solid: cSFC analytical tR: 1.73 min., purity 100.0%; LCMS (F): 1.4 min., 313.2 m/z (M+l); Ή-NMR (CD3OD, 400 MHz): δ 7.65-7.63 (d, IH, J=8.8), 7.57 (s, IH), 7.19-7.17 (d, J=8.8 ΗΖ, Ι Η), 3.77-3.74 (m, I H), 3.67-3.63 (m, I H), 3.58-3.55 (m, 2H), 3.45-3.40 (m, 3H), 3.19 (s, 3H), 2.96-2.93 (m, 2H), 2.41 (m, 3H), 2.18-2.02(m, 5H);
cSFC analytical conditions: Column: Chiralpak AD-3 100 x 4.6 mm, I.D., 3 μπι; Mobile phase: 40% methanol (0.05% DEA) in C02; Flow rate: 3.0 mL/min.; Back pressure: 120 bar.
[00690] Example 29 - (+/-)-3-(4-chlorophenyl)-4-phenyl-4H-l'-azaspiror L2,41oxadiazole- 5,3'-bicvclo[2.2.21octanel (34)
Figure imgf000168_0001
34
[00691] To a mixture of compound B-101 (500 mg, 3.2 mmol) and compound C-110 (640 mg, 3.2 mmol) in dichloromethane (5 mL) was added 10% aqueous sodium hypochlorite (4.8 g, 6.4 mmol) at 0 °C. The mixture was then stirred at room temperature overnight. On completion, the reaction was quenched by sodium sulfite, organics were extracted with dichloromethane (3 x 30mL). The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, concentrated and purified by prep-HPLC [Instrument: GX-C; Column:
Phenomenex Gemini C18 150*30 mm; Mobile phase: 49-79% acetonitrile in H20 (0.05 % ammonia, v/v)] to afford racemate 34 (80 mg, 7% yield), a mixture of (R)-3-(4-chlorophenyl)-4- phenyl-4H-l '-azaspiro[[l,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane] and (S)-3-(4-chlorophenyl)-4- phenyl-4H-l'-azaspiro[[l,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane], as a white solid.
[00692] Chiral Separation:
[00693] A solution of racemate 34 (160 mg, 0.45 mmol) in methanol (5 ml) was separated by SFC (Instrument: SFC-80-A; Column: AD-10 μπι; Mobile phase: 40% IPA in C02) at room temperature. To each collected fraction was quickly added 0.2 N HCl/EtOH until pH=5 was attained. Each solution was then concentrated at room temperature to give:
3-(4-chlorophenyl)-4-phenyl-4H-l'-azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane]- enantiomerl hydrochloride (compound 34a) (44 mg, 28% yield): cSFC analytical tR: 2.94 min., purity: 98.8%; LCMS (F): 1.38 min., 354.1 m/z (M+l ); Ή-NMR (CD3OD, 400 MHz): δ 7.62- 7.60 (d, J=8.4 Hz, 2H), 7.44-7.14 (m, 7H), 3.39-3.33 (m, 1H), 3.30-3.20 (m, 4H), 3.06-3.03 (m, 1H), 2.52 (s, 1H), 2.42-2.36 (m, 1 H), 2.20-2.17 (m, 1 H), 1.94-1.88 (m, 2H), and
3-(4-chlorophenyl)-4-phenyl-4H-l'-azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane]- enantiomer2 hydrochloride (compound 34b) (41 mg, 26% yield) as a white solid: cSFC analytical tR: 3.88 min., purity: 98.5%; LCMS (F): 1.38 min., 354.1 m/z (M+l); Ή-NMR (CD3OD, 400 MHz): δ 7.62-7.60 (d, J=8.8 Hz, 2H), 7.42-7.12 (m, 7H), 3.20-3.00 (m, 5H), 2.93- 2.87 (m, 1H), 2.42 (s, 1H), 2.34-2.30 (s, 1H), 2.19-2.17 (m, 1 H), 1.87-1.76 (m, 2H);
cSFC analytical conditions: Column: Chiralpak AD-3 100 x 4.6 mm, I.D., 3 μπι; Mobile phase: 5% to 40% isopropanol (0.05% DEA) in C02; Flow rate: 3.0 mL/min.
[00694] Example 30 - (+/-V3-(benzorblthiophen-2-vn-4-phenyl-4H-l'-
Figure imgf000169_0001
B-102 35
[00695] To a mixture of compound B-102 (500 mg, 2.82 mmol) and compound C-110 (564 mg, 2.82 mmol) in dichloromethane (15 mL) was added 10% aqueous sodium hypochlorite (4.23 g, 5.64 mmol) at 0 °C. The mixture was stirred at room temperature overnight. On completion the reaction was quenched with sodium sulfite, organics were extracted by dichloromethane (3 x 30 mL). The combined organics were washed with water, dried, concentrated and purified by prep- HPLC [Instrument: GX-C; Column: Phenomenex Gemini CI 8 150><30 mmx5 μηι; Mobile phase: 51 %-81 % acetonitrile in H20 (0.05% ammonia v/v)] to afford racemate 35 (1 10 mg, 1 1 % yield), a mixture of (R)-3-(benzo[b]thiophen-2-yl)-4-phenyl-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane] and (S)-3-(benzo[b]thiophen-2-yl)-4-phenyl-4H-l'- azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane], as a white solid.
[00696] Chiral Separation:
[00697] A solution of racemate 35 (1 10 mg, 0.29 mmol) was separated by SFC (Instrument: SFC-80-A; Column: Chiralpak AD-H 250x25 mm I.D., 10 μιη; Mobile phase: 40% MeOH in CO2 with 0.01 % NH3 H20) at room temperature. Each set of collected fractions were concentrated at room temperature to give free base 3-(benzo[b]thiophen-2-yl)~4-phenyl-4H-l '- azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane]-enantiomerl and free base 3- (benzo[b]thiophen-2-yl)-4-phenyl-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane]- enantiomer2. Each free base was dissolved in deionized water and adjusted to pH=3~5 by 0.2 mol/L aqueous hydrochloric acid respectively. Each was then subjected to lyophilization to give:
3-(benzo[b]thiophen-2-yl)-4-phenyl-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane]-enantiomerl hydrochloride (compound 35a) (47.6 mg, 40% yield) as a white solid: cSFC analytical tR: 1.53 min., purity: 100.0%; LCMS (F): 1.42 min., 376.1 m/z (M+l ); Ή-NMR (CD3OD, 400 MHz): δ 7.85-7.83 (d, J = 8.0 Hz, 1 H), 7.70-7.68 (d, J = 7.6 Hz, 1 H), 7.60 (s, 2H), 7.49 (s, 2H), 7.42-7.33 (m, 4H), 3.70-3.66 (dd, J = 14.8 Hz, 1 H), 3.53-3.49 (m, 1 H), 3.47-3.43 (m, 2H), 3.26-3.24 (m, 2H), 2.69 (s, 1 H), 2.51 -2.49 (m, 1 H), 2.20-2.1 8 (m, 1 H), 2.06-2.00 (m, 2H), and
3-(benzo[b]thiophen-2-yl)-4-phenyl-4H- 1 '-azaspiro[[ 1 ,2,4]oxadiazole-5 ,3 '- bicyclo[2.2.2]octane]-enantiomer2 hydrochloride (compound 35b) (46 mg, 39% yield) as a white solid: cSFC analytical tR: 2.5 min., purity: 99.5%; LCMS (F): 1.42 min., 376.2 m/z (M+l); Ή- NMR (CD3OD, 400 MHz): δ 7.85-7.83 (d, J = 8 Hz, 1 H), 7.70-7.68 (d, J = 7.6 Hz, 1 H), 7.60 (s, 2H), 7.49 (s, 2H), 7.42-7.33 (m, 4H), 3.70-3.66 (dd, J = 14.8 Hz, 1 H), 3.53-3.49 (m, 1 H), 3.46- 3.41 (m, 2H), 3.26-3.21 (m, 2H), 2.69 (s, 1 H), 2.51 -2.48 (m, 1 H), 2.23-2.18 (m, 1 H), 2.06-2.00 (m, 2H);
cSFC analytical conditions: Column: Chiralpak AD-3 100 x 4.6 mm, I.D., 3 μιη; Mobile phase: 40% methanol (0.05% DEA) in C02; Flow rate: 3.0 mL/min.; Back pressure: 120 bar.
[00698] Example 31 - (+/-)-4-benzyl-3-(,4-chlorophenyl)-4H-l '-azaspirorri .2,41oxadiazole- 5,3'-bicvclor2.2.21octanel (36)
Figure imgf000171_0001
36
[00699] To a mixture of compound B-101 (500 mg, 3.2 mmol) and compound C-107 (680 mg, 3.2 mmol) in dichloromethane (5 mL) was added 10% aqueous sodium hypochl orite (4.8 g, 6.4 mmol) at 0 °C. The mixture was stirred at room temperature overnight. On completion, the reaction was quenched by sodium sulfite and organics were extracted with dichloromethane (3 x 30 mL). The combined organics were washed with water and brine, dried over anhydrous sodium sulfate, concentrated and purified by prep-HPLC [Instrument: GX-C; Column: Phenomenex Gemini CI 8 150*30 mm; Mobile phase: 48-78% acetonitrile in H20 (0.05% ammonia, v/v)] to afford racemate 36 (60 mg, 6% yield), a mixture of (R)-4-benzyl-3-(4-chlorophenyl)-4H-l '- azaspiro[[l,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane] and (S)-4-benzyl-3-(4-chlorophenyl)-4H-l '- azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane], as a white solid.
[00700] Chiral Separation:
[00701] A solution of racemate 36 (120 mg, 0.32 mmol) in methanol (5 mL) was separated by SFC (Instrument: SFC-80-A; Column: AD-10 μπι; Mobile phase: 50% EtOH in C02) at room temperature. Each set of collected fractions were dissolved in deionized water and adjusted to pH=3~5 by 0.2 mol/L aqueous hydrochloric acid respectively. Each solution was then subjected to lyophilization to give:
4-benzyl-3-(4-chlorophenyl)-4H- -azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane]- enantiomerl hydrochloride (compound 36a) (15.4 mg, 13% yield): cSFC analytical tR: 1.59 min., purity: 97.9%; LCMS (F): 1.35 min., 368.2 m/z (M+l ); Ή-NMR (CD3OD, 400 MHz): δ 7.64-7.62 (d, J=8.4 Hz, 2H), 7.49-7.47 (d, J=8.8 Hz, 2H), 7.35-7.32 (t, J=7.2 Hz, 2H), 7.28-7.24 (t, J=7.2 Hz, I H), 7.20-7.18 (d, J=7.2 Hz, 2H), 4.80-4.64 (m, 2H), 3.89-3.85 (d, J=14.4 Hz, I H), 3.70-3.66 (d, J=14.0 Hz, I H), 3.45-3.33 (m, 4H), 2.57 (s, I H), 2.44 (m, IH), 2.16 (m, I H), 2.06- 1.92 (m, 2H), and
4-benzyl-3-(4-chlorophenyl)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane]- enantiomer2 hydrochloride (compound 36b) (17.2 mg, 14% yield) as a white solid: cSFC analytical tR: 2.32 min., purity: 97.1 %; LCMS (F): 1.35 min., 368.2 m/z (M+l); Ή-NMR (CD3OD, 400 MHz): δ 7.64-7.62 (d, J=8.4 Hz, 2H), 7.49-7.47 (d, J=8.0 Hz, 2H), 7.35-7.31 (t, J=7.2 Hz, 2H), 7.28-7.24 (t, J=8.4 Hz, I H), 7.20-7.18 (d, J=7.6 Hz, 2H), 4.80-4.64 (m, 2H), 3.89- 3.86 (d, J-14.4 Hz, IH), 3.69-3.66 (d, J=lHz, I H), 3.45-3.33 (m, 4H), 2.57 (s, I H), 2.44 (m, I H), 2.17 (m, I H), 2.05-1.95 (m, 2H); cSFC analytical conditions: Column: Chiralpak AD-3 100 x 4.6 mm, I.D., 3 μιη; Mobile phase:
50% ethanol (0.05% DEA) in C02; Flow rate: 3.0 mL/min.
[00702] Example 32 - (+/-)-3-(benzorblthiophen-2-yl)-4-benzyl-4H-r-
Figure imgf000172_0001
B-102 37
[00703] To a mixture of compound B-102 (500 mg, 2.82 mmol) and compound C-107 (603 mg, 2.82 mmol) in dichloromethane (15 mL) was added sodium hypochlorite (10% aq) (4.23 g, 5.64 mmol) at 0 °C. The mixture was then stirred from 0 °C to room temperature overnight. On completion, the reaction was quenched by sodium sulfite and organics were extracted with dichloromethane (3 x 30mL). The combined organics were washed with water and brine, dried over anhydrous sodium sulfate, concentrated and purified by prep-HPLC [Instrument: GX-C; Column: Phenomenex Gemini CI 8 150x30 mmx5 μπι; Mobile phase: 55%-85% acetonitrile in H20 (0.05% ammonia v/v)] to afford racemate 37 (90 mg, 8% yield), a mixture of (R)-3- (benzo[b]thiophen-2-yl)-4-benzyl-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane] and (S)-3-(benzo[b]thiophen-2-yl)-4-benzyl-4H-l '-azaspiro[[l ,2,4]oxadiazole-5)3'- bicyclo[2.2.2]octane], as a white solid.
[00704] Chiral Separation:
[00705] A solution of racemate 37 (90 mg, 0.23 mmol) was separated by SFC (Instrument: SFC-80-A; Column: Chiralpak AD-H 250x25 mm I.D., 10 μιη; Mobile phase: 50% EtOH in C02 with 0.01 % NH3 ¾0) at room temperature. Each set of collected fractions were concentrated at room temperature to give free base 3-(benzo[b]thiophen-2-yl)-4-benzyl-4H-l '- azaspiro[(l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane]-enantiomerl and 3-(benzo[b]thiophen-2- yl)-4-benzyl-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane]-enantiomer2. Each free base was dissolved in deionized water and the pH was adjusted to 3-5 by 0.2 mol/L aqueous hydrochloric acid. Each solution was then subjected to lyophilization to give:
3-(benzo[b]thiophen-2-yl)-4-benzyl-4H- l '-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane]-enantiomerl hydrochloride (compound 37a) (30.1 mg, 31 % yield) as a white solid: cSFC analytical tR: 1.82 min., purity: 98.7%; LCMS (J): 3.07 min., 390.1 m/z (M+l); Ή-NMR (CD3OD, 400 MHz): δ 7.92-7.84 (m, H=3), 7.47-7.28 (m, H=7), 5.06-5.02 (d, J = 18 Hz ,1H), 4.81 (s, 1 H), 3.91-3.88 (d, J = 14.8 Hz, 1H), 3.73-3.69 (d, J = 14.4 Hz, 1 H), 3.44-3.37 (m, 3H), 3.26 (m, 1H), 2.60 (s, 1H), 2.46-2.42 (m, 1H), 2.15-2.12 (m, 1 H), 2.06-1.95 (m, 2H), and 3-(benzo[b]thiophen-2-yl)-4-benzyl-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane]-enantiomer2 hydrochloride (compound 37b) (22.2 mg, 23% yield) as a white solid: cSFC analytical tR: 2.73 min., purity: 98.5%; LCMS (J): 3.07 min, 390.2 m/z (M+1 ); Ή-NMR (CD3OD, 400 MHz): δ 7.92-7.84 (m, 3H), 7.47-7.28 (m, 7H), 5.06-5.02 (d, J = 18 Hz ,1 H), 4.80 (s, I H), 3.92-3.88 (d, J = 14.8 Hz, IH), 3.74-3.69 (d, J = 14.8 Hz, I H), 3.50-3.37 (m, 3H), 3.33-3.26 (m, I H), 2.60 s, IH), 2.47-2.42 (m, IH), 2.15-2.13 (m, I H), 2.06-1.95 (m, IH); cSFC analytical conditions: Column: Chiralpak AD-3 100 x 4.6 mm, I.D, 3 μπι; Mobile phase: 50% ethanol (0.05% DEA) in C02; Flow rate: 3.0 mL/min.
[00706] Example 33 - (+/-)-3-(benzorb1thiophen-2-yl)-4-isopropyl-4H-l '- azaspiro[[l ,2,41oxadiazole-5 J'-bicyclor2.2.2"|octane1 (38)
Figure imgf000173_0001
[00707] To a mixture of compound B-102 (3.4 g, 0.019 mol) and compound C-103 (4.8 g, 0.029 mol) in dichloromethane (200 mL) was added 10% aqueous sodium hypochlorite (57 g, 0.077 mol) slowly at 0 °C and the reaction was stirred at room temperature for 6 hours. The reaction was then filtered and the resulting filtrate was concentrated and the residue purified by prep-HPLC [Instrument: Shimadzu pump LC-20A; Column: GEMINI 250*50 mm, particle size: 10 μιη; Mobile phase: 45-65% acetonitrile in H20 (add 1% NH3 H20, v/v)] to racemate 38 (1.5 g, 23% yield), a mixture of (R)-3-(benzo[b]thiophen-2-yl)-4-isopropyl-4H-l '- azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane] and (S)-3-(benzo[b]thiophen-2-yl)-4- isopropyl-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane], as a white solid.
[00708] Chiral Separation:
[00709] A solution of racemate 38 (0.15 g, 0.44 mmol) in methanol (3 mL) was separated by SFC (Instrument: SFC 80; Column: Chiralpak AD-H 250x25 mm I.D., 10 μιη; Mobile phase: 60 ethanol (0.01% NH3 H20) in C02) at room temperature. Each set of collected fractions were concentrated under reduced pressure at 0 °C and purified by prep-HPLC [Instrument: GX-E; Column: Agella Venusil ASB C18 150*21.2 mm*5 μπι; Mobile phase: 18-48% acetonitrile in H20 (add 0.5% HC1, v/v)] to give:
3-(benzo[b]thiophen-2-yl)-4-isopropyl-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane]-enantiomerl hydrochloride (compound 38a) (30.1 mg, 20% yield): cSFC analytical tR: 1.59 min., purity: 100.0%; LCMS (E): 1.60 min, 342.1 m/z (M+1 ); Ή-NMR (CD3OD, 400 MHz): δ 7.95-7.91 (m, 2H), 7.81 (s, IH), 7.49-7.43 (m, 2H), 4.14-4.10 (d, J=13.6 Hz, IH), 3.90-3.83 (m, I H), 3.77-3.73 (d, J=14.4 Hz, IH), 3.54-3.38 (m, 4H), 2.50 (s, IH), 2.39- 2.36 (m, 1H), 2.23-2.20 (m, 1 H), 2.14-2.10 (m, 1H), 1.99-1.96 (m, 1H) , 1.31-1.29 (d, J = 6.8 Hz, 3H) , 1.26-1.24 (d, J = 7.2 Hz, 3H), and
3-(benzo[b]thiophen-2-yl)-4-isopropyl-4H-r-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane]-enantiomer2 hydrochloride (compound 38b) (28.5 mg, 19% yield) as a white solid: cSFC analytical tR: 2.78 min., purity: 99.2%; LCMS (E): 1.61 min., 342.1 m/z (M+1); Ή-NMR (CD3OD, 400 MHz): δ 7.95-7.91 (m, 2H), 7.81 (s, 1H), 7.49-7.43 (m, 2H), 4.15- 4.1 1 (dd, Jl=14.4 Hz, J2=1.6 Hz, 1 H), 3.89-3.85 (m, 1 H), 3.78-3.74 (dd, Jl=14.4 Hz, J2=2.0 Hz, 1H), 3.51-3.38 (m, 4H), 2.50 (s, 1 H), 2.37-2.36 (m, 1H), 2.23-2.20 (m, 1H), 2.14-2.1 1 (m, 1 H), 1.99-1.96 (m, 1H) , 1.31-1.29 (d, J = 7.2 Hz, 3H) , 1.26-1.24 (d, J = 7.2 Hz, 3H);
cSFC analytical conditions: Column: Chiralpak AD-3 100 x 4.6 mm, I.D., 3 μιη; Mobile phase: 40% ethanol (0.05% DEA) in C02; Flow rate: 3.0 mL/min.
[00710] Example 34 - (+/-V3-(benzorblthiophen-2-yl)-4-isobutyl-4H-r- azaspiro[|~h2,4"|oxadiazole-5,3'-bicyclo["2.2.2"[octaneT (39)
Figure imgf000174_0001
[00711] To a solution of compound B-102 (0.1 g, 0.56 mmol) and compound C-104 (0.15 g, 0.85 mmol) in dichloromethane (3 mL) was added 10% aqueous sodium hypochlorite (0.8 g, 1.12 mmol) slowly at 0 °C. The reaction mixture was then stirred at room temperature for 2 hours before being filtered. The filtrate was concentrated and the resulting residue was purified by prep- HPLC [Instrument: GX-E; Column: Agella Venusil ASB C18 150*21.2 mm*5 μιη; Mobile phase: 18-48% acetonitrile in H20 (add 0.5% HCI, v/v)] to give racemate 39 (30 mg, 15% yield), a mixture of HCI salts of (R)-3-(benzo[b]thiophen-2-yl)-4-isobutyl-4H-l '- azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane] and (S)-3-(benzo[b]thiophen-2-yl)-4- isobutyl-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane], as a white solid: LCMS (E): 0.73 min., 356.1 m/z (M+1); Ή-NMR (CD3OD, 400 MHz): δ 7.97-7.94 (m, 2H), 7.90 (s, 1H), 7.51 -7.46 (m, 2H), 4.04-4.00 (m, 1H), 3.79-3.73 (m, 2H), 3.49-3.41 (m, 4H), 3.30-3.26 (m, 1H), 2.54 (s, 1H), 2.44-2.39 (m, 1H), 2.19-2.10 (m, 2H) , 1.98-1.94 (m, 1 H), 1.71-1.64 (m, 1 H), 0.90- 0.83 (m, 6H).
[00712] Example 35 - (+/-)-3-(benzorblthiophen-2-vn-4-r(tetrahvdro-2H-pyran-4-yl)methvn- 4H-r-azaspiro [l ,2,41oxadiazole-5,3'-bicyclo 2.2.21octanel hydrochloride (40)
Figure imgf000175_0001
[00713] To a mixture of compound B-102 (0.5 g, 2.82 mmol) and compound C-106 (0.94 g, 4.23 mmol) in dichloromethane (20 mL) was slowly added 10% aqueous sodium hypochlorite (4.0 g, 5.64 mmol) at 0 °C. The reaction mixture was then stirred at room temperature for 4 hours before being filtered. The filtrate was concentrated and the resulting residue was purified by prep- HPLC [Instrument: GX-E; Column: Agella Venusil ASB CI 8 150*21.2 mm*5 μιη; Mobile phase: 18-48% acetonitrile in H20 (add 0.5% HCl, v/v)] to give racemate 40 (20 mg, 18% yield), a mixture of HCl salts of (R)-3-(benzo[b]thiophen-2-yl)-4-((tetrahydro-2H-pyran-4-yl)methyl)-4H- -azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane] hydrochloride and (S)-3- (benzo[b]thiophen-2-yl)-4-((tetrahydro-2H-pyran-4-yl)methyl)-4H-l '-azaspiro[[l ,2,4]oxadiazole- 5,3'-bicyclo[2.2.2]octane] hydrochloride, as a white solid: LCMS (H): 1 .68 min., 398.1 m/z (M+l); Ή-NMR (CD3OD, 400 MHz): δ 7.96-7.91 (m, 3H), 7.49-7.46 (m, 2H), 4.04-4.00 (m, 1 H), 3.82-3.74 (m, 4H), 3.61-3.56 (m, 1 H), 3.43-3.35 (m, 4H), 3.28-3.20 (m, 2H), 2.52 (s, 1 H), 2.38-2.36 (m, 1 H), 2.18-2.08 (m, 2H), 1.96-1.93 (m, 1 H), 1.62-1.49 (m, 3H) , 1 .22-1.08 (m, 2H).
[00714] Example 36 - (+/-)-3-(benzorblthiophen-2-vn-4-(pyridin-3-ylmethvn-4H-l '-
Figure imgf000175_0002
41
[00715] To a mixture of compound B-102 (1.0 g, 5.64 mmol) and compound C-109 (1.8 g, 8.46 mmol) in dichloromethane (50 mL) was slowly added 10% aqueous sodium hypochlorite (16.7 g, 22.56 mmol) at 0 °C. The reaction mixture was then stirred at room temperature for 4 hours before being filtered. The filtrate was concentrated and the resulting residue was purified by prep-HPLC [Instrument: GX-E; Column: Agella Venusil ASB CI 8 150*21.2 mm*5 μιη; Mobile phase: 18-48% acetonitrile in H20 (add 0.5% HCl, v/v)] to give racemate 41 (155 mg, 7% yield), a mixture of HCl salts of (R)-3-(benzo[b]thiophen-2-yl)-4-(pyridin-3-ylmethyl)-4H-l '- azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane] and (S)-3-(benzo[b]thiophen-2-yl)-4- (pyridin-3-ylmethyl)-4H- -azaspiro[[l ,2,4]oxadiazole-5,3'-bicyc]o[2.2.2]octane], as a yellow solid: LCMS (E): 1.25 min., 391.1 m/z (M+l); Ή-NMR (CD3OD, 400 MHz): δ 8.57-8.55 (m, 2H), 8.06-8.04 (m, I H), 7.90-7.87 (m, 3H), 7.70-7.67 (m, IH), 7.47-7.39 (m, 2H), 5.24-5.20 (d, J = 18.4 Hz, I H), 5.04-4.99 (d, J = 18.4 Hz, IH), 4.02-3.98 (m, IH), 3.82-3.78 (m, I H), 3.51 -3.41 (m, 4H), 2.65 (s, I H), 2.49-2.43 (m, IH), 2.16-2.07 (m, 2H) , 2.01 -1 .99 (m, IH).
[00716] Example 37 - (+/-~)-3-Cbenzorblthiophen-2-yl')-4-ethyl-4H-l l- azaspiro[[ 1 ,2,41oxadiazole-5,3'-bic clo 2.2.2 octane 42
Figure imgf000176_0001
[00717] To a mixture of compound B-102 (1.0 g, 5.65 mmol) and compound C-102 (0.7 g, 4.6 mmol) in dichloromethane (25 mL) was slowly added 10% aqueous sodium hypochlorite (14 g, 18.4 mmol) at 0 °C. The reaction mixture was then stirred at room temperature for 4 hours before being filtered. The filtrate was concentrated and the resulting residue was purified by prep- HPLC [Instrument: GX-E; Column: Agella Venusil ASB CI 8 150*21.2 mm*5 μπι; Mobile phase: 18-48% acetonitrile in H20 (add 0.5% HCI, v/v)] to give racemate 42 (60 mg, 5% yield), a mixture of HCI salts of (R)-3-(benzo[b]thiophen-2-yl)-4-ethyl-4H-l'-azaspiro[[l,2,4]oxadiazole- 5,3'-bicyclo[2.2.2]octane] and (S)-3-(benzo[b]thiophen-2-yl)-4-ethyl-4H-l '- azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane], as a yellow solid: LCMS (G): 2.70 min., 328.1 m/z (M+l ); Ή-NMR (CD3OD, 400 MHz): δ 7.93-7.90 (m, 2H), 7.82 (s, I H), 7.47-7.41 (m, 2H), 3.84-3.75 (m, I H), 3.49-3.38 (m, 2H), 3.12-3.08 (m, I H), 2.96-2.87 (m, 4H), 2.16-2.10 (m, 2H), 1.95-1.93 (m, IH), 1.72-1.68 (m, IH), 1.59-1.56 (m, IH), 1.05-1.02 (t, J = 7.2 Hz, 3H).
[00718] Example 38 - (+/-)-3-(benzorblthiophen-2-vn-4-r2.2.2-trifluoroethvn-4H-l '- azaspiro[ri,2,4]oxadiazole-5,3'-bic clo 2.2.2 octanel 43
Figure imgf000176_0002
43
[00719] To a mixture of compound B-102 (0.93 g, 5.23 mmol) and compound C-105 (0.9 g, 4.36 mmol) in dichloromethane (25 mL) was added 10% aqueous sodium hypochlorite (12.9 g, 17.44 mmol) dropwise at 0 °C. The reaction mixture was then stirred at room temperature for 6 hours before being filtered. The filtrate was concentrated and the resulting residue was purified by prep-HPLC [Instrument: HPLC-D; Column: GEMINI 200*50mm, 10 μηι; Mobile phase: 40-70% acetonitrile in H20 (add 0.5% NH3 H20, v/v)] to give racemate 43 (170 mg, 1 1 % yield), a mixture of (R)-3-(benzo[b]thiophen-2-yl)-4-(2,2,2-trifluoroethyl)-4H-l '- azaspiro[[l,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane] and (S)-3-(benzo[b]thiophen-2-yl)-4-(2,2,2- trifluoroethyl)-4H-r-azaspiro[[l,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane], as a white solid: LCMS (G): 0.69 min., 382.1 m/z (M+l); Ή-NMR (DMSO-d6, 400 MHz): δ 8.05-8.02 (m, 2H),
7.96- 7.93 (m, 1 H), 7.50-7.44 (m, 2H), 4.63-4.52 (m, 1 H), 4.49-4.40 (m, 1 H), 3.47-3.43 (s, 1 H),
2.97- 2.90 (m, 1 H), 2.79-2.62 (m, 3H), 2.00 (s, 1 H), 1 .90-1 .88 (m, 1 H), 1 .68-1 .66 (m, 1 H), 1 .54- 1 .41 (m, 3H).
[00720] Example 39 - (+/-)-3-(4-chlorophenyl)-4-methyl-4H-r-azaspiro[[L2,41 oxadiazole- 5,3'-bicyclo[2.2.21octanel (44)
I
Figure imgf000177_0001
44
[00721] A solution of compound B-101 (2.29 g, 0.014 mol) and compound C-101 ( 1 .0 g, 0.014 mol) in dichloromethane (10 mL) was cooled to 0 °C. Then sodium hypochlorite (2.09 g, 0.028 mol) was added slowly and stirred at room temperature for 3 hours. On completion, organics were extracted with dichloromethane (3 10 mL). The combined organics were washed with brine, dried over anhydrous sodium sulfate, concentrated and purified by prep-HPLC
[Instrument: Shimadzu pump LC-20A; Column: GEMINI 150*30 mm, particle size: 5 μιη;
Mobile phase: 55-86% acetonitrile in H20 (add 1 % NH3 H20, v/v)] to afford racemate 44 (0.25 g, 6% yield), a mixture of (R)-3-(4-chlorophenyl)-4-methyl-4H-l'-azaspiro[[ 1 ,2,4] oxadiazole-5,3'- bicyclo[2.2.2]octane] and (S)-3-(4-chlorophenyl)-4-methyl-4H-l '-azaspiro[[l,2,4] oxadiazole- 5,3'-bicyclo[2.2.2]octane], as a white solid.
[00722] Chiral Separation:
[00723] A solution of racemate 44 (0.20 g, 0.7 mmol) in ethanol (5 mL) was separated by SFC (Instrument: SFC 80; Column: Chiralpak OD 250x25 mm I.D., 5 μπι; Mobile phase: 40% iso-propanol (0.01 % NH3 H20) in C02) at room temperature. Each set of collected fractions were concentrated under reduced pressure at room temperature. Then, to each sample, 0.2 N hydrochloric acid aqueous solution was added quickly until pH=5 was reached. Each sample was then subjected to lyophiliation to give:
3-(4-chlorophenyl)-4-methyl-4H-l '-azaspiro[[l,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane]- enantiomerl hydrochloride (compound 44a) (14.9 mg, 8% yield) as a white solid: cSFC analytical tR: 2.94 min„ purity: 93.7%; LCMS (E): 1.60 min., 292.1 m/z (M+l); Ή-NMR (CD3OD, 400 MHz): δ 7.66-7.64 (d, J=8.4 Hz, 2H), 7.59-7.57 (d, J=8.8 Hz, 2H), 4.03-3.99 (m, 1H), 3.67-3.63 (m, 1 H), 3.51-3.39(m, 4H), 3.02 (s, 3H), 2.59 (s, 1H), 2.46-2.41 (m, 1H), 2.30- 2.27 (m, 1H), 2.17-2.13 (m, 1H), 1.99-1.93 (m, 1H), and
3-(4-chlorophenyl)-4-methyl-4H-l'-azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane]- enantiomer2 hydrochloride (compound 44b) (12.9 mg, 7% yield) as a purple solid: cSFC analytical tR: 3.24 min., purity: 93.6%; LCMS (E): 1.70 min., 292.1 m/z (M+l); Ή-NMR (CD3OD, 400 MHz): δ 7.66-7.64 (d, J=8.8 Hz, 2H), 7.59-7.57 (d, J=8.4 Hz, 2H), 4.02-3.99 (m, 1 H), 3.67-3.63 (m, 1H), 3.50-3.39 (m, 4H), 3.01 (s, 3H), 2.59 (s, 1H), 2.45-2.42 (m, 1 H), 2.30- 2.25 (m, 1H), 2.17-2.13 (m, 1 H), 2.01-1.95 (m, 1H);
cSFC analytical conditions: Column: Chiralpak OD-3 150 x 4.6 mm, I.D., 3 μπι; Mobile phase: 40% isopropanol (0.05% DEA) in C02; Flow rate: 2.8 mL/min.
[00724] Example 40 - (+/-V3-fbenzorblthiophen-2-ylV4-methyl-4H-r- azaspiro[[l,2,41oxadiazole-5 3'-bicyclo[2.2.2]octanel (45)
Figure imgf000178_0001
[00725] A solution of compound B-102 (2.5 mg, 0.014 mol) and compound C-101 (2.9 mg, 0.021 mol) in dichloromethane (30 mL) was cooled to 0 °C. Then sodium hypochlorite (2.0 g, 0.028 mol) was added slowly and the reaction was stirred at room temperature for 3 hours. On completion, organics were extracted with dichloromethane (3 x 10 mL). The combined organics were washed with brine, dried over anhydrous sodium sulfate, concentrated and purified by prep- HPLC [Instrument: Shimadzu pump LC-20A; Column: GEMINI 250*50 mm, particle size: 10 μιη; Mobile phase: 5-30% acetonitrile in H20 (add 1% NH3 H20, v/v) ] to afford racemate 45 (0.25 mg, 6% yield), a mixture of (R)-3-(benzo[b]thiophen-2-yl)-4-methyl-4H-l - azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane] and (S)-3-(benzo[b]thiophen-2-yl)-4- methyl-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane], as a white solid.
[00726] Chiral Separation:
[00727] A solution of racemate 45 (0.25 g, 0.8 mmol) in ethanol (5 ml) was separated by SFC (Instrument: SFC 80; Column: Chiralpak AD-H 250x25 mm I.D., 10 μπι; Mobile phase: 60 ethanol (0.01% NH3 H20) in C02) at room temperature. Each set of collected fractions were concentrated at room temperature, the residues were treated with 0.2 N hydrochloric acid aqueous solution to pH = 3-5 and each was then subjected to lyophilization to give: 3-(benzo[b]thiophen-2-yl)-4-methyl-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane]-enantiomerl hydrochloride (compound 45a) (90 mg, 36% yield) as a white solid: cSFC analytical tR: 1.34 min., purity: 97.9%; LCMS (E): 1.72 min., 314.1 m/z (M+l ); Ή- NMR (CD3OD, 400 MHz): δ 7.95-7.93 (m, 2H), 7.87 (s, 1 H), 7.50-7.44 (m, 2H), 4.04-4.00 (m, 1H), 3.69-3.65 (m, 1 H), 3.50-3.41 (m, 4H), 3.24 (s, 3H), 2.60 (s, 1H), 2.46-2.41 (m, 1H), 2.30-
2.27 (m, 1 H), 2.17-2.14 (m, 1 H), 1.98-1 .95 (m, lH), and
3-(benzo[b]thiophen-2-yl)-4-methyl-4H-l '-azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane]-enantiomer2 hydrochloride (compound 45b) (99 mg, 40% yield) as a white solid: cSFC analytical tR: 1.70 min., purity: 100.0%; LCMS (E): 1.71 min., 314.1 m/z (M+l ); Ή- NMR (CD3OD, 400 MHz): δ 7.97-7.94 (m, 2H), 7.88 (s, 1H), 7.51-7.45 (m, 2H), 4.06-4.02 (m, 1H), 3.71-3.66 (m, 1 H), 3.53-3.41 (m, 4H), 3.25 (s, 3H), 2.61 (s, 1H), 2.48-2.42 (m, 1H), 2.32-
2.28 (m, 1 H), 2.19-2.15 (m, 1H), 2.00-1.96 (m, 1 H);
cSFC analytical conditions: Column: Chiralpak AD-3 100 x 4.6 mm, I.D., 3 μιη; Mobile phase: 60% ethanol (0.05% DEA) in C02; Flow rate: 3.0 mL/min.
[00728] Example 41 - (+/-)-3-(benzofuran-2-yl)-4-methyl-4H-l'-azaspiro[rK2,41oxadiazole-
Figure imgf000179_0001
46
[00729] The solution of compound B-104 (100 mg, 0.62 mmol) and compound C-101 (129 mg, 0.93 mmol) in dichloromethane (5 mL) was cooled to 0 °C. Then sodium hypochlorite (920 mg, 1.24 mmol) was added slowly and stirred at room temperature for 3 hours. On completion, organics were extracted with dichloromethane (3 x 10 mL). The combined organics were washed with brine, dried over anhydrous sodium sulfate, concentrated and purified by prep-HPLC
[Instrument: Shimadzu pump LC-20A; Column: GEMINI 250*50 mm, particle size: 10 μπι;
Mobile phase: 30-55% acetonitrile in H20 (add 1% NH3 H20, v/v)] to afford racemate 46 (80 mg, 43% yield), a mixture of (R)-3-(benzofuran-2-yl)-4-methyl-4H-l '-azaspiro[[l ,2,4]oxadiazole- 5,3'-bicyclo[2.2.2]octane] and (S)-3-(benzofuran-2-yl)-4-methyl-4H-l '- azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane], as a white solid.
[00730] Chiral Separation:
[00731] A solution of racemate 46 (100 mg, 0.34 mmol) in ethanol (5 ml) was separated by SFC (Instrument: SFC 80; Column: Chiralpak OD-H 250x25 mm I.D., 10 μπι; Mobile phase: 25% methanol (0.01% NH3 H20) in C02) at room temperature. Each set of collected fractions were concentrated at room temperature, the residues were treated with 0.2 N hydrochloric acid aqueous solution to pH = 3~5 and each was then subjected to lyophilization to give:
3-(benzofuran-2-yl)-4-methyl-4H-l'-azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane]-enantiomerl hydrochloride (compound 46a) (40 mg, 40% yield) as a white solid: cSFC analytical tR: 2.20 min., purity: 95.0%; LCMS (E): 0.74 min., 298.1 m/z (M+l); Ή- NMR (CD3OD, 400 MHz ): δ 7.76-7.74 (d, J = 8.0 Hz, 1H), 7.62-7.60 (d, J = 8.0 Hz, 1H), 7.49- 7.47 (m, 2H), 7.45 (s, 2H), 7.38-7.34 (t, J = 7.6 Hz, 1 H), 4.07-4.02 (dd, Jl = 14.8 Hz, J2 = 2.0 Hz, 1H), 3.69-3.65 (dd, Jl = 14.0 Hz, J2 = 2.0 Hz, 1H), 3.52-3.42 (m, 4H), 3.30 (s, 3H), 2.62 (s, 1 H), 2.48-2.42 (m, 1H) , 2.31-2.27 (m, 1H), 2.19-2.15 (m, 1 H), 1.99-1.96 (m, 1 H), and
3-(benzofuran-2-yl)-4-methyl-4H-l'-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane]-enantiomer2 hydrochloride (compound 46b) (40 mg, 40%) as a white solid: cSFC analytical tR: 2.40 min., purity: 94.3%; LCMS (E): 0.74 min., 298.1 m/z (M+l); Ή- NMR (CD3OD, 400 MHz ): δ 7.76-7.74 (d, J = 7.6 Hz, 1H), 7.62-7.60 (d, J = 8.4 Hz, 1H), 7.49- 7.47 (m, 2H), 7.45 (s, 2H), 7.38-7.34 (t, J = 7.6 Hz, 1H), 4.07-4.03 (m, 1H), 3.69-3.65 (dd, Jl = 14.4 Hz, J2 = 2.0 Hz, 1H), 3.52-3.42 (m, 4H), 3.30 (s, 3H), 2.62 (s, 1 H), 2.48-2.43 (m, 1 H) , 2.31 - 2.28 (m, 1H), 2.19-2.15 (m, 1H), 1.99-1.96 (m, 1 H);
cSFC analytical conditions: Column: Chiralpak OD-3 100 x 4.6 mm, I.D., 3 μιη; Mobile phase: 5% to 40% ethanol (0.05% DEA) in C02; Flow rate: 3.0 mL/min.
[00732] Example 42 - (+/-)-3-(7-chlorobenzo[blthiophen-2-yl)-4-methyl-4H-l '-azaspiro rn,2,41oxadiazole- '-bicvclor2.2.21octanel (47)
Figure imgf000180_0001
47
[00733] A solution of compound B-109 (1 g, 4.74 mmol) and compound C-101 (1.3 g, 9.48 mmol) in dichloromethane (5 mL) was cooled to 0 °C. Then sodium hypochlorite (10.5 g, 14.22 mmol) was added slowly and stirred at room temperature for 3 hours. On completion, organics were extracted with dichloromethane (3 10 mL). The combined organics were washed with brine, dried over anhydrous sodium sulfate, concentrated and purified by prep-HPLC [Instrument: Shimadzu pump GX-B; Column: GEMINI 150*30 mm, particle size: 4 μιη; Mobile phase: 14-44% acetonitrile in H20 (add 0.7% HC1, v/v)] to afford racemate 47 (200 mg, 13% yield), a mixture of HC1 salts of (R)-3-(7-chlorobenzo[b]thiophen-2-yl)-4-methyl-4H-l '-azaspiro [[l ,2,4]oxadiazole- 5,3'-bicyclo[2.2.2]octane] and (S)-3-(7-chlorobenzo[b]thiophen-2-yl)-4-methyl-4H-l '-azaspiro [[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane], as a white solid. [00734] Chiral Separation:
[00735] A solution of racemate 47 (100 mg, 0.29 mmol) in ethanol (10 ml) was separated by SFC (Instrument: SFC 80; Column: Chiralpak AD-H 250x25 mm I.D., 10 μηι; Mobile phase: 50% ethanol (0.01% NH3 H20) in C02) at room temperature. Each set of collected fractions were concentrated at room temperature, the residues were treated with 0.2 N hydrochloric acid aqueous solution to pH = 3~5 and each was then subjected to lyophilization to give:
3-(7-chlorobenzo[b]thiophen-2-yl)-4-methyl-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane]-enantiomerl hydrochloride (compound 47a) (42 mg, 42% yield) as a white solid: cSFC analytical tR: 2.2 min., purity: 96.6%; LCMS (E): 1.60 min., 348.0 m/z (M+l ); Ή- NMR (CD3OD, 400 MHz ): δ 7.97 -7.91 (m, 2H), 7.54-7.47 (m, 2H), 4.08-4.04 (dd, J = 14.8 Hz, J = 2.0 Hz, 1 H), 3.71-3.67 (dd, J = 14.8 Hz, J = 2.0 Hz, 1H), 3.52-3.43 (m, 4H), 3.26 (s, 3H), 2.61 (s, 1 H), 2.48-2.44 (m, 1H), 2.32-2.28 (m, 1H), 2.19-2.15 (m, 1 H) , 2.00-1.97 (m, 1 H), and
3-(7-chlorobenzo[b]thiophen-2-yl)-4-methyl-4H-l '-azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane]-enantiomer2 hydrochloride (compound 47b) (41 mg, 41%) as a white solid: cSFC analytical tR: 3.2 min., purity: 99.6%; LCMS (E): 1.65 min., 348.0 m/z (M+l ); Ή- NMR (CD3OD, 400 MHz ): δ 7.96 -7.91 (m, 2H), 7.54-7.47 (m, 2H), 4.08-4.03 (dd, J = 14.8 Hz, J = 2.0 Hz, 1H), 3.71-3.67 (dd, J = 14.4 Hz, J = 2.4 Hz, 1 H), 3.53-3.43 (m, 4H), 3.26 (s, 3H), 2.61 (s, 1 H), 2.47-2.44 (m, 1H), 2.31 -2.28 (m, 1H), 2.19-2.15 (m, 1H) , 2.00-1.97 (m, 1 H);
cSFC analytical conditions: Column: Chiralpak AD-3 100 x 4.6 mm, I.D., 3 μπι; Mobile phase: 40% ethanol (0.05% DEA) in C02; Flow rate: 1.2 mL/min.
[00736] Example 43 - (+/-)-3-(l H-indol-2-vn-4-methyl-4H-l '-azaspirorn .2.41oxadiazole- 5.3'-bicvclor2.2.21octane1 (48)
Figure imgf000181_0001
48
[00737] A solution of compound B-105 (1.5 g, 9.38 mmol) and compound C-101 (1.94 g, 14.06 mmol) in anhydrous dichloromethane (30 mL) was added tert-butyl hypochlorite (1.01 g, 9.38 mmol) at -50 °C. The mixture was stirred at -50 °C to room temperature for 6 hours. On completion, the reaction was quenched with sodium sulfite and organics were extracted with dichloromethane (3 x 10 mL). The combined organics were washed with brine, dried over anhydrous sodium sulfate, concentrated and purified by prep-HPLC [Instrument: HPLC-C;
Column: GEMINI 250x50 mm, particle size: 10 μπι; Mobile phase: 20-45% acetonitrile in H20 (add 1% TFA, v/v)] to afford racemate 48 (90 mg, 3% yield), a mixture of TFA salts of (R)-3- (lH-indol-2-yl)-4-methyl-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane] and (S)-3- (lH-indol-2-yl)-4-methyl-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane], as a yellow oil.
[00738] Chiral Separation:
[00739] A solution of racemate 48 (90 mg, 0.3 mmol) in ethanol (5 mL) was separated by SFC (Instrument: SFC 80; Column: Chiralpak AS-H 250^25 mm I.D., 10 μιη; Mobile phase: 50% ethanol (0.01% NH3 H20) in C02) at room temperature. Each set of collected fractions were concentrated at room temperature, the residues were treated with 0.2 N hydrochloric acid aqueous solution to pH = 3-5 and each was then subjected to lyophilization to give:
3-(l H-indol-2-yl)-4-methyl-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane]- enantiomerl hydrochloride (compound 48a) (28.7 mg, 29% yield) as a yellow semi-solid: cSFC analytical tR: 2.26 min., purity: 100.0%; LCMS (B): 0.62 min., 297.3 m/z (M+l ); Ή-NMR (CD3OD, 400 MHz): δ 7.65-7.63 (d, J=8.0 Hz, I H), 7.46-7.44 (d, J=8.0 Hz, I H), 7.27-7.23 (t, J=7.2 Hz, IH ), 7.12-7.08 (t, J=7.2 Hz, IH), 6.96 (s, I H), 3.88-3.84 (d, J=15.2 Hz, I H,), 3.48-3.44 (d, J=14.8 Hz, IH), 3.37 (s, IH), 3.29-3.27 (m, 3H), 3.24 (s, 3H), 2.48 (s, IH), 2.39-2.34 (m, IH), 2.23-2.18 (m, I H), 2.07-2.00 (m, I H), 1.86-1.81 (m, I H), and
3-(l H-indol-2-yl)-4-methyl-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane]- enantiomer2 hydrochloride (compound 48b) (31.2 mg, 31 % yield) as a yellow semi-solid: cSFC analytical tR: 2.82 min., purity: 99.2%; LCMS (B): 0.62 min., 297.2 m/z (M+l ); Ή-NMR (CD3OD, 400 MHz): δ 7.66-7.64 (d, J=8.0 Hz, IH), 7.47-7.44 (d, J=8.4 Hz, I H), 7.27-7.23 (t, J=8.0 Ηζ,Ι Η), 7.12-7.09 (t, J=7.6 Hz, IH), 6.98 (s, IH), 4.05-4.01 (dd, Jl=14.4 Hz, J2=1.6 Hz, IH), 3.68-3.64 (d, Jl=14.4 Hz, J2=2.4 Hz, IH), 3.51-3.43 (m, 4H), 3.26 (s, 3H), 2.59 (s, IH), 2.48-2.42 (m, IH), 2.32-2.27 (m, IH), 2.18-2.12 (m, I H), 2.01 -1.96 (m, I H);
cSFC analytical conditions: Column: Chiralpak AS-3 100 x 4.6 mm, I.D., 3 μπι; Mobile phase: 40% ethanol (0.05% DEA) in C02; Flow rate: 3.0 mL/min.
[00740] Example 44 - (+/-)-3-(7-fluorobenzofuran-2-yl)-4-methyl-4H-l '-azaspiro lTh2,4"loxadiazo -5,3'-bicyclo[2.2.2"|octane1 (49)
Figure imgf000182_0001
49
[00741] To a solution of compound B-119 and compound C-101 (1.33 g, 9.6 mmol) in dichloromethane (20 mL), sodium hypochlorite (0.95 g, 12.8 mmol) was added dropwise at 0 °C. The reaction was then stirred at ambient temperature for 2 hours. On completion, water was added into the reaction and organics were extracted with dichloromethane (3 10 mL). The combined organic layers were dried, concentrated under reduced pressure and the resulting residue was purified by prep-HPLC [Instrument: pre_HPLC-B; Column: GEMINI 250*50 mm, particle size: 10 μπι; Mobile phase: B 25-50% acetonitrile in H20 (add 1 % NH3 H20, v/v)] to give racemate 49 (0.3 g, 10 %), a mixture of (R)-3-(7-fluorobenzofuran-2-yl)-4-methyl-4H-l'-azaspiro
[[l,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane] and (S)-3-(7-fluorobenzofuran-2-yl)-4-methyl-4H- l'-azaspiro [[l,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane], as a solid.
[00742] Chiral Separation:
[00743] A solution of racemate 49 (300 mg, 0.95 mmol) in methanol (20 mL) was separated by SFC (Instrument: SFC 80; Column: Chiralpak AD-H 250x25 mm I.D., 10 μπι; Mobile phase: 50% methanol (0.01 % NH3 H20) in C02) at room temperature. Each set of collected fractions were concentrated at room temperature and subjected to lyophilization to give:
3-(7-fluorobenzofuran-2-yl)-4-methyl-4H-l'-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane]-enantiomerl hydrochloride (compound 49a) (77.0 mg, 26% yield) as a yellow solid: cSFC analytical tR: 1.339 min., purity: 100.0%; LCMS (E): 0.640 min., 316.2 m/z (M+1); Ή-NMR (CD3OD, 400 MHz): δ 7.58 - 7.52 (m, 2H), 7.34 (m, I H), 7.29 - 7.23 (m, I H), 4.04 (dd, J=2.0, 14.7 Hz, IH), 3.69 (dd, J=2.0, 14.8 Hz, I H), 3.58 - 3.36 (m, 4H), 3.30 (s, 3H), 2.64 (m, IH), 2.45 (m, , IH), 2.36 - 2.25 (m, I H), 2.16 (m, J= I H), 1.98 (m, J=m I H), and
3-(7-fluorobenzofuran-2-yl)-4-methyl-4H-l'-azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane]-enantiomer2 hydrochloride (compound 49b) (48.0 mg, 16% yield) as a white solid: cSFC analytical tR: 1.714 min., purity: 96.1 %; LCMS (B): 0.640 min., 316.2 m/z (M+1); Ή-NMR (CD3OD, 400 MHz): δ 7.58 - 7.52 (m, 2H), 7.34 (m, IH), 7.29 - 7.23 (m, I H), 4.04 (dd, J=2.0, 14.8 Hz, IH), 3.69 (dd, J=2.0, 14.8 Hz, IH), 3.58 - 3.36 (m, 4H), 3.30 (s, 3H), 2.64 (m, I H), 2.45 (m, IH), 2.36 - 2.25 (m, I H), 2.16 (m, I H), 1.98 (m, IH);
cSFC analytical conditions: Column: Chiralpak AD-H 250 x 4.6 mm, I.D., 5 μηι; Mobile phase: 40% methanol (0.05% DEA) in C02; Flow rate: 3.0 mL/min.; Back pressure: 120 bar.
[00744] Example 45 - (+/- )-3-(7-fluorobenzorblthiophen-2-vn-4-methyl-4H-l '-
Figure imgf000183_0001
50
[00745] To the solution of compound B-108 (1.2 g, 6.15 mmol) and compound C-101 (1.27 g, 9.22 mmol) in anhydrous dichloromethane (10 mL) was added dropwise 10% aqueous sodium hypochlorite (6.86 g, 9.22 mmol) at 0 °C. The reaction was stirred at room temperature for 2 hours. On completion, the reaction was quenched with aqueous sodium sulfite and the reaction was filtered. The resulting filtrate was washed with water and brine, dried over anhydrous sodium sulfate, concentrated in vacuo and the residue was purified by prep-HPLC [Instrument: Shimadzu pump LC-20A; Column: GEMINI 250x50 mm, particle size: 10 μιη; Mobile phase: 30-54% acetonitrile in H20 (add 1% NH3 H20, v/v)] to afford racemate 50 (1 10 mg, 5% yield), a mixture of (R)-3-(7-fluorobenzo[b]thiophen-2-yl)-4-methyl-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane] and (S)-3-(7-fluorobenzo[b]thiophen-2-yl)-4-methyl-4H-l'- azaspiro[[l,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane], as a white solid.
[00746] Chiral Separation:
[00747] A solution of racemate 50 (1 10 mg, 0.33 mmol) in MeOH (5 mL) was separated by SFC (Instrument: SFC 80; Column: Chiralpak OJ-3 250x25 mm I.D., 10 μπι; Mobile phase: 35% ethanol (0.01% NH3 H20) in C02) at room temperature. Each set of collected fractions were concentrated at room temperature before 0.2 mol/L aqueous hydrochloric acid was added to each until pH=5 was attained. The respective solutions were then subjected to lyophilization to give:
3-(7-fIuorobenzo[b]thiophen-2-yl)-4-methyl-4H-l '-azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane]-enantiomerl hydrochloride (compound 50a) (30.8 mg, 25% yield) as a white solid: cSFC analytical tR: 2.44 min., purity: 100.0%; LCMS (E): 1.52 min., 332.1 m/z (M+1); 1 H-NMR (CD3OD, 400 MHz): 57.96-7.95 (d, J=3.6 Hz, IH), 7.81-7.79 (d, J=8.0 Hz, I H), 7.52-7.47 (m, I H), 7.28-7.24(m, IH), 4.06-4.02 (m, I H), 3.72-3.67 (m, I H), 3.52-3.43 (m, 4H), 3.26 (s, 1H), 2.62 (s, I H) , 2.48-2.42 (m, I H) , 2.31-2.28 (m, I H) , 2.19-2.15 (m, I H) , 2.00-1 .96 (m, IH), and
3-(7-fluorobenzo[b]thiophen-2-yl)-4-methyl-4H-l'-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane]-enantiomer2 hydrochloride (compound 50b) (31 mg, 26% yield) as a white solid: cSFC analytical tR: 2.83 min., purity: 100.0%; LCMS (E): 1.54 min., 332.0 m/z (M+1 ); Ή- NMR (CD3OD, 400 MHz): 57.97-7.96 (d, J=3.2 Hz, I H ), 7.81 -7.79 (d, J=8.0 Hz, I H), 7.52-7.47 (m, I H), 7.28-7.23(m, I H), 4.07-4.03 (m, I H), 3.71 -3.67 (m, IH), 3.54-3.43 (m, 4H), 3.26 (s, 3H), 2.62 (s, IH) , 2.46-2.43 (m, IH) , 2.31-2.28 (m, I H) , 2.19-2.15 (m, IH) , 2.00-1.96(m, IH); cSFC analytical conditions: Column: Chiralpak OJ-3 100 x 4.6 mm, I.D., 3 μ ι; Mobile phase: 40% ethanol (0.05% DEA) in C02; Flow rate: 3.0 mL/min. [00748] Example 46 - (+/-)-3-fbenzo[blthiazol-2-yn-4-methyl-4H-l '-azaspiro
["[l,2,41oxadiazole-5,3'-bicvclo 2.2.21octanel (51)
Figure imgf000185_0001
[00749] To a mixture of compound B-106 (2.1 g, 0.005 mol) and compound C-101 (1.16 g, 0.008 mol) in DCM (10 mL) was added sodium hypochlorite (0.6 g, 0.008 mol) at 0 °C. The mixture was stirred at this temperature for 6 hours. On completion, the reaction mixture was quenched with aqueous sodium sulfite and organics were extracted with DCM (3 x 30 mL). The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, concentrated in vacuo and purified by prep-HPLC [Instrument: GX-E; Column: Agella Venusil ASB C18 150*21.2 mm; Mobile phase: 20-50% acetonitrile in H20 (add 1% HC1, v/v)] to afford racemate 51 (0.2 g, 12% yield), a mixture of HC1 salts of (R)-3-(benzo[b]thiazol-2-yl)-4-methyl- 4H-l'-azaspiro [[l,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane] and (S)-3-(benzo[b]thiazol-2-yl)-4- methyl-4H-l '-azaspiro [[l,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane], as a yellow solid.
[00750] Chiral Separation:
[00751] A solution of racemate 51 (200 mg, 0.63 mmol) in MeOH (5 mL) was separated by SFC (Instrument: SFC 80; Column: OD-5 μ ι; Mobile phase: 20% IPA in C02 with 0.01 % NH3 H20) at room temperature. Each set of collected fractions were concentrated in vacuo to get the free bases of 3-(benzo[b]thiazol-2-yl)-4-methyl-4H- -azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane]-enantiomerl and 3-(benzo[b]thiazol-2-yl)-4-methyl-4H-l '- azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane]-enantiomer2. The free bases were each diluted with 0.2 N HC1 at 0 °C, and subjected to lyophilization to give:
3-(benzo[b]thiazol-2-yl)-4-methyl-4H- -azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane]-enantiomerl hydrochloride (compound 51a) (15 mg, 5% yield) as a white solid: cSFC analytical tR: 2.84 min., purity: 100.0%; LCMS (E): 0.63 min., 315.1 m/z (M+l); Ή- NMR (CD3OD, 400 MHz): δ 8.14-8.12 (d, J=8.0 Hz, IH), 8.08-8.06 (d, J=7.6 Hz, I H), 7.63-7.54 (m, 2H), 3.68-3.55 (m, 4H), 3.24-3.20 (m, IH), 3.08-3.01 (m, 4H), 2.38-2.36 (m, 1 Η),2.30-2.27 (m, I H) 2.13-2.10 (m, IH), 1.88-1.86 (m, IH) , 1.69-1.66 (m, lH), and
3-(benzo[d]thiazol-2-yl)-4-methyl-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane]-enantiomer2 hydrochloride (compound 51b) (30 mg, 15% yield) as a white solid: cSFC analytical tR: 2.94 min., purity: 98.1%; LCMS (E): 0.63 min., 315.1 m/z (M+l); Ή- NMR (CD3OD, 400 MHz): δ 8.14-8.12 (d, J=8.4 Hz, I H), 8.08-8.06 (d, J=7.2 Hz, IH), 7.64-7.55 (m, 2H) 3.87-3.83 (m, I H), 3.60-3.44 (m, 5H), 3.27-3.20 (m, 3H), 2.52-2.50 (m, IH), 2.39-2.38 (m, IH), 2.24-2.21 (m, IH), 2.04-2.01 (m, IH), 1.84-1.81 (m, IH);
cSFC analytical conditions: Column: Chiralcel OD-3 100 x 4.6 mm, I.D., 3 μιη; Mobile phase: 5% to 40% isopropanol (0.05% DEA) in C02; Flow rate: 3.0 mL/min.
[00752] Example 47 - C+/-')-3-(6-methoxybenzorblthiazol-2-ylV4-methyl-4H-l '- azaspiroff 1 ,2,41oxadiazole-5,3'-bicyclo|"2,2.2"|octane1 (52)
Figure imgf000186_0001
B-122 52
[00753] A solution of compound B-122 (330 mg, 2.16 mmol) and compound C-101 (300 mg, 2.16 mmol) in dichloromethane (10 mL) was cooled to 0 °C. Then 10 % aqueous sodium hypochlorite (3.22 g, 4.32 mmol) was added slowly and the reaction was stirred at room temperature for 3 hours. On completion, the reaction mixture was quenched with aqueous sodium sulfite and organics were extracted with DCM (3 x 30 mL). The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, concentrated in vacuo and purified by prep-HPLC [Instrument: Shimadzu pump LC-20A; Column: GEMINI 250*50 mm, particle size: 10 μπι; Mobile phase: 15-40%) acetonitrile in H20 (add 0.075% formic acid, v/v)] to afford racemate 52 (90 mg, 12% yield), a mixture of formic acid salts of (R)-3-(6- methoxybenzo[b]thiazol-2-yl)-4-methyl-4H- -azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane] and (S)-3-(6-methoxybenzo[b]thiazol-2-yl)-4-methyl-4H-l '- azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane], as a white solid.
[00754] Chiral Separation:
[00755] A solution of racemate 52 (90 mg, 0.26 mmol) in ethanol(5 mL) was separated by SFC (Instrument: SFC 80; Column: Chiralpak AS-H 250x25 mm I.D., 10 μπι; Mobile phase: 50% ethanol (0.01 % NH3 H20) in C02) at room temperature. Each set of collected fractions were concentrated at room temperature and then subjected to lyophilization respectively to give:
3-(6-methoxybenzo[b]thiazol-2-yl)-4-methyl-4H-l '-azaspiro[[l ,2,4]oxadiazole -5,3'- bicyclo[2.2.2]octane]~enantiomerl (compound 52a) (10 mg, 1 1% yield) as a white solid: cSFC analytical tR: 2.08 min, purity: 99.6%; LCMS (E): 0.65 min, 345.1 m/z (M+l ); Ή-NMR
(CD3OD, 400 MHz): δ 8.00-7.98 (d, J=8.8 HZ, IH), 7.58-7.57 (d, J=2.4 HZ, I H), 7.20-7.17 (dd, Jl=8.4 HZ, J2=2.4 HZ, I H), 3.9 (s, 3H), 3.60-3.56 (d, J=15.2 HZ, I H), 3.51 (s, 3H), 3.14-3.10 (d, J=15.2 HZ, IH), 3.00-2.93 (m, 4H), 2.30-2.29 (d, 2H) , 2.08-2.04 (m, IH), 1.83-1.78 (m, IH), 1.63-1.60 (m, IH), and
3-(6-methoxybenzo[b]thiazol-2-yl)-4-methyl-4H-l '-azaspiro[[l,2,4]oxadiazole -5,3'- bicyclo[2.2.2]octane]-enantiomer2 (compound 52b) (10 mg, 1 1% yield) as a white solid: cSFC analytical tR: 2.45 min, purity: 98.4%; LCMS (E): 0.66 min., 345.1 m/z (M+l); Ή-NMR (CD3OD, 400 MHz): δ 8.00-7.98 (d, J=9.2 HZ, IH), 7.58-7.57 (d, J=2.4 HZ, I H), 7.21 -7.18 (dd, Jl=8.4 HZ, J2=2.4 HZ, IH), 3.92 (s, 3H), 3.55 (s, IH), 3.50 (s, 3H), 3.08-3.04 (m, I H), 2.97-2.88 (m, 4H), 2.27-2.19 (m, 2H) , 2.04-2.01 (m, IH), 1.79-1.78 (m, IH), 1.60-1.57(m, I H);
cSFC analytical conditions: Column: Chiralpak AS-3 150 x 4.6 mm, I.D., 3 μπι; Mobile phase: 5% to 40% ethanol (0.05% DEA) in C02; Flow rate: 3.0 mL/min.
[00756] Example 48 - +/-)-3- 5-fluorobenzorblthiophen-2-vn-4-methyl-4H-l,- azaspiro [[ 1.2.4"|oxadiazole-5 ,3 '-bicyclo 2.2.2]octane] (53)
Figure imgf000187_0001
53
[00757] A solution of compound B-114 (1 g, 5.12 mmol) and compound C-101 (708 mg, 5.12 mmol) in anhydrous dichloromethane (10 mL) was cooled to 0 °C. Then 10 % aqueous sodium hypochlorite (7.63 g, 10.25 mmol) was added slowly and the reaction was stirred at room temperature for 2 hours. On completion, the reaction mixture was quenched with aqueous sodium sulfite and organics were extracted with DCM (3 x 30 mL). The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, concentrated in vacuo and purified by prep-HPLC [Instrument: Shimadzu pump LC-20A; Column: GEMINI 250x50 mm, particle size: 10 μηι; Mobile phase: 30-54%) acetonitrile in H20 (add 1% NH3 H20, v/v)] to afford racemate 53 (210 mg, 12%> yield), a mixture of (R)-3-(5-fluorobenzo[b]thiophen-2-yl)-4-methyl- 4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane] and (S)-3-(5-fluorobenzo[b]thiophen- 2-yl)-4-methyl-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane], as a white solid.
[00758] Chiral Separation:
[00759] A solution of racemate 53 (210 mg, 0.63 mmol) in MeOH (5 mL) was separated by SFC (Instrument: SFC 80; Column: Chiralpak AD-H 250x25 mm I.D., 10 μπι; Mobile phase: 40 ethanol (0.01%> NH3 H20) in C02) at room temperature. Each set of collected fractions were concentrated at room temperature before each was treated with 0.2 mol/L aqueous hydrochloric acid until pH=5 was attained. The solutions were each then subjected to lyophilization to give: 3-(5-fluorobenzo[b]thiophen-2-yl)-4-methyl-4H-l '-azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane]-enantiomerl hydrochloride (compound 53a) (32.6 mg, 28 yield) as a white solid: cSFC analytical tR: 2.28 min., purity: 100.0%; LCMS (E): 1.46 min., 332.1 m/z (M+l); Ή- NMR (CD3OD, 400 MHz): δ 7.99-7.93 (m, IH), 7.86 (s, I H), 7.70-7.64 (dd, Jl=9.2 Hz, J2=2.4 Hz, IH), 7.33-7.26(m, IH), 4.02-3.98 (dd, Jl=14.4 Hz, J2=1.6 Hz, I H), 3.67-3.62 (dd, Jl=14.4 Hz, J2=2.0 Ηζ,ΙΗ), 3.51 -3.39 (m, 4H), 3.24 (s, IH), 2.58 (s, IH) , 2.46-2.39 (m, I H) , 2.29-2.26 (m, IH) , 2.17-2.12 (m, I H) , 1.97-1.93 (m, IH), and
3-(5-fluorobenzo[b]thiophen-2-yl)-4-methyl-4H -l'-azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane]-enantiomer2 hydrochloride (compound 53b) (30.9 mg, 27% yield) as a white solid: cSFC analytical tR: 3.09 min., purity: 100.0%; LCMS (E): 1.46 min., 332.1 m/z (M+l); Ή-NMR (CD3OD, 400 MHz): 57.98-7.94 (m, IH), 7.86 (s, IH), 7.69-7.66 (dd, Jl=9.2 Hz, J2=2.4 Hz, IH), 7.32-7.27(m, I H), 4.06-4.02 (dd, Jl=14.8 Hz, J2=2.0 Hz, I H), 3.70-3.66 (dd, Jl=14.0 Hz, J2=2.4 Hz, IH), 3.53-3.41 (m, 4H), 3.24 (s, I H), 2.60 (s, IH) , 2.45-2.40 (m, I H) , 2.31-2.25 (m, I H) , 2.18-2.12 (m, I H) , 1.99-1.96 (m, I H);
cSFC analytical conditions: Column: Chiralpak AD-3 100 x 4.6 mm, I.D., 3 μπι; Mobile phase: 40% ethanol (0.05% DEA) in C02; Flow rate: 3.0 mL/min.
[00760] Example 49 - (+/-)-2-(4-methyl-4H-l '-azaspirorri ,2,41oxadiazole-53'- bicyclo[2.2.21oct -3-yl)benzo[b1thiophene-7-carbonitrile (54)
Figure imgf000188_0001
54
[00761] A solution of compound B-112 (100 mg, 0.50 mmol) and compound C-101 (138 mg, 1.0 mmol) in dichloromethane (5 mL) was cooled to 0 °C. Then 10% aqueous sodium
hypochlorite (740 mg, 1.0 mmol) was added slowly and stirred at room temperature for 3 hours. On completion, the reaction mixture was quenched with aqueous sodium sulfite and organics were extracted with DCM (3 x 30 mL). The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, concentrated in vacuo and purified by prep-HPLC [Instrument: Shimadzu pump GX-B; Column: GEMINI 150*30 mm, particle size: 4um; Mobile phase: 10-45% acetonitrile in H20 (add 0.7% HC1, v/v)] to afford racemate 54 (50 mg, 30% yield), a mixture of HC1 salts of (R)-2-(4-methyl-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octan]-3-yl)benzo[b]thiophene-7-carbonitrile and (S)-2-(4-methyl-4H-l '- azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octan]-3-yl)benzo[b]thiophene-7-carbonitrile, as a white solid.
[00762] Chiral Separation: [00763] A solution of racemate 54 (50 mg, 0.15 mmol) in ethanol (5 mL) was separated by SFC (Instrument: SFC 80; Column: Chiralpak AD-H 250x25 mm I.D., 10 μπι; Mobile phase: 60% ethanol (0.01% NH3 Ή20) in C02) at room temperature. Each set of collected fractions were concentrated at room temperature and subject to lyophilization to give:
2-(4-methyl-4H-l '-azaspiro[[l,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octan]-3-yl)
benzo[b]thiophene-7-carbonitrile-enantiomerl (compound 54a) (9.2 mg, 18% yield) as a white solid: cSFC analytical tR: 0.99 min., purity: 96.9%; LCMS (H): 1.43 min., 339.1 m/z (M+l ); Ή- NMR (CD3OD, 400 MHz ): δ 8.24-8.22 (d, J= 8.0 Hz, 1H), 7.98 (s, 1 H), 7.90-7.88 (d, J= 7.6 Hz, 1 H), 7.63-7.59 (t, J= 8.0 Hz, 1H), 3.58-3.54 (m, 1 H), 3.23 (s, 3H), 3.10-3.06 (m, 1 H), 2.97- 2.90(m, 4H), 2.24-2.17 (m, 2H), 2.03-1.99 (m, 1H) , 1.79-1.77 (m, 1 H), 1.62-1.59 (m, 1 H), and
2-(4-methyl-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octan]-3-yl)
benzo[b]thiophene-7-carbonitrile-enantiomer-2 (compound 54b) (7.1 mg, 14% yield) as a white solid: cSFC analytical tR: 1.42 min., purity: 91.3%; LCMS (H): 2.83 min., 339.1 m/z (M+l ); Ή- NMR (CD3OD, 400 MHz ): δ 8.25-8.23 (d, J= 8.0 Hz, 1H), 7.99 (s, 1 H), 7.91 -7.89 (d, J= 7.6 Hz, 1H), 7.64-7.60 (t, J= 8.0 Hz, 1 H), 3.58-3.54 (m, 1 H), 3.23 (s, 3H), 3.09-3.05 (m, 1 H), 2.95-2.89 (m, 4H), 2.24-2.18 (m, 2H), 2.02-1.99 (m, 1H) , 1.79-1.76 (m, 1 H), 1.61 -1.59 (m, 1H);
cSFC analytical conditions: Column: Chiralpak AD-3 100 x 4.6 mm, I.D., 3 μηι; Mobile phase: 60% ethanol (0.05% DEA) in C02; Flow rate: 3.0 mL/min.
[00764] Example 50 - (+/-)-3-f7-bromobenzorb1thiophen-2-yl)-4-methyl-4H-r-
Figure imgf000189_0001
55
[00765] The solution of compound B-113 (100 mg, 0.39 mmol) and compound C-101 (108 mg, 0.78 mmol) in dichloromethane (5 mL) was cooled to 0 °C. Then 10% aqueous sodium hypochlorite (577 mg, 0.78 mmol) was added slowly and stirred at room temperature for 3 hours. On completion, the reaction mixture was quenched with aqueous sodium sulfite and organics were extracted with DCM (3 x 30 mL). The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, concentrated in vacuo and purified by prep-HPLC [Instrument: Agella Venusil *5 μιη; Column: ASB CI 8 150*21.2 mm, particle size: 5 μιη; Mobile phase: 25-55% acetonitrile in H20 (add 1 % HC1, v/v)] to afford racemate 55 (20 mg, 13% yield), a mixture of HC1 salts of (R)-3-(7-bromobenzo[b]thiophen-2-yl)-4-methyl-4H-l '- azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane] and (S)-3-(7-bromobenzo[b]thiophen-2-yl)- 4-methyl-4H-l '-azaspiro[[l,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane], as a white solid. [00766] Chiral Separation:
[00767] A solution of racemate 55 (200 mg, 0.51 mmol) in ethanol (5 mL) was separated by SFC (Instrument: SFC 80; Column: Chiralpak AD-H 250x25 mm I.D., 10 μπι; Mobile phase: 60 ethanol (0.01% NH3 H20) in C02) at room temperature. Each set of collected fractions were concentrated at room temperature before each was treated with 0.2 mol/L aqueous hydrochloric acid until pH=5 was attained. The solutions were each then subjected to lyophilization to give:
3-(7-bromobenzo[b]thiophen-2-yl)-4-methyl-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane]-enantiomerl hydrochloride (compound 55a) (50 mg, 25% yield) as a white solid: cSFC analytical tR: 2.61 min., purity: 92.5%; LCMS (E): 1.65 min., 394.0 m/z (M+1 ); Ή- NMR (CD3OD, 400 MHz ): δ 8.03 (s, 1H), 7.98-7.96 (d, J = 8.0 Hz, 1H), 7.68-7.66 (d, J = 8.0 Hz, 1 H), 7.43-7.39 (t, J = 8.0 Hz, 1 H), 4.08-4.04 (dd, J = 14.4 Hz, J = 2.0 Hz, 1 H), 3.71 -3.67 (dd, J = 14.4 Hz, J = 2.0 Hz, 1 H), 3.54-3.42 (m, 4H), 3.26 (s, 3H), 2.61 (s, 1 H), 2.47-2.41 (m, 1 H), 2.32- 2.29 (m, 1H), 2.19-2.15 (m, 1H) , 2.00-1 .97 (m, 1 H), and
3-(7-bromobenzo[b]thiophen-2-yl)-4-methyl-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane]-enantiomer2 hydrochloride (compound 55b) (50 mg, 25% yield) as a white solid: cSFC analytical tR: 3.95 min., purity: 100.0%; LCMS (E): 1 .65 min., 394.0 m/z (M+1 ); Ή- NMR (CD3OD, 400 MHz ): δ 8.02 (s, 1 H), 7.97-7.95 (d, J = 8.0 Hz, 1 H), 7.68-7.66 (d, J = 8.0 Hz, 1H), 7.43-7.39 (t, J = 7.6 Hz, 1H), 4.05-4.01 (m, 1 H), 3.67-3.63 (m, 1H), 3.50-3.44 (m, 4H), 3.26 (s, 3H), 2.59 (s, 1 H), 2.47-2.43 (m, 1 H), 2.32-2.29 (m, 1 H), 2.19-2.15 (m, 1H) , 2.00-1.97 (m, 1 H);
cSFC analytical conditions: Column: Chiralpak AD-3 100 x 4.6 mm, I.D., 3 μπι; Mobile phase: 40% ethanol (0.05% DEA) in C02; Flow rate: 3.0 mL/min.
[00768] Example 51 - (+/-)-3-(benzorb1thiophen-5-yl)-4-methyl-4H-r-
Figure imgf000190_0001
56
[00769] The solution of compound B-115 (460 mg, 2.6 mmol) and compound C-101 (1 .08 g, 7.8 mmol) in dichloromethane (30 mL) was cooled to 0 oC. Then chlorosylsodium (5.8 g, 7.8 mmol) was added slowly and stirred at rt for 3 h. On completion, the reaction mixture was quenched with aqueous sodium sulfite and organics were extracted with DCM (3 x 30 mL). The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, concentrated in vacuo and purified by prep-HPLC [Instrument: Shimadzu pump GX-B; Column: GEMINI 150*30 mm, particle size: 4um; Mobile phase: 30-60 % acetonitrile in H20 (add 0.7% HC1, v/v)] to afford racemate 56 (200 mg, 25% yield), a mixture of HQ salts of (R)-3- (benzo[b]thiophen-5-yl)-4-methyl-4H-l'-azaspiro[[l,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane] and (S)-3-(benzo[b]thiophen-5-yl)-4-methyl-4H-l'-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane], as a white solid.
[00770] Chiral Separation:
[00771] A solution of racemate 56 (200 mg, 0.64 mmol) in ethanol (5 mL) was separated by SFC (Instrument: SFC 80; Column: Chiralpak AD-H 250x25 mm I.D., 10 μηι; Mobile phase: 40 methanol (0.01% NH3 H20) in C02) at room temperature. Each set of collected fractions were concentrated, and subjected to lyophilization to give:
3-(benzo[b]thiophen-5-yl)-4-methyl-4H-l '-azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane]-enantiomerl (compound 56a) (50 mg, 25% yield) as a white solid: cSFC analytical tR: 2.71 min., purity: 100.0%; LCMS (E): 1.44 min., 314.1 m/z (M+l ); Ή-NMR (CD3OD, 400 MHz ): δ 7.94-7.93 (m, 2H), 7.82 (s, 1 H), 7.48-7.44 (m, 2H), 3.56-3.52 (d, J=15.6 Hz, 1 H), 3.21 (s, 3H), 3.07-3.03 (d, J=15.6 Hz, 1H), 2.96-2.88 (m, 4H), 2.23-2.22 (m, 2H), 2.00- 1.98 (m, 1 H) , 1.77-1.75 (m, 1 H), 1.60-1.56 (m,l H), and
3-(benzo[b]thiophen-5-yl)-4-methyl-4H-l '-azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane]-enantiomer2 (compound 56b) (50 mg, 25% yield) as a white solid: cSFC analytical tR: 3.1 min., purity: 99.7%; LCMS (E): 1.45 min., 314.1 m/z (M+l ); Ή-NMR
(CD3OD, 400 MHz ): δ 7.94-7.92 (m, 2H), 7.83 (s, 1 H), 7.48-7.44 (m, 2H), 3.55-3.52 (d, J=15.2 Hz, 1H), 3.21 (s, 3H), 3.07-3.03 (m, d, J=15.6 Hz, 1 H), 2.95-2.88 (m, 4H), 2.23-2.22 (m, 2H), 2.01-1.98 (m, 1 H) , 1.77-1 .75 (m, 1 H), 1 .60-1.56 (m,l H);
cSFC analytical conditions: Column: Chiralpak OD-3 100 x 4.6 mm, I.D., 3 μπι; Mobile phase: 5% to 40% ethanol (0.05% DEA) in C02; Flow rate: 3.0 mL/min.
[00772] Example 52 - (+/-)-3-(isoquinolin-3-yl)-4-methyl-4H-r-azaspirorn ,2,41oxadiazole-
Figure imgf000191_0001
57
[00773] To a mixture of compound B-107 (1 .0 g, 5.8 mmol) and compound C-101 (1.2 g,
8.7 mmol) in DCM (10 mL) was added 10%) aqueous sodium hypochlorite (0.64 g, 8.7 mmol) at 0 °C. The mixture was stirred at this temperature for 2 hours. On completion, the reaction mixture was quenched with aqueous sodium sulfite and organics were extracted with DCM (3 x 30 mL). The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, concentrated in vacuo and purified by prep-HPLC [Instrument: GX-E; Column: Agella Venusil ASB C18 150*21.2 mm; Mobile phase: B 6-36% acetonitrile in H20 (add 1% HCl, v/v)] to afford racemate 57 (0.2 g, 12% yield), a mixture of HCl salts of (R)-3-(isoquinolin-3-yl)-4- methyl-4H- -azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane] and (S)-3-(isoquinolin-3-yl)- 4-methyl-4H-l '-azaspiro[[l,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane], as a red solid.
[00774] Chiral Separation:
[00775] A solution of racemate 57 (200 mg, 0.63 mmol) in methanol (5 mL) was separated by SFC (Instrument: SFC 80; Column: AD-10 μηι; Mobile phase: 50% EtOH in C02 with 0.01% NH3H20) at room temperature. Each set of collected fractions were concentrated at room temperature to give:
3-(isoquinolin-3-yl)-4-methyl-4H- -azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane]-enantiomerl (compound 57a) (20 mg, 10% yield) as a brown solid: cSFC analytical tR: 2.70 min., purity: 100.0%; LCMS (E): 0.56 min., 309.1 m/z (M+l ); Ή-NMR (CD3OD, 400 MHz): δ 9.38 (s, 1 H), 8.24-8.19 (m, 2H), 8.07-8.05 (d, J = 8.0 Hz, 1H), 7.91 -7.87 (t, J = 7.2 Hz, 1H), 7.84-7.80 (t, J = 7.2 Hz, 1H), 3.56-3.52 (d, J = 15.2 Hz, 1H), 3.18 (s, 3H), 3.10-3.06 (d, J = 15.2 Hz, 1H) 2.96-2.90 (m, 4H), 2.34-2.33 (m, 1H) , 2.26-2.22 (m, 1 H), 2.09- 2.07 (m, 1H), 1 .80-1 .77 (m, 1H), 1.61-1.58 (m, l H), and
3-(isoquinolin-3-yl)-4-methyl-4H- -azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane]-enantiomer2 (compound 57b) (30 mg, 25% yield) as a brown solid: cSFC analytical tR: 3.84 min., purity: 100.0%; LCMS (E): 0.56 min., 309.1 m/z (M+l); Ή-NMR (CD3OD, 400 MHz): δ 9.39 (s, 1H), 8.24-8.20 (m, 2H), 8.07-8.05 (d, J = 8.0 Hz, 1 H), 7.91-7.88 (t, J = 7.2 Hz, 1H), 7.84-7.81 (t, J = 7.6 Hz, 1 H), 3.56-3.52 (d, J = 15.2 Hz, 1 H), 3.18 (s, 3H), 3.10-3.06 (d, J = 15.2 Hz, 1 H) 2.96-2.90 (m, 4H), 2.34-2.33 (m, 1 H) , 2.25-2.23 (m, 1H), 2.10- 2.06 (m, 1H), 1.81-1.77 (m, 1H), 1.62-1.58 (m, 1 H);
cSFC analytical conditions: Column: Chiralpak AD-3 100 x 4.6 mm, I.D., 3 μπι; Mobile phase: 40% methanol (0.05% DEA) in C02; Flow rate: 3.0 mL/min.
[00776] Example 53 - (+/-)-4-methyl-3-(l-methyl-L2,3,4-tetrahvdroquinolin-6-vn-4H-l'- azaspiro [l,2,41oxadiazole-5,3'-bic clo 2.2.2 octane (58)
Figure imgf000192_0001
58
[00777] A solution of compound B-123 (1.6 g, 8.42 mmol) and compound C-101 (1.74 g,
12.63 mmol) in anhydrous dichloromethane (30 mL) were added tert-butyl hypochlorite (0.91 g, 8.42 mmol) at -50 °C. The mixture was slowly warmed to room temperature and stirred for 6 hours. On completion, the reaction mixture was quenched with aqueous sodium sulfite and organics were extracted with DCM (3 x 30 mL). The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, concentrated in vacuo and purified by silica column chromatography [dichloromethane/methanol=70: l] and prep-HPLC [Instrument: GX-E; Column: Agella Venusil ASB CI 8 150x21 .2 mm><5 μηι; Mobile phase: 13-43% acetonitrile in H20 (add 1 % HCl, v/v)] to afford racemate 58 (200 mg, 7% yield), a mixture of HCl salts of (R)- 4-methyl-3-(l -methyl-l ,2,3,4-tetrahydroquinolin-6-yl)-4H- -azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane] and (S)-4-methyl-3-(l-methyl-l ,2,3,4-tetrahydroquinolin-6-yl)-4H-l '- azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane], as a yellow solid.
[00778] Chiral Separation:
[00779] A solution of racemate 58 (200 mg, 0.64 mmol) in methanol (5 mL) was separated by SFC (Instrument: SFC 80; Column: Chiralpak AS-H 250x25 mm I.D., 10 μπι; Mobile phase: 60% ethanol (0.01 % NH3 H20) in C02) at room temperature. Each set of collected fractions were concentrated at room temperature and then subjected to lyophilization to give:
4-methyl-3-(l-methyl-l ,2,3,4-tetrahydroquinolin-6-yl)-4H-l '-azaspiro[[l,2,4]oxadiazole- 5,3'-bicyclo[2.2.2]octane]-enantiomerl (compound 58a) (61.7 mg, 31% yield) as a white solid: cSFC analytical tR: 2.14 min., purity: 100.0%; LCMS (B): 0.63 min., 327.2 m/z (M+l ); Ή-NMR (CD3OD, 400 MHz): δ 7.27-7.25 (d, J=8.4 Hz, IH), 7.14 (s, IH), 6.66-6.64 (d, J=8.8 Hz, IH ), 3.52 (s, IH), 3.48 (s, IH), 3.33 (s, IH), 3.01 (s, IH), 2.98 (s, 3H), 2.96 (s, 3H), 2.93-2.87 (m, 4H), 2.80-2.77 (m, 2H), 2.18 (m, 2H), 2.02-1.96 (m, 3H), 1.74-1.72 (m, IH), 1.58-1.56 (m, IH), and
4-methyl-3-( 1 -methyl- 1 ,2,3 ,4-tetrahydroquinolin-6-yl)-4H- 1 '-azaspiro[[ 1 ,2,4]oxadiazole- 5,3'-bicyclo[2.2.2]octane]-enantiomer2 (compound 58b) (61.8 mg, 31% yield) as a brown solid: cSFC analytical tR: 2.95 min., purity: 99.2%; LCMS (B): 0.63 min., 327.2 m/z (M+l ); Ή-NMR (CD3OD, 400 MHz): δ 7.29-7.27 (d, J=8.4 Hz, IH), 7.16 (s, I H), 6.67-6.65 (d, J=8.4 Hz, I H), 3.52 (s, IH), 3.98-3.94 (d, J=13.6 Hz, I H ), 3.61-3.57 (d, J=14.0 Hz, IH), 3.48-3.35 (m, 6H), 3.02 (s, 3H), 2.97 (s, 3H), 2.80-2.77 (m, 2H), 2.52 (s, IH), 2.41 (m, I H), 2.27 (m, I H), 2.14-2.08 (m, IH), 2.02-1.91 (m, 3H);
cSFC analytical conditions: Column: Chiralpak AS-3 100 x 4.6 mm, I.D., 3 μηι; Mobile phase: 40% ethanol (0.05% DEA) in C02; Flow rate: 3.0 mL/min.
[00780] Example 54 - f+/-V4-methyl-3-(2-methyl-1.2.3,4-tetrahydroisoquinolin-6-yl)-4H-l'- azaspiro[[L2,41oxadiazole-5,3'-bicyclo[2.2.2]octane] (59)
Figure imgf000193_0001
59 [00781] To a mixture of compound B-126 (0.6 g, 3.15 mmol) and compound C-101 (0.5 g, 3.79 mmol) in dichloromethane (50 mL) was added slowly sodium hypochlorite (0.9 g, 12.60 mmol) at 0 °C. After stirring at room temperature for 6 hours, the reaction mixture was filtered, concentrated and purified by prep-HPLC [Instrument: GX-A; Column: Phenomenex Gemini CI 8 150*25 mm* 10 μιη; Mobile phase: 18-43% acetonitrile in H20 (add 1% NH3 H20, v/v)] to give racemate 59 (0.25 g, 25% yield), a mixture of (R)-4-methyl-3-(2-methyl-l ,2,3,4- tetrahydroisoquinolin-6-yl)-4H-l '-azaspiro[[l,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane] and (S)- 4-methyl-3 -(2-methyl- 1 ,2,3 ,4-tetrahydroisoquinolin-6-y 1)-4H- 1 '-azaspiro[[ 1 ,2,4]oxadiazole-5 ,3 '- bicyclo[2.2.2]octane], as a white solid.
[00782] Chiral Separation:
[00783] A solution of racemate 59 (0.25 g, 0.77 mmol) in methanol (3 mL) was separated by SFC (Instrument: SFC 80; Column: Chiralcel OD-H 250x25 mm I.D., 10 μιη; Mobile phase: 40% iso-propanol 0.01% NH3 H20) in C02) at room temperature. Each set of collected fractions were concentrated under reduced pressure at 0 °C to give:
4-methyl-3-(2-methyl-l ,2,3,4-tetrahydroisoquinolin-6-yl)-4H-l'-azaspiro[[l ,2,4] oxadiazole-5,3'-bicyclo[2.2.2]octane]-enantiomerl (compound 59a) (80.2 mg, 32% yield): cSFC analytical tR: 2.63 min, purity: 99.3%; LCMS (G): 1.96 min., 327.2 m/z (M+l ); Ή-NMR (CD3OD, 400 MHz): δ 7.38-7.36 (m, , 2H), 7,23-7.21 (d, J=7.6 Hz, 1 H), 3.68 (s, 2H), 3.53-3.49 (d, J=15.2 Hz, 1H), 3.05-2.99 (m, 3H), 2.96 (s, 3H), 2.94-2.88 (m, 4H), 2.80-2.77 (m, 2H), 2.49 (s, 3H), 2.21 -2.17 (m, 2H), 2.03-1.96 (m, 1 H), 1.78-1.73 (m, 1 H) , 1.61-1.56 (m, 1 H), and
4-methyl-3-(2-methyl-l ,2,3,4-tetrahydroisoquinolin-6-yl)-4H-r-azaspiro[[l,2,4] oxadiazole-5,3'-bicyclo[2.2.2]octane]-enantiomer2 (compound 59b) (78.8 mg, 32% yield) as a white solid: cSFC analytical tR: 2.90 min., purity: 97.9%; LCMS (G): 1.96 min., 327.2 m/z (M+l); Ή-NMR (CD3OD, 400 MHz): δ 7.37-7.35 (m, 2H), 7.23-7.21 (d, J=7.6 Hz, 1 H), 3.69 (s, 2H), 3.54-3.50 (d, J=14.8 Hz, 1 H), 3.06-2.89 (m, 10H), 2.81 -2.78 (m, 2H), 2.49 (s, 3H), 2.22-2.17 (m, 2H), 2.02-1 .96 (m, 1H), 1.80-1.73 (m, 1H), 1.62-1.57 (m, 1H);
cSFC analytical conditions: Column: Chiralcel OD-3 100 x 4.6 mm, I.D., 3 μπι; Mobile phase: 5% to 40% isopropanol (0.05% DEA) in C02; Flow rate: 3.0 mL/min.
[00784] Example 55 - nr.3R.^.5S.7^-3'-(4-chlorophenvn-4'-methyl-4'H-l - azaspiro[adamantane-4,5'-[l ,2,4"|oxadiazolel hydrochloride (60) and (lr,3R^r,5S,7^)-3'-(4- chlorophenyl -4'-methyl-4'H-l-azaspiro[adamantane-4,5'-[l,2,41oxadiazole1 hydrochloride (61)
Figure imgf000194_0001
[00785] A solution of compound B-101 (417 mg, 2.75 mmol) and compound C-lll (450 mg, 2.75 mmol) in dichloromethane was cooled to 0 °C and a 10% aqueous sodium hypochlorite (4.06 g, 5.49 mmol) was added slowly at 0 °C. The reaction was warmed to room temperature and stirred for 3 hours. On completion, the reaction mixture was quenched with aqueous sodium sulfite and organics were extracted with DCM (3 30 mL). The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, concentrated in vacuo and purified by prep-HPLC [Instrument: Shimadzu pump LC-20A; Column: Phenomenex Synergi CI 8 150*30 mm particle size: 4um; Mobile phase: 30-50% acetonitrile in H20 (add 0.75% TFA, v/v)] to give a clean mixture of compounds 60 and 61 (200 mg, 23% yield) as a yellow solid.
[00786] Separation:
[00787] A solution of compounds 60 and 61 (200 mg, 1.5 mmol) in methanol (5 mL) was then separated by SFC (Instrument: SFC 80; Column: Chiralpak AD-H 250x25 mm I.D., 10 μπι; Mobile phase: 40% ethanol (0.01% NH3 H20) in C02) at room temperature. Each set of collected fractions were each then concentrated at room temperature before the two products were each dissolved in 0.2 N hydrochloric acid aqueous solutions. Both samples were then subjected to lyophilization to give:
(lr,3 ,^,5S,7_;)-3'-(4-chlorophenyl)-4'-methyl-4'H-l -azaspiro[adamantane-4,5'- [l ,2,4]oxadiazole] hydrochloride (compound 60) (45 mg, 23% yield) as a yellow solid: cSFC analytical tR: 2.56 min., purity: 100.0%; LCMS (D): 1.41 min., 317.1 m/z (M+l ); Ή-NMR. (CD3OD, 400 MHz): δ 7.79-7.77 (d, J = 8.4 Hz, 2H), 7.56-7.54(d, J = 8.8 Hz, 2H), 3.86-3.83 (d, J = 12.8 Hz, 2H), 3.3.70-3.67 (d, J = 13.2 Hz, 2H), 3.61 (s, 2H), 2.81 (s, 3H), 2.53 (s, 2H), 2.42- 2.39 (d, J = 12.8 Hz, 2H), 2.24 (s, 1H), 2.1 1-2.09 (d, J = 12.8 Hz, 2H), and
(l r,3R,^,5S,7i)-3'-(4-chlorophenyl)-4'-methyl-4,H-l -azaspiro[adamantane-4,5'- [l ,2,4]oxadiazole] hydrochloride (compound 61) (40 mg, 20% yield) as a yellow solid: cSFC analytical tR: 3.89 min., purity: 98.6%; LCMS (A): 1.33 min., 317.1 m/z (M+l); Ή-NMR
(CD3OD, 400 MHz): δ 7.76-7.74 (d, J = 8.8 Hz, 2H), 7.55-7.53 (d, J = 8.4 Hz, 2H), 3.85-3.82 (d, J = 12.4 Hz, 2H), 3.65-3.62 (m, 4H), 2.88 (s, 3H), 2.53 (s, 2H), 2.38-2.31 (m, 3H ), 2.24-2.20 ( d, J = 13.2 Hz, 2H);
cSFC analytical conditions: Column: Chiralpak AD-3 100 x 4.6 mm, I.D., 3 μπι; Mobile phase: 40% ethanol (0.05% DEA) in C02; Flow rate: 3.0 mL/min.
[00788] Example 56 - (lrJR,^.5S.7^V3'-rbenzorblthiophen-2-vn-4l-methyl-4lH-l- azaspiro[adamantane-4,5'-|"L2,4"|oxadiazolel hydrochloride (62) and (lr,3R^r,5S,7s)-3'- (benzo b]thiophen-2-yl)-4'-methyl-4'H-l -azaspiro adamantane-4,5'-[L2,41oxadiazolel hydrochloride (63)
Figure imgf000196_0001
[00789] A solution of compound B-102 (417 mg, 2.75 mmol) and compound C-111 (450 mg, 2.75 mmol) in dichloromethane was cooled to 0°C and 10% aqueous sodium hypochlorite solution (4.07 g, 5.49 mmol) was added slowly at 0°C. The reaction mixture was warmed to room temperature and stirred for 3 hours. On completion, the reaction mixture was quenched with aqueous sodium sulfite and organics were extracted with DCM (3 x 30 mL). The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, concentrated in vacuo and purified by prep-HPLC [Instrument: Shimadzu pump LC-20A; Column: Phenomenex Synergi CI 8 150*30 mm, particle size: 4um; Mobile phase: 20-50% acetonitrile in H20 (add 0.75% TFA, v/v)] to give a clean mixture of compounds 62 and 63 (150 mg, 1 8%) as a yellow solid.
[00790] Separation:
[00791] A solution of compounds 62 and 63 (150 mg, 0.44 mmol) in methanol (4 mL) was separated by SFC (Instrument: SFC 80; Column: Chiralpak AD-H 250x25 mm I.D., 10 μχη;
Mobile phase: 40% IPA (0.01 % NH3.H20) in C02) at room temperature. Each set of collected fractions were concentrated at room temperature. The two products were then each dissolved in 0.2 N hydrochloric acid aqueous solution and subjected to lyophilization to give:
( l r,3R,45,5S,75)-3'-(benzo[b]thiophen-2-yl)-4'-methyl-4'H-l -azaspiro[adamantane-4,5'- [l ,2,4]oxadiazole] hydrochloride (compound 62) (50 mg, 33% yield) as a yellow solid: cSFC analytical tR: 1 .18 min., purity: 100.0%; LCMS (D): 1.91 min., 339.1 m/z (M+l ); Ή-NMR (CD3OD, 400 MHz): δ 7.94-7.90 (m, 3H), 7.50 - 7.44 (m, 2H), 4.06-3.78 (m, 2H), 3.72-3.68 (d, J = 12.8 Hz, 2H), 3.61 (s, 2H), 2.98 (s, 3H), 2.57 (s, 2H), 2.42-2.39 (d, J = 12.8 Hz, 2H), 2.25 (s, 1 H), 2.1 -2.10 (d, J = 13.2 Hz, 2H), and
(l ,3R,^r,5S,75)-3'-(benzo[b]thiophen-2-yl)-4'-methyl-4'H-l -azaspiro[adamantane-4,5'- [l ,2,4]oxadiazole] hydrochloride (compound 63) (30 mg, 20% yield) as a yellow solid: cSFC analytical tR: 1 .64 min., purity: 100.0%; LCMS (D): 2.79 min., 339.1 m/z (M+l ); Ή-NMR (CD3OD, 400 MHz): δ 7.95-7.89 (m, 3H), 7.49-7.44 (m, 2H), 3.88-3.85 (d, J = 12.0 Hz, 2H), 3.64-3.61 (d, J = 9.6 Hz, 4H), 3.06 (s, 3H), 2.57 (s, 2H), 2.41 -2.37 (d, J = 13.6 Hz, 2H), 2.31 (s, 1 H), 2.24-2.20 (d, J = 13.2 Hz, 2H);
cSFC analytical conditions: Column: Chiralpak AD-3 100 x 4.6 mm, I.D., 3 μπι; Mobile phase: 40% ethanol (0.05% DEA) in C02; Flow rate: 3.0 mL/min. [00792] Example 57 - n^R^SSJ^^benzofuran^-vn^-methvMTT-l - azaspiro[adamantane-4,5'-[l ,2,41oxadiazole] hydrochloride (64) and (lrJR,^5S,7^ -3 - (benzofuran-2-yl")-4'-methyl-4'H-l-azaspiro adamantane-4,5'- l,2,4]oxadiazole1 hydrochloride {65}
Figure imgf000197_0001
[00793] A solution of compound B-104 (431 mg, 2.68 mmol) and compound C-lll (440 mg, 2.68 mmol) in dichloromethane was cooled to 0 °C and 10% aqueous sodium hypochlorite solution (3.97 g, 5.36 mmol) was added slowly at 0 °C. The reaction was then warmed to room temperature and stirred at this temperature for 3 hours. On completion, the reaction mixture was quenched with aqueous sodium sulfite and organics were extracted with DCM (3 x 30 mL). The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, concentrated in vacuo and purified by prep-HPLC [Instrument: Shimadzu pump LC-20A; Column: Phenomenex Synergi CI 8 150*30 mm, particle size: 4um; Mobile phase: 24-54% acetonitrile in H20 (add 0.75% TFA, v/v)] to give a clean mixture of compounds 64 and 65 (160 mg, 18% yield) as a yellow solid.
[00794] Separation:
[00795] A solution of compounds 64 and 65 (160 mg, 0.49 mmol) in methanol (4 mL) was separated by SFC (Instrument: SFC 80; Column: Chiralpak AD-H 250x25 mm I.D., 10 μπα;
Mobile phase: 40% ethanol (0.01% methyl ethyl amine) in C02) at room temperature. Each set of collected fractions was concentrated at room temperature. The two products were then each dissolved in 0.2 N hydrochloric acid aqueous solution and subjected to lyophilization to give:
(lr,3R,^,5S,75)-3'-(benzofuran-2-yl)-4'-methyl-4'H-l -azaspiro[adamantane-4,5'- [l ,2,4]oxadiazole] hydrochloride (compound 64) (30 mg, 19% yield) as a yellow solid: cSFC analytical tR: 3.51 min., purity: 97.6%; LCMS (D): 1.40 min., 324.1 m/z (M+l); Ή-NMR
(CD3OD, 400 MHz): δ 7.75-7.73 (d, J=7.6 Hz, 1 H), 7.61 -7.59 (d, J=8.4 Hz, 1 H), 7.49-7.45 (m, 2H), 7.37-7.34 (m, 1H), 3.86-3.83(d, J=12.8 Hz, 2H), 3.72-3.68 (d, J=12.8 Hz, 2H), 3.61 (s, 2H), 3.01 (s, 3H), 2.58 (s, 2H), 2.44-2.41 (d, J=13.2 Hz, 2H), 2.26 (s, 1H), 2.14-2.10(d, J=13.6 Hz, 2H), and
(lr,3R,^,5S,7j)-3'-(benzofuran-2-yl)-4'-methyl-4'H-l -azaspiro[adamantane-4,5'- [l ,2,4]oxadiazole] hydrochloride (compound 65) (40 mg, 25% yield) as a yellow solid: cSFC analytical tR: 1.83 min., purity: 99.6%; LCMS (D): 1.42 min, 324.1 m/z (M+l ); Ή-NMR
(CD3OD, 400 MHz): δ 7.76-7.74 (d, J=8.0 Hz, 1H), 7.62-7.59 (d, J=8.4 Hz, 1 H), 7.49-7.45 (m, 2H), 7.38-7.34 (m, 1H), 3.89-3.86 (d, J=12.8 Hz, 2H), 3.64-3.62 (d, J=9.6 Hz, 4H), 3.10 (s, 2H), 2.58 (s, 2H), 2.41 -2.37 (d, J=13.6 Hz, 2H), 2.31 (s, 1H), 2.24-2.21 (d, J=12.8 Hz, 2H);
cSFC analytical conditions: Column: Chiralpak AD-3 100 x 4.6 mm, I.D., 3 μ ι; Mobile phase: 40% ethanol (0.1% methyl-ethyl-amine ("MEA") in C02; Flow rate: 3.0 mL/min.
[00796] Example 58 - (lr.3R,^.5S.7 V3'-(7-chlorobenzorblthiophen-2-vn-4'-methyl-4'H-l- azaspiro|"adamantane-4,5'-[1.2,4~|oxadiazole1 hydrochloride (66) and (lr,3R, r,5S,7^ -3'-(7- chlorobenzo[b1thiophen-2-yn-4'-methyl-4'H-l -azaspiro adamantane-4,5'-[l ,2,41oxadiazole1 hydrochloride (67)
Figure imgf000198_0001
[00797] A solution of compound B-109 (565 mg, 2.68 mmol) and compound C-111 (440 mg, 2.68 mmol) in dichloromethane was cooled to 0 °C and 10% aqueous sodium hypochlorite (3.97 g, 5.36 mmol) was added slowly at 0 °C. The reaction mixture was then warmed to room temperature and stirred for 3 hours. On completion, the reaction mixture was quenched with aqueous sodium sulfite and organics were extracted with DCM (3 x 30 mL). The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, concentrated in vacuo and purified by prep-HPLC [Instrument: Shimadzu pump LC-20A; Column: Phenomenex Synergi C18 150*30 mm, particle size: 4um; Mobile phase: 30-55% acetonitrile in H20 (add 0.75% TFA, v/v)] to give a clean mixture of compounds 66 and 67 (160 mg, 16% yield) as a yellow solid.
[00798] Separation:
[00799] A solution of compounds 66 and 67 (160 mg, 0.43 mmol) in methanol (4 mL) was separated by SFC (Instrument: SFC 80; Column: Chiralpak AD-H 250x25 mm I.D., 10 μηι;
Mobile phase: 40% ethanol (0.01% NH3.H20) in C02) at room temperature. Each set of collected fractions were concentrated at room temperature. The two products were then each dissolved in 0.2 N hydrochloric acid aqueous solution and subjected to lyophilization to give:
(l r^R^i^S^^HV-chlorobenzo^thiophen^-ylH'-methyl^'H-l - azaspiro[adamantane-4,5'-[l ,2,4]oxadiazole] hydrochloride (compound 66) (23 mg, 14% yield) as a yellow solid: cSFC analytical tR: 2.09 min., purity: 100.0%; LCMS (D): 1.72 min., 374.1 m/z (M+l); Ή-NMR (CD3OD, 400 MHz): δ 7.97 (s, 1 H), 7.92-7.90 (d, J=7.2 Hz, 1 H), 7.52-7.48 (m, 2H), 3.88-3.85 (d, J=12.4 Hz, 2H), 3.64-3.62 (d, J=10.4 Hz, 4H), 3.06 (s, 3H), 2.58 (s, 2H), 2.40- 2.37 (d, J=13.6 Hz, 2H), 2.31 (s, 1H), 2.24-2.10 (d, J=12.8 Hz, 2H), and (lr,3R,^,5S, 75)-3'-(7-chlorobenzo[b]thiophen-2-yl)-4'-methyl-4'H-l- azaspiro[adamantane-4,5'-[l ,2,4]oxadiazole] hydrochloride (compound 67) (25 mg, 16% yield) as a yellow solid: cSFC analytical tR: 1.49 min., purity: 100.0%; LCMS (D): 1.73 min, 374.1 m/z (M+l); Ή-NMR (CD3OD, 400 MHz): δ 7.97 (s, 1H), 7.90-7.88 (d, J=7.2 Hz, 1H), 7.52-7.45 (m, 2H), 3.87-7.84 (d, J=12.8 Hz, 2H), 3.80-3.78 (d, J=l 1.6 Hz, 2H), 3.61 (s, 2H), 2.98 (s, 3H), 2.57 (s, 2H), 2.43-2.40 (d, J=12.8 Hz, 2H), 2.25 (s, 1H), 2.14-2.10 (d, J=13.6 Hz, 2H);
cSFC analytical conditions: Column: Chiralpak AD-3 100 x 4.6 mm, I.D., 3 μπι; Mobile phase: 40% ethanol (0.05% DEA) in C02; Flow rate: 1.2 mL/min.
[00800] Example 59 - (+/- -2-(4-(2,4-dimethoxybenzyl)-4H-l'-azaspirorri.2.41oxadiazole- 5,3'-bicyclo|"2.2.21octa -3-yl)benzo[b1thiophene-7-carbonitrile (68)
Figure imgf000199_0001
[00801] To a mixture of compound B-112 (0.46 g, 2.3 mmol) and compound C-108 (1.3 g,
4.6 mmol) in dichloromethane (10 mL) was added 10% aqueous sodium hypochlorite (3.4 g, 4.6 mmol) dropwise at 0 °C. The reaction was allowed to warm to room temperature and was stirred at this temperature for 3 hours. On completion, the reaction mixture was filtered and the filtrate was concentrated. The residue was purified by prep-HPLC [Instrument: HPLC-C; Column:
GEMINI 200*50 mm, particle size: 10 μπι; Mobile phase: 45-65% acetonitrile in H20 (add 0.5% NH3 H20, v/v)] to give racemate 68 (600 mg, 55% yield) as a white solid. Racemate 68 is a mixture of (R)-2-(4-(2,4-dimethoxybenzyl)-4H-l '-azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octan]-3-yl)benzo[b]thiophene-7-carbonitrile (when deprotected provides (R)-2- (4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octan]-3-yl)benzo[b]thiophene-7- carbonitrile), and (S)-2-(4-(2,4-dimethoxybenzyl)-4H- r-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octan]-3-yl)benzo[b]thiophene-7-carbonitrile (when deprotected provides (S)-2- (4H-l'-azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octan]-3-yl)benzo[b]thiophene-7- carbonitrile).
[00802] Chiral Separation:
[00803] A solution of racemate 68 (0.20 g, 0.42 mmol) in 5 ml of ethanol was separated by SFC (Instrument: SFC 80; Column: Chiralpak OD-3 100x4.6mm I.D., particle size: 3 μπι; Mobile phase: 50% ethanol (0.01% NH3 H20) in C02) at room temperature. Each set of collected fractions was concentrated at room temperature and then subjected to lyophilization to give:
2-(4-(2,4-dimethoxybenzyl)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octan]-3- yl)benzo[b]thiophene-7-carbonitrile -enantiomerl (compound 68a) (80 mg, 40% yield), and 2-(4-(2,4-dimethoxybenzyl)-4H-r-azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octan]-3- yl) benzo[b]thiophene-7-carbonitrile -enantiomer2 (compound 68b) (90 mg, 45% yield) as white solid
[00804] Example 60 - 2-(4H-l '-azaspirorn ,2.41oxadiazole-5.3'-bicvclor2.2.21octan1-3- yDbenzo[b]thiophene-7-carbonitrile (69a)
[00805] Compound 68a (15 mg, 0.030 mmol) was dissolved in 10% trifluoroacetic acid in dichloromethane (3 mL) and the reaction was stirred at 0 °C for 1 hour. On completion, the reaction was filtered and the resulting filtrate was concentrated and purified by prep-HPLC
[Instrument: Shimadzu pump LC-20A; Column: Phenomenex Synergi CI 8 200*25mm, particle size: 5 μπι; Mobile phase: 24-53% acetonitrile in H20 (Add 0.5%o TFA, v/v)]. The product was then subjected to lyophilization to give 2-(4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octan]-3-yl)benzo[b]thiophene-7-carbonitrile -enantiomerl trifluoroacetate
(compound 69a) (8.0 mg, 80% yield ) as a yellow solid: cSFC analytical tR: 1.56 min., purity: 98.6%; LCMS (C): 1.44 min., 325 m/z (M+l ); 1 H-NMR (CD3OD, 400 MHz): δ 8.19-8.17 (d, J=8.0 Hz, 1H), 7.88-7.87 (m, 2H), 7.61 -7.57 (t, J=8.0 Hz, 1 H), 3.80-3.76 (m, 1 H), 3.63-3.59 (m, 1 H), 3.46-3.37 (m, 4H), 2.43-2.40 (m, 2H), 2.26-2.25 (m, 1 H), 2.17-2.01 (m, 2H);
cSFC analytical conditions: Column: Chiralpak AD-3 100x4.6mm I.D., 3 μπι; Mobile phase: 50%> ethanol (0.05% DEA) in C02; Flow rate: 3.0 mL/min.; Back pressure: .100 bar.
[00806] Example 61 - 2-(4H-l '-azaspirorri ,2,41oxadiazole-5.3'-bicvclor2.2.21octanl-3- yl)benzorb]thiophene-7-carbonitrile (69b)
[00807] Compound 68b (15 mg, 0.030 mmol) was dissolved in 10% trifluoroacetic acid in dichloromethane (3 mL) and the reaction was stirred at 0 °C for 1 hours. On completion, the reaction was filtered and the resulting filtrate was concentrated and purified by prep-HPLC
[Instrument: GX-B; Column: Phenomenex Synergi CI 8 200*25mm, particle size: 5 μπι; Mobile phase: 24-53%> acetonitrile in H20 (Add 0.5%o TFA, v/v)]. The product was then subjected to lyophilization to give 2-(4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octan]-3- yl)benzo[b]thiophene-7-carbonitrile-enantiomer2 trifluoroacetate (compound 69b) (6.0 mg, 60% yield) as a yellow solid: cSFC analytical tR: 1.02 min., purity: 99.6%; LCMS (C): 1.44 min., 325 m/z (M+l ); 1H-NMR (CD3OD, 400 MHz): δ 8.20-8.18 (d, J=8 Hz, 1 H), 7.90-7.88 (m, 2H), 7.62- 7.58 (t, J=8 Hz, 1 H), 3.80-3.76 (m, 1H), 3.62-3.58 (m, 1H), 3.46-3.35 (m, 4H), 2.43-2.40 (m, 2H), 2.26-2.15 (m, 1H), 2.14-1.98 (m, 2H);
cSFC analytical conditions: Column: Chiralpak AD-3 100x4.6mm I.D., 3 μπι; Mobile phase: 50%> ethanol (0.05% DEA) in C02; Flow rate: 3.0 mL/min.; Back pressure: 100 bar.
[00808] Example 62 - r+/-V4-(2.4-dimethoxybenzvn-3-(,isoquinolin-3-vn-4H-l '- azaspirorn ,2,4]oxadiazole-5,3'-bicvclo[2,2.2"|octanel (70)
Figure imgf000201_0001
[00809] To a mixture of compound B-107 (0.60 g, 3.5 mmol) and compound C-108 (1.0 g,
3.5 mmol) in dichloromethane (6 mL) was added 10% aqueous sodium hypochlorite (10 g, 14 mmol) dropwise at 0 °C. The reaction was allowed to warm to room temperature and stirred at this temperature for 3 hours. On completion, the reaction was filtered and the resulting filtrate was concentrated and purified by prep-HPLC [Instrument: GX-A; Column: Phenomenex Gemini CI 8 150*25 mm, particle size: 10 μπι; Mobile phase: 36-66% acetonitrile in H20 (add 0.5% NH3 H20, v/v)] to give racemate 70 (0.3 g, 20% yield) as a white solid.
[00810] Example 63 - (+/-)-3-(isoquinolin-3-yl)-4H-l '-azaspirorrK2,41oxadiazole-5,3'- bicvclor2.2.21octanel (71)
Figure imgf000201_0002
[00811] To racemate 70 (40 mg, 70 μπιοΐ) was added 10% trifluoroacetic
acid/dichloromethane (3 mL) and the reaction was stirred at 0 °C for 2 hours. On completion, the reaction was diluted with water (5 mL) and 0.5% aqueous hydrochloric acid (2 mL). The resulting solution was concentrated under reduced pressure at room temperature and then lyophilized to give racemate 71 (19.0 mg, 85% yield) as a yellow solid: LCMS (A): 0.63 min., 295.0 m/z (M+l); Ή-NMR (CD3OD, 400 MHz): δ 9.55 (s, 1 H), 8.52 (s, 1 H), 8.38-8.36 (d, J=8.0 Hz, 1 H), 8.21-8.19 (d, J=8.4 Hz, 1 H), 8.09-8.05 (t, J=7.2 Hz, 1H), 7.97-7.95 (m, 1H), 3.84-3.81 (d, J=14.0 Hz, 1 H), 3.74-3.71 (d, J=14.0 Hz, 1H) , 3.48-3.44 (m, 4H), 2.49-2.35 (m, 3H), 2.17-2.06 (m, 2H). Racemate 71 is a mixture of HCI salts of (R)-3-(isoquinolin-3-yl)-4H-l '- azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane] and (S)-3-(isoquinolin-3-yl)-4H-l '- azaspiro[[l,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane].
[00812] Example 64 - (+/-)-4-(2,4-dimethoxybenzvn-3-(5-phenyl-1.3.4-oxadiazol-2-yl)-4H- l 'azaspirorrL2,41adiazole-5,3'-bicyclo 2.2.21octanel (72)
[00813] To a solution of B-129 (0.90 g, 4.0 mmol) and C-108 (1.1 g, 4.0 mmol) in dichloromethane (20 mL) was added triethylamine (0.4 g, 4.0 mmol) at room temperature and the resulting mixture was stirred at room temperature for 2 hours. On completion, the reaction was concentrated and purified by silica gel chromatography [dichloromethane : methanol = 20: 1] and prep-HPLC [Instrument: GX-F; Column: Phenomenex Gemini CI 8 150*25mm, particle size: 5 μπι; Mobile phase: 37-67% acetonitrile in H20 (add 0.5% NH3.H20, v/v)] to give racemate 72 (0.1 g, 6% yield) as a white solid. LCMS: (ES+) m/z (M+H)+ = 462.2, tR=0.668.
[00814] Example 65 - (+/-)-3-(5-phenyl-l ,3,4-oxadiazol-2-ylV4H-l '-
Figure imgf000202_0002
[00815] To racemate 72 (50 mg, 0.1 1 mmol) was added 10% trifluoroacetic
acid/dichloromethane (3 mL) and the reaction was stirred at 0 °C for 2 hours. On completion, the reaction was filtered and the resulting filtrate was concentrated and purified by prep-HPLC
[Instrument: GX-E; Column: Agella Venusil ASB C18 150*21.2mm, particle size: 5 μηι; Mobile phase: 12-42% acetonitrile in H20 (add 0.5% HCI, v/v)]. The product was then subjected to lyophilization to give 3-(5-phenyl-l ,3,4-oxadiazol-2-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane]-hydrochloride (racemate 73) (15 mg, 39% yield) as a yellow solid: LCMS (A): 0.644 min., 312.0 m/z (M+l); Ή-NMR (CD3OD, 400 MHz): δ 8.16-8.14 (d, J=8.0 Hz, 2H), 7.70-7.64 (m, 3H), 3.85-3.81 (dd, Jl=14.4 Hz, J2=2.0 Hz, IH), 3.67-3.63 (dd, Jl=14.4 Hz, J2=1.6 Hz, IH), 3.50-3.33 (m, 4H), 2.50-2.40 (m, 2H), 2.28-2.25 (m, IH), 2.18-2.01 (m, 2H). Racemate 73 is a mixture of HCI salts of (R)-3-(5-phenyl-l ,3,4-oxadiazol-2-yl)-4H-l '- azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane] and (S)-3-(5-phenyl-l ,3,4-oxadiazol-2-yl)- 4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane]. [00816] Example 66 - (,+/-')-4-(2,4-dimethoxybenzyl)-3-(6-methoxybenzo[dlthiazol-2-yl)- 4H-l '-azaspiro [[l,2,41oxadiazole-5,3'-bicyclo[2.2.21octane1 (74)
Figure imgf000203_0001
[00817] To a solution of compound B-122 (1.3 g, 6.3 mmol) and compound C-108 (2.1 g, 7.5 mmol) in dichloromethane (13 mL) was added 10% aqueous sodium hypochlorite (18.5 g, 25 mmol) dropwise at 0 °C. The resulting solution was warmed to room temperature and stirred at this temperature for 3 hours. On completion, the reaction was filtered, and the filtrate was concentrated. The residue was purified by prep-HPLC [Instrument: GX-C; Column: Phenomenex SYNERGI CI 8 150*30mm; particle size: 4μπι; Mobile phase: 60-90% acetonitrile in H20 (add 0.5% NH3 ■ H20, v/v)] to give racemate 74 (65 mg, 2% yield) as a yellow solid. LCMS: (ES+) m/z (M+H)+ = 481.2, tR = 3.025. Racemate 74 is a mixture of (R)-4-(2,4-dimethoxybenzyl)-3- (6-methoxybenzo[d]thiazol-2-yl)-4H-l '-azaspiro [[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane] (when deprotected provides (R)-3-(6-methoxybenzo[d]thiazoI-2-yl)-4H-l '- azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane]), and (S)-4-(2,4-dimethoxybenzyl)-3-(6- methoxybenzo[d]thiazol-2-yl)-4H-l '-azaspiro [[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane] (when deprotected provides (S)-3-(6-methoxybenzo[d]thiazol-2-yl)-4H-l '- azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane]).
[00818] Chiral Separation:
[00819] A solution of racemate 74 (65 mg, 0.16 mmol) in 5 mL of ethanol was separated by SFC (Instrument: SFC 80; Column: Chiralpak AD-H 250^25 mm I.D., 10 μπι; Mobile phase: 60% ethanol (0.01% NH3 H20) in C02) at room temperature. Each set of collected fractions was concentrated at room temperature and then subjected to lyophilization to give:
4-(2,4-dimethoxybenzyl)-3-(6-methoxybenzo[d]thiazol-2-yl)-4H-l '- azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane] -enantiomerl (compound 74a) (32 mg, 50% yield), and
4-(2,4-dimethoxybenzyl)-3-(6-methoxybenzo[d]thiazol-2-yl)-4H-l '- azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane] -enantiomer2 (compound 74b) (26 mg, 40% yield) as a yellow solid.
[00820] Example 67 - 3-(6-methoxybenzo[d1thiazol-2-yl)-4H-l'-azaspiro L2,41oxadiazole- 5.3'-bicvclor2.2.21octanel (75a) [00821] To compound 74a (37 mg, 0.077 mmol) was added 10% trifluoroacetic
acid/dichloromethane (4 mL), and the reaction was stirred at 0 °C for 1 hour. On completion, the reaction was filtered, and the resulting filtrate was concentrated and purified by prep-HPLC [Instrument: GX-B; Column: Phenomenex Synergi CI 8 200*25mm; particle size: Ι Ομηι; Mobile phase: 18-48% acetonitrile in H20 (add 0.5% TFA, v/v)]. The collected fractions were then subjected to lyophilization to give 3-(6-methoxybenzo[d]thiazol-2-yl)-4H-l'- azaspiro[[l ,2,4]oxadiazoIe-5,3'-bicyclo[2.2.2]octane]-enantiomerl trifluoroacetate (compound 75a) (22 mg, 87% yield ) as a yellow solid: cSFC analytical tR: 1.23 min„ purity: 95.9%; LCMS (C): 1.39 min., 331.1 m/z (M+l ); Ή-NMR (CD3OD, 400 MHz): δ 7.99-7.96 (d, J = 9.2 Hz, 1 H), 7.60-7.59 (d, J = 2.4 Hz, 1 H), 7.22-7.19 (dd, J = 8.8 Hz, 2.4 Hz, 1H), 3.92 (s, 3H), 3.82-3.78 (dd, J = 14.4 Hz, 2.0 Hz, 1 H), 3.64-3.60 (dd, J = 14.0 Hz, 2.0 Hz, 1 H), 3.45-3.38 (m, 4H), 2.47-2.41 (m, 2H), 2.29-2.25 (m, 1 H), 2.18-2.13 (m, 1 H). 2.08-2.03 (m, 1 H);
cSFC analytical conditions: Column: Chiralpak AD-3 100x4.6mm, I.D., 3μιη; Mobile phase: 40% ethanol (0.05% DEA) in C02; Flow rate: 3mL/min.; Wavelength: 220nm.
[00822] Example 68 - 3-(6-methoxybenzord1thiazol-2-yl)-4H-r-azaspirorn ,2,41oxadiazole- S,3'-bicvclor2.2.21octane1 (75b)
[00823] To compound 74b (26 mg, 0.054 mmol) was added 10% trifluoroacetic
acid/dichloromethane (3 mL), and the reaction was stirred at 0 °C for 1 hour. On completion, the reaction was filtered, and the resulting filtrate was concentrated and purified by prep-HPLC [Instrument: GX-B; Column: Phenomenex Synergi CI 8 200*25mm; particle size: Ι Ομπι; Mobile phase: 18-48% acetonitrile in H20 (add 0.5% TFA, v/v)]. The collected fractions were then subjected to lyophilization to give 3-(6-methoxybenzo[d]thiazol-2-yl)-4H-l '- azaspiro[[l,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane]-enantiomer2 trifluoroacetate (compound 75b) (18 mg, 90% yield) as a yellow solid: cSFC analytical tR: 1.80 min., purity: 95.8%; LCMS (C): 1.36 min., 331.1 m/z (M+l); Ή-NMR (CD3OD, 400 MHz): δ 7.98-7.96 (d, J = 8.4 Hz, 1 H), 7.60-7.59 (d, J = 2.0 Hz, 1H), 7.22-7.19 (dd, J = 8.8 Hz, 2.4 Hz, 1H), 3.92 (s, 3H), 3.82-3.79 (d, J = 14.4 Hz, 1 H), 3.64-3.60 (dd, J = 14.2 Hz, 2.0 Hz, 1H), 3.44-3.38 (m, 4H), 2.47-2.41 (m, 2H), 2.33-2.25 (m, 1 H), 2.16-2.10 (m, 1H). 2.08-2.00 (m, 1 H);
cSFC analytical conditions: Column: Chiralpak AD-3 100x4.6mm, I.D., 3μηι; Mobile phase: 40% ethanol (0.05% DEA) in C02; Flow rate: 3mL/min.; Wavelength: 220nm.
[00824] Example 69 - (+/-)-4-(2,4-dimethoxybenzyl)-3-(6-methoxybenzord1thiazol-2-yl)- 4H-1 '-azaspiro [[ 1 ,2,4]oxadiazole-5,3'-bicyclo[2.2.21octane] (76)
Figure imgf000205_0001
[00825] To a mixture of compound B-133 (1.0 g, 60 μηιοΐ) and compound C-108 (1.9 g, 70 μπιοΐ) in dich!oromethane (25 mL) was added 10% aqueous sodium hypochlorite (8.4 g, 1 1 mmol) slowly at 0 °C. After stirring at room temperature overnight, the mixture was filtered. The filtrate was concentrated in vacuo and purified by prep-HPLC [Instrument: Shimadzu pump LC- 20A; Column: GEMINI 200^50 mm, particle size: 10 μιη; Mobile phase: 35-58.5% acetonitrile in H20 (add 0.5% NH3 H20, v/v)] to give racemate 76 (0.2 g, 8% yield) as a yellow solid. LCMS: (ES+) m/z (M+H)+ = 451.2, tR=l .722. Racemate 76 is a mixture of (R)-4-(2,4- dimethoxybenzyl)-3-(6-methoxybenzo[d]thiazol-2-yl)-4H-l '-azaspiro [[1 ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane] (when deprotected provides (R)-3-(thieno[2,3-b]pyridin-2-yl)-4H-l '- azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2] octane]), and (S)-4-(2,4-dimethoxybenzyl)-3-(6- methoxybenzo[d]thiazol-2-yl)-4H-l '-azaspiro [[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane] (when deprotected provides (S)-3-(thieno[2,3-b]pyridin-2-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2] octane]).
[00826] Chiral Separation:
[00827] A solution of racemate 76 (0.2 g, 0.44 mmol) in 5 mL of ethanol was separated by SFC (Instrument: SFC 80; Column: Chiralpak AD-H 250x25 mm I.D., 10 μπι; Mobile phase: 50% ethanol (0.1% NH3 H20) in C02) at room temperature. Each set of collected fractions was concentrated at room temperature and then subjected to lyophilization to give:
4-(2,4-dimethoxybenzyl)-3-(thieno[2,3-b] pyridine-2-yl)-4H-l '- azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane]-enantiomerl (compound 76a) (70 mg, 35% yield), and
4-(2,4-dimethoxybenzyl)-3-(thieno[2,3-b] pyridine-2-yl)-4H-l '- azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane]-enantiomer2 (compound 76b) (70 mg, 35% yield) as a yellow solid.
[00828] Example 70 - 3-(thienor2.3-b1pyridin-2-yl)-4H-l '-azaspirorrK2.41oxadiazole-5.3l- bicyclo[2.2.2] octanel- enantiomerl hydrochloride (77a)
[00829] To compound 76a (65 mg, 0.14 mmol) was added 10% trifluoroacetic
acid/dichloromethane (2 mL) and the reaction was stirred at 0 °C for 2 hour. On completion, the reaction was filtered, and the resulting filtrate was concentrated and purified by prep-HPLC
[Instrument: GX-E; Column: Agella Venusil ASB C18 150x21.2mm, particle size: 5μιη; Mobile phase: 13-43% acetonitrile in H20 (add 0.5% HC1, v/v)]. The product was then subjected to lyophilization to give 3-(thieno[2,3-b]pyridin-2-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane] -enantiomerl hydrochloride (compound 77a) (31 mg, 72% yield ) as a yellow solid: cSFC analytical tR: 0.943 min., purity: 95.05%; LCMS (E): 0.902 min, 301.1 m/z (M+1); 1 H-NMR (CD3OD, 400 MHz): δ 8.80-7.79 (d, J=4.8 Hz, IH), 8.67-8.65 (d, J=8.4 Hz, I H), 7.98 (s, I H), 7.77-7.74 (t, J=6.4 Hz, IH), 3.80-3.76 (d, J=14.4 Hz, IH), 3.71 -3.67 (d, J=14.4 Hz, I H), 3.45-3.36 (m, 4H), 2.44-2.31 (m, 3H), 2.16-2.00 (m, 2H).
cSFC analytical conditions: Column: Chiralpak AD-3 100x4.6mm, I.D., 3μπι; Mobile phase: 40% ethanol (0.05% DEA) in C02; Flow rate: 3mL/min.; Wavelength: 220nm.
[00830] Example 71 - 3-(thienor23-b1pyridin-2-vn-4H-l '-azaspirorrL2,41oxadiazole-5.3'- bicyclo[2,2.2] octane]- enantiomer2 hydrochloride (77b)
[00831] To compound 76b (65 mg, 0.14 mmol) was added 10% trifluoroacetic
acid/dichloromethane (2 mL) and the reaction was stirred at 0 °C for 2 hour. On completion, the reaction was filtered, and the resulting filtrate was concentrated and purified by prep-HPLC
[Instrument: GX-E; Column: Agella Venusil ASB C18 150x21.2mm, particle size: 5μπι; Mobile phase: 13-43%» acetonitrile in H20 (add 0.5% HC1, v/v)]. The product was then subjected to lyophilization to give 3-(thieno[2,3-b]pyridin-2-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane] -enantiomer2 hydrochloride (compound 77b) (32 mg, 74% yield) as a yellow solid: cSFC analytical tR: 1.630 min., purity: 96.19%; LCMS (E): 0.904 min., 301.1 m/z (M+1); 1 H-NMR (CD3OD, 400 MHz): δ 8.80-7.79 (d, J=5.6 Hz, IH), 8.67-8.65 (d, J=8.4 Hz , I H), 7.98 (s, IH), 7.77-7.74 (t, J= 6.8 Hz, I H), 3.80-3.76 (d, J=14.4 Hz, I H), 3.71-3.67 (d, J=14.4 Hz, I H), 3.45-3.36 (m, 4H), 2.44-2.31 (m, 3H), 2.16-2.00 (m, 2H).
cSFC analytical conditions: Column: Chiralpak AD-3 100x4.6mm, I.D., 3 μηι; Mobile phase: 40% ethanol (0.05% DEA) in C02; Flow rate: 3mL/min.; Wavelength: 220nm.
[00832] Example 72 - (+/-)-4-(2,4-dimethoxybenzvn-3-(thienor3.2-blpyridin-2-yl)-4H-l '- azaspiro 1 ,2,41 oxadiazole-5.3'-bicyclo 2.2.2]octane] (78)
Figure imgf000206_0001
[00833] To a mixture of compound B-137 (2.0 g, 1 1 mmol) and compound C-108 (3.0 g, 1 1 mmol) in dichloromethane (20 mL) was added 10% aqueous sodium hypochlorite (16 g, 22 mmol) slowly at 0 °C. The reaction was allowed to warm to room temperature and was stirred for 2 hours. On completion, the reaction was filtered, and the resulting filtrate was concentrated and purified by prep-HPLC [Instrument: Shimadzu pump LC-20A; Column: GEMINI 200 χ 50 mm, particle size: 10 μπι; Mobile phase: 55-66.7% acetonitrile in H20 (add 0.5% NH3 H20, v/v)] to give racemate 78 ( 1 .1 g, 30% yield) as a white solid. Racemate 78 is a mixture of (R)-4-(2,4- dimethoxyben2yl)-3-(thieno[3,2-b]pyridin-2-yl)-4H-l '-azaspiro[[l ,2,4] oxadiazole-5,3'- bicyclo[2.2.2]octane] (when deprotected provides (R)-3-(thieno[3,2-b]pyridin-2-yl)-4H-l '- azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2] octane]), and (S)-4-(2,4-dimethoxybenzyl)-3- (thieno[3,2-b]pyridin-2-yl)-4H-l '-azaspiro[[l ,2,4] oxadiazole-5,3'-bicyclo[2.2.2]octane] (when deprotected provides (S)-3-(thieno[3,2-b]pyridin-2-yl)-4H-l '-azaspiro[[ l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2] octane]).
[00834] Chiral Separation:
[00835] A solution of racemate 78 (0.50 g, 1.1 mmol) in 10 mL of ethanol was separated by SFC (Instrument: SFC 80; Column: Chiralpak AD-H 250 25 mm I.D., 10 μιη; Mobile phase: 60%) ethanol (0.01% NH3 H20) in C02) at room temperature. Each set of collected fractions was concentrated at room temperature and then subjected to lyophilization to give:
4-(2,4-dimethoxybenzyl)-3-(thieno[3,2-b]pyridin-2-yl)-4H-l '-azaspiro[[ l ,2,4]oxadiazole- 5,3'-bicyclo[2.2.2]octane]-enantiomerl (compound 78a) (0.1 1 g, 22%> yield), and
4-(2,4-dimethoxybenzyl)-3-(thieno[3,2-b]pyridin-2-yl)-4H-l '-azaspiro[[ l ,2,4]oxadiazole- 5,3'-bicyclo[2.2.2]octane]-enantiomer2 (compound 78b) (0.13 g, 26% yield) as white solid.
[00836] Example 73 - 3-(thienor3.2-b1pyridin-2-yl)-4H-l '-azaspirorri ,2,41oxadiazole-5.3'- bicyclo[2.2.2] octane] (79a)
[00837] To compound 78a (30 mg, 67 μιηοΐ) was added 10% trifluoroacetic acid in dichloromethane (4 mL), and the reaction was stirred at 0 °C for 0.5 hour. On completion, the reaction was concentrated and purified by prep-HPLC [Instrument: Shimadzu pump LC-20A; Column: Phenomenex Gemini CI 8 150 x 30 mm, particle size: 5 μιη; Mobile phase: 42-72% acetonitrile in H20 (add 0.5% HC1, v/v)]. The product was then subjected to lyophilization to give 3-(thieno[3,2-b]pyridin-2-yl)-4H-l '-azaspiro[[l ,2,4] oxadiazole-5,3'-bicyclo[2.2.2]octane]- enantiomerl hydrochloride (compound 79a) (15 mg, 80% yield ) as a yellow solid: cSFC analytical tR: 3.55 min., purity: 90.3%; LCMS (D): 1.90 min., 301 .4 m/z (M+l ); Ή-NMR (CD3OD, 400 MHz): δ 8.76-8.75 (d, J=4.8 Hz, 1 H), 8.56-8.54 (d, J=8.0 Hz, 1 H), 7.92 (s, 1 H), 7.58-7.54 (dd, J,=8.4 Hz, J2=4.8 Hz, 1 H), 3.84-3.80 (dd, J,=14.4 Hz, J2=2.0 Hz, 1 H), 3.66-3.62 (dd, J,=14.0 Hz, J2=2.0 Hz, 1 H), 3.46-3.33 (m, 4H), 2.47-2.43 (m, 2H), 2.30-2.28 (m, 1 H), 2.20- 2.04 (m, 2H);
cSFC analytical conditions: Column: Chiracel IC 250 χ 4.6 mm, I.D., 5 μηι; Mobile phase: 50% isopropanol (0.05% DEA) in C02; Flow rate: 2.4 mL/min.; Back pressure: 120 bar.
[00838] Example 74 - 3-fthienor3.2-b1pyridin-2-ylV4H-r-azaspiro[n,2,4]oxadiazole-5.3'- bicyclo["2.2.21 octane] (79b)
[00839] To compound 78b (60 mg, 0.13 mmol) was added 10% trifluoroacetic acid in dichloromethane (5 mL), and the reaction was stirred at 0 °C for 0.5 hour. On completion, the reaction was concentrated and purified by prep-HPLC [Instrument: Shimadzu pump LC-20A; Column: Phenomenex Gemini C18 150 χ 30 mm, particle size: 5 μηι; Mobile phase: 42-72% acetonitrile in H20 (add 0.5% HCl, v/v)]. The product was then subjected to lyophilization to give 3-(thieno[3,2-b]pyridin-2-yl)-4H-l '-azaspiro[[l ,2,4] oxadiazole-5,3'-bicyclo[2.2.2]octane]- enantiomer2 hydrochloride (compound 79b) (17 mg, 44% yield) as a yellow solid: cSFC analytical tR: 2.92 min., purity: 96%; LCMS (B): 0.47 min., 301.4 m/z (M+1 ); Ή-NMR (CD3OD, 400 MHz): δ 8.76-8.75 (d, J=4.0 Hz, I H), 8.56-8.54 (d, J=8.4 Hz, IH), 7.93 (s, IH), 7.58-7.55 (q, J,=8.4 Hz, J2=4.8 Hz, IH), 3.84-3.80 (dd, J,=14.4 Hz, J2=2.8 Hz, IH), 3.66-3.62 (dd, J,=14.4 Hz, J2=2.0 Hz, IH), 3.46-3.33 (m, 4H), 2.47-2.43 (m, 2H), 2.29-2.28 (m, IH), 2.19-2.01 (m, 2H); cSFC analytical conditions: Column: Chiracel IC 250 χ 4.6 mm, I.D., 5 μπι; Mobile phase: 50% isopropanol (0.05% DEA) in C02; Flow rate: 2.4 mL/min.; Back pressure: 120 bar.
[00840] Example 75 - (•+/- -4-(2.4-dimethoxybenzylV3-('pyrazolon .5-a1pyridin-2-vn-4H-l'- azaspiro[[l ,2,4]oxadiazole-5J'-bicyclo[2.2.2]octane] (80)
Figure imgf000208_0001
[00841] To a mixture of compound B-144 (2.0 g, 14 mmol) and compound C-108 (3.8 g, 14 mmol) in dichloromethane (20 mL) was added 10% aqueous sodium hypochlorite (20 g, 28 mmol) slowly at 0 °C. The reaction was allowed to warm to room temperature and stirred at this temperature for 2 hours. On completion, the reaction was filtered, and the resulting filtrate was concentrated and purified by prep-HPLC [Instrument: Shimadzu pump LC-20A; Column:
GEMINI 200x50 mm, particle size: 10 μπι; Mobile phase: 55-66.7% acetonitrile in H20 (add 0.5% NH3 H20, v/v)] to give racemate 80 (0.30 g, 5% yield) as a white solid. Racemate 80 is a mixture of (R)-4-(2,4-dimethoxybenzyl)-3-(pyrazolo[l,5-a]pyridin-2-yl)-4H-l '- azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane] (when deprotected provides (R)-3- (pyrazolo[l,5-a]pyridin-2-yl)-4H- -azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane]), and (S)-4-(2,4-dimethoxybenzyl)-3-(pyrazoIo[l ,5-a]pyridin-2-yl)-4H-l'-azaspiro[[l,2,4]oxadiazole- 5,3'-bicyclo[2.2.2]octane] (when deprotected provides (S)-3-(pyrazolo[l,5-a]pyridin-2-yl)-4H-l '- azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane]).
[00842] Chiral Separation:
[00843] A solution of racemate 80 (0.30 g, 0.69 mmol) in 10 mL of ethanol was separated by SFC (Instrument: SFC 80; Column: Chiralpak AD-H 250x25 mm I.D., 10 μηι; Mobile phase: 60% ethanol (0.01% NH3 H20) in C02) at room temperature. Each set of collected fractions was concentrated at room temperature and then subjected to lyophilization to give: 4-(2,4-dimethoxybenzyl)-3-(pyrazolo[l,5-a]pyridin-2-yl)-4H-l'- azaspiro[[l,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane]-enantiomerl (compound 80a) (0.13 g, 43% yield), and
4-(2,4-dimethoxybenzyl)-3-(pyrazolo[l ,5-a]pyridin-2-yl)-4H-l'- azaspiro[[l,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane]-enantiomer2 (compound 80b) (0.13 g, 43% yield) as a white solid.
[00844] Example 76 - 3-(pyrazolori .5-alpyridin-2-yl)-4H-l'-azaspirorn ,2.41oxadiazole-5,3'- bicyclo[2.2.2"|octane] (81a)
[00845] To compound 80a (50 mg, 0.12 mmol) was added 10% trifluoroacetic
acid/dichloromethane (5 mL), and the reaction was stirred at 0 °C for 0.5 hour. On completion, the reaction was concentrated and purified by prep-HPLC [Instrument: Shimadzu pump LC-20A; Column: Phenomenex Gemini CI 8 150x30 mm, particle size: 5 μπι; Mobile phase: 42-72% acetonitrile in H20 (add 0.5% HC1, v/v)]. The product was subjected to lyophilization to give 3- (pyrazolo[l,5-a]pyridin-2-yl)-4H- -azaspiro[[l,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane]- enantiomerl hydrochloride (compound 81a) (21 mg, 57% yield ) as a yellow solid: cSFC analytical tR: 0.77 min., purity: 98.1%; LCMS (D): 1.75 min., 284.2 mix (M+l ); Ή-NMR (CD3OD, 400 MHz): δ 8.60-8.58 (d, J=6.8 Hz, 1 H), 7.73-7.70 (d, J=9.2 Hz, 1 H), 7.32-7.28 (t, 1 H), 7.02-6.99 (t, 1 H), 6.94 (s, 1H), 3.80-3.76 (dd, J,=14.0 Hz, J2=2.0 Hz, 1 H), 3.62-3.58 (dd, J,=14.4 Hz, J2=2.0 Hz, 1H), 3.44-3.38 (m, 4H), 2.44 (m, 2H), 2.33-2.28 (m, 1H), 2.17-2.00 (m, 2H);
cSFC analytical conditions: Column: Chiracel IC 250x4.6 mm, I.D., 5 μιη; Mobile phase: 50% isopropanol (0.05% DEA) in C02; Flow rate: 2.4 mL/min.; Back pressure: 120 bar.
[00846] Example 77 - 3-(pyrazolori .5-a1pyridin-2-vn-4H-l'-azaspirorn .2.41oxadiazole-5.3'- bicyclo[2.2.21octanel (81b)
[00847] To compound 80b (50 mg, 0.12 mmol) was added 10% trifluoroacetic
acid/dichloromethane (5 mL), and the reaction was stirred at 0 °C for 0.5 hour. On completion, the reaction was concentrated and purified by prep-HPLC [Instrument: Shimadzu pump LC-20A; Column: Phenomenex Gemini CI 8 150x30 mm, particle size: 5 μπι; Mobile phase: 42-72% acetonitrile in H20 (add 0.5% HC1, v/v)]. The product was then subjected to lyophilization to give 3-(pyrazolo[l,5-a]pyridin-2-yl)-4H-l'-azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane]- enantiomer2 hydrochloride (compound 81b) (16 mg, 43% yield) as yellow solid: cSFC analytical tR: 1.44 min., purity: 97 %; LCMS (B): 1.02 min., 284.2 m/z (M+l ); Ή-NMR (CD3OD, 400 MHz): 88.60-8.58 (d, J=6.8 Hz, 1H), 7.73-7.70 (d, J=9.2 Hz, 1H), 7.32-7.28 (t, 1H), 7.02-6.99 (t, 1H), 6.94 (s, 1Η)3.79-3.76 (dd, J,=14.0 Hz, J2=2.0 Hz, 1 H), 3.62-3.58 (dd, J,=14.4 Hz, J2=2.0 Hz, 1H), 3.44-3.38 (m, 4H), 2.44 (m, 2H), 2.30-2.28 (m, 1H), 2.17-2.00 (m, 2H);
cSFC analytical conditions: Column: Chiracel IC 250x4.6 mm, I.D., 5 μιη; Mobile phase: 50% isopropanol (0.05% DEA) in C02; Flow rate: 2.4 mL/min.; Back pressure: 120 bar. [00848] Example 78 - (+/-)-4-(2,4-dimethoxybenzvn-3-(6-fluorobenzorb1thiophen-2-vn-4H- l '-azaspiro [[L2,4]oxadiazole-5,,3'-bicyclo[2.2.21octanel (82)
Figure imgf000210_0001
[00849] To a mixture of compound B-148 (2.6 g, 13 mmol) and compound C-108 (3.8 g, 14 mmol) in dichloromethane (20 mL) was added 10% aqueous sodium hypochlorite (20 g, 26 mmol) slowly at 0 °C. The reaction was allowed to warm to room temperature and was stirred for 2 hours. On completion, the reaction was filtered, and the resulting filtrate was concentrated and purified by prep-HPLC [Instrument: Shimadzu pump LC-20A; Column: GEMINI 200 x 50 mm, particle size: 10 μπι; Mobile phase: 55-66.7% acetonitrile in H20 (add 0.5% NH3 H20, v/v)] to give racemate 82 (0.43 g, 12% yield) as a white solid. Racemate 82 is a mixture of (R)-4-(2,4- dimethoxybenzyl)-3-(6-fluorobenzo[b]thiophen-2-yl)-4H-l '-azaspiro [[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane] (when deprotected provides (R)-3-(6-fluorobenzo[b]thiophen-2-yl)-4H-l '- azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo [2.2.2]octane]), and (S)-4-(2,4-dimethoxybenzyl)-3-(6- fluorobenzo[b]thiophen-2-yl)-4H-l '-azaspiro [[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane] (when deprotected provides (S)-3-(6-fluorobenzo[b]thiophen-2-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole- 5,3'-bicyclo [2.2.2] octane]).
[00850] Chiral Separation:
[00851] A solution of racemate 82 (0.28 g, 0.60 mmol) in 10 mL of ethanol was separated by SFC (Instrument: SFC 80; Column: Chiralpak AD-H 250 * 25 mm I.D., 10 μιη; Mobile phase: 60% ethanol (0.01% NH3 H20) in C02) at room temperature. Each set of collected fractions was concentrated at room temperature and then subjected to lyophilization to give:
4-(2,4-dimethoxybenzyl)-3-(6-fluorobenzo[b]thiophen-2-yl)-4H-l '- azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane]-enantiomerl (compound 82a) (80 mg, 33% yield), and
4-(2,4-dimethoxybenzyl)-3-(6-fluorobenzo[b]thiophen-2-yl)-4H-l'- azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane]-enantiomer2 (compound 82b) (75 mg, 31 % yield) as white solid.
[00852] Example 79 - 3-(6-fluorobenzorb1thiophen-2-vn-4H-l'-azaspirorri .2.41oxadiazole- 5,3'-bicyclo r2.2.21octane1 (83a)
[00853] To compound 82a (80 mg, 0.10 mmol) was added 10% trifluoroacetic acid in dichloromethane (5 mL), and the reaction was stirred at 0 °C for 0.5 hour. On completion, the reaction was concentrated and purified by prep-HPLC [Instrument: Shimadzu pump LC-20A; Column: Phenomenex Gemini CI 8 150 x 30 mm, particle size: 5 μπι; Mobile phase: 42-72% acetonitrile in H20 (add 0.5% HCl, v/v)]. The product was then subjected to lyophilization to give 3-(6-fluorobenzo [b]thiophen-2-yl)-4H-l '-azaspiro [[l,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane]- enantiomerl hydrochloride (compound 83a) (44 mg, 82% yield ) as a white solid: cSFC analytical tR: 2.98 min., purity: 98.8%; LCMS (E): 1.52 min., 318.2 m/z (M+l); 1 H-NMR (CD3OD, 400 MHz): δ 7.93-7.90 (dd,
Figure imgf000211_0001
Hz, J2=5.2 Hz, I H), 7.77 (s, IH), 7.73-7.71 (d, J=8.8 Hz, IH), 7.28-7.23 (dt, J,=8.8 Hz, J2=2.4 Hz, IH), 3.81-3.77 (d, J=14.4 Hz, IH), 3.63-3.59 (d, J=14.0 Hz, IH), 3.45-3.37 (m, 4H), 2.44 (s, 2H), 2.28-2.24 (m, I H), 2.18-2.12 (m, I H), 2.07-2.00 (m, I H);
cSFC analytical conditions: Column: Chiracel IC 250 χ 4.6 mm, I.D., 5 μηι; Mobile phase: 50% isopropanol (0.05% DEA) in C02; Flow rate: 2.4 mL/min.; Back pressure: 120 bar.
[00854] Example 80 - 3-(6-fluorobenzo [b]thiophen-2-yl)-4H-r-azaspiro[Tl ,2,41oxadiazole- 5,3'-bicvclo r2.2.21octanel (83b)
[00855] To compound 82b (75 mg, 0.10 mmol) was added 10% trifluoroacetic acid in dichloromethane (5 mL) and the reaction was stirred at 0 °C for 0.5 hour. On completion, the reaction was filtered, and the resulting filtrate was concentrated and purified by prep-HPLC
[Instrument: Shimadzu pump LC-20A; Column: Phenomenex Gemini CI 8 150 x 30 mm, particle size: 5 μπι; Mobile phase: 42-72% acetonitrile in H20 (add 0.5% HCl, v/v)]. The product was then subjected to lyophilization to give 3-(6-fluorobenzo [b]thiophen-2-yl)-4H-l '- azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane]-enantiomer2 hydrochloride (compound 83b) (45 mg, 82% yield) as a yellow solid: cSFC analytical tR: 2.71 min., purity: 100%; LCMS (E): 1.50 min., 318.2 m/z (M+l); 1 H-NMR (CD3OD, 400 MHz): δ 7.93-7.90 (dd, J,=8.8 Hz, J2=5.2 Hz, I H), 7.77 (s, I H), 7.73-7.71 (d, J=9.2 Hz, IH), 7.28-7.23 (td, J,=9.2 Hz, J2=2.4 Hz, I H), 3.81 -3.77 (d, J=14.0 Hz, I H), 3.63-3.59 (d, J=14.0 Hz, I H), 3.45-3.37 (m, 4H), 2.44 (s, 2H), 2.28-2.26 (m, I H), 2.19-2.15 (m,l H), 2.07-2.02 (m, I H);
cSFC analytical conditions: Column: Chiracel IC 250 x 4.6 mm, I.D., 5 μηι; Mobile phase: 50% isopropanol (0.05% DEA) in C02; Flow rate: 2.4 mL/min.; Back pressure: 120 bar.
[00856] Example 81 - (+/-V4-(,2.4-dimethoxybenzyl)-3-('l -methyl- 1Η-ϊηάο1-2-νΠ-4Η-Γ-
Figure imgf000211_0002
[00857] To a mixture of compound B-149 (1.0 g, 5.7 mmol) and compound C-108 (2.4 g, 8.6 mmol) in dichloromethane (50 mL) was added 10% aqueous sodium hypochlorite (8.1 g, 1 1 mmol) slowly at 0 °C. The reaction was allowed to warm to room temperature and stirred at room temperature for 5 hours. On completion, the reaction was filtered, and the resulting filtrate was concentrated in vacuo and purified by prep-HPLC [Instrument: Shimadzu pump LC-20A;
Column: GEMINI 200 <50 mm, particle size: 10 μηι; Mobile phase: 8-42% acetonitrile in H20 (add 0.5% NH3 H20, v/v)] to give racemate 84 (0.35 g, 14% yield) as a yellow solid. LCMS: (ES+) m/z (M+H)+ = 447.3, tR=l .544.
[00858] Example 82 - (+/-)-3-( 1 -methyl- 1 H-indol-2-vn-4H- 1 '-azaspirorr 1 ,2.41oxadiazole- 5,3'-bicyclo[2.2.2"|octane1 hydrochloride (85)
Figure imgf000212_0001
[00859] To racemate 84 (0.10 g, 0.22 mmol) was added 20% trifluoroacetic
acid/dichloromethane (10 mL), and the reaction was stirred at 25 °C for 24 hours. On completion, the reaction was filtered, and the resulting filtrate was concentrated in vacuo and purified by prep- HPLC [Instrument: GX-E; Column: Agella Venusil ASB C18 150x21 .2mm, particle size: 5 μπι; Mobile phase: 12-42% acetonitrile in H20 (add 0.5% HC1, v/v)]. The collected fractions were concentrated at room temperature and subjected to lyophilization to give (+/-)-3-( l -methyl- 1 H- benzo[d]imidazol-2-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane] hydrochloride (compound 85) (30 mg, 45% yield) as white solid. LCMS (A): 1 .535 min., 297.0 m/z (M+l); Ή- NMR (CD3OD, 400 MHz): δ 7.64-7.62 (d, J=8.4 Hz, I H), 7.48-7.46 (d, J=8.4 Hz, I H), 7.34-7.30 (t, J=7.2 Hz, I H), 7.15-7.1 1 (t, J=7.2 Hz, I H), 7.03 (s, I H), 4.00 (s, 3H), 3.79-3.75 (m, I H), 3.64- 3.60 (m, I H), 3.46-3.41 (m, 4H), 2.48-2.42 (m, 2H), 2.33-2.29 (m, I H), 2.17-2.13 (m, I H), 2.06- 1 .99 (m, I H). Racemate 85 is a mixture of HC1 salts of (R)-3-(l-methyl-l H-indol-2-yl)-4H-l '- azaspiro[[l,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane] and (S)-3-(l -methyl-l H-indol-2-yl)-4H-l'- azaspiro[[l,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane].
[00860] Example 83 - (+/-)-4-(2.4-dimethoxybenzvn-3-(l -methyl- lH-benzord1imidazol-2- yl)-4H- l '-azaspiro[[l ,2,41oxadiazole-5,3'-bicyclo[2.2.2]octane] (86)
Figure imgf000212_0002
[00861] To a mixture of compound B-150 (2.2 g, 13 mmol) and compound C-108 (4.1 g, 15 mmol) in dichloromethane (50 mL) was added 10% aqueous sodium hypochlorite (37 g, 0.50 mol) dropwise at 0 °C. The reaction was allowed to warm to room temperature and stirred at this temperature for 5 hours. On completion, the reaction was filtered, and the resulting filtrate was concentrated and purified by prep-HPLC [Instrument: Shimadzu pump LC-20A; Column:
GEMINI 200x50 mm, particle size: 10 μπα; Mobile phase: 10-40% acetonitrile in H20 (add 0.5% NH3 · H20, v/v)] to give racemate 86 (1.1 g, 20% yield) as a yellow solid. LCMS: (ES+) m/z (M+H)+ = 448.2, tR=l .342.
[00862] Example 84 - (+/-V3-d -methyl-l H-benzordlimidazol-2-vn-4H-l'-
Figure imgf000213_0001
[00863] To racemate 86 (0.10 g, 0.22 mmol) was added 20% trifluoroacetic
acid/dichloromethane (10 mL), and the reaction was stirred at 0 °C for 2 hours. On completion, the reaction was filtered, and the resulting filtrate was concentrated and purified by prep-HPLC [Instrument: GX-E; Column: Agella Venusil ASB CI 8 150x21.2mm, particle size: 5 μηι; Mobile phase: 10-40% acetonitrile in H20 (add 0.5% HCl, v/v)]. The collected fractions were concentrated at room temperature and then subjected to lyophilization to give (+/-)-3-(l -methyl- l H-benzo[d]imidazol-2-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane] hydrochloride (racemate 87) (60 mg, 92% yield) as a white solid. LCMS (C): 1.15 min., 298.1 m/z (M+1 ); Ή-NMR (CD3OD, 400 MHz): δ 7.93-7.91 (d, J=8.0 Hz, 1H), 7.88-7.86 (d, J=7.6 Hz, 1 H), 7.71-7.64 (m, 2H), 4.27 (s, 3H), 3.90-3.81 (m, 2H), 3.50-3.37 (m, 4H), 2.53-2.52 (m, 1 H), 2.43-2.32 (m, 2H), 2.18-2.06 (m, 2H). Racemate 87 is a mixture of HCl salts of (R)-3-(l -methyl- lH-benzo[d]imidazol-2-yl)-4H-l'-azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane] and (S)- 3-(l-methyl-l H-benzo[d]imidazol-2-yl)-4H-l '-azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane],
[00864] Example 85 - (+/-V4-(2.4-dimethoxybenzylV3-(6-fluorobenzofuran -2-yl>4H-l '-
Figure imgf000213_0002
[00865] To a mixture of compound B-154 (1.0 g, 5.6 mmol) and compound C-108 (1.8 g,
6.7 mmol) in dichloromethane (10 mL) was added 10% aqueous sodium hypochlorite (17 g, 22 mmol) dropwise at 0 °C. The reaction was allowed to warm to room temperature and stirred at this temperature for 5 hours. On completion, the reaction was filtered, and the filtrate was concentrated and purified by prep-HPLC [Instrument: GX-A; Column: Phenomenex Gemini CI 8 150*25mm, particle size: 10 μιη; Mobile phase: 40-70% acetonitrile in H20 (add 0.5% NH3 H20, v/v)] to give racemate 88 (0.80 g, 32% yield) as a white solid. Racemate 88 is a mixture of (R)- 4-(2,4-dimethoxybenzyl)-3-(6-fluorobenzofuran -2-yl)-4H-l'-azaspiro[[ 1 ,2,4] oxadiazole-5,3'- bicyclo[2.2.2]octane] (when deprotected provides (R)-3-(6-fluorobenzofuran-2-yl)-4H-l '- azaspiro[[l,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane]), and (S)-4-(2,4-dimethoxybenzyl)-3-(6- fluorobenzofuran -2-yl)-4H-l '-azaspiro[[ 1 ,2,4] oxadiazole-5,3'-bicyclo[2.2.2]octane] (when deprotected provides (S)-3-(6-fluorobenzofuran-2-yl)-4H-l '-azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane]).
[00866] Chiral Separation:
[00867] A solution of racemate 88 (0.80 g, 1.8 mmol) in 10 mL of ethanol was separated by SFC (Instrument: SFC 80; Column: Chiralpak AD-H 250x25 mm I.D., 10 μπι; Mobile phase: 60% IPA(NH3 H20) in C02) at room temperature. Each set of collected fractions was concentrated at room temperature and then subjected to lyophilization to give:
4-(2,4-dimethoxybenzyl)-3-(6-fluorobenzofuran-2-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole- 5,3'-bicyclo[2.2.2]octane] -enantiomerl (compound 88a) (0.20 g, 25% yield), and
4-(2,4-dimethoxybenzyl)-3-(6-fluorobenzofuran-2-yl)-4H-l'-azaspiro[[l ,2,4]oxadiazole- 5,3'-bicyclo[2.2.2]octane] -enantiomer2 (compound 88b) (0.20 g, 25% yield) as a white solid.
[00868] Example 86 - 3-(6-fluorobenzofuran-2-vn-4H-l '-azaspirorri .2,4]oxadiazole-5,3'- bicyclor2.2.2]octane1 (89a)
[00869] To compound 88a (0.10 g, 0.22 mmol) was added 10% trifluoroacetic
acid/dichloromethane (10 mL), and the reaction was stirred at 0 °C for 2 hours. On completion, the reaction was filtered, and the filtrate was concentrated and purified by prep-HPLC
[Instrument: GX-E; Column: AgellaVenusil ASB CI 8 150*21.2mm, particle size: 5 μπι; Mobile phase: 15-45% acetonitrile in H20 (add 0.5% HC1, v/v)]. The collected fractions were subjected to lyophilization to give 3-(6-fluorobenzofuran-2-yl)-4H-r-azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane] -enantiomerl hydrochloride (compound 89a) (34 mg, 52% yield ) as a white solid: cSFC analytical tR: 2.81 min., purity: 99.6%; LCMS (G): 0.63 min., 302.1 m/z (M+l); Ή-NMR (CD3OD, 400 MHz): δ 7.75-7.71 (m, 1 H), 7.41 (s, 1 H), 7.39 (s, 1H), 7.19-7.14 (m, 1H), 3.81-3.77 (m, 1H), 3.66-3.62 (m, 1H), 3.49-3.33 (m, 4H), 2.44-2.38 (m, 2H), 2.31 -2.27 (m, 1 H) , 2.17-2.13 (m, 1 H), 2.06-2.03(m, 1 H);
cSFC analytical conditions: Column: Chiralpak AD-3 100x4.6mm, I.D., 3μπι; Mobile phase: methanol (0.05% DEA) in C02 from 5% to 40%; Flow rate: 3mL/min.; Wavelength: 220nm. [00870] Example 87 - 3-f6-fluorobenzofuran-2-ylV4H-l '-azaspirorri.2.41oxadiazole-5.3'- bicvclor2.2.21octane1 (89b)
[00871] To compound 88b (0.10 g, 0.22 mmol) was added 10% trifluoroacetic
acid/dichloromethane (10 mL), and the reaction was stirred at 0 °C for 2 hours. On completion, the reaction was filtered, and the filtrate was concentrated and purified by prep-HPLC
[Instrument: GX-E; Column: AgellaVenusil ASB CI 8 150*21.2mm, particle size: 5 μπι; Mobile phase: 15-45% acetonitrile in H20 (add 0.5% HC1, v/v)]. The collected fractions were subjected to lyophilization to give 3-(6-fluorobenzofuran-2-yl)-4H-l'-azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane] -enantiomer2 hydrochloride (compound 89b) (35 mg, 53% yield) as a white solid: cSFC analytical tR: 3.80 min., purity: 99.3%; LCMS (E): 1.97 min., 300.1 m/z (M+1); Ή-NMR (CD3OD, 400 MHz): δ 7.75-7.72 (m, IH), 7.42-7.39 (2, 2H), 7.20-7.15 (m, I H), 3.71 -3.77 (m, I H), 3.64-3.60 (m, IH), 3.48-3.33 (m, 4H), 2.44-2.40 (m, 2H), 2.30-2.26 (m, I H), 2.19-2.1 1 (m, I H) , 2.07-2.03 (m, I H);
cSFC analytical conditions: Column: Chiralpak AD-3 100x4.6mm, I.D., 3 μπι; Mobile phase: methanol (0.05% DEA) in C02 from 5% to 40%; Flow rate: 3mL/min.; Wavelength: 220nm.
[00872] Example 88 - f+/-V4-(2.4-dimethoxybenzvn-3-(5-fluorobenzofuran-2-yl)-4H-l '- azaspiro[[l,2,41oxadiazole-5,3'-bicyclo|~2.2.21octanel (90)
Figure imgf000215_0001
[00873] To a mixture of compound B-158 (0.50 g, 2.8 mmol) and compound C-108 (0.92 g, 3.4 mmol) in dichloromethane (15 mL) was added 10% aqueous sodium hypochlorite (8.3 g, 0.84 mmol) dropwise at 0 °C. The reaction was allowed to warm to room temperature and stirred at this temperature for 2 hours. On completion, the reaction mixture was filtered, and the filtrate was concentrated and purified by prep-HPLC [Instrument: HPLC-C; Column: GEMINI 200*50 mm, particle size: 10 μιη; Mobile phase: 30-55% acetonitrile in H20 (add 0.5% NH3 H20, v/v)] to give racemate 90 (0.20 g, 16% yield) as a white solid. Racemate 90 is a mixture of (R)-4-(2,4- dimethoxybenzyl)-3-(5-fluorobenzofuran-2-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane] (when deprotected provides (R)-3-(5-fluorobenzofuran-2-yl)-4H-l '- azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane]), and (S)-4-(2,4-dimethoxybenzyl)-3-(5- fluorobenzofuran-2-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane] (when deprotected provides (S)-3-(5-fluorobenzofuran-2-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane]). [00874] Chiral Separation:
[00875] A solution of racemate 90 (0.20 g, 0.45 mmol) in 10 ml of ethanol was separated by SFC (Instrument: SFC 80; Column: Chiralpak AD-3 100x4.6mm I.D., particle size: 10 μηι;
Mobile phase: 40% isopropyl alcohol (0.01 % NH3 H20) in CO2) at room temperature. Each set of collected fractions was concentrated at room temperature and then subjected to lyophilization to give:
4-(2,4-dimethoxybenzyl)-3-(5-fluorobenzofuran-2-yl)-4H-r-azaspiro[[l,2,4]oxadiazole- 5,3'-bicyclo[2.2.2]octane] -enantiomerl (compound 90a) (75 mg, 38% yield), and
4-(2,4-dimethoxybenzyl)-3-(5-fIuorobenzofuran-2-yl)-4H- -azaspiro[[l ,2,4]oxadiazole- 5,3'-bicyclo[2.2.2]octane] -enantiomer2 (compound 90b) (90 mg, 45% yield) as a white solid.
[00876] Example 89 - 3-(S-fluorobenzofuran-2-vn-4H-l '-azaspirorr 2,41oxadiazole-SJ'- bicyclo|"2.2.2]octane] (91a)
[00877] Compound 90a (75 mg, 0.17 mmol) was dissolved in 10% trifluoroacetic acid in dichloromethane (5 mL), and the reaction was stirred at 0 °C for 1 hour. On completion, the reaction was filtered, and the resulting filtrate was concentrated and purified by prep-HPLC
[Instrument: GX-E; Column: Agella Venusil ASB C18 150*21.2mm, particle size: 5 μιη; Mobile phase: 17-47% acetonitrile in H20 (Add 0.5% HC1, v/v)]. The product was subjected to lyophilization to give 3-(5-fluorobenzofuran-2-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane] -enantiomerl hydrochloride (compound 91a) (20 mg, 39% yield ) as a yellow solid: cSFC analytical tR: 2.76 min., purity: 99.6%; LCMS (C): 0.62 min., 302.1 m/z (M+l); 'HNMR (CD3OD, 400 MHz): 5 7.61 -7.58 (dd, Jl = 9.2 Hz, J2 = 3.6 Hz, 1 H), 7.46-7.44 (dd, Jl = 8.4 Hz, J2 = 2.8 Hz, 1 H), 7.38 (s, 1H), 7.38 (s, 1H), 7.25-7.20 (m, 1 H), 3.81 -3.77 (m, 1H), 3.65-3.61 (m, 1 H), 3.45-3.39 (m, 4H), 2.44-2.42 (m, 2H), 2.29-2.27 (m, 1H), 2.16-2.14 (m, 1 H) , 2.06-2.03 (m, 1H);
cSFC analytical conditions: Column: Chiralpak AD-3 100x4.6mm I.D., 3 μηι; Mobile phase: ethanol (0.05% DEA) in C02 from 5% to 40%; Flow rate: 3.0 mL/min.; Back pressure: 100 bar.
[00878] Example 90 - 3-(5-fluorobenzofuran-2-yl)-4H-r-azaspirorri.2.41oxadiazole-5.3'- bicyclor2.2.2"|octanel (91b)
[00879] To compound 90b (90 mg, 0.20 mmol) was added 10% trifluoroacetic
acid/dichloromethane (3 mL), and the reaction was stirred at 0 °C for 1 hour. On completion, the reaction was filtered, and the resulting filtrate was concentrated and purified by prep-HPLC
[Instrument: GX-E; Column: Agella Venusil ASB CI 8 150*21.2mm, particle size: 5 μπι; Mobile phase: 17-47% acetonitrile in H20 (Add 0.5% HC1, v/v)]. The product was then subjected to lyophilization to give 3-(5-fluorobenzofuran-2-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane] -enantiomer2 hydrochloride (compound 91b) (15 mg, 25% yield) as a yellow solid: cSFC analytical tR: 3.05 min., purity: 99.5%; LCMS (C): 0.576 min., 302.2 m/z (M+l); 'HNMR (CD3OD, 400 MHz): δ 7.61-7.58 (dd, Jl = 9.2 Hz, J2 = 4.0 Hz, 1H), 7.46-7.43 (dd, Jl = 8.8 Hz, J2 = 2.8 Hz, 1H), 7.37 (s, 1 H), 7.25-7.20 (m, 1 H), 3.80-3.77 (m, 1 H), 3.64-3.61 (m, 1 H), 3.45-3.39 (m, 4H), 2.44-2.42 (m, 2H), 2.28-2.27 (m, 1H), 2.17-2.14 (m, 1 H) , 2.06-2.03 (m, 1H);
cSFC analytical conditions: Column: Chiralpak AD-3 100x4.6mm I.D., 3 μιη; Mobile phase: ethanol (0.05% DEA) in C02 from 5% to 40%; Flow rate: 3.0 mL/min.; Back pressure: 100 bar.
[00880] Example 91 - (+/- -4-('2.4-dimethoxybenzvn-3-(4-fluoro-lH-inden-2-ylV4H-l l- azaspiro[[1.2,4"|oxadiazole-5,3'-bicyclo[2.2.2]octane] (92)
Figure imgf000217_0001
[00881] To a mixture of compound B-162 (0.10 g, 0.56 mmol) and compound C-108 (0.17 g, 0.62 mmol) in dichloromethane (10 mL) was added 10% aqueous sodium hypochlorite (0.62 g, 0.84 mmol) dropwise at 0 °C. The reaction was allowed to warm to room temperature and was stirred at this temperature for 2 hours. On completion, the reaction mixture was filtered, and the filtrate was concentrated. The residue was purified by prep-HPLC [Instrument: HPLC-C;
Column: GEMINI 200*50 mm, particle size: 10 μιη; Mobile phase: 30-55% acetonitrile in H20 (add 0.5% NH3 H20, v/v)] to give racemate 92 (75 mg, 30% yield) as a white solid. Racemate 92 is a mixture of (R)-4-(2,4-dimethoxybenzyl)-3-(4-fluoro-l H-inden-2-yl)-4H-l'- azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane] (when deprotected provides (R)-3-(4- fluorobenzofuran-2-yl)-4H-r-azaspiro[[l,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane]), and (S)-4- (2,4-dimethoxybenzyl)-3-(4-fluoro-lH-inden-2-yl)-4H-r-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane] (when deprotected provides (S)-3-(4-fluorobenzofuran-2-yl)-4H-l '- azaspiro[[l,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane]).
[00882] Chiral Separation:
[00883] A solution of racemate 92 (0.20 g, 0.45 mmol) in 10 mL of ethanol was separated by SFC (Instrument: SFC 80; Column: Chiralpak AD-3 100x4.6mm I.D., 10 μιη; Mobile phase: 40% isopropyl alcohol (0.01% NH3 H20) in C02) at room temperature. Each set of collected fractions was concentrated at room temperature and then subjected to lyophilization to give:
4-(2,4-dimethoxybenzyl)-3-(4-fluoro-lH-inden-2-yl)-4H- -azaspiro[[l ,2,4]oxadiazole- 5,3'-bicyclo[2.2.2]octane] -enantiomerl (compound 92a) (80 mg, 40% yield), and
4-(2,4-dimethoxybenzyl)-3-(4-fluoro-lH-inden-2-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole- 5,3'-bicyclo[2.2.2]octane] -enantiomer2 (compound 92b) (90 mg, 45% yield) as a white solid. [00884] Example 92 - 3-(4-fluorobenzofuran-2-yl)-4H-r-azaspiro[l"l ,2,41oxadiazole-5.3'- bicyclo[2.2.21octanel (93a)
[00885] Compound 92a (80 mg, 0.18 mmol) was dissolved in 10% trifluoroacetic acid in dichloromethane (5 mL) and the reaction was stirred at 0 °C for 1 hour. On completion, the reaction was filtered, and the resulting filtrate was concentrated in vacuo and purified by prep- HPLC [Instrument: GX-E; Column: Agella Venusil ASB C18 150*21.2 mm, particle size: 5 μπι; Mobile phase: 17-47% acetonitrile in H20 (Add 0.5 HC1, v/v)]. The product was then subjected to lyophilization to give 3-(4-fluorobenzofuran-2-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane] -enantiomerl hydrochloride (compound 93a) (20 mg, 37% yield ) as a yellow solid: cSFC analytical tR: 2.59 min., purity: 98.6%; LCMS (C): 1.30 min., 302.1 m/z (M+l); 1 H-NMR (CD3OD, 400 MHz): δ 7.49-7.45 (m, 3H), 7.1 1 -7.06 (m, 1 H), 3.81-3.78 (m, 1H), 3.69-3.65 (m, 1 H), 3.49-3.33 (m, 4H), 2.45-2.42 (m, 2H), 2.31-2.28 (m, 1H), 2.17-2.13 (m, 1 H) , 2.05-2.04 (m, 1 H).
cSFC analytical conditions: Column: Chiralpak AD-3 100x4.6mm I.D., 3 μπι; Mobile phase: ethanol (0.05% DEA) in C02 from 5% to 40%; Flow rate: 3.0 mL/min.; Back pressure: 100 bar.
[00886] Example 93 - 3-(4-fluorobenzofuran-2-yl)-4H-l '-azaspirorri .2,41oxadiazole-5.3'- bicyclo[2.2.21octane1 (93b)
[00887] Compound 92b (90 mg, 0.20 mmol) was dissolved in 10% trifluoroacetic acid in dichloromethane (3 mL) and the reaction was stirred at 0 °C for 1 hour. On completion, the reaction was filtered, and the resulting filtrate was concentrated in vacuo and purified by prep- HPLC [Instrument: GX-E; Column: Agella Venusil ASB CI 8 150*21.2 mm, particle size: 5 μπι; Mobile phase: 17-47% acetonitrile in H20 (Add 0.5%o HC1, v/v)]. The product was then subjected to lyophilization to give 3-(4-fluorobenzofuran-2-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane] -enantiomer2 hydrochloride (compound 93b) (20 mg, 33% yield) as a yellow solid: cSFC analytical tR: 2.76 min., purity: 99.4%; LCMS (C): 1.33 min., 302.1 m/z (M+l); 1 H-NMR (CD3OD, 400 MHz): δ 7.50-7.45 (m, 3H), 7.13-7.06 (m, 1 H), 3.82-3.78 (m, 1 H), 3.68-3.63 (m, 1 H), 3.49-3.38 (m, 4H), 2.45-2.42 (m, 2H), 2.31 -2.27 (m, 1 H), 2.18-2.14 (m, 1H) , 2.07-2.04 (m, 1 H);
cSFC analytical conditions: Column: Chiralpak AD-3 100x4.6mm I.D., 3 μιη; Mobile phase: ethanol (0.05% DEA) in C02 from 5% to 40%; Flow rate: 3.0 mL/min.; Back pressure: 100 bar.
[00888] Example 94 - f+/-)-3-fS.7-difluorobenzofiiran-2-yl)-4-(2.4- dimethoxybenzylV4H-l '- azaspiro[|"l ,2 41oxadiazole-5,3'-bicyclo[2.2.2]octane1 (94)
Figure imgf000219_0001
[00889] To a mixture of compound B-167 (0.50 g, 2.5 mmol) and compound C-108 (0.80 g, 3.1 mmol) in dichloromethane (5 mL) was added 10% aqueous sodium hypochlorite (7.5 g, 10 mmol) dropwise at 0 °C. The reaction was allowed to warm to room temperature and was stirred for 4 hours. On completion, the reaction was filtered, and the filtrate was concentrated and purified by prep-HPLC [Instrument: GX-A; Column: Phenomenex Gemini CI 8 150*25mm, particle size: 10 μπι; Mobile phase: 40-70% acetonitrile in H20 (add 0.5% NH3 H20, v/v)] to give racemate 94 (0.40 g, 34% yield) as a white solid. Racemate 94 is a mixture of (R)-3-(5,7- difluorobenzofuran-2-yl)-4-(2,4- dimethoxybenzyl)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane] (when deprotected provides (R)-3-(5,7-difluorobenzofuran-2-yl)-4H-l '- azaspiro[[l,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane]), and (S)-3-(5,7-difluorobenzofuran-2-yl)-4- (2,4- dimethoxybenzyl)-4H- -azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane] (when deprotected provides (S)-3-(5,7-difluorobenzofuran-2-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane]).
[00890] Chiral Separation:
[00891] A solution of racemate 94 (0.40 g, 1.8 mmol) in 10 mL of ethanol was separated by SFC (Instrument: SFC 80; Column: Chiralpak AD-H 250><25 mm I.D., 10 μπι; Mobile phase: 60% IPA(NH3 H20) in C02) at room temperature. Each set of collected fractions was concentrated at room temperature and then subjected to lyophilization to give:
3-(5,7-difluorobenzofuran-2-yl)-4-(2,4-dimethoxybenzyl)-4H-l'- azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane] -enantiomerl (compound 94a) (0.10 g, 25% yield), and
3-(5,7-difIuorobenzofuran-2-yl)-4-(2,4-dimethoxybenzyl)-4H-l'- azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane] -enantiomer2 (compound 94b) (0.10 g, 25% yield) as a white solid.
[00892] Example 95 - 3-(5 J-difluorobenzofuran^-vD^H-l '-azaspirorri ^^loxadiazole-SJ1- bicyclo[2.2.21octane1 (95a)
[00893] To compound 94a (0.10 g, 0.22 mmol) was added 10% trifluoroacetic
acid/dichloromethane (5 mL), and the reaction was stirred at 0 °C for 2 hours. On completion, the reaction was filtered, and the resulting filtrate was concentrated and purified by prep-HPLC
[Instrument: GX-E; Column: AgellaVenusil ASB CI 8 150*21.2mm, particle size: 5 μιη; Mobile phase: 15-45% acetonitrile in H20 (add 0.5% HC1, v/v)]. The collected fractions were then subjected to lyophilization to give 33-(5,7-difluorobenzofuran-2-yl)-4H-l '- azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane] -enantiomerl hydrochloride (compound 95a) (19.2 mg, 28% yield ) as a white solid: cSFC analytical tR: 2.25 min., purity: 99.2%; LCMS (C): 0.66 min., 320.1 m/z (M+l ); Ή-NMR (CD3OD, 400 MHz): δ 7.45-7.44 (d, J=4.0 Hz, I H), 7.34-7.32 (d, J=8.0 Hz, I H), 7.20-7.15 (t, J=12.0 Hz, I H), 3.82-3.78 (m, I H), 3.64-3.60 (m, I H), 3.48-3.33 (m, 4H), 2.45-2.42 (m, 2H), 2.27-2.26 (m, I H), 2.17-2.1 1 (m, I H) , 2.08-2.00 (m, I H); cSFC analytical conditions: Column: Chiralpak AD-3 100x4.6mm, I.D., 3 μπι; Mobile phase: ethanol (0.05% DEA) in C02 from 5% to 40%; Flow rate: 3mL/min.; Wavelength: 220nm.
[00894] Example 96 - 3-(5,7-difluorobenzofuran-2-yl)-4H-l '-azaspirorr i ,2,41oxadiazole-5,3'- bicyclo 2.2.2]octanel (95b)
[00895] To compound 94b (0.10 g, 0.22 mmol) was added 10% trifluoroacetic
acid/dichloromethane (5 mL), and the reaction was stirred at 0 °C for 2 hours. On completion, the reaction was filtered, and the resulting filtrate was concentrated and purified by prep-HPLC
[Instrument: GX-E; Column: AgellaVenusil ASB CI 8 150*21 .2mm, particle size: 5 μπι; Mobile phase: 15-45% acetonitrile in H20 (add 0.5% HC1, v/v)] . The collected fractions were then subjected to lyophilization to give 3-(5,7-difluorobenzofuran-2-yl)-4H-l '- azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane] -enantiomer2 hydrochloride (compound 95b) (18.9 mg, 28% yield) as a white solid: cSFC analytical tR: 2.56 min., purity: 98.5%; LCMS (C): 0.66 min., 320.1 m/z (M+l ); Ή-NMR (CD3OD, 400 MHz): δ 7.45-7.44 (d, J=4.0 Hz, I H), 7.34-7.32 (d, J=8.0 Hz, I H), 7.20-7.15 (t, J=12.0 Hz, I H), 3.82-3.78 (m, I H), 3.64-3.60 (m, I H), 3.48-3.33 (m, 4H), 2.45-2.42 (m, 2H), 2.27-2.26 (m, I H), 2.17-2.1 1 (m, I H) , 2.08-2.00 (m, I H); cSFC analytical conditions: Column: Chiralpak AD-3 100x4.6mm, I.D., 3 μπι; Mobile phase: ethanol (0.05% DEA) in C02 from 5% to 40%; Flow rate: 3mL/min.; Wavelength: 220nm.
[00896] Example 97 - (+/-)-3-(\ 1.1 '-biphenvn-4-yn-4-(2.4-dimethoxybenzviy4H- 1 '- azaspiro[[ 1.2.4]oxadiazole-5.3'-bicyclo[2.2.2]octane] (96
Figure imgf000220_0001
[00897] To a mixture of compound B-168 (1 .0 g, 5.1 mmol) and compound C-108 (2.1 g, 7.7 mmol) in dichloromethane (50 mL) was added 10% aqueous sodium hypochlorite (7.5 g, 10 mmol) dropwise at 0 °C. The reaction was allowed to warm to room temperature and stirred at this temperature for 2 hours. On completion, the reaction was filtered, and the filtrate was concentrated and purified by prep-HPLC [Instrument: GX-C; Column: Phenomenex Gemini 150x30 mm, particle size: 5 μπι; Mobile phase: 55-85% acetonitrile in H20 (add 0.5% NH3 · H20, v/v)] to give racemate 96 (0.8 g, 33 %) as a yellow solid. Racemate 96 is a mixture of (R)-(+/- )3-([l , 1 '-biphenyl]-4-yl)-4-(2,4-dimethoxybenzyl)-4H- 1 '-azaspiro[[ 1 ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane] (when deprotected provides (R)-3-([l ,l '-biphenyl]-4-yl)-4H-l '- azaspiro[[l,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane]), and (S)-(+/-)3-([l,l'-biphenyl]-4-yl)-4- (2,4-dimethoxybenzyl)-4H- l '-azaspiro[[l,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane] (when deprotected provides (S)-3-([l , -biphenyl]-4-yl)-4H-l '-azaspiro[[ l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane]).
[00898] Chiral Separation:
[00899] A solution of racemate 96 (0.20 g, 0.43 mmol) in 10 ml of ethanol was separated by SFC (Instrument: SFC 80; Column: Chiralpak AD-H 250x25 mm I.D., particle size: 10 μιη;
Mobile phase: 50% ethanol (0.01 % NH3 ■ H20) in C02) at room temperature. Each set of collected fractions was concentrated at room temperature and then subjected to lyophilization to give:
3-([l , l '-biphenyl]-4-yl)-4-(2,4-dimethoxybenzyl)-4H-r-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane]-enantiomerl (compound 96a) (75 mg, 38% yield), and
3-([ l , l '-biphenyl]-4-yl)-4-(2,4-dimethoxybenzyl)-4H-l'-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane]-enantiomer2 (compound 96b) (80 mg, 40% yield) as a yellow solid.
[00900] Example 98 - 3-(ri, l '-biphenyll-4-ylV4H-l'-azaspirorn .2.41oxadiazole-5.3'- bicyclo[2.2.21octane"|-enantiomerl hydrochloride (97a)
[00901] To compound 96a (60 mg, 0.13 mmol) was added 10% trifluoroacetic acid in dichloromethane (10 ml), and the reaction was stirred at 0 °C for 4 hours. On completion, the reaction was filtered, and the filtrate was concentrated and purified by prep-HPLC [Instrument: GX-E; Column: Agella Venusil ASB CI 8 150x21 .2 mm, particle size: 5 μιη; Mobile phase: 23- 53% acetonitrile in H20 (add 0.5% HCl, v/v)]. The product was then subjected to lyophilization to give 3-([l , l '-biphenyI]-4-yl)-4H-l '-azaspiro[[ l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane]- enantiomerl hydrochloride (compound 97a) (19.1 mg, 47% yield ) as a yellow solid: cSFC analytical tR: 1.15 min., purity: 96.9%; LCMS (C): 1 .65 min, 320.1 , m/z (M+1 ); Ή-NMR (D20 : CD3OD = 10: 1 , 400 MHz): 57.79 (m, 4H), 7.73-7.71 (d, J=7.6 Hz, 2H), 7.55-7.51 (t, J=7.2 Hz, 2H), 7.47-7.44 (m, 1 H), 3.78-3.74 (d, J=14.8 Hz, 1 H), 3.63-3.60 (d, J=14 Hz, 1 H), 3.42-3.38 (m, 4H), 2.45 (m, 1 H), 2.37 (m, 1 H), 2.21 -2.19 (m, 2H), 2.07-2.04 (m, 1 H);
cSFC analytical conditions: Column: Chiralpak AD-3 100x4.6mm, I.D., 3 μπι; Mobile phase: 40% ethanol (0.05% DEA) in C02; Flow rate: 3 mL/min.; Back pressure: 120 bar.
[00902] Example 99 - 3-(ri. l '-biphenvn-4-vn-4H-l '-azaspirorn ,2,41oxadiazole-5 J1- bicyclo[2.2.2]octane] -enantiomer2 hydrochloride (97b)
[00903] To compound 96b (60 mg, 0.13 mmol) was added 10% trifluoroacetic acid in dichloromethane (10 ml), and the reaction was stirred at 0 °C for 4 hours. On completion, the reaction was filtered, and the resulting filtrate was concentrated and purified by prep-HPLC
[Instrument: GX-E; Column: Agella Venusil ASB CI 8 150x21.2 mm, particle size: 5 μπι; Mobile phase: 23-53% acetonitrile in H20 (add 0.5% HC1, v/v)]. The product was then subjected to lyophilization to give 3-([l,r-biphenyl]-4-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane]-enantiomer2 hydrochloride (compound 97b) (12.3 mg, 30% yield) as yellow solid: cSFC analytical tR: 1.60 min., purity: 99.2%; LCMS (D): 1.65 min., 320.1 m/z (M+l); Ή-NMR (D20 : CD3OD=10: 1 , 400 MHz): 57.66-7.58 (m, 5H), 7.42-7.38 (t, J=7.6 Hz, 2H), 7.34-7.30 (m, 1H), 3.64-3.61 (d, J=14.4 Hz, 1 H), 3.50-3.47 (d, J=14 Hz, 1H), 3.29-3.25 (m, 4H), 2.33-2.25 (m, 2H), 2.09-1.91 (m, 3H);
cSFC analytical conditions: Column: Chiralpak AD-3 100x4.6mm, I.D., 3 μπι; Mobile phase: 40% ethanol (0.05% DEA) in CO2; Flow rate: 3 mL/min.; Back pressure: 120 bar.
[00904] Example 100 - (+/-)-tert-butyl 6-(4-methyl-4H-r-azaspiro[TL2.41oxadiazole-5.3'- bicyclo[2.2.21 octan]-3-yl)-3,4-dihydroquinoline-l (2H)-carboxylate (98)
Figure imgf000222_0001
[00905] To a mixture of compound B-173 (0.70 g, 2.5 mmol) and compound C-101 (1.0 g,
7.5 mmol) in dichloromethane (10 mL) was added tert-butyl hypochlorite (0.54 g, 5.0 mmol) dropwise at -78 °C. The resulting mixture was stirred at -78 °C for 3 hours. On completion, the reaction mixture was quenched with water and extracted with dichloromethane (3 30 mL). The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give crude racemate 98 (0.35 g, 33% yield) as a yellow solid.
LCMS: (ES+) m/z (M+H)+ = 413.3, tR= 2.819.
[00906] Example 101 - (+/-)-4-methyl-3-n.2.3,4-tetrahvdroquinolin-6-yl)-4H-l '- azaspiro[[L2,4~|oxadiazole -5J'-bicyclo[2.2.2]octanel (99)
Figure imgf000222_0002
[00907] To racemate 98 (0.35 g, 0.85 mmol) was added 20% trifluoroacetic
acid/dichloromethane (10 mL) and the reaction was stirred at room temperature for 2 hours. On completion, the reaction was filtered, and the resulting filtrate was concentrated and purified by prep-HPLC [Instrument: GX-C; Column: Phenomenex Gemini CI 8 150*30mm, particle size: 5 μσι; Mobile phase: 35-36% acetonitrile in H20 (add 0.5% NH3 H20, v/v)] to give racemate 99 (80 mg, 30% yield) as a white solid: Racemate 99 is a mixture of (R)-4-methyl-3-(l,2,3,4- tetrahydroquinolin-6-yl)-4H-l'-azaspiro[[l ,2,4]oxadiazole -5,3'-bicyclo[2.2.2]octane] and (S)-4- methy 1-3 -( 1 ,2,3 ,4-tetrahydroquinolin-6-yl)-4H- 1 '-azaspiro[ [ 1 ,2,4]oxadiazole -5,3'- bicyc lo [2.2.2] octane] .
[00908] Chiral Separation:
[00909] A solution of racemate 99 (80 mg, 0.26 mmol) in 5 mL of ethanol was separated by SFC (Instrument: SFC 80; Column: Chiralpak AD-H 250x25 mm I.D., 10 μιη; Mobile phase: 60% ethanol (NH3 H20) in C02) at room temperature. Each set of collected fractions was concentrated at room temperature and then subjected to lyophilization to give:
4-methyl-3-(l,2,3,4-tetrahydroquinolin-6-yl)-4H- -azaspiro[[l,2,4]oxadiazole -5,3'- bicyclo[2.2.2]octane] -enantiomerl (compound 99a) (25 mg, 31 % yield), and
4-methyl-3-(l ,2,3,4-tetrahydroquinolin-6-yl)-4H-l'-azaspiro[[l,2,4]oxadiazole -5,3'- bicyclo[2.2.2]octane] -enantiomer2 (compound 99b) (25 mg, 31 % yield) as a white solid.
[00910] Example 102 - 4-methyl-3-n,2,3,4-tetrahvdroquinolin-6-yl)-4H-l'- azaspiroff L2,4]oxadiazole -5,3'-bicyclo 2.2.2]octane] (100a)
[00911] To compound 99a (25 mg, 0.080 mmol) was added 0.2N hydrochloric acid (1 mL). The resulting solution was subjected to lyophilization to give 4-methyl-3-(l,2,3,4- tetrahydroquinolin-6-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole -5,3'-bicyclo[2.2.2]octane]- enantiomerl hydrochloride (compound 100a) (28 mg, 100% yield ) as a white solid: cSFC analytical tR: 2.07 min., purity: 100.0%; LCMS (C): 0.86 min., 313.1 m/z (M+1); Ή-NMR (D20, 400 MHz): δ 7.1 1 -7.09 (d, J=6.8 Hz, 2H), 6.61-6.59 (d, J=8.8 Hz, I H), 3.81-3.77 (dd, J,=14.8 Hz, J2=2.0 Hz, IH), 3.49-3.45 (dd, J,=16.0 Hz, J2=1.2 Hz, IH), 3.34-3.22 (m, 4H), 3.16-3.13 (q, J=5.6 Hz, 2H), 2.90 (s, 3H), 2.67-2.64 (q, J=6.4 Hz, 2H), 2.46 (s, IH), 2.23-2.10 (m, 2H), 2.01-1.99 (m, I H), 1.83-1.77 (m, 3H);
cSFC analytical conditions: Column: Chiralpak AD-3 100x4.6mm, I.D., 3μιη; Mobile phase: 40% ethanol (0.05% DEA) in C02; Flow rate: 3mL/min.; Wavelength: 220nm.
[00912] Example 103 - 4-methyl-3-d .2.3,4-tetrahvdroquinolin-6-yl)-4H-l '- azaspirorn ,2,4]oxadiazole -5,3'-bicyclo[2.2.2]octane1 (100b)
[00913] To compound 99b (25 mg, 0.080 mmol) was added 0.2N hydrochloric acid (1 mL). The resulting solution was subjected to lyophilization to give 4-methyl-3-(l , 2,3,4- tetrahydroquinolin-6-yl)-4H-l'-azaspiro[[l,2,4]oxadiazole -5,3'-bicyclo[2.2.2]octane]- enantiomer2 hydrochloride (compound 100b) (28 mg, 100% yield ) as white solid: cSFC analytical tR: 3.07 min., purity: 100.0%; LCMS (C): 0.88 min., 313.1 m/z (M+1); Ή-NMR (D20, 400 MHz): δ 7.14-7.12 (d, J=7.2 Hz, 2H), 6.66-6.64 (d, J=8.8 Hz, I H), 3.83-3.79 (dd, J,=14.8 Hz, J2=2.0 Hz, I H), 3.52-3.48 (d, J=14.8 Hz, I H), 3.36-3.21 (m, 4H), 3.18-3.16 (q, J=5.6 Hz, 2H), 2.91 (s, 3H), 2.69-2.66 (q, J=6.4 Hz, 2H), 2.49 (s, 1 H), 2.24-2.12 (m, 2H), 2.04-2.01 (m, 1 H), 1 .85-1 .78 (m, 3H);
cSFC analytical conditions: Column: Chiralpak AD-3 100x4.6mm, I.D., 3 μιη; Mobile phase: 40% ethanol (0.05% DEA) in C02; Flow rate: 3mL/min.; Wavelength: 220nm.
[00914] Example 104 - (l r,3R,4s,5S.7sV4l-(2,4-dimethoxybenzvn-3'-(6- fluorobenzo blthiophen-2-vn-4'H- l -azaspirofadamantane-4,5'- l ,2.41oxadiazolel (101) and d r,3R.4r.5S.7sV4'-C2.4-dimethoxybenzvn -3'-(6-fluorobenzo b1thiophen-2-yl)-4'H-l -
Figure imgf000224_0001
[00915] To a mixture of compound B-148 (0.20 g, 1.0 mmol) and compound C-112 (0.50 g, 2.0 mmol) in dichloromethane (10 mL) was added sodium hypochlorite (0.20 g, 2.0 mmol) slowly at 0 °C. The mixture was stirred at room temperature for 2 hours. On completion, the reaction was quenched with sodium sulfite solution (20 mL) and organics were extracted with dichloromethane (3 x 20 mL). The combined organic layers were concentrated and purified by prep-HPLC
[Instrument: HPLC-A Column: Phenomenex Gemini C I 8 150x30 mm; Mobile phase: 20%-50% acetonitrile in H20 (0.05% TFA v/v)] to give a mixture of compounds 101 and 102 ( 180 mg, 30% yield) as yellow solid.
[00916] Example 105 - ( l r,3R.4s.5S.7sV3'-(6-fluorobenzorb1thiophen-2-vn-4'H-l - azaspiro[adamantane-4,5'-[L2,4]oxadiazole] (103) and ( l r,3R,4r,5SJs)-3'-(6- fluorobenzo[b]thiophen-2-yl)-4'H-l -azaspirofadamantane-4,5'-[ L2,4]oxadiazole] (104)
Figure imgf000224_0002
[00917] To the mixture of compounds 101 and 102 (0.18 g, 0.36 mmol) in dichloromethane (10 mL) was added 10% trifluoroacetic acid and the reaction was stirred at room temperature for 2 hours. The resulting solution was concentrated in vacuo and the resulting residue was purified by prep-HPLC [Instrument: GX-E; Column: Agella Venusil ASB CI 8 150x21.2 mm; Mobile phase: 17%-47% acetonitrile in H20 (0.05% HC1 v/v)] to give: (lr,3R,4s,5S,7s)-3'-(6-fluorobenzo[b]thiophen-2-yl)-4'H-l -azaspiro[adamantane-4,5'- [l ,2,4]-oxadiazole] hydrochloride (compound 103) (1 1 mg, 8% yield) as a yellow solid: LCMS (C): 1.54 min., 344.1 m/z (M+l ); Ή-NMR (CD3OD, 400 MHz): δ 7.93-7.90 (q, J = 8.0 Hz, 1H), 7.83 (s, 1 H), 7.73-7.70 (dd, J, = 8.0 Hz, J2 = 4.0 Hz, 1H), 7.27-7.22 (t, J = 8.8 Hz, 1 H), 3.80-3.71 (m, 4H), 3.61 (s, 2H), 2.40-2.36 (d, J = 16.0 Hz, 4H), 2.21 (s, 1H), 2.12-2.09 (d, J = 12.0 Hz, 2 H), and
(lr,3R,4r,5S,7s)-3'-(6-fluorobenzo[b]thiophen-2-yl)-4'H-l -azaspiro[adamantane-4,5'- [1 ,2,4]- oxadiazole] hydrochloride (compound 104) (11 mg, 8% yield) as a yellow solid: LCMS (C): 1.41 min., 344.1 m/z (M+l ); Ή-NMR (CD3OD, 400 MHz): δ 7.93-7.89 (q, J = 8.0 Hz, 1 H), 7.86 (s, 1H), 7.73-7.70 (dd, J, = 8.0 Hz, J2 = 4.0 Hz, 1 H), 7.27-7.22 (t, J = 8.0 Hz, 1 H), 3.82-3.79 (d, J = 12.0 Hz, 2H), 3.62-3.59 (d, J = 12.0 Hz, 4H), 2.40 (s, 2H), 2.31 -2.20 (m, 5H).
[00918] Example 106 - ( lrJR,4s.5S.7sV3l-(5-fluorobenzorblthiophen-2-vn-4'H-l - azaspiro[adamantane-4.5'-[l ,2,4]oxadiazole]-hvdrochloride (105) and (l r,3R,4r,5S,7s)-3'-(5- fluorobenzo[b1thiophen-2-yl)-4'H-l -azaspiro[adamantane-4,5'-[1.2,41oxadiazole1-hydrochloride
Figure imgf000225_0001
[00919] To a mixture of compound B-114 (0.40 g, 2.1 mmol) and compound C-112 (1.2 g, 4.0 mmol) in dichloromethane (10 mL) was added sodium hypochlorite (6.1 g, 8.0 mmol) slowly at 0 °C. The mixture was stirred at room temperature for 2 hours. On completion, the reaction was quenched with sodium sulfite solution (20 mL) and extracted with dichloromethane (3 χ20 mL). The organic layer was concentrated and purified by prep-HPLC [Instrument: HPLC-A Column: Phenomenex Gemini CI 8 150x25 mm, particle size: 10 μιη; Mobile phase: 31 %-30% acetonitrile in H20 (0.05% TFA v/v)] to give a mixture of compounds 105 and 106. (80 mg, 8% yield). The mixture was purified by prep-HPLC [Instrument: GX-E Column: Agella Venusil ASB CI 8 150x21.2 mm; particle size: 10 μηι; Mobile phase: 20%-50% acetonitrile in H20 (0.05% HCl v/v)] to give:
(lr,3R,4s,5S,7s)-3'-(5-fluorobenzo[b]thiophen-2-yl)-4'H-l -azaspiro[adamantane-4,5'- [l ,2,4]oxadiazole] -hydrochloride (compound 105) (28 mg, 36% yield) as a white solid: LCMS (C): 1.83 min., 344.0 m/z (M+l ); Ή-NMR (CD3OD, 400 MHz): δ 7.94-7.91 (dd, J,=9.2 Hz, J2 = 4.8 Hz, 1 H), 7.86 (s, 1 H), 7.64-7.61 (dd, J=9.2 Hz, J2=2.4 Hz, 1H), 7.30-7.25 (td, J,=9.2 Hz, J2=2.4 Hz, 1 H), 3.83-3.80 (d, J=12.8 Hz, 2H), 3.74-3.70 (d, J=12.8 Hz, 2H), 3.61 (s, 2H), 2.68 (s, 1 H), 2.40-2.36 (m, 4H), 2.21 (s, 1H), 2.12-2.09 (d, J=12.8 Hz, 2 H), and
(lr,3R,4r,5S,7s)-3'-(5-fluorobenzo[b]thiophen-2-yl)-4'H-l -azaspiro[adamantane-4,5'- [l ,2,4]oxadiazole] -hydrochloride (compound 106) (30 mg, 38% yield) as a white solid: LCMS (C): 1.46 min., 344.1 m/z (M+l ); 1 H-NMR (CD3OD, 400 MHz): δ 7.94-7.91 (dd, J,=8.8 Hz, J2=4.8 Hz, 1 H), 7.87-7.86 (d, J,=1 .6 Hz, 1 H), 7.64-7.61 (dd, J,=10.4 Hz, J2=2.8 Hz, 1H), 7.30- 7.25 (td, J,=8.8 Hz, J2=2.4 Hz, 1H), 3.81-3.78 (d, J=12.8 Hz, 2H), 3.63-3.60 (d, J=12.0 Hz, 4H), 2.41 (s, 2H), 2.32-2.20 (m, 5H).
[00920] Example 107 - (l r.3R.4s.SS.7sV3'-<benzorblthiophen-5-vn-4'-f2.4- dimethoxybenzyl)-4'H-l-azaspiro adamantane-4,5'-[l ,2,41oxadiazole] (107) and (l r,3R,4r,5S,7s)- 3'-(benzo[b]thiophen-5-yl)-4'-(2,4-dimethoxybenzyl)-4'H-l -azaspiro adamantane-4,5'- ri ,2,41oxadiazole1 (108
Figure imgf000226_0001
[00921] To a mixture of compound B-115 (1.0 g, 5.6 mmol) and compound C-112 (2.1 g, 7.0 mmol) in dichloromethane (10 mL) was added 10% sodium hypochlorite (9.2 g, 12 mmol) slowly at 0 °C. The mixture was stirred at room temperature for 1 hour. On completion, the reaction was quenched with sodium sulfite solution and extracted with dichloromethane (3 x 30 mL). The combined organic layers were concentrated and purified by prep-HPLC [Instrument: HPLC-A; Column: Phenomenex Gemini CI 8 150x30 mm; Mobile phase: 20%-50% acetonitrile in H20 (0.05% TFA v/v)] to give a mixture of compounds 107 and 108 (0.38 g, 14%) as a yellow solid.
[00922] Example 108 - OrJR.4s,5S Jsy3 'benzorblthiophen-5-yly4Ή-l- azaspiro[adamantane-4,5'-[1.2.,4^o adiazole^ (109) and (l r,,3R,4r,5SJs)-3'-(benzorb"]thiophen-5- -4'H-l -azaspirofadamantane-4,5'-[L2,4]oxadiazole] (110)
Figure imgf000226_0002
[00923] A mixture of compounds 107 and 108 (0.0.18 g, 540 μιηοΐ) in 10% trifluoroacetic acid/dichloromethane (5 mL) was stirred at room temperature for 2 hours. The solution was concentrated in vacuo, and the residue was purified by prep-HPLC [Instrument: GX-E; Column: Agella Venusil ASB CI 8 150x21.2 mm; Mobile phase: 28%-36% acetonitrile in H20 (0.05% HC1 v/v)] to give:
(lr,3R,4s,5S,7s)-3'-(benzo[b]thiophen-5-yl)-4'H-l -azaspiro[adamantane-4,5'- [l ,2,4]oxadiazole] hydrochloride (compound 109) (1 1 mg, 8%) as a yellow solid: LCMS (B): 0.57 min, 326.2 m/z (M+l); Ή-NMR (CD3OD, 400 MHz): δ 8.29 (s, 1 H), 8.04-8.02 (d, J = 8.4 Hz, 1H), 7.77-7.72 (m, 2H), 7.50-7.48 (d, J = 5.2 Hz, 1H), 3.84-3.81 (d, J = 12.8 Hz, 2H), 3.74- 3.70 (d, J = 13.2 Hz, 2H), 2.40 (s, 4H), 2.22 (s, 1 H), 2.12-2.10 (d, J = 12.4 Hz, 2H), and
(lr,3R,4r,5S,7s)-3'-(benzo[b]thiophen-5-yl)-4'H-l -azaspiro[adamantane-4,5'- [l ,2,4]oxadiazole] hydrochloride (compound 110) (1 1 mg, 8%) as a yellow solid: LCMS (B): 0.56 min., 326.2 m/z (M+l); Ή-NMR (CD3OD, 400 MHz): δ 8.28 (s, 1H), 8.04-8.02 (d, J = 8.4 Hz, 1H), 7.76-7.72 (m, 2H), 7.50-7.48 (d, J = 5.6 Hz, 1 H), 3.83-3.80 (d, J = 12.0 Hz, 2H), 3.63- 3.60 (d, J = 1 1.6 Hz, 4H), 2.41 (s, 2H), 2.34-2.31 (d, J = 13.6 Hz 2H), 2.26-2.19 (m, 3H).
[00924] Example 109 - (lr.3R.4s,5S Js)-4l-(,2.4-dimethoxybenzyl)-3'-(5,6.7.8- tetrahvdroisoquinolin-3-yl)-4'H-l-azaspiro[adamantane-4,5'-[l ,2,41oxadiazolel (111) and nr,3R,4r,5S.7sV4'-('2.4-dimethoxybenzyl)-3'-(5.6.7,8-tetrahvdroisoquinolin-3-yl)-4'H-l - azaspiro[adamantane-4,5'-[l ,2,4]oxadiazolel (112)
Figure imgf000227_0001
[00925] To a mixture of compound B-178 (0.90 g, 5.1 mmol) and compound C-112 (1.7 g, 5.6 mmol) in dichloromethane (15 mL) was added 10% aqueous sodium hypochlorite (7.6 g, 10 mmol) slowly at 0 °C. The mixture was stirred at room temperature for 4 hours. On completion, the reaction was filtered, and the resulting filtrate was concentrated and purified by prep-HPLC [Instrument: GX-A Column: Phenomenex Gemini CI 8 150x25 mm, particle size: 10 μπι; Mobile phase: 20%-50% acetonitrile in H20 (added 0.5% NH3 H20, v/v)] to give a mixture of
compounds 111 and 112 (0.40 g, 17% yield) as a yellow solid.
[00926] Separation:
[00927] The mixture of 111 and 112 (0.40 g, 0.84 mmol) in 10 mL of ethanol was separated by SFC (Instrument: SFC 80; Column: Chiralpak AD-H 250x25 mm I.D., 10 μητ, Mobile phase: 40% ethanol (added 0.01% NH3 H20) in C02) at room temperature. Each set of collected fractions was concentrated at room temperature and then subjected to lyophilization to give:
(lr,3R,4s,5S,7s)-4'-(2,4-dimethoxybenzyl)-3'-(5,6,7,8-tetrahydroisoquinolin-3-yl)-4'H-l - azaspiro[adamantane-4,5'-[l ,2,4]oxadiazole] (compound 111) (0.15 g, 37% yield), and
(lr,3R,4r,5S,7s)-4'-(2,4-dimethoxybenzyl)-3'-(5,6,7,8-tetrahydroisoquinolin-3-yl)-4'H-l - azaspiro[adamantane-4,5'-[l ,2,4]oxadiazole] (compound 112) (0.15 g, 37% yield) as white solid.
[00928] Example 110 - f l r.3R.4s.SS.7sV3'-(S.6.7,8-tetrahvdroisoquinolin-3-ylV 'H-l - azaspiro[adamantine-4,5'-[ L2,4]oxadiazole1 (113)
[00929] To compound 111 (80 mg, 0.17 mmol) was added 10% trifluoroacetic
acid/dichloromethane (5 mL), and the reaction was stirred at 0 °C for 2 hours. On completion, the reaction was filtered, and the resulting filtrate was concentrated and purified by prep-HPLC
[Instrument: GX-E; Column: Agella Venusil ASB C18 150x21.2mm, particle size: 5 μιη; Mobile phase: 20-38% acetonitrile in ¾0 (add 0.5% HC1, v/v)]. The product was then subjected to lyophilization to give (lr,3R,4s,5S,7s)-3'-(5,6,7,8-tetrahydroisoquinolin-3-yl)-4'H-l- azaspiro[adamantine-4,5'-[l ,2,4]oxadiazole] hydrochloride (compound 113) (30 mg, 60% yield ) as a white solid: LCMS (G): 1.27 min., 325.1 m/z (M+l); Ή-NMR (CD3OD, 400 MHz): δ 8.58 (s, 1 H), 8.17 (s, 1 H), 3.90-3.86 (d, J=12.8 Hz, 2H), 3.74-3.71 (d, J=12.8 Hz, 2H), 3.66 (s, 2H), 3.12 (s, 2H), 3.00 (s, 2H), 2.44 (s, 2H), 2.38-2.34 (d, J=13.2 Hz, 2H), 2.22 (m, 1H), 2.14-2.1 1 (d, J=12.8 Hz, 2H), 1.97-1.96 (m, 4H).
[00930] Example 111 - (lrJR.4r.5S.7sV3'-r5.6.7.8-tetrahvdroisoquinolin-3-yl)-4'H-l - azaspiro[adamantine-4,5'-[l ,2,41oxadiazole] (114)
[00931] To compound 112 (80 mg, 0.17 mmol) was added 10% trifluoroacetic
acid/dichloromethane (5 mL), and the reaction was stirred at 0 °C for 2 hours. On completion, the reaction was filtered, and the resulting filtrate was concentrated and purified by prep-HPLC
[Instrument: GX-E; Column: Agella Venusil ASB CI 8 150x21 .2mm, particle size: 5 μπι; Mobile phase: 20-38% acetonitrile in H20 (add 0.5% HC1, v/v)]. The product was then subjected to lyophilization to give (l r,3R,4r,5S,7s)-3'-(5,6,7,8-tetrahydroisoquinolin-3-yl)-4'H-l - azaspiro[adamantine-4,5'-[l ,2,4]oxadiazole] hydrochloride (compound 114) (30 mg, 60% yield ) as a white solid: LCMS (G): 2.27 min, 325.3 m/z (M+l); Ή-NMR (CD3OD, 400 MHz): δ 8.57 (s, 1 H), 8.1 1-8.10 (m, 1 H), 3.81-3.78 (d, J=12.4 Hz, 2H), 3.66-3.61 (m, 4H), 3.1 1 (s, 2H), 3.00 (s, 2H), 2.45 (s, 2H), 2.32-2.21 (m, 5H), 1.97-1.95 (m, 4H).
[00932] Example 112 - (+/-)-2-(4H-r-azaspirorri .2.41oxadiazole-5.3'-bicvclor2.2.21octan1-3- yl)benzo[b]thiophene-7-carboxamide hydrochloride (115)
Figure imgf000229_0001
[00933] To racemate 68 (50 mg, 1.7 mmol) was added 10% trifluoroacetic
acid/dichloromethane (5 mL). After stirring for 1 hour at 0 °C, the reaction mixture was partially concentrated under reduced pressure at 0 °C, and 0.2 mL 4 N hydrochloric acid in dioxane was added to the residue at 0 °C. The resulting mixture was diluted with water (2 mL) and then lyophilized. The crude product was purified by prep-HPLC [Instrument: GX-E; Column: Agella Venusil ASB CI 8 150*21.2mm, particle size: 5 μηι; Mobile phase: 34-64% acetonitrile in H20 (add 0.5% HCI, v/v)]. The collected fractions were concentrated at 0 °C, and the product was subjected to lyophilization to give racemate 115- hydrochloride (18 mg, 50% yield) as a white solid: LCMS (C): 1 .10 min., 343.1 m/z (M+l ); Ή-NMR (CD3OD, 400 MHz): δ 8.10-8.08 (d, J = 8.0 Hz, 1H), 8.04-8.03 (d, J = 7.6 Hz, 1 H), 7.87 (s, 1H), 7.57-7.53 (t, J = 7.6 Hz, 1H), 3.80-3.76 (m, 1H), 3.69-3.65 (m, 1H), 3.46-3.36 (m, 4H), 2.44-2.32 (m, 3H), 2.16-2.03 (m, 2H). Racemate 115 is a mixture of HCI salts of (R)-2-(4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octan]-3-yl)benzo[b]thiophene-7-carboxamide and (S)-2-(4H-T- azaspiro[[l,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octan]-3-yl)benzo[b]thiophene-7-carboxamide.
[00934] Example 113 - (+/-)-4-(2,4-dimethoxybenzvn-3-('quinolin-3-vn-4H-l l- azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane1 (116)
Figure imgf000229_0002
[00935] To a mixture of compound B-179 (2.3 g, 13 mmol) and compound C-108 (4.7 g, 17 mmol) in dichloromethane (20 mL) was added 10% aqueous sodium hypochlorite (20 g, 26 mmol) slowly at 0 °C. The reaction was allowed to warm to room temperature and was stirred for 2 hours. On completion, the reaction was filtered, and the resulting filtrate was concentrated and purified by prep-HPLC [Instrument: Shimadzu pump LC-20A; Column: GEMINI 200 x 50 mm, particle size: 10 μπι; Mobile phase: 55-66.7% acetonitrile in H20 (add 0.5% NH3 H20, v/v)] to give racemate 116 (2.6 g, 74% yield) as a white solid. Racemate 116 is a mixture of (R)-4-(2,4- dimethoxybenzyl)-3-(quinolin-3-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane] (when deprotected provides (R)-3-(quinolin-3-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane]), and (S)-4-(2,4-dimethoxybenzyl)-3-(quinolin-3-yl)-4H-l '- azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane] (when deprotected provides (S)-3-(quinolin- 3-yl)-4H-l '-azaspiro[[l,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane]).
[00936] Chiral Separation:
[00937] A solution of racemate 116 (1.0 g, 2.3 mmol) in 10 mL of ethanol was separated by SFC (Instrument: SFC 80; Column: Chiralpak AD-H 250 x 25 mm I.D., 10 μπι; Mobile phase: 60% ethanol (0.01% NH3 H20) in CO2) at room temperature. Each set of collected fractions was concentrated at room temperature and then subjected to lyophilization to give:
4-(2,4-dimethoxybenzyl)-3-(quinolin-3-yl)-4H- -azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2] octane] -enantiomerl (compound 116a) (0.13 g, 13% yield), and
4-(2,4-dimethoxybenzyl)-3-(quinolin-3-yl)-4H-r-azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2] octane]-enantiomer2 (compound 116b) (0.15 g, 15% yield) as a yellow solid.
[00938] Example 114 - 3-(quinolin-3-yl)-4H-l l-azaspirorri .2.41oxadiazole-5.3l- bicyclor2.2.21octanel (117a)
[00939] To compound 116a (50 mg, 0.1 1 mmol) was added 10% trifluoroacetic acid in dichloromethane (5 mL), and the reaction was stirred at 0 °C for 2 hours. On completion, the reaction was filtered, and the resulting filtrate was concentrated and purified by prep-HPLC
[Instrument: Shimadzu pump LC-20A; Column: Phenomenex Gemini CI 8 150 χ 30 mm, particle size: 5 μιη; Mobile phase: 42-72% acetonitrile in H20 (add 0.5% HC1, v/v)]. The product was then subjected to lyophilization to give 3-(quinolin-3-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane]-enantiomerl hydrochloride (compound 117a) (30 mg, 97% yield ) as yellow solid: cSFC analytical tR: 3.38 min., purity: 94.2%; LCMS (G): 0.87 min., 295.4 m/z (M+l); Ή-NMR (CD3OD, 400 MHz): δ 9.28 (s,l H), 8.83 (s, I H), 8.18-8.13 (t, J=9.2 Hz, 2H), 8.01-7.97 (t, J=4.4 Hz, IH), 7.84-7.80 (t, J=7.6 Hz, I H), 3.84-3.80 (d, J=14.0 Hz, IH), 3.70-3.66 (d, J=14.0 Hz, I H), 3.50-3.33 (m, 4H), 2.48-2.34 (m, 2H), 2.33-2.31 (m, I H), 2.21 -2.05 (m, 2H); cSFC analytical conditions: Column: Chiracel IC 250 χ 4.6 mm, I.D., 5 μπι; Mobile phase: 50% isopropanol (0.05% DEA) in C02; Flow rate: 2.4 mL/min.; Back pressure: 120 bar.
[00940] Example 115 - 3-(quinolin-3-vn-4H-l'-azaspirorri .2.41oxadiazole-5.3'- bicyclor2.2.21octanel (117b)
[00941] To compound 116b (60 mg, 0.14 mmol) was added 10%> trifluoroacetic acid in dichloromethane (5 mL), and the reaction was stirred at 0 °C for 2 hours. On completion, the reaction was filtered, and the resulting filtrate was concentrated and purified by prep-HPLC
[Instrument: Shimadzu pump LC-20A; Column: Phenomenex Gemini CI 8 150 χ 30 mm, particle size: 5 μιη; Mobile phase: 42-72% acetonitrile in H20 (add 0.5% HC1, v/v)]. The product was then subjected to lyophilization to give 3-(quinolin-3-yl)-4H- -azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane]-enantiomer2 hydrochloride (compound 117b) (43 mg, 53% yield) as a yellow solid: cSFC analytical tR: 4.01 min., purity: 96.1%; LCMS (G): 0.84 min„ 295.4 m/z (M+l); Ή-NMR (CD3OD, 400 MHz): δ 9.61 (s, lH), 9.53 (s, 1 H), 8.49-8.47 (d, J=8.4 Hz, 1 H), 8.35-8.28 (m, 2H), 8.12-8.08 (t, J=8.0 Hz, 1H), 3.82 (s, 2H), 3.50-3.33 (m, 4H), 2.50-2.44 (m, 3H), 2.21-2.04 (m, 2H);
cSFC analytical conditions: Column: Chiracel IC 250 χ 4.6 mm, I.D., 5 μιη; Mobile phase: 50% isopropanol (0.05% DEA) in C02; Flow rate: 2.4 mL/min.; Back pressure: 120 bar.
[00942] Example 116 - (+/-)-3-(benzofuran-5-vn-4-(2,4-dimethoxybenzvn-4H-r- azaspirorn ,2, "|oxadiazole-5,3'-bicyclo|"2.2,2]octane] (118)
Figure imgf000231_0001
[00943] To a solution of compound B-180 (3.0 g, 19 mmol) and compound C-108 (10 g, 37 mmol) in dichloromethane (30 mL) was added 10% aqueous sodium hypochlorite (2.1 g, 2.8 mmol) dropwise at 0 °C. The resulting solution was warmed to room temperature and was stirred for 3 hours. On completion, the reaction mixture was extracted with dichloromethane (3 χ 20 mL), and the combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, concentrated in vacuo and purified by prep-HPLC [Instrument: GX-C; Column:
Phenomenex SY ERGI C I 8 150*30mm; particle size: 4μιη; Mobile phase: 60-90% acetonitrile in H20 (add 0.5% NH3 H20, v/v)] to give racemate 118 (5.0 g, 62% yield) as a yellow solid. Racemate 118 is a mixture of (R)-3-(benzofuran-5-yl)-4-(2,4-dimethoxybenzyl)-4H-l '- azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane] (when deprotected provides (R)-3- (benzofuran-5-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane]), and (S)-3- (benzofuran-5-yl)-4-(2,4-dimethoxybenzyl)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane] (when deprotected provides (S)-3-(benzofuran-5-yl)-4H-l '- azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane]).
[00944] Chiral Separation:
[00945] A solution of racemate 118 (0.12 g, 0.28 mmol) in 5 mL of ethanol was separated by SFC (Instrument: SFC 80; Column: Chiralpak AD-H 250x25 mm I.D., 10 μιη; Mobile phase: 60% ethanol (0.01% NH3 H20) in C02) at room temperature. Each set of collected fractions was concentrated at room temperature and then subjected to lyophilization to give:
3-(benzofuran-5-yl)-4-(2,4-dimethoxybenzyl)-4H- -azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane] -enantiomerl (compound 118a) (57 mg, 48% yield), and
3-(benzofuran-5-yl)-4-(2,4-dimethoxybenzyl)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane] -enantiomer2 (compound 118b) (60 mg, 50% yield) as a yellow solid. [00946] Example 117 - 3-(benzofuran-5-viy4H-r-azaspirolT1.2.41oxadiazole-5.3'- bicyclo[2.2.2"|octane"|-enantiomerl (119a)
[00947] Compound 118a (57 mg, 0.13 mmol) was dissolved in 10% trifluoroacetic acid/dichloromethane (4 mL) and stirred at 0 °C for 1 hour. On completion, the reaction was filtered, and the resulting filtrate was concentrated and purified by prep-HPLC [Instrument: GX- B; Column: Phenomenex Synergi CI 8 200*25mm; particle size: Ι Ομπι; Mobile phase: 18-48% acetonitrile in ¾0 (add 0.5% HC1, v/v)]. The collected fractions were concentrated at room temperature and subjected to lyophilization to give 3-(benzofuran-5-yl)-4H-l '- azaspiro[[ l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane] -enantiomerl hydrochloride (compound 119a) (9 mg, 24% yield ) as a yellow solid: cSFC analytical tR: 2.659 min., purity: 99.6%; LCMS (B): 0.1 14 min., 284.2 m/z (M+l ); Ή-NMR (CD3OD, 400 MHz): δ 8.05-8.05 (d, J = 1 .2 Hz, 1 H), 7.89-7.88 (d, J = 2.0 Hz, 1 H), 7.74-7.71 (dd, J = 8.4 Hz, 1.2 Hz, 1 H), 7.64-7.62 (d, J = 8.4 Hz, 1 H), 6.96-6.96 (d, J = 1 .6 Hz, 1 H), 3.78-3.74 (d, J = 14 Hz, 1 H), 3.67-3.63 (dd, J = 14.4 Hz, 2Hz, 1 H), 3.48-3.37 (m, 4H), 2.43-2.32 (m, 3H), 2.15-2.03 (m, 2H);
cSFC analytical conditions: Column: Chiralpak AD-3 100><4.6mm, I.D., 3 μηι; Mobile phase: 40% ethanol (0.05% DEA) in C02; Flow rate: 3mL/min.; Wavelength: 220nm.
[00948] Example 118 - 3-(benzofuran-5-vn-4H-l '-azaspirorrL2.41oxadiazole-5,3'- bicyc lo [2.2.2) octanel -enantiomer2 (119b)
[00949] Compound 118b (60 mg, 0.14 mmol) was dissolved in 10% trifluoroacetic acid/dichloromethane (4 mL) and stirred at 0 °C for 1 hour. On completion, the reaction was filtered, and the resulting filtrate was concentrated and purified by prep-HPLC [Instrument: GX- B; Column: Phenomenex Synergi CI 8 200*25mm; particle size: Ι Ομπι; Mobile phase: 18-48% acetonitrile in ¾0 (add 0.5% HC1, v/v)]. The collected fractions were concentrated at room temperature and subjected to lyophilization to give 3-(benzofuran-5-yl)-4H-l'- azaspiro[[l,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane] -enantiomer2 hydrochloride (compound 119b) (15 mg, 38% yield ) as a yellow solid: cSFC analytical tR: 3.448 min., purity: 99.4%; LCMS (B): 0.557 min., 284.2 m/z (M+l); Ή-NMR (CD3OD, 400 MHz): δ 8.05 (s, 1 H), 7.88- 7.88 (d, J = 2.0 Hz, 1 H), 7.74-7.72 (d, J = 7.2 Hz„ 1 H), 7.63-7.61 (d, J = 8.8 Hz, 1 H), 6.96-6.96 (d, J = 1 .6 Hz, 1 H), 3.77-3.74 (d, J = 14 Hz, 1 H), 3.69-3.65 (dd, J = 14.4 Hz, 2Hz, 1 H), 3.46-3.37 (m, 4H), 2.42-2.33 (m, 3H), 2.15-2.00 (m, 2H);
cSFC analytical conditions: Column: Chiralpak AD-3 100x4.6mm, I.D., 3 μιη; Mobile phase: 40% ethanol (0.05% DEA) in C02; Flow rate: 3mL/min.; Wavelength: 220nm.
[00950] Example 119 - i+/-V4- .4-dimethoxybenzvn-3-d H-indol-5-vn-4H-l '- azaspiro[[L2,41oxadiazole-5,3'-bicyclo[2.2.21octane1 (120)
Figure imgf000233_0001
[00951] To a mixture of compound B-181 (1.2 g, 7.5 mmol) and compound C-108 (2.5 g, 9.1 mmol) in dichloromethane (40 mL) was added 10% aqueous sodium hypochlorite (1 1 g, 0.15 mol) dropwise at 0 °C. The reaction was allowed to warm to room temperature and stirred at this temperature for 3 hours. On completion, the reaction was filtered, and the resulting filtrate was concentrated and purified by prep-HPLC [Instrument: Shimadzu pump LC-20A; Column:
GEMINI 200x50 mm, particle size: 10 μπι; Mobile phase: 32-57% acetonitrile in H20 (add 0.5% NH3 H20, v/v)] to give racemate 120 (1.1 g, 20% yield) as a yellow solid. LCMS: (ES+) m/z (M+H)+ = 433.2, tR=1.282. Racemate 120 is a mixture of (R)-4-(2,4-dimethoxybenzyl)-3-(l H- indol-5-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane] (when deprotected provides (R)-3-(lH-indol-5-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane]), and (S)-4-(2,4-dimethoxybenzyl)-3-(lH-indol-5-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane] (when deprotected provides (S)-3-(lH-indol-5-yl)-4H-l '- azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane]).
[00952] Chiral Separation:
[00953] A solution of racemate 120 (0.40 g, 0.93 mmol) in 5 mL of methanol was separated by SFC (Instrument: SFC 80; Column: OD-10 μπι; Mobile phase: 60% methanol (0.01 % NH3 H20) in C02) at room temperature. Each set of collected fractions was concentrated at room temperature and then subjected to lyophilization to give:
4-(2,4-dimethoxybenzyl)-3-(lH-indol-5-yl)-4H-r-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane]-enantiomerl (compound 120a) (0.20 g, 50% yield), and
4-(2,4-dimethoxybenzyl)-3-(l H-indol-5-yl)-4H-r-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane]-enantiomer2 (compound 120b) (0.20 g, 50% yield) as a yellow solid.
[00954]
Figure imgf000233_0002
bicyclo 2.2.21octane]-enantiomerl trifluoroacetate (121a)
[00955] To compound 120a (0.20 g, 0.46 mmol) was added 50% trifluoroacetic
acid/dichloromethane (5 mL), and the reaction was stirred at room temperature overnight. On completion, the reaction was filtered, and the filtrate was concentrated and purified by prep-HPLC [Instrument: GX-F; Column: YMC-pack ODS-AQ 150x30 mm, particle size: 5 μπι; Mobile phase: 9-39% acetonitrile in H20 (add 0.5% TFA, v/v)]. The product was then subjected to lyophilization to give 3-(l H-indol-5-yl)-4H-l '-azaspiro [[l ,2,4]oxadiazole-5,3 - bicyclo[2.2.2]octane]-enantiomerl trifluoroacetate (compound 121a) (12 mg, 9% yield) as a white solid: cSFC analytical tR: 0.74 min., purity: 94.5%; LCMS (A): 1.51 min., 283.0 m/z (M+1); Ή-NMR (CD3OD, 400 MHz): δ 7.95 (s, 1H), 7.50-7.44 (m, 2H), 7.34-7.33 (d, J=2.0 Hz, 1H), 6.54-6.53 (d, J=2.8 Hz, 1H), 3.76-3.72 (dd, J,=14.0 Hz, J2=2.0 Hz, 1H), 3.59-3.55 (dd, J,=14.0 Hz, J2=1.6 Hz, 1H), 3.45-3.35 (m, 4H), 2.44-2.40 (m, 2H), 2.30-2.27 (m, 1 H), 2.14-2.1 1 (m, 1H), 2.04-1.96 (m, 1H);
cSFC analytical conditions: Column: Chiralpak AD-3 100><4.6mm, I.D., 3 μηι; Mobile phase: 40% methanol (0.05% DEA) in C02; Flow rate: 3 mL/min.; Back pressure: 120 bar.
[00956] Example 121 - 3-(lH-indol-5-yl)-4H-l'-azaspirorri.2.41oxadiazole-5,3'- bicyclo 2.2,21octane~l-enantiomer2 trifluoroacetate (121b)
[00957] To compound 120b (0.20 g, 0.46 mmol) was added 50% trifluoroacetic
acid/dichloromethane (5 mL), and the reaction was stirred at room temperature overnight. On completion, the reaction was filtered, and the resulting filtrate was concentrated and purified by prep-HPLC [Instrument: GX-F; Column: YMC-pack ODS-AQ 150*30 mm, particle size: 5 μιη; Mobile phase: 9-39% acetonitrile in H20 (add 0.5% TFA, v/v)]. The product was then subjected to lyophilization to give 3-(lH-indol-5-yl)-4H-l '-azaspiro [[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane]-enantiomer2 trifluoroacetate (compound 121b) (14 mg, 1 1 % yield) as a white solid: cSFC analytical tR: 1.38 min., purity: 99.6%; LCMS (A): 1.52 min., 283.0 m/z (M+1); Ή-NMR (CD3OD, 400 MHz): δ 7.94 (s, 1H), 7.50-7.44 (m, 2H), 7.33 (s, 1H), 6.54-6.53 (d, J=2.4 Hz, 1 H), 3.76-3.72 (dd, J,=14.4 Hz, J2=2.0 Hz, 1 H), 3.58-3.54 (dd, J,=14.4 Hz, J2=2.0 Hz, 1H), 3.45-3.35 (m, 4H), 2.44-2.39 (m, 2H), 2.30-2.27 (m, 1 H), 2.14-2.1 1 (m, 1 H), 2.04-1.96 (m, 1 H).;
cSFC analytical conditions: Column: Chiralpak AD-3 100*4.6mm, I.D., 3 μπι; Mobile phase: 40% methanol (0.05% DEA) in C02; Flow rate: 3 mL/min.; Back pressure: 120 bar.
[00958] Example 122 - (+/-V3-(benzord1thiazol-6-vn-4-(2.4-dimethoxybenzyl)-4H-l '- azaspiro[ L2,41 oxadiazole-5,3'-bicyclo[2.2.2]octane1 (122)
Figure imgf000234_0001
[00959] To a mixture of compound B-185 (1.0 g, 5.6 mmol) and compound C-108 (1.8 g, 6.7 mmol) in dichloromethane (10 mL) was added 10% aqueous sodium hypochlorite (8.3 g, 1 1 mmol) slowly at 0 °C. The reaction was allowed to warm to room temperature and was stirred for 2 hours. On completion, the reaction was filtered, and the resulting filtrate was concentrated and purified by prep-HPLC [Instrument: Shimadzu pump LC-20A; Column: GEMINI 200 χ 50 mm, particle size: 10 μπι; Mobile phase: 55-66.7% acetonitrile in H20 (add 0.5% NH3 H20, v/v)] to give racemate 122 (1 .1 g, 40% yield) as a white solid. Racemate 122 is a mixture of (R)-3- (benzo[d]thiazol-6-yl)-4-(2,4-dimethoxybenzyl)-4H-l '-azaspiro[[l ,2,4] oxadiazole-5,3'- bicyclo[2.2.2]octane] (when deprotected provides (R)-3-(benzo[d]thiazol-6-yl)-4H-l '- azaspiro[[l,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane] and (S)-3-(benzo[d]thiazol-6-yl)-4-(2,4- dimethoxybenzyl)-4H-l '-azaspiro[[ 1 ,2,4] oxadiazole-5,3'-bicyclo[2.2.2]octane] (when deprotected provides (S)-3-(benzo[d]thiazol-6-yl)-4H-l'-azaspiro[[l,2,4]oxadiazole-5,3'- bicycIo[2.2.2]octane]).
[00960] Chiral Separation:
[00961] A solution of racemate 122 (0.60 g, 1.3 mmol) in 10 mL of ethanol was separated by SFC (Instrument: SFC 80; Column: Chiralpak AD-H 250 χ 25 mm I.D., 10 μπι; Mobile phase: 60% ethanol (0.01% NH3 H20) in CO2) at room temperature. Each set of collected fractions was concentrated at room temperature and then subjected to lyophilization to give:
3-(benzo[d]thiazol-6-yl)-4-(2,4-dimethoxybenzyl)-4H-r-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo [2.2.2]octane]-enantiomerl (compound 122a) (0.26 g, 43% yield), and
3-(benzo[d]thiazol-6-yl)-4-(2,4-dimethoxybenzyl)-4H-l'-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo [2.2.2]octane]-enantiomer2 (compound 122b) (0.25 g, 42% yield) as a white solid.
[00962] Example 123 - 3-(benzordlthiazol-6-vn-4H-l'-azaspirorn .2,41oxadiazole-5.3'- bicyclo[2.2.2]octane]-enantiomerl hydrochloride (123a)
[00963] To compound 122a (65 mg, 0.14 mmol) was added 10% trifluoroacetic acid in dichloromethane (5 mL), and the reaction was stirred at 0 °C for 0.5 hour. On completion, the reaction was concentrated and purified by prep-HPLC [Instrument: Shimadzu pump LC-20A; Column: Phenomenex Gemini CI 8 150 χ 30 mm, particle size: 5 μηι; Mobile phase: 42-72%) acetonitrile in H20 (add 0.5% HC1, v/v)]. The product was then subjected to lyophilization to give 3-(benzo[d]thiazol-6-yl)-4H-l'-azaspiro[[l ,2,4] oxadiazole-5,3'-bicycIo[2.2.2]octane]- enantiomerl hydrochloride (compound 123a) (35 mg, 78% yield ) as a white solid: cSFC analytical tR: 3.61 min., purity: 97.67%; LCMS (D): 1.01 min., 301.1 m/z (M+l); Ή-NMR (CD3OD, 400 MHz): δ 9.40 (s, IH), 8.47 (s, IH), 8.19-8.16 (d, J=8.8 Hz, IH), 7.95-7.93 (d, J=8.8 Hz, IH), 3.81-3.77 (d, J=14.0 Hz, I H), 3.64-3.61 (d, J=14.4 Hz, I H), 3.49-3.33 (m, 4H), 2.45 (m, 2H), 2.34-2.27 (m, I H), 2.18-2.00 (m, 2H);
cSFC analytical conditions: Column: Chiracel IC 250 * 4.6 mm, I.D., 5 μπι; Mobile phase: 50% isopropanol (0.05% DEA) in C02; Flow rate: 2.4 mL/min.; Back pressure: 120 bar.
[00964] Example 124 - 3-(benzo[d1thiazol-6-yl)-4H-r-azaspiro[Tl ,2,41oxadiazole-5,3'- bicyclo[2.2.2]octane]-enantiomer hydrochloride (123b)
[00965] To compound 122b (65 mg, 0.14 mmol) was added 10% trifluoroacetic acid in dichloromethane (5 mL), and the reaction was stirred at 0 °C for 0.5 hour. On completion, the reaction was concentrated and purified by prep-HPLC [Instrument: Shimadzu pump LC-20A; Column: Phenomenex Gemini CI 8 150x30 mm, particle size: 5 μπι; Mobile phase: 42-72% acetonitrile in H20 (add 0.5% HCl, v/v)]. The product was then subjected to lyophilization to give 3-(benzo[d]thiazol-6-yl)-4H-l'-azaspiro[[l,2,4] oxadiazole-5,3'-bicyclo[2.2.2]octane]- enantiomer2 hydrochloride (compound 123b) (36 mg, 77% yield) as yellow solid: cSFC analytical tR: 2.94 min, purity: 98.21 %; LCMS (B): 1.00 min., 301.1 m/z (M+l); Ή-NMR (CD3OD, 400 MHz): δ 9.40 (s, I H), 8.47 (s, IH), 8.19-8.16 (d, J=8.8 Hz, I H), 7.95-7.93 (d, J=8.8 Hz, IH), 3.81-3.77 (d, J=14.0 Hz, I H), 3.64-3.60 (d, J=14.0 Hz, IH), 3.49-3.33 (m, 4H), 2.45 (m, 2H), 2.34-2.27 (m, 1 H), 2.18-2.02 (m, 2H);
cSFC analytical conditions: Column: Chiracel IC 250 x 4.6 mm, I.D., 5 μιη; Mobile phase: 50% isopropanol (0.05% DEA) in CO2; Flow rate: 2.4 mL/min.; Back pressure: 120 bar.
[00966] Example 125 - (+/- -4-(2,4-dimethoxybenzyl)-3-(auinolin-6-vn-4H-l'-
Figure imgf000236_0001
[00967] To a mixture of compound B-186 (1.0 g, 6.0 mmol) and compound C-108 (1.9 g,
7.2 mmol) in dichloromethane (50 mL) was added 10% aqueous sodium hypochlorite (8.5 g, 12 mmol) dropwise at 0 °C. The reaction was allowed to warm to room temperature and stirred for 2 hours. On completion, the reaction was filtered, and the resulting filtrate was concentrated and purified by prep-HPLC [Instrument: GX-A; Column: Phenomenex Gemini CI 8 150x25mm, particle size: 10 μπι; Mobile phase: 50-80% acetonitrile in H20 (add 0.5% NH3 ■ H20, v/v)] to give racemate 124 (0.15 g, 6%) as a yellow solid. Racemate 124 is a mixture of (R)-4-(2,4- dimethoxybenzyl)-3-(quinolin-6-yl)-4H- -azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane] (when deprotected provides (R)-3-(quinolin-6-yl)-4H-r-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane]), and (S)-4-(2,4-dimethoxybenzyl)-3-(quinolin-6-yl)-4H-l '- azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane] (when deprotected provides (S)-3-(quinolin- 6-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane]).
[00968] Chiral Separation:
[00969] A solution of racemate 124 (0.15 g, 0.34 mmol) in 10 mL of ethanol was separated by SFC (Instrument: SFC 80; Column: Chiralpak AS I.D., particle size: 10 μιη; Mobile phase: 40% ethanol (0.01 % NH3 H20) in C02) at room temperature. Each set of collected fractions was concentrated at room temperature and then subjected to lyophilization to give:
4-(2,4-dimethoxybenzyl)-3-(quinolin-6-yl)-4H-l '-azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane]-enantiomerl (compound 124a) (70 mg, 47% yield), and
4-(2,4-dimethoxybenzyl)-3-(quinolin-6-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane]-enantiomer2 (compound 124b) (70 mg, 47% yield) as a yellow solid. [00970] Example 126 - 3-(quinolin-6-vn-4H-l '-azaspirorn ,2,41oxadiazole-5,3'- bicyclor2,2.21octanel-enantiomerl (compound 125a)
[00971] To compound 124a (70 mg, 0.16 mmol) was added 10% trifluoroacetic acid in dichloromethane (10 mL), and the reaction was stirred at 0 °C for 4 hours. On completion, the reaction was filtered, and the resulting filtrate was concentrated and purified by prep-HPLC
[Instrument: GX-G; Column: Phenomenex Synergi CI 8 150x30mm, particle size: 4 μπι; Mobile phase: 16-46% acetonitrile in H20 (add 0.5% HC1, v/v)]. The product was then subjected to lyophilization to give 3-(quinolin-6-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane]-enantiomerl hydrochloride (compound 125a) (15 mg, 33% yield ) as a yellow solid: cSFC analytical tR: 3.10 min., purity: 98.4%; LCMS (C): 1.01 min.,295.2, m/z (M+1); Ή-NMR (CD3OD, 400 MHz): δ 9.08-9.07 (d, J=4.0 Hz, IH), 8.73-8.71 (d, J=8.0 Hz, I H), 8.44 (s, IH), 8.27-8.25 (d, J=8.8 Hz, I H), 8.20-8.18 (d, J=9.2 Hz, IH), 7.84-7.81 (dd, J=8.4 Hz, IH), 3.83-3.80 (d, J=14.4 Hz, IH), 3.68-3.65 (d, J=13.2 Hz, IH), 3.47-3.37 (m, 4H), 2.46 (m, 2H), 2.34-2.33 (m, IH), 2.19-2.17 (m, IH), 2.09-2.05 (m, I H);
cSFC analytical conditions: Column: Chiralcel OD-3 100x4.6 mm I.D., 3 μπι; Mobile phase: methanol (0.05% DEA) in C02 from 5% to 40%; Flow rate: 3 mL/min.; Back pressure: 120 bar.
[00972] Example 127 - 3-(quinolin-6-yl)-4H-l '-azaspirorri .2.41oxadiazole-5.3'- bicyclor2.2.2"joctane"|-enantiomer2 hydrochloride (125b)
[00973] To compound 124b (70 mg, 0.16 mmol) was added 10% trifluoroacetic acid in dichloromethane (10 mL), and the reaction was stirred at 0 °C for 4 hours. On completion, the reaction was filtered, and the resulting filtrate was concentrated and purified by prep-HPLC
[Instrument: GX-E; Column: Agella Venusil ASB CI 8 150x21.2 mm, particle size: 12 μιη;
Mobile phase: 17-47% acetonitrile in H20 (add 0.5% HC1, v/v)]. The product was then subjected to lyophilization to give 3-(quinolin-6-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane]-enantiomerl hydrochloride (compound 125b) (15 mg, 33% yield ) as a semi-solid: cSFC analytical tR: 2.74 min., purity: 97.4%; LCMS (C): 1.00 min., 295.2 m/z (M+1 ); Ή-NMR (CD3OD, 400 MHz): δ 9.1 1 -9.10 (d, J=3.6 Hz, I H), 8.81 -8.79 (d, J=8.4 Hz, I H), 8.46 (s, I H), 8.31 -8.29 (d, J=8.8 Hz, I H), 8.22-8.20 (d, J=9.2 Hz, IH), 7.90-7.86 (dd, J=8.4 Hz, I H), 3.84-3.80 (d, J=15.6 Hz, IH); 3.68-3.64 (d, J=14.4 Hz, IH), 3.47-3.43 (m, 4H), 2.46 (m, 2H), 2.32 (m, I H), 2.20-2.17 (m, I H ), 2.07-2.04 (m, IH);
cSFC analytical conditions: Column: Chiralpak AD-3 100x4.6 mm, I.D., 3 μπι; Mobile phase: 40% ethanol (0.05% DEA) in C02; Flow rate: 3 mL/min.; Back pressure: 120 bar.
[00974] Example 128 - (+/-)-3-(benzordlthiazol-5-yl)-4-(2.4-dimethoxybenzvn-4H-l '- azaspiro l ,2,4] oxadiazole-5J'-bicyclor2.2.2]octane1 (126)
Figure imgf000238_0001
[00975] To a mixture of compound B-190 (1.0 g, 5.6 mmol) and compound C-108 (1.8 g, 6.6 mmol) in dichloromethane (10 mL) was added 10% aqueous sodium hypochlorite (8.3 g, 12 mmol) dropwise at 0 °C. The reaction was allowed to warm to room temperature and stirred at this temperature for 2 hours. On completion, the reaction mixture was concentrated and purified by prep-HPLC [Instrument: Shimadzu pump LC-20A; Column: GEMINI 200 x 50 mm, particle size: 10 μιη; Mobile phase: 55-66.7% acetonitrile in H20 (add 0.5% NH3 H20, v/v)] to give racemate 126 (0.70 g, 26% yield) as a white solid. Racemate 126 is a mixture of (R)-3- (benzo[d]thiazol-5-yl)-4-(2,4-dimethoxybenzyl)-4H-l'-azaspiro[[l,2,4] oxadiazole-5,3'- bicyclo[2.2.2]octane] (when deprotected provides (R)-3-(benzo[d]thiazol-5-yl)-4H-l '- azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane]), and (S)-3-(benzo[d]thiazol-5-yl)-4-(2,4- dimethoxybenzyl)-4H-l'-azaspiro[[l ,2,4] oxadiazole-5,3'-bicyclo[2.2.2]octane] (when deprotected provides (S)-3-(benzo[d]thiazol-5-yl)-4H-l'-azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane]).
[00976] Chiral Separation:
[00977] A solution of racemate 126 (0.35 g, 0.78 mmol) in 10 mL of ethanol was separated by SFC (Instrument: SFC 80; Column: Chiralpak AD-H 250 χ 25 mm I.D., 10 μιη; Mobile.phase: 60% ethanol (0.01 % NH3 H20) in C02) at room temperature. Each set of collected fractions was concentrated at room temperature and then subjected to lyophilization to give:
3-(benzo[d]thiazol-5-yl)-4-(2,4-dimethoxybenzyl)-4H-l'-azaspiro[[l,2,4]oxadiazoIe-5,3'- bicyclo[2.2.2]octane]-enantiomerl (compound 126a) (58 mg, 17% yield), and
3-(benzo[d]thiazol-5-yl)-4-(2,4-dimethoxybenzyl)-4H-r-azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane]-enantiomer2 (compound 126b) (60 mg, 17% yield) as a white solid.
[00978] Example 129 - 3-ibenzordlthiazol-5-yiy4H-r-azaspirorri ,2.41oxadiazole-5.3'- bicyclo[2.2.21octane1 (127a)
[00979] To compound 126a (53 mg, 0.12 mmol) was added 10% trifluoroacetic acid in dichloromethane (5 mL), and the reaction was stirred at 0 °C for 0.5 hour. On completion, the reaction mixture was concentrated and purified by prep-HPLC [Instrument: Shimadzu pump LC- 20A; Column: Phenomenex Gemini C18 150 χ 30 mm, particle size: 5 μπι; Mobile phase: 42- 72% acetonitrile in H20 (add 0.5% HC1, v/v)]. The product was subjected to lyophilization to give 3-(benzo[d]thiazol-5-yl)-4H-l '-azaspiro [[1 ,2,4] oxadiazole-5,3'-bicyclo[2.2.2]octane]- enantiomerl hydrochloride (compound 127a) (12 mg, 30% yield ) as a white solid: cSFC analytical tR: 4.03 min., purity: 97.61%; LCMS (D): 1.04 min., 301.1 m/z (M+l); Ή-NMR (CD3OD, 400 MHz): δ 9.46 (s, IH), 8.45 (s, IH), 8.24-8.22 (d, J=8.4 Hz, I H), 7.93-7.90 (d, J=8.4 Hz, IH), 3.81-3.77 (d, J=14.0 Hz, IH), 3.68-3.64 (d, J,=14.4 Hz, J2=2.0 Hz, I H), 3.50-3.38 (m, 4H), 2.45-2.30 (m, 3H), 2.20-2.03 (m, 2H);
cSFC analytical conditions: Column: Chiracel IC 250 x 4.6 mm, I.D., 5 μηι; Mobile phase: 50% isopropanol (0.05% DEA) in CO2; Flow rate: 2.4 mL/min.; Back pressure: 120 bar.
[00980] Example 130 - 3-(benzord1thiazol-5-vn-4H-l l-azaspirorn .2,41oxadiazole-5.3'- bicyclo|"2.2.21octane] (127b)
[00981] To compound 126b (55 mg, 0.18 mmol) was added 10% trifluoroacetic acid in dichloromethane (5 mL), and the reaction was stirred at 0 °C for 0.5 hour. On completion, the reaction was concentrated and purified by prep-HPLC [Instrument: Shimadzu pump LC-20A; Column: Phenomenex Gemini CI 8 150 χ 30 mm, particle size: 5 μηι; Mobile phase: 42-72% acetonitrile in H20 (add 0.5% HC1, v/v)]. The product was subjected to lyophilization to give 3- (benzo[d]thiazol-5-yl)-4H-l'-azaspiro[[ 1 ,2,4] oxadiazole-5,3'-bicyclo[2.2.2]octane]-enantiomer2 hydrochloride (compound 127b) (12 mg, 21 % yield) as a white solid: cSFC analytical tR: 3.09 min., purity: 95.78 %; LCMS (B): 1.04 min., 301.1 m/z (M+l); Ή-NMR (CD3OD, 400 MHz): δ 9.42 (s, IH), 8.44 (s, I H), 8.23-8.21 (d, J=8.0 Hz, I H), 7.92-7.89 (d, J=8.4 Hz, IH), 3.81-3.78 (d, J=14.0 Hz, IH), 3.67-3.63 (d, J=14.0 Hz, I H), 3.49-3.39 (m, 4H), 2.45-2.31 (m, 3H), 2.18-2.01 (m, 2H);
cSFC analytical conditions: Column: Chiracel IC 250 χ 4.6 mm, I.D., 5 μιη; Mobile phase: 50% isopropanol (0.05% DEA) in C02; Flow rate: 2.4 mL/min.; Back pressure: 120 bar.
[00982] Example 131 - (+/-V3-(benzofuran-6-vn-4-r2,4-dimethoxybenzvn-4H-l '- azaspiro 1 ,2,4] oxadiazole-5,3'-bicyclo[2.2.2]octane] (128)
Figure imgf000239_0001
[00983] To a mixture of compound B-196 (0.60 g, 3.7 mmol) and compound C-108 (1.8 g,
6.6 mmol) in dichloromethane (10 mL) was added 10% aqueous sodium hypochlorite (5.9 g, 7.4 mmol) slowly at 0 °C. The reaction was allowed to warm to room temperature and was stirred for 2 hours. On completion, the reaction was concentrated and purified by prep-HPLC [Instrument: Shimadzu pump LC-20A; Column: GEMINI 200 x 50 mm, particle size: 10 μτη; Mobile phase: 55-66.7% acetonitrile in H20 (add 0.5% NH3 H20, v/v)] to give racemate 128 (0.22 g, 18% yield) as a yellow solid. Racemate 128 is a mixture of (R)-3-(benzofuran-6-yl)-4-(2,4- dimethoxybenzyl)-4H-l '-azaspiro[[l ,2,4] oxadiazole-5,3'-bicyclo[2.2.2]octane] (when deprotected provides (R)-3-(benzofuran-6-yl)-4H- -azaspiro[[l,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane])5 and (S)-3-(benzofuran-6-yl)-4-(2,4-dimethoxybenzyl)-4H-l'-azaspiro[[l,2,4] oxadiazole-5,3'- bicyclo[2.2.2]octane] (when deprotected provides (S)-3-(benzofuran-6-yl)-4H-l'- azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane]).
[00984] Chiral Separation:
[00985] A solution of racemate 128 (0.20 g, 0.46 mmol) in 10 niL of ethanol was separated by SFC (Instrument: SFC 80; Column: Chiralpak AD-H 250 * 25 mm I.D., 10 μιη; Mobile phase: 60% ethanol (0.01% NH3 H20) in C02) at room temperature. Each set of collected fractions was concentrated at room temperature and then subjected to lyophilization to give:
3-(benzofuran-6-yl)-4-(2,4-dimethoxybenzyl)-4H- -azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo [2.2.2]octane]-enantiomerl (compound 128a) (63 mg, 32% yield), and
3-(benzofuran-6-yl)-4-(2,4-dimethoxybenzyl)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo [2.2.2]octane]-enantiomer2 (compound 128b) (58 mg, 29% yield) as a white solid.
[00986] Example 132 - 3-(,benzofuran-6-vn-4H-l '-azaspirorn ,2,41oxadiazole-5.3l- bicyclor2.2.21octane1 (129a)
[00987] To compound 128a (63 mg, 0.15 mmol) was added 10% trifluoroacetic acid in dichloromethane (5 mL), and the reaction was stirred at 0 °C for 0.5 hour. On completion, the reaction was filtered, and the resulting filtrate was concentrated and purified by prep-HPLC
[Instrument: Shimadzu pump LC-20A; Column: Phenomenex Gemini CI 8 150 χ 30 mm, particle size: 5 μηι; Mobile phase: 42-72% acetonitrile in H20 (add 0.5% HC1, v/v)]. The product was then subjected to lyophilization to give 3-(benzofuran-6-yl)-4H-l'-azaspiro[[l ,2,4]oxadiazole- 5,3'-bicyclo[2.2.2]octane]-enantiomerl hydrochloride (compound 129a) (12 mg, 28% yield ) as a white solid: cSFC analytical tR: 2.82 min., purity: 100%; LCMS (D): 1.13 min., 284.3 m/z (M+l); Ή-NMR (CD3OD, 400 MHz): δ 7.92 (s, 2H), 7.75-7.73 (d, J=8.0 Hz, 1 H), 7.68-7.66 (d, J=8.4 Hz, 1 H), 6.95 (s, 1 H), 3.78-3.75 (d, J=14.4 Hz, 1H), 3.68-3.64 (d, J=14.4 Hz, 1 H), 3.49- 3.37 (m, 4H), 2.46-2.32 (m, 3H), 2.16-2.02 (m, 2H);
cSFC analytical conditions: Column: Chiracel IC 250 χ 4.6 mm, I.D., 5 μπι; Mobile phase: 50% isopropanol (0.05% DEA) in C02; Flow rate: 2.4 mL/min.; Back pressure: 120 bar.
[00988] Example 133 - 3-rbenzofuran-6-yl)-4H-ll-azaspirorn ,2.41oxadiazole-5.3'- bicyclo|"2.2.21octanel (129b)
[00989] To compound 128b (55 mg, 0.13 mmol) was added 10% trifluoroacetic acid in dichloromethane (5 mL), and the reaction was stirred at 0 °C for 0.5 hour. On completion, the reaction was filtered, and the resulting filtrate was concentrated and purified by prep-HPLC
[Instrument: Shimadzu pump LC-20A; Column: Phenomenex Gemini CI 8 150 x 30 mm, particle size: 5 μπι; Mobile phase: 42-72% acetonitrile in H20 (add 0.5% HC1, v/v)]. The product was then subjected to lyophilization to give 3-(benzofuran-6-yl)-4H-l '-azaspiro[[l,2,4]oxadiazole- 5,3'-bicyclo[2.2.2]octane]-enantiomer2 hydrochloride (compound 129b) (12 mg, 32% yield) as a white solid: cSFC analytical tR: 3.38 min., purity: 98.42 %; LCMS (B): 1.13 min., 284.3 m/z (M+l ); Ή-NMR (CD3OD, 400 MHz): δ 7.92 (s, 2H), 7.75-7.73 (d, J=8.0 Hz, 1 H), 7.68-7.65 (d, J=8.4 Hz, 1H), 6.95 (s, 1H), 3.79-3.75 (d, J=14.4 Hz, 1H), 3.67-3.63 (dd, J=14.4 Hz, 1H), 3.49- 3.38 (m, 4H), 2.46-2.31 (m, 3H), 2.17-2.02 (m, 2H);
cSFC analytical conditions: Column: Chiracel IC 250 x 4.6 mm, I.D., 5 μηι; Mobile phase: 50% isopropanol (0.05% DEA) in CO2; Flow rate: 2.4 mL/min.; Back pressure: 120 bar.
[00990] Example 134 - (+/- -3-(benzo[blthiophen-6-vn-4-(2.4-dimethoxybenzvn-4Hrl '- azaspiro[[l ,2,4] oxadiazole-5,3'-bicyclo[2.2,2]octane] (130)
Figure imgf000241_0001
[00991] To a mixture of compound B-203 (0.73 g, 4.1 mmol) and compound C-108 (1.4 g,
4.9 mmol) in dichloromethane (10 mL) was added 10% aqueous sodium hypochlorite (12 g, 16 mmol) dropwise at 0 °C. The reaction was allowed to warm to room temperature and was stirred for 3 hours. On completion, the reaction was filtered, and the resulting filtrate was concentrated and purified by prep-HPLC [Instrument: GX-A; Column: Phenomenex Gemini CI 8 150*25mm, particle size: 10 μπι; Mobile phase: 44-74% acetonitrile in H20 (add 0.5% NH3 H20, v/v)] to give racemate 130 (0.40 g, 22% yield) as a white solid. Racemate 130 is a mixture of (R)-3- (benzo[b]thiophen-6-yl)-4-(2,4-dimethoxybenzyl)-4H-l '-azaspiro[[l ,2,4] oxadiazole-5,3'- bicyclo[2.2.2]octane] (when deprotected provides (R)-3-(benzo[b]thiophen-6-yl)-4H-l '- azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane]), and (S)-3-(benzo[b]thiophen-6-yl)-4-(2,4- dimethoxybenzyl)-4H-l '-azaspiro[[l,2,4] oxadiazole-5,3'-bicyclo[2.2.2]octane] (when deprotected provides (S)-3-(benzo[b]thiophen-6-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane]).
[00992] Chiral Separation:
[00993] A solution of racemate 130 (0.40 g, 0.89 mmol) in 10 mL of ethanol was separated by SFC (Instrument: SFC 80; Column: Chiralpak AS-H 250x25 mm I.D., 10 μπι; Mobile phase: 30% ethanol (NH3 H20) in C02) at room temperature. Each set of collected fractions was concentrated at room temperature and then subjected to lyophilization to give:
3-(benzo[b]thiophen-6-yl)-4-(2,4-dimethoxybenzyl)-4H-l '-azaspiro[[l ,2,4] oxadiazole- 5,3'-bicyclo[2.2.2]octane]-enantiomerl (compound 130a) (60 mg, 15% yield), and
3-(benzo[b]thiophen-6-yl)-4-(2,4-dimethoxybenzyl)-4H-l '-azaspiro[[l,2,4] oxadiazole- 5,3'-bicyclo[2.2.2]octane]-enantiomer2 (compound 130b) (60 mg, 15% yield) as a white solid. [00994] Example 135 - 3-(benzo|"blthiophen-6-ylV4H-l'-azaspiror|"1.2,41oxadiazole-5,3'- bicyclo[2.2.21octanel-enantiomerl (131a)
[00995] To compound 130a (60 mg, 0.13 mmol) was added 10% trifluoroacetic
acid/dichloromethane (5 mL), and the reaction was stirred at 0 °C for 2 hours. On completion, the reaction was filtered, and the resulting filtrate was concentrated and purified by prep-HPLC
[Instrument: GX-E; Column: AgellaVenusil ASB CI 8 150*21.2mm, particle size: 5 μπι; Mobile phase: 7-37% acetonitrile in H20 (add 0.5% HC1, v/v)]. The collected fractions were then subjected to lyophilization to give 3-(benzo[b]thiophen-6-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole- 5,3'-bicyclo[2.2.2]octane]-enantiomerl hydrochloride (compound 131a) (15 mg, 38% yield ) as a white solid: cSFC analytical tR: 0.96 min„ purity: 100.0%; LCMS (C): 1.20 min., 300.2 m/z (M+l); Ή-NMR (CD3OD, 400 MHz): δ 8.31 (s, 1H), 7.96-7.94 (d, J=8.0 Hz, 1 H), 7.79-7.74 (m, 2H), 7.49-7.47 (d, J=5.2 Hz, 1H), 3.79-3.76 (d, J=14.4 Hz, 1 H), 3.66-3.63 (d, J=14.0 Hz, 1H), 3.49-3.33 (m, 4H), 2.44 (s, 2H), 2.35-2.29 (m, 1 H) , 2.17-2.13 (m, 1 H), 2.07-2.00 (m, 1H);
cSFC analytical conditions: Column: Chiralpak AD-3 100*4.6mm, I.D., 3μηι; Mobile phase: 40% ethanol (0.05% DEA) in C02; Flow rate: 3mL/min.; Wavelength: 220nm.
[00996] Example 136 - 3-(,benzorblthiophen-6-yl)-4H-l '-azaspirorri.2.41oxadiazole-5.3'- bicyclo[2.2.2]octane]-enantiomer2 (131b)
[00997] To compound 130b (60 mg, 0.13 mmol) was added 10% trifluoroacetic
acid/dichloromethane (5 mL), and the reaction was stirred at 0 °C for 2 hours. On completion, the reaction was filtered, and the resulting filtrate was concentrated and purified by prep-HPLC
[Instrument: GX-E; Column: AgellaVenusil ASB C18 150*21.2mm, particle size: 5 μπι; Mobile phase: 7-37%) acetonitrile in H20 (add 0.5% HCl, v/v)]. The collected fractions were then subjected to lyophilization to give 3-(benzo[b]thiophen-6-yl)-4H-l '-azaspiro[[l,2,4]oxadiazole- 5,3'-bicyclo[2.2.2]octane]-enantiomerl hydrochloride (compound 131b) (15 mg, 38% yield ) as a white solid: cSFC analytical tR: 1.67 min., purity: 98.4%; LCMS (C): 1.20 min., 300.2 m/z (M+l); δ 8.32 (s, 1 H), 7.96-7.94 (d, J=8.4 Hz, 1 H), 7.79-7.75 (m, 2H), 7.48-7.47 (d, J=5.2 Hz, 1H), 3.79-3.75 (d, J=14.4 Hz, 1H), 3.68-3.64 (d, J=14.0 Hz, 1H), 3.49-3.33 (m, 4H), 2.44-2.36 (m, 2H), 2.35-2.30 (m, 1H) , 2.18-2.15 (m, 1H), 2.07-2.00 (m, 1H);
cSFC analytical conditions: Column: Chiralpak AD-3 100x4.6mm, I.D., 3μπι; Mobile phase: 40% ethanol (0.05% DEA) in C02; Flow rate: 3mL/min.; Wavelength: 220nm.
[00998] Example 137 - (+/-)-4-('2.4-dimethoxybenzyl)-3-('4-fluorophenvn-4H-l '- azaspiro[[ 1 ,2,4] oxadiazole-5,3'-bicvclo[2.2.2]octane] (132)
Figure imgf000243_0001
[00999] To a mixture of compound B-204 (1 .5 g, 10 mmol) and compound C-108 (3.3 g, 12 mmol) in dichloromethane (10 mL) was added 10% aqueous sodium hypochlorite (15 g, 20 mmol) slowly at 0 °C. The reaction was allowed to warm to room temperature and stirred for 2 hours. On completion, the reaction was filtered, and the resulting filtrate was concentrated and purified by prep-HPLC [Instrument: Shimadzu pump LC-20A; Column: GEMINI 200^50 mm, particle size: 10 μηι; Mobile phase: 55-66.7% acetonitrile in H20 (add 0.5% NH3 H20, v/v)] to give racemate 132 (1.4 g, 34% yield) as a white solid. Racemate 132 is a mixture of (R)-4-(2,4- dimethoxybenzyl)-3-(4-fluorophenyl)-4H-l '-azaspiro[[l ,2,4] oxadiazole-5,3'- bicyclo[2.2.2]octane] (when deprotected provides (R)-3-(4-fluorophenyl)-4H-l '- azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane]), and (S)-4-(2,4-dimethoxybenzyl)-3-(4- fluorophenyl)-4H-l '-azaspiro[[l,2,4] oxadiazoIe-5,3'-bicyclo[2.2.2]octane] (when deprotected provides (S)-3-(4-fluorophenyl)-4H-r-azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane]).
[001000] Chiral Separation:
[001001] A solution of racemate 132 (0.60 g, 1 .5 mmol) in 10 mL of ethanol was separated by SFC (Instrument: SFC 80; Column: Chiralpak AD-H 250x25 mm I.D., 10 μπι; Mobile phase: 60% ethanol (0.01% NH3 H20) in C02) at room temperature. Each set of collected fractions was concentrated at room temperature and then subjected to lyophilization to give:
4-(2,4-dimethoxybenzyl)-3-(4-fluorophenyl)-4H-r-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo [2.2.2]octane]-enantiomerl (compound 132a) (0.22 g, 34% yield), and
4-(2,4-dimethoxybenzyl)-3-(4-fluorophenyl)-4H-r-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo [2.2.2]octane]-enantiomer2 (compound 132b) (0.18 g, 30% yield) as white solid.
[001002] Example 138 - 3-C4-fluorophenvn-4H-l'-azaspirorn .2.41oxadiazole-5.3'- bicyclo[2.2.21octanel (133a)
[001003] To compound 132a (60 mg, 0.15 mmol) was added 10% trifluoroacetic acid in dichloromethane (5 mL), and the reaction was stirred at 0 °C for 2 hours. On completion, the reaction was filtered, and the resulting filtrate was concentrated and purified by prep-HPLC
[Instrument: Shimadzu pump LC-20A; Column: Phenomenex Gemini CI 8 150x30 mm, particle size: 5 μπι; Mobile phase: 42-72% acetonitrile in H20 (add 0.5% HC1, v/v)]. The product was then subjected to lyophilization to give 3-(4-fluorophenyl-4H- -azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane]-enantiomerl hydrochloride (compound 133a) (28 mg, 73% yield ) as a white solid: cSFC analytical tR: 2.06 min., purity: 97.6%; LCMS (G): 1.10 min., 262.3 m/z (M+1); Ή-NMR (CD3OD, 400 MHz): δ 7.82-7.79 (dd, J,=8.8 Hz, J2=5.2 Hz, 2H), 7.27-7.23 (t, J=8.8 Hz, 2H), 3.76-3.72 (d, J=14.0 Hz, 1H), 3.65-3.61 (d, J=14.4 Hz, 1H), 3.47-3.56 (m, 4H), 2.44-2.28 (m, 3H), 2.15-1.99 (m, 2H);
cSFC analytical conditions: Column: Chiracel IC 250x4.6 mm, I.D., 5 μπι; Mobile phase: 50% isopropanol (0.05% DEA) in C02; Flow rate: 2.4 mL/min.; Back pressure: 120 bar.
[001004] Example 139 - 3-(4-fluorophenyl')-4H-l'-azaspirorri ,2,41oxadiazole-5<3'- bicyclor2.2.21octane1 (133b)
[001005] To compound 132b (60 mg, 0.15 mmol) was added 10% trifluoroacetic acid in dichloromethane (10 mL), and the reaction was stirred at 0 °C for 2 hours. On completion, the reaction was filtered, and the resulting filtrate was concentrated and purified by prep-HPLC
[Instrument: Shimadzu pump LC-20A; Column: Phenomenex Gemini CI S 150x30 mm, particle size: 5 μηι; Mobile phase: 42-72% acetonitrile in H20 (add 0.5% HC1, v/v)]. The product was then subjected to lyophilization to give 3-(4-fluorophenyl) -4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane]-enantiomer2 hydrochloride (compound 133b) (29 mg, 76% yield) as a white solid: cSFC analytical tR: 2.38 min, purity: 95.7%; LCMS (G): 1.09 min, 262.3 m/z (M+1); Ή-NMR (CD3OD, 400 MHz): δ 7.82-7.79 (m, 2H), 7.27-7.23 (t, J=8.8 Hz, 2H), 3.76-3.72 (d, J=14.0 Hz, 1H), 3.65-3.61 (d, J=14.4 Hz, 1H), 3.49-3.36 (m, 4H), 2.43-2.29 (m, 3H), 2.15- 2.01 (m, 2H);
cSFC analytical conditions: Column: Chiracel IC 250x4.6 mm, I.D., 5 μπι; Mobile phase: 50% isopropanol (0.05% DEA) in C02; Flow rate: 2.4 mL/min.; Back pressure: 120 bar.
[001006] Example 140 - (+/-)-3-(3,4-dichlorophenvn-4-('2,4-dimethoxybenzvn-4H-l l- azaspiro[ l ,2,41 oxadiazole-5,3'-bicyclo 2.2.2]octanel (134)
Figure imgf000244_0001
[001007] To a mixture of compound B-205 (0.64 g, 3.4 mmol) and compound C-108 (1.2 g, 4.4 mmol) in dichloromethane (15 mL) was added 10% aqueous sodium hypochlorite (7.5 g, 0.10 mol) dropwise at 0 °C. The reaction was allowed to warm to room temperature and was stirred at this temperature for 6 hours. On completion, the reaction was filtered, and the filtrate was concentrated and purified by prep-HPLC [Instrument: Shimadzu pump LC-20A; Column:
GEMINI 200x50 mm, particle size: 10 μιη; Mobile phase: 40-65% acetonitrile in H20 (add 0.5% NH3 H20, v/v)] to give racemate 134 (0.37 g, 23% yield) as a yellow solid. LCMS: (ES+) m/z (M+H)+ = 462.1, tR=1.754. Racemate 134 is a mixture of (R)-3-(3,4-dichlorophenyl)-4-(2,4- dimethoxybenzyl)-4H-l '-azaspiro[[l ,2,4] oxadiazole-5,3'-bicyclo[2.2.2]octane] (when deprotected provides (R)-3-(3,4-dichlorophenyl)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane]), and (S)-3-(3,4-dichlorophenyl)-4-(2,4-dimethoxybenzyl)-4H-l '-azaspiro[[l ,2,4] oxadiazole-5,3'- bicyclo[2.2.2]octane] (when deprotected provides (S)-3-(3,4-dichlorophenyl)-4H- l '- azaspiro[[l,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane]).
[001008] Chiral Separation:
[0010091 A solution of racemate 134 (0.30 g, 0.65 mmol) in 5 mL of methanol was separated by SFC (Instrument: SFC 80; Column: AD-10 μπι; Mobile phase: 50% ethanol (0.01% NH3 H20) in C02) at room temperature. Each set of collected fractions was concentrated at room temperature and then subjected to lyophilization to give:
3-(3,4-dichlorophenyl)-4-(2,4-dimethoxybenzyl)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane]-enantiomerl (compound 134a) (0.15 g, 50% yield), and
3 -(3 ,4-dichlorophenyl)-4-(2,4-dimethoxybenzyl)-4H- 1 '-azaspiro[ [ 1 ,2,4] oxadiazole-5 ,3 '- bicyclo[2.2.2]octane]-enantiomer2 (compound 134b) (0.15 g, 50% yield) as yellow solid.
[001010] Example 141 - 3-n.4-dichlorophenyl)-4H-l '-azaspirorrL2,41oxadiazole-5,3'- bicvclo[2.2.2]octane"l-enantiomerl hydrochloride (135a)
[001011] To compound 134a (0.10 g, 0.22 mmol) was added 10% trifluoroacetic
acid/dichloromethane (2 mL), and the reaction was stirred at 0 °C for 1 hours. On completion, the reaction was filtered, and the filtrate was concentrated and purified by prep-HPLC [Instrument: GX-F; Column: Phenomenex Synergi C18 150x30 mm, particle size: 4 μηι; Mobile phase: 17- 47% acetonitrile in H20 (add 0.5% TFA, v/v)]. The product was dissolved 0.2 N hydrochloric acid (1 mL) and subjected to lyophilization to give 3-(3,4-dichIorophenyl)-4H-l '- azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane]-enantiomerl hydrochloride (compound 135a) (40 mg, 64% yield) as a white solid: cSFC analytical tR: 2.59 min., purity: 99.5%; LCMS (A): 1.55 min., 31 1.9 m/z (M+l); Ή-NMR (CD3OD, 400 MHz): δ 7.90 (s, 1 H), 7.69-7.64 (m, 2H), 3.76-3.72 (dd, J,=14.4 Hz, J2=2.0 Hz, 1H), 3.62-3.57 (dd, J,=14.0 Hz, J2=2.4 Hz, 1 H), 3.46- 3.36 (m, 4H), 2.41 -2.37 (m, 2H), 2.28-2.24 (m, 1 H), 2.14-2.10 (m, 1 H), 2.04-1 .99 (m, 1H);
cSFC analytical conditions: Column: Chiralpak AD-3 100><4.6mm, I.D., 3 μιη; Mobile phase: ethanol (0.05% DEA) in C02 from 5% to 40%; Flow rate: 3 mL/min.; Back pressure: 120 bar.
[001012] Example 142 - 3-(3,4-dichlorophenvn-4H-l '-azaspirorn .2.41oxadiazole-5.3'- bicyclo[2.2.2]octane]-enantiomer2 hydrochloride (135b)
[001013] To compound 134b (0.10 g, 0.22 mmol) was added 10% trifluoroacetic
acid/dichloromethane (2 mL), and the reaction was stirred at 0 °C for 1 hours. On completion, the reaction was filtered, and the filtrate was concentrated and purified by prep-HPLC [Instrument: GX-F; Column: Phenomenex Synergi CI 8 150x30 mm, particle size: 4 μιη; Mobile phase: 17- 47%) acetonitrile in H20 (add 0.5% TFA, v/v)]. The product was dissolved in 0.2 N hydrochloric acid (1 mL) and subjected to lyophilization to give 3-(3,4-dichlorophenyl)-4H-l '- azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane]-enantiomer2 hydrochloride (compound 135b) (44 mg, 71 % yield) as a white solid: cSFC analytical tR: 3.37 min„ purity: 99.5%; LCMS (A): 1.55 min., 31 1.9 m/z (M+l); Ή-NMR (CD3OD, 400 MHz): δ 7.90-7.89 (d, J=l .6 Hz, 1H), 7.69-7.64 (m, 2H), 3.75-3.71 (dd, J,=14.0 Hz, J2=2.0 Hz, 1H), 3.62-3.58 (dd, J,=14.0 Hz, J2=2.4 Hz, 1H), 3.45-3.34 (m, 4H), 2.41-2.36 (m, 2H), 2.29-2.24 (m, 1H), 2.13-2.10 (m, 1H), 2.04-2.00 (m, 1H);
cSFC analytical conditions: Column: Chiralpak AD-3 100x4.6mm, I.D., 3 μπι; Mobile phase: ethanol (0.05% DEA) in C02 from 5% to 40%; Flow rate: 3 mL/min.; Back pressure: 120 bar.
[001014] Example 143 - (+/-)-3-(3-chlorobenzorblthiophen-2-ylV4-(2,4-dimethoxybenzyl)- 4H-l '-azaspiro rri .2.41oxadiazole-5.3'-bicvclor2.2.21octanel (136
Figure imgf000246_0001
[001015] To a mixture of compound B-206 (0.80 g, 3.8 mmol) and compound C-108 (1 .1 g,
4.2 mmol) in dichloromethane (10 mL) was added 10% aqueous sodium hypochlorite (5.7 g, 7.6 mmol) slowly at 0 °C. The reaction was allowed to warm to room temperature and stirred at this temperature for 2 hours. On completion, the reaction mixture was filtered, and the resulting filtrate was concentrated in vacuo. The residue was purified by prep-HPLC [Instrument:
Shimadzu pump LC-20A; Column: GEMINI 200 x 50 mm, particle size: 10 μπι; Mobile phase: 55-66.7% acetonitrile in H20 (add 0.5% NH3 H20, v/v)] to give racemate 136 (0.36 g, 20% yield) as a white solid. Racemate 136 is a mixture of (R)-3-(3-chlorobenzo[b]thiophen-2-yl)-4- (2,4-dimethoxybenzyl)-4H-l '-azaspiro [[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane] (when deprotected provides (R)-3-(3-chlorobenzo[b]thiophen-2-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole- 5,3'-bicyclo[2.2.2]octane]), and (S)-3-(3-chIorobenzo[b]thiophen-2-yl)-4-(2,4-dimethoxybenzyl)- 4H-l '-azaspiro [[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane] (when deprotected provides (S)-3-(3- chlorobenzo[b]thiophen-2-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane]).
[001016] Chiral Separation:
[001017] A solution of racemate 136 (0.36 g, 0.75 mmol) in 10 mL of ethanol was separated by SFC (Instrument: SFC 80; Column: Chiralpak AD-H 250 χ 25 mm I.D., 10 μπι; Mobile phase: 60% ethanol (0.01% NH3 H20) in C02) at room temperature. Each set of collected fractions was concentrated at room temperature and subjected to lyophilization to give:
3-(3-chlorobenzo[b]thiophen-2-yl)-4-(2,4-dimethoxybenzyl)-4H-l '-azaspiro
[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane]-enantiomerl (compound 136a) (0.13 g, 36% yield), and 3-(3-chlorobenzo[b]thiophen-2-yl)-4-(2,4-dimethoxybenzyl)-4H- -azaspiro
[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane]-enantiomer2 (compound 136b) (0.13 g, 36% yield) as a white solid.
[001018] Example 144 - 3-(3-chlorobenzo[b]thiophen-2-yl)-4H-l'-azaspiro[[L2,41oxadiazole- 5,3'-bicvclor2.2.21octanel (137a)
[001019] To compound 136a (60 mg, 0.12 mmol) was added 10% trifluoroacetic acid in dichloromethane (5 mL), and the reaction was stirred at 0 °C for 2 hours. On completion, the reaction was filtered, and the resulting filtrate was concentrated and purified by prep-HPLC
[Instrument: Shimadzu pump LC-20A; Column: Phenomenex Gemini CI 8 150 x 30 mm, particle size: 5 μηι; Mobile phase: 42-72% acetonitrile in H20 (add 0.5% HC1, v/v)]. The product was then subjected to lyophilization to give 3-(3-chlorobenzo [b]thiophen-2-yl)-4H-l '- azaspiro[[l,2,4]oxadiazole-5,3'-bicyclo [2.2.2]octane]-enantiomerl hydrochloride (compound 137a) (34 mg, 85% yield ) as a white solid: cSFC analytical tR: 3.30 min., purity: 97.4%; LCMS (G): 1.35 min., 334.8 m/z (M+l); Ή-NMR (CD3OD, 400 MHz): δ 7.98-7.93 (m, 2H), 7.61 -7.56 (m, 2H), 3.81-3.77 (d, J=14.4 Hz, 1 H), 3.73-3.69 (d, J=14.4 Hz, 1 H), 3.50-3.37 (m, 4H), 2.48-
2.40 (m, 2H), 2.28-2.25 (m, 1 H), 2.19-2.04 (m, 2H);
cSFC analytical conditions: Column: Chiracel IC 250 χ 4.6 mm, I.D., 5 μπι; Mobile phase: 50% isopropanol (0.05% DEA) in CO2; Flow rate: ,2.4 mL/min.; Back pressure: 120 bar.
[001020] Example 145 - 3-(3-chlorobenzo[blthiophen-2-yl)-4H-l '-azaspiro[ l ,2,41oxadiazole- 5,3'-bicvclor2.2.21octanel (137b)
[001021] To compound 136b (60 mg, 0.12 mmol) was added 10% trifluoroacetic acid in dichloromethane (5 mL), and the reaction was stirred at 0 °C for 2 hours. On completion, the reaction was filtered, and the resulting filtrate was concentrated and purified by prep-HPLC
[Instrument: Shimadzu pump LC-20A; Column: Phenomenex Gemini CI 8 150 x 30 mm, particle size: 5 μηι; Mobile phase: 42-72% acetonitrile in H20 (add 0.5% HC1, v/v)]. The product was then subjected to lyophilization to give 3-(3-chlorobenzo [b]thiophen-2-yl)-4H-l '- azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo [2.2.2]octane]-enantiomer2 hydrochloride (compound 137b) (30 mg, 75% yield) as a white solid: cSFC analytical tR: 3.98 min., purity: 96.2%; LCMS (G): 1.35 min., 334.8 m/z (M+l ); Ή-NMR (CD3OD, 400 MHz): 5 7.98-7.94 (m, 2H), 7.60-7.58 (m, 2H), 3.81-3.77 (d, J=14.4 Hz, 1 H), 3.73-3.69 (d, J=14.4 Hz, 1 H), 3.46-3.37 (m, 4H), 2.48-
2.41 (m, 2H), 2.28-2.25 (m, 1H), 2.19-2.04 (m, 2H);
cSFC analytical conditions: Column: Chiracel IC 250 χ 4.6 mm, I.D., 5 μπι; Mobile phase: 50% isopropanol (0.05% DEA) in CO2; Flow rate: 2.4 mL/min.; Back pressure: 120 bar.
[001022] Example 146 - (+/-V4-(2,4-dimethoxybenzylV3-(4-(4-fluorophenoxy phenvn-4H-l '- azaspiro[[l ,2,4"[oxadiazole-5,3'-bicyclo[2.2.21octane] (138)
Figure imgf000248_0001
[001023] To a mixture of compound B-207 (0.80 g, 3.5 mmol) and compound C-108 (1.0 g, 3.8 mmol) in dichloromethane (10 mL) was added 10% aqueous sodium hypochlorite (4.5 g, 7.0 mmol) slowly at 0 °C. The reaction was allowed to warm to room temperature and stirred at this temperature for 2 hours. On completion, the reaction was filtered, and the resulting filtrate was concentrated and purified by prep-HPLC [Instrument: Shimadzu pump LC-20A; Column:
GEMINI 200 χ 50 mm, particle size: 10 μηι; Mobile phase: 55-66.7% acetonitrile in H20 (add 0.5% NH3 H20, v/v)] to give racemate 138 (0.13 g, 26% yield) as a white solid. Racemate 138 is a mixture of (R)-4-(2,4-dimethoxybenzyl)-3-(4-(4-fluorophenoxy)phenyl)-4H-l'- azaspiro[[l,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane] (when deprotected provides (R)-3-(4-(4- fluorophenoxy)phenyl)-4H-r-azaspiro[[l,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane]), and (S)-4- (2,4-dimethoxybenzyl)-3-(4-(4-fluorophenoxy)phenyl)-4H-l'-azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane] (when deprotected provides (S)-3-(4-(4-fluorophenoxy)phenyl)-4H-l'- azaspiro[[l,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane]).
[001024] Chiral Separation:
[001025] A solution of racemate 138 (0.13 g, 0.26 mmol) in 10 mL of ethanol was separated by SFC (Instrument: SFC 80; Column: Chiralpak AD-H 250 x 25 mm I.D., 10 μιτι; Mobile phase: 60% ethanol (0.01% NH3 H20) in C02) at room temperature. Each set of collected fractions was concentrated at room temperature and then subjected to lyophilization to give:
4-(2,4-dimethoxybenzyl)-3-(4-(4-fluorophenoxy)phenyl)-4H- 1 '- azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane]-enantiomerl (compound 138a) (35 mg, 27% yield), and
4-(2,4-dimethoxybenzyl)-3-(4-(4-fluorophenoxy)phenyl)-4H- 1 '- azaspiro[[l,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane]-enantiomer2 (compound 138b) (40 mg, 31% yield) as a white solid.
[001026] Example 147 - 3-(4-(4-fluorophenoxy phenyl -4H-r-azaspiro[[L2,41oxadiazole- 5,3'-bicvclor2.2.21octanel (139a)
[001027] To compound 138a (30 mg, 60 μηιοΐ) was added 10% trifluoroacetic acid in dichloromethane (4 mL), and the reaction was stirred at 0 °C for 0.5 hour. On completion, the reaction was filtered, and the resulting filtrate was concentrated and purified by prep-HPLC
[Instrument: Shimadzu pump LC-20A; Column: Phenomenex Gemini CI 8 150 x 30 mm, particle size: 5 μηι; Mobile phase: 42-72% acetonitrile in H20 (add 0.5% HC1, v/v)]. The product was then subjected to lyophilization to give 3-(4-(4-fluorophenoxy)phenyl)-4H-l '- azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane]-enantiomerl hydrochloride (compound 139a) (16 mg, 76% yield ) as a white solid: cSFC analytical tR: 2.75 min., purity: 99.2%; LCMS (G): 1.35 min., 354.4 m/z (M+l); Ή-NMR (CD3OD, 400 MHz): δ 7.73-7.71 (d, J=8.8 Hz, 2H), 7.21 -7.16 (t, J=8.8 Hz, 2H), 7.13-7.09 (m, 2H), 7.05-7.03 (d, J=8.8 Hz, 2H), 3.77-3.73 (d, J=14.0 Hz, 1 H), 3.60-3.56 (d, J=14.4 Hz, 1 H), 3.47-3.36 (m, 4H), 2.40 (s, 2H), 2.27-2.26 (m, 1 H), 2.15- 1.98 (m, 2H);
cSFC analytical conditions: Column: Chiracel IC 250 x 4.6 mm, I.D., 5 μπι; Mobile phase: 50% isopropanol (0.05% DEA) in C02; Flow rate: 2.4 mL/min.; Back pressure: 120 bar.
[001028] Example 148 - 3-(4-(4-fluorophenoxy)phenyl)-4H-l '-azaspiro [L2,41oxadiazole- 5,3'-bicvclor2.2.21octanel (139b)
[001029] To compound 138b (35 mg, 70 μιηοΐ) was added 10% trifluoroacetic acid in dichloromethane (4 mL), and the reaction was stirred at 0 °C for 0.5 hour. On completion, the reaction was filtered, and the resulting filtrate was concentrated and purified by prep-HPLC
[Instrument: Shimadzu pump LC-20A; Column: Phenomenex Gemini CI 8 1 50 x 30 mm, particle size: 5 μπι; Mobile phase: 42-72% acetonitrile in H20 (add 0.5% HC1, v/v)]. The product was then subjected to lyophilization to give 3-(4-(4-fluorophenoxy)phenyl)-4H-l '- azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane]-enantiomer2 hydrochloride (compound 139b) ( 12 mg, 50% yield) as a white solid: cSFC analytical tR: 3.12 min., purity: 98.5%; LCMS (G): 1 .35 min., 354.4 m/z (M+l); Ή-NMR (CD3OD, 400 MHz): δ 7.73-7.71 (d, J=8.8 Hz, 2H), 7.21 -7.16 (t, J=8.8 Hz, 2H), 7.13-7.09 (m, 2H), 7.05-7.03 (d, J=8.8 Hz, 2H), 3.76-3.73 (d, J=14.0 Hz, 1 H), 3.60-3.56 (d, J=14.0 Hz, 1 H), 3.47-3.36 (m, 4H), 2.40 (s, 2H), 2.27-2.26 (m, 1 H), 2.15- 1.98 (m, 2H);
cSFC analytical conditions: Column: Chiracel IC 250 x 4.6 mm, I.D., 5 μιη; Mobile phase: 50% isopropanol (0.05% DEA) in C02; Flow rate: 2.4 mL/min.; Back pressure: 120 bar.
[001030] Example 149 - (+/-V4-(2.4-dimethoxybenzvn-3-nH-indol-6-vn-4H-l'- azaspiro[[l ,2,4"|oxadiazole-5,3'-bicyclo[2.2.21octane1 (140)
Figure imgf000249_0001
[001031] To a solution of compound B-208 (1 .0 g, 6.3 mmol) and compound C-108 (2.1 g, 7.5 mmol) in dichloromethane (20 mL) was added 10% aqueous sodium hypochlorite (9.3 g, 13 mmol) dropwise at 0 °C. The resulting solution was warmed to room temperature and stirred at this temperature for 1 hour. On completion, the reaction was filtered, and the resulting filtrate was and purified by prep-HPLC [Instrument: GX-C; Column: Phenomenex SY ERGI CI 8
150*30mm; particle size: 4μπι; Mobile phase: 45-70% acetonitrile in H20 (add 0.5% NH3 ' H20, v/v)] to give racemate 140 (1.3 g, 48% yield) as a yellow solid. LCMS: (ES+) m/z (M+H)+ = 433.3, tR = 1.338. Racemate 140 is a mixture of (R)-4-(2,4-dimethoxybenzyl)-3-(l H-indol-6- yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane] (when deprotected provides (R)- 3-(l H-indol-6-yl)-4H- -azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane]), and (S)-4-(2,4- dimethoxybenzyl)-3-(lH-indol-6-yl)-4H-l '-azaspiro[[l,2,4]oxadiazole-5,3'-bicycIo[2.2.2]octane] (when deprotected provides (S)-3-(l H-indol-6-yl)-4H-l'-azaspiro[[l ,2,4]oxadiazoIe-5,3'- bicyclo[2.2.2]octane]).
[001032] Chiral Separation:
[001033] A solution of racemate 140 (500 mg, 1.2 mmol) in 10 mL of ethanol was separated by SFC (Instrument: SFC 80; Column: OJ, 5 μιη; Mobile phase: 40% ethanol (0.01 % NH3 H20) in C02) at room temperature. Each set of collected fractions was concentrated at room
temperature and then subjected to lyophilization to give:
4-(2,4-dimethoxybenzyl)-3-(l H-indol-6-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane] -enantiomerl (compound 140a) (150 mg, 30% yield), and
4-(2,4-dimethoxybenzyl)-3-(l H-indol-6-yl)-4H-r-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane] -enantiomer2 (compound 140b) (150 mg, 30% yield) as a yellow solid.
[001034] Example 150 - 3-nH-indol-6-ylV4H-l l-azaspirorri .2.41oxadiazole-5.3'- bicyclo Γ2.2.21 octanel-enantiomer 1 (141a)
[001035] To compound 140a (150 mg, 0.35 mmol) was added 10% trifluoroacetic acid in dichloromethane (10 mL), and the reaction was stirred at 0 °C for 1 hour. On completion, the reaction was filtered, and the resulting filtrate was concentrated and purified by prep-HPLC
[Instrument: GX-B; Column: Phenomenex Synergi CI 8 150*30mm; particle size: 4μιη; Mobile phase: 13-43% acetonitrile in H20 (add 0.5%TFA, v/v)]. The collected fractions were then subjected to lyophilization to give 3-(lH-indol-6-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane]-enantiomerl trifluoroacetate (compound 141a) (9.8 mg, 10% yield ) as a yellow oil: cSFC analytical tR: 3.83 min., purity: 96.7%; LCMS (E): 0.91 min., 283.2 m/z (M+l); Ή-NMR (CD3OD, 400 MHz): δ 7.80 (s, 1H), 7.66-7.64 (d, J = 8.4 Hz, 1H), 7.41-7.38 (m, 2H), 6.54-6.53 (d, J = 2.8 Hz, 1H), 3.79-3.75 (dd, J = 14.0 Hz, 2.4 Hz, 1H), 3.61-3.56 (dd, J = 16.4 Hz, 2.4 Hz, 1H), 3.48-3.33 (m, 4H), 2.43-2.33 (m, 2H), 2.32-2.29 (m, 1 H), 2.17-2.14 (m, 1H). 2.06- 2.01 (m, 1 H);
cSFC analytical conditions: Column: Chiralpak AD-3 100x4.6mm, I.D., 3μπι; Mobile phase: ethanol (0.05% DEA) in C02 from 5% to 40%; Flow rate: 3mL/min.; Wavelength: 220nm.
[001036] Example 151 - 3-nH-indol-6-vn-4H-l '-azaspirorri .2,41oxadiazole-5.3'- bicyclo[2.2.21octane1-enantiomer2 (141b) [001037] To compound 140a (150 mg, 0.35 mmol) was added 10% trifluoroacetic acid in dichloromethane (10 mL), and the reaction was stirred at 0 °C for 1 hour. On completion, the reaction was filtered, and the resulting filtrate was concentrated and purified by prep-HPLC
[Instrument: GX-B; Column: Phenomenex Synergi CI 8 150*30mm; particle size: 4μιη; Mobile phase: 13-43%) acetonitrile in H20 (add 0.5%>TFA, v/v)]. The collected fractions were then subjected to lyophilization to give 3-(lH-indol-6-yl)-4H-l'-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane]-enantiomer2 trifluoroacetate (compound 141a) (9.1 mg, 9%> yield ) as a yellow oil: cSFC analytical tR: 3.55 min., purity: 100.0%; LCMS (E): 0.91 min., 283.2 m/z (M+l); Ή-NMR (CD3OD, 400 MHz): δ 7.80 (s, 1 H), 7.66-7.63 (d, J = 8.4 Hz, 1 H), 7.41 -7.38 (m, 2H), 6.54-6.53 (d, J = 2.8 Hz, 1 H), 3.78-3.74 (dd, J = 14.4 Hz, 2.0 Hz, 1 H), 3.64-3.57 (dd, J = 25.6 Hz, 2.4 Hz, 1 H), 3.48-3.33 (m, 4H), 2.47-2.33 (m, 2H), 2.32-2.29 (m, 1 H), 2.17-2.13 (m, 1 H). 2.05-2.01 (m, 1 H);
cSFC analytical conditions: Column: Chiralpak AD-3 100x4.6mm, I.D., 3μιη; Mobile phase: ethanol (0.05% DEA) in C02 from 5% to 40%; Flow rate: 3mL/min.; Wavelength: 220nm.
[001038] Example 152 - (lr,3R,4s,5S.7s)-3'-(benzofuran-5-yl)-4'-(2,4-dimethoxybenzyl)-4'H- l-azaspirofadamantane-4,5'-[l ,2,41oxadiazole] (142) and (lr.3R.4r,5S,7s)-3'-(benzofuran-5-yl)-4'- (2,4-dimethoxybenzyl)-4'H-l-azaspiro[adamantane-4,5'- l ,2,4]oxadiazole1 (143)
Figure imgf000251_0001
[001039] To a mixture of B-180 (0.5 g, 3.1 mmol) and compound C-112 (1.1 g, 3.8 mmol) in dichloromethane (20 mL) was added 10%) aqueous sodium hypochlorite (4.6 g, 63 mmol) dropwise at 0 °C. The mixture was stirred at room temperature for 4 hours. On completion, the reaction was filtered, and the resulting filtrate was concentrated and purified by prep-HPLC
[Instrument: PREP-B; Column: Gemini CI 8 150x30 mm; particle size: 10 μπι; Mobile phase: 25%-60% acetonitrile in H20 (0.5% NH3 H20 v/v)] to give a mixture of compounds 142 and 143 (0.3 g, 21 %o) as a yellow solid. LCMS: (ES+) m/z (M+H)+ = 460.3, tR,=l .444, tR2=l .492.
[001040] Separation:
[001041] A solution of compounds 142 and 143 (0.20 g, 0.44 mmol) in 5 mL of methanol was separated by SFC (Instrument: SFC 80; Column: AD- 10 μιη; Mobile phase: 50% methanol (0.01 o NH3 H20) in C02) at room temperature. Each set of collected fractions was concentrated at room temperature and then subjected to lyophilization to give: (lr,3R,4s,5S,7s)-3,-(benzofuran-5-yl)-4'-(2,4-dimethoxybenzyl)-4'H-l - azaspiro[adamantane-4,5'-[l ,2,4]oxadiazole] (142) (0.10 g, 50% yield), and
( 1 r,3R,4r,5 S,7s)-3'-(benzofuran-5-yl)-4'-(2,4-dimethoxybenzyl)-4'H- 1 - azaspiro[adamantane-4,5'-[l ,2,4]oxadiazole] (143) (0.10 g, 50% yield) as yellow solid.
[001042] Example 153 - (lr,3R,4s,5S,7s)-3'-(benzofuran-5-yl)-4'H-l -azaspiroradamantane- 4.5'-[l ,2,4]oxadiazolel hydrochloride (144)
Figure imgf000252_0001
142
[001043] A mixture of compound 142 (90 mg, 0.20 mmol) in 10% trifluoroacetic
acid/dichloromethane (3 mL) was stirred at room temperature for 2 hours. The resulting solution was concentrated in vacuo, and the resulting residue was purified by prep-HPLC [Instrument: GX-E; Column: Agella Venusil ASB CI 8 150x21.2 mm; particle size: 5 μπι; Mobile phase: 10%- 40% acetonitrile in H20 (0.5% HCI v/v)] to give (l r,3R,4s,5S,7s)-3'-(benzofuran-5-yl)-4'H-l - azaspiro[adamantane-4,5'-[l ,2,4]oxadiazole] hydrochloride (compound 144) (32 mg, 53% yield) as a white solid: LCMS (A): 1.29 min., 310.0 m/z (M+1); Ή-NMR (CD3OD, 400 MHz): δ 8.08 (s, 1H), 7.86 (s, 1 H), 7.75-7.73 (d, J=8.8 Hz, 1 H), 7.61-7.59 (d, J=8.8 Hz, 1 H), 6.94 (s, 1H), 3.83- 3.80 (d, J=12.4 Hz, 2H), 3.70-3.67 (d, J=12.4 Hz, 2H), 3.58 (s, 2H), 2.37 (m, 4H), 2.19 (s, 1 H), 2.10-2.06 (d, J=12.8 Hz, 2H).
[001044] Example 154 - (l r,3R,4r,5S.7s)-3'-(benzofuran-5-yl)-4'H-l -azaspiroradamantane- 4.5'-[l,2,41oxadiazole] hydrochloride ("145)
Figure imgf000252_0002
[001045] A mixture of compound 143 (90 mg, 0.20 mmol) in 10% trifluoroacetic
acid dichloromethane (3 mL) was stirred at room temperature for 2 hours. The resulting solution was concentrated in vacuo, and the resulting residue was purified by prep-HPLC [Instrument: GX-E; Column: Agella Venusil ASB CI 8 150x21.2 mm; particle size: 5 μπι; Mobile phase: 10%- 40% acetonitrile in H20 (0.5% HCI v/v)] to give (lr,3R,4r,5S,7s)-3'-(benzofuran-5-yl)-4'H-l - azaspiro[adamantane-4,5'-[l ,2,4]oxadiazole] hydrochloride (compound 145) (35 mg, 57% yield) as a white solid: LCMS (A): 1.27 min., 310.0 m/z (M+1 ); Ή-NMR (CD3OD, 400 MHz): δ 8.07- 8.06 (d, J=1.2 Hz, IH), 7.87-7.86 (d, J=2.0 Hz, IH), 7.74-7.72 (dd, J,=8.4 Hz, J2=1.2 Hz, IH), 7.62-7.59 (d, J=8.8 Hz, IH), 6.94-6.94 (d, J=1.6 Hz, IH), 3.80-3.77 (d, J=12.4 Hz, 2H), 3.61-3.58 (m, 4H), 2.38 (s, 2H), 2.31-2.28 (m, 2H), 2.23-2.17 (m, 3H).
[001046] Example 155 - nr.3R.4s.5S.7sV3'-(benzo[blthiophen-6-yl)-4l-(2,4- dimethoxybenzyl)-4'H-l -azaspiroradamantane-4,5'- l ,2,41oxadiazolel (146) and (l r,3R,4r,5SJs)- 3'-fbenzo|"b]thiophen-6-yn-4'-(2,4-dimethoxybenzyl)-4'H-l -azaspiro['adamantane-4,5'-
Figure imgf000253_0001
[001047] To a mixture of B-203 (0.30 g, 1.7 mmol) and compound C-112 (0.61 g, 2.0 mmol) in dichloromethane (10 mL) was added 10% aqueous sodium hypochlorite (2.5 g, 34 mmol) dropwise at 0 °C. The mixture was stirred at room temperature for 4 hours. On completion, the reaction was filtered, and the resulting filtrate was concentrated and purified by prep-HPLC
[Instrument: GX-A; Column: Phenomenex Gemini CI 8 150x25 mm; particle size: 10 μιη; Mobile phase: 55%-85% acetonitrile in H20 (0.5% NH3 H20 v/v)] to give compound 146 (0.15 g, 37%) as a yellow solid, LCMS: (ES+) m/z (M+H)+ = 476.2, tR=l .545; and compound 147 (0.14 g, 35%) as a yellow solid. LCMS: (ES+) m/z (M+H)+ = 476.2, tR=l .596.
[001048] Example 156 - (lrJR,4s,5S.7s -3l-(benzorblthiophen-6-yl)-4lH-l- azaspiroradamantane-4.5'-rL2,41oxadiazole] hydrochloride (148)
Figure imgf000253_0002
[001049] A solution of compound 146 (60 mg, 0.13 mmol) in 10% trifluoroacetic
acid/dichloromethane (4 mL) was stirred at room temperature for 2 hours. At this time, the reaction was concentrated in vacuo and the residue was purified by prep-HPLC [Instrument: GX- E; Column: Agella Venusil ASB CI 8 150x21 .2 mm; particle size: 5 μιη ; Mobile phase: 14%- 44% acetonitrile in H20 (0.5% HCI v/v)] to give (lr,3R,4s,5S,7s)-3'-(benzo[b]thiophen-6-yl)-4'H- l-azaspiro[adamantane-4,5'-[l,2,4]oxadiazole] hydrochloride (compound 148) (18 mg, 48% yield) as a white solid: LCMS (A): 1.43 min., 326.0 m/z (M+1 ); Ή-NMR (CD3OD, 400 MHz): δ 8.36 (s, 1H), 7.97-7.92 (d, J=8.4 Hz, 1H), 7.79-7.75 (m, 2H), 7.47-7.45 (d, J=5.2 Hz, 1H), 3.84- 3.81 (d, J=12.4 Hz, 2H), 3.71 -3.68 (d, J=13.2 Hz, 2H), 3.59 (s, 2H), 2.38-2.35 (m, 4H), 2.20 (s, 1H), 2.10-2.07 (d, J=13.2 Hz, 2H).
[001050] Example 157 - (lr.3R.4r.5S.7s)-3'-(benzorblthiophen-6-vn-4'H-l - azaspiro[adamantane-4,5'-[ "|oxadiazole] hydrochloride
Figure imgf000254_0001
[001051] A mixture of compound 147 (56 mg, 0.12 mmol) in 10% trifluoroacetic acid/dichloromethane (4 mL) was stirred at room temperature for 2 hours. At this time, the reaction was concentrated in vacuo and the resulting residue was purified by prep-HPLC
[Instrument: GX-E; Column: Agella Venusil ASB C18 150x21.2 mm; particle size: 5 μπι ; Mobile phase: 14%-44% acetonitrile in H20 (0.5% HCI v/v)] to give (lr,3R,4r,5S,7s)-3'- (benzo[b]thiophen-6-yl)-4'H-l-azaspiro[adamantane-4,5'-[l ,2,4]oxadiazole] hydrochloride
(compound 149) (17 mg, 48% yield) as a white solid: LCMS (A): 1.44 min., 326.0 m/z (M+1 ); Ή-NMR (CD3OD, 400 MHz): δ 8.34 (s, 1H), 7.94-7.92 (d, J=8.4 Hz, 1 H), 7.77-7.75 (m, 2H), 7.47-7.45 (d, J=5.6 Hz, 1H), 3.81 -3.78 (d, J=12.4 Hz, 2H), 3.61-3.58 (m, 4H), 2.38 (s, 2H), 2.32- 2.28 (m, 2H), 2.23-2.17 (m, 3H).
[001052] Example 158 - (+/-)-4-(2,4-dimethoxybenzyl)-3-(3-(trifluoromethyl)benzofuran-5- yl)-4H-l '-azaspiror|"l ,2,41oxadiazole-5,3'-bicyclor2.2.21octane1 (150)
Figure imgf000254_0002
[001053] To a solution of compound B-212 (0.21 g, 0.92 mmol) and compound C-108 (0.30 g, 1.1 mmol) in dichloromethane (10 mL) was added 10% aqueous sodium hypochlorite (2.1 g, 2.8 mmol) dropwise at 0 °C. The resulting solution was warmed to room temperature and stirred at this temperature for 3 hours. On completion, the reaction mixture was extracted with dichloromethane (3 χ 20 mL), and the combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, concentrated in vacuo and purified by prep-HPLC [Instrument: GX-C; Column: Phenomenex SY ERGI CI 8 150*30mm; particle size: 4μηι; Mobile phase: 60-90% acetonitrile in H20 (add 0.5% ΝΗ3Ή20, v/v)] to give racemate 150 (1 15mg, 25% yield ) as a yellow solid. Racemate 150 is a mixture of (R)-4-(2,4- dimethoxybenzyl)-3-(3-(trifluoromethyl)benzofuran-5-yl)-4H- -azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane] (when deprotected provides (R)-3-(3-(trifluoromethyl)benzofuran-5-yl)-4H- l'-azaspiro[[l,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane]), and (S)-4-(2,4-dimethoxybenzyl)-3-(3- (trifluoromethyl)benzofuran-5-yl)-4H-r-azaspiro[[l,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane] (when deprotected provides (S)-3-(3-(trifluoromethyl)benzofuran-5-yl)-4H-l'- azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane]).
[001054] Chiral Separation:
[001055] A solution of racemate 150 (0.10 g, 0.20 mmol) in 5 mL of ethanol was separated by SFC (Instrument: SFC 80; Column: Chiralpak AD-H 250x25 mm I.D., 10 μπι; Mobile phase: 60% ethanol (0.01% NH3.H20) in C02) at room temperature. Each set of fractions was concentrated at room temperature and subjected to lyophilization to give:
4-(2,4-dimethoxybenzyl)-3 -(3 -(trifiuoromethy l)benzofuran-5 -y 1)-4H- 1 '- azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane]-enantiomerl (compound 150a) (45 mg, 45% yield), and
4-(2,4-dimethoxybenzyl)-3 -(3 -(trifluoromethyl)benzofuran-5 -yl)-4H- 1 '- azaspiro[[l,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane]-enantiomer2 (compound 150b) (45 mg, 45% yield) as a yellow solid.
[001056] Example 159 - 3-(3-(trifluoromethvnbenzofuran-5-vn-4H-l '- azaspiro [L2,41oxadiazole-5,3'-bicyclo[2.2.21octanel (151a)
[001057] Compound 150a (45 mg, 90 μηιοΐ) was dissolved in 10% trifluoroacetic acid/dichloromethane (4 mL) and stirred at 0 °C for 1 hour. On completion, the reaction was filtered, and the resulting filtrate was concentrated and purified by prep-HPLC [Instrument: GX- B; Column: Phenomenex Synergi CI 8 200*25mm; particle size: Ι Ομιη; Mobile phase: 18-48% acetonitrile in H20 (add 0.5% HC1, v/v)]. The product was then subjected to lyophilization to give 3-(3-(trifluoromethyl)benzofuran-5-yl)-4H- -azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane]-enantiomerl hydrochloride (compound 151a) (25 mg, 79% yield ) as a yellow solid: cSFC analytical tR: 1.821 min., purity: 98.7%; LCMS (B): 0.672 min„ 352.2 m/z (M+l); Ή-NMR (D20, 400 MHz): δ 8.26 (s, 1H), 7.94 (s, 1 H), 7.66 (s, 1H), 7.64 (s, 1H), 3.71 - 3.67 (d, J = 14.4 Hz, 1H), 3.56-3.52 (dd, J = 14.8 Hz, 1 H), 3.38-3.21 (m, 4H), 2.42 (s, 1H), 2.26- 2.1 (m, 1 H), 2.10-2.05 (m, 2H). 1.97-1.93 (m, 1H);
cSFC analytical conditions: Column: Chiralpak AD-3 100x4.6mm, I.D., 3μπι; Mobile phase: 40% ethanol (0.05% DEA) in C02; Flow rate: 3mL/min.; Wavelength: 220nm.
[001058] Example 160 - 3-C3-rtrifluoromethvnbenzofuran-5-ylV4H-l'- azaspiro[[l,2,4"loxadiazole-5,3'-bicyclo[2.2.21octane] (151b)
[001059] Compound 150b (45 mg, 90 μιηοΐ) was dissolved in 10% trifluoroacetic acid/dichloromethane (4 mL) and stirred at 0 °C for 1 hour. On completion, the reaction was filtered, and the resulting filtrate was concentrated and purified by prep-HPLC [Instrument: GX- B; Column: Phenomenex Synergi CI 8 200*25mm; particle size: Ι Ομπι; Mobile phase: 18-48% acetonitrile in H20 (add 0.5% HCl, v/v)]. The product was then subjected to lyophilization to give 3-(3-(trifluoromethyl)benzofuran-5-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane]-enantiomer2 hydrochloride (compound 151b) (25 mg, 79% yield ) as a yellow solid: cSFC analytical tR: 2.064 min., purity: 98.25%; LCMS (B): 0.673 min., 352.1 m/z (M+l); Ή-NMR (D20, 400 MHz): δ 8.24-8.24 (d, J=1.2 Hz, 1H), 7.90 (s, 1H), 7.64-7.59 (m, 2H), 3.70-3.67 (d, J=14.4 Hz, 1H), 3.56-3.52 (dd, J = 14.8 Hz, 2.4 Hz, 1 H), 3.35-3.24 (m, 1H), 2.40- 2.40 (d, J=2.8 Hz, 1H), 2.26-2.12 (m, 1H), 2.12-2.06 (m, 2H), 1.96-1.93 (m, 1H);
cSFC analytical conditions: Column: Chiralpak AD-3 100x4.6mm, I.D., 3μπι; Mobile phase: 40% ethanol (0.05% DEA) in C02; Flow rate: 3mL/min.; Wavelength: 220nm.
[001060] Example 161 - (+/-)-4-(2,4-dimethoxybenzyl)-3-(2-(trifluoromethyl) benzofuran-5- yl)-4H-l'-azaspirorrL2,4]oxadiazole-5J'-bicyclo[2.2.2]octane] (152)
Figure imgf000256_0001
[001061] To a mixture of compound B-216 (0.40 g, 1.5 mmol) and compound C-108 (0.49 g, 1.8 mmol) in dichloromethane (10 mL) was added 10% aqueous sodium hypochlorite (4.3 g, 5.8 mmol) dropwise at 0 °C. The reaction was allowed to warm to room temperature and was stirred at this temperature for 2 hours. On completion, the reaction was filtered, and the resulting filtrate was concentrated and purified by prep-HPLC [Instrument: GX-C; Column: Phenomenex Gemini CI 8 15O*30mm, particle size: 5 μηι; Mobile phase: 43-73% acetonitrile in H20 (add 0.5% NH3 H20, v/v)] to give racemate 152 (0.25 g, 29% yield) as a white solid. Racemate 152 is a mixture of (R)-4-(2,4-dimethoxybenzyl)-3-(2-(trifluoromethyl)benzofuran-5-yl)-4H-l '- azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane] (when deprotected provides (R)-3-(2- (trifluoromethyl) benzofuran-5-yl)-4H-l '-azaspiro [[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane]), and (S)-4-(2,4-dimethoxybenzyl)-3-(2-(trifluoromethyl)benzofuran-5-yl)-4H- - azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane] (when deprotected provides (S)-3-(2- (trifluoromethyl) benzofuran-5-yl)-4H-l '-azaspiro [[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane]).
[001062] Chiral Separation:
[001063] A solution of racemate 152 (0.25 g, 0.50 mmol) in 10 ml of ethanol was separated by SFC (Instrument: SFC 80; Column: Chiralpak OD-H 250x25 mm I.D., 10 μιη; Mobile phase: 30% methanol (0.01 % NH3 H20) in C02) at room temperature. Each set of collected fractions was concentrated at room temperature and then subjected to lyophilization to give:
(R)-4-(2,4-dimethoxybenzyl)-3-(2-(trifluoromethyl)benzofuran-5-yl)-4H-r- azaspiro[[l,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane]-enantiomerl (compound 152a) (0.10 g, 40% yield) as a white solid, and
4-(2,4-dimethoxybenzyl)-3 -(2-(trifluoromethyl)benzofuran-5 -yl)-4H- 1 '- azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane]-enantiomer2 (compound 152b) (90 mg, 36% yield) as a white solid.
[001064] Example 162 - 3-(2-(trifluoromethyl) benzofuran-5-yl)-4H-r-azaspiro
[l,2,41oxadiazole-5,3'-bicyclo 2.2.21octanel-enantiomerl (153a)
[001065] To compound 152a (0.10 g, 0.20 mmol) was added 10% trifluoroacetic
acid/dichloromethane (5 mL), and the reaction was stirred at 0 °C for 2 hours. On completion, the reaction was filtered and the resulting filtrate was concentrated and purified by prep-HPLC
[Instrument: GX-E; Column: Agella Venusil ASB CI 8 150*21.2mm, particle size: 5 μπι; Mobile phase: 24-54% acetonitrile in H20 (add 0.5% HC1, v/v)]. The product was then subjected to lyophilization to give 3-(2-(trifluoromethyl)benzofuran-5-yl)-4H- -azaspiro[[l ,2,4]oxadiazole- 5,3'-bicyclo[2.2.2]octane]-enantiomerl hydrochloride (compound 153a) (20 mg, 29%) as a yellow solid: cSFC analytical tR: 2.10 min., purity: 98.2%; LCMS (A): 1.69 min., 352.0 m/z (M+l); Ή-NMR (CD3OD, 400 MHz): δ 8.18 (s, 1H), 7.93-7.91 (d, J= 8.8 Hz, 1H), 7.79-7.77 (d, J= 8.8 Hz, 1H), 7.58 (s, 1 H), 3.79-3.76 (m, 1H), 3.66-3.62 (m, 1H), 3.48-3.39 (m, 4 H), 2.43 (m, 1 H), 2.31 (m, 1H) , 2.17-2.00 (m, 2H).
cSFC analytical conditions: Column: Chiralpak AD-3 100x4.6mm I.D., 3 μιη; Mobile phase: methanol (0.05% DEA) in C02 from 5% to 40%; Flow rate: 3.0 mL/min.; Back pressure: 120 bar.
[001066] Example 163 - 3-(2-(trifluoromethvnbenzofuran-5-yl)-4H-r- azaspiro[[l,2,41oxadiazole-5,3'-bicyclo[2.2.21octanel-enantiomer2 (153b)
[001067] To compound 152b (90 mg, 0.18 mmol) was added 10% trifluoroacetic
acid/dichloromethane (6 mL), and the reaction was stirred at 0 °C for 2 hours. On completion, the reaction was filtered, and the resulting filtrate was concentrated and purified by prep-HPLC
[Instrument: GX-E; Column: Agella Venusil ASB C18 150*21.2mm, particle size: 5 μηι; Mobile phase: 24-54% acetonitrile in H20 (add 0.5% HC1, v/v)]. The product was then subjected to lyophilization to give 3-(2-(trifluoromethyl)benzofuran-5-yl)-4H- -azaspiro[[l,2,4]oxadiazole- 5,3'-bicyclo[2.2.2]octane]-enantiomer2 hydrochloride (compound 153b) (21 mg, 33%) as yellow solid: cSFC analytical tR: 2.43min„ purity: 97.9%; LCMS (A): 1.67 min., 352.0 m/z (M+l); Ή- NMR (CDjOD, 400 MHz): δ 8.19 (s, 1H), 7.93-7.91 (d, J= 8.8 Hz, 1 H), 7.78-7.76 (d, J= 8.8 Hz, 1H), 7.58 (s, 1 H), 3.79-3.75 (m, 1 H), 3.68-3.64 (m, 1 H), 3.49-3.38 (m, 4 H), 2.43-2.32 (m, 3 H), 2.16-2.00 (m, 2H). cSFC analytical conditions: Column: Chiralpak AD-3 100x4.6mm I.D., 3 μπι; Mobile phase: methanol (0.05% DEA) in C02 from 5% to 40%; Flow rate: 3.0 mL/min.; Back pressure: 120 bar.
[001068] Example 164 - (+/-V4-(2.4-dimethoxybenzyl')-3-(3- (trifluoromethyl)benzo blthiophen-6-yl)-4H- -azaspiro[ l ,2,4]oxadiazole-5J'- bicvclo|"2.2.21octanel (154)
Figure imgf000258_0001
[001069] To a solution of compound B-223 (0.39g, 1.5 mmo!) and compound C-108 (0.78 g, 2.9 mmol) in dichloromethane (10 mL) was added 10% aqueous sodium hypochlorite (1 1 g, 15 mmol) dropwise at 0 °C. The resulting solution was warmed to room temperature and stirred at this temperature for 3 hours. On completion, the reaction was filtered, and the resulting filtrate was concentrated in vacuo. The residue was purified by prep-HPLC [Instrument: GX-C; Column: GEMINI-B 200*50mm; particle size: 10 μπι; Mobile phase: 50-80% acetonitrile in H20 (add 0.5% NH3 ' H20, v/v)] to give racemate 154 (92 mg, 13% yield) as a white solid. LCMS: (ES+) m/z (M+H)+ = 452.2, tR = 0.762. Racemate 154 is a mixture of (R)-4-(2,4-dimethoxybenzyl)-3- (3-(trifluoromethyl)benzo[b]thiophen-6-yl)-4H- -azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane] (when deprotected provides (R)-3-(3-(trifluoromethyl)benzo[b]thiophen-6- yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane]), and (S)-4-(2,4- dimethoxybenzy l)-3 -(3 -(trifluoromethyl)benzo [b]thiophen-6-yl)-4H- 1 '- azaspiro[[l,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane] (when deprotected provides (S)-3-(3- (trifluoromethyl)benzo[b]thiophen-6-yl)-4H- -azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane]).
[001070] Chiral Separation:
[001071] A solution of racemate 154 (0.14 g, 0.26 mmol) in 5 ml of ethanol was separated by SFC (Instrument: SFC 80; Column: Chiralpak AD-H 250x25 mm I.D., 10 μπι; Mobile phase: 60% ethanol (0.01% NH3 ¾0) in C02) at room temperature. Each set of collected fractions was concentrated at room temperature and then subjected to lyophilization to give:
4-(2,4-dimethoxybenzyl)-3-(3-(trifluoromethyl)benzo[b]thiophen-6-yl)-4H- - azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane]-enantiomerl (compound 154a) (57 mg, 41% yield), and 4-(2,4-dimethoxybenzyl)-3-(3-(trifluoromethyl)benzo[b]thiophen-6-yl)-4H- - azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane]-enantiomer2 (compound 154b) (53 mg, 38% yield) as a white solid.
[001072] Example 165 - 3-(3-(trifluoromethvnbenzorb1thiophen-6-vn-4H-l '- azaspiro [L2,41oxadiazole-5.3'-bicvclo 2.2.2]octanel-enantiomerl (155a)
[001073] To compound 154a (57 mg, 0.1 1 mmol) was added 50% trifluoroacetic
acid/dichloromethane (10 mL), and the reaction was stirred at 0 °C for 1 hour. On completion, the reaction was filtered, and the resulting filtrate was concentrated and purified by prep-HPLC
[Instrument: GX-E; Column: Agella Venusil ASB CI 8 150*21.2mm; particle size: 10 μπι;
Mobile phase: 25-55% acetonitrile in H20 (add 0.5% HCI, v/v)]. The collected fractions were then subjected to lyophilization to give 3-(3-(trifluoromethyl)benzo[b]thiophen-6-yl)-4H-l '- azaspiro[[l,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane]-enantiomerl hydrochloride (compound 155a) (20 mg, 50% yield ) as a white solid: cSFC analytical tR: 3.21 min., purity: 98.8%; LCMS (B): 0.73 min., 368.1 m/z (M+1 ); 1 H-NMR (CD3OD, 400 MHz): δ 8.42 - 8.40 (m, 2H), 8.01 - 7.99 (d, J=8.4 Hz, 1H), 7.90 - 7.87 (dd, J=8.4 Hz, J=0.8 Ηζ,Ι Η), 3.78-3.75 (m, 1 H), 3.66 - 3.63 (m, 1H), 3.28 (m., 1H), 3.44 - 3.41 (m, 4H), 2.42 - 2.32 (m, 2H), 2.32 - 2.31 (m, 1H), 2.16 - 2.14 (m, 1 H), 2.06 - 2.02 (m, 1H);
cSFC analytical conditions: Column: Chiralpak IC-3 100x4.6mm, I.D., 3 μηι; Mobile phase: 5% to 40% methanol (0.05% DEA) in C02; Flow rate: 3 mL/min.; Wavelength: 220 nm.
[001074] Example 166 - 3-(3-(trifluoromethvnbenzorblthiophen-6-vn-4H-l'- azaspiro[ 1.2.41oxadiazole-5,3'-bicvclo[2.2.2]octanel-enantiomer2 (155b)
[001075] To compound 154b (53 mg, 0.10 mmol) was added 50% trifluoroacetic
acid/dichloromethane (10 mL), and the reaction was stirred at 0 °C for 1 hour. On completion, the reaction was concentrated and purified by prep-HPLC [Instrument: GX-E; Column: Agella Venusil ASB CI 8 150*21.2mm; particle size: 10 μπι; Mobile phase: 25-55% acetonitrile in H20 (add 0.5% HCl, v/v)]. The collected fractions were then subjected to lyophilization to give 3-(3- (trifluoromethyl)benzo[b]thiophen-6-yl)-4H- -azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane]-enantiomer2 hydrochloride (compound 155b) (18 mg, 45% yield) as a white solid: cSFC analytical tR: 4.27 min., purity: 98.9%; LCMS (B): 0.70 min., 368.1 m/z (M+1); 1 H-NMR (CD3OD, 400 MHz): δ 8.40 (s, 2H), 7.99 - 7.96 (d, J=8.4 Hz, 1 H), 7.89 - 7.87 (d, J=8.4 Hz, 1 H), 3.74-3.70 (m, 2H), 3.43 - 3.35 (m, 4H), 2.41 - 2.33 (m, 2H), 2.13 - 2.02 (m, 2H);
cSFC analytical conditions: Column: Chiralpak IC-3 100x4.6mm, I.D., 3 μιη; Mobile phase: 5% to 40% ethanol (0.05% DEA) in C02; Flow rate: 3 mL/min.; Wavelength: 220 nm.
[001076] Example 167 - dr.3R.4s.5S.7s^3'-(benzofuran-6-yl)-4l-(2.4-dimethoxybenzvn-4lH- 1-azaspiro [adamantane-4,5'-|"1.2.4]oxadiazole1 (156) and (lr,3R,4r,5SJs)-3'-(benzofuran-6-ylV 4'-(2,4-dimethoxybenzyl)-4'H-l-azaspiro|"adamantane-4,5'-[l ,2,41oxadiazole1 (157)
Figure imgf000260_0001
[001077] To a mixture of compound B-196 (1.0 g, 6.2 mmol) and compound C-112 (2.2 g, 7.4 mmol) in dichloromethane (10 mL) was added 10% sodium hypochlorite (9.2 g, 12 mmol) slowly at 0 °C. The mixture was stirred at room temperature for 1 hour. On completion, the reaction was quenched with aqueous sodium sulfite solution and extracted with dichloromethane (3 x 20 mL). The combined organic layers were concentrated in vacuo and purified by prep- HPLC [Instrument: HPLC-A Column: Phenomenex Gemini CI 8 150 χ 30 mm; Mobile phase: 20%-50% acetonitrile in H20 (0.05% TFA v/v)] to give a mixture of compounds 156 and 157 (0.41 g, 13% yield) as a yellow solid.
[001078] Example 168 - (lr.3R.4s.5S,7s)-3'-(benzofuran-6-vn-4'H-l-azaspiroradamantane- 4.5'-[1.2.41 oxadiazolel (158) and (lrJR,4r.5SJsy3^-(benzofuran-6-vn-4'H-l - azaspiro[adamantane-4,5'-[L2,41oxadiazole] (159)
Figure imgf000260_0002
[001079] The mixture of compounds 156 and 157 (0.25 g, 0.54 mmol) in 10% trifluoroacetic acid in dichloromethane (5 mL) was stirred at room temperature for 2 hours. The solution was concentrated in vacuo, and the residue was purified by prep-HPLC [Instrument: GX-E; Column: Agella Venusil ASB CI 8 150 21.2 mm; Mobile phase: 28%-36% acetonitrile in H20 (0.05% HC1 v/v)] to give:
(lr,3R,4s,5S,7s)-3'-(benzofuran-6-yl)-4'H-l -azaspiro[adamantane-4,5'-[l ,2,4]oxadiazole] hydrochloride (compound 158) (28 mg, 33% yield) as a yellow solid: LCMS (B): 0.60 min., 310.2 m/z (M+1); Ή-NMR (CD3OD, 400 MHz): δ 8.01 (s, IH), δ 7.91 (s, I H), δ 7.72 (s, 2H), δ 6.95 (s, I H), 3.92-3.89 (d, J = 12.8 Hz, 2H), 3.72-3.69 (d, J = 12.8 Hz, 2H), 3.60 (s, 2H), 2.39- 2.34 (d, J = 21.2 Hz, 4H), 2.20 (s, I H), 2.12-2.09 (d, J = 12.8 Hz, 2H), and
(lr,3R,4r,5S,7s)-3'-(benzofuran-6-yl)-4'H-l-azaspiro[adamantane-4,5'-[l ,2,4]oxadiazole] hydrochloride (compound 159) (36 mg, 41% yield) as a yellow solid: LCMS (B): 0.55 min., 310.2 m/z (M+1); Ή-NMR (CD3OD, 400 MHz): δ 7.96 (s, IH), δ 7.92 (s, IH), δ 7.75-7.68 (dd, J,= 17.2 Hz, J2= 8.4 Hz, 2H), δ 6.96 (s, l H), 3.82-3.79 (d, J = 12.4 Hz, 2H), 3.63-3.60 (d, J = 1 1.6 Hz, 4H), 2.40 (s, 2H), 2.33-2.30 (d, J = 13.2 Hz, 2H), 2.25-2.19 (m, 3H).
[001080] Example 169 - (+/-V4-('2.4-dirnethoxybenzvn-3-(,3-fluorobenzofuran-5-vn-4H-r-
Figure imgf000261_0001
[001081] To a mixture of compound B-227 (0.40 g, 2.2 mmol) and compound C-108 (0.92 g, 3.4 mmol) in dichloromethane (10 mL) was added 10% aqueous sodium hypochlorite (6.6 g, 8.9 mmol) dropwise at 0 °C. The reaction was allowed to warm to room temperature and was stirred at this temperature for 2 hours. On completion, the reaction was filtered, and the resulting filtrate was concentrated and purified by prep-HPLC [Instrument: GX-C; Column: Phenomenex Gemini CI 8 150*30mm, particle size: 5 μπι; Mobile phase: 40-70% acetonitrile in H20 (add 0.5% NH3 H20, v/v)] to give racemate 160 (0.4 g, 40% yield) as a white solid. Racemate 160 is a mixture of (R)-4-(2,4-dimethoxybenzyl)-3-(3-fluorobenzofuran-5-yl)-4H-r-azaspiro[[l ,2,4]oxadiazole- 5,3'-bicyclo[2.2.2]octane] (when deprotected provides (R)-3-(3-fluorobenzofuran-5-yl)-4H-l '- azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane]), and (S)-4-(2,4-dimethoxybenzyl)-3-(3- fluorobenzofuran-5-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane] (when deprotected provides (S)-3-(3-fluorobenzofuran-5-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane]).
[001082] Chiral Separation:
[001083] A solution of racemate 160 (0.25 g, 0.55 mmol) in 10 mL of ethanol was separated by SFC (Instrument: SFC 80; Column: Chiralpak AD-H 250x25 mm I.D., 10 μιη; Mobile phase: 30% methanol (0.01 % NH3 H20) in C02) at room temperature. Each set of collected fractions was concentrated at room temperature and then subjected to lyophilization to give:
4-(2,4-dimethoxybenzyl)-3 -(3 -fluorobenzofuran-5 -y 1)-4H- 1 '-azaspirof [ 1 ,2,4]oxadiazole- 5,3'-bicyclo[2.2.2]octane]-enantiomerl (compound 160a) (0.10 g, 40% yield)as a white solid, and
4-(2,4-dimethoxybenzy l)-3 -(3 -fluorobenzofuran-5 -yl)-4H- 1 '-azaspiro[[ 1 ,2,4] oxadiazole- 5,3'-bicyclo[2.2.2]octane]-enantiomer2 (compound 160b) (90 mg, 36% yield)as a white solid.
[001084] Example 170 - 3-(3-fluorobenzofuran-5-vn-4H-l'-azaspiro[rL2,41oxadiazole-5.3'- bicyclo [2.2.21 octane] -enantiomer 1 (161a) [001085] To compound 160a (0.10 g, 0.22 mmol) was added 10% trifluoroacetic
acid/dichloromethane (5 ml), and the reaction was stirred at 0 °C for 2 hours. On completion, the reaction was filtered, and the resulting filtrate was concentrated and purified by prep-HPLC
[Instrument: GX-E; Column: Agella Venusil ASB C18 150*21.2 mm, particle size: 5 μπι; Mobile phase: 15-45%) acetonitrile in H20 (add 0.5% HC1, v/v)]. The product was then subjected to lyophilization to give 3-(3-fluorobenzofuran-5-yl)-4H-l'-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane]-enantiomerl hydrochloride (compound 161a) (20 mg, 30% yield) as a yellow solid: cSFC analytical tR: 2.29 min., purity: 99.7%; LCMS (E): 0.74 min., 302.1 m/z (M+l); Ή-NMR (CD3OD, 400 MHz): δ 8.03 (s, 1 H), 8.02-8.01 (d, J= 4.4 Hz, 1 H), 7.82-7.80 (d, J= 8.4 Hz, 1H), 7.64-7.62 (d, J= 8.4 Hz, 1H), 3.80-3.76 (m, 1 H), 3.64-3.60 (m, 1 H), 3.46-3.43 (m, 4H), 2.44 (m, 2 H), 2.32 (m, 1 H) , 2.17-2.03 (m, 2H).
cSFC analytical conditions: Column: Chiralpak AD-3 100x4.6mm I.D., 3 μηι; Mobile phase: methanol (0.05% DEA) in C02 from 5% to 40%; Flow rate: 3.0 mL/min.; Back pressure: 120 bar.
[001086] Example 171 - 3-(3-fluorobenzofuran-5-yl)-4H-l'-azaspiro[[K2,41oxadiazole-5 ,3'- bicyclo[2.2.2]octane]-enantiomer2 (161b)
[001087] To compound 160b (90 mg, 0.20 mmol) was added 10% trifluoroacetic
acid/dichloromethane (5 mL) and the reaction was stirred at 0 °C for 2 hours. On completion, the reaction was filtered and the resulting filtrate was concentrated and purified by prep-HPLC
[Instrument: GX-E; Column: Agella Venusil ASB CI 8 150*21.2 mm, particle size: 5 μιη; Mobile phase: 15-45% acetonitrile in H20 (add 0.5% HC1, v/v)]. The product was then subjected to lyophilization to give 3-(3-fluorobenzofuran-5-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane]-enantiomer2 hydrochloride (compound 161b) (21 mg, 35% yield) as a yellow solid: cSFC analytical tR: 3.45 min., purity: 99.1%; LCMS (E): 1.15min., 302.1m/z (M+l); Ή-NMR (CD3OD, 400 MHz): 5 8.04 (s, 1 H), 8.02-8.00 (d, J= 4.4 Hz, 1 H), 7.83-7.81 (d, J= 8.8 Hz, 1 H), 7.64-7.61 (dd, J= 8.8 Hz, J= 1.6 Hz, 1H), 3.79-3.76 (m, 1H), 3.65-3.61 (m, 1 H), 3.48-3.38 (m, 4H), 2.44 (m, 2 H), 2.36-2.28 (m, 1 H) , 2.17-2.13 (m, 1 H), 2.07-2.00 (m, 1 H). cSFC analytical conditions: Column: Chiralpak AD-3 100><4.6mm I.D., 3 μιη; Mobile phase: methanol (0.05% DEA) in C02 from 5% to 40%; Flow rate: 3.0 mL/min.; Back pressure: 120 bar.
[001088] Example 172 - (+/-)-4-(2,4-dimethoxybenzyl)-3-(pyrimidin-5-vn-4H-l '- azaspiro l ,2,41oxadiazole-5J'-bicyclo 2.2.2]octanel (162)
Figure imgf000262_0001
162 [001089] To a mixture of compound B-228 (0.50 g, 4.1 mmol) and compound C-108 (1 .3 g,
4.7 mmol) in dichloromethane (20 mL) was added 10% aqueous sodium hypochlorite (6.0 g, 81 mmol) dropwise at 0 °C. The reaction was allowed to warm to room temperature and stirred at this temperature for 4 hours. On completion, the reaction was filtered, and the resulting filtrate was concentrated and purified by prep-HPLC [Instrument: Shimadzu pump LC-20A; Column: GEMINI 200x50 mm, particle size: 10 μιη; Mobile phase: 40-65% acetonitrile in H20 (add 0.5% NH3 · H20, v/v)] to give racemate 162 (0.60 g, 37% yield) as a white solid. LCMS: (ES+) m/z (M+H)+ = 396.2, tR=l .121. Racemate 162 is a mixture of (R)-4-(2,4-dimethoxybenzyl)-3- (pyrimidin-5-yl)-4H-r-azaspiro[[l ,2,4]oxadiazoIe-5,3'-bicyclo[2.2.2]octane] (when deprotected provides (R)-3-(pyrimidin-5-yl)-4H-r-azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane]), and (S)-4-(2,4-dimethoxybenzyl)-3-(pyrimidin-5-yl)-4H- -azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane] (when deprotected provides (S)-3-(pyrimidin-5-yl)-4H-l '- azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane]).
[001090] Chiral Separation:
[001091] A solution of racemate 162 (0.60 g, 1.5 mmol) in 10 mL of methanol was separated by SFC (Instrument: SFC 80; Column: AD-10 μηι; Mobile phase: 50% ethanol (0.01 % NH3 H20) in C02) at room temperature. Each set of collected fractions was concentrated at room temperature and then subjected to lyophilization to give:
4-(2,4-dimethoxybenzyl)-3-(pyrimidin-5-yl)-4H-r-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane]-enantiomerl (compound 162a) (0.30 g, 50% yield), and
4-(2,4-dimethoxybenzyl)-3-(pyrimidin-5-yl)-4H-r-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane]-enantiomer2 (compound 162b) (0.30 g, 50% yield) as yellow solid.
[001092] Example 173 - 3-(,pyrimidin-5-vn-4H-l'-azaspiro[[1.2.41oxadiazole-5.3'- bicyclo[2.2.2]octane]-enantiomerl hydrochloride (163a)
[001093] To compound 162a (0.20 g, 0.51 mmol) was added 10% trifluoroacetic
acid/dichloromethane (5 mL) and the reaction was stirred at 0 °C for 3 hours. On completion, the reaction was filtered, and the resulting filtrate was concentrated and purified by prep-HPLC
[Instrument: GX-E; Column: Agella Venusil ASB C18 150x21.2 mm, particle size: 5 μηι; Mobile phase: 2-32% acetonitrile in H20 (add 0.5% HC1, v/v)] and subjected to lyophilization to give 3- (pyrimidin-5-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane]-enantiomerl hydrochloride (compound 163a) (80 mg, 64% yield) as a yellow solid: cSFC analytical tR: 2.51 min., purity: 96.8%; LCMS (D): 1.23 min., 246.2 m/z (M+l); Ή-NMR (DMSO-d6, 400 MHz): δ 10.69 (s, 1 H), 9.30 (s, 1 H), 9.24 (s, 1 H), 9.17 (s, 2H), 3.64-3.53 (q, J=14.4 Hz, 2H), 3.26-3.17 (m, 4H), 2.24 (m, 2H), 2.1 1 (m, 1 H), 1.94-1.83 (m, 2H);
cSFC analytical conditions: Column: Chiralpak AD-3 100x4.6mm, I.D., 3 μπι; Mobile phase: ethanol (0.05% DEA) in C02 from 5% to 40%; Flow rate: 3 mL/min.; Back pressure: 120 bar. [001094] Example 174 - 3-(pyrimidin-5-yl)-4H-l'-azaspirorn ,2,41oxadiazole-5.3'- bicyclo[2.2.21octane1-enantiomer2 hydrochloride (163b)
[001095] To compound 162b (0.20 g, 0.51 mmol) was added 10% trifluoroacetic
acid/dichloromethane (5 mL) and the reaction was stirred at 0 °C for 3 hours. On completion, the reaction was filtered, and the resulting filtrate was concentrated and purified by prep-HPLC
[Instrument: GX-E; Column: Agella Venusil ASB C18 150x21.2 mm, particle size: 5 μπι; Mobile phase: 2-32% acetonitrile in H20 (add 0.5% HC1, v/v)] and subjected to lyophilization to give 3- (pyrimidin-5-yl)-4H- -azaspiro[[l,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane]-enantiomer2 hydrochloride (compound 163b) (72 mg, 58% yield) as a yellow solid: cSFC analytical tR: 3.70 min., purity: 98.9%; LCMS (D): 1.19 min., 246.1 m/z (M+l); Ή-NMR (DMSO-d6, 400 MHz): δ 10.61 (s, 1H), 9.30 (s, 1H), 9.16 (s, 3H), 3.58-3.54 (m, 2H), 3.27 (m, 4H), 2.24 (m, 2H), 2.12 (m, 1H), 1.90-1.88 (m, 2H);
cSFC analytical conditions: Column: Chiralpak AD-3 100x4.6mm, I.D., 3 μιη; Mobile phase: ethanol (0.05% DEA) in C02 from 5% to 40%; Flow rate: 3 mL/min.; Back pressure: 120 bar.
[001096] Example 175 - (+/-)-4-r2.4-dimethoxybenzyl)-3-(2-fluorobenzofuran-5-yl)-4H- razaspiro [l ,2,4]oxadiazole-5,3'-bicvclo[2.2.2]octanel (164)
Figure imgf000264_0001
[001097] To a solution of compound B-229 (1.1 g, 6.0 mmol) and compound C-108 (2.0 g, 7.3 mmol) in dichloromethane (20 mL) was added 10% aqueous sodium hypochlorite (22 g, 30 mmol) dropwise at 0 °C. The resulting solution was warmed to room temperature and stirred at this temperature for 3 hours. On completion, the reaction solution was extracted with
dichloromethane (3 χ 50 mL). The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, and concentrated in vacuo to dryness. The residue was purified by prep-HPLC [Instrument: GX-C; Column: Phenomenex SYNERGI CI 8 150*30mm; particle size: 4 μπι; Mobile phase: 60-90% acetonitrile in H20 (add 0.5% NH3 · H20, v/v)] to give racemate 164 (1.1 g, 41% yield) as a white solid. LCMS: (ES+) m/z (M+H)+ = 452.2, tR = 0.762. Racemate 164 is a mixture of (R)-4-(2,4-dimethoxybenzyl)-3-(2-fluorobenzofuran-5-yl)-4H- l 'azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane] (when deprotected provides (R)-3-(2- fluorobenzofuran-5-yl)-4H-r-azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane]), and (S)-4- (2,4-dimethoxybenzyl)-3-(2-fluorobenzofuran-5-yl)-4H-razaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane] (when deprotected provides (S)-3-(2-fluorobenzofuran-5-yl)-4H-l '- azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane]).
[001098] Chiral Separation:
[001099] A solution of racemate 164 (1.1 g, 2.4 mmol) in 5 mL of ethanol was separated by SFC (Instrument: SFC 80; Column: Chiralpak AD-H 250x25 mm I.D., 10 μηι; Mobile phase: 50% ethanol (0.01% NH3 H20) in C02) at room temperature. Each set of collected fractions was concentrated at room temperature and then subjected to lyophilization to give:
4-(2,4-dimethoxybenzyl)-3-(2-fluorobenzofuran-5-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole- 5,3'-bicyclo[2.2.2]octane] -enantiomerl (compound 164a) (0.48 g, 44% yield), and
4-(2,4-dimethoxybenzyl)-3-(2-fluorobenzofuran-5-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole- 5,3'-bicyclo[2.2.2]octane] -enantiomer2 (compound 164b) (0.47 g, 43% yield) as a white solid.
[001100] Example 176 - 3-(2-fluorobenzofuran-5-yl)-4H-l '-azaspirorri .2.41oxadiazole-5.3'- bicyclo[2.2 ,21octane1-enantiomer 1 (165a)
[001101] To compound 164a (0.10 g, 0.22 mmol) was added 20% trifluoroacetic acid in dichloromethane (20 mL), and the reaction was stirred at 0 °C for 1 hour. On completion, the resulting mixture was concentrated in vacuo, and the residue was purified by prep-HPLC
[Instrument: GX-E; Column: Agella Venusil ASB C18 150*21.2mm; particle size: 10 μπι;
Mobile phase: 14-44% acetonitrile in H20 (add 0.5%HC1, v/v)]. The collected fractions were subjected to lyophilization to give 3-(2-fluorobenzofuran-5-yl)-4H-l '-azaspiro[[l,2,4]oxadiazole- 5,3'-bicyclo[2.2.2]octane]-enantiomerl hydrochloride (compound 165a) (50 mg, 75% yield ) as a white solid: cSFC analytical tR: 2.57 min., purity: 99.3%; LCMS (C): 0.62 min., 302.1 m/z (M+1); I H-NMR (CD3OD, 400 MHz): δ 7.92 (s, IH), 7.69 - 7.67 (d, J=8.4 Hz, I H), 7.56 - 7.54 (d, J=8.4 Hz, I H), 6.18 - 6.16 (d, J=6.4 Hz, IH), 3.76 - 3.73 (m, I H), 3.61 -3.58 (m, 1 H), 3.46 - 3.36 (m, 4H), 2.40 (m, 2H), 2.27 (m, 1Ή), 2.15 - 2.12 (m, I H), 2.05 - 1.98 (m, IH);
cSFC analytical conditions: Column: Chiralpak AD-3 100x4.6mm, I.D., 3μπι; Mobile phase: 5% to 40% ethanol (0.05% DEA) in C02; Flow rate: 3mL/min.; Wavelength: 220nm.
[001102] Example 177 - 3-(2-fluorobenzofuran-5-yl)-4H-r-azaspiro[[l ,2,4"|oxadiazole-5.3'- bicyclo[2.2.21octane1-enantiomer2 (165b)
[001103] To compound 164b (0.10 g, 0.22 mmol) was added 20% trifluoroacetic acid in dichloromethane (20 mL), and the reaction was stirred at 0 °C for 1 hour. On completion, the resulting mixture was concentrated in vacuo, and the residue was purified by prep-HPLC
[Instrument: GX-E; Column: Agella Venusil ASB CI 8 150*21.2mm; particle size: 10 μηι; Mobile phase: 14-44%) acetonitrile in H20 (add 0.5%HC1, v/v)]. The collected fractions were subjected to lyophilization to give 3-(2-fluorobenzofuran-5-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole- 5,3'-bicyclo[2.2.2]octane]-enantiomer2 hydrochloride (compound 165b) (56 mg, 84% yield) as a white solid: cSFC analytical tR: 2.85 min., purity: 98.9%; LCMS (C): 0.61 min., 302.2 m/z (M+1); 'H-NMR (CD3OD, 400 MHz): δ 7.93 (s, I H), 7.69 - 7.67 (d, J=8.8 Hz, IH), 7.56 - 7.54 (d, J=8.4 Hz, 1 H), 6.18 - 6.16 (d, J=6.4 Hz, 1H), 3.75 - 3.72 (m, 1H), 3.64-3.60 (m, 1H), 3.43 -
3.39 (m, 4H), 2.40 (m, 2H), 2.34-2.27 (m, 1H), 2.13 - 2.12 (m, 1H), 2.05 - 2.00 (m, 1H);
cSFC analytical conditions: Column: Chiralpak AD-3 100*4.6mm, I.D., 3μηι; Mobile phase: 5% to 40% ethanol (0.05% DEA) in C02; Flow rate: 3mL/min.; Wavelength: 220nm.
[001104] Example 178 - C+/-')-4-('2,4-dimethoxybenzvn-3-('2-
(trifluoromethyl')benzo[blthiophen-6-yl)-4H-r-azaspirof[K2,4]oxadiazole-5,3'- bicyclo[2.2.21octane] (166)
Figure imgf000266_0001
[001105] To a mixture of compound B-233 (0.50 g, 2.0 mmol) and compound C-108 (0.70 g, 3.0 mmol) in dichloromethane (10 mL) was added 10% aqueous sodium hypochlorite (4.6 g, 6.0 mmol) dropwise at 0 °C. The reaction was allowed to warm to room temperature and was stirred at this temperature for 4 hours. On completion, the reaction was filtered, and the resulting filtrate was concentrated and purified by prep-HPLC [Instrument: GX-A; Column: Phenomenex Gemini CI 8 150x25mm, particle size: 10 μιη; Mobile phase: 50-80% acetonitrile in H20 (add 0.5% NH3 H20, v/v)] to give racemate 166 (0.12 g, 1 1 % yield) as a white solid. Racemate 166 is a mixture of (R)-4-(2,4-dimethoxybenzyl)-3-(2-(trifluoromethyl)benzo[b]thiophen-6-yl)-4H-l '- azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane] (when deprotected provides (R)-3-(2- (trifluoromethyl)benzo[b]thiophen-6-yl)-4H-r-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane]), and (S)-4-(2,4-dimethoxybenzyl)-3-(2-(trifluoromethyl)benzo[b]thiophen- 6-yl)-4H-l'-azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane] (when deprotected provides (S)- 3-(2-(trifluoromethyl)benzo[b]thiophen-6-yl)-4H- -azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane]).
[001106] Chiral Separation:
[001107] A solution of racemate 166 (0.12 g, 0.23 mmol) in 10 mL of ethanol was separated by SFC (Instrument: SFC 80; Column: Chiralpak AD-H 250x25 mm I.D., 10 μπι; Mobile phase: 60%) ethanol (0.01% NH3 H20) in C02) at room temperature. Each set of collected fractions was concentrated at room temperature and then subjected to lyophilization to give:
4-(2,4-dimethoxybenzyl)-3-(2-(trifluoromethyl)benzo[b]thiophen-6-yl)-4H- - azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane]-enantiomerl (compound 166a) (50 mg, 42% yield), and 4-(2,4-dimethoxyben2yl)-3-(2-(trifluorornethyl)benzo[b]thiophen-6-yl)-4H-l '- azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane]-enantiomer2 (compound 166b) (50 mg, 42% yield) as white solid.
[001108] Example 179 - 3-(2- rifluoromethvnbenzorblthiophen-6-yl)-4H-l'- azaspiro[[L2^1oxadiazole-53'-bicyclo[2,2,2]octane]-enantiomerl (167a)
[001109] To compound 166a (50 mg, 0.096 mmol) was added 10% trifluoroacetic acid/dichloromethane (5 mL), and the reaction was stirred at 0 °C for 2 hours. On completion, the reaction was filtered, and the resulting filtrate was concentrated and purified by prep-HPLC
[Instrument: GX-B; Column: Phenomenex Synergi CI 8 150x30mm, particle size: 4 μπι; Mobile phase: 22-52% acetonitrile in H20 (add 0.5% CF3COOH, v/v)]. The product was then subjected to lyophilization to give 3-(2-(trifluoromethyl)benzo[b]thiophen-6-yl)-4H-l'- azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane]-enantiomerl trifluoroacetate (compound 167a) (10 mg, 22% yield ) as a white solid: cSFC analytical tR: 2.25 min., purity: 98.0%; LCMS (G): 2.77 min., 368.1 m/z (M+l); Ή-NMR (CD3OD, 400 MHz): δ 8.38 (s, 1 H), 8.10-8.08 (d, J=8.0 Hz, 1H), 8.0 (s, 1H), 7.88-7.86 (d, J=8.0 Hz, 1 H), 3.81-3.78 (d, J=14.0 Ηζ,Ι Η), 3.63-3.59 (d, J=14.0 Hz, 1H), 3.46-3.39 (m, 4H), 2.45 (m, 2H), 2.31-2.29 (m, 1H), 2.18-2.16 (m, 1H), 2.06- 2.03 (m, 1H);
cSFC analytical conditions: Column: Chiralcel OD-3 100x4.6mm, I.D., 3 μιη; Mobile phase: ethanol (0.05% DEA) in C02 from 5% to 40%; Flow rate: 3 mL/min.; Back pressure: 120 bar.
[001110] Example 180 - 3-(2-(trifluoromethyl)benzorblthiophen-6-vn-4H-ll- azaspiro[[l,2,41oxadiazole-5,3'-bicyclo[2.2.21octane1-enantiomer2 (167b)
[001111] To compound 166b (50 mg, 0.096 mmol) was added 10% trifluoroacetic acid/dichloromethane (5 mL), and the reaction was stirred at 0 °C for 2 hours. On completion, the reaction was filtered, and the resulting filtrate was concentrated and purified by prep-HPLC
[Instrument: GX-B; Column: Phenomenex Synergi CI 8 150x30mm, particle size: 4 μπι; Mobile phase: 22 52% acetonitrile in H20 (add 0.5% CF3COOH, v/v)]. The product was then subjected to lyophilization to give 3-(2-(trifluoromethyl)benzo[b]thiophen-6-yl)-4H-l'- azaspiro[[l,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane]-enantiomerl trifluoroacetate (compound 167b) (10 mg, 22% yield ) as a white solid: cSFC analytical tR: 2.62 min., purity: 97.92%; LCMS (G): 2.77 min., 368.1 m/z (M+l); Ή-NMR (CD3OD, 400 MHz): δ 8.38 (s, 1H), 8.10-8.08 (d, J=8.8 Hz, 1H), 8.00 (s, 1H), 7.88-7.86 (d, J=8.4 Hz, 1 H), 3.81 -3.78 (d, J=14.0 Ηζ,Ι Η), 3.64-3.60 (d, J=14.0 Hz, 1H), 3.49-3.39 (m, 4H), 2.45 (m, 2H), 2.31-2.29 (m, 1H), 2.18-2.12(m, 1 H), 2.07- 2.00 (m, 1H);
cSFC analytical conditions: Column: Chiralcel OD-3 100x4.6mm, I.D., 3 μιη; Mobile phase: ethanol (0.05% DEA) in C02 from 5% to 40%; Flow rate: 3 mL/min.; Back pressure: 120 bar.
[001112] Example 181 - (+/-V4-C2,4-dimethoxybenzyl)-3-r2-fluorobenzorblthiophen-6-ylV 4H-l '-azaspiror[l ,2,41oxadiazole-5,3'-bicyclo 2.2.2]octane] (168)
Figure imgf000268_0001
[001113] To a mixture of compound B-236 (0.70 g, 3.6 mmol) and compound C-108 (1.1 g, 4.0 mmol) in dichloromethane (10 mL) was added 10% aqueous sodium hypochlorite (8.3 g, 1 1 mmol) dropwise at 0 °C. The reaction was allowed to warm to room temperature and was stirred at this temperature for 4 hours. On completion, the reaction was filtered and the resulting filtrate was concentrated and purified by prep-HPLC [Instrument: GX-A; Column: Phenomenex Gemini CI 8 150x25mm, particle size: 10 μηι; Mobile phase: 40-65% acetonitrile in H20 (add 0.5% NH3 H20, v/v)] to give racemate 168 (0.30 g, 18% yield) as a white solid. Racemate 168 is a mixture of (R)-4-(2,4-dimethoxybenzyl)-3 -(2-fluorobenzo[b]thiophen-6-yl)-4H- 1 '- azaspiro[[l,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane] (when deprotected provides (R)-3-(2- fluorobenzo[b]thiophen-6-yl)-4H-r-azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane]), and (S)-4-(2,4-dimethoxybenzyl)-3-(2-fluorobenzo[b]thiophen-6-yl)-4H-l '- azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane] (when deprotected provides (S)-3-(2- fluorobenzo[b]thiophen-6-yl)-4H- -azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane]).
[001114] Chiral Separation:
[001115] A solution of racemate 168 (0.30 g, 0.67 mmol) in 10 mL of ethanol was separated by SFC (Instrument: SFC 80; Column: Chiralpak AD-H 250x25 mm I.D., 10 μηι; Mobile phase: 50% isopropanol (0.01% NH3 H20) in C02) at room temperature. Each set of collected fractions was concentrated at room temperature and then subjected to lyophilization to give:
4-(2,4-dimethoxybenzyl)-3-(2-fluorobenzo[b]thiophen-6-yl)-4H-l '- azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane]-enantiomerl (compound 168a) (0.1 1 g, 37% yield), and
4-(2,4-dimethoxybenzyl)-3-(2-fluorobenzo[b]thiophen-6-yl)-4H-l '- azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane]-enantiomer2 (compound 168b) (0.1 1 g, 37%) yield) as white solid.
[001116] Example 182 - 3-(2-fluorobenzorb1thiophen-6-yl)-4H-l '-azaspiro [L2,41oxadiazole- 5,3'-bicyclo[2.2.21octane]-enantiomerl (169a)
[001117] To compound 168a (0.10 g, 0.21 mmol) was added 10% trifluoroacetic
acid/dichloromethane (5 mL), and the reaction was stirred at 0 °C for 2 hours. On completion, the reaction was filtered, and the resulting filtrate was concentrated and purified by prep-HPLC
[Instrument: GX-F; Column: Phenomenex Synergi CI 8 150x30 mm, particle size: 4 μ ι; Mobile phase: 15-45% acetonitrile in H20 (add 0.5% HC1, v/v)]. The product was then subjected to lyophilization to give 3-(2-fluorobenzo[b]thiophen-6-yl)-4H-l '-azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane]-enantiomerl hydrochloride (compound 169a) (45 mg, 60% yield ) as a white solid: cSFC analytical tR: 2.99 min., purity: 95.7%; LCMS (G): 1.32 min., 318.1 m/z (M+1); Ή-NMR (CD3OD, 400 MHz): δ 8.15 (s, IH), 7.82-7.80 (d, J=8.0 Hz, IH), 7.76-7.74 (d, J=8.0 Hz, IH), 6.99-6.98 (m, I H), 3.79-3.75 (d, J=14.0 Ηζ,ΙΗ), 3.64-3.61 (d, J=14.4 Hz, I H), 3.48-3.37 (m, 4H), 2.43 (m, 2H), 2.32-2.27 (m, IH) , 2.17-2.1 1 (m, IH), 2.07-2.01 (m, I H); cSFC analytical conditions: Column: Chiralpak AD-3 100x4.6mm, I.D., 3 μπι; Mobile phase: ethanol (0.05% DEA) in C02 from 5% to 40%; Flow rate: 3 mL/min.; Back pressure: 120 bar.
[001118] Example 183 - 3-(2-fluorobenzo[blthiophen-6-yl)-4H-l'-azaspirorrU2,41oxadiazole- 5,3'-bicyclo[2.2.21octane1-enantiomer2 (169b)
[001119] To compound 168b (0.10 g, 0.21 mmol) was added 10% trifluoroacetic
acid/dichloromethane (5 mL) and the reaction was stirred at 0 °C for 2 hours. On completion, the reaction was filtered and the resulting filtrate was concentrated and purified by prep-HPLC
[Instrument: GX-F; Column: Phenomenex Synergi CI 8 150x30mm, particle size: 4 μιη; Mobile phase: 15-45% acetonitrile in H20 (add 0.5% HC1, v/v)]. The product was then subjected to lyophilization to give 3-(2-fluorobenzo[b]thiophen-6-yl)-4H- -azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane]-enantiomer2 hydrochloride (compound 169b) (45 mg, 60% yield ) as a white solid: cSFC analytical tR: 3.49 min., purity: 95.3%; LCMS (G): 1.31 min., 318.1 m/z (M+1); Ή-NMR (CD3OD, 400 MHz): δ 8.16 (s, I H), 7.82-7.79 (d, J=8.4 Hz, IH), 7.76-7.74 (d, J=8.4 Hz, IH), 6.99-6.98 (m, IH), 3.79-3.75 (d, J=14.0 Ηζ,Ι Η), 3.65-3.61 (d, J=14.4 Hz, I H), 3.48-3.37 (m, 4H), 2.43 (m, 2H), 2.31-2.30 (m, IH), 2.17-2.12(m, I H), 2.07-2.01 (m, I H);
cSFC analytical conditions: Column: Chiralpak AD-3 100x4.6mm, I.D., 3 μπι; Mobile phase: ethanol (0.05% DEA) in C02 from 5% to 40%; Flow rate: 3 mL/min.; Back pressure: 120 bar.
[001120] Example 184 - (+/-V4-(2,4-dimethoxybenzylV3-(3-fluorobenzorblthiophen-6-vn- 4Η-Γ -azaspiro[[L2,4]oxadiazole-5,3'-bicvclo[2.2.2]octane1 (170)
Figure imgf000269_0001
[001121] To a solution of compound B-240 (0.44 g, 2.3 mmol) and compound C-108 (0.75 g, 2.7 mmol) in dichloromethane (25 mL) was added 10% aqueous sodium hypochlorite (5.4 g, 7.3 mmol) dropwise at 0 °C. The resulting solution was warmed to room temperature and stirred at this temperature for 3 hours. On completion, the reaction was filtered and the filtrate was concentrated and purified by prep-HPLC [Instrument: GX-C; Column: Phenomenex SYNERGI CI 8 1 50*30mm; particle size: 4 μπι; Mobile phase: 60-90% acetonitrile in H20 (add 0.5% NH3 ' H20, v/v)] to give racemate 170 (0.20 g, 19% yield) as a yellow solid. Racemate 170 is a mixture of (R)-4-(2,4-dimethoxybenzyl)-3-(3-fluorobenzo[b]thiophen-6-yl)-4H-r - azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane] (when deprotected provides (R)-3-(3- fluorobenzo[b]thiophen-6-yl)-4H- -azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane]), and (S)-4-(2,4-dimethoxybenzyl)-3 -(3 -fluorobenzo[b]thiophen-6-yl)-4H- 1 ' - azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane] (when deprotected provides (S)-3-(3- fluorobenzo[b]thiophen-6-yl)-4H- -azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane]).
[001122] Chiral Separation:
[001123] A solution of racemate 170 (0.20 g, 0.43 mmol) in 15 mL of ethanol was separated by SFC (Instrument: SFC 80; Column: Chiralpak AD-H 250^25 mm I.D., 10 μηι; Mobile phase: 60%) ethanol (0.01 % NH3 H20) in C02) at room temperature. Each set of collected fractions was concentrated at room temperature and then subjected to lyophilization to give:
4-(2,4-dimethoxybenzyl)-3 -(3 -fluorobenzo [b]thiophen-6-y 1)-4H- 1 ' - azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane] -enantiomerl (compound 170a) (90 mg, 45% yield), and
4-(2,4-dimethoxybenzyl)-3-(3 -fluorobenzo[b]thiophen-6-yl)-4H- 11 - azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane] -enantiomer2 (compound 170b) (80 mg, 40%) yield) as a yellow solid.
[001124] Example 185 - 3-(3-fluorobenzoJb1thiophen-6-ylV4H-l '-azaspirorn ,2.41oxadiazole- 5 ,3 '-bicyclo [2.2.2] octanel-enantiomer 1 (171a)
[001125] Compound 170a (45 mg, 0.10 mmol) was dissolved in 10% trifluoroacetic acid in dichloromethane (5 mL), and the reaction was stirred at 0 °C for 1 hour. On completion, the reaction was filtered, and the resulting filtrate was concentrated and purified by prep-HPLC
[Instrument: GX-E; Column: Agella Venusil ASB C18 150*21.2mm, particle size: 5 μιη; Mobile phase: 17-47% acetonitrile in H20 (Add 0.5%> HC1, v/v)] . The product was then subjected to lyophilization to give 3-(3-fluorobenzo[b]thiophen-6-yl)-4H-l '-azaspiro[[ l ,2,4] oxadiazole-5,3'- bicyclo[2.2.2]octane]-enantiomerl hydrochloride (compound 171a) ( 1 1 mg, 35% yield ) as a yellow solid: cSFC analytical tR: 2.92 min„ purity: 94.9%; LCMS (C): 0.65 min., 31 8.1 m/z (M+l ); 'HNMR (CD3OD, 400 MHz): δ 8.26 (s, 1 H), 7.88-7.82 (m, 2H), 7.34 (s, 1 H), 3.79-3.65 (m, 2H), 3.49-3.33 (m, 4H), 2.43-2.33 (m, 3H), 2.16-2.03 (m, 2H).
cSFC analytical conditions: Column: Chiralpak AD-3 100x4.6mm I.D., 3 μπι; Mobile phase: ethanol (0.05% DEA) in C02 from 5% to 40%; Flow rate: 3.0 mL/min.; Back pressure: 100 bar.
[001126] Example 186 - 3-(3-fluorobenzo[b]thiophen-6-yl)-4H-l '-azaspiro[[L2,41oxadiazole- 5,3'-bicyclo[2.2.21octane1-enantiomer2 (171b) [001127] Compound 170b (50 mg, 0.1 1 mmol) was dissolved in 10% trifluoroacetic acid in dichloromethane (5 mL), and the reaction was stirred at 0 °C for 1 hour. On completion, the reaction was filtered, and the resulting filtrate was concentrated and purified by prep-HPLC
[Instrument: GX-E; Column: Agella Venusil ASB C18 150*21.2mm, particle size: 5 μιη; Mobile phase: 17-47% acetonitrile in H20 (Add 0.5% HC1, v/v)]. The product was then subjected to lyophilization to give 3-(3-fluorobenzo[b]thiophen-6-yl)-4H- -azaspiro[[l ,2,4] oxadiazole-5,3'- bicyclo[2.2.2]octane] -enantiomer2 hydrochloride (compound 171b) (7.0 mg, 20% yield) as a yellow solid: cSFC analytical tR: 3.59 min., purity: 95.2%; LCMS (C): 0.665 min., 318.1 m/z (M+l); 'HNMR (CD3OD, 400 MHz): δ 8.25 (s, IH), 7.89-7.82 (m, 2H), 7.34 (s, I H), 3.80-3.76 (m, IH), 3.66-3.62 (m, IH), 3.46-3.40 (m, 4H), 2.44-2.42 (m, 2H), 2.28-2.27 (m, IH), 2.17-2.14 (m, IH) , 2.06-2.03 (m, IH);
cSFC analytical conditions: Column: Chiralpak AD-3 100x4.6mm I.D., 3 μηι; Mobile phase: ethanol (0.05% DEA) in C02 from 5% to 40%; Flow rate: 3.0 mL/min.; Back pressure: 100 bar.
[001128] Example 187 - (+/-) -4-(2.4-dimethoxybenzyl)-3-(thienor3.2-blpyridin-6-vn-4H-ll-
Figure imgf000271_0001
[001129] To a mixture of compound B-244 (0.30 g, 1.7 mmol) and compound C-108 (0.55 g, 2.0 mmol) in dichloromethane (10 mL) was added 10% aqueous sodium hypochlorite (5.0 g, 6.7 mmol) dropwise at 0 °C. The reaction was allowed to warm to room temperature and was stirred at this temperature for 3 hours. On completion, the reaction mixture was filtered, and the filtrate was concentrated. The residue was purified by prep-HPLC [Instrument: GX-A; Column:
Phenomenex Gemini CI 8 150*25mm, particle size: 10 μιη; Mobile phase: 28-58% acetonitrile in H20 (add 0.5% NH3 H20, v/v)] to give racemate 172 (0.30 g, 40% yield) as a white solid. Racemate 172 is a mixture of (R)-4-(2,4-dimethoxybenzyl)-3-(thieno[3,2-b]pyridin-6-yl)-4H-l '- azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane] (when deprotected provides (R)-3- (thieno[3,2-b]pyridin-6-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane]), and (S)- 4-(2,4-dimethoxybenzyl)-3-(thieno[3,2-b]pyridin-6-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane] (when deprotected provides (S)-3-(thieno[3,2-b]pyridin-6-yl)-4H-l '- azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane]). [001130] Chiral Separation:
[001131] A solution of racemate 172 (0.20 g, 0.42 mmol) in 10 ml of ethanol was separated by SFC (Instrument: SFC 80; Column: Chiralpak OD-3 100x4.6mm I.D., particle size: 10 μπι;
Mobile phase: 50% methanol (0.01 % NH3 H20) in C02) at room temperature. Each set of collected fractions was concentrated at room temperature and then subjected to lyophilization to give:
4-(2,4-dimethoxybenzyl)-3-(thieno[3,2-b]pyridin-6-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole- 5,3'-bicyclo[2.2.2]octane] -enantiomerl (compound 172a) (60 mg, 30% yield), and
4-(2,4-dimethoxybenzyl)-3-(thieno[3,2-b]pyridin-6-yl)-4H-l '-azaspiro[[ l ,2,4]oxadiazole- i
5,3'-bicyclo[2.2.2]octane] -enantiomer2 (compound 172b) (50 mg, 25% yield) as a white solid.
[001132] Example 188 - 3-rthienor3.2-blpyridin-6-vn-4H-l '-azaspirorn .2.41oxadiazole-5.3'- bicyclo[2.2 ,2] octanel-enantiomer 1 (173a)
[001133] To compound 172a (60 mg, 0.13 mmol) was added 10% trifluoroacetic
acid/dichloromethane (5 mL) and the reaction was stirred at 0 °C for 1 hour. On completion, the reaction was filtered, and the resulting filtrate was concentrated and purified by prep-HPLC
[Instrument: GX-F; Column: Phenomenex Synergi CI 8 1 50*30 mm, particle size: 4 μιη; Mobile phase: 5-30% acetonitrile in H20 (Add 0.5%o TFA, v/v)]. The product was then subjected to lyophilization to give 3-(thieno[3,2-b]pyridin-6-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane]-enantiomerl trifluoroacetate (compound 173a) (8.0 mg, 20% yield ) as a yellow solid: cSFC analytical tR: 1 .46 min, purity: 96.8%; LCMS (A): 1 .55 min., 301 .0 m/z (M+1 ); l H-NMR (CD3OD, 400 MHz): δ 9.0 (s, I H), 8.77 (s, I H), 8.24-8.23 (d, J=5.6 Hz, I H), 7.63-7.62 (d, J=5.6 Hz, I H), 3.82-3.78 (m, I H), 3.67-3.63 (m, I H), 3.49-3.36 (m, 4H), 2.46-2.41 (m, 2H), 2.33-2.29 (m, I H), 2.19-2.15 (m, I H), 2.06-2.00 (m, I H);
cSFC analytical conditions: Column: Chiralcel OJ-3 100x4.6mm I.D., 3 μιη; Mobile phase:
methanol (0.05% DEA) in C02 from 5% to 40%; Flow rate: 3.0 mL/min.; Back pressure: 100 bar.
[001134] Example 189 - 3-(thienor3,2-b1pyridin-6-yl)-4H-l '-azaspirorri .2.41oxadiazole-5.3'- bicyclo[2.2,2"loctane1-enantiomer2 (173b)
[001135] To compound 172b (50 mg, 0.1 1 mmol) was added 10% trifluoroacetic
acid/dichloromethane (3 mL) and the reaction was stirred at 0 °C for 1 hours. On completion, the reaction was filtered, and the resulting filtrate was concentrated and purified by prep-HPLC
[Instrument: GX-F; Column: Phenomenex Synergi CI 8 1 50*30 mm, particle size: 4 μιη; Mobile phase: 5-30% acetonitrile in H20 (Add 0.5% TFA, v/v)]. The product was then subjected to lyophilization to give 3-(thieno[3,2-b]pyridin-6-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane]-enantiomer2 trifluoroacetate (compound 173b) (8.0 mg, 24% yield) as a yellow solid: cSFC analytical tR: 2.88 min., purity: 97.6%; LCMS (A): 1.15 min., 301 .0 m/z (M+1 ); 1 H-NMR (CD30D, 400 MHz): 9.00-8.99 (d, J=1 .6 Hz, I H), 8.75-8.75 (d, J=1 .2 Hz, I H), 8.23-8.22 (d, J-5.6 Hz, 1H), 7.63-7.62 (d, J=5.2 Hz, 1H), 3.82-3.78 (m, 1 H), 3.66-3.62 (m, 1H), 3.49-3.37 (m, 4H), 2.47-2.43 (m, 2H), 2.32-2.29 (m, 1 H), 2.18-2.15 (m, 1 H), 2.06-2.00 (m, 1 H); cSFC analytical conditions: Column: Chiralcel OJ-3 100x4.6mm I.D., 3 μιη; Mobile phase:
methanol (0.05% DEA) in C02 from 5% to 40%; Flow rate: 3.0 mL/min.; Back pressure: 100 bar.
[001136] Example 190 - (+/-V4-(2>4-dimethoxybenzyl')-3-Cpyrazolon .5-a1pyridin-5-vn-4H-l '-
Figure imgf000273_0001
[001137] To a solution of compound B-249 (0.60 g, 3.7 mmol) and compound C-108 (1.2 g, 4.5 mmol) in dichloromethane (10 mL) was added 10% aqueous sodium hypochlorite (8.2 g, 1 1 mmol) dropwise at 0 °C. The resulting solution was warmed to room temperature and stirred at this temperature for 3 hours. On completion, the reaction was filtered, and the resulting filtrate was concentrated and purified by prep-HPLC [Instrument: GX-C; Column: Phenomenex
SYNERGl CI 8 150*30mm; particle size: 4μιη; Mobile phase: 60-90% acetonitrile in H20 (add 0.5% NH3 H20, v/v)] to give racemate 174 as a yellow solid. LCMS: (ES+) m/z (M+H)+ = 434.2, tR = 1.704.
[001138] Example 191 - ('+/-V3-(pyrazolori .5-alpyridin-5-vn-4H-l '- azaspiro[[L2,41oxadiazole-5,3'-bicyclo[2,2.2"|octane] (175)
Figure imgf000273_0002
[001139] Racemate 174 (43 mg, 0.099 mmol) was dissolved in 10% trifluoroacetic acid/dichloromethane (4 mL) and stirred at 0 °C for 1 hour. On completion, the mixture was filtered, and the resulting filtrate was concentrated and purified by prep-HPLC [Instrument: GX- B; Column: Phenomenex Synergi CI 8 200*25mm; particle size: Ι Ομπι; Mobile phase: 18-48% acetonitrile in H20 (add 0.5% HCI, v/v)]. The product was then subjected to lyophilization to give racemate 175-hydrochloride (8.2 mg, 29% yield ) as a yellow solid: LCMS (A): 0.859 min., 284.0 m/z (M+l ); Ή-NMR (CD3OD, 400 MHz): δ 8.59-8.57 (d, J = 7.2 Hz, 1 H), 8.04 (s, 1H), 8.04 (s, 1H), 7.21-7.19 (dd, J=7.6HZ, 2Hz,lH), 6.80-6.80 (d, J = 2 Hz, 1 H), 3.76-3.67 (dd, J = 14.0 Hz, 2.0 Hz, 1 H), 3.64-3.64 (d, J=2 Hz, 1H), 2.40-2.31 (m, 3H), 2.14-2.01 (m, 2H). Racemate 175 is a mixture of HC1 salts of (R)- 3-(pyrazolo[l ,5-a]pyridin-5-yl)-4H-l '- azaspiro[[ l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane] and (S)- 3-(pyrazolo[ l ,5-a]pyridin-5-yl)- 4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane].
[001140] Example 192 - (+/- -4-('2.4-dimethoxybenzyl)-3-(furo 2.3-blpyridin-5-vn-4H-l l- azaspiro[[L2,41oxadiazole-5,3'-bicyclo[2.2,2]octane] (176)
Figure imgf000274_0001
[001141] To a mixture of compound B-256 (0.20 g, 1.2 mmol) and compound C-108 (0.41 g, 1 .5 mmol) in dichloromethane (10 mL) was added 10% aqueous sodium hypochlorite (1 .8 g, 2.5 mmol) dropwise at 0 °C. The reaction was allowed to warm to room temperature and was stirred for 2 hours. On completion, the reaction mixture was filtered, and the filtrate was concentrated and purified by prep-HPLC [Instrument: GX-A; Column: Phenomenex Gemini CI 8 150*25mm, particle size: 10 μπι; Mobile phase: 33-63% acetonitrile in H20 (add 0.5% NH3 H20, v/v)] to give racemate 176 (0.12 g, 22% yield) as a white solid. LCMS: (ES+) m/z (M+H)+ = 453.2, tR= 1 .241 .
[001142] Example 193 - (+/-)-3-ifuror2.3-blpyridin-5-vn-4H-l '-azaspirorn .2.41oxadiazole- 5,3'-bicvclo[2.2.21octanel (177
Figure imgf000274_0002
[001143] Racemate 176 (80 mg, 0.1 8 mmol) was dissolved in 10% trifluoroacetic acid in dichloromethane (5 mL) and the reaction was stirred at 0 °C for 1 hour. On completion, the reaction was filtered, and the resulting filtrate was concentrated and purified by prep-HPLC [Instrument: GX-E; Column: Phenomenex Synergi CI 8 150*30mm, particle size: 4 μπι; Mobile phase: 10-30% acetonitrile in H20 (Add 0.5% TFA, v/v)]. The product was then subjected to lyophilization to give 3-(furo[2,3-b]pyridin-5-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane]-trifluoroacetate (racemate 177) (20 mg, 38% yield ) as a yellow solid: LCMS (E): 0.845 min., 285.1 m/z (M+l ); 1 HNMR (D20, 400 MHz): δ 8.33-8.32 (d, J= 2.0 Hz, 1 H), 8.14-8.13 (d, J= 2.4 Hz, 1 H), 7.81 -7.81 (d, J= 2.8 Hz, 1 H), 6.86-6.85 (d, J= 2.4 Hz, 1 H), 3.70-3.66 (m, IH), 3.56-3.52 (m, IH), 3.33-3.25 (tn, 4H), 2.41-2.25 (m, IH), 2.23-2.10 (m, I H) , 2.08-2.05 (m, 2H), 1.96-1.93 (m, IH). Racemate 177 is a mixture of (R)-3-(furo[2,3-b]pyridin-5- yl)-4H-l '-azaspiro[[l,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane] and (S)-3-(furo[2,3-b]pyridin-5- yl)-4H-l '-azaspiro[[l,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane].
[001144] Example 194 - (+/-)-4-(2,4-dimethoxybenzyl)-3-(4-(4-methoxybenzyl)-3,4-dihvdro-
Figure imgf000275_0001
[001145] To a mixture of compound B-262 (0.30 g, 1.0 mmol) and compound C-108 (0.33 g, 1.2 mmol) in dichloromethane (5 mL) was added 10% aqueous sodium hypochlorite (3.0 g, 4.0 mmol) dropwise at 0 °C. The reaction was allowed to warm to room temperature and was stirred at this temperature for 2 hours. On completion, the reaction was filtered, and the resulting filtrate was concentrated in vacuo and purified by prep-HPLC [Instrument: GX-C; Column: Waters Xbridge CI 8 150x50 mm, particle size: 5 μηι; Mobile phase: 43-73% acetonitrile in H20 (add 0.5% NH3 ■ H20, v/v)] to give racemate 178 (0.10 g, 17 %) as a yellow solid.
[001146]
Figure imgf000275_0002
azaspiro|T 1 ,2,41 oxadiazole-5,3'-bicyclo 2.2.2"|octane1 (racemate 179)
Figure imgf000275_0003
[001147] To racemate 178 (0.10 g, 0.18 mmol) was added 50% trifluoroacetic acid in dichloromethane (2 mL) at 0 °C. The reaction was allowed to warm to room temperature and was stirred at this temperature overnight. On completion, the reaction was filtered, and the resulting filtrate was concentrated in vacuo and purified by prep-HPLC [Instrument: GX-E; Column: Agella Venusil ASB CI 8 150x21.2 mm, particle size: 5 μιη; Mobile phase: 18-48% acetonitrile in H20 (add 0.5% HC1, v/v)]. The product was then subjected to lyophilization to give racemate 3- (3,4-dihydro-2H-benzo[b][l,4]oxazin-5-yl)-4H-l '-azaspiro[[l ,2,4] oxadiazole-5,3'- bicyclo[2.2.2]octane] hydrochloride racemate 179 (30 mg, 46% yield ) as a yellow solid: LCMS (F): 2.24 min.,301.1 , m/z (M+l); Ή-NMR (CD3OD, 400 MHz): δ 7.09-7.06 (dd, J=8.0 Hz, I H), 6.85-6.82 (dd, J=8.0 Hz, I H), 6.66-6.62 (t, J=8.0 Hz , IH), 4.22-4.20 (t, J=4.8 Hz, 2H), 3.75-3.71 (dd, J=14.4 Hz, IH), 3.58-3.53 (m, 3H), 3.41-3.36 (m, 3H), 2.43-2.37 (m, 2H), 2.29-2.27 (m, I H), 2.14-2.01 (m, 3H). Racemate 179 is a mixture of HC1 salts of (R)-3-(3,4-dihydro-2H- benzo[b][l,4]oxazin-5-yl)-4H-l'-azaspiro[[l ,2,4] oxadiazole-5,3'-bicyclo[2.2.2]octane] and (S)-3- (3,4-dihydro-2H-benzo[b][l ,4]oxazin-5-yl)-4H-l '-azaspiro[[l ,2,4] oxadiazole-5,3'- bicyclo[2.2.2]octane].
[001148] Example 196 - (+/-)-7-(4-(2,4-dimethoxybenzyl -4H-l '-azaspiro ri ,2,41oxadiazole- 5,3'-bicycl -3-yl)indolin-2-one (180)
Figure imgf000276_0001
[001149] To a mixture of compound B-265 (0.30 g, 1.7 mmol) and compound C-108 (0.51 g, 1.9 mmol) in dichloromethane (10 mL) was added 10% aqueous sodium hypochlorite (5.1 g, 3.4 mmol) slowly at 0 °C. The reaction was allowed to warm to room temperature and stirred at this temperature for 2 hours. On completion, the reaction mixture was diluted with water (10 mL) and extracted with dichloromethane (3 χ 20 mL). The combined organic layers were washed with brine (2 χ 200 mL), dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography [dichloromethane: methanol = 100: 1] and prep- HPLC [Instrument: Shimadzu pump LC-20A; Column: GEMINI 200 χ 50 mm, particle size: 10 μπι; Mobile phase: 55-66.7% acetonitrile in H20 (add 0.5% NH3 H20, v/v)] to give racemate 180 (12 mg, 2% yield) as a brown solid.
[001150] Example 197 - (+/-)-7-f4H-r-azaspirorri .2.41oxadiazole-5.3'-bicvclor2.2.21octanl-3- yl)indolin-2-one (181)
Figure imgf000276_0002
[001151] To racemate 180 (12 mg, 26 μπιοΐ) was added 10% trifluoroacetic acid in dichloromethane (2 mL), and the reaction was stirred at 0 °C for 0.5 hour. On completion, the mixture was concentrated at room temperature and purified by prep-HPLC [Instrument: GX-A; Column: Phenomenex Gemini C18 150 x 25mm; Mobile phase: 16-43% acetonitrile in H20 (add 0.5% NH3 H20, v/v)] to give racemate 181 (4.0 mg, 51 % yield ) as a brown solid: LCMS (C): 1.03 min., 299.3 m/z (M+1); H-NMR (CD3OD, 400 MHz): δ 7.51-7.49 (d, J=7.6 Hz, 1 H), δ 7.38- 7.36 (d, J=7.2 Hz, 1H), 7.15-7.1 1 (t, J=7.6 Hz, 1H), 4.55-4.52 (m, 2H), 3.21 -3.08 (m, 2H), 2.90- 2.86 (m, 4H), 2.16-2.00 (m, 3H), 1.76-1.64 (m, 2H). Racemate 181 is a mixture of (R)-7-(4H-l '- azaspirq[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octan]-3-yl)indolin-2-one and (S)-7-(4H-l '- azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octan]-3-yl)indolin-2-one.
[001152] Example 198 - (+/-V4-i2,4-dimethoxybenzylV3-(,imidazorK2-alpyridin-6-vn-4H-l l- azaspiro [[ "|oxadiazole-5,3'- (182)
Figure imgf000277_0001
[001153] To a solution of compound B-269 (0.30 g, 1.9 mmol) and compound C-108 (0.60 g, 2.2 mmol) in dichloromethane (20 mL) was added 10% aqueous sodium hypochlorite (0.55 g, 7.4 mmol) dropwise at 0 °C. The resulting solution was warmed to room temperature and stirred at this temperature for 3 hours. On completion, the reaction was filtered, and the resulting filtrate was concentrated in vacuo. The residue was purified by prep-HPLC [Instrument: GX-C; Column: Phenomenex SY ERGI CI 8 150*30mm; particle size: 4 μιη; Mobile phase: 60-90% acetonitrile in H20 (add 0.5% NH3 ' H20, v/v)] to give racemate 182 (0.15 g, 18% yield) as a yellow solid. LCMS: (ES+) m/z (M+H)+ = 434.2, tR = 2.020.
[001154] Example 199 - (+/-)-3-rimidazori .2-alpyridin-6-vn-4H-l '- azaspiro[[L2,4~|oxadiazole-5,3'-bicvclo[2.2.21octane1 (183)
Figure imgf000277_0002
[001155] To compound racemate 182 (0.15 g, 0.35 mmol) was added 10% trifluoroacetic acid in dichloromethane (12 mL), and the reaction was stirred at 0 °C for 1 hour. On completion, the reaction was filtered, and the resulting filtrate was concentrated and purified by prep-HPLC
[Instrument: Shimadzu pump LC-20A; Column: Phenomenex Gemini CI 8 150x30 mm, particle size: 5 μπι; Mobile phase: 42-72% acetonitrile in H20 (add 0.5% HC1, v/v)]. The product was then subjected to lyophilization to give racemate 183 (1.0 mg, 1.0% yield ) as a white solid: LCMS (D): 0.812 min., 284.1 m/z (M+l); 'HNMR (CD3OD, 400 MHz): δ 9.25 (s, 1H), 8.35 (s, 1H), 8.27-8.25 (d, J = 13.2 Hz, 1H), 8.13 (s, 1H), 8.04-8.02 (d, J = 9.6 Hz, 1H), 3.81-3.75 (m, 2H), 3.48-3.44 (m, 4H), 2.45-2.35 (m, 3H), 2.18-2.15 (m, 1H), 2.08-2.04 (m, 1H). Racemate 183 is a mixture of (R)-3-(imidazo[l,2-a]pyridin-6-yl)-4H-r-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane] and (S)-3-(imidazo[l ,2-a]pyridin-6-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole- 5,3'-bicyclo[2.2.2]octane].
[001156] Example 200 - C+/-')-4-(,2.4-dimethoxybenzvn-3-(pyrrolon .2-blpyridazin-6-vn-4H- r-azaspirorn ,2,41oxadiazole-5,3'-bicyclo["2.2.2~|octane] (184)
Figure imgf000278_0001
[001157] To a mixture of compound B-276 (0.40 g, 2.5 mmol) and compound C-108 (0.82 g, 3.0 mmol) in dichloromethane (10 mL) was added 10% aqueous sodium hypochlorite (3.7 g, 5.0 mmol) dropwise at 0 °C. The reaction was allowed to warm to room temperature and was stirred for 3 hours. On completion, the reaction mixture was filtered, and the filtrate was concentrated and purified by prep-HPLC [Instrument: GX-C; Column: Waters Xbridge C18 150*30mm, particle size: 5μηι; Mobile phase: 35-65% acetonitrile in H20 (add 0.5% NH3 Ή20, v/v)] to give racemate 184 (90 mg, 9% yield) as a yellow solid. Racemate 184 is a mixture of (R)-4-(2,4- dimethoxybenzyl)-3-(pyrrolo[l,2-b]pyridazin-6-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane] (when deprotected provides (R)-3-(pyrrolo[l ,2-b]pyridazin-6-yl)-4H-l '- azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane]), and (S)-4-(2,4-dimethoxybenzyl)-3- (pyrrolo[l ,2-b]pyridazin-6-yl)-4H-r-azaspiro[[l,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane] (when deprotected provides (S)-3-(pyrrolo[l,2-b]pyridazin-6-yl)-4H-l'-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane]).
[001158] Chiral Separation:
[001159] A solution of racemate 184 (90 mg, 0.42 mmol) in 5 mL of ethanol was separated by SFC (Instrument: SFC 80; Column: AS., particle size: 10 μπι; Mobile phase: 35% ethanol (0.01% NH3 H20) in C02) at room temperature. Each set of collected fractions was concentrated at room temperature to give:
4-(2,4-dimethoxybenzyl)-3-(pyrrolo[l ,2-b]pyridazin-6-yl)-4H-l'- azaspiro[[l,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane] -enantiomerl (compound 184a) (17 mg, 19% yield), and 4-(2,4-dimethoxybenzyl)-3-(pyrrolo[l ,2-b]pyridazin-6-yl)-4H-l '- azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane]-enantiomer2 (compound 184b) (20 rng, 22% yield) as a white solid.
[001160] Example 201 - 3-(pyrrolori ,2-b1pyridazin-6-yl)-4H-l '-azaspiro l ,2,41oxadiazole- 5.3'-bicvclor2.2.21octane1 (185)
[001161] Compound 184a (17 mg, 39 mmol) was dissolved in 50% trifluoroacetic acid in dichloromethane (3 mL), and the reaction was stirred at 0 °C for 1 hour. On completion, the reaction was filtered, and the resulting filtrate was concentrated and purified by prep-HPLC
[Instrument: GX-E; Column: Agella Venusil ASB C18 150*21.2mm, particle size: 5 μ ι; Mobile phase: 25-55% acetonitrile in H20 (Add 0.5% HC1, v/v)]. The product was then subjected to lyophilization to give 3-(pyrrolo[l ,2-b]pyridazin-6-yl)-4H-r-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane]-enantiomerl hydrochloride (compound 185a) (1.6 mg, 14% yield) as a brown oil.
[001162] Compound 184b (20 mg, 46 mmol) was dissolved in 10% trifluoroacetic acid in dichloromethane (3 mL), and the reaction was stirred at 0 °C for 1 hour. On completion, the reaction was filtered, and the resulting filtrate was concentrated and purified by prep-HPLC
[Instrument: GX-E; Column: Agella Venusil ASB CI 8 150*21.2mm, particle size: 5 μιη; Mobile phase: 26-56% acetonitrile in H20 (Add 0.5% HC1, v/v)]. The product was then subjected to lyophilization to give 3-(pyrrolo[l ,2-b]pyridazin-6-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane]-enantiomer2 hydrochloride (compound 185b) (2.1 mg, 16% yield) as a brown oil.
[001163] Compounds 185a and 185b were combined to give 3-(pyrrolo[l ,2-b]pyridazin-6-yl)- 4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane] hydrochloride, racemate 185 (3.7 mg, 15% yield) as a brown oil. LCMS (D): 1.33 min., 284.1 m/z (M+l )+; 'HNMR (CD3OD, 300 MHz): δ 8.16-8.13 (m, 2H), 7.93-7.90 (d, J= 9.3 Hz, I H), 6.83-6.83 (d, J=1.5 Hz, IH), 3.78-3.73 (m, IH), 3.62-3.57 (m, IH), 3.44-3.36 (m, 4H), 2.41-2.27 (m, 3H), 2.17-2.00 (m, 2H). Racemate 185 is a mixture of (R)-3-(pyrrolo[l,2-b]pyridazin-6-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane] and (S)-3-(pyrrolo[l ,2-b]pyridazin-6-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole- 5,3'-bicyclo[2.2.2]octane]. [001164] Example 202 - (+/-V4-(2,4-dimethoxybenzvn-3-(3-methylbenzofuran-5-vn-4H-l '- azaspiro[[l ,2,4]oxadiazole-S,3'-bicyclo 2.2.2]octane1 (186)
Figure imgf000280_0001
[001165] To a mixture of compound B-278 (0.80 g, 4.6 mmol) and compound C-108 (1.5 g,
5.5 mmol) in dichloromethane (15 mL) was added 10% aqueous sodium hypochlorite (10 g, 14 mmol) dropwise at 0 °C. The reaction was allowed to warm to room temperature and was stirred for 5 hours. On completion, the reaction was filtered, and the resulting filtrate was concentrated and purified by prep-HPLC [Instrument: GX-A; Column: Phenomenex Gemini CI 8 150x25mm, particle size: 10 μπι; Mobile phase: 40-65% acetonitrile in H20 (add 0.5% NH3 H20, v/v)] to give racemate 186 (0.60 g, 29% yield) as a white solid. Racemate 186 is a mixture of (R)-4- (2,4-dimethoxybenzyl)-3-(3-methylbenzofuran-5-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane] (when deprotected provides (R)-3-(3-methylbenzofuran-5-yl)-4H-l '- azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane]), and (S)-4-(2,4-dimethoxybenzyl)-3-(3- methylbenzofuran-5-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane] (when deprotected provides (S)-3-(3-methylbenzofuran-5-yl)-4H-l'-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane]).
[001166] Chiral Separation:
[001167] A solution of racemate 186 (0.40 g, 0.89 mmol) in 10 mL of ethanol was separated by SFC (Instrument: SFC 80; Column: Chiralpak AD-H 250x25 mm I.D., 10 μηι; Mobile phase: 40% ethanol (0.01 % NH3 H20) in C02) at room temperature. Each set of collected fractions was concentrated at room temperature and subjected to lyophilization to give:
4-(2,4-dimethoxybenzyl)-3-(3-methylbenzofuran-5-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole- 5,3'-bicyclo[2.2.2]octane]-enantiomerl (compound 186a) (0.15 g, 38% yield) and
4-(2,4-dimethoxybenzyl)-3-(3-methylbenzofuran-5-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole- 5,3'-bicyclo[2.2.2]octane]-enantiomer2 (compound 186b) (0.15 g, 38% yield) as a white solid.
[001168] Example 203 - 3-(3-methylbenzofuran-5-yl)-4H-l '-azaspirorn .2.41oxadiazole-5.3'- bicyclo[2.2.21octanel-enantiomerl (187a)
[001169] To compound 186a (0.14 g, 0.31 mmol) was added 10% trifluoroacetic
acid/dichloromethane (5 mL), and the reaction was stirred at 0 °C for 2 hours. On completion, the reaction was filtered, and the resulting filtrate was concentrated and purified by prep-HPLC
[Instrument: GX-E; Column: Phenomenex Synergi CI 8 150x30mm, particle size: 10 μπι; Mobile phase: 8-38% acetonitrile in ¾0 (add 0.5%> HCl, v/v)]. The collected fractions were concentrated at room temperature and subjected to lyophilization to give 3-(3-methylbenzofuran-5-yl)-4H-l '- azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane]-enantiomerl hydrochloride (compound 187a) (35 mg, 34% yield ) as a white solid: cSFC analytical tR: 2.40 min., purity: 98.2%; LCMS (D): 1.14 min, 298.1 m/z (M+l); 'H-NMR (CD3OD, 400 MHz): δ 7.99 (s, 1H), 7.73-7.71 (d, J=8.4 Hz, 1H), 7.66 (s, 1H), 7.57-7.54 (d, J=8.8 Hz, 1H), 3.79-3.75 (d, J=14.4 Ηζ,ΙΗ), 3.66-3.62 (d, J=14.4 Hz, 1 H), 3.48=3.38 (m, 4H), 2.47-2.43 (m, 2H), 2.35-2.31 (m, 4H), 2.17-2.13 (m, 1 H), 2.06-2.00 (m, 1H);
cSFC analytical conditions: Column: Chiralcel AD-3 100x4.6mm, I.D, 3 μηι; Mobile phase: ethanol (0.05% DEA) in C02 from 5% to 40%; Flow rate: 3 mL/min.; Back pressure: 120 bar.
[001170] Example 204 - 3-(3-methylbenzofuran-5-yl)-4H-l '-azaspirolTl ,2,41oxadiazole-5.3'- bicyclor2.2.2]octane]-enantiomer2 (187b)
[001171] To compound 186b (0.14 g, 0.31 mmol) was added 10% trifluoroacetic
acid/dichloromethane (5 mL), and the reaction was stirred at 0 °C for 2 hours. On completion, the reaction was filtered, and the resulting filtrate was concentrated and purified by prep-HPLC
[Instrument: GX-E; Column: Phenomenex Synergi CI 8 150x30mm, particle size: 4 μπι; Mobile phase: 8-38%) acetonitrile in H20 (add 0.5% HCl, v/v)]. The collected fractions were concentrated at room temperature and subjected to lyophilization to give 3-(3-methylbenzofuran-5-yl)-4H-l '- azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane]-enantiomer2 hydrochloride (compound 187b) (35 mg, 34% yield ) as a white solid: cSFC analytical tR: 3.14 min, purity: 97.7%; LCMS (D): 1.14 min, 298.1 m/z (M+l ); Ή-NMR (CD3OD, 400 MHz): δ 7.99 (s, 1 H), 7.73-7.71 (d, J=8.8 Hz, 1 H), 7.66 (s, 1H), 7.57-7.55 (d, J=8.8 Hz, 1 H), 3.79-3.75 (d, J=14.4 Ηζ,Ι Η), 3.65-3.61 (d, J=14.4 Hz, 1H), 3.46-3.40 (m, 4H), 2.47-2.43 (m, 2H), 2.38-2.31 (m, 4H), 2.17-2.13 (m, 1 H), 2.06-2.00 (m, 1H);
cSFC analytical conditions: Column: Chiralcel AD-3 100x4.6mm, I.D, 3 μιη; Mobile phase: ethanol (0.05% DEA) in C02 from 5% to 40%; Flow rate: 3 mL/min.; Back pressure: 120 bar.
[001172] Example 205 - (+/-)-4-(2.4-dimethoxybenzyl')-3-(,3-methylbenzorb1thiophen-5-ylV 4H-l '-azaspirorri.2.41oxadiazole-5.3'-bicvclor2.2.21octanel (188)
Figure imgf000281_0001
[001173] To a mixture of compound B-280 (0.50 g, 2.6 mmol) and compound C-108 (0.85 g, 3.1 mmol) in dichloromethane (10 mL) was added 10% aqueous sodium hypochlorite (0.39 g, 5.2 mmol) slowly at 0 °C. The reaction was allowed to warm to room temperature and was stirred for 2 hours. On completion, the reaction was filtered, and the resulting filtrate was concentrated in vacuo and purified by prep-HPLC [Instrument: Shimadzu pump LC-20A; Column: GEMINI 200 x 50 mm, particle size: 10 μπι; Mobile phase: 55-66.7% acetonitrile in H20 (add 0.5% NH3 H20, v/v)] to give racemate 188 (0.25 g, 21 % yield) as a white solid. Racemate 188 is a mixture of (R)-4-(2,4-dimethoxybenzy l)-3 -(3 -methylbenzo [b]thiophen-5 -yl)-4H- 1 '- azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane] (when deprotected provides (R)-3-(3- methylbenzo[b]thiophen-5-yl)-4H-l'-azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane]), and (S)-4-(2,4-dimethoxybenzyl)-3-(3-methylbenzo[b]thiophen-5-yl)-4H-l'- azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane] (when deprotected provides (S)-3-(3- methylbenzo[b]thiophen-5-yl)-4H-l'-azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane]).
[001174] Chiral Separation:
[001175] A solution of racemate 188 (0.24 g, 0.52 mmol) in 10 mL of ethanol was separated by SFC (Instrument: SFC 80; Column: Chiralpak AD-H 250 25 mm I.D., 10 μιη; Mobile phase: 60% ethanol (0.01 % NH3 H20) in C02) at room temperature. Each set of collected fractions was concentrated at room temperature and then subjected to lyophilization to give:
4-(2,4-dimethoxybenzyl)-3-(3-methylbenzo[b]thiophen-5-yl)-4H-l '- azaspiro[[l,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane]-enantiomerl (compound 188a) (0.1 1 g, 44% yield), and
4-(2,4-dimethoxybenzy l)-3 -(3 -methylbenzo [b]thiophen-5 -yl)-4H- 1 '- azaspiro[[l,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane]-enantiomer2 (compound 188b) (75 mg, 31 % yield) as a white solid.
[001176] Example 206 - 3-(3-methylbenzorblthiophen-5-yl)-4H-l'- azaspiro[[l ,2,41oxadiazole-5,3'-bicyclo[2.2.2]octanel -enantiomerl (189a)
[001177] To compound 188a (30 mg, 96 μηιοΐ) was added 10% trifluoroacetic acid in dichloromethane (5 mL), and the reaction was stirred at 0 °C for 1 hour. On completion, the reaction was concentrated in vacuo and purified by prep-HPLC [Instrument: Shimadzu pump LC- 20A; Column: Phenomenex Gemini CI 8 150 * 30 mm, particle size: 5 μπι; Mobile phase: 42- 72% acetonitrile in H20 (add 0.5% HCl, v/v)]. The collected fractions were concentrated at room temperature and subjected to lyophilization to give 3-(3-methylbenzo[b]thiophen-5-yl)-4H-l '- azaspiro[[l,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane]-enantiomerl hydrochloride (compound 189a) (1 1 mg, 55% yield ) as a white semi-solid: cSFC analytical tR: 3.60 min., purity: 98.0%; LCMS (G): 0.67 min., 314.1 m/z (M+1); 1 H-NMR (CD3OD, 400 MHz): δ 8.15 (s, 1H), 7.99-7.97 (d, J=8.4 Ηζ,ΙΗ), 7.75-7.73 (d, J=8.4 Ηζ,ΙΗ), 7.36 (s, 1H), 3.80-3.76 (d, J=14.0 Hz, 1H), 3.67- 3.63 (d, J=14.4 Hz, 1 H), 3.49-3.39 (m, 4H), 2.50 (s, 3H), 2.45-2.31 (m, 3H), 2.19-2.01 (m, 2H); cSFC analytical conditions: Column: Chiracel IC 250 4.6 mm, I.D., 5 μπι; Mobile phase: 50% isopropanol (0.05% DEA) in C02; Flow rate: 2.4 mL/min.; Back pressure: 120 bar. [001178] Example 207 - 3-C3-methylbenzorblthiophen-5-yl)-4H-r- azaspiro L2,4]oxadiazole-5J'-bicvclor2.2.2]octane] -enantiomer2 (189b)
[001179] To compound 188b (30 mg, 96 μηιοΐ) was added 10% trifluoroacetic acid in dichloromethane (5 mL), and the reaction was stirred at 0 °C for 1 hour. On completion, the reaction was concentrated in vacuo and purified by prep-HPLC [Instrument: Shimadzu pump LC- 20A; Column: Phenomenex Gemini CI 8 150 x 30 mm, particle size: 5 μπι; Mobile phase: 42- 72% acetonitrile in H20 (add 0.5% HCl, v/v)]. The collected fractions were concentrated at room temperature and subjected to lyophilization to give 3-(3-methylbenzo[b]thiophen-5-yl)-4H-l '- azaspiro[[l,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane]-enantiomer2 hydrochloride (compound 189b) (10 mg, 50% yield) as a white semi-solid: cSFC analytical tR: 2.93 min., purity: 97.9%; LCMS (G): 0.67 min., 314.1 m/z (M+1 ); Ή-NMR (CD3OD, 400 MHz): δ 8.16 (s, 1H), 7.99-7.96 (d, J=8.0 Ηζ,Ι Η), 7.75-7.72 (d, J=8.4 Ηζ,ΙΗ), 7.35 (s, 1H), 3.80-3.76 (d, J=14.4 Hz, 1H), 3.68- 3.64 (d, J=14.0 Hz, 1H), 3.49-3.38 (m, 4H), 2.50 (s, 3H), 2.45-2.34 (m, 3H), 2.17-2.02 (m, 2H); cSFC analytical conditions: Column: Chiracel IC 250 χ 4.6 mm, I.D., 5 μιη; Mobile phase: 50% isopropanol (0.05% DEA) in C02; Flow rate: 2.4 mL/min.; Back pressure: 120 bar.
[001180] Example 208 - r+/-V4-r2,4-dimethoxybenzvn-3-f3-methylbenzofuran-6-vn-4H-l '- azaspiro[[l ,2.4] oxadiazole-5,3'-bicyclo|"2.2.2]octane] (190)
Figure imgf000283_0001
[001181] To a mixture of compound B-286 (0.25 g, 1.4 mmol) and compound C-108 (0.47 g, 1.7 mmol) in dichloromethane (10 mL) was added 10% aqueous sodium hypochlorite (4.3 g, 5.6 mmol) dropwise at 0 °C. The reaction was allowed to warm to room temperature and was stirred for 2 hours. On completion, the reaction was filtered, and the resulting filtrate was concentrated and purified by prep-HPLC [Instrument: GX-H; Column: Waters Xbridge C18 150*30mm, particle size: 5 μηι; Mobile phase: 43-73% acetonitrile in H20 (add 0.5% NH3 H20, v/v)] to give racemate 190 (0.20 g, 31 % yield) as a white solid. Racemate 190 is a mixture of (R)-4-(2,4- dimethoxybenzyl)-3-(3-methylbenzofuran-6-yl)-4H-l '-azaspiro[[l ,2,4] oxadiazole-5,3'- bicyclo[2.2.2]octane] (when deprotected provides (R)-3-(3-methylbenzofuran-6-yl)-4H-l '- azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2] octane]), and (S)-4-(2,4-dimethoxybenzyl)-3-(3- methylbenzofuran-6-yl)-4H-l '-azaspiro[[l ,2,4] oxadiazole-5,3'-bicyclo[2.2.2]octane] (when deprotected provides (S)-3 -(3 -methy lbenzofuran-6-y 1)-4H- 1 '-azaspiro[[ 1 ,2,4] oxadiazole-5 ,3 '- bicyclo[2.2.2] octane]). [001182] Chiral Separation:
[001183] A solution of racemate 190 (0.20 g, 0.45 mmol) in 5 mL of ethanol was separated by SFC (Instrument: SFC 80; Column: Chiralpak OD-H 250x25 mm I.D., 10 μπι; Mobile phase: 40% ethanol (NH3 H20) in C02) at room temperature. Each set of collected fractions was concentrated at room temperature and then subjected to lyophilization to give:
4-(2,4-dimethoxybenzyl)-3-(3-methylbenzofuran-6-yl)-4H-l '-azaspiro[[l ,2,4] oxadiazole- 5,3'-bicyclo[2.2.2]octane]-enantiomerl (compound 190a) (60 mg, 30% yield), and
4-(2,4-dimethoxybenzyl)-3-(3-methylbenzofuran-6-yl)-4H-l '-azaspiro[[l ,2,4] oxadiazole- 5,3'-bicyclo[2.2.2]octane]-enantiomer2 (compound 190b) (50 mg, 25% yield) as white solid.
[001184] Example 209 - 3-(3-methylbenzofuran-6-vn-4H-l '-azaspirorn .2.41oxadiazole-5.3'- bicvclo 2.2.2] octane]-enantiomerl (191a)
[001185] Compound 190a (60 mg, 0.13 mmol) was dissolved in 10% trifluoroacetic acid in dichloromethane (5 mL), and the reaction was stirred at 0 °C for 1 hour. On completion, the reaction was filtered, and the resulting filtrate was concentrated and purified by prep-HPLC
[Instrument: GX-E; Column: Phenomenex Synergi CI 8 150*30 mm, particle size: 10 μηι; Mobile phase: 19-49% acetonitrile in H20 (Add 0.5%> HCl, v/v)]. The collected fraction were subjected to lyophilization to give 3-(3-methylbenzofuran-6-yl)-4H-l '-azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2] octane]-enantiomerl hydrochloride (compound 191a) (8.0 mg, 20% yield ) as a yellow solid: cSFC analytical tR: 3.27 min., purity: 98.5%; LCMS (A): 0.75 min., 298.0 m/z (M+l); 1 H-NMR (CD30D, 400 MHz): δ 7.84 (s, 1 H), 7.69-7.67 (m, 3H), 3.78-3.76 (dd, J,=14.4 Hz, J2=1.6 Hz, 1 H), 3.65-3.61 (dd, J,=14.4 Hz, J2=2.4 Hz, 1 H), 3.48-3.37 (m, 4H), 2.46-2.34 (m, 2H), 2.34-2.29 (m, 4H), 2.18-2.12 (m, 1 H), 2.07-2.02 (m, 2H);
cSFC analytical conditions: Column: Chiralcel AD-3 100x4.6mm I.D., 3 μιτι; Mobile phase: methanol (0.05% DEA) in C02 from 5% to 40%; Flow rate: 3 mL/min.; Wavelength: 220nm.
[001186] Example 210 - 3-(3-methylbenzofuran-6-ylV4H-l '-azaspirorri ,2,41oxadiazole-5.3'- bicvclo 2.2.2] octane] -enantiomer2 (191b)
[001187] Compound 190b (50 mg, 0.1 1 mmol) was dissolved in 10% trifluoroacetic acid in dichloromethane (5 mL), and the reaction was stirred at 0 °C for 1 hour. On completion, the reaction was filtered, and the resulting filtrate was concentrated and purified by prep-HPLC
[Instrument: GX-E; Column: Phenomenex Synergi CI 8 150*30 mm, particle size: 10 μπι; Mobile phase: 19-49% acetonitrile in H20 (Add 0.5% HCl, v/v)]. The collected fraction were subjected to lyophilization to give 3-(3-methylbenzofuran-6-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2] octane]-enantiomer2 hydrochloride (compound 191b) (8.0 mg, 24% yield ) as a yellow solid: cSFC analytical tR: 4.43 min., purity: 98.8%; LCMS (A): 0.75 min., 298.0 m/z (M+l); 1 H-NMR (CD3OD, 400 MHz): δ 7.84 (s, 1H), 7.69-7.67 (m, 3H), 3.78-3.76 (dd, J,=14.4 Hz, J2=1.6 Hz, 1H), 3.65-3.61 (dd, J,=14.4 Hz, J2=2.4 Hz, 1 H), 3.48-3.38 (m, 4H), 2.47-2.34 (m, 2H), 2.34-2.29 (m, 4H), 2.18-2.12 (m, 1H), 2.07-2.02 (m, 2H); cSFC analytical conditions: Column: Chiralcel AD-3 100x4.6mm I.D., 3 μιη; Mobile phase: methanol (0.05% DEA) in C02 from 5% to 40%; Flow rate: 3 mL/min.; Wavelength: 220nm.
[001188] Example 211 - (+/-)-4-(2,4-dimethoxybenzylV3-(3-methylbenzo blthiophen-6-yl')-
Figure imgf000285_0001
[001189] To a mixture of compounds B-294 and B-295 (0.90 g, 4.7 mmol), and compound C-108 ( 1.5 g, 5.6 mmol), in dichloromethane (10 mL), was added 10% aqueous sodium hypochlorite (17 g, 24 mmol) dropwise at 0 °C. The reaction was allowed to warm to room temperature and was stirred for 1 hour. On completion, the reaction was filtered, and the resulting filtrate was concentrated and purified by prep-HPLC [Instrument: GX-A; Column: Phenomenex Gemini CI 8 150*25mm, particle size: 10 μπι; Mobile phase: 54-64% acetonitrile in H20 (add 0.5% NH3 H20, v/v)] to give racemate 192 (0.20 g, 9.2% yield) as a yellow solid. Racemate 192 is a mixture of (R)-4-(2,4-dimethoxybenzyl)-3-(3-methylbenzo[b]thiophen-6-yl)-4H-l '- azaspiro[[l,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane] (when deprotected provides (R)-3-(3- methylbenzo[b]thiophen-6-yl)-4H- -azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane]), and (S)-4-(2,4-dimethoxybenzyl)-3-(3-methylbenzo[b]thiophen-6-yl)-4H-l'- azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane] (when deprotected provides (S)-3-(3- methylbenzo[b]thiophen-6-yl)-4H-l'-azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane]).
[001190] Chiral Separation:
[001191] A solution of racemate 192 (0.20 g, 0.43 mmol) in 5 mL of ethanol was separated by SFC (Instrument: SFC 80; Column: Chiralpak AD-H 250x25 mm I.D., 10 μιη; Mobile phase: 60% methanol (NH3 H20) in C02) at room temperature. Each set of collected fractions was concentrated at room temperature and then subjected to lyophilization to give:
4-(2,4-dimethoxybenzyl)-3-(3-methylbenzo[b]thiophen-6-yl)-4H-l'- azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane]-enantiomerl (compound 192a) (70 mg, 35% yield), and
4-(2,4-dimethoxybenzyl)-3-(3-methylbenzo[b]thiophen-6-yl)-4H-l'- azaspiro[[l,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane]-enantiomer2 (compound 192b) (70 mg, 30% yield) as a yellow solid. [001192] Example 212 - 3^3-methylbenzorb1thiophen-6-yl -4H- - azaspiro[ l,2,41oxadiazole-5,3'-bicyclo 2.2.21octanel -enantiomerl (193a)
[001193] To compound 192a (70 mg, 0.15 mmol) was added 10% trifluoroacetic
acid/dichloromethane (5 mL), and the reaction was stirred at 0 °C for 2 hours. On completion, the reaction was filtered, and the resulting filtrate was concentrated and purified by prep-HPLC
[Instrument: GX-E; Column: Phenomenex Synergi CI 8 150*30mm, particle size: 4 μπι; Mobile phase: 15-45% acetonitrile in H20 (add 0.5% HC1, v/v)]. The collected fractions were concentrated and subjected to lyophilization to give 3-(3-methylbenzo[b]thiophen-6-yl)-4H-l '- azaspiro[[l,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane]-enantiomerl hydrochloride (compound 193a) (20 mg, 43% yield ) as a white solid: cSFC analytical tR: 3.26 min., purity: 98.0%; LCMS (B): 0.64 min., 314.1 m/z (M+l); Ή-NMR (CD3OD, 400 MHz): δ 8.26 (s, 1H), 7.87-7.85 (d, J=8.0 Hz, 1 H), 7.79-7.77 (dd, J^.O Hz, J2=0.8 Hz, 1H), 7.41 (s, 1H), 3.79-3.76 (d, J=14.0 Hz, 1 H), 3.66-3.62 (dd, J,=14.0 Hz, J2=2.0 Hz, 1 H), 3.49-3.38 (m, 4H), 2.49 (s, 3H), 2.46-2.35 (m, 2H) , 2.34-2.31 (m, 1 H), 2.18-2.14 (m, 1 H), 2.07-2.02 (m, 1 H);
cSFC analytical conditions: Column: Chiralpak AD-3 100x4.6mm, I.D., 3μπι; Mobile phase: ethanol (0.05% DEA) from 5% to 40% in C02; Flow rate: 3mL/min.; Wavelength: 220nm.
[001194] Example 213 - 3-(3-methylbenzorblthiophen-6-vn-4H-l '- azaspiro[ l,2,41oxadiazole-5,3'-bicyclo 2.2.2]octanel -enantiomer2 (193b)
[001195] To compound 192b (70 mg, 0.15 mmol) was added 10% trifluoroacetic
acid/dichloromethane (5 mL), and the reaction was stirred at 0 °C for 2 hours. On completion, the reaction was filtered, and the resulting filtrate was concentrated and purified by prep-HPLC [Instrument: GX-E; Column: Phenomenex Synergi CI 8 150*30mm, particle size: 4 μιη; Mobile phase: 15-45% acetonitrile in H20 (add 0.5% HC1, v/v)]. The collected fractions were concentrated and subjected to lyophilization to give 3-(3-methylbenzo[b]thiophen-6-yl)-4H-l'- azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane]-enantiomer2 hydrochloride (compound 193b) (20 mg, 43% yield ) as awhite solid: cSFC analytical tR: 3.97 min., purity: 98.0%; LCMS (B): 0.67 min., 314.1 m/z (M+l ); Ή-NMR (CD3OD, 400 MHz): δ 8.25 (s, 1 H), 7.88-7.85 (d, J=8.4 Hz, 1 H), 7.79-7.77 (dd, J=8.4 Hz, 1H), 7.42 (s, 1H), 3.80-3.76 (d, J=14.0 Hz, 1 H), 3.65- 3.60 (m, 1H), 3.48-3.39 (m, 4H), 2.49 (s, 3H), 2.44 (m, 2H) , 2.32 (m, 1 H), 2.18-2.13 (m, 1H), 2.07-2.02 (m, 1H);
cSFC analytical conditions: Column: Chiralpak AD-3 100x4.6mm, I.D., 3 μπι; Mobile phase: ethanol (0.05% DEA) from 5% to 40% in C02; Flow rate: 3mL/min.; Wavelength: 220nm.
[001196] Example 214
[001197] Additional compounds prepared include the following:
[001198] (+/-)-3-(5,6,7,8-tetrahydroisoquinolin-3-yl)-4H-l'-azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane] (194);
Figure imgf000287_0001
Compound 194 was chirally separated to provide separate enantiomers:
3-(5,6,7,8-tetrahydroisoquinolin-3-yl)-4H-r-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane]-enantiomerl (194a), and
3-(5,6,7,8-tetrahydroisoquinolin-3-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane]-enantiomer2 (194b).
[001199] (+/-)-4-methyl-3 -(2-methyl- 1 ,2,3 ,4-tetrahydroisoquinol in-6-yl)-4H- 1 '- azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane] (195);
Figure imgf000287_0002
Compound 195 was chirally separated to provide separate enantiomers:
4-methyl-3-(2-methyl-l ,2,3,4-tetrahydroisoquinolin-6-yl)-4H-l '- azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane]-enantiomerl (195a), and
4-methyl-3 -(2-methyl- 1 ,2,3,4-tetrahydroisoquinolin-6-yl)-4H- 1 '- azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane]-enantiomer2 (195b).
[001200] (+/-)-3-(quinolin-7-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane]
(196);
Figure imgf000287_0003
Compound 196 was chirally separated to provide separate enantiomers:
3-(quinolin-7-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane]- enantiomerl (196a), and
3-(quinolin-7-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane]- enantiomer2 (196b). [001201] (+/-)-3-(l-methyl-lH-indol-6-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane (197);
Figure imgf000288_0001
Compound 197 was chirally separated to provide separate enantiomers:
3-(l-methyl-lH-indol-6-yl)-4H- -azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane- enantiomerl (197a), and
3-(l -methyl-lH-indol-6-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane- enantiomer2 (197b).
[001202] (+/-)-3-(imidazo[l ,5-a]pyridin-7-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane] (198);
Figure imgf000288_0002
(+/-)
198
[001203] (+/-)-3-(3,4-dihydro-2H-benzo[b][l ,4]oxazin-5-yl)-4-methyl-4H- r- azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[ (199);
(+
Figure imgf000288_0003
[001204] (+/-)-3-(pyrrolo[l ,2-a]pyrimidin-7-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane] (200);
Figure imgf000288_0004
[001205] Rat l nAChR Binding Assay [001206] The ability of compounds to displace binding of radioactive ligands from the a7 nAChR was determined, as a measure of the affinity of the compounds for these ligand-gated ion channels. Binding assays were performed by Perkin Elmer Discovery Services (formerly Caliper / Novascreen) according to their standard protocols and followed published methods (Meyer et al., J. Pharmacol. Exp. Ther. 1998, 287(3), 918-925; Marks et al., Mol. Pharmacol. 1986, 30, 427- 436). Rat brains were rapidly removed, homogenized in buffer, and prepared for incubation with the radioactive ligand [125I]-a-bungarotoxin. The reference compound was methyllycaconitine. Briefly, receptor binding assays incubated preparations of the receptors with radioactive ligand and terminated the reaction by diluting with buffer, followed immediately by filtration through glass fiber filters soaked in buffer containing polyethylenimine. Binding of the radioactive ligand was measured in a scintillation counter. Nonspecific binding was determined with unlabeled ligand. Each condition was measured in duplicate. The Kj values were calculated by the equation of Cheng and Prusoff (Biochem. Pharmacol. 1973, 22, 3099-3108.). Results are provided in Table 2 (reported as Rat al nAChR Binding Ki, nM (%inh @ 10 mM)).
[001207] FLIPR Functional Assays
[001208] Functional activity of compounds on ligand-gated ion channels can be determined using high throughput screening for real-time kinetic cellular assays with a FLIPR® brand Fluorometric Imaging Plate Reader and measuring calcium flux or membrane potential. Both agonist and antagonist activities can be determined.
[001209] Cell Culture Procedures
[001210] Cloned human a7 nicotinic acetylcholine receptor (nAChR) (encoded by the
CHRNA7 gene) was stably co-expressed in CHO cells with the human chaperone RIC-3 (encoded by the RIC 3 gene). RIC-3 promotes expression of nicotinic acetylcholine receptors at the plasma membrane.
[001211] CHO cells were cultured in Ham's F-12 supplemented with 10% fetal bovine serum, 100 U/mL penicillin G sodium, 100 μg/mL streptomycin sulfate and appropriate selection antibiotics (selection pressure was maintained on the stock plates by including selection antibiotics in the culture medium).
[001212] Cells were harvested from stock plates for preparation of FLIPR assay plates. Cells were washed with Hank's Balanced Salt Solution and detached from the culture plates using trypsin. Cells were counted and diluted to the appropriate density (15,000-30,000 cells per 50 μΐ,) in culture medium without selection antibiotics. Cells were dispensed into flat-bottom poly-D- lysine-coated, black-wall, clear-bottom, 384-well plates. After plating, cells were incubated for 10-20 minutes at room temperature (to allow cells to settle), and then incubated overnight in a humidified, 37 °C, 5% C02 cell culture incubator. [001213] Overview of Test Method
[001214] The ability of the test articles to act as agonists of the human <x7 nAChR receptor was evaluated. The test and control article formulations were loaded into a 384-well compound plate and transferred to the assay plate by a FLIPRTETRA™ (MDS-AT) instrument while recording fluorescence.
[001215] Fluorescence changes elicited by the reference compounds and the test articles were recorded by FLIPRTETRA and displayed with FLIPR Screen Works3.1 software. Test and control article solutions were added to the assay plate 10 seconds after starting fluorescence recordings. During the first 60 seconds, data were acquired at 1 sample/second and for the remaining 240 seconds, data were sampled every 5 seconds. Results are provided in Table 2 (reported both as Human <x7 nAChR FLIPR agonist EC50 (nM) and as Human a l nAChR FLIPR Response relative to 30 μΜ ACh).
[001216] Dye Loading
[001217] For a7 nAChRs, experiments were performed with the FLIPR Fluo-8 dye kit (ABDbioquest) according to the manufacturer's instructions. Twenty-four hours (+/- 6 hours) after plating cells in the assay plate, the culture medium was removed and replaced with 20 / well of dye loading buffer (dye in HBPS: NaCl, 137mM; KC1, 4mM; CaCl2, 1.8mM; MgCl2, I mM; HEPES, l OmM; Glucose, l OmM; pH adjusted to 7.4 with NaOH). Cells were incubated for 30 min in a humidified, 37 °C, 5% CO2 cell culture incubator. Five / well of control and test article solutions (HBPS + a total of 1.5% DMSO + reference compound or test articles at 5X test concentration) were added to the assay plate by the FLIPRTETRA.
[001218] Test method for human a7 nAChR
[001219] Agonist: Fluorescence was measured at excitation wavelength 470-495 nm / emission wavelength 515-575 nm for 30 seconds prior to and for 270 seconds after addition of solutions. Test article solutions contained 1 μΜ PNU- 120596.
[001220] Analysis
[001221] Data acquisition was performed via the FLIPR Control software that was supplied with the FLIPR System (MDS-AT) and data were analyzed using Microsoft Excel 2003
(Microsoft Corp., Redmond, WA). Kinetic data obtained by the FLIPR were reduced to the maximum fluorescence value for each well after subtracting bias based on sample 1 for each well. Reduced data were normalized to the averages for the vehicle control wells (0% inhibition) and for the highest concentration of the ω-conotoxin GVIA wells (100% inhibition).
[001222] Concentration-response data were fitted to a Hill equation of the following form: RESPONSE
Figure imgf000291_0001
where Base is the response at low concentrations of test article, Max is the maximum response at high concentrations, xhalf is the EC50, or IC50, the concentration of test article producing either half-maximal activation or inhibition, and rate is the Hill coefficient. Nonlinear least squares fits were made assuming a simple one-to-one binding model. If appropriate, fits were weighted by the standard deviation. No assumptions about the fit parameters were made; the fit parameters were determined by the algorithm.
[001223] Oocyte Electrophysiology
[001224] Functional activity of compounds, as agonists or antagonists, can be measured in Xenopus laevis oocytes expressing ligand-gated ion channels. Using standard voltage clamp methods, inward calcium currents elicited by application of the natural Iigands or compounds can be recorded and quantitated. In this manner, the agonist or antagonist nature of compounds, as well as their potency relative to the natural ligand, can be ascertained.
[001225] Methods
[001226] All experiments were carried out at human nAChRs or related ligand-gated channels expressed in Xenopus oocytes using the method of cDNA expression. Currents evoked by . acetylcholine or other agonist Iigands were recorded using the standard two-electrode
voltage-clamp configuration (TEVC). Xenopus oocytes were prepared and injected using standard procedures.
[001227] Briefly, ovaries were harvested from Xenopus laevis females that were deeply anesthetized and pithed following the animal rights rule from the Geneva canton. A small piece of ovary was isolated for immediate preparation while the remaining part was placed at 4 °C in a sterile Barth solution (containing: NaCl, 88mM; KC1, ImM; NaHC03, 2.4mM; HEPES, l OmM; MgS04.7H20, 0.82mM; Ca(N03)2.4H20, 0.33mM; CaCl2.6H20, 0.4 ImM; at pH 7.4), and supplemented with 20 μg/mL of kanamycin, 100 unit/mL penicillin and 100 μg/mL streptomycin. On the second day following dissociation, oocytes were injected with 2 ng of cDNA per oocyte containing the genes encoding for the appropriate nAChR subunits using an automated injector (Hogg et al., J. Neurosci. Methods, 2008, 169, 65-75). All recordings were performed at 18 °C and cells were supervised with OR2 medium (containing: NaCl, 82.5nM; KG, 2.5mM; HEPES, 5mM; CaCl2.2H20, 2.5mM; pH 7.4). Cells were held at -80 mV. Data were filtered at 10 Hz, captured at 100 Hz and analyzed using proprietary data acquisition and analysis software running under Matlab (Mathworks Inc.). [001228] Experiments
[001229] I) Primary screen at the human a7 nAChRs. A first characterization of newly synthetized compound requires the determination of the capacity of the compound to bind at the target membrane protein and/or to functionally interact with the receptor. The aim of these experiments was to determine at three concentrations (e.g., 10 μΜ, 1 μΜ, and 100 nM; or slightly modified range) 50% activation or inhibition at the human a 7 receptor the effect of the compounds relative to 200 μΜ ACh. Putative inhibition of the agonist-evoked current was determined by pre- (45 s) and co-application (5 s) of compound with ACh at the three concentrations.
[001230] II) Dose-response activity. To further characterize the most active compounds concentration activity studies were conducted to determine the dose-response activation profile for the oc7 nAChRs. Agonistic responses were determined using a protocol of 9 data points with a reference ACh response before and after compound testing. The dose-response inhibition profile was determined using a pre- and co-application protocol with 45 s pre-application and at least 6 concentrations. All data were determined in at least triplicate. Results are provided in Table 2 (reported as Human a7 nAChR Activity Range in Oocyte (μΜ)).
[001231] Data Analysis for Dose-Response Activity
[001232] Concentration-activation curves were fit using the empirical Hill equation with either a single or dual component. Single component concentration-activation curves were in the form: Y=Scale / 1+( EC5o/ x)AnH; where: y = the fraction of evoked current, EC50 = concentration for 50% activation and, nn = the apparent co-operativity and Scale the relative activity of the compound versus ACh or other natural ligand.
[001233] When necessary concentration activation curves were fitted with a dual Hill equation in the form: Y=a / 1+( EC5OH/ Χ)λΠΗΗ + (1-a) / 1+( EC50L/ x)AnnLi where: y = the fraction of evoked current, a = the fraction of high affinity component, EC50H = concentration for 50% activation of the high affinity, nHH = the apparent co-operativity for the high affinity, EC50L = concentration for 50% activation of the low affinity, nHL = the apparent co-operativity for the high affinity x = agonist concentration, (see Buisson and Bertrand, J. Neurosci., 2001 , 21 , 1819- 1829).
[001234] Concentration-inhibition curves were fitted with Hill equations in the form: Y-l / l+(x/IC5o)AnH; where: y = the fraction of evoked current, IC50 = concentration for 50% inhibition and, nH = the apparent co-operativity. If incomplete blockade is observed the equation is modified as follows: Y=(l-Cte) / 1 +(x/IC5o)AnH; where: y = the fraction of evoked current, IC50 = concentration for 50% inhibition and, nH = the apparent co-operativity and addition of a constant Cte to account for the incomplete inhibition: Y=(l + n * f * cB / CA) * ((l+cA)/(l+cA+cB)An * (1/(1 + b/Kblock)); where: y = the fraction of the evoked current, f = an arbitrary factor, n = number of sites, cB = b/ (Kb / 1+cA), b = the concentration of antagonist, Kb the antagonist affinity, cA = a / KA, a = the agonist concentration and KA the agonist affinity. This equation was derived from the work of (Smulders et al., Eur. J. Pharmacol., 2005, 509, 97-108; Cachelin and Rust, Mol. Pharmacol., 1994, 46, 1 168-1 174).
[001235] Statistical analysis was performed either using Matlab (Mathworks inc.) or Excel (Microsoft).
Table 2:
Figure imgf000293_0001
b 1%@ 10 uM) ND ND NDa 523 ND ND NDb 424 ND ND NDa 6710 ND ND NDb 31200 ND ND NDa 12200 ND ND NDb 17300 ND ND NDa (7%@ ΙΟμΜ) ND ND NDb (2%@ ΙΟμΜ) ND ND NDa (25% @ ΙΟμΜ) ND ND NDb (27% @ ΙΟμΜ) ND ND NDa (6%@ ΙΟμΜ) ND ND NDb (11%@ ΙΟμΜ) ND ND NDa (13% @ ΙΟμΜ) ND ND NDb (9%@ ΙΟμΜ) ND ND NDa (10% @ ΙΟμΜ) ND ND NDb (1%@ ΙΟμΜ) ND ND ND
(13% @ ΙΟμΜ) ND ND ND
(10% @ ΙΟμΜ) ND ND ND
(29% @ ΙΟμΜ) ND ND ND
(0%@ ΙΟμΜ) ND ND ND
(2%@ ΙΟμΜ) ND ND NDa 3830 34 0.9 NDb 1070 258 0.8 NDa 146 28 0.9 > 10b 808 95 0.8 NDa 538 52 0.8 NDb 125 11 0.9 1 to 10a 280 2407 0.8 NDb 9840 ND ND NDa 6160 ND ND NDb 1300 76 0.9 NDa 177 85 1.1 1 to 10b 1680 ND ND NDa 2010 1214 0.8 NDb 198 145 0.7 NDa 437 99 0.7 NDb 41 45 0.8 1 to 10a 4240 ND ND NDb 542 ND ND NDa 672 151 0.8 NDb 6680 ND ND NDa 164 ND ND ND b 4260 ND ND NDa 495 > 3000 0.3 NDb 13700 ND ND NDa 599 ND ND NDb 149 ND ND > 10a 2270 238 0.9 NDb 260 76 0.7 1 to 10a (29% @ ΙΟμΜ) ND ND NDb (1 1 % @ Ι ΟμΜ) ND ND ND
13200 1 129 0.3 ND1 (23% @ ΙΟμΜ) 2733 0.5 ND
14600 2381 (EC30) 0.6 ND
(8% @ ΙΟμΜ) 2857 0.5 ND
1 100 185 0.5 ND
6930 ND ND ND
(17% @ Ι ΟμΜ) ND ND ND
(16% @ Ι ΟμΜ) ND ND NDa ND 18 1 NDb ND 47 0.9 ND1 ND 83 1.1 ND
ND 1674 0.5 NDa ND 145 0.9 NDb ND 195 1 NDa ND 86 1.3 NDb ND 72 1 NDa ND >3000 0.4 NDb ND 1561 0.7 NDa ND 212 1.1 NDb ND 179 1.2 NDa ND 526 1.1 NDb ND 317 0.9 ND
ND >3000 0.2 ND
ND 1340 0.8 NDa ND 75 0.9 NDb ND 83 1.1 NDa ND 56 1.3 NDb ND 51 1.1 NDa ND 59 1 NDb ND 75 1 NDa ND 1065 0.9 NDb ND 72 1.2 NDa ND >3000 ND NDb ND 2966 0.5 ND 100a ND >3000 0.4 ND
100b ND >3000 ND ND
103 ND 361 1 ND
104 ND 889 0.9 ND
105 ND 138 0.8 ND
106 ND 304 1.1 ND
109 ND 30 0.9 ND
110 ND 59 0.8 ND
113 ND 1250 0.8 ND
114 ND 1915 0.5 ND
115 ND 850 0.8 ND
117a ND 1502 0.8 ND
117b ND 473 0.9 ND
119a ND 11 1 2240
119b ND 10 1 1350
121a ND 72 0.9 ND
121b ND 80 1.1 ND
123a ND 84 0.9 ND
123b ND 118 0.9 ND
125a ND 1581 0.8 ND
125b ND 1602 0.9 ND
127a ND 213 1.3 ND
127b ND 317 0.9 ND
129a ND 60 0.5 ND
129b ND 111 0.8 ND
131a ND 14 1 ND
131b ND 21 0.9 ND
133a ND 163 1 ND
133b ND 142 1 ND
135a ND 80 1.2 ND
135b ND 127 1 ND
137a ND 1769 0.8 ND
137b ND 1198 0.8 ND
139a ND 256 0.8 ND
139b ND 214 0.9 ND
141a ND 361 0.9 ND
141b ND 24 0.9 ND
144 ND 9 0.9 ND
145 ND 49 0.9 ND
148 ND 19 0.9 2010
149 ND 76 0.8 ND
151a ND 64 1 4840
151b ND 108 0.9 ND 153a ND >3000 0.4 ND
153b ND >3000 0.3 ND
155a ND >3000 ND ND
155b ND >3000 ND ND
158 ND 37 0.9 ND
159 ND 235 1 ND
161 a ND 25 1 ND
161b ND 31 1 ND
163a ND >3000 1 ND
163b ND >3000 1 ND
165a ND 36 0.9 ND
165b ND 38 0.9 ND
167a ND >3000 1 ND
167b ND >3000 1 ND
169a ND 40 0.9 ND
169b ND 57 1 ND
194a ND 825 0.8 ND
195a ND >3000 0.2 ND
195b ND >3000 0 ND
Table note: ND = Not Determined.
[001236] Human a7 nAChR Binding Assay
[001237] The ability of compounds to displace binding of radioactive ligands from human a7 nAChR was determined, as a measure of the affinity of the compounds for these ligand-gated ion channels. The [125I]-aBungarotoxin competition binding assay was performed under contract by Cerep Poitiers, France following published the methods (Sharpies et al., J Neurosci. 2000;
20(8):2783-91 ). "SH-SY5Y cells stably expressing human a7 nicotinic acetylcholine receptors, grown to confluency in 175 cm2 flasks, were washed briefly with warm PBS containing (in mm): (150 NaCl, 8 K2HP04, 2 KH2P04, pH 7.4, 37°C) and scraped into cold phosphate buffer. Cells were washed by centrifugation for 3 min at 500 χ g and resuspended in 10 mL of ice-cold phosphate buffer. The suspension was homogenized for 10 sec using an Ultraturax and centrifuged for 30 min at 45,000 xg. The pellet was resuspended in phosphate buffer (0.5 mL per original flask). SH-SY5Y membranes (30 μg protein) were incubated in a total volume of 2 mL in 50 mM phosphate buffer with 0.05 nM [125I]-aBgt and serial dilutions of test compound.
Nonspecific binding was determined in the presence of ct-bungarotoxin (1 μΜ). Samples were incubated for 120 min at 37°C. The reaction was terminated by filtration through Whatman GFA/E filter paper (presoaked overnight in 0.3% polyethyleneimine in PBS), using a Brandel Cell Harvester. Each condition was measured in duplicate. Filters were counted for radioactivity using a scintillation counter. The results were expressed as a percent inhibition of control specific binding obtained in the presence of the test compounds where Inhibition (%) = 100 - [(measured specific binding/control specific binding) x 100].
[001238] The IC50 values (concentration causing a half-maximal inhibition of control specific binding) and Hill coefficients (nH) were determined by non-linear regression analysis of the competition curves generated with mean replicate values using Hill equation:
A-D
Y=D+[ ]
1 +(C/C50)nH
where Y = specific binding, A = left asymptote of the curve, D = right asymptote of the curve, C = compound concentration, C50 = IC50, and nH = slope factor.
This analysis was performed using software developed at Cerep (Hill software) and validated by comparison with data generated by the commercial software SigmaPlot® 4.0 for Windows® (© 1997 by SPSS Inc.). The inhibition constants (Kj ) were calculated using the Cheng Prusoff equation:
K— -≥→-
' (1 +L/KD) where L = concentration of radioligand in the assay, and KD = affinity of the radioligand for the receptor.
A scatchard plot is used to determine the Kd." Results are provided in Table 3 (reported as h-a7 Ki (uM)).
[001239] Oocyte Electrophysiology Screen
[001240] The Oocyte Electrophysiology Screen studies were performed under contract by HiQScreen Geneva, Switzerland. All experiments were carried out at human a 7 nAChRs transiently expressed in Xenop s laevis oocytes using the method of cDNA expression. Currents evoked by acetylcholine or other agonist ligands were recorded using the standard two-electrode voltage-clamp configuration (TEVC). X. laevis oocytes were prepared and injected using standard procedures. Briefly, ovaries were harvested from X. laevis females that were deeply anesthetized and pithed following the animal rights rule from the Geneva canton. A small piece of ovary was isolated for immediate preparation while the remaining part was placed at 4°C in a sterile Barth solution containing in mM: NaCl 88, KCl 1 , NaHC03 2.4, HEPES 10, MgS04.7H20 0.82, Ca(N03)2.4H20 0.33, CaCl2.6H20 0.41 , at pH 7.4, and supplemented with 20 μg/mL of kanamycin, 100 unit/mL penicillin and 100 μg/mL streptomycin. On the second day following dissociation, oocytes were injected with 2 ng of cDNA per oocyte containing the gene encoding human l nicotinic acetylcholine receptor subunits using an automated injector (Hogg et al., 2008). All recordings were performed at 18°C and cells were superfused with OR2 medium containing in mM: NaCl 82.5, KCl 2.5, HEPES 5, CaCl2.2H20 2.5, pH 7.4. Cells were held at - 80 mV. Data were filtered at 10 Hz, captured at 100 Hz and analyzed using proprietary data acquisition and analysis software running under Matlab (Mathworks Inc.).
[001241] Experimental protocol and analysis
[001242] After establishing a baseline transmembrane current, acetylcholine (ACh) was applied for 5 seconds at a concentration of 0.2 mM to establish a control ACh-evoked current response. Following a wash period of 90 s in OR2 medium (free of ACh), cells were then exposed for 30 s to the test compound applied at 0.01 mM. The same reference ACh test pulse was immediately given at the end of the compound exposure and again after 90 s of recovery in OR2 Medium (free of ACh or test compound). All data were determined in triplicate. The response evoked by the test compound was expressed as a percentage of that evoked by ACh:
Response (% ACh) = 100 x (I,es, / ch)
where Itest is the peak inward current measured during exposure to 0.01 mM of test compound and IACh is the peak inward current measured in the presence of ACh.
[001243] Results are provided in Table 3 (reported as % ACh @ 1 ΟμΜ Oocyte).
Table 3:
Figure imgf000299_0001
115 1.1 ND
117a >30 ND
117b 25 ND
119a 0.9 383
119b 0.78 421
121a 5.1 ND
121b 6 ND
123a 6.1 ND
123b 6 ND
129a 3.1 ND
129b 4.9 ND
131a 0.53 ND
131b 0.58 ND
135a 2.2 ND
135b 2.9 ND
137a ND 2
137b ND 3
139a ND 34
139b ND 61
141a 3.4 2243
141b 1.6 697
144 0.79 533
145 5,1 144
148 0.65 432
149 ND 92
151a 0.87 327
151b ND 77
153a ND 1
153b ND 1
155a ND 2
155b ND 2
158 4.1 41
159 ND 4
161a 0.44 254
161b 0,8 311
163a ND 4
163b ND 3
165a 2 259
165b 1.2 322
167a 10 2
167b 15 2
169a 1.6 142
169b 2.2 200 171a 0.67 919
171b 0.7 892
173a >30 1
173b >30 1
175 >30 ND
177 >30 ND
179 >30 ND
181 >30 ND
183 >30 ND
185 >30 ND
187a 1.1 342
187b 0.64 620
189a 0.86 413
189b 3.3 155
191 a 14 28
191b 8 23
196a >30 6
196b >30 4
197a 2.1 418
197b 2.4 360
[001244] Novel Object Recognition Task:
[001245] The Novel Object Recognition (NOR) task is a behavioral assay commonly used to evaluate cognition, particularly recognition memory, in rodent models of CNS disorders. This test is based on the spontaneous tendency of rodents to spend more time exploring a novel object compared to a familiar one. The choice to explore the novel object reflects the use of learning and recognition memory. The assay is commonly used to evaluate potential therapeutic agents for Alzheimer's disease, other neurodegenerative diseases and psychiatric disorders.
[001246] Procedure:
[001247] Male Wistar rats (Harlan Laboratories) weighing 350-400 grams were housed under a reversed light cycle and are tested during the dark cycle. Testing was done under low lux conditions, measured to be~2-7 lux under red light. Animals were habituated and weighed one day prior to testing. During habituation, animals were placed in a cylindrical arena and allowed to explore for 3 minutes. Training (Tl) was conducted approximately 24 hours later, with one set of identical objects placed on opposite sides of the arena. Animals were allowed to explore the objects in 3-minute sessions. Animals were dosed with a designated treatment 15-60 minutes prior to testing depending on the pharmacokinetic profile of the compound before the start of Tl . Drug or vehicle was dosed subcutaneously based on body weight at 5 mL/kg. Testing (T2) was done at 48 hours after Tl . During testing, one familiar object is replaced with a novel object. Animals were allowed to explore both objects in 3-minute sessions.
[001248] Equipment Specification:
[001249] Animals were tracked using Noldus Ethovision XT (EthoVision XT version: 8.5, Noldus Inc. Wageningen, Netherlands) tracking software, using a 2 centimeter (cm) perimeter for each object as a separate zone. The test arena consisted of a cylinder, 80 cm diameter with 40 cm high walls of black acrylic that was opaque and matte. Objects were custom fabricated shapes (cone and bullet) similar in overall size (8cm high x 8cm diameter) and were counterbalanced between treatment groups.
[001250] Data Analysis and Statistics:
[001251] Contact time was defined as the amount of time (seconds) an animal spent within the 2 cm perimeter of an object. All animals that had <5 seconds total contact time were excluded from the study. Statistical significance was determined using a Mann Whitney U-test and the criterion was set at p<0.05.
[001252] Example:
[001253] Natural forgetting in an object recognition task. Compound 3a (n=8-27/group) was administered 30 minutes before Tl . Compound 3a (s.c.) improved object recognition using a 48- hour retention interval in male Wistar rats (mean + SEM). *p < 0.05 = novel (N) vs. familiar (F) object. Results are illustrated in Figure 1.
[001254] All publications and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference.
[001255] While preferred embodiments of the present invention have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. It is intended that the following claims define the scope of the invention and that methods and structures within the scope of these claims and their equivalents be covered thereby.

Claims

What is claimed is:
A spiro-oxadiazoline compound represented by Formula (I), (Ila), or (lib): Formula (lib)
Figure imgf000303_0001
wherein:
R independently represents -H; a CrC6-alkyl radical; a C3-C6- cycloalkyl radical; a (3-6 membered)-heterocycloalkyl radical; an aryl radical; or a heteroaryl radical; wherein the C]-C6-alkyl radical, the (3-6 membered)-heterocycloalkyl radical, the aryl radical, and the heteroaryl radical may be substituted with up to 4 radical substituents comprising: -D, -F, -CI, -Br, -I, -CN, -N02, -OR2, -(CH2)mOR2, - N(R2)(R3), -(CH2)mN(R2)(R3), -S02(CH2)mR2, -(CO)(CH2)mR2, - (CO)N(R2)(R3), -OCF3, a branched or unbranched CrC6-alkyl radical, a C3-C6-cycloalkyl radical, a Ci-C6-hydroxyalkyl radical, or a Ci-C6-haloalkyl radical;
R and RJ independently represent -H; a branched or unbranched Ci-C6-alkyl radical; C3-C6-cycloalkyl radical; or the N(R2)(R3) moiety forms a cycle, wherein R2 and R3 taken together represent a C2-C6-alkyl di- radical or a (3-6 membered)-heteroalkyl di-radical;
n independently represents an integer from 0 to 6;
m independently represents an integer from 1 to 6;
W represents a moiety represented by ring system M-I, M-II, M-III, M-
Figure imgf000303_0002
Zl, Z2, Z3, Z4, and Z5 independently represent N or CR4; with the proviso that no more than two of Z1, Z2, Z3, Z4, and Z5 are N; R4 independently represents -H; -D; -F; -CI; -Br; -I; -CN; -N02; -
OR5; -(CH2)mOR5; -N(R5)(R6); -(CH2)mN(R5)(R6); -S02(CH2)mR5; - (CO)(CH2)mR5; -(CO)N(R5)(R6); -OCF3; a C,-C6-alkyl radical; a C,- C6-hydroxyalkyl radical, a Ci-C6-haloalkyl radical; a C3-C6- cycloalkyl radical; a (3-6 membered)-heterocycloalkyl radical; an aryl radical; or a heteroaryl radical; wherein the Ci-Ce-alkyl radical, the (3-6 membered)-heterocycloalkyl radical, the aryl radical, and the heteroaryl radical may be substituted with up to 4 radical substituents comprising: -D, -F, -CI, -Br, -I, -CN, -N02, -OR5, -(CH2)mOR5, - N(R5)(R6), -<CH2)mN(R5)(R6), -S02(CH2)mR5, -(CO)(CH2)mR5, - (CO)N(R5)(R6), -OCF3, a branched or unbranched C,-C6-alkyl radical, a C3-C6-cycloalkyl radical, a Ci-C6-hydroxyalkyl radical, or a C) -C6-haloalkyl radical;
R5 and R6 independently represent -H; a branched or unbranched C] -C6-alkyl radical; a C3-C6-cycloalkyl radical; or the N(R5)(R6) moiety forms a cycle, wherein R5 and R6 taken together represent a C2-Cg-alkyl di- radical or a (3-6 membered)-heteroalkyl di-radical;
Z6, Z7, Z8, and Z9 independently represent N or CR7; with the proviso that no more than two of Z6, Z7, Z8, and Z9 are N;
R7 independently represents -H; -D; -F; -CI; -Br; -I; -CN; -N02; -
OR8; -(CH2)mOR8; -N(R8)(R9); -(CH2)mN(R8)(R9); -S02(CH2)mR8; - (CO)(CH2)mR8; -(CO)N(R8)(R9); -OCF3; a C,-C6-alkyl radical; a C,- C6-hydroxyalkyl radical, a Ci-C6-haloalkyl radical; a C3-C6- cycloalkyl radical; a (3-6 membered)-heterocycloalkyl radical; an aryl radical; a heteroaryl radical; or the bond directly attaching the W moiety with the oxadiazoline moiety; wherein the C C6-alkyl radical, the (3-6 membered)-heterocycloalkyl radical, the aryl radical, and the heteroaryl radical may be substituted with up to 4 radical substituents comprising: -D, -F, -CI, -Br, -I, -CN, -N02, -OR8, -(CH2)mOR8, - N(R8)(R9), - CH2)mN(R8)(R9), -S02(CH2)mR8, -(CO)(CH2)mR8, - (CO)N(R8)(R9), -OCF3, a branched or unbranched C,-C6-alkyl radical, a C3-C6-cycloalkyl radical, a C| -C6-hydroxyalkyl radical, or a Ci-C6-haloalkyl radical;
R8 and R9 independently represent -H; a branched or unbranched Ci-C6-alkyl radical; a C3-C6-cycloalkyl radical; or the N(R8)(R9) moiety forms a cycle, wherein R8 and R9 taken together represent a C2-C6-alkyl di- radical or a (3-6 membered)-heteroalkyl di-radical; X1 independently represents N or C;
A1, A2, A3 and A4 independently represent N; NR.10; N(CH2)mR10; O; S; or CR11; with the proviso that only one A1, A2, A3 and A4 is NR10, O, or S; with the further proviso that when X1 is present and is N, then A1, A2, and A3 independently represent N or CR11;
R10 independently represents -H; -D; -(CH2)mOR12; -(CH2)mN(R12)(R13);
-S02(CH2)mR12; -(CO)(CH2)mR12; -(CO)N(R12)(R13); a Q-C6-alkyl radical; a CpCe-hydroxyalkyl radical, a Ci-C6-haloaIkyl radical; a C3- C6-cycloalkyl radical; a (3-6 membered)-heterocycloalkyl radical; an aryl radical; or a heteroaryl radical; wherein the Ci-C6-alkyl radical, the (3-6 membered)-heterocycloalkyl radical, the aryl radical, and the heteroaryl radical may be substituted with up to 4 radical substituents comprising: -D, -F, -CI, -Br, -I, -CN, -N02, -OR12, -(CH2)mOR12, -N(R12)(R13), -(CH2)mN(R12)(R13), -S02(CH2)mR12, -(CO)(CH2)mR13, -(CO)N(R12)(R13), -OCF3, a branched or unbranched CrC6-alkyl radical, a C3-C6-cycloalkyl radical, a Ci-C6-hydroxyalkyl radical, or a Ci-C6-haloalkyl radical;
R1 1 independently represents -H; -D; -F; -CI; -Br; -I; -CN; -N02; -
OR12; -(CH2)mOR12; -N(R12)(R13); -(CH2)mN(R12)(R13); - S02(CH2)mR12; -i(CO)(CH2)mR12; -(CO)N(R12)(R13); -OCF3; a CrC6- alkyl radical; a C,-C6-hydroxyalkyl radical; a CrC6-haloalkyl radical; a C3-C6-cycloalkyl radical; a (3-6 membered)-heterocycloalkyl radical; an aryl radical; or a heteroaryl radical; wherein the CrC6- alkyl radical, the (3-6 membered)-heterocycloalkyl radical, the aryl radical, and the heteroaryl radical may be substituted with up to 4 radical substituents comprising: -D; -F; -CI; -Br; -I; -CN; -N02; - OR12; -(CH2)raOR12; -N(R12)(R13); -(CH2)mN(R12)(R13); - S02(CH2)mR12; -(CO)(CH2)mR12; -(CO)N(R12)(R13); -OCF3; a branched or unbranched C C6-alkyl radical, a C3-C6-cycloalkyl radical, a CrC6-hydroxyalkyl radical, or a C C6-haloalkyl radical;
R12 and R13 independently represent -H; a branched or unbranched Ci-C6-alkyl radical; a C3-C6-cycloalkyl radical; or the N(R12)(R13) moiety forms a cycle, wherein R12 and R13 taken together represent a C2-C6-alkyl di- radical or a (3-6 membered)-heteroalkyl di-radical;
X2 independently represents N or C;
A5, A6, and A7 independently represent N; NR14; N(CH2)mR14; O; S; or CR15; with the proviso that only one A5, A6, and A7 is NR14, O, or S; with the further proviso that when X2 is N, then A5, A6, and A7 independently represent N or CR15;
R14 independently represents -H; -D; -(CH2)mOR16; -(CH2)mN(R16)(R17);
-S02(CH2)mR16; -(CO)(CH2)mR16; -(CO)N(R,6)(R17); a C,-C6-alkyl radical; a Ci-C6-hydroxyalkyl radical, a Ci-C6-haloalkyl radical; a C3- C6-cycloalkyl radical; a (3-6 membered)-heterocycloalkyl radical; an aryl radical; a heteroaryl radical; or the bond directly attaching the W moiety with the oxadiazoline moiety; wherein the Ci-C6-alkyl radical, the (3-6 membered)-heterocycloalkyl radical, the aryl radical, and the heteroaryl radical may be substituted with up to 4 radical substituents comprising: -D, -F, -CI, -Br, -I, -CN, -N02, -OR16, -(CH2)mOR16, -N(R16)(R17), -(CH2)mN(R16)(R17), -S02(CH2)mR16, -(CO)(CH2)mR16, -(CO)N(R16)(R17), -OCF3, a branched or unbranched CrC6-alkyl radical, a C3-C6-cycloalkyl radical, a Ci-C6-hydroxyalkyl radical, or a CrC6-haloalkyl;
R15 independently represents -H; -D; -F; -CI; -Br; -I; -CN; -N02; -
OR16; -(CH2)mOR16; -N(R16)(R17); -(CH2)mN(R16)(R17); - S02(CH2)mR16; -(CO)(CH2)mR16; -(CO)N(R16)(R17); -OCF3; a C,-C6- alkyl radical; a Q-Cg-hydroxyalkyl radical; a Ci-Ce-haloalkyl radical; a C3-C6-cycloalkyl radical; a (3-6 membered)-heterocycloalkyl radical; an aryl radical; a heteroaryl radical; or the bond directly attaching the W moiety with the oxadiazoline moiety; wherein the C]-C6-alkyl radical, the (3-6 membered)-heterocycloalkyl radical, the aryl radical, and the heteroaryl radical may be substituted with up to 4 radical substituents comprising: -D; -F; -CI; -Br; -I; -CN; -N02; -OR'6; -(CH2)mOR'6; -N(R16)(R17); -(CH2)mN(R,6)(R17); - S02(CH2)mR16; -(CO)(CH2)mR16; -(CO)N(R,6)(R17); -OCF3; a branched or unbranched Ci-C6-alkyl radical, a C3-C6-cycloalkyl radical, a Ci-C6-hydroxyalkyl radical, or a C]-C6-haloalkyl radical;
R16 and R17 independently represent -H; a branched or unbranched Ci-C6-alkyl radical; a C3-C6-cycloalkyl radical; or the N(R16)(R17) moiety forms a cycle, wherein R16 and R17 taken together represent a C2-C6-alkyl di- radical or a (3-6 membered)-heteroalkyl di-radical;
G1, G2, G3, and G4 independently represent C(R18)(R18); C(RI9)(R20); -NH; -
N(CH2)mR18; O; S; S02; or (CO); with the proviso that no more than two of G1, G2, G3, and G4 represent -NH; -N(CH2)mR18, O; S; S02; or (C=0); R18 independently represents -H; -D; -F; -CI; -Br; -I; -CN; -N02; -
OR'9; -(CH2)mOR19; -N(R19)(R20); -(CH2)mN(R19)(R20); - S02(CH2)mR19; -{CO)(CH2)mR19; -(CO)N(R19)(R20); -OCF3; a C,-C6- alkyl radical; a CrC6-hydroxyaIkyl radical, a C] -C6-haloalkyl radical; a C3-C6-cycloalkyl radical; a (3-6 membered)-heterocycloalkyl radical; an aryl radical; or a heteroaryl radical; wherein the Q-Ce- alkyl radical, the (3-6 membered)-heterocycloalkyl radical, the aryl radical, and the heteroaryl radical may be substituted with up to 4 radical substituents comprising: -D, -F, -CI, -Br, -I, -CN, -N02> - OR19, -(CH2)mOR19, -N(R19)(R20), -<CH2)raN(R,9)(R20), - S02(CH2)mR19, -(CO)(CH2)raR19, -<CO)N(R,9)(R20), -OCF3, a branched or unbranched C,-C6-alkyl radical, a C3-C6-cycloalkyl radical, a C]-C6-hydroxyalkyl radical, or a C]-C6-haloalkyl radical; and
R19 and R20 independently represent -H; a branched or unbranched Q-Ce-alkyl radical; a C3-C6-cycloalkyl radical; or the N(R, 9)(R20) moiety forms a cycle, wherein R19 and R20 taken together represent a C2-C6-alkyl di- radical or a (3-6 membered)-heteroalkyl di-radical; or the C(R19)(R20) moiety forms a cycle, wherein R19 and R20 taken together represent a C2-C6-alkyl di-radical or a (3-6 membered)-heteroalkyl di-radical; or a pharmaceutically acceptable salt thereof.
2. The compound of claim 1 , wherein W represents the moiety represented by the ring system M-I.
3. The compound of claim 2, wherein Z1 represents N; and Z2, Z3, Z4, and Z5 each independently represent CR4.
4. The compound of claim 2, wherein Z2 represents N; and Z1, Z3, Z4, and Z5 each independently represent CR4.
5. The compound of claim 2, wherein Z3 represents N; and Z1, Z2, Z4, and Z5 each independently represent CR4.
6. The compound of claim 2, wherein Z1 and Z2 each represent N; and Z3, Z4, and Z5 each independently represent CR4.
7. The compound of claim 2, wherein Z1 and Z3 each represent N; and Z2, Z4, and Z5 each independently represent CR4.
8. The compound of claim 2, wherein Z1 and Z4 each represent N; and Z2, Z3, and Z5 each independently represent CR4.
9. The compound of claim 2, wherein Z1 and Z5 each represent N; and Z2, Z3, and Z4 each independently represent CR4.
10. The compound of claim 2, wherein Z2 and Z3 each represent N; and Z1, Z4, and Z5 each independently represent CR4.
1 1. The compound of claim 2, wherein Z2 and Z4 each represent N; and Z1, Z3, and Z5 each independently represent CR4.
12. The compound of claim 2, wherein at least one or two of Z1, Z2, Z3, Z4, and Z5, represent CR4 with said R4 representing -D; -F; -CI; -Br; -I; -CN; -N02; -OR5; -(CH2)mOR5; -N(R5)(R6); -(CH2)mN(R5)(R6); -S02(CH2)mR5; -(CO)(CH2)mR5; -(CO)N(R5)(R6); -OCF3; a CrC6-alkyl radical; a CrC6-hydroxyalkyl radical, a CrC6-haloalkyl radical; a C3-C6-cycloalkyl radical; or a (3-6 membered)-heterocycloalkyl radical; wherein the Ci-C6-alkyl radical and the (3-6
membered)-heterocycloalkyl radical, may be substituted with up to 4 radical substituents comprising: -D, -F, -CI, -Br, -I, -CN, -N02, -OR5, -(CH2)mOR5, -N(R5)(R6), -(CH2)mN(R5)(R6), -S02(CH2)mR5, -(CO)(CH2)mR5, -(CO)N(R5)(R6), -OCF3, a branched or unbranched C,-C6-alkyl radical, a C3-C6-cycloalkyl radical, a Ci-C6-hydroxyalkyl radical, or a Ci-C6-haloalkyl radical.
13. The compound of claim 12, wherein the at least one or two of Z Z2, Z3, Z4, and Z5, represent CR4 with said R4 representing -F; -CI; -Br; -I; or -CN.
14. The compound of claim 2, wherein the at least one or two of Z1, Z2, Z3, Z4, and Z5, represent CR4 with said R4 representing an aryl radical or a heteroaryl radical; wherein the aryl radical and the heteroaryl radical may be substituted with up to 4 radical substituents comprising: -D, -F, -CI, -Br, -I, -CN, -N02, -OR5, -(CH2)mOR5, -N(R5)(R6), -(CH2)mN(R5)(R6), - S02(CH2)mR5, -(CO)(CH2)mR5, -(CO)N(R5)(R6), -OCF3, a branched or unbranched C,-C6-alkyl radical, a C3-C6-cycloalkyl radical, a CrC6-hydroxyalkyl radical, or a Ci-C6-haloalkyl radical.
15. The compound of claim 1, wherein W represents the moiety represented by the ring system M-II.
16. The compound of claim 15, wherein X1 represents C.
17. The compound of claim 16, wherein M-II represents a moiety represented by one of the
Figure imgf000309_0001
wherein:
independently represent N or CR1 ' ; and
independently represents NR10; O; or S.
18. The compound of claim 15, wherein X1 represents N.
19. The compound of claim 18, wherein M-II represents a moiety represented by one of the following:
Figure imgf000309_0002
wherein A1, A2, and A3, independently represent N or CR1 1.
20. The compound of claim 19, wherein A1 independently represents CR1 1; and A2 and A3 independently represent N or CR11.
21. The compound of claim 19, wherein A2 independently represents CR1 1; and A1 and A3 independently represent N or CR11.
22. The compound of claim 19, wherein A3 independently represents CR10; and A1 and A2 independently represent N or CR1'.
23. The compound of claim 19, wherein each of A1, A2, and A3, represents N.
24. The compound of any one of claims 15-23, wherein either Z6 or Z7 represents CR7 with said R7 representing the bond directly attaching the W moiety with the oxadiazoline moiety.
25. The compound of any one of claims 15-23, wherein either Z8 or Z9 represents CR7 with said R7 representing the bond directly attaching the W moiety with the oxadiazoline moiety.
26. The compound of claim 1 , wherein W represents the moiety represented by the ring system M-III.
27. The compound of claim 26, wherein M-III represents a moiety represented by one of the followi
Figure imgf000310_0001
28. The compound of claim 26, wherein M-III represents a moiety represented by one of the followi
Figure imgf000310_0002
The compound of claim 26, wherein M-III represents a moiety represented by one of the
Figure imgf000311_0001
30. The compound of claim 1, wherein W represents the moiety represented by the ring system M-TV.
31. The compound of claim 30, wherein X2 represents C.
32. The compound of claim 31 , wherein M-IV represents a moiety represented by one of the following:
Figure imgf000311_0002
wherein A7 represents NR14; O; or S.
33. The compound of claim 31 , wherein M-IV represents a moiety represented by one of the following:
Figure imgf000311_0003
wherein A5 represents NR14; O; or S.
The compound of claim 30, wherein X2 represents N.
The compound of claim 34, wherein M-IV represents a moiety represented by one of the
Figure imgf000311_0004
Figure imgf000312_0001
36. The compound of claim 1 , wherein W represents the moiety represented by the ring system M-V.
The compound of claim 36, wherein M-V represents a moiety represented by one of the
Figure imgf000312_0002
38. The compound of claim 1, wherein W represents the moiety represented by the ring system M-VI.
39. The compound of claim 38, wherein M-VI represents a moiety represented by one of the follo
Figure imgf000312_0003
40. The compound of any one of claims 1-39, wherein the compound is represented by Formula (I): Formula (I)
Figure imgf000313_0001
41. The compound of any one of claims 1 -39, wherein the compound is represented by Formula (Ila): Formula (Ila)
42. The compound of any one of claims 1-39, wherein the compound is represented by Formula (lib): Formula (lib)
Figure imgf000313_0003
43. The compound of any one of claims 1-42, wherein R1 represents -H, and n is 0-3.
44. The compound of any one of claims 1-43, wherein R1 represents a (3-6 membered)- heterocycloalkyl radical; an aryl radical; or a heteroaryl radical; and wherein n is 0-3.
45. The compound of any one of claims 1-44, wherein the compound is a single enantiomer or a single diastereomer.
46. The compound of claim 45, wherein the compound is a single enantiomer.
47. The compound of claim 45, wherein the compound is a single diastereomer.
48. The compound of claim 1 , wherein the compound is selected from the group consisting of:
(+/-)-3 -phenyl-4H- 1 '-azaspiro [[ 1 ,2,4] oxadiazole-5 ,3 '-bicyclo[2.2 ,2]octane] ; (+/-)-3-(4-chlorophenyl)-4H-l'-azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane];
(+/-)-3-(benzo[b]thiophen-2-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazol-5,3'- bicyclo[2.2.2]octane] ;
(+/-)-3-(benzofuran-2-yl)-4H-l '-azaspiro[[l,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane];
(+/-)-3-(lH-indol-2-yl)-4H-l'-azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane];
(+/-)-3-(7-fluorobenzo[b]thiophen-2-yl)-4H- -azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(+/-)-3 -(7-chlorobenzo[b]thiophen-2-yl)-4H- 1 '-azaspiro[[ 1 ,2,4]oxadiazole-5,3 '- bicyclo[2.2.2]octane];
(+/-)-3 -(7-bromobenzo [b]thiophen-2-y 1)-4H- 1 '-azaspiro [[ 1 ,2,4] oxadiazole-5 ,3 '- bicyclo[2.2.2]octane];
(+/-)-3-(7-fIuorobenzofuran-2-yl)-4H-l'-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(+/-)-3-(benzo[b]thiophen-5-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(+/-)-3-(2-methyl-l ,2,3,4-tetrahydroisoquinolin-6-yl)-4H-l '-aza-spiro[[l ,2,4]oxadiazole- 5,3'-bicyclo[2.2.2]octane];
(+/-)-3-(5-fluorobenzo[b]thiophen-2-yl)-4H- -azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(+/-)-3-(benzo[b]thiazol-2-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(+/-)-3-(benzo[b]thiophen-3-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(+/-)-3-(l -methyl-l ,2,3,4-tetrahydroquinolin-6-yl)-4H-l'-azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(+/-)-3-(4-chlorophenyl)-4-phenyl-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(+/-)-3-(benzo[b]thiophen-2-yl)-4-phenyl-4H-l '-azaspiro[[l ,2,4]oxadiazoIe-5,3'- bicyclo[2.2.2]octane];
(+/-)-4-benzy 1-3 -(4-chloropheny 1)-4H- 1 '-azaspiro[ [ 1 ,2,4] oxadiazole-5 ,3 '- bicyclo[2.2.2]octane];
(+/-)-3-(benzo[b]thiophen-2-yl)-4-benzyl-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(+/-)-3-(benzo[b]thiophen-2-yl)-4-isopropyl-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(+/-)-3-(benzo[b]thiophen-2-yl)-4-isobutyl-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane]; (+/-)-3-(benzo[b]thiophen-2-yl)-4-((tetrahydro-2H-pyran-4-yl)methyl)-4H-l'- azaspiro[[l,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane];
(+/-)-3-(benzo[b]thiophen-2-yl)-4-(pyridin-3-ylmethyl)-4H-l'-azaspiro[[l ,2,4]oxadiazole- 5,3'-bicyclo[2.2.2]octane];
(+/-)-3-(benzo[b]thiophen-2-yl)-4-ethyl-4H-l'-azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(+/-)-3-(benzo[b]thiophen-2-yl)-4-(2,2,2-trifluoroethyl)-4H-l '-azaspiro[[l,2,4]oxadiazole- 5,3'-bicyclo[2.2.2]octane];
(+/-)-3-(4-chlorophenyl)-4-methyl-4H-r-azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(+/-)-3-(benzo[b]thiophen-2-yl)-4-methyl-4H-l '-azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(+/-)-3-(benzofuran-2-yl)-4-methyl-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(+/-)-3-(7-chlorobenzo[b]thiophen-2-yl)-4-methyl-4H-r-azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(+/-)-3 -( 1 H-indol-2-y l)-4-methy 1-4H- 1 '-azaspiro [[ 1 ,2,4]oxadiazole-5 ,3 '- bicyclo[2.2.2]octane];
(+/-)-3-(7-fluorobenzofuran-2-yl)-4-methyl-4H- -azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane] ;
(+/-)-3-(7-fluorobenzo[b]thiophen-2-yl)-4-methyl-4H-l'-azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(+/-)-3-(benzo[b]thiazol-2-yl)-4-methyl-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(+/-)-3-(6-methoxybenzo[b]thiazol-2-yl)-4-methyl-4H-l'-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(+/-)-3-(5-fluorobenzo[b]thiophen-2-yl)-4-methyl-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(+/-)-2-(4-methyl-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octan]-3- yl)benzo[b]thiophene-7-carbonitrile;
(+/-)-3-(7-bromobenzo[b]thiophen-2-yl)-4-methyl-4H-r-azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2] octane] ;
(+/-)-3-(benzo[b]thiophen-5-yl)-4-methyl-4H-r-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(+/-)-3-(isoquinolin-3-yl)-4-methyl-4H- -azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane]; (+/-)-4-methyl-3-(l -methyl-l ,2,3,4-tetrahydroquinolin-6-yl)-4H-r- azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane];
(+/-)-4-methy 1-3 -(2-methyl- 1 ,2,3 ,4-tetrahydroisoquinolin-6-y 1)-4H- 1 '- azaspiro[[l,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane];
(+/-)-2-(4H-l'-azaspiro[[l,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octan]-3- yl)benzo[b]thiophene-7-carbonitrile;
(+/-)-3-(isoquinolin-3-yl)-4H-l'-azaspiro[[l,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane];
(+/-)-3-(5-phenyl-l ,3,4-oxadiazol-2-yl)-4H-l'-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(+/-)-3-(l,2,3,4-tetrahydroquinolin-6-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(+/-)-3-(6-methoxybenzo[d]thiazol-2-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo [2.2.2] octane] ;
(+/-)-3-(5,6,7,8-tetrahydroisoquinolin-3-yl)-4H-l'-azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane] ;
(+/-)-3-(thieno[2,3-b]pyridin-2-y])-4H- -azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(+/-)-3-(thieno[3,2-b]pyridin-2-yl)-4H-l '-azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(+/-)-3-(pyrazolo[l ,5-a]pyridin-2-yl)-4H-l'-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2] octane] ;
(+/-)-3-(6-fluorobenzo[b]thiophen-2-yl)-4H-l'-azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(+/-)-3 -( 1 -methyl- 1 H-indol-2-yl)-4H- 1 '-azaspiro[[ 1 ,2,4]oxadiazole-5,3 '- bicyclo[2.2.2]octane];
(+/-)-3-(l-methyl-lH-benzo[d]imidazol-2-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'- bicycIo[2.2.2]octane];
(+/-)-3-(6-fluorobenzofuran-2-yl)-4H-l'-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(+/-)-3 -(5-fluorobenzofuran-2-yl)-4H- 1 '-azaspiro[[ 1 ,2,4]oxadiazole-5,3 '- bicyclo[2.2.2]octane];
(+/-)-3-(4-fluorobenzofuran-2-yl)-4H-r-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(+/-)-3-(3-fluorobenzofuran-2-yl)-4H- -azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2] octane] ;
(+/-)-3-(5,7-difluorobenzofuran-2-yl)-4H- -azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane]; (+/-)-3 -(pyrimidin-2-yl)-4H- 1 '-azaspiro[ [ 1 ,2,4]oxadiazole-5 ,3 '-bicyclo[2.2.2] octane] ;
(+/-)-3-benzyl-4H-l '-azaspiro[[l,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane];
(+/-)-3-([l,l '-biphenyl]-4-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane];
(+/-)-4-methyl-3-(5,6,7,8-tetrahydroisoquinolin-3-yl)-4H-r-azaspiro[[l ,2,4]oxadiazole- 5,3'-bicyclo[2.2.2]octane];
(+/-)-4-methyl-3-(5-phenyl-l,3,4-oxadiazol-2-yl)-4H-l'-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(+/-)-4-methyl-3-(l ,2,3,4-tetrahydroquinolin-6-yl)-4H-l'-azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(+/-)-4-methyl-3-(l,2,3,4-tetrahydroisoquinolin-6-yl)-4H-l '-azaspiro[[l,2,4]oxadiazole- 5,3'-bicyclo[2.2.2]octane];
(+/-)-2-(4H- l '-azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octan]-3- yl)benzo[b]thiophene-7-carbonitrile;
(+/-)-3-(isoquinolin-3-yl)-4H-r-azaspiro[[l,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane];
(+/-)-3 -(5 -phenyl- 1 ,3 ,4-oxadiazol-2-yl)-4H- 1 '-azaspiro[[ 1 ,2,4]oxadiazole-5 ,3 '- bicyclo[2.2.2]octane];
(+/-)-(R)-3-(6-methoxybenzo[d]thiazol-2-yl)-4H-l'-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(+/-)-3-(thieno[2,3-b]pyridin-2-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2] octane];
(+/-)-3-(thieno[3,2-b]pyridin-2-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazoIe-5,3'-bicyclo[2.2.2] octane];
(+/-)-3-(pyrazolo[l,5-a]pyridin-2-yl)-4H-l'-azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(+/-)-3-(6-fluorobenzo[b]thiophen-2-yl)-4H-l '-azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(+/-)-3 -( 1 -methyl- 1 H-indol-2-yl)-4H- 1 '-azaspiro[[ 1 ,2,4]oxadiazole-5,3 '- bicyclo[2.2.2]octane];
(+/-)-3 -( 1 -methyl- 1 H-benzo[d] imidazol-2-yl)-4H- 1 '-azaspiro[[ 1 ,2,4]oxadiazole-5 ,3 '- bicyclo[2.2.2]octane];
(+/-)-3-(6-fluorobenzofuran-2-yl)-4H-l '-azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(+/-)-3 -(5-fluorobenzofuran-2-yl)-4H- 1 '-azaspiro[[ 1 ,2,4]oxadiazole-5 ,3 '- bicyclo[2.2.2]octane];
(+/-)-3 -(4-fluorobenzofuran-2-yl)-4H- 1 '-azaspiro [[ 1 ,2,4] oxadiazole-5 ,3 '- bicyclo[2.2.2]octane]; (+/-)-3 -(5 ,7-difluorobenzofuran-2-yl)-4H- 1 '-azaspiro [[ 1 ,2,4] oxadiazole-5 ,3 '- bicyclo[2.2.2]octane];
(+/-)-3-([l,l'-biphenyl]-4-yl)-4H-l'-azaspiro[[l,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane];
(+/-)-4-methyl-3-(l,2,3,4-tetrahydroquinolin-6-yl)-4H-l'-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(+/-)-2-(4H-l'-azaspiro[[l,2,4]oxadiazoIe-5,3'-bicyclo[2.2.2]octan]-3- yl)benzo[b]thiophene-7-carboxamide;
(+/-)-3-(quinolin-3-yl)-4H-l '-azaspiro[[l,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane];
(+/-)-3-(benzofuran-5-yl)-4H-l'-azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane];
(+/-)-3 lH-indol-5-yl)-4H-l'-azaspiro[[l,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane];
(+/-)-3-(benzo[d]thiazol-6-yl)-4H-l'-azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(+/-)-3-(quinolin-6-yl)-4H-l'-azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane];
(+/-)-3-(benzo[d]thiazol-5-yl)-4H-l'-azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(+/-)-3-(benzofuran-6-yl)-4H-l'-azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane];
(+/-)-3 -(benzo [b]thiophen~6-y 1)-4H- 1 '-azaspiro[ [ 1 ,2,4]oxadiazole-5 ,3 '- bicyclo[2.2.2]octane];
(+/-)-3-(4-fluorophenyl)-4H-l'-azaspiro[[l,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane];
(+/-)-3 -(3 ,4-dichlorophenyl)-4H- 1 '-azaspiro[[ 1 ,2,4]oxadiazole-5 ,3 '-bicyclo [2.2.2]octane] ;
(+/-)-3 -(3 -chlorobenzo[b]thiophen-2-yl)-4H- 1 '-azaspiro [[ 1 ,2,4] oxadiazole-5 ,3 '- bicyclo[2.2.2]octane];
(+/-)-3 -(4-(4-fluorophenoxy)phenyl)-4H- 1 '-azaspiro[ [ 1 ,2,4]oxadiazole-5 ,3 '- bicyclo[2.2.2]octane];
(+/-)-3-(lH-indol-6-yl)-4H-l'-azaspiro[[l,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane];
(+/-)-3-(3-(trifluoromethyl)benzofuran-5-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(+/-)-3-(2-(trifluoromethyl)benzofuran-5-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2] octane] ;
(+/-)-3-(3-(trifluoromethyl)benzo[b]thiophen-6-yl)-4H- -azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(+/-)-3 -(3 -fluorobenzofuran-5-yl)-4H- 1 '-azaspiro[[ 1 ,2,4]oxadiazole-5,3 '- bicyclo[2.2.2]octane];
(+/-)-3-(pyrimidin-5-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane];
(+/-)-3-(2-fluorobenzofuran-5-yl)-4H-l'-azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane]; (+/-)-3-(2-(trifluoromethyl)benzo[b]thiophen-6-yl)-4H- -azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane] ;
(+/-)-3-(2-fluorobenzo[b]thiophen-6-yl)-4H-l'-azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(+/-)-3 -(3 -fluorobenzo[b]thiophen-6-yl)-4H- 1 '-azaspiro[ [ 1 ,2,4]oxadiazole-5 ,3 '- bicyclo[2.2.2]octane];
(+/-)-3 -(thieno[3 ,2-b]pyridin-6-yl)-4H- 1 '-azaspiro[[ 1 ,2,4] oxadiazole-5 ,3 '- bicyclo[2.2.2]octane] ;
(+/-)-3-(pyrazolo[l,5-a]pyridin-5-yl)-4H- -azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(+/-)-3-(furo[2,3-b]pyridin-5-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(+/-)-3-(3,4-dihydro-2H-benzo[b][l,4]oxazin-5-yl)-4H-l'-azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(+/-)-7-(4H-l'-azaspiro[[l,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octan]-3-yl)indolin-2-one;
(+/-)-3-(imidazo[l,2-a]pyridin-6-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(+/-)-3-(pyrrolo[l ,2-b]pyridazin-6-yl)-4H- -azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(+/-)-3-(3-methylbenzofuran-5-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(+/-)-3-(3-methylbenzo[b]thiophen-5-yl)-4H-l'-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(+/-)-3-(3-methylbenzofuran-6-yl)-4H-l'-azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2] octane];
(+/-)-3-(3-methylbenzo[b]thiophen-6-yl)-4H-l'-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2 ,2]octane] ;
(+/-)-3-(5,6,7,8-tetrahydroisoquinolin-3-yl)-4H-r-azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo [2.2.2] octane] ;
(+/-)-4-methy 1-3 -(2-methy 1- 1 ,2,3 ,4-tetrahydroisoquinolin-6-yl)-4H- 1 '- azaspiro[[l,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane];
(+/-)-3-(quinolin-7-yl)-4H-l'-azaspiro[[l,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane];
(+/-)-3-(l -methyl-lH-indol-6-yl)-4H-l'-azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane;
(+/-)-3-(imidazo[l,5-a]pyridin-7-yl)-4H- -azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane]; (+/-)-3 -(3 ,4-dihydro-2H-benzo[b] [ 1 ,4]oxazin-5 -y l)-4-methyl-4H- 1 '- azaspiro[[l,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane];
(+/-)-3-(pyrrolo[l ,2-a]pyrimidin-7-yl)-4H- -azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(R)-3-phenyl-4H-l '-azaspiro[[l,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane];
(S)-3-phenyl-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane];
(R)-3-(4-chlorophenyl)-4H-l'-azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane];
(S)-3-(4-chlorophenyl)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane];
(R)-3 -(benzo [b]thiophen-2-yl)-4H- 1 '-azaspiro[[ 1 ,2,4] oxadiazole-5 ,3 '- bicyclo[2.2.2]octane];
(S)-3-(benzo[b]thiophen-2-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(R)-3-(benzofuran-2-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane];
(S)-3-(benzofuran-2-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane];
(R)-3-(l H-indol-2-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane];
(S)-3-(l H-indol-2-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane];
(R)-3-(7-fluorobenzo[b]thiophen-2-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(S)-3-(7-fIuorobenzo[b]thiophen-2-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(R)-3-(7-chlorobenzo[b]thiophen-2-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(S)-3-(7-chlorobenzo[b]thiophen-2-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(R)-3 -(7-bromobenzo [b]thiophen-2-y 1)-4H- 1 '-azaspiro[ [ 1 ,2,4] oxadiazole-5 ,3 '- bicyclo[2.2.2]octane];
(S)-3-(7-bromobenzo[b]thiophen-2-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(R)-3 -(7-fluorobenzofuran-2-yl)-4H- 1 '-azaspiro[[ 1 ,2,4] oxadiazole-5 ,3 '- bicyclo[2.2.2]octane];
(S)-3-(7-fluorobenzofuran-2-yl)-4H-l'-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(R)-3-(benzo[b]thiophen-5-yl)-4H-l'-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(S)-3-(benzo[b]thiophen-5-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane]; (R)-3-(2-methyl-l ,2,3,4-tetrahydroisoquinolin-6-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole- 5,3'-bicyclo[2.2.2]octane];
(S)-3-(2-methyl-l ,2,3,4-tetrahydroisoquinolin-6-yl)-4H-r-azaspiro[[l ,2,4]oxadiazole- 5 ,3 '-bicyclo[2.2.2] octane];
(lr,3R,^,5S,75')-3,-(4-chlorophenyl)-4,H-l-azaspiro[adamantane-4,5'-[l ,2,4]oxadiazole];
(lr,3R, ,5S,75)-3'-(4-chlorophenyl)-4'H-l-azaspiro[adamantane-4,5'-[l,2,4]oxadiazole];
(l ,3R,^5,5S,75)-3'-(benzo[b]thiophen-2-yl)-4'H-l -azaspiro[adamantane-4,5'- [l,2,4]oxadiazole];
(l r,3R, r,5S,75,)-3'-(benzo[b]thiophen-2-yl)-4'H-l-azaspiro[adamantane-4,5'- [l ,2,4]oxadiazole];
(l ,3R,^,5S,7i)-3'-(7-chlorobenzo[b]thiophen-2-yl)-4'H-l -azaspiro[adamantane-4,5'- [l ,2,4]oxadiazole];
( 1 r,3 R,4r,5S,7s)-3 '-(7-chlorobenzo[b]thiophen-2-yl)-4'H- 1 -azaspiro[adamantane-4,5'- [l ,2,4]oxadiazole];
(l ,3R,^,5S,7j)-3'-(7-fluorobenzo[b]thiophen-2-yl)-4'H-l -azaspiro[adamantane-4,5'- [l ,2,4]oxadiazole];
(l r,3R,^ ,5S,75')-3,-(7-fluorobenzo[b]thiophen-2-yl)-4'H-l -azaspiro[adamantane-4,5'- [l ,2,4]oxadiazole];
(l ,3R, 5,5S,75)-3'-(benzofuran-2-yl)-4'H-l -azaspiro[adamantane-4,5'-[l ,2,4]oxadiazole];
(l r,3R, r,5S,7j)-3'-(benzofuran-2-yl)-4'H-l -azaspiro[adamantane-4,5'-[l ,2,4]oxadiazole];
(R)-3-(5-fluorobenzo[b]thiophen-2-yl)-4H-r-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(S)-3-(5-fluorobenzo[b]thiophen-2-yl)-4H- -azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(R)-3-(benzo[b]thiazol-2-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane];
(S)-3-(benzo[b]thiazol-2-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane];
(R)-3 -(benzo [b]thiophen-3 -yl)-4H- 1 '-azaspiro [[ 1 ,2,4]oxadiazole-5,3 '- bicyclo[2.2.2]octane];
(S)-3 -(benzo[b]thiophen-3-yl)-4H- 1 '-azaspiro[[ 1 ,2,4]oxadiazole-5 ,3 '- bicyclo[2.2.2]octane];
(R)-3 -( 1 -methyl- 1 ,2,3 ,4-tetrahydroquinolin-6-y 1)-4H- 1 '-azaspiro[ [ 1 ,2,4] oxadiazole-5 ,3 '- bicyclo[2.2.2]octane];
(S)-3-(l -methyl-l ,2,3,4-tetrahydroquinolin-6-yl)-4H-l '-azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2] octane] ;
(R)-3-(4-chlorophenyl)-4-phenyl-4H-r-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane]; (S)-3 -(4-chlorophenyl)-4-pheny 1-4H- 1 '-azaspiro [[ 1 ,2,4] oxadiazole-5 ,3 '- bicyclo[2.2.2]octane] ;
(R)-3 -(benzo[b]thiophen-2-yl)-4-phenyl-4H- 1 '-azaspiro[ [ 1 ,2,4]oxadiazole-5 ,3 '- bicyclo[2.2.2]octane];
(S)-3 -(benzo[b]thiophen-2-yl)-4-pheny 1-4H- 1 '-azaspiro [[ 1 ,2,4] oxadiazole-5 ,3 '- bicyclo[2.2.2]octane];
(R)-4-benzyl-3-(4-chlorophenyl)-4H- -azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(S)-4-benzyl-3-(4-chlorophenyl)-4H-l '-azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(R)-3-(benzo[b]thiophen-2-yl)-4-benzyl-4H-l'-azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2] octane] ;
(S)-3-(benzo[b]thiophen-2-yl)-4-benzyl-4H-l'-azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(R)-3-(benzo[b]thiophen-2-yl)-4-isopropyl-4H-l'-azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(S)-3-(benzo[b]thiophen-2-yl)-4-isopropyl-4H-l '-azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(R)-3-(benzo[b]thiophen-2-yl)-4-isobutyl-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(S)-3-(benzo[b]thiophen-2-yl)-4-isobutyl-4H- -azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(R)-3 -(benzo[b]thiophen-2-yl)-4-((tetrahydro-2H-pyran-4-yl)methyl)-4H- 1 '- azaspiro[[l,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane];
(S)-3-(benzo[b]thiophen-2-yl)-4-((tetrahydro-2H-pyran-4-yl)methyl)-4H-l '- azaspiro[[l,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane];
(R)-3-(benzo[b]thiophen-2-yl)-4-(pyridin-3-ylmethyl)-4H- -azaspiro[[l,2,4]oxadiazole- 5,3'-bicyclo[2.2.2]octane];
(S)-3-(benzo[b]thiophen-2-yl)-4-(pyridin-3-ylmethyl)-4H-l'-azaspiro[[l,2,4]oxadiazole- 5,3'-bicyclo[2.2.2]octane];
(R)-3-(benzo[b]thiophen-2-yl)-4-ethyl-4H-l'-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(S)-3-(benzo[b]thiophen-2-yl)-4-ethyl-4H-l'-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(R)-3-(benzo[b]thiophen-2-yl)-4-(2,2,2-trifluoroethyl)-4H-l'-azaspiro[[l,2,4]oxadiazole- 5,3'-bicyclo[2.2.2]octane]; (S)-3-(benzo[b]thiophen-2-yl)-4-(2,2,2-trifluoroethyl)-4H-l '-azaspiro[[l,2,4]oxadiazole- 5,3'-bicyclo[2.2.2]octane];
(R)-3-(4-chlorophenyl)-4-methyl-4H-l'-azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(S)-3-(4-chlorophenyl)-4-methyl-4H-l '-azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(R)-3 -(benzo [b]thiophen-2-yl)-4-methyl-4H- 1 '-azaspiro [ [ 1 ,2,4]oxadiazole-5 ,3 '- bicyclo[2.2.2]octane];
(S^S-ibenzoCbJthiophen^-y ^-methyl^H-r-azaspirotf l ^^Joxadiazole-S^'- bicyclo[2.2.2]octane];
(R)-3-(benzofuran-2-yl)-4-methyl-4H-l'-azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
( S)-3 -(benzofuran-2-y l)-4-methy 1-4H- 1 '-azaspiro[[ 1 ,2,4] oxadiazole-5 ,3'- bicyclo[2.2.2]octane];
(R)-3-(7-chlorobenzo[b]thiophen-2-yl)-4-methyl-4H-l'-azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(S)-3-(7-chlorobenzo[b]thiophen-2-yl)-4-methyl-4H-r-azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(R)-3-(lH-indol-2-yl)-4-methyl-4H-l '-azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(S)-3 -( 1 H-indol-2-yl)-4-methyl-4H- 1 '-azaspiro[[ 1 ,2,4]oxadiazole-5,3 '- bicyclo[2.2.2]octane];
(R)-3 -(7-fluorobenzofuran-2-yl)-4-methyl-4H- 1 '-azaspiro [[ 1 ,2,4] oxadiazole-5 ,3 '- bicyclo[2.2.2]octane];
(S)-3-(7-fluorobenzofuran-2-yl)-4-methyl-4H-l'-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(R)-3-(7-fluorobenzo[b]thiophen-2-yl)-4-methyl-4H- -azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(S)-3-(7-fluorobenzo[b]thiophen-2-yI)-4-methyl-4H-r-azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(R)-3-(benzo[b]thiazol-2-yl)-4-methyl-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2] octane] ;
(S)-3 -(benzo [b]thiazol-2-y l)-4-methyl-4H- 1 '-azaspiro [[ 1 ,2,4] oxadiazole-5 ,3 '- bicyclo[2.2.2]octane];
(R)-3-(6-methoxybenzo[b]thiazol-2-yI)-4-methyl-4H- -azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane]; (S)-3-(6-methoxybenzo[b]thiazol-2-yl)-4-methyl-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(R)-3-(5-fluorobenzo[b]thiophen-2-yl)-4-methyl-4H-l '-azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(S)-3-(5-fluorobenzo[b]thiophen-2-yl)-4-methyl-4H- -azaspiro[[l ,2,4]oxadiazo]e-5,3'- bicyclo[2.2.2]octane];
(R)-2-(4-methyl-4H-l '-azaspiro[[l,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octan]-3- yl)benzo[b]thiophene-7-carbonitrile;
(S)-2-(4-methyl-4H-l '-azaspiro[[l,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octan]-3- yl)benzo[b]thiophene-7-carbonitrile;
(R)-3-(7-bromobenzo[b]thiophen-2-yl)-4-methyl-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(S)-3-(7-bromobenzo[b]thiophen-2-yl)-4-methyl-4H- -azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(R)-3-(benzo[b]thiophen-5-yl)-4-methyl-4H-l'-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2] octane] ;
(S)-3-(benzo[b]thiophen-5-yl)-4-methyl-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(R)-3 -(isoquinolin-3 -yl)-4-methyl-4H- 1 '-azaspiro [[ 1 ,2,4] oxadiazole-5 ,3 '- bicyclo[2.2.2]octane];
(S)-3-(isoquinolin-3-yl)-4-methyl-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(R)-4-methy 1-3 -( 1 -methyl- 1 ,2,3 ,4-tetrahydroquinolin-6-y 1)-4H- 1 '- azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane];
(S)-4-methyl-3-(l-methyl-l ,2,3,4-tetrahydroquinolin-6-yl)-4H-l '- azaspiro[[l,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane];
(R)-4-methyI-3-(2-methyl-l ,2,3,4-tetrahydroisoquinolin-6-yl)-4H-r- azaspiro[[ 1 ,2,4]oxadiazole-5 ,3 '-bicyclo[2.2.2]octane] ;
(S)-4-methyl-3-(2-methyl-l ,2,3,4-tetrahydroisoquinolin-6-yl)-4H-l '- azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane];
(l r,3R,^,5S,75)-3'-(4-chlorophenyl)-4'-methyl-4'H-l -azaspiro[adamantane-4,5'- [l ,2,4]oxadiazole];
11 r,3 R,4r,5 S, 7s)-3 '-(4-chloropheny l)-4'-methyl-4'H- 1 -azaspiro[adamantane-4, 5 '- [l ,2,4]oxadiazole];
( 1 r,3 R,4s,5 S, 7s)-3 '-(benzo [b]thiophen-2-y l)-4'-methyl-4'H- 1 -azaspiro[adamantane-4,5 '- [l ,2,4]oxadiazole]; (l r,3R, r,5S, 7i)-3'-(benzo[b]thiophen-2-yl)-4'-methyl-4'H-l -azaspiro[adamantane-4,5'- [l ,2,4]oxadiazole];
(l r,3R,^,5S, 7s)-3'-(benzofuran-2-yl)-4'-methyl-4'H-l -azaspiro[adamantane-4,5'- [l ,2,4]oxadiazole];
(lr,3R,^r,5S, 7i)-3'-(benzofuran-2-yl)-4'-methyI-4'H-l -azaspiro[adamantane-4,5'- [ l ,2,4]oxadiazole];
( 1 r,3R,4s,5 S, 7s)-3 ,-(7-chlorobenzo[b]thiophen-2-yl)-4'-methyl-4'H- 1 - azaspiro[adamantane-4,5'-[ l ,2,4]oxadiazole];
(lr,3R,^r,5S, 75)-3'-(7-chlorobenzo[b]thiophen-2-yl)-4'-methyl-4'H- l - azaspiro[adamantane-4,5'-[l ,2,4]oxadiazole];
(R)-2-(4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octan]-3- yl)benzo[b]thiophene-7-carbonitrile;(S)-2-(4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octan]-3-yl)benzo[b]thiophene-7-carbonitrile;
(R)-3-(isoquinolin-3-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane];
(S)-3-(isoquinolin-3-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane];
(R)-3-(5-phenyl-l ,3,4-oxadiazol-2-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyc lo [2.2.2] octane] ;
(S)-3-(5-phenyl-l ,3,4-oxadiazol-2-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(R)-3-(l ,2,3,4-tetrahydroquinolin-6-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(S)-3-(l ,2,3,4-tetrahydroquinolin-6-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(R)-3-(6-methoxybenzo[d]thiazol-2-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(S)-3-(6-methoxybenzo[d]thiazol-2-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(R)-3 -(5 ,6,7, 8-tetrahydroisoquinolin-3 -y 1)-4H- 1 '-azaspiro[[ 1 ,2,4]oxadiazole-5 ,3 '- bicyclo[2.2.2]octane];
(S)-3 -(5 ,6,7, 8-tetrahydroisoquinolin-3 -yl)-4H- 1 '-azaspiro[[ 1 ,2,4]oxadiazole-5 ,3 '- bicyclo[2.2.2]octane];
(R^-CthienoP^-^pyridin^-y ^H- l '-azaspiroftl^^oxadiazole-S^'- bicyclo[2.2.2]octane];
(S)-3-(thieno[2,3-b]pyridin-2-yl)-4H- l '-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(R)-3 -(thieno[3 ,2-b]pyridin-2-yl)-4H- 1 '-azaspiro[[ 1 ,2,4]oxadiazole-5,3 '- bicyclo[2.2.2]octane]; (S)-3 -(thieno[3 ,2-b]pyridin-2-yl)-4H- 1 '-azaspiro[[ 1 ,2,4]oxadiazole-5,3 '- bicyclo[2.2.2]octane];
(R)-3-(pyrazolo[l ,5-a]pyridin-2-yl)-4H-l'-azaspiro[[l . ^Jo adiazole-S^'- bicyclo[2.2.2]octane];
(S)-3-(pyrazolo[l,5-a]pyridin-2-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(R)-3-(6-fluorobenzo[b]thiophen-2-yl)-4H-l'-azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(S)-3-(6-fluorobenzo[b]thiophen-2-yl)-4H-l'-azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(R)-3-(l -methyl- 1 H-indol-2-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(S)-3-(l -methyl-lH-indol-2-yl)-4H-l'-azaspiro[[l ,2,4]oxadiazole-5,3'- bicycIo[2.2.2]octane];
(R)-3 -( 1 -methyl- 1 H-benzo[d] imidazol-2-yl)-4H- 1 '-azaspiro [[ 1 ,2,4]oxadiazole-5 ,3 '- bicyclo[2.2.2]octane];
(S)-3-(l -methyl-lH-benzo[d]imidazol-2-yl)-4H-r-azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(R)-3-(6-fluorobenzofuran-2-yl)-4H- -azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(S)-3-(6-fluorobenzofuran-2-yl)-4H- -azaspiro[[l ,2,4]oxadiazoIe-5,3'- bicyclo[2.2.2]octane];
(R)-3 -(5 -fluorobenzofuran-2-yl)-4H- 1 '-azaspiro[ [ 1 ,2,4]oxadiazole-5 ,3 '- bicyclo[2.2.2]octane];
(S)-3-(5-fluorobenzofuran-2-yl)-4H-l'-azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(R)-3-(4-fluorobenzofuran-2-yl)-4H-r-azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(S)-3-(4-fluorobenzofuran-2-yl)-4H-r-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(R)-3-(3-fluorobenzofuran-2-yl)-4H-r-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(S)-3 -(3 -fluorobenzofuran-2-y 1)-4H- 1 '-azaspiro[[ 1 ,2,4] oxadiazole-5 ,3 '- bicyclo[2.2.2]octane];
(R)-3-(5,7-difluorobenzofuran-2-yl)-4H-l'-azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane]; (S)-3-(5,7-difluorobenzofuran-2-yl)-4H-l '-azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2 ,2]octane] ;
(R)-3-(pyrimidin-2-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane];
(S)-3-(pyrimidin-2-yl)-4H-l'-azaspiro[[l,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane];
(R)-3-benzyl-4H-l'-azaspiro[[l,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane];
(S)-3-benzyl-4H- -azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane];
(R)-3 -([1 ,1 '-bipheny 1] -4-yl)-4H- 1 '-azaspiro [[ 1 ,2,4]oxadiazole-5 ,3 '-bicyclo [2.2.2] octane] ;
(S)-3-([l ,l '-biphenyl]-4-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'-bicyc[o[2.2.2]octane];
(R)-4-methyl-3-(5,6,7,8-tetrahydroisoquinolin-3-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole- 5,3'-bicyclo[2.2.2]octane];
(S)-4-methyl-3-(5,6,7,8-tetrahydroisoquinolin-3-yl)-4H- -azaspiro[[l ,2,4]oxadiazole- 5 ,3 '-bicyclo [2.2.2]octane] ;
(R)-4-methyl-3-(5-phenyl-l ,3,4-oxadiazol-2-yl)-4H-l'-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(S)-4-methyl-3-(5-phenyl-l ,3,4-oxadiazol-2-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(R)-4-methyl-3-(l ,2J3,4-tetrahydroquinolin-6-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(S)-4-methy 1-3 -( 1 ,2,3 ,4-tetrahydroquinolin-6-yl)-4H- 1 '-azaspiro[ [ 1 ,2,4] oxadiazole-5 ,3 '- bicyclo[2.2.2]octane];
(R)-4-methyl-3 -( 1 ,2,3 ,4-tetrahydroisoquinolin-6-y 1)-4H- 1 '-azaspiro[[ 1 ,2,4] oxadiazole- 5,3'-bicyclo[2.2.2]octane];
(S)-4-methyl-3-(l ,2,3,4-tetrahydroisoquinolin-6-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole- 5,3'-bicyclo[2.2.2]octane];
( 1 r,3R,4s,5S,7s)-3 '-(6-fluorobenzo[b]thiophen-2-yl)-4'H- 1 -azaspiro[adamantane-4,5'- [l ,2,4]oxadiazole];
(lr,3R,^r,5S,7s)-3'-(6-fluorobenzo[b]thiophen-2-yl)-4'H-l-azaspiro[adamantane-4,5'- [l ,2,4]oxadiazole];
(lr,3R,^,5S,7i)-3'-(5-fluorobenzo[b]thiophen-2-yl)-4'H-l-azaspiro[adamantane-4,5'- [l ,2,4]oxadiazo!e];
(l ,3R, r,5S,75)-3'-(5-fluorobenzo[b]thiophen-2-yl)-4'H-l -azaspiro[adamantane-4,5'- [l ,2,4]oxadiazole];
(lr,3R,^j,5S,75)-3'-(benzo[d]thiazol-2-yl)-4'H-l-azaspiro[adamantane-4,5'- [l ,2,4]oxadiazole];
(l ,3R, r,5S,7j)-3'-(benzo[d]thiazol-2-yl)-4'H-l -azaspiro[adamantane-4,5'- [l ,2,4]oxadiazole]; (l r,3R,^s,5S,75)-3'-(benzo[b]thiophen-5-yl)-4'H-l -azaspiro[adamantane-4,5'- [l,2,4]oxadiazole];
(lr,3R, r,5S,75)-3'-(benzo[b]thiophen-5-yl)-4'H-l -azaspiro[adamantane-4,5'- [l ,2,4]oxadiazole];
(lr,3R,^s,5S,75)-3H5,6,7,8 etrahydroisoquinolin-3-yl)-4'H-l-azaspiro[adamantane-4,5'- [l,2,4]oxadiazole];
(l r,3R, r,5S,75)-3'-(5,6,7,8-tetrahydroisoquinolin-3-yl)-4'H-l-azaspiro[adamantane-4,5'- [l ,2,4]oxadiazole];
(lr,3R,^,5S,75)-3'-(thiazol-2-yl)-4'H-l -azaspiro[adamantane-4,5'-[l ,2,4]oxadiazole]; (l ,3R,^r,5S,75)-3'-(thiazol-2-yl)-4,H-l -azaspiro[adamantane-4,5'-[l ,2,4]oxadiazole]; (l r,3R,45,5S,7s)-3'-(l-methyl-l H-imidazol-2-yl)-4'H-l -azaspiro[adarnantane-4,5'- [l ,2,4]oxadiazole];
(lr,3R,^r,5S,75)-3'-(l -methyl-lH-imidazol-2-yl)-4'H-l -azaspiro[adamantane-4,5'- [l ,2,4]oxadiazole];
(R)-2-(4H-l '-azaspiro[[l,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octan]-3- yl)benzo[b]thiophene-7-carbonitrile;
(S)-2-(4H-l'-azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octan]-3- yl)benzo[b]thiophene-7-carbonitrile;
(R)-3-(isoquinolin-3-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane];
(S)-3-(isoquinolin-3-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane];
(R)-3-(5-phenyl-l ,3,4-oxadiazol-2-yl)-4H- -azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(S)-3-(5-phenyl-l ,3,4-oxadiazol-2-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(R)-3-(6-methoxybenzo[d]thiazol-2-yl)-4H-l'-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(S)-3-(6-methoxybenzo[d]thiazol-2-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(R^-ithienop^-bjpyridin^-y ^H-l '-azaspiroCCl ^^oxadiazole-S^'-bicyclop^^] octane];
(S)-3-(thieno[2,3-b]pyridin-2-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2] octane];
(R)-3-(thieno[3,2-b]pyridin-2-yl)-4H-l'-azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2] octane];
(S)-3-(thieno[3,2-b]pyridin-2-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2] octane]; (R)-3-(pyrazolo[l,5-a]pyridin-2-yl)-4H- -azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(S)-3-(pyrazolo[l ,5-a]pyridin-2-yl)-4H-r-azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(R)-3-(6-fluorobenzo[b]thiophen-2-yl)-4H-l'-azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(S)-3-(6-fluorobenzo[b]thiophen-2-yl)-4H-l '-azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(R)-3-(l -methyl-l H-indoI-2-yl)-4H-l'-azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(S)-3-(l-methyl-lH-indol-2-yl)-4H-l'-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(R)-3-(l -methyl-lH-benzo[d]imidazol-2-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(S)-3-(l -methyl-lH-benzo[d]imidazol-2-yl)-4H-l'-azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane] ;
(R)-3-(6-fluorobenzofuran-2-yl)-4H-l'-azaspiro[[l ,2,4]oxadiazole-5,3'- bicycIo[2.2.2]octane];
(S)-3-(6-fluorobenzofuran-2-yl)-4H-l '-azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(R)-3 -(5-fluorobenzofuran-2-y 1)-4H- 1 '-azaspiro[ [ 1 ,2,4] oxadiazole-5 ,3 '- bicyclo[2.2.2]octane];
(S)-3-(5-fluorobenzofuran-2-yl)-4H-l'-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(R)-3-(4-fluorobenzofuran-2-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(S)-3 -(4-fluorobenzofuran-2-yl)-4H- 1 '-azaspiro[ [ 1 ,2,4] oxadiazole-5 ,3 '- bicyclo[2.2.2]octane];
(R)-3-(5,7-difluorobenzofuran-2-yl)-4H-l '-azaspiro[[l,2,4]oxadiazole-5,3'- bicyc!o[2.2.2]octane];
(S)-3-(5,7-difluorobenzofuran-2-yl)-4H-l'-azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(R)-3-([l ,l'-biphenyl]-4-yl)-4H-l'-azaspiro[[l,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane]; (S)-3-([l,l'-biphenyl]-4-yl)-4H-l '-azaspiro[[l,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane]; (R)-4-methyl-3-(l ,2,3,4-tetrahydroquinolin-6-yl)-4H-l'-azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane]; (S)-4-methy 1-3 -( 1 ,2,3 ,4-tetrahydroquinolin-6-yl)-4H- 1 '-azaspiro[ [ 1 ,2,4] oxadiazole-5 ,3 '- bicyclo[2.2.2]octane];
(lr,3R,4s,5S,7s)-3'-(6-fluorobenzo[b]thiophen-2-yl)-4'H-l -azaspiro[adamantane-4,5'- [l ,2,4]oxadiazole];
(lr,3R,4r,5S,7s)-3'-(6-fluorobenzo[b]thiophen-2-yl)-4'H-l-azaspiro[adamantane-4,5'- [l,2,4]oxadiazole];
( 1 r,3 R,4s,5 S,7s)-3 '-(5 -fluorobenzo [b]thiophen-2-yl)-4'H- 1 -azaspiro[adamantane-4,5 '- [l ,2,4]oxadiazole];
(lr,3R,4r,5S,7s)-3'-(5-fluorobenzo[b]thiophen-2-yl)-4'H-l-azaspiro[adamantane-4,5'- [l ,2,4]oxadiazole];
(l r,3R,4s,5S,7s)-3'-(benzo[b]thiophen-5-yl)-4'H-l -azaspiro[adamantane-4,5'- [l ,2,4]oxadiazole];
(lr,3R,4r,5S,7s)-3'-(benzo[b]thiophen-5-yl)-4'H-l -azaspiro[adamantane-4,5'- [l,2,4]oxadiazole];
(lr,3R,4s,5S,7s)-3 5,6,7,8-tetrahydroisoquinolin-3-yl)-4^1 -azaspiro[adamantine-4,5'- [l ,2,4]oxadiazole];
(l r,3R,4r,5S,7s)-3'-(5,6,7,8-tetrahydroisoquinolin-3-yl)-4'H-l-azaspiro[adamantine-4,5'- [l ,2,4]oxadiazole];
(R)-2-(4H-l'-azaspiro[[l,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octan]-3- yl)benzo[b]thiophene-7-carboxamide;
(S)-2-(4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octan]-3- yl)benzo[b]thiophene-7-carboxamide;
(R)-3-(quinolin-3-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane];
(S)-3-(quinolin-3-yl)-4H-l '-azaspiro[[l,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane];
(R)-3-(benzofuran-5-yl)-4H-l'-azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane];
(S)-3-(benzofuran-5-yl)-4H- -azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane];
(R)-3-(l H-indol-5-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazoIe-5,3'-bicyclo[2.2.2]octane];
(S)-3-(lH-indol-5-yl)-4H-l '-azaspiro[[l,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane];
(R)-3-(benzo[d]thiazol-6-yl)-4H-l '-azaspiro[[l,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane];
(S)-3-(benzo[d]thiazol-6-yl)-4H-l '-azaspiro[[l,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane];
(R)-3-(quinolin-6-yl)-4H-l '-azaspiro[[l,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane];
(S)-3-(quinolin-6-yl)-4H-l'-azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane];
(R)-3-(benzo[d]thiazoI-5-yl)-4H-l'-azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane];
(S)-3-(benzo[d]thiazol-5-yl)-4H-l'-azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane];
(R)-3-(benzofuran-6-yl)-4H-l'-azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane];
(S)-3-(benzofuran-6-yl)-4H-l '-azaspiro[[l,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane]; (R)-3-(benzo[b]thiophen-6-yl)-4H-l'-azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(S)-3-(benzo[b]thiophen-6-yl)-4H-l'-azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(R)-3-(4-fluorophenyl)-4H-r-azaspiro[[l,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane];
(S)-3-(4-fluorophenyl)-4H-l'-azaspiro[[l,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane];
(R)-3-(3,4-dichlorophenyl)-4H-l'-azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane];
(S)-3-(3,4-dichlorophenyl)-4H-l'-azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane];
(R)-3 -(3 -chlorobenzo[b]thiophen-2-yl)-4H- 1 '-azaspiro[[ 1 ,2,4]oxadiazole-5,3 '- bicyclo[2.2.2]octane];
(S)-3-(3-chlorobenzo[b]thiophen-2-yl)-4H-l'-azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(R)-3 -(4-(4-fluorophenoxy)pheny 1)-4H- 1 '-azaspiro [[ 1 ,2,4] oxadiazole-5 ,3 '- bicyclo[2.2.2]octane];
(S)-3-(4-(4-fluorophenoxy)phenyl)-4H-l'-azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(R)-3-(lH-indol-6-yl)-4H-l'-azaspiro[[l,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane];
(S)-3-( 1 H-indol-6-yl)-4H- 1 '-azaspiro[[ 1 ,2,4]oxadiazole-5,3 '-bicyclo[2.2.2]octane] ;
(lr,3R,4s,5S,7s)-3'-(benzofuran-5-yl)-4'H-l-azaspiro[adamantane-4,5'-[l,2,4]oxadiazole];
( 1 r,3 R,4r,5 S,7s)-3 '-(benzofuran-5 -y 1)-4'H- 1 -azaspiro [adamantane-4,5 '- [ 1 ,2,4] oxadiazole] ;
( 1 r,3R,4s,5 S,7s)-3 '-(benzo[b]thiophen-6-yl)-4'H- 1 -azaspiro[adamantane-4,5'- [l,2,4]oxadiazole];
(lr,3R,4r,5S,7s)-3Hbenzo[b]thiophen-6-yl)-4'H-l -azaspiro[adarnantane-4,5'- [l ,2,4]oxadiazole];
(R)-3-(3-(trifluoromethyl)benzofuran-5-yl)-4H-l '-azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(S)-3-(3-(trifluoromethyl)benzofuran-5-yl)-4H- -azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(R)-3-(2-(trifluorornethyl)benzofuran-5-yl)-4H-r-azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(S)-3-(2-(trifluoromethyl)benzofliran-5-yl)-4H- -azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(R)-3-(3-(trifluoromethyl)benzo[b]thiophen-6-yl)-4H-r-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(S)-3-(3-(trifluoromethyl)benzo[b]thiophen-6-yl)-4H-r-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(lr,3R,4s,5S,7s)-3'-(benzofuran-6-yl)-4'H-l -azaspiro[adamantane-4,5'-[l,2,4]oxadiazole]; (l r,3R,4r,5S,7s)-3'-(benzofuran-6-yl)-4'H-l -azaspiro[adamantane-4,5'-[l,2,4]oxadiazole];
(R)-3-(3-fluorobenzofuran-5-yl)-4H-l'-azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(S)-3-(3-fluorobenzofuran-5-yl)-4H- -azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2] octane] ;
(R)-3-(pyrimidin-5-yl)-4H- -azaspiro[[l,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane];
(S)-3-(pyrimidin-5-yl)-4H-l'-azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane];
(R)-3-(2-fluorobenzofuran-5-yl)-4H-l '-azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2] octane] ;
(S)-3-(2-fluorobenzofuran-5-yl)-4H-l'-azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(R)-3-(2-(trifluoromethyl)benzo[b]thiophen-6-yl)-4H-r-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(S)-3-(2-(trifluoromethyl)benzo[b]thiophen-6-yl)-4H- -azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2] octane] ;
(R)-3-(2-fluorobenzo[b]thiophen-6-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(S)-3-(2-fIuorobenzo[b]thiophen-6-yl)-4H- -azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(R)-3-(3-fluorobenzo[b]thiophen-6-yl)-4H- -azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2] octane] ;
( S)-3 -(3 -fluorobenzo[b]thiophen-6-y 1)-4H- 1 '-azaspiro[[ 1 ,2,4]oxadiazole-5 ,3 '- bicyclo[2.2.2]octane];
(R)-3-(thieno[3,2-b]pyridin-6-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(S)-3-(thieno[3,2-b]pyridin-6-yl)-4H-l'-azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane] ;
(R)-3-(pyrazolo[l,5-a]pyridin-5-yl)-4H- -azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(S)-3-(pyrazolo[l,5-a]pyridin-5-yl)-4H-r-azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(R)-3-(furo[2,3-b]pyridin-5-yl)-4H-l'-azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(S^-CfuroP^-^pyridin-S-ylHH-l'-azaspiroCtl ^^oxadiazole-S^'- bicyclo[2.2.2]octane];
(R)-3-(3,4-dihydro-2H-benzo[b][l,4]oxazin-5-yl)-4H-l'-azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane]; (S)-3-(3,4-dihydro-2H-benzo[b][l,4]oxazin-5-yl)-4H-l'-azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(R)-7-(4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octan]-3-yl)indolin-2-one;
(S)-7-(4H-l '-azaspiro[[l,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octan]-3-yl)indolin-2-one;
(R)-3-(imidazo[l ,2-a]pyridin-6-yl)-4H- -azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(S)-3-(imidazo[l,2-a]pyridin-6-yl)-4H-r-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(R)-3-(pyrrolo[l,2-b]pyridazin-6-yl)-4H-r-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2] octane] ;
(S)-3-(pyrrolo[l ,2-b]pyridazin-6-yl)-4H-r-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(R)-3 -(3 -methylbenzofuran-5-y 1)-4H- 1 '-azaspiro[[ 1 ,2,4] oxadiazole-5 ,3 '- bicyclo[2.2.2]octane];
(S)-3-(3-methylbenzofuran-5-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(R)-3-(3-methylbenzo[b]thiophen-5-yl)-4H-l'-azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(S)-3 -(3 -methylbenzo [b]thiophen-5 -yl)-4H- 1 '-azaspiro[[ 1 ,2,4]oxadiazole-5 ,3 '- bicyclo[2.2.2]octane];
(R)-3-(3-methylbenzofuran-6-yl)-4H- -azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2] octane];
(S)-3-(3-methylbenzofuran-6-yl)-4H-l'-azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2] octane];
(R)-3 -(3 -methylbenzo [b]thiophen-6-yl)-4H- 1 '-azaspiro[ [ 1 ,2,4] oxadiazole-5 ,3 '- bicyclo[2.2.2]octane];
(S)-3-(3-methylbenzo[b]thiophen-6-yl)-4H-l '-azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(R)-3-(5,6,7,8-tetrahydroisoquinolin-3-yl)-4H-l '-azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(S)-3-(5,6,7,8-tetrahydroisoquinolin-3-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2] octane] ;
(R)-4-methyl-3-(2-methyl-l,2,3,4-tetrahydroisoquinolm-6-yl)-4H-l'- azaspiro[[l,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane];
(S)-4-methyl-3-(2-methyl-l ,2,3,4-tetrahydroisoquinolin-6-yl)-4H-l'- azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane];
(R)-3-(quinolin-7-yl)-4H-l'-azaspiro[[l,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane]; (S)-3-(quinolin-7-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane];
(R)-3 -( 1 -methyl- 1 H-indol-6-yl)-4H- 1 '-azaspiro[[ 1 ,2,4] oxadiazole-5 ,3 '- bicyclo[2.2.2]octane;
(S)-3-(l -methyl-lH-indol-6-yl)-4H-l ,-azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane;
(R)-3 -(imidazo[ 1 , 5-a]pyridin-7-y 1)-4H- 1 '-azaspiro[ [ 1 ,2,4] oxadiazole-5 ,3 '- bicyclo[2.2.2]octane];
(S)-3-(imidazo[l ,5-a]pyridin-7-yl)-4H-r-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(R)-3 -(3 ,4-dihydro-2H-benzo [b] [1 ,4] oxazin-5 -y l)-4-methyl-4H- 1 '- azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane];
(S)-3 -(3 ,4-dihydro-2H-benzo[b] [ 1 ,4]oxazin-5-yl)-4-methyl-4H- 1 '- azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane];
(R)-3-(pyrrolo[l ,2-a]pyrimidin-7-yl)-4H-l '-azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane]; and
(S)-3-(pyrrolo[l ,2-a]pyrimidin-7-yl)-4H- -azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
Figure imgf000334_0001
Figure imgf000335_0001
Figure imgf000336_0001
49. The compound of claim 1 , wherein W represents a moiety represented by one of the following:
Figure imgf000336_0002
independently represent N or CR11;
independently represents NR10; O; or S;
represent CR7, wherein Rn preferably independently represents -H; -F; CI; -Br; -I; -CN; -OR12; -(CH2)mOR12; -OCF3; a C,-C6-alkyl radical; a CrC6-haloalkyl radical, preferably -CF3; or a C3-C6-cycloalkyl radical; represents N or CR15;
represents NR14; O; or S; and
independently represent N or CR4; with the proviso that no more than two of Z1, Z2, Z3, and Z4 are N.
50. The compound of claim 1 or claim 49, wherein the compound is selected from the group consisting of: (+/-)-3-(benzo[b]thiophen-5-yl)-4H-l'-azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(+/-)-3-(benzofuran-5-yl)-4H-l '-azaspiro[[l,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane];
(+/-)-3-(benzo[b]thiophen-6-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(+/-)-3 -(3 -(trifluoromethyl)benzofuran-5 -yl)-4H- 1 '-azaspiro[[ 1 ,2,4] oxadiazole-5 ,3 '- bicyclo[2.2.2]octane];
(+/-)-3 -(3 -fluorobenzofuran-5 -yl)-4H- 1 '-azaspiro[[ 1 ,2,4] oxadiazole-5 ,3 '- bicyclo[2.2.2]octane];
(+/-)-3-(2-fluorobenzofuran-5-yl)-4H-l'-azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(+/-)-3 -(3 -fluorobenzo[b]thiophen-6-yl)-4H- 1 '-azaspiro[[ 1 ,2,4] oxadiazole-5 ,3 '- bicyclo[2.2.2]octane];
(R)-3-(benzo[b]thiophen-5-yl)-4H-l'-azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(S)-3-(benzo[b]thiophen-5-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(lr,3R,4s,5S,7s)-3'-(benzo[b]thiophen-2-yl)-4'H-l-azaspiro[adamantane-4,5'- [l,2,4]oxadiazole];
(lr,3R,4r,5S,7s)-3'-(benzo[b]thiophen-2-yl)-4'H-l -azaspiro[adamantane-4,5'- [l ,2,4]oxadiazole];
(R)-3-(benzofuran-5-yl)-4H- -azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane];
(S)-3-(benzofuran-5-yl)-4H-l'-azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane];
(R)-3-(benzo[b]thiophen-6-yl)-4H-l '-azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(S)-3 -(benzo[b]thiophen-6-yl)-4H- 1 '-azaspiro[[ 1 ,2,4] oxadiazole-5 ,3 '- bicyclo[2.2.2]octane];
(R)-3-(3-(trifluoromethyl)benzofuran-5-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(S)-3-(3-(trifIuoromethyl)benzofuran-5-yl)-4H-l '-azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(R)-3-(3-fluorobenzofuran-5-yl)-4H-l'-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2] octane] ;
(S)-3-(3-fluorobenzofuran-5-yl)-4H- -azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(R)-3-(2-fluorobenzofuran-5-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2] octane] ; (S)-3-(2-fluorobenzofuran-5-yl)-4H-l'-azaspiro[[l,2,4]oxadiazole-5,3'- bicyc lo [2.2.2] octane] ;
( )-3-(3-fluorobenzo[b]thiophen-6-yl)-4H- -azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane]; and
(S)-3 -(3 -fluorobenzo[b]thiophen-6-yl)-4H- 1 '-azaspiro [[ 1 ,2,4]oxadiazole-5 ,3 '- bicyclo[2.2.2]octane].
51. The compound of claim 50, wherein the compound is selected from the group consisting of:
(+/-)-3-(benzo[b]thiophen-5-yl)-4H-l'-azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(+/-)-3-(benzofuran-5-yl)-4H-l'-azaspiro[[l,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane];
(+/-)-3-(benzo[b]thiophen-6-yl)-4H-l'-azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(+/-)-3-(3-(trifiuoromethyl)benzofuran-5-yl)-4H-l'-azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(+/-)-3-(3-fluorobenzofuran-5-yl)-4H- -azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(+/-)-3 -(2-fluorobenzofuran-5 -y 1)-4H- 1 '-azaspiro [[ 1 ,2,4] oxadiazole-5 ,3 '- bicyclo[2.2.2]octane];
(+/-)-3-(3-fluorobenzo[b]thiophen-6-yl)-4H-l'-azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(R)-3 -(benzo[b]thiophen-5-yl)-4H- 1 '-azaspiro[[ 1 ,2,4]oxadiazole-5,3 '- bicyclo[2.2.2]octane];
(S)-3-(benzo[b]thiophen-5-yl)-4H-r-azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(lr,3R,4s,5S,7s)-3'-(benzo[b]thiophen-2-yl)-4'H-l-azaspiro[adamantane-4,5'- [l,2,4]oxadiazole]; and
(l r,3R,4r,5S,7s)-3'-(benzo[b]thiophen-2-yl)-4'H-l-azaspiro[adamantane-4,5'- [l,2,4]oxadiazole].
52. The compound of claim 50, wherein the compound is selected from the group consisting of:
(R)-3 -(benzo[b]thiophen-5-yl)-4H- 1 '-azaspiro[[ 1 ,2,4]oxadiazole-5,3 '- bicyclo[2.2.2]octane];
(S)-3-(benzo[b]thiophen-5-yl)-4H-l'-azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane]; (lr,3R,4s,5S,7s)-3'-(benzo[b]thiophen-2-yl)-4'H-l-azaspiro[adamantane-4,5'- [l ,2,4]oxadiazole];
(lr,3R,4r,5S,7s)-3'-(benzo[b]thiophen-2-yl)-4'H-l-azaspiro[adamantane-4,5'- [l ,2,4]oxadiazole];
(R)-3-(benzofuran-5-yl)-4H-l'-azaspiro[[l,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane];
(S)-3-(benzofuran-5-yl)-4H- -azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane];
(<R)-3-(benzo[b]thiophen-6-yl)-4H- -azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(S)-3-(benzo[b]thiophen-6-yl)-4H-l'-azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(R)-3-(3-(trifIuorornethyl)benzofuran-5-yl)-4H- -azaspiro[[l,2,4]oxadiazole-5>31- bicyclo[2.2.2]octane];
(S)-3-(3-(trifluoromethyl)benzofuran-5-yl)-4H-l '-azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(R)-3-(3-fluorobenzofuran-5-yl)-4H- -azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(S)-3-(3-fluorobenzofuran-5-yl)-4H- -azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(R)-3-(2-fluorobenzofuran-5-yl)-4H-r-azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(S)-3-(2-fluorobenzofuran-5-yl)-4H- -azaspiro[[l ,2,4]oxadiazole-5,3'- bicycl.o[2.2.2]octane];
(R)-3-(3-fluorobenzo[b]thiophen-6-yl)-4H-r-azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane]; and
(S)-3-(3-fluorobenzo[b]thiophen-6-yl)-4H- -azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane].
53. The compound of claim 49, wherein W represents a moiety represented by the ring system M-IIa.
54. The compound of claim 53, wherein the compound is selected from the group consisting of:
(+/-)-3-(benzo[b]thiophen-5-yl)-4H-l'-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(+/-)-3-(benzofuran-5-yl)-4H-r-azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane];
(+/-)-3-(3-(trifluoromethyl)benzofuran-5-yl)-4H- -azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane]; (+/-)-3 -(3 -fluorobenzofuran-5-yl)-4H- 1 '-azaspiro [[ 1 ,2,4] oxadiazole-5 ,3 '- bicyclo[2.2.2]octane];and
(+/-)-3-(2-fluorobenzofuran-5-yl)-4H-r-azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane].
55. The compound of claim 53, wherein the compound is selected from the group consisting of:
(R)-3 -(benzo[b]thiophen-5 -yl)-4H- 1 '-azaspiro [[ 1 ,2,4] oxadiazole-5 ,3 '- bicyclo[2.2.2]octane];
(S)-3-(benzo[b]thiophen-5-yl)-4H-l '-azaspiro[[l,2,4]oxadiazole-5,3'- bicycIo[2.2.2]octane];
(R)-3-(benzofuran-5-yl)-4H-l'-azaspiro[[l,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane];
(S)-3-(benzofuran-5-yl)-4H- -azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane];
(R)-3 -(3 -(trifluoromethyl)benzofuran-5 -y 1)-4H- 1 '-azaspiro[ [ 1 ,2,4]oxadiazole-5 ,3 '- bicyclo[2.2.2]octane];
(S)-3-(3-(trifluoromethyl)benzofuran-5-yl)-4H-r-azaspiro[[l,2,4]oxadiazole-5,3'- bicyc lo [2.2.2] octane] ;
(R)-3-(3-fluorobenzofuran-5-yl)-4H-r-azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(S)-3-(3-fluorobenzofuran-5-yl)-4H-l '-azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(R)-3-(2-fluorobenzofuran-5-yl)-4H-l'-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane]; and
(S)-3-(2-fluorobenzofuran-5-yl)-4H-r-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane].
56. The compound of claim 53, wherein the compound is selected from the group consisting of:
(R)-3-(benzo[b]thiophen-5-yl)-4H-l'-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(R)-3-(benzofuran-5-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane];
(R)-3-(3-(trifluoromethyl)benzofuran-5-yl)-4H- -azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(R)-3-(3-fluorobenzofuran-5-yl)-4H- -azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane]; and
(R)-3-(2-fluorobenzofuran-5-yl)-4H-l '-azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane].
57. The compound of claim 53, wherein the compound is selected from the group consisting of:
(S)-3 -(benzo[b]thiophen-5 -yl)-4H- 1 '-azaspiro[[ 1 ,2,4] oxadiazole-5 ,3 '- bicyclo [2.2.2] octane] ;
(S)-3-(benzofuran-5-yl)-4H-l '-azaspiro[[l,2,4]oxadiazole-5,3'-bicyclo[2.2.2]octane];
(S)-3-(3-(trifluoromethyl)benzofuran-5-yl)-4H-l'-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(S)-3-(3-fluorobenzofuran-5-yl)-4H- -azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane]; and
(S)-3 -(2-fluorobenzofuran-5-y 1)-4H- 1 '-azaspiro[ [ 1 ,2,4]oxadiazole-5 ,3 '- bicyclo[2.2.2]octane],
58. The compound of claim 49, wherein W represents a moiety represented by the ring system M-IIb.
59. The compound of claim 58, wherein the compound is selected from the group consisting of:
(+/-)-3-(benzo[b]thiophen-6-yI)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane]; and
(+/-)-3-(3-fluorobenzo[b]thiophen-6-yl)-4H-l '-azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane].
60. The compound of claim 58, wherein the compound is selected from the group consisting of:
(R)-3-(benzo[b]thiophen-6-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(S)-3-(benzo[b]thiophen-6-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane];
(R)-3-(3-fluorobenzo[b]thiophen-6-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane]; and
(S)-3-(3-fluorobenzo[b]thiophen-6-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane].
61. The compound of claim 58, wherein the compound is selected from the group consisting of: (R)-3-(benzo[b]thiophen-6-yl)-4H-l '-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane]; and
(R)-3-(3-fluorobenzo[b]thiophen-6-yl)-4H-r-azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane].
62. The compound of claim 58, wherein the compound is selected from the group consisting of:
(S)-3-(benzo[b]thiophen-6-yl)-4H-l '-azaspiro[[l,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane]; and
(S)-3-(3-fluorobenzo[b]thiophen-6-yl)-4H-r-azaspiro[[l ,2,4]oxadiazole-5,3'- bicyclo[2.2.2]octane].
63. The compound of claim 49, wherein W represents a moiety represented by the ring system M-IVa.
64. The compound of claim 63, wherein the compound is selected from the group consisting of:
(l r,3R,4s,5S,7s)-3'-(benzo[b]thiophen-2-yl)-4'H-l-azaspiro[adamantane-4,5'- [l,2,4]oxadiazole]; and
(lr,3R,4r,5S,7s)-3'-(benzo[b]thiophen-2-yl)-4'H-l-azaspiro[adamantane-4,5'- [l,2,4]oxadiazole].
65. The compound of claim 63, wherein the compound is selected from the group consisting of:
(lr,3R,4s,5S,7s)-3'-(benzo[b]thiophen-2-yl)-4'H-l-azaspiro[adamantane-4,5'- [l ,2,4]oxadiazole].
66. The compound of claim 63, wherein the compound is selected from the group consisting of:
(lr,3R,4r,5S,7s)-3'-(benzo[b]thiophen-2-yl)-4'H-l-azaspiro[adamantane-4,5'- [l ,2,4]oxadiazole].
67. A pharmaceutical composition, comprising the compound of any one of claims 1 -66.
68. A method of treating a patient in need thereof, comprising administering the compound of any one of claims 1-66.
69. A method of treating a patient in need thereof, comprising administering the
pharmaceutical composition of claim 67.
70. The method of any one of claims 68-69, wherein the patient suffers from a cognitive impairment or suffers from one or more symptoms associated with a cognitive impairment.
71. The method of claim 70, wherein the cognitive impairment comprises Limited Cognitive Impairment (LCI), Mild Cognitive Impairment (MCI), Alzheimer's disease, dementia of an Alzheimer's-type, schizophrenia, schizophreniform disorder, schizoaffective disorder, delusional disorder, positive symptoms of schizophrenia, negative symptoms of schizophrenia, or schizophrenia with dementia.
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