Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D453/00—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids
  • C07D453/02—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids containing not further condensed quinuclidine ring systems
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

• Nicotinic acetylcholine receptors play a large role in central nervous system (CNS) activity. Particularly, they are known to be involved in cognition, learning, mood, emotion, and neuroprotection. There are several types of nicotinic acetylcholine receptors, and each one appears to have a different role in regulating CNS function. Nicotine affects all such receptors, and has a variety of activities. Unfortunately, not all of the activities are desirable. In fact, one of the least desirable properties of nicotine is its addictive nature and the low ratio between efficacy and safety.
• the present invention relates to molecules that have a greater effect upon the al nAChRs as compared to other closely related members of this large ligand-gated receptor family. Thus, the invention provides compounds that are active drug molecules with fewer side effects.
• US Patent 5,977,144 discloses compositions for benzylidene- and cinnamylidene-anabaseines and methods for using these compositions for treating conditions associated with defects or malfunctioning of nicotinic subtypes brain receptors. These compositions target the al receptor subtype with little or no activation of the 4 ⁇ 2 or other receptor subtypes.
• US Patent 5,837,489 discloses human neuronal nicotinic acetylcholine receptor and cells transformed with same DNA and mRNA encoding subunits.
• US Patent 5,712,270 discloses a group of 2-aroylaminothiazole derivatives which bind to and stimulate central muscarinic acetylcholine receptors and are useful agents for treating symptoms of cognitive disorders, specifically the impaired memory associated with a decrease in the neurotransmitter, acetylcholine. Some of the compounds of this invention also bind to 5HT ⁇ A receptors and dopamine D 2 receptors, making them useful as antipsychotic agents.
• US Patent 5,624,941 discloses pyrazole derivatives useful in pharmaceuticals in which cannabis is known to be involved.
• US Patent 5,561,149 discloses the use of a mono or bicyclic carbocyclic, or heterocyclic carboxylic, acid ester or amide or an imidazolyl carbazol in the manufacture of a medicament suitable for the treatment of stress-related psychiatric disorders, for increasing vigilance, for the treatment of rhinitis or serotonin-induced disorders and/or coadministralion with another active agent to increase the bioavailability thereof, or for nasal administration.
• US Patent 5,510,478 discloses a group of 2-aroylaminothiazole derivatives which bind to and stimulate central muscarinic acetylcholine receptors and are useful agents for treating symptoms of cognitive disorders, specifically the impaired memory associated with a decrease in the neurotransmitter, acetylcholine. Some of the compounds of this invention also bind to 5HT IA receptors and dopamine D 2 receptors, making them useful as antipsychotic agents.
• US Patent 5,364,863 discloses bicyclic carboxylic esters and amides, their pharmaceutical formulations, and a method for their use in treating migraine, emesis, gastrointestinal disorders, schizophrenia, or anxiety in mammals.
• US Patent 5,342,845 discloses indole derivatives and drugs effective as gastrointestinal motor activity regulator, antimigraine, antipsychotic or anti anxiety drugs.
• US Patent 5,273,972 discloses novel 2-substituted-3-quinuclidinyl arylcarboxamides and arylthiocarboxamides and corresponding arylcarboxylates which have utility as therapeutic agents which exhibit gastric prokinetic, antiemetic, anxiolytic and 5-HT (serotonin) antagonist effects in warm blooded animals.
• US Patent 5,246,942 discloses certain dibenzofurancarboxamides and their use as 5-HT 3 antagonists having unique CNS, anti-emetic and gastric prokinetic activity void of any significant D 2 receptor binding properties.
• US Patent 5,237,066 discloses enantiomers of absolute configuration S of amide derivatives of 3-aminoquinuclidine, the process for preparing them and their use as medicinal products having activity in respect of gastric movements and antiemetic activity.
• US Patent 5,236,931 discloses novel 3-quinuclidinyl benzamides and benzoates which have utility as therapeutical agents which exhibit anxiolytic, antipsychotic, cognition improvement, antiemetic and gastric prokinetic effects in warm blooded animals.
• US Patent 5,217,975 discloses azabicyclic compounds for treating dementia.
• US Patent 5,206,246 discloses anxiolytic-R-N-(l-azabicyclo[2.2.2]oct-3-yl) benzamides and thiobenzamides, their N-oxides and pharmaceutically acceptable salts thereof.
• a preferred compound is R-(+)-4-amino-N-(l-azabicyclo[2.2.2]oct-3-yl)-5- chloro-2-methoxybenzamide.
• US Patent 5,183,822 discloses new heterocyclic compounds (3,4-annelated benzimidazole-2(lH)-ones) having an antagonistic activity on 5-hydroxytryptamine (5-HT) receptors.
• US Patent 5,175,173 discloses carboxamides useful as antiemetic or antipsychotic agents.
• US Patent 5,070,095 discloses novel l-(azabicyclo[2.2.2]oct-3- or -4- yl)benzamides substituted on the benzene ring with the basic substituted aminomethyleneamino group which have been found to be useful in treating emesis, including emesis due to chemical and radiation anticancer therapy, anxiety, and impaired gastric emptying.
• US Patent 5,057,519 discloses 5-HT 3 antagonists as being useful in reducing opiate tolerance.
• US Patent 5,039,680 discloses 5-HT antagonists in preventing or reducing dependency on dependency-inducing agents.
• US Patent 5,025,022 discloses a method of treating or preventing schizophrenia and/or psychosis using S-N-(l-azabicyclo[2.2.2]oct-3-yl)benzamides and thiobenzamides, their N-oxides and pharmaceutically acceptable salts thereof.
• a preferred compound is S(-)-4-amino-N-( 1 -azabicyclo[2.2.2]oct-3-yl)-5-chloro-2- methoxybenzamide.
• US Patent 5,017,580 discloses memory enhancing R-N-(l- azabicyclo[2.2.2.]oct-3-yl)benzamides and thiobenzamides, their N-oxides and pharmaceutically acceptable salts thereof.
• a preferred compound is R-(+)-4-amino- N-( 1 -azabicyclo[2.2.2]oct-3-yl)-5-chloro-2-methoxybenzamide.
• US Patent 4,988,691 discloses isoxazole-containing compounds exhibiting anti-serotonin activity.
• US Patent 4,921,982 discloses 5-halo-2,3-dihydro-2,2-dimethylbenzofuran-7- carboxylic acids which are useful as intermediates for 5-HT 3 antagonists.
• US Patent 4,835,162 discloses agonists and antagonists to nicotine as smoking deterrents.
• US Patent 4,822,795 discloses pharmaceutically useful esters and amides having 5-HT antagonist activity.
• US Patent 4,803,199 discloses pharmaceutically useful heterocyclic acid esters and amides or alkylene bridged peperidines as serotonin M antagonists.
• US Patent 4,798,829 discloses l-azabicyclo[3.2.2]nonane derivatives having gastric motility enhancing activity and/or anti -emetic activity and/or 5-HT receptor antagonist activity.
• US Patent 4,789,673 discloses dicarboxylic, heterocyclic and substituted benzoic acid alkylene-bridged piperidyl amides and esters as being serotonin M antagonists.
• US Patent 4,721,720 discloses a method of treating emesis, anxiety and/or irritable bowel syndrome.
• US Patent 4,657,911 discloses 3-amino quinuclidine derivatives and the application thereof as accelerators of gastro-intestinal motor function and as medicament potentiators.
• US Patent 4,605,652 discloses a method of enhancing memory or correcting memory deficiency with arylamido (and arylthioamido)-azabicycloalkanes, and the pharmaceutically acceptable acid addition salts, hydrates and alcoholates thereof.
• US Patent 3,702,324 discloses 3,4,5-trimethoxybenzamides of substituted anilines and of alkylpiperidines which exert a specific effect on the central nervous system and a somewhat lesser effect on muscle function, and thus have utility as tranquilizers.
• WO 01/36417 Al discloses novel N-azabicyclo-amide derivatives and use in therapy, especially in the treatment of prophylaxis of psychotic disorders and intellectual impairment disorders.
• WO 00/73431 A2 discloses two binding assays to directly measure the affinity and selectivity of compounds at the al nAChR and the 5-HT 3 R. The combined use of these functional and binding assays may be used to identify compounds that are selective agonists of the al nAChR.
• WO 92/15579 discloses multicyclic tertiary a ine polyaromatic squalene synthase inhibitors and method of treatment for lowering serum cholesterol levels using the compounds.
• WO 92/11259 discloses azabicyclic amides or esters of halogenated benzoic acids having 5-HT receptor antagonist activity.
• WO 90/14347 A as abstracted in chemical abstract 1991 : 143,158 discloses N- quinuclidinyl-indolecarboxamide derivatives as being antiemetics.
• EP 512 350 A2 discloses 3-(indolyl-2-carboxamido) quinuclidines useful for treating diseases characterized by an excess or enhanced sensitivity to serotonin, e.g., psychosis, nausea, vomiting, dementia or other cognitive diseases, migraine, diabetes.
• the compound may be used to control anxiety, aggression, depression, and pain.
• the compounds are disclosed as serotonin 5-HT antagonists.
• DE 3810552 Al discloses esters and amides of indolyl-, benzo[b]thiophenyl-, benzo[b]furancarboxylic acids or 4-amino-2 methoxy-benzoic acids with N- heterocyclic or N-heterobicyclic alcohols or amines.
• the compounds disclosed have activity against pain especially migraine, as an anti-a ⁇ hythmic for gastrointestinal disturbances, stomach disturbances, gastritis ulcer, gall bladder, spastic colon, Crohn's disease, ulcerative colitis, carcinoid syndrome, diarrhea of various types.
• the compounds are also disclosed as speeding stomach emptying, controlling gastro duodenal and gastro esophageal reflux, disturbances of esophageal motility, hiatal hernia, cardiac insufficiency, hypotonic stomach, paralytic ileus, manic depressive psychosis and other psychoses.
• the compounds are also disclosed as useful for stress related diseases, senility, and enhancement of nasal absorption of other agents, e.g., in the treatment of emesis.
• FR 2 625 678 discloses N-(quinuclidin-3-yl)-benzamides and thiobenzamides useful as diet-control agents.
• Ri is selected from -H, alkyl, cycloalkyl, halogenated alkyl, or aryl;
• Alkyl is both straight and branched-chain moieties having from 1-6 carbon atoms;
• Halogenated alkyl is an alkyl moiety having from 1-6 carbon atoms and having 1 to (2n+l) substituent(s) independently selected from -F, -CI, -Br, or -I where n is the maximum number of carbon atoms in the moiety;
• Cycloalkyl is a cyclic alkyl moiety having from 3-6 carbon atoms;
• Aryl is phenyl, substituted phenyl, naphthyl, or substituted naphthyl;
• Substituted phenyl is a phenyl either having 1-4 substituents independently selected from -F, -CI, -Br, or -I, or having 1 substituent selected from -R ⁇ 2 and 0-3 substituents independently selected from -F, -CI, -Br, or -I;
• Substituted naphthyl is a naphthalene moiety either having 1-4 substituents independently selected from -F, -CI, -Br, or -I, or having 1 substituent selected from -Ri 2 and 0-3 substituents independently selected from -F, -CI, -Br, or -I, where the substitution can be independently on either the same ring or different rings of said naphthalene moiety;
• R 2 is -H, alkyl, halogenated alkyl, substituted alkyl, cycloalkyl, benzyl, substituted benzyl, or aryl;
• Substituted alkyl is an alkyl moiety having from 1-6 carbon atoms and having 0-3 substituents independently selected from -F, -CI, -Br, or -I, and further having 1 substituent selected from -R 7 , -R 9 , -ORio, -SRio, -NRioRio, -C(O)R 10 , -NO 2 , -C(O)NR 10 R.o, -CN, -NR 10 C(O)R 10 , -S(O) 2 NR ⁇ 0 R ⁇ o, -NR 10 S(O) 2 R 10 , phenyl, or substituted phenyl;
• Substituted benzyl is a benzyl either having 1-4 substituents independently selected from -F, -CI, -Br, or -I, or having 1 substituent selected from -R ⁇ 2 and 0-3 substituents independently selected from -F, -CI, -Br, or -I, provided that all substitution is on the phenyl ring of the benzyl;
• X is O or S
• W is a cyclic heteroaromatic moiety where the heteroatoms can be from 1-3 atoms selected from oxygen, sulfur, or nitrogen of the following structures:
• Limited substituted alkyl is a substituted alkyl having from 1-6 carbon atoms and having 0-3 substituents independently selected from -F, -CI, -Br, or -I, and further having 1 substituent on either only the ⁇ carbon and selected from -ORn, -SRn, -NR supplementR ⁇ , -C(O)R n , -NO 2 , -C(O)NR ⁇ R graffiti, -CN, -NR ⁇ 0 C(O)R H , -S(O) 2 NR i0 R ⁇ o, or -NRioS(O) 2 Rio, or on any carbon with sufficient valency but not on the ⁇ carbon and selected from -R 7 , -R 9 , -ORjo, -SR 10 , -NR 10 R ⁇ o, -C(O)R ]0 , -NO 2 , -C(O)NR !0 R, 0 , -CN, -NRi 0
• Alkenyl is straight and branched-chain moieties having from 2-6 carbon atoms and having at least one carbon-carbon double bond;
• Halogenated alkenyl is an unsaturated alkenyl moiety having from 2-6 carbon atoms and having 1 to (2n-l) substituent(s) independently selected from -F, -CI, -Br, or -I where n is the maximum number of carbon atoms in the moiety;
• Substituted alkenyl is an unsaturated alkenyl moiety having from 2-6 carbon atoms and having 0-3 substituents independently selected from -F, or -CI, and further having 1 substituent selected from -R 7 , -R 9 , -OR 10 , -SR !0 , -NRioRio, -C(O)R, 0 , -C(O)NR 10 R 10 , -CN, -NRioC(O)R, 0 , -S(O) 2 NR 10 R ⁇ o, -NR lQ S(O) 2 R 10 , phenyl, or substituted phenyl;
• Alkynyl is straight and branched-chain moieties having from 2-6 carbon atoms and having at least one carbon-carbon triple bond;
• Halogenated alkynyl is an unsaturated alkynyl moiety having from 3-6 carbon atoms and having 1 to (2n-3) substituent(s) independently selected from -F, -CI, -Br, or -I where n is the maximum number of carbon atoms in the moiety;
• Substituted alkynyl is an unsaturated alkynyl moiety having from 3-6 carbon atoms and having 0-3 substituents independently selected from -F, or -CI, and further having 1 substituent selected from -R 7 , -R 9 , -OR ⁇ 0 , -SRio, -NRioRio, -C(O)R ⁇ 0 , -CN, -C(O)NR,oR.o, -NRi 0 C(O)R,o, -S(O) 2 NR ⁇ 0 R ⁇ o, -NR 10 S(O) 2 R ⁇ o, phenyl, or substituted phenyl;
• Halogenated cycloalkyl is a cyclic moiety having from 3-6 carbon atoms and having 1-4 substituents independently selected from -F, or -CI;
• Substituted cycloalkyl is a cyclic moiety having from 3-6 carbon atoms and having 0-3 substituents independently selected from -F, or -CI, and further having 1 substituent selected from -ORio, -SRio, -NR, 0 R ⁇ o, -C(O)R ⁇ 0 , -C(O)NR ⁇ 0 R ⁇ o, -CN, -NR ⁇ oC(O)R ⁇ o, -S(O) 2 NR ⁇ 0 R 10 , -NR ⁇ 0 S(O) 2 R ⁇ 0 , -NO 2 , phenyl, or substituted phenyl;
• Heterocycloalkyl is a cyclic moiety having 4-7 atoms with 1-2 atoms within the ring being
• Halogenated heterocycloalkyl is a cyclic moiety having from 4-7 atoms with 1-2 atoms within the ring being -S-, -N(R )-, or -O-, and having 1-4 substituents independently selected from -F, or -CI;
• Substituted heterocycloalkyl is a cyclic moiety having from 4-7 atoms with 1-2 atoms within the ring being -S-, -N(R 3 )-, or -O- and having 0-3 substituents independently selected from -F, or -CI, and further having 1 substituent selected from -OR 10 , -SRio, -NR.oRio, -C(O)R 10 , -C(O)NR ⁇ oR ⁇ o, -CN, -NR, 0 C(O)R 10 , -NO 2) -S(O) 2 NR 10 R ⁇ o, -NR )0 S(O) 2 R ⁇ o, phenyl, or substituted phenyl;
• R 5 is independently selected from the group consisting of -H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, halogenated alkyl, halogenated alkenyl, halogenated alkynyl, halogenated cycloalkyl, halogenated heterocycloalkyl, substituted alkyl, substituted alkenyl, substituted alkynyl, substituted cycloalkyl, substituted heterocycloalkyl, limited substituted alkyl, limited substituted alkenyl, limited substituted alkynyl, aryl, -OR 8 , -OR J4 , -SR 8 , -SR )4 , -F, -CI, -Br, -I, -NR 8 R 8 , -NR ]4 R 14 , -C(O)R 8 , -C(O)Ri 4 , -C(O)NR 8 R 8
• Limited substituted alkynyl is a substituted alkynyl having from 1-6 carbon atoms and having 0-3 substituents independently selected from -F, -CI, -Br, or -I, and further having 1 substituent on either only the ⁇ carbon and selected from -ORn, -SR, ,, -NR necessarilyR fate, -C(O)R u , -NO 2 , - OjNR ⁇ R,,, -CN, -NR, 0 C(O)R,,, -S(O) 2 NR ⁇ oR ⁇ o> or -NR ⁇ 0 S(O) 2 R ⁇ o, or on any carbon with sufficient valency but not on the ⁇ carbon and selected from -R 7 , -R , -ORio, -SRio, -NR
• E is O, S, or NR 3 ,
• E and G are independently selected from CR] 8 , O, S, or NR 3 , and A is CR ⁇ 8 or N, or wherein E and G are independently selected from CR ⁇ 8 , O, S, or NR 3 , and A is CR ⁇ 8 or N, each 9-membered fused-ring moiety having 0-1 substituent selected from -R ⁇ 2 and 0-3 substituent(s) independently selected from -F, -CI, -Br, or -I, and having a bond directly or indirectly attached to the core molecule where valency allows in either the 6-membered or the 5-membered ring of the fused-ring moiety;
• Each R 8 is independently selected from -H, alkyl, halogenated alkyl, substituted alkyl, cycloalkyl, halogenated cycloalkyl, substituted cycloalkyl, heterocycloalkyl, halogenated heterocycloalkyl, substituted heterocycloalkyl, -R 7 , -R , phenyl, or substituted phenyl;
• Each Rio is independently selected from -H, alkyl, cycloalkyl, heterocycloalkyl, alkyl substituted with 1 substituent selected from Rj 3 , cycloalkyl substituted with 1 substituent selected from R ⁇ 3 , heterocycloalkyl substituted with 1 substituent selected from R ⁇ 3 , halogenated alkyl, halogenated cycloalkyl, halogenated heterocycloalkyl, phenyl, substituted phenyl, -R 7 , or -R ;
• R ⁇ is independently selected from -H, alkyl, cycloalkyl, heterocyclo- alkyl, halogenated alkyl, halogenated cycloalkyl, or halogenated heterocycloalkyl
• R 12 is selected from -ORn, -SRn, alkyl, cycloalkyl, heterocycloalkyl, halogenated alkyl, halogenated cycloalkyl, halogenated heterocycloalkyl, substituted alkyl, substituted cycloalkyl, substituted heterocycloalkyl, -NRnRn, -C(O)Rn, -NO 2 , -C(O)NR
• Ri 3 is selected from -OR n , -SRn, -NR,,Rn, -C(O)Rn, -
• R ⁇ 4 is independently selected from -H, alkyl, halogenated alkyl, limited substituted alkyl, cycloalkyl, halogenated cycloalkyl, substituted cycloalkyl, heterocycloalkyl, halogenated heterocycloalkyl, substituted heterocycloalkyl; and
• Each Ris is independently selected from -H, alkyl, cycloalkyl, heterocycloalkyl, halogenated alkyl, halogenated cycloalkyl, halogenated heterocycloalkyl, substituted alkyl, substituted cycloalkyl, substituted heterocycloalkyl, -ORn, -SRn, -NR ⁇ Ru, -C(O)Rn, -NO 2 , -C(
• Compounds of Formula I are useful to treat any one of or combination of schizophrenia, or psychosis.
• Ri is selected from -H, alkyl, cycloalkyl, halogenated alkyl, or aryl;
• Alkyl is both straight and branched-chain moieties having from 1-6 carbon atoms;
• Halogenated alkyl is an alkyl moiety having from 1-6 carbon atoms and having 1 to (2n+l) substituent(s) independently selected from -F, -CI, -Br, or -I where n is the maximum number of carbon atoms in the moiety; Cycloalkyl is a cyclic alkyl moiety having from 3-6 carbon atoms; Aiyl is phenyl, substituted phenyl, naphthyl, or substituted naphthyl;
• Substituted phenyl is a phenyl either having 1-4 substituents independently selected from -F, -CI, -Br, or -I, or having 1 substituent selected from -Rj 2 and 0-3 substituents independently selected from -F, -CI, -Br, or -I;
• Substituted naphthyl is a naphthalene moiety either having 1-4 substituents independently selected from -F, -CI, -Br, or -I, or having 1 substituent selected from -R 1 2 and 0-3 substituents independently selected from -F, -CI, -Br, or -I, where the substitution can be independently on either the same ring or different rings of said naphthalene moiety;
• R 2 is -H, alkyl, halogenated alkyl, substituted alkyl, cycloalkyl, benzyl, substituted benzyl, or aryl;
• Substituted alkyl is an alkyl moiety having from 1-6 carbon atoms and having 0-3 substituents independently selected from -F, -CI, -Br, or -I, and further having 1 substituent selected from -R 7 , -R 9 , -ORio, -SRio, -NR
• Substituted benzyl is a benzyl either having 1-4 substituents independently selected from -F, -CI, -Br, or -I, or having 1 substituent selected from -Rj 2 and 0-3 substituents independently selected from -F, -CI, -Br, or -I, provided that all substitution is on the phenyl ring of the benzyl;
• X is O or S
• W is a cyclic heteroaromatic moiety where the heteroatoms can be from 1-3 atoms selected from oxygen, sulfur, or nitrogen of the following structures:
• Alkenyl is straight and branched-chain moieties having from 2-6 carbon atoms and having at least one carbon-carbon double bond;
• Halogenated alkenyl is an unsaturated alkenyl moiety having from 2-6 carbon atoms and having 1 to (2n-l) substituent(s) independently selected from -F, -CI, -Br, or -I where n is the maximum number of carbon atoms in the moiety;
• Substituted alkenyl is an unsaturated alkenyl moiety having from 2-6 carbon atoms and having 0-3 substituents independently selected from -F, or -CI, and further having 1 substituent selected from -R 7 , -R , -ORio, -SRio, -NRioRio, -C(O)R ⁇ o, -C(O)NR ⁇ oR ⁇ o, -CN, -NR ⁇ 0 C(O)R, 0) -S(O) 2 NR, 0 R l0 , -NR, 0 S(O) 2 R, 0 , phenyl, or substituted phenyl;
• Alkynyl is straight and branched-chain moieties having from 2-6 carbon atoms and having at least one carbon-carbon triple bond;
• Halogenated alkynyl is an unsaturated alkynyl moiety having from 3-6 carbon atoms and having 1 to (2n-3) substituent(s) independently selected from -F, -CI, -Br, or -I where n is the maximum number of carbon atoms in the moiety;
• Substituted alkynyl is an unsaturated alkynyl moiety having from 3-6 carbon atoms and having 0-3 substituents independently selected from -F, or -CI, and further having 1 substituent selected from -R 7 , -R , -ORio, -SR ⁇ 0 , -NR i0 R ⁇ o, -C(O)R ⁇ 0 , -CN, -C(O)NR ⁇ oR ⁇ o, -NR K )C(O)R,o, -S(O) 2 NR ⁇ 0 R ⁇ o, -NR ⁇ 0 S(O) 2 R ⁇ o, phenyl, or substituted phenyl;
• Halogenated cycloalkyl is a cyclic moiety having from 3-6 carbon atoms and having 1-4 substituents independently selected from -F, or -CI;
• Substituted cycloalkyl is a cyclic moiety having from 3-6 carbon atoms and having 0-3 substituents independently selected from -F, or -CI, and further having 1 substituent selected from -ORio, -SRio, -NR, 0 R ⁇ o, -C(O)R ⁇ 0 , -C(O)NR ⁇ 0 R ⁇ o, -CN, -NRi 0 C(O)Rio, -S(O) 2 NRi 0 Rio, -NR ⁇ 0 S(O) 2 R ⁇ o, -NO 2 , phenyl, or substituted phenyl;
• Heterocycloalkyl is a cyclic moiety having 4-7 atoms with 1-2 atoms within the ring being -S-
• Halogenated heterocycloalkyl is a cyclic moiety having from 4-7 atoms with 1-2 atoms within the ring being -S-, -N(R 3 )-, or -O-, and having 1-4 substituents independently selected from -F, or -CI;
• Substituted heterocycloalkyl is a cyclic moiety having from 4-7 atoms with 1-2 atoms within the ring being -S-, -N(R 3 )-, or -O- and having 0-3 substituents independently selected from -F, or -CI, and further having 1 substituent selected from -ORio, -SR.o, -NRioR.o, -C(O)R, 0 , -C(O)NR 10 R ⁇ o, -CN, -NR, 0 C(O)R 10 , -NO 2 , -S(O) 2 NR ⁇ oR ⁇ o, -NR ⁇ 0 S(
• alkyl alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, halogenated alkyl, halogenated alkenyl, halogenated alkynyl, halogenated cycloalkyl, halogenated heterocycloalkyl, substituted alkyl, substituted alkenyl, substituted alkynyl, substituted cycloalkyl, substituted heterocycloalkyl, limited substituted alkyl, limited substituted alkenyl, limited substituted alkynyl, aryl, -OR 8 , -ORu, -SR 8 , -SR , -F, -CI, -Br, -I, -NR 8 R 8 , -NR14R14, -C(O)R 8 , -C(O)R, 4 , -C(O)NR 8 R 8 , -C(O)NR, 4 R, 4 , -CN,
• Limited substituted alkenyl is a substituted alkenyl having from 1-6 carbon atoms and having 0-3 substituents independently selected from -F, -CI, -Br, or -I, and further having 1 substituent on either only the ⁇ carbon and selected from -ORn, -SRn, -NR,,Rn, -C(O)RNase, -NO 2 , -C(O)NR necessarilyRn, -CN, -NR, 0 C(O)R n , -S(O) 2 NRi 0 Rio, or -NR ⁇ 0 S(O) 2 R ⁇ 0 , or on any carbon with sufficient valency but not on the ⁇ carbon and selected from -R 7 , -R 9 , -ORio, -SRio, ⁇ NR
• Limited substituted alkynyl is a substituted alkynyl having from 1-6 carbon atoms and having 0-3 substituents independently selected from -F, -CI, -Br, or -I, and further having 1 substituent on either only the ⁇ carbon and selected from -ORn, -SR,,, -NRnRn, -C(O)Rlois, -NO 2 , -C(O)NR,,R,,, -CN, -NR 10 C(O)R punishment, -S(O)2NRi 0 Rio, or -NR ⁇ 0 S(O)2R ⁇ o, or on any carbon with sufficient valency but not on the ⁇ carbon and selected from -R 7 , -R 9 , -ORio, -SRio, -NRioRio, -C(O)R ⁇ 0 , -NO 2 , -C(O)NR ]0 Rio, -CN, -NR ⁇ 0 C
• R 7 is a 9-membered fused-ring moiety having a 6-membered ring fused to a 5-membered ring and having the formula
• E is O, S, or NR 3 ,
• E and G are independently selected from CR ⁇ , O, S, or NR , and A is CR ⁇ 8 or N, or
• E and G are independently selected from CR] 8 , O, S, or NR 3 , and A is CR ⁇ 8 or N, each 9-membered fused-ring moiety having 0-1 substituent selected from -R ⁇ 2 and 0-3 substituent(s) independently selected from -F, -CI, -Br, or -I, and having a bond directly or indirectly attached to the core molecule where valency allows in either the 6-membered or the 5-membered ring of the fused-ring moiety;
• Each R 8 is independently selected from -H, alkyl, halogenated alkyl, substituted alkyl, cycloalkyl, halogenated cycloalkyl, substituted cycloalkyl, heterocycloalkyl, halogenated heterocycloalkyl, substituted heterocycloalkyl, -R 7 , -R 9 , phenyl, or substituted phenyl;
• Each Rio is independently selected from -H, alkyl, cycloalkyl, heterocycloalkyl, alkyl substituted with 1 substituent selected from R ⁇ 3 , cycloalkyl substituted with 1 substituent selected from R ⁇ 3 , heterocycloalkyl substituted with 1 substituent selected from Rj 3 , halogenated alkyl, halogenated cycloalkyl, halogenated heterocycloalkyl, phenyl, substituted phenyl, -R 7 , or -R 9 ;
• Each R11 is independently selected from -H, alkyl, cycloalkyl, heterocycloalkyl, halogenated alkyl, halogenated cycloalkyl, or halogenated heterocycloalkyl;
• R1 2 is selected from -ORn, -SRn, alkyl, cycloalkyl, heterocycloalkyl, halogenated alkyl, halogenated cycloalkyl, halogenated heterocycloalkyl, substituted alkyl, substituted cycloalkyl, substituted heterocycloalkyl, -NRnRn, -C(O)R ⁇ 1, -NO 2 , -C(O)NR ⁇ ⁇ , -CN, -NRnC(O)R, rule -S(O)2NR,,Rn, or -NRnS(O) 2 Rn;
• Ri 3 is selected from -ORn, -SRn, -NRnRn, -C(O)Rn, -C(O)NR n Rn, -CN, -NR, ,C(O)Rn, -S(O) 2 NRnRn, -NR, ,S(O) 2 Rn, -CF 3 , or -NO 2 ;
• R ⁇ 4 is independently selected from -H, alkyl, halogenated alkyl, limited substituted alkyl, cycloalkyl, halogenated cycloalkyl, substituted cycloalkyl, heterocycloalkyl, halogenated heterocycloalkyl, substituted heterocycloalkyl;
• 8 is independently selected from -H, alkyl, cycloalkyl, heterocycloalkyl, halogenated alkyl, halogenated cycloalkyl, halogenated heterocycloalkyl, substituted alkyl, substituted cycloalkyl, substituted heterocycloalkyl, -ORn, -SR, ,, -NR, ,R, ⁇ , -C(O)Rn, -NO 2 , -C(O)NR n Rn, -CN, -NR, ⁇ C(O)R, ,, -S(O) 2 NR, iRn, or -NR ⁇ ,S(O) 2 Rn, -F, -CI, -Br, or -I, or a bond directly or indirectly attached to the core molecule, provided that there is only one said bond to the core molecule within the 9-membered fused-ring moiety, further provided that the fused-ring moiety has 0
• Room temperature is within the range of 15-25 degrees Celsius.
• AChR refers to acetylcholine receptor.
• nAChR refers to nicotinic acetylcholine receptor.
• 5HT 3 R refers to the serotonin-type 3 receptor.
• FLIPR refers to a device marketed by Molecular Devices, Inc. designed to precisely measure cellular fluorescence in a high throughput whole-cell assay.
• TLC refers to thin-layer chromatography
• HPLC refers to high pressure liquid chromatography.
• MeOH refers to methanol.
• EtOH refers to ethanol.
• IPA refers to isopropyl alcohol.
• THF refers to tetrahydrofuran
• DMSO dimethylsulfoxide
• DMF refers to dimethylformamide.
• EtOAc refers to ethyl acetate.
• TMS refers to tetramethylsilane.
• TEA refers to triethylamine
• HATU refers to O-(7-azabenzotriazol-l-yl)-N,N,N', N'-tetramethyluronium hexafluorophosphate.
• DIEA refers to N,N-diisopropylefhylarnine.
• MLA refers to methyllycaconitine
• Ether refers to diethyl ether.
• KH 2 PO 4 refers to potassium phosphate, monobasic.
• NaClO 2 refers to sodium chlorite.
• t-BuOH refers to tert-butanol.
• Na 2 SO 4 refers to sodium sulfate.
• MgSO refers to magnesium sulfate.
• K. 2 CO 3 refers to potassium carbonate.
• NH 4 OH refers to ammonium hydroxide
• NaHCO 3 refers to sodium bicarbonate.
• CH 3 CN refers to acetonitrile
• the ⁇ carbon is determined by counting the longest carbon chain of the alkyl moiety with the C-1 carbon being the carbon attached to the W moiety of the core molecule and the O carbon being the carbon furthest, e.g., separated by the greatest number of carbon atoms in the chain, from said C-1 carbon;
• the core molecule is the quinuclidinyl-(carboxamide-type moiety)-W:
• the O carbon is the carbon furthest from the core molecule and the C-1 carbon is the carbon attached to the core molecule by attachment to the W moiety of the core molecule.
• the carbon atom content of various hydrocarbon-containing moieties is indicated by a prefix designating the minimum and maximum number of carbon atoms in the moiety, i.e., the prefix . j indicates a moiety of the integer 'i" to the
• C ⁇ -6 alkyl refers to alkyl of one to six carbon atoms, inclusive.
• Halogen is F, CI, Br, or I.
• Alkyl is both straight and branched-chain moieties having from 1-6 carbon atoms.
• Halogenated alkyl is an alkyl moiety having from 1-6 carbon atoms and having 1 to (2n+l) halogen atom(s) independently selected from -F, -CI, -Br, or -I where n is the maximum number of carbon atoms in the moiety.
• Substituted alkyl is an alkyl moiety having from 1-6 carbon atoms and having 0-3 substituents independently selected from -F, -CI, -Br, or -I, and further having 1 substituent selected from -R 7 , -R 9 , -ORu,, -SR, 0 , -NRioRio, -C(O)R ⁇ 0 , -NO 2 , -C(O NR IO R ⁇ o, -CN, -NR,oC(O)R ⁇ o, -S(O) 2 NR ⁇ 0 R.o, -NR, 0 S(O) 2 R ⁇ o, phenyl, or substituted phenyl.
• Limited substituted alkyl is a substituted alkyl having from 1-6 carbon atoms and having 0-3 substituents independently selected from -F, -CI, -Br, or -I, and further having 1 substituent on either only the co carbon and selected from -ORn, -SRn, -NRnRn, -C(O)R ⁇ ,, -NO 2 , -C(O)NR, ⁇ R, puzzle -CN, -NR J0 C(O)R, ,, -S(O) 2 NR 10 R ⁇ o, or -NR] 0 S(O) 2 R ⁇ o, or on any carbon with sufficient valency but not on the co carbon and selected from -R 7 , -R 9 , -OR, 0 , -SRio, -NR, 0 R ⁇ o, -C(O)R ⁇ 0 , -NO 2 , -C(O)NR 10 R, 0 , -CN, -NRio
• Alkenyl is straight and branched-chain moieties having from 2-6 carbon atoms and having at least one carbon-carbon double bond.
• Halogenated alkenyl is an unsaturated alkenyl moiety having from 2-6 carbon atoms and having 1 to (2n-l) halogen atom(s) independently selected from -F, -CI, -Br, or -I where n is the maximum number of carbon atoms in the moiety.
• Substituted alkenyl is an unsaturated alkenyl moiety having from 2-6 carbon atoms and having 0-3 substituents independently selected from -F, or -CI, and further having 1 substituent selected from -R 7 , -R 9 , -ORio, -SRio, -NRioRio, -C(O)R ⁇ o, -C(O)NR ⁇ oR ⁇ o, -CN, -NR ⁇ 0 C(O)R, 0 , -S(O) 2 NR,oR 10 , -NR 10 S(O) 2 R ⁇ o, phenyl, or substituted phenyl.
• Limited substituted alkenyl is a substituted alkenyl having from 1-6 carbon atoms and having 0-3 substituents independently selected from -F, -CI, -Br, or -I, and further having 1 substituent on either only the co carbon and selected from -ORn, -SRn, -NR necessarilyRn, -C(O)R réelle, -NO 2 , -C(O)NRnR n , -CN, -NR, 0 C(O)R, mecanic -S(O) 2 NRi 0 Rio, or -NR ⁇ 0 S(O) 2 R ⁇ 0 , or on any carbon with sufficient valency but not on the co carbon and selected from -R 7 , -R 9 , -OR ⁇ 0 , -SRio, -NRioRio, -C(O)R ⁇ 0 , -NO 2 , -C(O)NRi 0 R 10 , -CN, -NR
• Alkynyl is straight and branched-chain moieties having from 2-6 carbon atoms and having at least one carbon-carbon triple bond.
• Halogenated alkynyl is an unsaturated alkynyl moiety having from 3-6 carbon atoms and having 1 to (2n-3) halogen atom(s) independently selected from -F, -CI, -Br, or -I where n is the maximum number of carbon atoms in the moiety.
• Substituted alkynyl is an unsaturated alkynyl moiety having from 3-6 carbon atoms and having 0-3 substituents independently selected from -F, or -CI, and further having 1 substituent selected from -R 7 , -R 9 , -ORio, -SRio, -NRioRio, -C(O)R ⁇ 0 , -CN, -C(O)NR ⁇ oR ⁇ o, -NR ⁇ oC(O)R,o, -S(O) 2 NR ⁇ 0 R ⁇ o, -NR, 0 S(O) 2 R ⁇ o, phenyl, or substituted phenyl.
• Limited substituted alkynyl is a substituted alkynyl having from 1-6 carbon atoms and having 0-3 substituents independently selected from -F, -CI, -Br, or -I, and further having 1 substituent on either only the ⁇ carbon and selected from -ORn, -SR M , -NRnR , -C(O)RNase, -NO 2 , -C(O)NR necessarilyRn, -CN, -NR, 0 C(O)Rn, -S(O) 2 NR ⁇ oR ⁇ o, or -NR ⁇ oS(O) 2 R ⁇ o, or on any carbon with sufficient valency but not on the ⁇ carbon and selected from -R 7 , -R 9 , -ORj 0 , -SRio, -NRioRio, -C(O)R ⁇ o, -NO 2 , -C(O)NR, 0 Rio, -CN, -NR 10 C(
• Cycloalkyl is a cyclic alkyl moiety having from 3-6 carbon atoms.
• Halogenated cycloalkyl is a cyclic moiety having from 3-6 carbon atoms and having 1-4 substituents independently selected from -F, or -CI.
• Substituted cycloalkyl is a cyclic moiety having from 3-6 carbon atoms and having 0-3 substituents independently selected from -F, or -CI, and further having 1 substituent selected from -OR
• Heterocycloalkyl is a cyclic moiety having 4-7 atoms with 1-2 atoms within the ring being -S-, -N(R 3 )- or -O-.
• Halogenated heterocycloalkyl is a cyclic moiety having from 4-7 atoms with 1-2 atoms within the ring being -S-, -N(R 3 )-, or -O-, and having 1-4 substituents independently selected from -F, or -CI.
• Substituted heterocycloalkyl is a cyclic moiety having from 4-7 atoms with 1-2 atoms within the ring being -S-, -N(R 3 )-, or -O- and having 0-3 substituents independently selected from -F, or -CI, and further having 1 substituent selected from -ORio, -SRio, -NRioRio, -C(O)R 10 , -C(O)NR l0 R l0 , -CN, -NR, 0 C(O)R, 0 , -NO 2 , -S(0) 2 NR ⁇ 0 R ⁇ o, -NRi 0 S(O) 2 Rio, phenyl, or substituted phenyl.
• Substituted benzyl is a benzyl either having 1-4 substituents independently selected from -F, -CI, -Br, or -I, or having 1 substituent selected from -R 12 and 0-3 substituents independently selected from -F, -CI, -Br, or -I, provided that all substitution is on the phenyl ring of the benzyl.
• Aryl is phenyl, substituted phenyl, naphthyl, or substituted naphthyl.
• Substituted phenyl is a phenyl either having 1-4 substituents independently selected from -F, -CI, -Br, or -I, or having 1 substituent selected from -R 12 and 0-3 substituents independently selected from -F, -CI, -Br, or -I.
• Substituted naphthyl is a naphthalene moiety either having 1-4 substituents independently selected from -F, -CI, -Br, or -I, or having 1 substituent selected from -Ri 2 and 0-3 substituents independently selected from -F, -CI, -Br, or -I, where the substitution can be independently on either the same ring or different rings of said naphthalene moiety.
• Mammal denotes human and other mammals.
• Brine refers to an aqueous saturated sodium chloride solution.
• IR refers to infrared spectroscopy.
• Lv refers to leaving groups within a molecule, including Br, CI, OH, or mixed anhydride.
• NMR nuclear (proton) magnetic resonance spectroscopy
• MS refers to mass spectrometry expressed as m e or mass/charge unit.
• HRMS refers to high resolution mass spectrometry expressed as m/e or mass/charge unit.
• M+H + refers to the positive ion of a parent plus a hydrogen atom.
• M-H " refers to the negative ion of a parent minus a hydrogen atom.
• M+Na + refers to the positive ion of a parent plus a sodium atom.
• M+K + refers to the positive ion of a parent plus a potassium atom.
• El refers to electron impact.
• ESI refers to electrospray ionization.
• CI refers to chemical ionization.
• FAB refers to fast atom bombardment.
• compositions of the present invention may be in the form of pharmaceutically acceptable salts.
• pharmaceutically acceptable salts refers to salts prepared from pharmaceutically acceptable non-toxic bases including inorganic bases and organic bases, and salts prepared from inorganic acids, and organic acids. Salts derived from inorganic bases include aluminum, ammonium, calcium, ferric, ferrous, lithium, magnesium, potassium, sodium, zinc, and the like.
• Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, such as arginine, betaine, caffeine, choline, N, N- dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylamino- ethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, and the like.
• cyclic amines such as arginine, betaine, caffeine, choline, N, N
• Salts derived from inorganic acids include salts of hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, phosphorous acid and the like.
• Salts derived from pharmaceutically acceptable organic non-toxic acids include salts of C ⁇ _6 alkyl carboxylic acids, di-carboxylic acids, and tri-carboxylic acids such as acetic acid, propionic acid, fumaric acid, succinic acid, tartaric acid, maleic acid, adipic acid, and citric acid, and aryl and alkyl sulfonic acids such as toluene sulfonic acids and the like.
• an effective amount of a compound as provided herein is meant a nontoxic but sufficient amount of the compound(s) to provide the desired effect.
• the exact amount required will vary from subject to subject, depending on the species, age, and general condition of the subject, the severity of the disease that is being treated, the particular compound(s) used, the mode of administration, and the like. Thus, it is not possible to specify an exact "effective amount.” However, an appropriate effective amount may be determined by one of ordinary skill in the art using only routine experimentation.
• the compounds of Formula I have optically active center(s) on the quinuclidine ring. Although it is desirable that the stereochemical purity be as high as possible, absolute purity is not required.
• This invention involves racemic mixtures and compositions of varying degrees of streochemical purities. It is preferred to carry out stereoselective syntheses and/or to subject the reaction product to appropriate purification steps so as to produce substantially optically pure materials. Suitable stereoselective synthetic procedures for producing optically pure materials are well known in the art, as are procedures for purifying racemic mixtures into optically pure fractions.
• the preferred compounds of the present invention have the R configuration at the C3 position of the quinuclidine ring. It is also preferred for the compounds of the present invention that X is O. Another group of compounds of Formula I includes compounds wherein X is O and Ri is H. Another group of compounds of Formula I includes compounds wherein X is O and R 2 is H. Another group of compounds of Formula I includes compounds wherein X is O and R 2 is alkyl, halogenated alkyl, substituted alkyl, cycloalkyl, benzyl, substituted benzyl, or aryl.
• the amount of therapeutically effective compound(s) that is administered and the dosage regimen for treating a disease condition with the compounds and/or compositions of this invention depends on a variety of factors, including the age, weight, sex and medical condition of the subject, the severity of the disease, the route and frequency of administration, and the particular compound(s) employed, and thus may vary widely.
• the compositions contain well know carriers and excipients in addition to a therapeutically effective amount of compounds of Formula I.
• the pharmaceutical compositions may contain active ingredient in the range of about 0.001-100 mg/kg/day for an adult, preferably in the range of about 0.1-50 mg/kg/day for an adult. A total daily dose of about 1-1000 mg of active ingredient may be appropriate for an adult.
• the daily dose can be administered in 1-4 doses per day.
• the composition for therapeutic use may also comprise one or more non-toxic, pharmaceutically acceptable carrier materials or excipients.
• carrier material or excipient herein means any substance, not itself a therapeutic agent, used as a carrier and/or diluent and/or adjuvant, or vehicle for delivery of a therapeutic agent to a subject or added to a pharmaceutical composition to improve its handling or storage properties or to permit or facilitate formation of a dose unit of the composition into a discrete article such as a capsule or tablet suitable for oral administration.
• Excipients can include, by way of illustration and not limitation, diluents, disintegrants, binding agents, adhesives, wetting agents, polymers, lubricants, glidants, substances added to mask or counteract a disagreeable taste or odor, flavors, dyes, fragrances, and substances added to improve appearance of the composition.
• Acceptable excipients include lactose, sucrose, starch powder, cellulose esters of alkanoic acids, cellulose alkyl esters, talc, stearic acid, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric and sulfuric acids, gelatin, acacia gum, sodium alginate, polyvinyl- pyrrolidone, and/or polyvinyl alcohol, and then tableted or encapsulated for convenient administration.
• Such capsules or tablets may contain a controlled-release formulation as may be provided in a dispersion of active compound in hydroxypropyl- methyl cellulose, or other methods known to those skilled in the art.
• the pharmaceutical composition may be in the form of, for example, a tablet, capsule, suspension or liquid. If desired, other active ingredients may be included in the composition.
• compositions of the present invention may be administered by any suitable route, in the form of a pharmaceutical composition adapted to such a route, and in a dose effective for the treatment intended.
• the compositions may, for example, be administered parenterally, e.g., intravascularly, intraperitoneally, subcutaneously, or intramuscularly.
• parenteral administration e.g., saline solution, dextrose solution, or water may be used as a suitable carrier.
• Formulations for parenteral administration may be in the form of aqueous or non-aqueous isotonic sterile injection solutions or suspensions.
• solutions and suspensions may be prepared from sterile powders or granules having one or more of the carriers or diluents mentioned for use in the formulations for oral administration.
• the compounds may be dissolved in water, polyethylene glycol, propylene glycol, ethanol, corn oil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodium chloride, and/or various buffers.
• Other adjuvants and modes of administration are well and widely known in the pharmaceutical art.
• the serotonin type 3 receptor is a member of a superfamily of ligand- gated ion channels, which includes the muscle and neuronal nAChR, the glycine receptor, and the ⁇ -aminobutyric acid type A receptor. Like the other members of this receptor superfamily, the 5HT 3 R exhibits a large degree of sequence homology with 7 nAChR but functionally the two ligand-gated ion channels are very different. For example, al nAChR is rapidly inactivated, is highly permeable to calcium and is activated by acetylcholine and nicotine. On the other hand, 5HT 3 R is inactivated slowly, is relatively impermeable to calcium and is activated by serotonin.
• al nAChR and 5HT 3 R proteins have some degree of homology, but function very differently. Indeed the pharmacology of the channels is very different. For example, Ondansetron, a highly selective 5HT R antagonist, has little activity at the al nAChR. The converse is also true. For example, GTS-21, a highly selective ⁇ 7 nAChR agonist, has little activity at the 5HT R.
• al nAChR is a ligand-gated Ca ++ channel formed by a homopentamer of al subunits.
• al nAChR binds selectively to this homopetameric, al nAChR subtype, and that al nAChR has a high affinity binding site for both ⁇ -btx and methyllycaconitine (MLA).
• al nAChR is expressed at high levels in the hippocampus, ventral tegmental area and ascending cholinergic projections from nucleus basilis to thalamocortical areas, al nAChR agonists increase neurotransmitter release, and increase cognition, arousal, attention, learning and memory.
• Schizophrenia is a complex multifactorial illness caused by genetic and non- genetic risk factors that produce a constellation of positive and negative symptoms.
• the positive symptoms include delusions and hallucinations and the negative symptoms include deficits in affect, attention, cognition and information processing.
• No single biological element has emerged as a dominant pathogenic factor in this disease. Indeed, it is likely that schizophrenia is a syndrome that is produced by the combination of many low penetrance risk factors.
• Clozapine an "atypical" antipsychotic drug, is novel because it is effective in treating both the positive and some of the negative symptoms of this disease. Clozapine' s utility as a drug is greatly limited because continued use leads to an increased risk of agranulocytosis and seizure. No other antipsychotic drag is effective in treating the negative symptoms of schizophrenia. This is significant because the restoration of cognitive functioning is the best predictor of a successful clinical and functional outcome of schizophrenic patients (Green, M.F., Am J Psychiatry, 153:321- 30, 1996). By extension, it is clear that better drugs are needed to treat the cognitive disorders of schizophrenia in order to restore a better state of mental health to patients with this disorder.
• One aspect of the cognitive deficit of schizophrenia can be measured by using the auditory event-related potential (P50) test of sensory gating.
• P50 auditory event-related potential
• EEG electroencepholographic
• Normal individuals respond to the first click with greater degree than to the second click.
• schizophrenics and schizotypal patients respond to both clicks nearly the same (Cullum, CM. et. al., Schizophr. Res., 10:131-41, 1993).
• biochemical data indicate that schizophrenics have 50% fewer of al nAChR receptors in the hippocampus, thus giving a rationale to partial loss of al nAChR functionality (Freedman, R. et. al., Biol. Psychiatry, 38:22-33, 1995).
• genetic data indicate that a polymorphism in the promoter region of the al nAChR gene is strongly associated with the sensory gating deficit in schizophrenia (Freedman, R. et. al., Proc. Natl. Acad. Sci. USA, 94(2):587-92, 1997; Myles-Worsley, M. et. al, Am. J. Med.
• schizophrenics express the same ⁇ 7 nAChR as non-schizophrenics.
• Selective ⁇ 7 nAChR agonists may be found using a functional assay on FLIPR (see WO 00/73431 A2).
• FLIPR is designed to read the fluorescent signal from each well of a 96 or 384 well plate as fast as twice a second for up to 30 minutes.
• This assay may be used to accurately measure the functional pharmacology of ⁇ 7 nAChR and 5HT 3 R.
• To conduct such an assay one uses cell lines that expressed functional forms of the ⁇ 7 nAChR using the ⁇ 7/5-HT 3 channel as the drug target and cell lines that expressed functional 5HT 3 R. In both cases, the ligand-gated ion channel was expressed in SH-EPl cells.
• the compounds of the present invention are ⁇ 7 nAChR agonists and may be used to treat a wide variety of diseases. For example, they may be used in treating schizophrenia, and psychosis.
• Schizophrenia is a disease having multiple aspects.
• drugs are generally aimed at controlling the positive aspects of schizophrenia, such as delusions.
• One drug, Clozapine is aimed at a broader spectrum of symptoms associated with schizophrenia. This drug has many side effects and is thus not suitable for many patients.
• a drug to treat the cognitive and attention deficits associated with schizophrenia.
• schizoaffective disorders or similar symptoms found in the relatives of schizophrenic patients.
• Psychosis is a mental disorder characterized by gross impairment in the patient's perception of reality.
• the patient may suffer from delusions, and hallucinations, and may be incoherent in speech. His behavior may be agitated and is often incomprehensible to those around him.
• psychosis has been applied to many conditions that do not meet the stricter definition given above. For example, mood disorders were named as psychoses.
• the conventional antipsychotic drugs include Chlo romazine, Fluphenazine, Haloperidol, Loxapine, Mesoridazine, Molindone, Peiphenazine, Pimozide, Thioridazine, Thiothixene, and Trifluoperazine. These drugs all have an affinity for the dopamine 2 receptor.
• Atypical antipsychotic drugs generally are able to alleviate positive symptoms of psychosis while also improving negative symptoms of the psychosis to a greater degree than conventional antipsychotics. These drugs may improve neurocognitive deficits. Extrapyramidal (motor) side effects are not as likely to occur with the atypical antipsychotic drugs, and thus, these atypical antipsychotic drags have a lower risk of producing tardive dyskinesia. Finally these atypical antipsychotic drugs cause little or no elevation of prolactin. Unfortunately, these drags are not free of side effects.
• the side effects include: agranulocytosis; increased risk of seizures, weight gain, somnolence, dizziness, tachycardia, decreased ejaculatory volume, and mild prolongation of QTc interval.
• the compounds of the present invention may be used in combination therapy with typical and atypical anti-psychotic drugs. All compounds within the present invention are useful for and may also be used in combination with each other to prepare pharmaceutical compositions. Such combination therapy lowers the effective dose of the anti-psychotic drug and thereby reduces the side effects of the anti-psychotic drugs.
• Some typical anti-psychotic drugs that may be used in the practice of the invention include Haldol.
• Some atypical anti-psychotic drugs include Ziprasidone, Olanzapine, Resperidone, and Quetiapine.
• the acid when W is a thiophene or in some furan cases, the acid is converted into a mixed anhydride by treatment with diphenylchlorophosphate in the presence of TEA and CH 2 C1 2 as the solvent.
• the resulting anhydride solution is directly reacted with aminoquinuclidine using aqueous DMF as the solvent.
• W is furan, oxazole, oxadiazole, pyrrole, 5-thiazole, thiophene, or triazole
• the acid is activated with a uronium salt, preferably HATU (see J. Am. Chem.
• the thiophene acids required in Examples 1-11, 13, and 41-42 can be synthesized from the corresponding aldehydes by oxidation with NaClO 2 as described in J. Chem. Soc. Perkin Trans. I., 789-794 (1999). The requisite aldehydes can be made as described in J. Med. Chem., 1585-1599 (1997).
• An aryl boronic acid is reacted with a bromothiophene in the presence of a palladium (0) source, such as tetrakis- (triphenylphosphine)palladium (0), and a base, preferably aqueous sodium carbonate.
• a palladium (0) source such as tetrakis- (triphenylphosphine)palladium (0)
• a base preferably aqueous sodium carbonate.
• the reaction works best if heated at reflux in THF/water for 24 hours.
• the thiophene acids for Examples 31-40 are synthesized from the corresponding esters by base catalyzed hydrolysis. Typical hydrolysis procedures are well known in the art.
• the thiophene ester is treated with aqueous lithium hydroxide in a solvent such as dioxane.
• the esters are either commercially available or synthesized by reaction of a bromothiophene ester with the appropriate thiophenol or phenol as described in Coll. Czech. Chem. Comm., 2360-2363 (1980). Namely, the sodium salt of the thiophenol or phenol is formed by treatment with a strong base like sodium hydride. The sodium salt is then reacted with a bromothiophene in a solvent such as acetone.
• the required acids for Examples 44-49 are prepared by nucleophilic addition of the requisite phenol or thiophenol to 2-bromo-l,3-thiazole-5- carboxylic ethyl ester according to the procedure described in Helv. Chim. Ada., 2002-2022 (1997).
• EtOH utilizing K 2 CO 3 as a base (Scheme 3).
• the esters are hydiolyzed to the corresponding acids by procedures well known in the art.
• the 2-bromo-l,3-thiazole is prepared by the method described in Roczniki Chemii
• the aryl 1,3-thiazole for Example 50 is prepared according to the procedure of Huntress and Pfister in J. Am. Chem. Soc, 2167-2169 (1943).
• the requisite l,3-thiazoles-5-acids for Examples 51 and 58-62 are commercially available.
• the l,3-thiazole-5-acids required in Examples 52-57 can be synthesized from the corresponding esters by base hydrolysis via procedures well known in the art.
• the requisite esters can be prepared by a Suzuki reaction as described in J. Med. Chem., 4985-92 (1995).
• aryl boronic acid is reacted with a bromothiazole ester in the presence of a palladium (0) source, such as tetrakis- (triphenylphosphine)palladium (0), and a base, preferably aqueous sodium carbonate.
• a palladium (0) source such as tetrakis- (triphenylphosphine)palladium (0)
• a base preferably aqueous sodium carbonate.
• 1,3,4-thiadiazole esters for Examples 64-72 are synthesized by nucleophilic addition of the requisite phenol or thiophenol to 2-bromo-l,3,4-thiadiazolezole-5- carboxylic ethyl ester as described in Can. J. Chem., 243-250 (1977) (Scheme 3).
• Example 75 and the oxadiazole for Example 76 are prepared by the methods of McKillop et al., Tetrahedron Lett. 23, 3357-3360 (1982) with modifications as described herein.
• the oxadiazole for Example 77 is prepared following the procedures of Snyder in J. Org. Chem. 3257-3269 (1990), Muchowski in Can. J. Chem. 3079-3082 (1972), and Crenshaw in US 4,001,238.
• the 5-substituted-l,3-oxazole-2-esters for Examples 79-88 are synthesized according to procedures described in J. Pharm. Soc. Japan, 305-7 (1956) as shown in Scheme 4.
• the 5-substituted-l,3-thiazole-2-esters for Examples 89-102 are synthesized according to procedures described in Chem. Pharm. Bull., 4195-4198 (1982).
• furans for Examples 103-130 are commercially available or can be prepared from their corresponding aldehydes or esters as described for the thiophenes (Examples 1-11). hi the event that the furan is not commercially available, it can be prepared by the method of Bussolari and Rehborn described in Org. Lett. 965-7 ( 1999).
• Furan Examples 131 - 146 are prepared in a convergent means by a direct palladium catalyzed Suzuki coupling N-[(3R)-l-azabicyclo[2.2.2]oct-3-yl]-5-bromo- furan-2-carboxamide with the requisite boronic acid by the method described in Org. Lett. 965-7 (1999), to yield directly the desired aryl amides (Scheme 5).
• Examples 12, and 147- 149 are prepared by reduction of the corresponding aryl nitro compounds by methods well known in the art, preferably by reduction with Pd/C in an alcoholic solvent such as EtOH under H 2 .
• the acid for example 150 is prepared by a Pd(0) catalyzed Sonogashira coupling of 5-bromo-2-furanal and phenyl acetylene as described in Tetrathedron Lett., 4467-70 (1975). The resulting aldehyde is converted to the desired analog by methods as described for Example 103.
• Example 151 is prepared by addition of the sodium salt of phenol to N-[(3R)-l-azabicyclo[2.2.2]oct-3-yl]-5- bromo-furan-2-carboxamide.
• the requisite acid for Example 152 is prepared by bromination of methyl-5-bromo- 1 -methyl- 1 H-pyrrole-2-carboxylate, followed by similar Pd-catalyzed coupling as described for Example 1.
• Example 153 The l,3-oxazole-2-carboxylic acid required for Example 153 is prepared by the method described in J. Pharm. Sci. Japan 305-7, (1956). 3-Phenyl- 1,2,4- oxadiazole-5-carboxylic acid required for Example 154 is prepared by the method of Wurm as described in Chem. Ber., 3133, (1889). The 2-phenyl-l,3-oxazole-5- carboxylic acid required for Example 155 is prepared by the method described in Chem. Heterocycl. Compd. (Engl.Transl.), 654-663, (1986).
• Example 156 2-Phenyl-l,3-oxazole-4- carboxylic acid required for Example 156 is prepared as described by Korte and Stoeriko, in Chem. Ber., 1033-1042, (1960).
• the 5-phenylisoxazole-3-carboxylic acid for Example 157 is prepared by the method of Vaughan and Spencer as described in J. Org. Chem. 1160-4, (1960).
• Thioamides such as Example 159
• the thioester can be prepared as described in J. Organometallic Chem., 95-98 (1987).
• One of ordinary skill in the art would quickly identify that compounds such as Example 159 could also be prepared directly from the amides exemplified throughout this patent by direct treatment with a reagent such and Lawesson's reagent (see Lawesson et. al. in Bull. Soc. Chim. Belg., 229 (1978)) or P 4 S ⁇ 0 (see Chem. Rev., 45 (1961)).
• Step 1 a Preparation of 5-phenylthiophene-2-carboxaldehyde.
• 5-Bromothiophene-2-carboxaldehyde (l.Og, 5.2 mmol) is added to a solution of tetrakis(triphenylphosphine)palladium(0) (180 mg, 0.16 mmol) in degassed THF (lOmL). The resulting solution is stirred for 5 minutes. A solution of phenylboronic acid (760 mg, 6.2 mmol) in THF (lOmL) is added followed by aqueous Na 2 CO 3 (2M, 5.2mL). The mixture is heated at reflux for 24 hours. The reaction mixture is allowed to cool, poured into ether, and washed twice with water. The ether layer is dried over Na 2 SO 4 and concentrated in vaeuo.
• Step lb Preparation of 5-phenylthiophene-2-carboxylic acid.
• Step la The product of Step la (750 mg, 4 mmol) is dissolved in a mixture of THF, t- BuOH, and water (2: 1:1, 60 mL). KH 2 PO 4 (1.36 g, 10 mmol) is added followed by NaClO 2 (900 mg, 10 mmol). The mixture is stirred at room temperature for 5 days. Aqueous NaOH (2M, 10 mL) is added, and a majority of the organic solvents are removed in vaeuo yielding an aqueous suspension. This suspension is diluted with water and washed three times with CH 2 C1 2 . The aqueous layer is acidified to pH ⁇ 6 with 25% H 2 SO and the product is extracted three times with CH 2 C1 2 .
• Step lc Preparation of N-[(3R)-l-azabicyclo[2.2.2]oct-3-yl]-5-phenyl- thiophene-2-carboxamide hydrochloride.
• TEA 210 ⁇ L, 1.5mmol
• Example 2 N-[(3R)-l-azabicyclo[2.2.2]oct-3-yl]-5-(4-chlorophenyl)-thiophene-2- carboxamide hydrochloride (from 4-chlorophenylboronic acid). Yield 24% for 3 steps. MS for C, 8 H ⁇ 9 ClN 2 OS (ESI) (M+H) + m/z 347.
• Example 3 N-[(3R)-l-azabicyclo[2.2.2]oct-3-yl]-5-(3-chlorophenyl)-thiophene-2- carboxamide hydrochloride (from 3-chlorophenylboronic acid). Yield 16%. MS for C, 8 H ⁇ 9 ClN 2 OS (ESI) (M+H) + m/z 347.
• Example 5 N-[(3R)-l-azabicyclo[2.2.2]oct-3-yl]-2,3'-bithiophene-5-carboxamide hydrochloride (from 3-thiopheneboronic acid). Yield 49%. HRMS (FAB) calculated for C 16 Hi 8 N 2 OS 2 +H 319.0939, found 319.0939.
• Example 6 N-[(3R)-l-azabicyclo[2.2.2]oct-3-yl]-5-(2-nitrophenyl)-thiophene-2- carboxamide hydrochloride (from 2-nitrophenylboronic acid). Yield 45%. HRMS (FAB) calculated for C l8 H ⁇ 9 N 3 O 3 S+H 358.1225, found 358.1224.
• Example 8 N-[(3R)-l-azabicyclo[2.2.2]oct-3-yl]-4-phenyl-thiophene-2- carboxamide hydrochloride (starting with phenyl boronic acid and 4-bromothiophene- 2-carboxaldehyde in place of 5-bromothiophene-2-carboxaldehyde). Yield 35%. MS for C ⁇ 8 H 20 N 2 OS (ESI) (M+H) + m/z 313.
• Example 10 N-[(3R)-l-azabicyclo[2.2.2]oct-3-yl]-5-(4-benzyloxyphenyl)- thiophene-2-carboxamide hydrochloride (from 4-benzyloxyphenylboronic acid). Yield 34%. MS for C 25 H 26 N 2 O 2 S (ESI) (M+H) + m/z 419.
• Example 11 N-[(3R)- 1 -azabicyclo[2.2.2]oct-3 ⁇ yl]-5-(3-fluoro-4-benzyloxyphenyl)- thiophene-2-carboxamide hydrochloride (from 3-fluoro-4-benzyloxyphenylboronic acid). Yield 41%. MS for C 25 H 25 FN 2 O 2 S (ESI) (M+H) + m/z 436.
• Step 12a Preparation of 5-(2-aminophenyl)-N-[(3R)-l-azabicyclo[2.2.2]oct-3- yl]thiophene-2-carboxamide.
• Example 6 In a 200 mL Parr flask is placed the compound Example 6 (0.200 g, 0.51 mmol), EtOH (5 mL) and CH 2 C1 2 (5 mL). The flask is shaken under 30 psi H 2 for 16 hours. The contents are then filtered through a pad of celite with 10% MeOH-CH 2 Cl 2 (150 mL). The solvents are removed in vaeuo. This lot is then combined with a second lot prepared in a similar manner on the scale of 0.25 mmol. The product is re- dissolved in MeOH and loaded onto a column of AG50Wx2 ion exchange resin (H+ form). The resin is washed with MeOH then the product is eluted with 5% TEA in MeOH.
• H+ form AG50Wx2 ion exchange resin
• Step 13a Preparation of 5-(3-pyridinyl)-2-thiophenecarboxaldehyde.
• 3-pyridinediethylborane (0.81 g, 5.5 mmol)
• 2- bromothiophene-5-carboxaldehyde (0.59 mL, 5.0 mmol)
• Pd(PPh 3 ) 4 (0.17g, 0.15 mmol).
• the flask is vacuum purged and nitrogen filled three times followed by addition of a 4: 1 mixture of toluene-EtOH (8.3 mL) by syringe.
• Step 13b Preparation of N-[(3R)-1 -azabicyclo[2.2.2]oct-3-yl]-5- ⁇ yridin-3-yl- thiophene-2-carboxamide dihydiOchloride.
• Step 14a Preparation of methyl 5 -methyl-2,2'-bithiophene-5-carboxylate.
• Step 14b Preparation of 5 -methyl-2,2'-bithiophene-5-carboxylic acid.
• Step 14a The product of Step 14a (0.37 g, 1.54 mmol), dioxane (5 mL) and LiOH (IN, 3.1 mL, 3.1 mmol) are placed in a flask. Additional dioxane (5 mL) is then added for solubility and stirred for 24 h at rt. IN HC1 is added slowly until pH ⁇ 6, whereupon a precipitate forms. The precipitate is then collected by filtration, rinsed with water, and dried in a 70°C vacuum oven to provide the product as a yellow solid (0.30 g, 86%). MS for Ci 0 H 8 O 2 S 2 (ESI) (M-H) + m/z 223.
• Step 14c Preparation of N-[(3R)- l-azabicyclo[2.2.2]oct-3-yl]-5 -methyl-2,2 - bithiophene-5-carboxamide hydrochloride.
• Step 15a Preparation of 5 -chloro-2,2'-bithiophene-5-carboxaldehyde.
• Step 15b Preparation of N-[(3R)-l-azabicyclo[2.2.2]oct-3-yl]-5 -chloro-2,2 - bithiophene-5-carboxamide hydrochloride.
• Step 16a Preparation of N-[(3R)-l-azabicyclo[2.2.2]oct-3-yl]-5-nilrothiophene-
• This compound is made from 2-nitrothiophene-5-carboxaldehyde by using the procedure discussed in Steps lb and lc, making non-critical variations. Yield for 2 steps 48%.
• Step 17a Preparation of tert-butyl 2-thienylmethylcarbamate.
• a 500 mL receiving flask is placed in an ice bath, and to the flask is added thiophene-2-methylamine (5.0 mL, 48.7 mmol), CH 2 C1 2 (250 mL) then di-tert-butyl dicarbonate (12.7 g, 73.0 mmol) in 2-3 g portions over 5 min.
• the reaction mixture is stirred for 3 h then washed with IN HC1 (3X), IN NaOH (3X) and brine (2X).
• the organic layer is dried over MgSO , filtered and concentrated to a yellow oil.
• Step 17b Preparation of 5- ⁇ [(tert-butoxycarbonyl)amino]methyl ⁇ -2- thiophenecarboxylic acid.
• Step 17a In a flask is placed the product of Step 17a (3.50 g, 16.4 mmol) and dry THF (80 mL) then cooled in an acetone/solid CO 2 bath. Lithium diisopropylamide (18.0 mL, 36.1 mmol, 2.0 M solution in heptane/THF/ethylbenzene) is added in a slow stream by syringe. The resulting orange solution is stirred for 10 min and then quenched with excess dry ice. The solution is warmed over lh and the THF removed in vaeuo. The crude product is diluted with CH 2 C1 2 and washed with IN HC1 (3X).
• Step 17c Preparation of 5-(aminomethyl)-N-[(3R)-l-azabicyclo[2.2.2]oct-3- yl]thiophene-2-carboxamide dihydrochloride.
• Step 18a Preparation of 5-cyano-thiophene-2-carboxylic acid.
• thiophene-2-carbonitrile 5.0 mL, 53.8 mmol
• THF 270 mL
• Lithium diisopropylamide (40.3 mL, 80.7 mmol, 2.0M solution in heptane/THF/ethylbenzene) is added in a slow stream via syringe.
• the solution is stirred for 10 min then quenched with an excess of dry ice.
• the reaction mixture is warmed in a water bath and the THF removed in vaeuo.
• the slurry is taken up in IN NaOH and extracted with ether (3X).
• Step 20a TEA (50 ⁇ L, 0.35mmol) is added to a suspension of 5-(pyridin-2-yl)-2- thiophenecarboxylic acid (72mg, 0.35mmol) in CH 2 C1 2 :DMF (2: 1, 1.5mL). Diphenylchlorophosphate (62 ⁇ L, 0.3mmol) is added and the resulting solution is stirred at room temperature for 30 minutes. A solution of (R)-3-aminoquinuclidine (1M, 0.2mmol, 0.2mL) in DMF is added and the resulting solution is stirred overnight at room temperature. MeOH is added and the mixture is poured through a column of AG50Wx2 ion exchange resin (H + form).
• Example 21 N-[(3R)-l-azabicyclo[2.2.2]oct-3-yl]-[2,2 : ]bithiophenyl-5-carboxamide (from 2,2 -bithiophene-5-carboxylic acid). Yield 13%. MS for C ⁇ 6 H ⁇ 8 N 2 OS 2 (ESI) (M+H) + m/z 319.
• Example 22 N-[(3R)-l-azabicyclo[2.2.2]oct-3-yl]-5-(methylsulfanyl)-thiophene-2- carboxamide (from 5-methylsulfanylthiophene-2-carboxylic acid). Yield 84%. MS for C 13 H 18 N 2 OS 2 (ESI) (M+H) + m/z 283.
• Example 23 N-[(3R)-l-azabicyclo[2.2.2]oct-3-yl]-5-chloro-thiophene-2- carboxamide (from 5-chlorothiophene-2-carboxylic acid). Yield 6%. MS for C ⁇ 2 H ⁇ 5 ClN 2 OS (ESI) (M+H) + m/z 271.
• Example 24 N-[(3R)-l-azabicyclo[2.2.2]oct-3-yl]-5-acetyl-thiophene-2- carboxamide (from 5-acetylthiophene-2-carboxylic acid). Yield 7%. MS for C ⁇ 4 H, 8 N 2 O 2 S (ESI) (M+H) + m/z 279.
• Example 25 N-[(3R)-l-azabicyclo[2.2.2]oct-3-yl]-5-methyl-thiophene-2- carboxamide (from 5-methylthiophene-2-carboxylic acid). Yield 6%. MS for C, 3 H ⁇ 8 N 2 OS (ESI) (M+H) + m/z 251.
• Example 26 N-[(3R)-l-azabicyclo[2.2.2]oct-3-yl]-5-bromo-thiophene-2- carboxamide (from 5-bromothiophene-2-carboxylic acid). Yield 8%. MS for C, 2 H ⁇ 5 BrN 2 OS (ESI) (M+H) + m/z 315/317.
• Example 27 N-[(3R)-l-azabicyclo[2.2.2]oct-3-yl]-5-(phenylsulfanyl)-thiophene-2- carboxamide (from 5-phenylsulfanylthiophene-2-carboxylic acid). Yield 68%. MS for Ci 8 H 2 oN 2 OS2 (ESI) (M+H) + m/z 345.
• Example 28 N-[(3R)-l-azabicyclo[2.2.2]oct-3-yl]-5-(acetylamino)-furan-2- carboxamide (from 5-acetylaminofuran-2-carboxylic acid). Yield 16%. MS for C ⁇ 4 H 19 N 3 O 3 (ESI) (M+H) + m/z 278.
• Example 29 N-[(3R)- l-azabicyclo[2.2.2]oct-3-yl]-5-trifluoromethyl-furan-2- cai-boxamide (from 5-trifluoiOmelhylfuran-2-carboxylic acid). Yield 11%. MS for C, 3 H 15 F 3 N2 ⁇ 2 (ESI) (M+H) + m/z 289.
• Example 30 N-[(3R)- l-azabicyclo[2.2.2]oct-3-yl]-5-(2-methyl-5-trifluoromethyl- 2H-pyrazole-3-yl)-thiophene-2-carboxamide (from 5-(2-methyl-5-trifluoromethyl-2H- pyrazole-3-yl)thiophene-2-carboxylic acid). Yield 9%. MS for 7 ⁇ 9 F 3 N 4 OS (ESI)
• Step 31a Preparation of 5-(2-methylthiazol-4-yl)-thiophene-2-carboxylic acid.
• This compound is prepared from methyl 5-[2-(3-chlorophenyl) vinyl]- thiophene-2-carboxylate according to the procedure used to make the compound of Example 31, making non-critical variations. Yield 19%. MS for C 2 oH 2 iClN 2 OS (ESI) (M+H) + m/z 373.
• Step 33a Preparation of 5-(4-chlorophenylsulfanyl)-thiophene-2- carboxaldehyde.
• Step 33b Preparation of 5-(4-chlorophenylsulfanyl)-thiophene-2-carboxylic acid.
• Step 33a The product of Step 33a (6.1g, 24mmol) is dissolved in a mixture of THF, t- BuOH, and water (3:3:1, 255mL). 2-Methyl-2-butene (20.3mL, 192mmol) is added followed by KH 2 PO 4 (9.8g, 72mmol) and then NaClO 2 (80%, 8.17g, 72.3mmol). The mixture is stirred at room temperature for 2 hours. Aqueous KHSO (0.5M, 200mL) is added and the organic solvents are removed in vaeuo to produce an aqueous suspension of the product. The precipitate is collected by filtration, dissolved in IN NaOH and washed two times with ether.
• Step 33c Preparation of N-[(3R)-l-azabicyclo[2.2.2]oct-3-yl]-5-(4- chlorophenylsulfanyl)-thiophene-2-carboxamide.
• Example 34 N-[(3R)-l-azabicyclo[2.2.2]oct-3-yl]-5-(2,4 difluorophenyl-sulfanyl)- thiophene-2 carboxamide hydrochloride (from 2,4-difluorothiophenol). Yield for 3 steps 9%. MS for C, 8 H 18 F2N 2 OS 2 (ESI) (M+H) + m/z 381.
• Example 35 N-[(3R)-l-azabicyclo[2.2.2]oct-3-yl]-5-(3-chlorophenyl-sulfanyl)- thiophene-2-carboxamide (from 3-chlorothiophenol). Yield 50%. MS for C l8 H ⁇ 9 ClN 2 OS 2 (ESI) (M+H) + m/z 379.
• Example 36 N-[(3R)-l-azabicyclo[2.2.2]oct-3-yl]-5-(3-chloro-4-fluoro- phenylsulfanyl)-thiophene-2-carboxamide (from 3-chloro-4-fluorothiophenol). Yield 29%. MS for C ] 8 H, 8 ClFN 2 OS 2 (ESI) (M+H) + m/z 397.
• Example 37 N-[(3R)-l-azabicyclo[2.2.2]oct-3-yl]-5-(2,3-dichlorophenyl-sulfanyl)- thiophene-2-carboxamide hydrochloride (from 2,3-dichlorothiophenol). Yield 44%. MS for C ⁇ 8 H ⁇ 8 Cl 2 N 2 OS 2 (ESI) (M+H) + m/z 413.
• Example 38 N-[(3R)-l-azabicyclo[2.2.2]oct-3-yl]-5-(2,4,5-trichlorophenyl- sulfanyl)-thiophene-2-carboxamide (from 2,4,5-trichlorothiophenol). Yield 53%. MS for C )8 H ⁇ 7 Cl 3 N 2 OS 2 (ESI) (M+H) + m/z 449.
• Example 39 N-[(3R)-l-azabicyclo[2.2.2]oct-3-yl]-5-(3,4-dichlorophenyl-sulfanyl)- thiophene-2-carboxamide (from 3,4-dichlorothiophenol). Yield 21%. MS for C, 8 H ⁇ 8 Cl 2 N 2 OS 2 (ESI) (M+H) + m/z 413.
• Step 40a 5-Phenoxy-thiophene-2-carboxaldehyde.
• Phenol (3.3g, 35mmol) is added in portions to a suspension of 60% NaH (1.3g, 35mmol) in DMSO (lOOmL). The resulting mixture is stirred for 30 minutes then 5- nitrothiophene-2-carboxaldehyde (5g, 32mmol) is added. After 1 hour the reaction mixture is poured into water (IL) and washed with ether (4x500mL). The combined organic layers are dried over Na 2 SO 4 , filtered and evaporated to dryness. The resulting material is dissolved in MeOH and passed through a column (2.5cm x 20cm) of Amberjet 4400 (OH " form). The eluent is dried in vaeuo then evaporated twice from CH 3 CN.
• Step 40b 5-Phenoxy-thiophene-2-carboxylic acid.
• 5-Phenoxy-thiophene-2-carboxaldehyde (325mg, l. ⁇ mmol) is dissolved in a mixture of THF (lOmL), t-BuOH (5mL) and water (5mL).
• NaH 2 PO 4 (650mg, 4.8mmol) is added followed by NaClO 2 (432mg, 4.8mmol).
• Aqueous NaOH (2M, 5mL) is added, and the organic solvents are removed in vaeuo.
• the resulting aqueous suspension is poured into water (50mL) and washed with ether (3x50mL).
• Step 40c N-[(3R)-l-azabicyclo[2.2.2]oct-3-yl]-5-phenoxy-thiophene-2- carboxamide hydrochloride.
• the compound is made according to the procedure of Step lc, starting with 5- phenoxy-thiophene-2-carboxylic acid and making non-critical variations. Yield (66%).
• Step 41a 5-(2-Hydroxyphenyl)-thiophene-2-carboxylic acid.
• Tetrakis(triphenylphosphine)palladium(0) (133mg, 0.12mmol) is added to a solution of 5-bromothiophene-2-carboxylic acid (850mg, 4.1 mmol) in degassed THF (lOmL). The resulting solution is stirred for 5 minutes and then 2-(4,4,5,5- tetramethyl)-l,3,2-dioxaborolan-2-yl) phenol (lg, 4.6mmol) is added followed by aqueous Na 2 CO 3 (2M, 6.9mL). The mixture is heated at reflux overnight. The reaction mixture is allowed to cool, poured into water (50mL), and washed with ether (3x50mL).
• Step 41b N-[(3R)-l-azabicyclo[2.2.2]oct-3-yl]-5-(2-hydroxyphenyl)-thiophene- 2-carboxamide hydrochloride.
• Step 43a The compound Example 11 (165mg, O.38mmol) is dissolved in MeOH and poured through a plug of Amberjet 4400 (OH " form). The solvent is removed in vaeuo and the product is redisolved in EtOH (2mL). This solution is added to a suspension of Pd/C (10%, 165mg) in EtOH (2mL). Cyclohexadiene (360mL, 3.8mmol) is added, and the reaction is heated at 60 ° C for 6 hours. The reaction mixture is diluted with MeOH and filtered through celite. The solvents are removed in vaeuo then the hydrochloride salt is formed and crystallized from MeOH/CH 3 CN to yield the desired product (52mg, 36%). MS for C ⁇ 8 H 20 FN 2 O 2 S (ESI) (M+H) + m/z 347.
• Step 44a Preparation of 2-phenylsuIfanyl-thiazole-5-carboxylic acid ethyl ester.
• Step 44b Preparation of 2-phenylsulfanyl-thiazole-5-carboxylic acid.
• Potassium hydroxide 1.58 g, 28.2 mmol, 10 eq
• 2- phenylsulfanyl-thiazole-5-carboxylic acid ethyl ester 0.748 g, 2.82 mmol, 1 eq
• EtOH 15 mL
• water 10.5 mL
• the reaction is stirred for 1.5 hours, diluted with water (30 mL) and EtOH (30 mL), and acidified by addition of 3 N HCI until a white precipitate forms.
• Step 44c N-[(3R)-l-a ⁇ abicyclo[2.2.2]oct-3-yl]-2-(phenylsulfanyl)-l,3-thia ⁇ ole- 5-carboxamide fumarate.
• HATU 0.93 g, 1.30 mmol, 1 eq
• 2-phenylsulfanyl- thiazole-5-carboxylic acid 0.307 g, 1.30 mmol, 1 eq
• (R)-(+)-3-aminoquinuclidine dihydrochloride 0.258 g, 1.30 mmol, 1 eq
• DIEA 0.677 L, 3.89 mmol, 3 eq
• Example 45 N-[(3R)-l-azabicyclo[2.2.2]oct-3-yl]-2-[(4-chlorophenyl)-sulfanyl]- 1 ,3-thiazole-5-carboxamide fumarate (from 4-chlorothiophenol). Yield 39%.
• HRMS (FAB) calculated for C ⁇ 7 H 18 ClN 3 OS 2 +H, 380.0658, found 380.0659.
• Example 46 N-[(3R)l-azabicyclo[2.2.2]oct-3-yl]-2-phenoxy-l,3-thiazole-5- carboxamide fumarate (from phenol). Yield 81%. HRMS (FAB) calculated for C ⁇ 7 H ⁇ 9 N 3 O 2 S+H, 330.1276, found 330.1269.
• Example 47 N-[(3R)-l-azabicyclo[2.2.2]oct-3-yl]-2-[(4-fluorophenyl)-sulfanyl]- l,3-thiazole-5-carboxamide fumarate (from 4-fluorothiophenol). Yield 43%. HRMS (FAB) calculated for C ⁇ 7 H
• Example 48 N-[(3R)-l-azabicy ⁇ lo[2.2.2]oct-3-yl]-2-(methylsulfanyl)-l,3-thiazoIe- 5-carboxamide fumarate (from methanethiol). Yield 28%. HRMS (FAB) calculated for C ⁇ 2 H, 7 N 3 OS 2 +H ⁇ 284.0891, found 284.0894.
• Example 49 N-[(3R)l-azabicyclo[2.2.2]oct-3-yl]-2-(4-chloro ⁇ henoxy)-l,3-thiazole- 5-carboxamide fumarate (from 4-chlorophenol). Yield 42%. HRMS (FAB) calculated for C ⁇ 7 H, 8 ClN 3 O 2 S+H, 364.0886, found 364.0885.
• Step 50a Preparation of 2-phenyl-thiazole-5-carboxylic acid ethyl ester.
• a solution of -formyl- ⁇ -chloroacetate (9.34 g, 49.5 mmol, 1 eq) and thiobenzamide (6.79 g, 49.5 mmol, 1 eq) in EtOH (37.0 mL) is refluxed for 1 hour.
• the solution changes from an orange/brown color to a deep green.
• This solution is washed with water and extracted with CH 2 C1 2 .
• the organic fraction is dried over Na 2 SO , filtered, and the solvent removed in vaeuo.
• Step 50b Preparation of N-[(3R)-l-azabicyclo[2.2.2]oct-3-yl]-2-phenyl-l ,3- thiazole-5-carboxamide fumarate.
• the 2-phenyl-thiazole-5-carboxylic acid (1-aza- bicyclo[2.2.2]oct-3-yl)-amide is prepared using Steps 44b and 44c, starting with 2- phenyl-thiazole-5-carboxylic acid ethyl ester.
• the fumaric acid salt of the product is made and recrystallized from MeOH and ether to give the product as a white crystalline salt (77.4 mg, 22%).
• HRMS (FAB) calculated for C ⁇ 7 H ⁇ 9 N 3 OS+H ⁇ 314.1327, found 314.1336.
• Example 51 N-[(3R)-l-azabicyclo[2.2.2]oct-3-yl]-2,4-dimethyl-l ,3-thiazole-5- carboxamide (from 2,3-dimethyl-thiazole-5-carboxylic acid as described in Step lc). Yield 18%.
• HRMS (FAB) calculated for C, 3 H, 9 N 3 OS+H ⁇ 266.1327, found 266.1332.
• Step 52a Preparation of ethyl 2-(2-fluorophenyl)- 1 ,3-thiazole-5-carboxylate.
• Tetrakis(triphenylphosphine)palladium (0) (0.58 g, 0.5 mmol)
• a degassed solution of 2.0M Na 2 CO 3 (10 mL)
• 2-bromo-l,3- thiazole-5-carboxylic ethyl ester (1.18 g, 5.0 mmol)
• 2-fluorophenylboronic acid (0.77 g, 5.5 mmol
• Step 52b Preparation of N-[(3R)-l-azabicyclo[2.2.2]oct-3-yl]-2-(2- fluorophenyl)- l,3-thiazole-5-carboxamide citrate.
• Example 53 N-[(3R)-l-azabicyclo[2.2.2]oct-3-yl]-2-(3-fluorophenyl)-l,3-thiazole- 5-carboxamide 4-methylbenzenesulfonate (from 3-fluorophenylboronic acid). Yield 20%.
• HRMS (FAB) calculated for C, 7 H (8 FN 3 OS+H 332.1233, found 332.1225.
• Example 54 N-[(3R)-l-azabicyclo[2.2.2]oct-3-yl]-2-(4-fluorophenyl)-l,3-thiazole- 5-carboxamide 4-methylbenzenesulfonate (from 4-fluorophenylboronic acid). Yield 51%.
• HRMS (FAB) calculated for C, 7 H ⁇ 8 FN 3 OS+H 332.1233, found 332.1239.
• Example 55 N-[(3R)-l-azabicyclo[2.2.2]oct-3-yl]-2-(2-hydroxyphenyl)-l,3- thiazole-5-carboxamide hydrochloride (from 2-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)phenol). This compound was purified by reverse-phase preparative chromatography prior to the formation of the salt. Yield 0.5%. HRMS (FAB) calculated for C ⁇ 7 H ⁇ 9 N 3 O 2 S+H 330.1276, found 330.1268.
• Example 56 N-[(3R)-l-azabicyclo[2.2.2]oct-3-yl]-2-(4-methylphenyl)-l,3-thiazole- 5-carboxamide hydrochloride (from 4-tolylphenylboronic acid). Yield 50%. MS (ESI) for C ⁇ 8 H 2 ⁇ N 3 OS m/z 328.2 (M+H) + .
• Example 57 N-[(3R)-l-azabicyclo[2.2.2]oct-3-yl]-2-[4-(benzyloxy)phenyl]-l,3- thiazole-5-carboxamide hydrochloride (from (4-benzyloxyphenyl)boronic acid). Yield 98%. MS (ESI) for C 24 H 25 N 3 O 2 S m/z 420.3 (M+H) + .
• Examples 58-62 The following compounds are prepared from their requisite carboxylic acids according the procedures from Step 44c.
• the desired salt form is prepared directly from the crude reaction mixture without chromatography, and crystallized.
• Example 58 N-[(3R)-l-azabicyclo[2.2.2]oct-3-yl]-2-pyridin-3-yl-l,3-thiazole-4- carboxamide dihydrochloride (from (2-pyrid-3-yl)thiazole-4-carboxylic acid).
• HRMS (FAB) calculated for C ⁇ 6 H ⁇ 8 N 4 OS- ⁇ -H 315.1279, found 315.1289.
• Example 59 N-[(3R)-l-azabicyclo[2.2.2]oct-3-yl]-4-methyl-2-phenyl-l ,3-thiazole- 5-carboxamide dihydrochloride (from 4-methyl-2-phenyl-l,3-thiazole-5-carboxylic acid). Yield 61%.
• HRMS (El) calculated for C ⁇ 8 H 2 ,N 3 OS 327.1405, found 327.1403.
• Example 60 N-[(3R)-l-azabicyclo[2.2.2]oct-3-yl]-2-(4-chlorophenyl)-4-methyl-l,3- thiazole-5-carboxamide 4-methylbenzenesulfonate (from 2-(4-chlorophenyl)-4- methyl-l,3-thiazole-5-carboxylic acid). Yield 85%. MS (ESI) for C )8 H 2 ⁇ N 3 OS m/z 328.2 (M+H) + .
• Example 61 N-[(3R)-l-azabicyclo[2.2.2]oct-3-yl]-4-methyl-2-pyridin-2-yl-l,3- thiazole-5-carboxamide hydrochloride (from 4-methyl-2-pyridin-2-yl-l,3-thiazole-5- carboxylic acid). Yield 57%. MS (ESI) for C ⁇ sH 20 ClN 3 OS m/z 362.2 (M+H) + .
• Example 62 N-[(3R)-l-azabicyclo[2.2.2]oct-3-yl]-4-methyl-2-pyridin-4-yl-l,3- thiazole-5-carboxamide dihydrochloride (from 4-methyl-2-pyridin-4-yl-l,3-thiazole- 5-carboxylic acid). Yield 87%. MS (ESI) for C ⁇ 7 H 20 N 4 OS m/z 329.2 (M+H) + .
• Step 63a Preparation of ethyl 2-[(tert-butoxycarbonyl)amino]- 1 ,3-thiazole-5- carboxylate:
• Step 63b Preparation of ethyl 2-[(tert-butoxycarbonyl)(methyl)amino]- 1 ,3- thiazole-5 -carboxylate .
• Step 63c Preparation of 2-[(tert-butoxycarbonyl)(methyl)amino]-l ,3-thiazole-5- carboxylic acid.
• Step 63b The product of Step 63b is hydrolyzed according lo Step 44b, making non-critical variations. Yield 49%.
• HRMS (FAB) calculated for C ⁇ oH, 4 N 2 O 4 S+H 259.0752, found 259.0750.
• Step 63d Preparation of tert-butyl 5- ⁇ [(3R)-l-azabicyclo[2.2.2]oct-3- ylaminojcarbonyl ⁇ -l ,3-lhiazol-2-yl(methyl)carbamate.
• Step 63e Preparation of N-[(3R)- 1 -azabicyclo[2.2.2]oct-3-yl]-2-(methylamino)-
• Step 64a Preparation of 5-phenylsulfanyl-[ 1 ,3,4]thiadiazole-2-carboxylic acid ethyl ester.
• Step 64b Preparation of 5-phenylsulfanyl-[ 1 ,3 ,4]thiadiazole-2-carboxylic acid.
• Step 64a (1.0 g, 3.76 mmol, 1 eq) is dissolved in EtOH (40 mL), and cooled in an ice bath. To this, 2N NaOH (1.88 mL, 3.76 mmol, 1 eq) is added drop wise. The sodium salt of the acid precipitates out of solution. The reaction mixture is concentrated in vaeuo to give a white crystalline product. The reaction mixture is carried through to the next step in its crude form to make the acid chloride. MS (ESI) for C 9 H 6 N 2 S 2 O 2 m/z 237.0 (M-H) ⁇ .
• Step 64c Preparation of N-[(3R)-l-azabicyclo[2.2.2]oct-3-yl]-5-(phenyl- sulfanyl)- 1 ,3 ,4-thiadiazole-2-carboxamide.
• 5-Phenylsulfanyl-[l,3,4]thiadiazole-2-carboxylic acid (3.76 mmol) is placed in a flask and put under nitrogen. The acid is chilled in an ice bath. Oxalyl chloride (9 mL) that has also been cooled in an ice bath is added drop wise to the acid. The excess oxalyl chloride is removed under reduced pressure. The acid chloride is dissolved in about 5 mL CH 2 C1 2 .
• Example 65 N-[(3R)-l-azabicyclo[2.2.2]oct-3-yl]-5-phenoxy-l,3,4-thiadiazole-2- carboxamide. This compound is prepared from phenol according to the procedures for Example 64, making non-critical variations. Yield 16%. HRMS (FAB) calculated for C 16 H 17 N 3 O 3 S 331.0991, found 331.1229 (M) + .
• Example 66 (0.0254 g, 20%) as a pale oil.
• HRMS (FAB) calculated for C I6 H, 7 ClN 4 OS 2 +H ⁇ 381.0610, found 381.0617.
• Example 68 N-[(3R)-l-azabicyclo[2.2.2]oct-3-yl]-5-(4-chlorophenoxy)- 1 ,3,4- thiadiazole-2-carboxamide (from 4-chlorophenol). Yield 18%. HRMS (FAB) calculated for C ⁇ 6 H ⁇ 7 ClN 4 O 2 S+H ⁇ 365.0839, found 365.0826.
• Example 69 N-[(3R)-l-azabicyclo[2.2.2]oct-3-yl]-5-[(3-fluorophenyl)-sulfanyl]- l,3,4-thiadiazole-2-carboxamide (from 3-fluorothiophenol). Yield 16%. HRMS (FAB) calculated for C ⁇ 6 H ⁇ 7 FN 4 OS 2 +H, 365.0906, found 365.0899.
• Example 70 N-[(3R)-l-azabicyclo[2.2.2]oct-3-yl]-5-[(2-chlorophenyl)-sulfanyl]- l,3,4-thiadiazoIe-2-carboxamide (from 2-chlorothiophenol). Yield 44%.
• HRMS (FAB) calculated for C ⁇ 6 H ⁇ 7 ClN 4 OS 2 +H ⁇ 381.0610, found 381.0625.
• Example 71 N-[(3R)-l-azabicyclo[2.2.2]oct-3-yl]-5-[(4-fluorophenyl)-sulfanyl]- l,3,4-thiadiazole-2-carboxamide (from 4-fluorothiophenol). Yield 34%. HRMS (FAB) calculated for 365.0906, found 365.0921.
• Example 72 N-[(3R)-l-azabicyclo[2.2.2]oct-3-yl]-5-[(3-chlorophenyl)-sulfanyl]- l,3,4-thiadiazole-2-carboxamide (from 3-chlorothiophenol). Yield 34%.
• HRMS (FAB) calculated for C ⁇ 6 H ⁇ 7 ClN OS 2 +H ⁇ 381.0610, found 381.0603.
• Step 75a Preparation of ethyl (2Z)-amino(benzoylhydrazono)ethanoate.
• Ethyl thioxamate (0.6g, 4.5mmol) and benzyl hydrazide 0.68g, 5.0mmol) in EtOH (20mL) are heated at reflux for 2 hours according to the procedure described in McKillop et al., Tetrahedron Lett. 23, 3357-3360 (1982). The resulting solids are collected and washed with EtOH, and dried in vaeuo to afford the desired product (0.5g, 50%).
• Step 75b Preparation of ethyl 5-phenyl- 1 ,3,4-oxadiazole-2-carboxylate and ethyl 5-phenyl- 1 H- 1 ,2,4-triazole-3-carboxylate.
• the resultant material is purified by silica gel chromatography (20% EtOAc/hexanes) to afford a 2.2: 1 mixture of ethyl 5-phenyl- 1, 3, 4-oxadiazole-2-carboxylate (310mg, 67%) and ethyl 5-phenyl- lH-l,2,4-triazole-3-carboxylate (140mg, 30%), respectively.
• Step 75c Preparation of N-[(3R)-l-azabicyclo[2.2.2]oct-3-ylJ-5-phenyl-lH- 1 ,2,4-triazole-3-carboxamide dihydrochloride.
• This material is prepared using ethyl 5-phenyl- 1 H- 1 ,2,4-triazole-3-carboxylate prepared in Step 75b and coupled to (R)-(+)-3-aminoquinuclidine.
• the product is purified as described in Example 66, making non-critical variations, to afford the desired product (13mg, 7.3%).
• Step 77a Preparation of ethyl- 1 ,3 ,4-oxadiazole-2-thione-5-carboxylate potassium salt dimethylsulfoxide solvate.
• a mixture of ethyl hydrazino(oxo)acetate (3.7g, 28mmol), prepared as described by Benson, Gross, and Snyder in J. Org. Chem. 3257-3269 (1990), EtOH (25mL), carbon disulfide (8.5g, 6.6mL, 112mmol), DMSO (6mL) and a solution of KOH (1.57g, 28mmol) in water (2mL) are heated at reflux overnight, as described by Horning and Muchowski in Can. J. Chem. 3079-3082 (1972).
• the resultant solid is collected by vacuum filtration and washed to afford the desired product as a DMSO solvate that was used without further purification (8.2g of a semi-solid).
• Step 77b Preparation of methyl ethyl-l,3,4-oxadiazole-2-thione-5-carboxylate.
• This material is prepared using methyl ethyl- 1,3, 4-oxadiazole-2-thione-5- carboxylate prepared in Step 77b and coupled to (R)-(+)-3-aminoquinuclidine as described in Example 66, making non-critical variations, to afford material that is purified by silica gel chromatography (10% MeOH/CHCl 3 + 0.5% NH 4 OH).
• the hydrochloride salt is prepared upon crystallization of the desired product from 1M HCl/Et 2 O (65mg, 42%). MS for CnH ⁇ 6 N 4 O 2 S (ESI) (M+H) + m/z 269.
• Step 79a Preparation of 2-amino-l-(3-chlorophenyl)ethanone hydrochloride.
• Step 79b Preparation of ethyl [[2-(3-chlorophenyl)-2-oxoethyl] amino](oxo) acetate.
• Step 79c Preparation of ethyl 5-(3-chlorophenyl)- 1 ,3-oxazole-2-carboxylate.
• Step 79d Preparation of N-[(3R)-l-azabicyclo[2.2.2]oct-3-yl]-5-(3- chlorophenyl)- 1 ,3-oxazole-2-carboxamide 4-methylbenzenesulfonate.
• Examples 80-88 The following compounds are prepared from the requisite acylhalides according to the procedures for Example 79, making non-critical variations.
• the product of Step 79a is commercially available.
• Example 80 N-[(3R)- 1 -azabicyclo[2.2.2]oct-3-yl]-5-(3-methoxyphenyl)-l ,3- oxazole-2-carboxamide 4-methylbenzenesulfonate (from 2-bromo-l-(3- methoxyphenyl)ethanone). Yield 20%.
• HRMS (FAB) calculated for C ⁇ 8 H 2 ,N 3 O 3 +H ⁇ 328.1661, found 328.1660.
• Example 81 N-[(3R)-l-azabicyclo[2.2.2]oct-3-yl]-5-(3-nitrophenyl)-l,3-oxazole-2- carboxamide 4-methylbenzenesulfonate (from 2-amino-l-(3-nitrophenyl)ethanone hydrochloride). Yield 8%.
• HRMS (FAB) calculated for C ⁇ 7 H ⁇ 8 N 4 O 4 +H, 343.1406, found 343.1405.
• Example 82 N-[(3R)-l-azabicyclo[2.2.2]oct-3-yl]-5-(4-methoxyphenyl)-l,3- oxazole-2-carboxamide 4-methylbenzenesulfonate (from 2-amino-l-(4- methoxyphenyl)ethanone hydrochloride). Yield 23%.
• HRMS (FAB) calculated for C ⁇ iNsO hH! 328.1661, found 328.1662.
• Example 83 N-[(3R)- 1 -azabicyclo[2.2.2]oct-3-yl]-5-(2-nitrophenyl)- 1 ,3-oxazole-2- carboxamide 4-methylbenzenesulfonate (from 2-bromo-l-(2-nitrophenyl)ethanone). Yield 4%.
• HRMS (FAB) calculated for C, 7 H ⁇ 8 N 4 O 4 +H, 343.1406, found 343.1405.
• Example 84 N-[(3R)-l-azabicyclo[2.2.2]ocl-3-yl]-5-(2-methoxyphenyl)-l,3- oxazole-2-carboxamide 4-methylbenzenesulfonate (from 2-bromo-l-(2- methoxyphenyl)ethanone). Yield 13%.
• HRMS (FAB) calculated for C )8 H 2 ⁇ N 3 O 3 +H] 328.1661, found 328.1661.
• Example 85 N-[(3R)-l-azabicyclo[2.2.2]oct-3-yl]-5-(4-fluorophenyl)-l,3-oxazolc- 2-carboxamide 4-methylbenzenesulfonate (from 2-bromo-l-(4-fluorophenyl)- ethanone). Yield 5%.
• HRMS (FAB) calculated for C ⁇ 7 H ⁇ 8 FN 3 O 2 +H ⁇ 316.1461, found 316.1470.
• Example 86 N-[(3R)-l-azabicyclo[2.2.2]oct-3-yl]-5-(2-chlorophenyl)-l,3-oxazole- 2-carboxamide 4-methylbenzenesulfonate (from 2-bromo-l-(2-chloiOphenyl)- ethanone). Yield 10%.
• HRMS (FAB) calculated for C ⁇ 7 H, 8 ClN 3 O 2 -i-H ⁇ 332.1165, found 332.1168.
• Example 87 N-[(3R)- l-azabicyclo[2.2.2]oct-3-yl]-5-(3-cyanophenyl)-l ,3-oxazole- 2-carboxamide 4-methylbenzenesulfonate (from 3-(bromoacetyl)-benzonitrile). Yield 3%.
• HRMS (FAB) calculated for C 18 H 2 ⁇ N 3 O 3 +H ⁇ 323.1508, found 323.1516.
• Example 88 N-[(3R)-l-azabicyclo[2.2.2]oct-3-yl]-5-(4-bromophenyl)-l,3-oxazole- 2-carboxamide 4-methylbenzenesulfonate (from 2-amino-l-(4-bromophenyl)- ethanone hydrochloride). Yield 6%.
• HRMS (FAB) calculated for C ⁇ H ⁇ B N ⁇ +H] 376.0661, found 376.0660.
• 2-Bromo-l-phenylpropan-l-one (8.97g, 42. Immol, leq) is added dropwise to a suspension of diformylimide sodium salt (4.80g, 50.5mmol, 1.2eq) in 80mL CH 3 CN.
• the reaction is stirred for 60h at 70-75°C.
• the hot mixture is filtered to remove the salts and the solids are washed with CH CN.
• the combined filtrates are concentrated in vaeuo, dissolved in 40mL 6N HCI and heated under reflux for 0.75h.
• the solvents are removed under reduced pressure and the product is recrystallized from IPA to give 2-amino-l -phenylpropan- 1 -one hydrochloride (6.15g, 79%).
• Step 89b Preparation of ethyl [(l-methyl-2-oxo-2-phenylethyl)amino] (oxo)acetate.
• TEA (3.22mL, 0.023 lmol, 2. leq) is added dropwise to a suspension of the product from Step 89a (2.05g, 1 Ommol, leq) and ethyl oxalyl chloride (1.24mL, 1 Ommol, leq) in 50mL CH 2 CI 2 in an ice/water bath. The mixture is allowed to slowly warm to room temperature. After stirring overnight, water and 20mL IN HCI are added. The aqueous layer is extracted with CH 2 C1 2 .
• Step 89d Preparation of N-[(3R)-l-azabicyclo[2.2.2]oct-3-yl]-4-methyl-5- phenyl- l,3-thiazole-2-carboxamide 4-methylbenzenesulfonate.
• the freebase of (R)-3-aminoquinuclidine (l.Og, 5.02mmol, 2.26eq) dissolved in THF ( ⁇ 5mL) is added to a solution of the product from Step 89c (0.55g, 2.22mmol, leq) in lOmL EtOH. The mixture is heated under reflux. After 48h, the mixture is cooled and concentrated in vaeuo.
• Example 90 N-[(3R)-l-azabicyclo[2.2.2]oct-3-yl]-5-phenyl-l,3-thiazole-2- carboxamide (from 2-amino-l-phenylethanone hydrochloride). Yield 36%.
• HRMS (FAB) calculated for C l7 H, 9 N 3 OS+H, 314.1327, found 314.1330.
• Example 91 N-[(3R)-l-azabicyclo[2.2.2]oct-3-yl]-5-(4-bromophenyl)-l,3-thiazole- 2-carboxamide 4-methylbenzenesulfonate (from 2-amino-l-(4-bromophenyl)- ethanone hydrochloride). Yield 18%.
• HRMS (FAB) calculated for C, 7 H, 8 BrN 3 OS+H, 392.0432, found 392.0423.
• Example 92 N-[(3R)-l-azabicyclo[2.2.2]oct-3-yl]-5-(3-nitrophenyl)-l,3-thiazole-2- carboxamide 4-methylbenzenesulfonate (from 2-amino-l-(3-nitrophenyl)-ethanone hydrochloride). Yield 47%.
• HRMS (FAB) calculated for C ⁇ 7 H, 8 N 4 O 3 S+H, 359.1178, found 359.1165.
• Example 93 N-[(3R)-l-azabicyclo[2.2.2]oct-3-yl]-5-(3-methoxyphenyl)-l,3- thiazole-2-carboxamide 4-methylbenzenesulfonate (from 2-bromo-l-(3- methoxyphenyl)-ethanone). Yield 14%.
• HRMS (FAB) calculated for C ⁇ 8 H2iN 3 O 2 S+H, 344.1432, found 344.1423.
• Example 94 N-[(3R)-l-azabicyclo[2.2.2]oct-3-yl]-5-(2-chlorophenyl)-l,3-thiazole- 2-carboxamide 4-methylbenzenesulfonate (from 2-bromo- 1 -(2-chlorophenyl)- ethanone). Yield 28%.
• HRMS (FAB) calculated for C, 7 H ⁇ 8 ClN 3 OS+H ⁇ 348.0937, found 348.0947.
• Example 95 N-[(3R)-l-azabicyclo[2.2.2]oct-3-yl]-5-(4-fluorophenyl)-l,3-thiazole- 2-carboxamide 4-melhylbenzenesulfonate (from 2-bromo-l-(4-fluorophenyl)- ethanone). Yield 16%.
• HRMS (FAB) calculated for C, 7 H ) 8 FN 3 OS+H, 332.1233, found 332.1233.
• Example 96 N-[(3R)-l-azabicyclo[2.2.2]oct-3-yl]-5-(2-methoxyphenyl)- 1 ,3- thiazole-2-carboxamide 4-methylbenzenesulfonate (from 2-bromo-l-(2- methoxyphenyl)ethanone). Yield 14%.
• HRMS (FAB) calculated for C ⁇ 8 H 2 ⁇ N 3 O 2 S+H ⁇ 344.1432, found 344.1436.
• Example 97 N-[(3R)-l-azabicyclo[2.2.2]oct-3-yl]-5-(4-chlorophenyl)-l,3-thiazole- 2-carboxamide 4-methylbenzenesulfonate (from 2-bromo-l-(4-chlorophenyl)- ethanone). Yield 12%. HRMS (FAB) calculated for C ⁇ 7 H 18 ClN 3 OS+H ⁇ 348.0937, found 348.0934.
• Example 98 N-[(3R)-l-azabicyclo[2.2.2]oct-3-yl]-5-methyl-l,3-thiazole-2- carboxamide 4-methylbenzenesulfonate (from 1-chloroacetone). Yield 2%. HRMS (FAB) calculated for C, 2 H l7 N 3 OS+H, 252.1171, found 252.1171.
• Example 99 N-[(3R)-l-azabicyclo[2.2.2]oct-3-yl]-5-(3-chlorophenyl)-l,3-thiazole- 2-carboxamide 4-methylbenzenesulfonate (from 2-bromo-l-(3-chlorophenyl)- ethanone). Yield 10%.
• HRMS (FAB) calculated for C ⁇ 7 H ⁇ 8 ClN 3 OS+H ⁇ 348.0937, found 348.0936.
• Example 100 N-[(3R)-l-azabicyclo[2.2.2]oct-3-yl]-5-(2-fluorophenyl)-l,3-thiazole- 2-carboxamide 4-methylbenzenesulfonate (from 2-bromo-l-(2-fluorophenyl)- ethanone). Yield 0.4%. MS (ESI) for C, 7 H ]8 FN 3 OS m/z 332.2 (M+H) + .
• ExampleTOl N-[(3R)-l-azabicyclo[2.2.2]oct-3-yl]-5-(3-fluorophenyl)-l,3-thiazole- 2-carboxamide 4-methylbenzenesulfonate (from 2-bromo-l-(3-fluorophenyl)- ethanone). Yield 6%.
• Example 102 N-[(3R)-l-azabicyclo[2.2.2]oct-3-yl]-5-thien-2-yl- 1 ,3-thiazole-2- carboxamide 4-methylbenzenesulfonate (from 2-bromo-l-thien-2-yl-ethanone). Yield 10%. MS (ESI) for C 15 H ⁇ 7 N 3 OS 2 m/z 320.2 (M+H) + .
• Example 103 N-[(3R)-l-azabicyclo[2.2.2]oct-3-yl]-5-thien-2-yl- 1 ,3-thiazole-2- carboxamide 4-methylbenzenesulfonate (from 2-bromo-l-thien-2-yl-ethanone). Yield 10%. MS (ESI) for C 15 H ⁇ 7 N 3 OS 2 m/z 320.2 (M+H) + .
• Example 103 N-[(3R)-l-azabicyclo[2.2.2]o
• Step 103a Synthesis of 5-phenyl-furan-2-carbaldehyde.
• Step 103b Synthesis of 5-phenyl-furan-2-carboxylic acid.
• Step 103c Preparation of N-[(3R)- 1 -azabicyclo[2.2.2]oct-3-yl]-5-phenyl-2- furamidc 4-methylbenzenesulfonate.
• the product of Step 103b (0.499 g, 2.65 mmol, 1 eq) and the dihydrochloride salt of R-(+)-aminoquinuclidine (0.528 g, 2.65 mmol, 1 eq) in DIEA (1.38 mL, 7.96 mmol, 3 eq), in THF (17.6 mL) are cooled to 0°C and HATU (1.01 g, 2.65 mmol, 1 eq) is added.
• Example 104 N-[(3R)-l-azabicyclo[2.2.2]oct-3-yl]-5-(2-chlorophenyl)-furan-2- carboxamide toluene sulfonate (from 5-(2-chlorophenyl)-2-furaldehyde). Yield 46%.
• HRMS (FAB) calculated for C, 8 H, 9 ClN 2 O 2 +H, 331.1213, found 331.1208.
• Example 105 N-[(3R)- l-azabicyclo[2.2.2]oct-3-yl]-5-(3-chlorophenyl)-furan-2- carboxamide toluene sulfonate (from 5-(3-chlorophenyl)-2-furaldehyde). Yield 72%.
• HRMS (FAB) calculated for C ⁇ 8 H 19 ClN 2 O 2 +H, 331.1213, found 331.1212.
• Example 106 N-[(3R)- l-azabicyclo[2.2.2]oct-3-yl]-5-(4-chlorophenyl)-furan-2- carboxamide fumarate (from 5-(4-chlorophenyl)-2-furoic acid). Yield 43%.
• HRMS (FAB) calculated for C, 8 H, 9 ClN 2 O 2 +H ⁇ 331.1213, found 331.1216.
• Example 107 N-[(3R)- 1 -azabicyclo[2.2.2]oct-3-yl]-5-(4-bromophenyl)-furan-2- carboxamide toluene sulfonate (from 5-(4-bromophenyl)-2-furaldehyde). Yield 38%.
• Example 109 N-[(3R)-l-azabicyclo[2.2.2]oct-3-yl]-5-[3-(trifluoromethyl)-phenyl]- furan-2-carboxamide fumarate (from 5-(3-(trifluoromethyl)-phenyl)-furan-2- carboxaldehyde). Yield 31%. MS (ESI) for (M+H) + .
• Example 110 N-[(3R)-l-azabicyclo[2.2.2]oct-3-yl]-5-(2-nitrophenyl)-furan-2- carboxamide 4-methylbenzenesulfonate (from 5-(2-nitro-phenyl)-furan-2-carboxylic acid). Yield 82%.
• HRMS (FAB) calculated for C, 8 H ⁇ 9 N 3 O 4 +H, 342.1454, found 342.1469.
• Example 111 N-[(3R)-l-azabicyclo[2.2.2]oct-3-yl]-5-(3-nitrophenyl)-furan-2- carboxamide 4-methylbenzenesulfonate (from 5-(3-nitro-phenyl)-furan-2-carboxylic acid). Yield 66%.
• HRMS (FAB) calculated for C 18 H ⁇ 9 N 3 O 4 +H ⁇ 342.1454, found 342.1463. '
• Example 112 N-[(3R)-l-azabicyclo[2.2.2]oct-3-yl]-5-(4-nitrophenyl)-furan-2- carboxamide 4-methylbenzenesulfonate (from 5-(4-nitro-phenyl)-furan-2-carboxylic acid). Yield 52%.
• HRMS (FAB) calculated for C ⁇ 8 H ]9 N 3 O 4 +H, 342.1454, found 342.1465.
• Example 113 N-[(3R)-l-azabicyclo[2.2.2]oct-3-yl]-5-(2-fluorophenyl)-furan-2- carboxamide 4-methylbenzenesulfonate (from 2-fluorophenylboronic acid). Yield 12%.
• HRMS (FAB) calculated for C 18 H 19 FN 2 O 2 +H, 315.1508, found 315.1519.
• Example 114 N-[(3R)-l-azabicyclo[2.2.2]oct-3-yl]-5-(3-fluorophenyl)-furan-2- carboxamide 4-methylbenzenesulfonate (from 3-fluorophenylboronic acid). Yield 29%.
• HRMS (FAB) calculated for C, 8 H ⁇ 9 FN 2 O 2 - ⁇ -H ⁇ 315.1508, found 315.1519.
• Example 115 N-[(3R)-l-azabicyclo[2.2.2]oct-3-yl]-5-(4-fluorophenyl)-furan-2- carboxamide 4-methylbenzenesulfonate (from 4-fluorophenylboronic acid). Yield 16%.
• HRMS (FAB) calculated for C, 8 H ⁇ 9 FN 2 O 2 +H, 315.1508, found 315.1500.
• Example 116 N-[(3R)-l-azabicyclo[2.2.2]oct-3-yl]-5-(2,4-difluorophenyl)-furan-2- carboxamide hydrochloride (from 2,4-difluorophenylboronic acid). Yield 46%. MS (ESI) for C 18 H ⁇ 8 F 2 N 2 O 2 m/z 333.2 (M+H) + .
• Example 117 N-[(3R)-l-azabicyclo[2.2.2]oct-3-yl]-5-(2,5-difluorophenyl)-furan-2- carboxamide hydrochloride (from 2,5-difluorophenylboronic acid). Yield 33%. MS (ESI) for C ⁇ 8 H I8 F 2 N 2 O 2 m/z 333.2 (M+H) + .
• Example 119 N-[(3R)-l-azabicyclo[2.2.2]oct-3-yl]-5-(3-methoxyphenyl)-furan-2- carboxamide 4-methylbenzenesulfonate (from 3-methoxyphenylboronic acid). Yield 83%.
• HRMS (FAB) calculated for C ⁇ 9 H 22 N 2 O 3 +H ⁇ 327.1708, found 327.1714.
• Example 120 N-[(3R)-l-azabicyclo[2.2.2]oct-3-yl]-5-[3-(trifluoromethoxy)phenyl]- furan-2-carboxamide 4-methylbenzenesulfonate (from 3-trifluoromethoxyphenyl- boronic acid). Yield 58%.
• HRMS (FAB) calculated for C ⁇ H ⁇ N ⁇ -i-H ! 381.1426, found 381.1440.
• Example 121 N-[(3R)-l-azabicyclo[2.2.2]oct-3-yl]-5-[2-chloro-5-(trifluoromethyl)- phenyl] -furan-2-carboxamide fumaric acid (from 2-chloro-5-trifluoromethylphenyl- boronic acid). Yield 55%.
• HRMS (FAB) calculated for Ci 9 Hi 8 ClF N 2 O 2 +Hi 399.1087, found 399.1097.
• Example 122 N-[(3R)-l-azabicyclo[2.2.2]oct-3-yl]-5-(4-fluoro-3-methylphenyl)- furan-2-carboxamide 4-methylbenzenesulfonate (from 4-fluoro-3-methylphenyl- boronic acid). Yield 77%.
• HRMS (FAB) calculated for C ⁇ 9 H 2 ⁇ FN 2 O 2 +H ⁇ 329.1665, found 329.1661.
• Example 123 N-[(3R)-l-azabicyclo[2.2.2]oct-3-yl]-5-(4-cyanophenyl)-furan-2- carboxamide hydrochloride (from 4-cyanophenyl-boronic acid). Yield 31%. MS (ESI) for C ⁇ 8 H ⁇ 9 N 3 O 2 m/z 322.2 (M+H) + .
• Example 124 N-[(3R)-l-azabicyclo[2.2.2]oct-3-yl]-5-thien-2-yl-furan-2-carboxamide 4-methylbenzenesulfonate (from 2-thiophene-boronic acid). MS (ESI) for C l6 H ⁇ 8 N 2 O 2 S m/z 303.2 (M+H) + .
• Example 125 N-[(3R)-l-azabicycIo[2.2.2]oct-3-yl]-5-thien-3-yl-furan-2-carboxamide 4-methylbenzenesulfonate (from 3-thiophene-boronic acid). MS (ESI) for C ⁇ 6 H, 8 N 2 O 2 S m/z 303.2 (M+H) + .
• Example 126 N-[(3R)-l-azabicyclo[2.2.2]oct-3-yl]-5-bromo-furan-2-ca ⁇ -boxamide 4- methylbenzenesulfonate (from 5-bromo-furan-2-carboxylic acid). Yield 75%. MS (ESI) for C ⁇ H, 5 N 2 O 2 Br m/z 299.0 (M+H) + .
• Example 127 N-[(3R)-l-azabicyclo[2.2.2]oct-3-yl]-5-nitro-furan-2 -carboxamide hydrochloride (from 5-nitro-furan-2-carboxylic acid). Yield 63%. MS (ESI) for C ⁇ 2 H, 5 N 3 O 4 m/z 265.1 (M+H) + .
• Example 128 N-[(3R)-l-azabicyclo[2.2.2]oct-3-yl]-4,5-dimethyl-furan-2- carboxamide hydrochloride (from 4,5-dimethyl-furan-2-carboxylic acid). Yield 75%. HRMS (FAB) calculated for C ⁇ 4 H 2 oN 2 O 2 +H 249.1603, found 249.1593.
• Example 129 N-[(3R)-l-azabicyclo[2.2.2Joct-3-yl]-5-(4-chloro-2-nitrophenyl)-furan- 2-carboxamide hydrochloride (from 4-chloro-2-nitrophenyl)-furan-2-carboxylic acid). Yield 7%. HRMS (FAB) calculated for C ⁇ 8 H ⁇ 8 ClN 3 O 4 +H 376.1064, found 376.1067.
• Example 130 N-[(3R)- 1 -azabicyclo[2.2.2]oct-3-yl]-5-(4-methyl-2-nitrophenyl)- furan-2-carboxamide hydrochloride (from 4-methyl-2-nitrophenyl)-furan-2-carboxylic acid). Yield 56%. MS (ESI) for C !9 H 2 ⁇ N 3 O 4 m/z 356.2 (M+H) + .
• Step 131a A solution of N-[(3R)-l-azabicyclo[2.2.2]oct-3-yl]-5-bromo-furan-2- carboxamide (0.258 g, 0.85 mmol, 1 eq), 2,3-difluorophenylboiOnic acid (0.147g, 0.93 mmol, 1.1 eq), tetrabutylammonium bromide (0.244 g, 0.85 mmol, 1 eq), palladium acetate (3.8 mg, 0.017 mmol, 0.02 eq), K 2 CO 3 (0.41 g, 2.97 mmol, 3.5 mmol) and water 1.4 mL is stirred under argon overnight. The reaction forms a brownish insoluble lump, but is complete by HPLC. The reaction is purified by silica gel chromatography using a Biotage Flash 40 M column (10%MeOH/l%TEA/CH 2 Cl 2 ).
• Example 132 N-[(3R)-l-azabicyclo[2.2.2]oct-3-yl]-5-(3,4-difluorophenyl)-furan-2- carboxamide hydrochloride (from 3,4-difluorophenyl-boronic acid). Yield 24%.
• HRMS (FAB) calculated for C, 8 H ⁇ 8 F 2 N 2 ⁇ 2 +H, 333.1414, found 333.1418.
• Example 133 N-[(3R)-l-azabicyclo[2.2.2]oct-3-yl]-5-(3,5-difluorophenyl)-furan-2- carboxamide hydrochloride (from 3, 5-difluorophenyl -boronic acid). Yield 60%.
• HRMS (FAB) calculated for C, 8 H ⁇ 8 F 2 N 2 O 2 +H ⁇ 333.1414, found 333.1424.
• Example 134 N-[(3R)-l-azabicyclo[2.2.2]oct-3-yl]-5-(4-methoxy-phenyl)-furan-2- carboxamide hydrochloride (from 4-methoxy-phenyl-boronic acid). Yield 17%.
• HRMS (FAB) calculated for C l9 H 22 N 2 O 3 +H ⁇ 327.1708, found 327.1707.
• Example 135 N-[(3R)-l-azabicyclo[2.2.2]oct-3-yl]-5-(2-methylphenyl)-furan-2- carboxamide 4-methylbenzenesulfonate (from ⁇ -tolylboronic acid). Yield 26%. HRMS (FAB) calculated for C ⁇ 9 H 22 N 2 O 2 +H ⁇ 311.1759, found 311.1763.
• Example 136 N-[(3R)-l-azabicyclo[2.2.2]oct-3-yl]-5-(3-methylphenyl)-furan-2- carboxamide 4-methylbenzenesulfonate (from m-tolylboronic acid). HRMS (FAB) calculated for C ⁇ 9 H 22 N 2 O 2 +H, 311.1759, found 311.1752.
• Example 137 N-[(3R)- l-azabicyclo[2.2.2]oct-3-yl]-5-(4-methylphenyl)-furan-2- carboxamide 4-methylbenzenesulfonate (from -tolylboronic acid). Yield 10 %.
• HRMS (FAB) calculated for C ⁇ 9 H 22 N 2 O 2 +H ⁇ 311.1759, found 311.1752.
• Example 138 N-[(3R)- l-azabicyclo[2.2.2]oct-3-yl]-5-[2-(trifluoromethoxy)phenyl]- furan-2-carboxamide 4-methylbenzenesulfonate (from 2-(trifluoromethoxy)phenyl- boronic acid). Yield 19%. MS (ESI) for C ⁇ 9 H ⁇ 9 F 3 N 2 O 3 m/z 381.3 (M + H) + .
• Example 139 N-[(3R)-l-azabicyclo[2.2.2]oct-3-yl]-5-[4-(trifluoromethoxy)phenyl]- furan-2-carboxamide 4-methylbenzenesulfonate (from 4-trifluoromethoxyphenyl- boronic acid). Yield 61%.
• HRMS (FAB) calculated for C19H1 9 F 3 N 2 O3+H 1 381.1426, found 381.1434.
• Example 140 N-[(3R)-l-azabicyclo[2.2.2]oct-3-yl]-5-(4-tert-butylphenyl)-furan-2- carboxamide 4-methylbenzenesulfonate (from 4-tert-butylphenyl-boronic acid). Yield 73%.
• HRMS (FAB) calculated for C 22 H 28 N 2 O 2 +H ⁇ 353.2229, found 353.2218.
• Example 141 N-[(3R)-l-azabicyclo[2.2.2]oct-3-yl]-5-(l-benzothien-2-yl)-furan-2- carboxamide 4-methylbenzenesulfonate (from benzothiophene-2-boronic acid). Yield 17%.
• HRMS (FAB) calculated for C 20 H 20 N 2 O 2 S+H ⁇ 353.1324, found 353.1326.
• Example 142 N-[(3R)-l-azabicyclo[2.2.2]oct-3-yl]-5-quinolin-3-yl-furan-2- carboxamide 4-methylbenzenesulfonate (from 3-quinoline-boronic acid). Yield 9%. MS (ESI) for C21H21N3O2 m/z 348.3 (M+H) + .
• Example 143 N-[(3R)-l-azabicyclo[2.2.2]oct-3-yl]-5-(4-ethylphenyl)-furan-2- carboxamide hydrochloride (from 4-ethylphenyl-boronic acid). MS (ESI) for C 20 H 24 N 2 O 2 m/z 325.3 (M+H) + .
• Example 144 N-[(3R)-l-azabicyclo[2.2.2]oct-3-yl]-5-(4-isopropylphenyl)-furan-2- carboxamide hydrochloride (from 4-isopropylphenyl-boronic acid). MS (ESI) for C 2 ⁇ H 26 N 2 O 2 m/z 339.3 (M+H) + .
• Example 145 N-[(3R)- 1 -azabicyclo[2.2.2]oct-3-yl]-5-(3-fluoro-4-methoxyphenyl)- furan-2-carboxamide hydrochloride (from 3-fluoro-4-methoxy-boronic acid). MS (ESI) for C ⁇ 9 H 21 FN 2 O 2 m/z 345.2 (M+H) + .
• Example 146 N-[(3R)-l-azabicyclo[2.2.2]oct-3-yl]-5-(l-benzofuran-2-yl)-furan-2- carboxamide 4-methylbenzenesulfonate (from benzofuran-2-boronic acid). MS (ESI) for C 20 H 20 N 2 O 3 m/z 337.2 (M+H) + .
• Step 147a To a solution of N-[(3R)-l-aza-bicyclo[2.2.2]oct-3-ylj-5-(2-nitro- phenyl)-furan-2-carboxamide (1.65 g, 3.22 mmol, 1 eq) in 100 mL EtOH was added Pd/C (50 mg). This mixture was placed on a Parr shaker under 40 psi hydrogen overnight. The palladium is removed by filtration over a pad of celite, and the solvent is removed.
• Example 148 5-(4-aminophenyl)-N-[(3R)-l-azabicyclo[2.2.2]oct-3-yl]-furan-2- carboxamide tris(4-methylbenzenesulfonate) (from N-[(3R)-l-azabicyclo[2.2.2]oct-3- yl]-5-(4-nitrophenyl)-2-furamide). Yield 84%.
• HRMS (FAB) calculated for C I8 H 2 ,N 3 O 2 +H ⁇ 312.1712, found 312.1727.
• Example 149 5-(2-amino-4-methylphenyl)-N-[(3R)-l-azabicyclo[2.2.2]oct-3-yl]- furan-2-carboxamide dihydrochloride (from 5-(4-methyl-2-nirophenyl)-N-[(3R)-l- azabicyclo[2.2.2]oct-3-yl]-2-furamide dihydrochloride). Yield 55%.
• HRMS (FAB) calculated for C 19 H 23 N 3 O 2 +H 326.1868, found 326.1871.
• Step 150a Preparation of 5-phenylethylnyl-furan-2-aldehyde.
• Step 150b Preparation of N-[(3R)-l-azabicyclo[2.2.2]oct-3-yI]-5-(phenylethynyl)- furan-2-carboxamide 4-methylbenzcnesulfonate.
• Step 151a Preparation of N-[(3R)-l-azabicyclo[2.2.2]oct-3-yl]-5-phenoxy-furan- 2-carboxamide 4-methylbenzenesulfonate.
• a solution of N-[(3R)-l-aza-bicyclo[2.2.2]oct-3-yl]-5-bromo-furan-2- carboxamide (0.200 g, 0.42 mmol, 1 eq), sodium phenoxide (0.500 g, 4.3 mmol, 10.1 eq), in DMSO (5 mL) is stirred under nitrogen at room temperature overnight.
• the reaction is diluted with 25 mL water and extracted with CH 2 C1 2 (50 mL).
• Step 152a Preparation of methyl 5-bromo- 1 -methyl- 1 H-pyrrole-2-carboxylate. To a dry flask is added methyl 1 -methyl- lH-pyrrole-2-carboxylate (12.0 g,
• Step 152b Preparation of methyl l-methyl-5-phenyl-lH-pyrrole-2-carboxylate.
• step 152a The product from step 152a is added to a solution of tetrakis(triphenylphosphine)palladium(0) (0.530 g, 0.459mmol) in 90 mL of ethylene glycol dimethyl ether. The resulting solution is stirred under nitrogen for 5 min and then phenylboronic acid (1.34 g, 11.0 mmol) is added followed by a solution of Na 2 CO 3 (19.5 g, 183 mmol) in 90 mL of H 2 O. The mixture is heated at reflux for 24 hours. The reaction mixture is allowed to cool to rt, 100 L of CH 2 C1 2 is added, and the layers are separated.
• Lithium hydroxide (1.39 g, 33.2 mmol) is added to a solution of the product from Step 152b (1.43 g, 6.64 mmol) in 96 mL of a 1.25:1:1 H 2 O:MeOH:THF solvent mixture. The reaction is stirred at 50°C for 2 h. Aqueous HCI (IN, 50 mL) is added and the resultant precipitate is collected by filtration, washed with water, and dried to give 0.851 g of l-methyl-5-phenyl-lH-pyrrole-2-carboxylic acid as a tan solid (64% yield). MS for C, 2 H, ,NO 2 (ESI) (M-H) + m/z 200.1.
• Step 152d Preparation of N-[(3R)-l-azabicyclo[2.2.2]oct-3-yl]-l-methyl-5- phenyl- 1 H- ⁇ yrrole-2-carboxamide.
• Example 153 N-[(3R)-l-azabicyclo[2.2.2]oct-3-yl]-5- ⁇ henyl-l,3-oxazole-2- carboxamide 4-methylbenzenesulfonate (from 5-phenyl- 1 ,3-oxazole-2-carboxylic acid, see Saito, S.; Tanaka, C. J. Pharm. Sci. Japan 76, 1956, 305-7). Yield 77%. HRMS (FAB) calculated for C ⁇ 7 H
• Example 154 N-[(3R)-l-azabicyclo[2.2.2]oct-3-yl]-3-phenyl-l,2,4-oxadiazole-5- carboxamide 4-methylbenzenesulfonate (from 3-phenyl- l,2,4-oxadiazole-5-carboxylic acid, see Wurm. Chem. Ber.; 22; 1889; 3133). Yield 54%.
• HRMS (FAB) calculated for C ⁇ 6 H ]8 ⁇ 4 O 2 +H ⁇ 299.1508, found 299.1512.
• Example 155 N-[(3R)-l-azabicyclo[2.2.2]oct-3-yl]-2-phenyl-l,3-oxazole-5- carboxamide 4-methylbenzenesulfonate (from 2-phenyl- 1 ,3-oxazole-5-carboxylic acid, see Belenl ⁇ i, L. I.; Cheskis, M. A.; Zvolinskii, V. P.; Obukhov, A. E. Chem. Heterocycl. Compd. (Engl.TransL); 22; 1986; 654-663). Yield 16%.
• HRMS (FAB) calculated for C ]7 H ⁇ 9 ⁇ 3 O 2 +H, 298.1555, found 298.1555.
• Example 156 N-[(3R)-l-azabicyclo[2.2.2]oct-3-yl]-2-phenyl-l,3-oxazole-4- carboxamide 4-methylbenzenesulfonate (from 2-phenyl- 1 ,3-oxazole-4-carboxylic acid, see Korte, F.; Stoeriko, K. Chem.Ber.; 93; 1960; 1033-1042). Yield 22%.
• HRMS (FAB) calculated for C, 7 H )9 ⁇ 3 O 2 +H ⁇ 298.1555, found 298.1559.
• Example 157 N-[(3R)-l-azabicyclo[2.2.2]oct-3-yl]-5-phenylisoxazole-3- carboxamide 4-methylbenzenesulfonate (from 5-phenylisoxazole-3-carboxylic acid, see Vaughan, W.R.; Spencer, J.L. J.Org.Chem.; 25; 1960; 1160-1164). Yield 76%. HRMS (FAB) calculated for C, 7 H ⁇ 9 N 3 O 2 +H ⁇ 298.1555, found 298.1556.
• Step 158a Preparation of 2-methylenequinuclidin-3-one.
• Step 158c Preparation of (3E/Z)-2-methyl- 1 -azabicyclo[2.2.2Joctan-3-one oxime.
• the product from Step 158b (3.2g, 23.0mmol, leq) and hydroxylamine hydrochloride (1.6g, 23.0mmol, leq) are dissolved in 20mL EtOH/pyridine (4:1) and stirred at room temperature. After 5 days, water and solid NaOH are added to adjust pH to pH 11. The mixture is extracted with several portions of CHC1 3 .
• Step 158d Preparation of 2-methylquinuclidin-3-amine dihydrochloride
• Step 158e Preparation of 5-bromo-N-(2-methyl-l-azabicyclo[2.2.2]oct-3- yl)thiophene-2-carboxamide 4-methylbenzenesulfonate.
• Step 159a Preparation of methyl 5-phenyl-thio ⁇ hene-2-carbodithioate.
• the resulting dark green solution is stirred at 0°C for 15 minutes, at which time, carbon disulfide (2.0 mL, 34.0 mmol) is added dropwise over 15 minutes.
• carbon disulfide 2.0 mL, 34.0 mmol
• iodomethane 2.9 mL, 46.4 mmol
• the resulting dark brown solution is allowed to warm to room temperature and stirred for 1 hour, then is quenched with a solution of potassium cyanide in water (100 mL).
• Step 159b Preparation of N-[(3R)-l-azabicyclo[2.2.2]oct-3-yl]-5-phenyl- thiophene-2-carbothioamide fumarate.
• a solution of the product of Step 159a (0.49 g, 2.0 mmol) and (R)-3- aminoquinulidine (0.55 g, 4.4 mmol) in THF is stirred at 50°C for 19 hours.
• the crude reaction mixture is absorbed on to silica gel and purified by flash chromatography (gradient of 7% [9:1 MeOH/NH 4 OH]/CH 2 Cl 2 to 9%[9: 1 MeOH/NH OH]/CH 2 Cl 2 ).
• the fumarate salt is prepared and crystallized.
• the present invention also includes, by representation but not limitation, any one of the following or combination of the following compounds and pharmaceutically acceptable salts thereof, both of which can be made by one of ordinary skill in the art using the procedures provided making non-critical changes: N-[(2S,3R)-2-methyl-l-azabicyclo[2.2.2]oct-3-yl]-5-phenyl-thio ⁇ hene-2- carboxamide; N-[(2S,3R)-2-methyl-l-azabicyclo[2.2.2]oct-3-yl]-5-(4-chlorophenyl)- thiophene-2-carboxamide; N-[(2S,3R)-2-methyl-l-azabicyclo[2.2.2]oct-3-yl]-5-(3- chlorophenyl)-thiophene-2-carboxamide; N-[[(2S,3R)-2-methyl-l-azabicyclo[2.2.2]oct-3-yl]-5-(3- chloroph
• Binding Assay For saturation studies, 0.4 mL homogenate are added to test tubes containing buffer and various concentrations of radioligand, and are incubated in a final volume of 0.5 mL for 1 hour at 25 °C. Nonspecific binding was determined in tissues incubated in parallel in the presence of 0.05 ml MLA for a final concentration of 1 ⁇ M MLA, added before the radioligand. hi competition studies, drugs are added in increasing concentrations to the test tubes before addition of 0.05 ml [ 3 H]-MLA for a final concentration of 3.0 to 4.0 nM [ 3 H]-MLA.
• the incubations are terminated by rapid vacuum filtration through Whatman GF/B glass filter paper mounted on a 48 well Brandel cell harvester. Filters are pre-soaked in 50 mM Tris HCI pH 7.0 - 0.05 % polyethylenimine. The filters are rapidly washed two times with 5 mL aliquots of cold 0.9% saline and then counted for radioactivity by liquid scintillation spectrometry.

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