The invention provides compounds of Formula I: compounds of the Formula I:

Nicotinic acetylcholine receptors (nAChRs) 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 xcex17 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.
Cell surface receptors are, in general, excellent and validated drug targets. nAChRs comprise a large family of ligand-gated ion channels that control neuronal activity and brain function. These receptors have a pentameric structure. In mammals, this gene family is composed of nine alpha and four beta subunits that co-assemble to form multiple subtypes of receptors that have a distinctive pharmacology. Acetylcholine is the endogenous regulator of all of the subtypes, while nicotine non-selectively activates all nAChRs.
The xcex17 nAChR is one receptor system that has proved to be a difficult target for testing. Native xcex17 nAChR is not routinely able to be stably expressed in most mammalian cell lines (Cooper and Millar, J. Neurochem., 1997, 68 (5):2140-51). Another feature that makes functional assays of xcex17 nAChR challenging is that the receptor is rapidly (100 milliseconds) inactivated. This rapid inactivation greatly limits the functional assays that can be used to measure channel activity.
Recently, Eisele et al. has indicated that a chimeric receptor formed between the N-terminal ligand binding domain of the xcex17 nAChR (Eisele et al., Nature, 366(6454), p 479-83, 1993), and the pore forming C-terminal domain of the 5-HT3 receptor expressed well in Xenopus oocytes while retaining nicotinic agonist sensitivity. Eisele et al. used the N-terminus of the avian (chick) form of the xcex17 nAChR receptor and the C-terminus of the mouse form of the 5-HT3 gene. However, under physiological conditions the xcex17 nAChR is a calcium channel while the 5-HT3R is a sodium and potassium channel. Indeed, Eisele et al. teaches that the chicken xcex17 nAChR/ mouse 5-HT3R behaves quite differently than the native xcex17 nAChR with the pore element not conducting calcium but actually being blocked by calcium ions. WO 00/73431 A2 reports on assay conditions under which the 5-HT3R can be made to conduct calcium. This assay may be used to screen for agonist activity at this receptor.
U.S. Pat. No. 6,255,490 B1 discloses 7-azabicyclo[2.2. 1]-heptane and -heptene derivatives as cholinergic receptor ligands.
U.S. Pat. No. 6,117,889 discloses discloses 7-azabicyclo[2.2.1]-heptane and -heptene derivatives as analgesics and anti-inflammatory agents.
U.S. Pat. No. 6,060,473 discloses 7-azabicyclo[2.2.1]-heptane and -heptene derivatives as cholinergic receptor ligands.
U.S. Pat. No. 6,054,464 discloses azabicyclic esters of carbamic acids useful in therapy, especially in the treatment or prophylaxis of psychotic disorders and intellectual impairment disorders, as well as intermediates and use of intermediates in synthesis.
U.S. Pat. No. 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 xcex17 receptor subtype with little or no activation of the xcex14xcex22 or other receptor subtypes.
U.S. Pat. No. 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 5HT1A receptors and dopamine D2 receptors, making them useful as antipsychotic agents.
U.S. Pat. No. 5,624,941 discloses pyrazole derivatives useful in pharmaceuticals in which cannabis is known to be involved.
U.S. Pat. No. 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 coadministration with another active agent to increase the bioavailability thereof, or for nasal administration.
U.S. Pat. No. 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 5HT1A receptors and dopamine D2 receptors, making them useful as antipsychotic agents.
U.S. Pat. No. 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.
U.S. Pat. No. 5,106,843 discloses heterocyclic compounds useful as 5-HT3 antagonists.
U.S. Pat. No. 5,057,519 discloses 5-HT3 antagonists as being useful in reducing opiate tolerance.
U.S. Pat. No. 5,039,680 discloses 5-HT3 antagonists in preventing or reducing dependency on dependency-inducing agents.
U.S. Pat. No. 4,988,691 discloses isoxazole-containing compounds exhibiting anti-serotonin activity.
U.S. Pat. No. 4,921,982 discloses 5-halo-2,3-dihydro-2,2-dimethylbenzofuran-7-carboxylic acids which are useful as intermediates for 5-HT3 antagonists.
U.S. Pat. No. 4,835,162 discloses agonists and antagonists to nicotine as smoking deterrents.
U.S. Pat. No. 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.
WO 01/60821 discloses novel biarylcarboxamides.
WO 01/36417 A1 discloses novel N-azabicyclo-amide derivatives and use in therapy, especially in the treatment of prophylaxis of psychotic disorders and intellectual impairment disorders.
WO 01/29304 discloses quinuclidine acrylamides.
WO 00/73431 A2 discloses two binding assays to directly measure the affinity and selectivity of compounds at the xcex17 nAChR and the 5-HT3R. The combined use of these functional and binding assays may be used to identify compounds that are selective agonists of the xcex17 nAChR.
WO 97/30998 discloses azabicyclic esters of carbamic acids useful in therapy.
WO 95/01793 discloses 5-HT3 antagonists as topical medicaments for treatment of peripheral disorders associated with pain.
WO 92/15579 discloses multicyclic tertiary amine polyaromatic squalene synthase inhibitors and method of treatment for lowering serum cholesterol levels using the compounds.
DE 3810552 A1 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-arrhythmic 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.
In Bioorg. and Med. Chem. Lett. 11 (2001) 319-321, the 5-HT3 antagonist tropisetron (ICS 205-930) is discussed as a potent and selective xcex17 Nicotinic receptor partial agonist.
In Behavioral Brain Res., 113 (2000) 169-181, it is discussed that the brain xcex17 nicotinic receptor may be an important therapeutic target for the treatment of Alzheimer""s disease using DMXBA which is known as GTS-21.
In general, the invention includes a compound of the formula Axe2x80x94Lxe2x80x94B or a pharmaceutically acceptable salt thereof, wherein A includes a 7-azabicyclo[2.2.1]heptane ring having 1S, 2R, and 4R stereochemistry; B is a heteroaryl; and L is a linking moiety including an amide, a thioamide, an acrylamide, an acrylthioamide, a propiolamide, or a propiolthioamide substituent having the linking moiety bonded to the C-2 carbon of the heptane ring in an exo orientation.
The present invention discloses compounds of the Formula I:
wherein the stereochemistry of the of the 7-azabicyclo[2.2.1]heptane ring is 1S, 4R and the nitrogen substituent at the C-2 carbon has the exo orientation and is R;
X is O or S;
R1 is H, alkyl, halogenated alkyl, cycloalkyl, or aryl;
R2 is H, alkyl, halogenated alkyl, substituted alkyl, cycloalkyl, or aryl;
W is xe2x80x94Q, xe2x80x94Cxe2x95x90Cxe2x80x94Q, or xe2x80x94Cxe2x89xa1xe2x80x94Cxe2x80x94Q;
Q is a cyclic heteroaromatic moiety where the heteroatoms can be from 1-3 atoms selected from oxygen, sulfur, or nitrogen of the following structures:
xe2x80x83wherein U is xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, or xe2x80x94N(R3)xe2x80x94;
V and Y are independently selected from xe2x95x90Nxe2x80x94, and xe2x95x90C(R5)xe2x80x94;
Z is xe2x95x90Nxe2x80x94, or xe2x95x90CHxe2x80x94;
R3 is H, alkyl, cycloalkyl, heterocycloalkyl, halogenated alkyl, halogenated cycloalkyl, halogenated heterocycloalkyl, substituted alkyl, substituted cycloalkyl, substituted heterocycloalkyl, R7, R9, aryl, xe2x80x94C(O)-alkyl, xe2x80x94C(O)-cycloalkyl, xe2x80x94C(O)-heterocycloalkyl, xe2x80x94C(O)-halogenated alkyl, xe2x80x94C(O)-halogenated cycloalkyl, xe2x80x94C(O)-halogenated heterocycloalkyl, xe2x80x94C(O)-substituted alkyl, xe2x80x94C(O)-substituted cycloalkyl, xe2x80x94C(O)-substituted heterocycloalkyl, xe2x80x94C(O)xe2x80x94R7, xe2x80x94C(O)xe2x80x94R9, or xe2x80x94C(O)-aryl;
Each R4 is independently H, alkyl, or substituted alkyl;
Each R5 is independently H, F, Cl, Br, I, 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, lactam heterocycloalkyl, aryl, xe2x80x94OR8, xe2x80x94SR8, xe2x80x94N(R8)2, xe2x80x94C(O)R8, xe2x80x94C(S)R8, xe2x80x94C(O)OR8, xe2x80x94C(O)N(R8)2, xe2x80x94NR8C(O)R8, xe2x80x94S(O)2N(R8)2, xe2x80x94OS(O)2R8, xe2x80x94S(O)2R8, xe2x80x94S(O)R8, xe2x80x94NR8S(O)2R8, xe2x80x94N(R8)C(O)N(R8)2, xe2x80x94CN, xe2x80x94NO2, R7, or R9;
R6 is H, alkyl, an amino protecting group, or an alkyl group having 1-3 substituents selected from F, Cl, Br, I, xe2x80x94OH, xe2x80x94CN, xe2x80x94NH2, xe2x80x94NH(alkyl), or xe2x80x94N(alkyl)2;
R7 is 5-membered heteroaromatic mono-cyclic moieties containing within the ring 1-3 heteroatoms independently selected from the group consisting of xe2x95x90Nxe2x80x94, xe2x80x94N(R20)xe2x80x94, xe2x80x94Oxe2x80x94, and xe2x80x94Sxe2x80x94, and having 0-1 substituent selected from R17 and further having 0-3 substituents independently selected from F, Cl, Br, or I, or R7 is 9-membered fused-ring moieties having a 6-membered ring fused to a 5-membered ring including the formula
wherein G1 is O, S or NR20,
wherein G is C(R14) or N, and each G2 and G3 is independently selected from C(R14)2, C(R14), O, S, N, and N(R20), provided that both G2 and G3 are not simultaneously O or S, or
wherein G is C(R14) or N, and each G2 and G3 is independently selected from C(R14)2, C(R14), O, S, N, and N(R20), each 9-membered bicyclic ring having 0-1 substituent selected from R17 and 0-3 substituents independently selected from F, Cl, Br, or I, wherein the R7 moiety attaches to other substituents as defined in formula I at any position on either ring as valency allows;
Each R8 is independently H, alkyl, halogenated alkyl, substituted alkyl, cycloalkyl, halogenated cycloalkyl, substituted cycloalkyl, heterocycloalkyl, halogenated heterocycloalkyl, substituted heterocycloalkyl, R7, R9, phenyl optionally substituted with 1-4 substituents independently selected from F, Cl, Br, I, R13, and R15, or naphthyl optionally substituted with 1-4 substituents independently selected from F, Cl, Br, I, R13, and R15;
R9 is 6-membered heteroaromatic mono-cyclic moieties containing within the ring 1-3 heteroatoms selected from xe2x95x90Nxe2x80x94 and having 0-1 substituent selected from R17 and 0-3 substituent(s) independently selected from F, Cl, Br, or I, or R9 is 10-membered heteroaromatic bi-cyclic moieties containing within one or both rings 1-3 heteroatoms selected from xe2x95x90Nxe2x80x94, including, but not limited to, quinolinyl or isoquinolinyl, each 10-membered fused-ring moiety having 0-1 substituent selected from R17 and 0-3 substituent(s) independently selected from F, Cl, Br, or I, wherein the R9 moiety attaches to other substituents as defined in formula I at any position on either ring as valency allows;
Each R10 is independently H, alkyl, cycloalkyl, heterocycloalkyl, R7, R9, alkyl substituted with 1 substituent selected from R13, cycloalkyl substituted with 1 substituent selected from R13, heterocycloalkyl substituted with 1 substituent selected from R13, halogenated alkyl, halogenated cycloalkyl, halogenated heterocycloalkyl, or phenyl optionally substituted with 1-4 substituents independently selected from F, Cl, Br, I, R13, and R15;
Each R11 is independently H, alkyl, cycloalkyl, heterocycloalkyl, halogenated alkyl, halogenated cycloalkyl, or halogenated heterocycloalkyl;
R12 is alkyl, cycloalkyl, heterocycloalkyl, halogenated alkyl, halogenated cycloalkyl, halogenated heterocycloalkyl, substituted alkyl, substituted cycloalkyl, substituted heterocycloalkyl, xe2x80x94OR11, xe2x80x94SR11, xe2x80x94S(O)2R11, xe2x80x94S(O)R11, xe2x80x94OS(O)2R11, xe2x80x94N(R11)2, xe2x80x94C(O)R11, xe2x80x94C(S)R11, xe2x80x94C(O)OR11, xe2x80x94NO2, xe2x80x94C(O)N(R11)2, xe2x80x94CN, xe2x80x94NR11C(O)R11, xe2x80x94NR11C(O)N(R11)2, xe2x80x94S(O)2N(R11)2, or xe2x80x94NR11S(O)2R11;
R13 is xe2x80x94OR11, xe2x80x94SR11, xe2x80x94SOR11, xe2x80x94SO2R11, xe2x80x94OSO2R11, xe2x80x94N(R11)2, xe2x80x94C(O)R11, xe2x80x94C(O)OR11, xe2x80x94C(S)R11, xe2x80x94C(O)N(R11)2, xe2x80x94NO2xe2x80x94CN, xe2x80x94CF3, xe2x80x94NR11C(O)R11, xe2x80x94NR11C(O)N(R11)2, xe2x80x94S(O)2N(R11)2, or xe2x80x94NR11S(O)2R11;
R14 is H or R19;
R15 is R7, R9, R19, or lactam heterocycloalkyl;
Each R16 is independently H, alkyl, cycloalkyl, halogenated alkyl, or halogenated cycloalkyl;
R17 is alkyl, cycloalkyl, or heterocycloalkyl, each optionally substituted with 1-4 substituents independently selected from F, Cl, Br, I, xe2x80x94NO2, xe2x80x94CN, xe2x80x94OR16, xe2x80x94SR16, xe2x80x94S(O)2R16, xe2x80x94S(O)R16, xe2x80x94OS(O)2R16, xe2x80x94N(R16)2, xe2x80x94C(O)R16, xe2x80x94C(S)R16, xe2x80x94C(O)OR16, xe2x80x94C(O)N(R16)2, xe2x80x94NR16C(O)R16, xe2x80x94NR16C(O)N(R16)2, xe2x80x94S(O)2N(R16)2, and xe2x80x94NR16S(O)2R16, and the cycloalkyl and heterocycloalkyl also being further optionally substituted with xe2x95x90O or xe2x95x90S;
R19 is alkyl, cycloalkyl, heterocycloalkyl, phenyl, or naphthyl, each optionally substituted with 1-4 substituents independently selected from F, Cl, Br, I, xe2x80x94CN, xe2x80x94NO2, xe2x80x94OR16, xe2x80x94SR16, xe2x80x94S(O)2R16, xe2x80x94S(O)R16, xe2x80x94OS(O)2R16, xe2x80x94N(R16)2, xe2x80x94C(O)R16, xe2x80x94C(S)R16, xe2x80x94C(O)OR16, xe2x80x94C(O)N(R16)2, xe2x80x94NR16C(O)R16, xe2x80x94NR16C(O)N(R16)2, xe2x80x94S(O)2N(R16)2, or xe2x80x94NR16S(O)2R16, and the cycloalkyl and heterocycloalkyl also being further optionally substituted with xe2x95x90O or xe2x95x90S;
R20 is H, alkyl, halogenated alkyl, substituted alkyl, cycloalkyl, halogenated cycloalkyl, substituted cycloalkyl, phenyl, xe2x80x94SO2R8, or phenyl having 1 substituent selected from R12 and further having 0-3 substituents independently selected from F, Cl, Br, or I;
or pharmaceutical composition, pharmaceutically acceptable salt, racemic mixture, or pure enantiomer thereof.
In another aspect, the invention includes a compound of formula Axe2x80x94Lxe2x80x94B or a pharmaceutically acceptable salt thereof, wherein A includes a 7-azabicyclo[2.2.1]heptane ring having 1S, 2R, and 4R stereochemistry; B is a heteroaryl; and L is a linking moiety including an amide, a thioamide, an acrylamide, an acrylthioamide, a propiolamide, or a propiolthioamide having the linking moiety bonded to the C-2 carbon of the heptane ring in an exo orientation.
In another aspect, the invention includes methods of treating a mammal suffering from schizophrenia or psychosis by administering compounds of formula Axe2x80x94Lxe2x80x94B or Formula I in conjunction with antipsychotic drugs (also called antipsychotic agents). The compounds of formula Axe2x80x94Lxe2x80x94B or Formula I and the antipsychotic drugs can be administered simultaneously or at separate intervals. When administered simultaneously the compounds of the present invention and the antipsychotic drugs can be incorporated into a single pharmaceutical composition. Alternatively, two separate compositions, i.e., one containing compounds of present invention and the other containing antipsychotic drugs, can be administered simultaneously.
The present invention also includes the compounds of the present invention, pharmaceutical compositions containing the active compounds, and methods to treat the identified diseases.
Embodiments of the invention may include one or more or combination of the following.
The compound of Formula I, where X is O.
The compound of Formula I, where X is S.
The compound of Formula I, where W is any one or more or combination of Q, xe2x80x94Cxe2x95x90Cxe2x80x94Q, or xe2x80x94Cxe2x89xa1Cxe2x80x94Q, optionally substituted as the definition of Q allows.
The compound of Formula I, where Q is either (a) or (b) or both (a) and (b), each optionally substituted on a carbon atom where substitution is allowed with any one of the following: F, Cl, Br, I, 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, lactam heterocycloalkyl, aryl, xe2x80x94OR8, xe2x80x94SR8, xe2x80x94N(R8)2, xe2x80x94C(O)R8, xe2x80x94C(S)R8, xe2x80x94C(O)OR8, xe2x80x94C(O)N(R8)2, xe2x80x94NR8C(O)R8, xe2x80x94S(O)2N(R8)2, xe2x80x94OS(O)2R8, xe2x80x94S(O)2R8, xe2x80x94S(O)R8, xe2x80x94NR8S(O)2R8, xe2x80x94N(R8)C(O)N(R8)2, xe2x80x94CN, xe2x80x94NO2, R7, or R9. One of ordinary skill in the art can identify where substitution is allowed by comparing moieties with (a) or (b).
The compound of Formula I, where Q is either (a) or (b) or both (a) and (b), each optionally substituted on a nitrogen atom where substitution is allowed with any one of the following: alkyl, cycloalkyl, heterocycloalkyl, halogenated alkyl, halogenated cycloalkyl, halogenated heterocycloalkyl, substituted alkyl, substituted cycloalkyl, substituted heterocycloalkyl, R7, R9, aryl, xe2x80x94C(O)-alkyl, xe2x80x94C(O)-cycloalkyl, xe2x80x94C(O)-heterocycloalkyl, xe2x80x94C(O)-halogenated alkyl, xe2x80x94C(O)-halogenated cycloalkyl, xe2x80x94C(O)-halogenated heterocycloalkyl, xe2x80x94C(O)-substituted alkyl, xe2x80x94C(O)-substituted cycloalkyl, xe2x80x94C(O)-substituted heterocycloalkyl, xe2x80x94C(O)xe2x80x94R7, xe2x80x94C(O)xe2x80x94R9, or xe2x80x94C(O)-aryl. One of ordinary skill in the art can identify where substitution is allowed by comparing moieties with (a) or (b).
Another group of compounds of Formula I includes compounds where R3 includes any one of the following: H, alkyl, cycloalkyl, heterocycloalkyl, halogenated alkyl, halogenated cycloalkyl, halogenated heterocycloalkyl, substituted alkyl, substituted cycloalkyl, substituted heterocycloalkyl, R7, R9, aryl, xe2x80x94C(O)-alkyl, xe2x80x94C(O)-cycloalkyl, xe2x80x94C(O)-heterocycloalkyl, xe2x80x94C(O)-halogenated alkyl, xe2x80x94C(O)-halogenated cycloalkyl, xe2x80x94C(O)-halogenated heterocycloalkyl, xe2x80x94C(O)-substituted alkyl, xe2x80x94C(O)-substituted cycloalkyl, xe2x80x94C(O)-substituted heterocycloalkyl, xe2x80x94C(O)xe2x80x94R7, xe2x80x94C(O)xe2x80x94R9, or xe2x80x94C(O)-aryl. Another group of compounds of Formula I includes compounds wherein R3 is H.
Another group of compounds of Formula I includes compounds where each R5 is independently any one of the following: H, F, Cl, Br, I, 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, lactam heterocycloalkyl, aryl, xe2x80x94OR8, xe2x80x94SR8, xe2x80x94NR8R8, xe2x80x94C(O)R8, xe2x80x94C(S)R8, xe2x80x94C(O)OR8, xe2x80x94C(O)NR8R8, xe2x80x94NR8C(O)R8, xe2x80x94S(O)2NR8R8, xe2x80x94OS(O)2R8, xe2x80x94S(O)2R8, xe2x80x94S(O)R8, xe2x80x94NR8S(O)2R8, xe2x80x94N(R8)C(O)NR8R8, xe2x80x94CN, xe2x80x94NO2, R7, or R9. Another group of compounds of Formula I includes compounds wherein each R5 is H.
Another group of compounds of Formula I includes compounds wherein both V and Y are xe2x95x90C(R5)xe2x80x94 and Z is xe2x95x90CHxe2x80x94, and wherein only one xe2x95x90C(R5)xe2x80x94 can be xe2x95x90CHxe2x80x94. Another group of compounds of Formula I includes compounds wherein U is xe2x80x94Oxe2x80x94, Y is xe2x95x90C(R5)xe2x80x94, Z is xe2x95x90C(H)xe2x80x94, and V is other than xe2x95x90Nxe2x80x94. Another group of compounds of Formula I includes compounds where W is Q and Q is (b), V and Y are C(R5), Z is xe2x95x90Nxe2x80x94, and U is N(R3), wherein R3 is other than phenyl, substituted phenyl, or benzyl substituted on the phenyl of the benzyl with xe2x80x94CH3. Benzyl is an allowed substitutent where substituted alkyl is allowed.
Another aspect of the invention includes a compound of formula Axe2x80x94Lxe2x80x94B or a pharmaceutically acceptable salt thereof, wherein A includes a 7-azabicyclo[2.2.1]heptane ring having 1S, 2R, and 4R stereochemistry; B is a heteroaryl; and L is a linking moiety including an amide, a thioamide, an acrylamide, an acrylthioamide, a propiolamide, or a propiolthioamide having the linking moiety bonded to the C-2 carbon of the heptane ring in an exo orientation. Heteroaryl is 5-membered heteroaromatic mono-cyclic moieties containing within the ring 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, optionally substituted with up to 4 substitutents where valency allows with substituents independently being F, Cl, Br, I, 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, lactam heterocycloalkyl, aryl, xe2x80x94OR8, xe2x80x94SR8, xe2x80x94N(R8)2, xe2x80x94C(O)R8, C(O)-aryl, xe2x80x94C(S)R8, xe2x80x94C(O)OR8, xe2x80x94C(O)N(R8)2, xe2x80x94NR8C(O)R8, xe2x80x94S(O)2N(R8)2, xe2x80x94OS(O)2R8, xe2x80x94S(O)2R8, xe2x80x94S(O)R8, xe2x80x94NR8S(O)2R8, xe2x80x94N(R8)C(O)N(R8)2, xe2x80x94CN, xe2x80x94NO2, R7, or R9.
The compound of Formula I, where R1 is H, alkyl, or cycloalkyl, and where R2 is H, alkyl, substituted alkyl, cycloalkyl, halogenated alkyl, or aryl.
The compound of Formula I, where (a) is any one or more or combination of the following: thiophen-2-yl, furan-2-yl, 1,3-thiazol-5-yl, or 1,3-oxazol-2-yl, 1,3-thiazole-2-yl, 1,3,4-oxadiazole-2-yl, 1,3-oxazole-5-yl, 1H-pyrrole-2-yl, or 1,2,4-oxadiazole-5-yl, any of which is optionally substituted on carbon (e.g., V or Y is independently CR5), with H, F, Cl, Br, I, 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, lactam heterocycloalkyl, aryl, xe2x80x94OR8, xe2x80x94SR8, xe2x80x94N(R8)2, xe2x80x94C(O)R8, xe2x80x94C(S)R8, xe2x80x94C(O)OR8, xe2x80x94C(O)N(R8)2, xe2x80x94NR8C(O)R8, xe2x80x94S(O)2N(R8)2, xe2x80x94OS(O)2R8, xe2x80x94S(O)2R8, xe2x80x94S(O)R8, xe2x80x94NR8S(O)2R8, xe2x80x94N(R8)C(O)N(R8)2, xe2x80x94CN, xe2x80x94NO2, R7, or R9; and
further optionally substituted on nitrogen (e.g., when U is Nxe2x80x94R3), with alkyl, cycloalkyl, heterocycloalkyl, halogenated alkyl, halogenated cycloalkyl, halogenated heterocycloalkyl, substituted alkyl, substituted cycloalkyl, substituted heterocycloalkyl, R7, R9, aryl, xe2x80x94C(O)-alkyl, xe2x80x94C(O)-cycloalkyl, xe2x80x94C(O)-heterocycloalkyl, xe2x80x94C(O)-halogenated alkyl, xe2x80x94C(O)-halogenated cycloalkyl, xe2x80x94C(O)-halogenated heterocycloalkyl, xe2x80x94C(O)-substituted alkyl, xe2x80x94C(O)-substituted cycloalkyl, xe2x80x94C(O)-substituted heterocycloalkyl, xe2x80x94C(O)xe2x80x94R7, xe2x80x94C(O)xe2x80x94R9, or xe2x80x94C(O)-aryl.
The compound of Formula I, where each R4 is independently H, lower alkyl, or substituted lower alkyl.
The compound of Formula I, where R6 is an amino protecting group.
The compound of Formula I, where R6 is H, or lower alkyl optionally substituted with up to 3 substituents independently selected from F, Cl, Br, I, xe2x80x94OH, xe2x80x94CN, xe2x80x94NH2, xe2x80x94NH(alkyl), or xe2x80x94N(alkyl)2.
The compound of Formula I, where R1 is H or lower alkyl, and where R2 is H or lower alkyl.
The compound of Formula I, where at least one R4 is H and one R4 is H or lower alkyl optionally substituted with 1 substituent selected from xe2x80x94CN, xe2x80x94NO2, xe2x80x94OR10, xe2x80x94SR10, xe2x80x94S(O)R10, xe2x80x94S(O)2R10, xe2x80x94OS(O)2R10, xe2x80x94NR10R10, xe2x80x94C(O)R10, xe2x80x94C(O)OR10, xe2x80x94C(S)R10, xe2x80x94C(O)NR10R10, xe2x80x94NR10C(O)R10, xe2x80x94NR10C(O)NR10R10, xe2x80x94S(O)2NR10R10, xe2x80x94NR10S(O)2R10, or phenyl optionally substituted with up to 4 substitutents independently selected from F, Cl, Br, I, R13, and R15, provided that when said lower alkyl is optionally substituted, said lower alkyl can be further optionally substituted with up to 3 substituents independently selected from F, Cl, Br, and I, and further provided that R10 is H, lower alkyl, or halogenated lower alkyl. This allows the lower alkyl of R4 to be substituted with one substituent selected from xe2x80x94CN, xe2x80x94NO2, xe2x80x94OR10, xe2x80x94SR10, xe2x80x94S(O)R10, xe2x80x94S(O)2, R10, xe2x80x94OS(O)2R10, xe2x80x94NR10R10, xe2x80x94C(O)R10, xe2x80x94C(O)OR10, xe2x80x94C(S)R10, xe2x80x94C(O)NR10R10, xe2x80x94NR10C(O)R10, xe2x80x94NR10C(O)NR10R10, xe2x80x94S(O)2NR10R10, xe2x80x94NR10S(O)2R10, or phenyl optionally substituted with up to 4 substitutents independently selected from F, Cl, Br, I, R13, and R15, and further optionally substituted with up to 3 substituents independently selected from F, Cl, Br, and I on any carbon with sufficient valency for said substitution. This further provides that R10 is H, lower alkyl or halogenated lower alkyl for the following optional substituents on R4: xe2x80x94OR10, xe2x80x94SR10, xe2x80x94S(O)R10, xe2x80x94S(O)2R10, xe2x80x94OS(O)2R10, xe2x80x94NR10R10, xe2x80x94C(O)R10, xe2x80x94C(O)OR10, xe2x80x94C(O)R10, xe2x80x94C(O)NR10R10, xe2x80x94NR10C(O)R10, xe2x80x94NR10C(O)NR10R10, xe2x80x94S(O)2NR10R10, xe2x80x94NR10S(O)2R10.
The compound of Formula I, where R1, R2, and each R4 are H.
The compound of Formula I or formula Axe2x80x94Lxe2x80x94B, where the compound is any one or more or combination of the following as the free base, or a pharmaceutically acceptable salt thereof:
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-bromo-2-thiophenecarboxamide;
(+/xe2x88x92) exo-N-[7-azabicyclo[2.2.1]hept-2-yl]-5-bromo-2-thiophenecarboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(methylthio)thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-phenylthiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(2-chlorophenyl)thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-[(4-chlorophenyl)thio]thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-methylthiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-pyridin-2-ylthiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(3-nitrophenyl)-2-furamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(4-nitrophenyl)-2-furamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(4-chlorophenyl)-2-furamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-chlorothiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(2-nitrophenyl)-2-furamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(4-aminophenyl)-2-furamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(2-fluorophenyl)-2-furamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(3-fluorophenyl)-2-furamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(4-fluorophenyl)-2-furamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(4-methylphenyl)-2-furamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-bromo-2-furamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-2-phenyl-1,3-thiazole-5-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-2-(2-fluorophenyl)-1,3-thiazole-5-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-phenyl-2-furamide; or
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-phenyl-1,3-oxazole-2-carboxamide.
The compound of Formula I or formula Axe2x80x94Lxe2x80x94B, where the compound is any one or more or combination of the following as the free base, or a pharmaceutically acceptable salt thereof: N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(4-chlorophenyl)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(3-chlorophenyl)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-2,3xe2x80x2-bithiophene-5-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(2-nitrophenyl)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(3-nitrophenyl)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-4-phenyl-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(3-benzyloxyphenyl)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(4-benzyloxyphenyl)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(3-fluoro-4-benzyloxyphenyl)-thiophene-2-carboxamide;
5-(2-aminophenyl)-N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-pyridin-3-yl-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5xe2x80x2-methyl-2,2xe2x80x2-bithiophene-5-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5xe2x80x2-chloro-2,2xe2x80x2-bithiophene-5-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-nitro-thiophene-2-carboxamide;
5-(aminomethyl)-N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-cyano-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-methoxy-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-[2,2]bithiophene-5-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-acetyl-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(phenylsulfanyl)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-phenyl-thiophene-2-carbothioamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(2-acetamidophenyl)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(3-acetamidophenyl)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(4-acetamidophenyl)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(2-trifluoroacetamidophenyl)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(3-trifluoroacetamidophenyl)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(4-trifluoroacetamidophenyl)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(2-methanesulfonylaminophenyl)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(3-methanesulfonylarminophenyl)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(4-methanesulfonylaminophenyl)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(2-trifluoromethanesulfonylaminophenyl)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(3-trifluoromethanesulfonylaminophenyl)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(4-trifluoromethanesulfonylaminophenyl)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(2-difluoroacetamidophenyl)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(3-difluoroacetamidophenyl)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(4-difluoroacetamidophenyl)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(2-carbamoylphenyl)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(3-carbamoylphenyl)-thiophene-2-carboxamide;
-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(4-carbamoylphenyl)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(2-sulfamoylphenyl)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(3-sulfamoylphenyl)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(4-sulfamoylphenyl)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(2-acetamidophenylsulfanyl)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(3-acetamidophenylsulfanyl)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(4-acetamidophenylsulfanyl)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(2-trifluoroacetamidophenylsulfanyl)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(3-trifluoroacetamidophenylsulfanyl)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(4-trifluoroacetamidophenylsulfanyl)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(2-methanesulfonylaminophenylsulfanyl)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(3-methanesulfonylaminophenylsulfanyl)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(4-methanesulfonylaminophenylsulfanyl)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(2-trifluoromethanesulfonylaminophenylsulfanyl)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(3-trifluoromethanesulfonylaminophenylsulfanyl)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(4-trifluoromethanesulfonylaminophenylsulfanyl)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(2-difluoroacetamidophenylsulfanyl)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(3-difluoroacetamidophenylsulfanyl)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(4-difluoroacetamidophenylsulfanyl)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(2-carbamoylphenylsulfanyl)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(3-carbamoylphenylsulfanyl)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(4-carbamoylphenylsulfanyl)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(2-sulfamoylphenylsulfanyl)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(3-sulfamoylphenylsulfanyl)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(4-sulfamoylphenylsulfanyl)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(2-hydroxyphenylsulfanyl)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(3-hydroxyphenylsulfanyl)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(4-hydroxyphenylsulfanyl)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(2-aminophenylsulfanyl)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(3-aminophenylsulfanyl)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(4-aminophenylsulfanyl)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(2-acetamidophenoxy)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(3-acetamidophenoxy)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(4-acetamidophenoxy)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(2-trifluoroacetamidophenoxy)-thiophene-2-carboxaminde;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(3-trifluoroacetamidophenoxy)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(4-trifluoroacetamidophenoxy)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(2-methanesulfonylaminophenoxy)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(3-methanesulfonylaminophenoxy)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(4-methanesulfonylaminophenoxy)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(2-trifluoromethanesulfonylaminophenoxy)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(3-trifluoromethanesulfonylaminophenoxy)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(4-trifluoromethanesulfonylaminophenoxy)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(2-difluoroacetamidophenoxy)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(3-difluoroacetamidophenoxy)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(4-difluoroacetamidophenoxy)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(2-carbamoylphenoxy)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(3-carbamoylphenoxy)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(4-carbamoylphenoxy)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(2-sulfamoylphenoxy)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(3-sulfamoylphenoxy)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(4-sulfamoylphenoxy)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(2-hydroxyphenoxy)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(3-hydroxyphenoxy)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(4-hydroxyphenoxy)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(2-aminophenoxy)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(3-aminophenoxy)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(4-aminophenoxy)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(2-chlorophenoxy)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(3-chlorophenoxy)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(4-chlorophenoxy)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(2-cyanophenoxy)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(3-cyanophenoxy)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(4-cyanophenoxy)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(2-methoxyphenyl)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(3-methoxyphenyl)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(4-methoxyphenyl)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(2-methylphenyl)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(3-methylphenyl)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(4-methylphenyl)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(2-trifluoromethylphenyl)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(3-trifluoromethylphenyl)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(4-trifluoromethylphenyl)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(2-acetylphenyl)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(3-acetylphenyl)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(4-acetylphenyl)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(2-cyanophenyl)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(3-cyanophenyl)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(4-cyanophenyl)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(2-morpholin-4-yl-phenyl)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(3-morpholin-4-yl-phenyl)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(4-morpholin-4-yl-phenyl)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(2-methoxyphenoxy)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(3-methoxyphenoxy)-thiophene-2-carboxamide; N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(4-methoxyphenoxy)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(2-methylphenoxy)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(3-methylphenoxy)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(4-methylphenoxy)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(2-trifluoromethylphenoxy)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(3-trifluoromethylphenoxy)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(4-trifluoromethylphenoxy)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(2-acetylyphenoxy)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(3-acetylphenoxy)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(4-acetylphenoxy)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(2-cyanophenoxy)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(3-cyanophenoxy)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(4-cyanophenoxy)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(2-morpholin-4-yl-phenoxy)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(3-morpholin-4-yl-phenoxy)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(4-morpholin-4-yl-phenoxy)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(2-methoxyphenylsulfanyl)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(3-methoxyphenylsulfanyl)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(4-methoxyphenylsulfanyl)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(2-methylphenylsulfanyl)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(3-methylphenylsulfanyl)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(4-methylphenylsulfanyl)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(2-trifluoromethylphenylsulfanyl)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(3-trifluoromethylphenylsulfanyl)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(4-trifluoromethylphenylsulfanyl)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(2-acetylyphenylsulfanyl)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(3-acetylphenylsulfanyl)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(4-acetylphenylsulfanyl)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(2-cyanophenylsulfanyl)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(3-cyanophenylsulfanyl)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(4-cyanophenylsulfanyl)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(2-morpholin-4-yl-phenylsulfanyl)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(3-morpholin-4-yl-phenylsulfanyl)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(4-morpholin4-yl-phenylsulfanyl)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(pyridin-4-yl)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(2-methylpyridin-4-yl)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(6-methylpyridin-3-yl)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(5-methylpyridin-2-yl)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(2-methoxypyridin-4-yl)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(6-methoxypyridin-3-yl)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(5-methoxypyridin-2-yl)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(2-chloropyridin-4-yl)-thiophene-2-carboxamide;
N-[(l1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(6-chloropyridin-3-yl)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(5-chloropyridin-2-yl)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(5-chloropyridin-3-yl)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(6-chloropyridin-2-yl)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(4-chloropyridin-2-yl)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(pyridin-4-yloxy)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(pyridin-3-yloxy)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(pyridin-2-yloxy)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(2-methylpyridin-4-yloxy)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(6-methylpyridin-3-yloxy)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(5-methylpyridin-2-yloxy)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(2-methoxypyridin-4-yloxy)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(6-methoxypyridin-3-yloxy)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(5-methoxypyridin-2-yloxy)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(2-chloropyridin-4-yloxy)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(6-chloropyridin-3-yloxy)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(5-chloropyridin-2-yloxy)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(2-chloropyridin-4-yloxy)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(6-chloropyridin-3-yloxy)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(5-chloropyridin-2-yloxy)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(5-chloropyridin-3-yloxy)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(6-chloropyridin-2-yloxy)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(4-chloropyridin-2-yloxy)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(pyridin-4-ylsulfanyl)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(pyridin-3-ylsulfanyl)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(pyridin-2-ylsulfanyl)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(2-methylpyridin-4-ylsulfanyl)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(6-methylpyridin-3-ylsulfanyl)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(5-methylpyridin-2-ylsulfanyl)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(2-methoxypyridin-4-ylsulfanyl)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(6-methoxypyridin-3-ylsulfanyl)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(5-methoxypyridin-2-ylsulfanyl)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(2-chloropyridin-4-ylsulfanyl)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(6-chloropyridin-3-ylsulfanyl)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(5-chloropyridin-2-ylsulfanyl)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(2-chloropyridin-4-ylsulfanyl)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(6-chloropyridin-3-ylsulfanyl)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(5-chloropyridin-2-ylsulfanyl)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(5-chloropyridin-3-ylsulfanyl)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(6-chloropyridin-2-ylsulfanyl)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(4-chloropyridin-2-ylsulfanyl)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(thiophen-4-yl)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(5-methylthiophen-2-yl)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(5-methoxythiophen-2-yl)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(5-chlorothiophen-2-yl)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(2-methyl-5-trifluoromethyl-2H-pyrazole-3-yl)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(2-methylthiazol-4-yl)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-[2-(3-chlorophenyl)-vinyl]-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(2,4-difluorophenyl-sulfanyl)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(3-chlorophenyl-sulfanyl)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(3-chloro-4-fluoro-phenylsulfanyl)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(2,3-dichlorophenyl-sulfanyl)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(2,4,5-trichlorophenyl-sulfanyl)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(3,4-dichlorophenyl-sulfanyl)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-phenoxy-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(2-hydroxyphenyl)-thiophene-2-25carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(3-hydroxyphenyl)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(3-fluoro-4-hydroxyphenyl)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(furan-4-yl)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(5-methylfuran-2-yl)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(5-methoxyfuran-2-yl)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(5-chlorofuran-2-yl)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(oxazol-2-yl)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(5-methyloxazol-2-yl)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(5-methoxyoxazol-2-yl)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(5-chlorooxazol-2-yl)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(oxazol-5-yl)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(2-methyloxazol-5-yl)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(2-methoxyoxazol-5-yl)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(2-chlorooxazol-5-yl)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(thiazol-2-yl)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(5-methylthiazol-2-yl)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(5-methoxythiazol-2-yl)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(5-chlorothiazol-2-yl)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(thiazol-5-yl)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(2-methylthiazol-5-yl)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(2-methoxythiazol-5-yl)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(2-chlorothiazol-5-yl)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(4-methylthiazol-2-yl)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(4-methoxythiazol-2-yl)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(4-chlorothiazol-2-yl)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(4-methyloxazol-2-yl)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(4-methoxyoxazol-2-yl)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(4-chlorooxazol-2-yl)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-([1,3,4]thiadiazol-2-yl)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(5-methyl[1,3,4]thiadiazol-2-yl)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(5-methoxy[1,3,4]thiadiazol-2-yl)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(5-chloro[1,3,4]thiadiazol-2-yl)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-([1,3,4]oxadiazol-2-yl)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(5-methyl[1,3,4]oxadiazol-2-yl)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(5-methoxy[1,3,4]oxadiazol-2-yl)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(5-chloro[1,3,4]oxadiazol-2-yl)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(thiophen-4-yloxy)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(5-methylthiophen-2-yloxy)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(5-methoxythiophen-2-yloxy)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(5-chlorothiophen-2-yloxy)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(furan-4-yloxy)-thiophene- 2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(5-methylfuran-2-yloxy)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(5-methoxyfuran-2-yloxy)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(5-chlorofuran-2-yloxy)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(oxazol-2-yloxy)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(5-methyloxazol-2-yloxy)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(5-methoxyoxazol-2-yloxy)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(5-chlorooxazol-2-yloxy)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(oxazol-5-yloxy)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(2-methyloxazol-5-yloxy)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(2-methoxyoxazol-
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(2-chlorooxazol-5-yloxy)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(thiazol-2-yloxy)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(5-methylthiazol-2-yloxy)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(5-methoxythiazol-2-yloxy)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(5-chlorothiazol-2-yloxy)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(thiazol-5-yloxy)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(2-methylthiazol-5-yloxy)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(2-methoxythiazol-5-yloxy)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(2-chlorothiazol-5-yloxy)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(4-methylthiazol-2-yloxy)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(4-methoxythiazol-2-yloxy)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(4-chlorothiazol-2-yloxy)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(4-methyloxazol-2-yloxy)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(4-methoxyoxazol-2-yloxy)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(4-chlorooxazol-2-yloxy)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-([1,3,4]thiadiazol-2-yloxy)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(5-methyl[1,3,4]thiadiazol-2-yloxy)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(5-methoxy[1,3,4]thiadiazol-2-yloxy)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(5-chloro[1,3,4]thiadiazol-2-yloxy)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-([1,3,4]oxadiazol-2-yloxy)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(5-methyl[1,3,4]oxadiazol-2-yloxy)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(5-methoxy[1,3,4]oxadiazol-2-yloxy)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(5-chloro[1,3,4]oxadiazol-2-yloxy)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(thiophen-4-ylsulfanyl)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(5-methylthiophen-2-ylsulfanyl)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(5-methoxythiophen-2-ylsulfanyl)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(5-chlorothiophen-2-ylsulfanyl)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(furan-4-ylsulfanyl)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(5-methylfuran-2-ylsulfanyl)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(5-methoxyfuran-2-ylsulfanyl)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(5-chlorofuran-2-ylsulfanyl)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(oxazol-2-ylsulfanyl)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(5-methyloxazol-2-ylsulfanyl)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(5-methoxyoxazol-2-ylsulfanyl)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(5-chlorooxazol-2-ylsulfanyl)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(oxazol-5-ylsulfanyl)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(2-methyloxazol-5-ylsulfanyl)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(2-methoxyoxazol-5-ylsulfanyl)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(2-chlorooxazol-5-ylsulfanyl)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(thiazol-2-ylsulfanyl)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(5-methylthiazol-2-ylsulfanyl)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(5-methoxythiazol-2-ylsulfanyl)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(5-chlorothiazol-2-ylsulfanyl)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(thiazol-5-ylsulfanyl)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(2-methylthiazol-5-ylsulfanyl)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(2-methoxythiazol-5-ylsulfanyl)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(2-chlorothiazol-5-ylsulfanyl)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(4-methylthiazol-2-ylsulfanyl)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(4-methoxythiazol-2-ylsulfanyl)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(4-chlorothiazol-2-ylsulfanyl)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(4-methyloxazol-2-ylsulfanyl)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(4-methoxyoxazol-2-ylsulfanyl)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(4-chlorooxazol-2-ylsulfanyl)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-([1,3,4]thiadiazol-2-ylsulfanyl)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(5-methyl[1,3,4]thiadiazol-2-ylsulfanyl)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(5-methoxy[1,3,4]thiadiazol-2-ylsulfanyl)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(5-chloro[1,3,4]thiadiazol-2-ylsulfanyl)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-([1,3,4]oxadiazol-2-ylsulfanyl)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(5-methyl[1,3,4]oxadiazol-2-ylsulfanyl)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(5-methoxy[1,3,4]oxadiazol-2-ylsulfanyl)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(5-chloro[1,3,4]oxadiazol-2-ylsulfanyl)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(pyrrole-2-yl)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(isothiazol-3-yl)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(isoxazol-3-yl)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(3H-imidazol-4-yl)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-4-(4-hydroxyphenylsulfanyl)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-4-(3-acetamidophenylsulfanyl)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-4-(2-methanesulfonylaminophenyl)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-4-(pyridin-2-yloxy)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-4-(2-methylpyridin-4-yloxy)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-4-(4-trifluoromethylphenyl)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-4-(2-acetylphenyl)-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-4-chloro-5-phenyl-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-4-methyl-5-phenyl-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-4-cyano-5-phenyl-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-4-methoxy-5-phenyl-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-chloro-4-phenyl-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-methyl-4-phenyl-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-cyano-4-phenyl-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-methoxy-4-phenyl-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-4-chloro-5-bromo-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-4-chloro-5-methylsulfanyl-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-4-chloro-5-methyl-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-4-chloro-5-cyano-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-chloro-4-bromo-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-chloro-4-methylsulfanyl-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-chloro-4-methyl-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-chloro-4-cyano-thiophene-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(acetylamino)-furan-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-trifluoromethyl-furan-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(2-bromophenyl)-furan-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(3-bromophenyl)-furan-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(2,3-dichlorophenyl)-furan-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(2,4-dichlorophenyl)-furan-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(2,5-dichlorophenyl)-furan-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(2,6-dichlorophenyl)-furan-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(3,4-dichlorophenyl)-furan-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(3,5-dichlorophenyl)-furan-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(4-amino-2-fluorophenyl)-furan-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(3-amino-2-fluorophenyl)-furan-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(4-amino-2-chlorophenyl)-furan-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(3-amino-2-chlorophenyl)-furan-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(3-aminophenyl)-furan-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(2-cyanophenyl)-furan-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(3-cyanophenyl)-furan-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(2-hydroxyphenyl)-furan-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(3-hydroxyphenyl)-furan-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(4-hydroxyphenyl)-furan-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(2-fluoro-4-methylphenyl)-furan-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(2-fluoro-3-methoxyphenyl)-furan-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(2-fluoro-4-methoxyphenyl)-furan-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(2-[(methylsulfonyl)amino]phenyl)-furan-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(3-[(methylsulfonyl)amino]phenyl)-furan-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(4-[(methylsulfonyl)amino]phenyl)-furan-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(2-([(trifluoromethyl)sulfonyl]amino)phenyl)-furan-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(3-([(trifluoromethyl)sulfonyl]amino)phenyl)-furan-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(4-([(trifluoromethyl)sulfonyl]amino)phenyl)-furan-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(2-[(phenylsulfonyl)amino]phenyl)-furan-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(3-[(phenylsulfonyl)amino]phenyl)-furan-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(4-[(phenylsulfonyl)amino]phenyl)-furan-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(2-[(methylamino)carbonyl]phenyl)-furan-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(3-[(methylamino)carbonyl]phenyl)-furan-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(4-[(methylamino)carbonyl]phenyl)-furan-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(2-[(methylamino)sulfonyl]phenyl)-furan-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(3-[(methylamino)sulfonyl]phenyl)-furan-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(4-[(methylamino)sulfonyl]phenyl)-furan-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-[2-(methylamino)phenyl]-furan-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-[3-(methylamino)phenyl]-furan-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-[4-(methylamino)phenyl]-furan-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-[2-(ethylamino)phenyl]-furan-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-[3-(ethylamino)phenyl]-furan-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-[4-(ethylamino)phenyl]-furan-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(2-acetylphenyl)-furan-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(3-acetylphenyl)-furan-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(4-acetylphenyl)-furan-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-[2-(methylthio)phenyl]-furan-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-[3-(methylthio)phenyl]-furan-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-[4-(methylthio)phenyl]-furan-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-[2-(phenylthio)phenyl]-furan-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-[3-(phenylthio)phenyl]-furan-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-[4-(phenylthio)phenyl]-furan-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(2-phenoxyphenyl)-furan-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(3-phenoxyphenyl)-furan-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(4-phenoxyphenyl)-furan-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(2-anilinophenyl)-furan-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(3-anilinophenyl)-furan-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(4-anilinophenyl)-furan-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(phenylthio)-furan-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-[(2-fluorophenyl)thio]-furan-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-[(3-fluorophenyl)thio]-furan-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-[(4-fluorophenyl)thio]-furan-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-[(2-chlorophenyl)thio]-furan-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-[(3-chlorophenyl)thio]-furan-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-[(4-chlorophenyl)thio]-furan-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(2-fluorophenoxy)-furan-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(3-fluorophenoxy)-furan-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(4-fluorophenoxy)-furan-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(2-chlorophenoxy)-furan-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(3-chlorophenoxy)-furan-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(4-chlorophenoxy)-furan-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-pyridin-2-yl-furan-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1hept-2-yl]-5-pyridin-3-yl-furan-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-pyridin-4-yl-furan-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(3-fluoropyridin-2-yl)-furan-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(4-fluoropyridin-2-yl)-furan-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(5-fluoropyridin-2-yl)-furan-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(6-fluoropyridin-2-yl)-furan-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(2-fluoropyridin-3-yl)-furan-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(4-fluoropyridin-3-yl)-furan-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(5-fluoropyridin-3-yl)-furan-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(6-fluoropyridin-3-yl)-furan-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(2-fluoropyridin-4-yl)-furan-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(3-fluoropyridin-4-yl)-furan-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(3-chloropyridin-2-yl)-furan-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(4-chloropyridin-2-yl)-furan-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(5-chloropyridin-2-yl)-furan-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(6-chloropyridin-2-yl)-furan-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(2-chloropyridin-3-yl)-furan-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(4-chloropyridin-3-yl)-furan-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(5-chloropyridin-3-yl)-furan-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(6-chloropyridin-3-yl)-furan-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(2-chloropyridin-4-yl)-furan-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(3-chloropyridin-4-yl)-furan-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(2-piperidin-1-ylphenyl)-furan-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(3-piperidin-1-ylphenyl)-furan-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(4-piperidin-1-ylphenyl)-furan-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(2-morpholin-4-ylphenyl)-furan-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(3-morpholin-4-ylphenyl)-furan-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(4-morpholin-4-ylphenyl)-furan-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(2-pyrrolidin-1-ylphenyl)-furan-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(3-pyrrolidin-1-ylphenyl)-furan-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(4-pyrrolidin-1-ylphenyl)-furan-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-[2-(1H-pyrrol-2-yl)phenyl]-furan-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-[3-(1H-pyrrol-2-yl)phenyl]-furan-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-[4-(1H-pyrrol-2-yl)phenyl]-furan-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-[2-(2-furyl)phenyl]-furan-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-[2-(3-furyl)phenyl]-furan-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-[2-(5-methyl-2-furyl)phenyl]-furan-2-carboxamide;
N-[(1S 2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-[3-(2-furyl)phenyl]-furan-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-[3-(3-furyl)phenyl]-furan-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-[3-(5-methyl-2-furyl)phenyl]-furan-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-[4-(2-furyl)phenyl]-furan-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-[4-(3-furyl)phenyl]-furan-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-[4-(5-methyl-2-furyl)phenyl]-furan-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-[2-(1,3-thiazol-2-yl)phenyl]-furan-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-[3-(1,3-thiazol-2-yl)phenyl]-furan-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-[4-(1,3-thiazol-2-yl)phenyl]-furan-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-[2-(1,3-oxazol-2-yl)phenyl]-furan-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-[3-(1,3-oxazol-2-yl)phenyl]-furan-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-[4-(1,3-oxazol-2-yl)phenyl]-furan-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(2-isothiazol-5-ylphenyl)-furan-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(3-isothiazol-5-ylphenyl)-furan-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(4-isothiazol-5-ylphenyl)-furan-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-[4-(1H-indol-2-yl)phenyl]-furan-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-[4-(1H-indol-3-yl)phenyl]-furan-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(1H-indol-5-yl)-furan-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(1H-indol-6-yl)-furan-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(2-chlorophenyl)-furan-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(3-chlorophenyl)-furan-2-carboxamide;
N[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(4-bromophenyl)-furan-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-[2-(trifluoromethyl)-phenyl]-furan-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-[3-(trifluoromethyl)-phenyl]-furan-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(2,4-difluorophenyl)-furan-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(2,5-difluorophenyl)-furan-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(2-methoxyphenyl)-furan-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(3-methoxyphenyl)-furan-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-[3-(trifluoromethoxy)phenyl]-furan-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-[2-chloro-5-(trifluoromethyl)phenyl]-furan-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(4-fluoro-3-methylphenyl)-furan-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(4-cyanophenyl)-furan-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-thien-2-yl-furan-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-thien-3-yl-furan-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-nitro-furan-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo(2.2.1]hept-2-yl]-4,5-dimethyl-furan-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(4-chloro-2-nitrophenyl)-furan-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(4-methyl-2-nitrophenyl)-furan-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(2,3-difluorophenyl)-furan-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(3,4-difluorophenyl)-furan-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(3,5-difluorophenyl)-furan-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(4-methoxy-phenyl)-furan-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(2-methylphenyl)-furan-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(3-methylphenyl)-furan-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-[2-(trifluoromethoxy)phenyl]-furan-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-[4-(trifluoromethoxy)phenyl]-furan-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(4-tert-butylphenyl)-furan-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(1-benzothien-2-yl)-furan-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-quinolin-3-yl-furan-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(4-ethylphenyl)-furan-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(4-isopropylphenyl)-furan-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(3-fluoro-4-methoxyphenyl)-furan-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(1-benzofuran-2-yl)-furan-2-carboxamide;
5-(2-aminophenyl)xe2x80x94N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-furan-2-carboxamide;
5-(2-amino-4-methylphenyl)xe2x80x94N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-furan-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(phenylethynyl)-furan-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-phenoxy-furan-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(methylthio)-1,3-thiazole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-chloro-1,3-thiazole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-bromo-1,3-thiazole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(phenylthio)-1,3-thiazole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-[(2-fluorophenyl)thio]-1,3-thiazole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-[(3-fluorophenyl)thio]-1,3-thiazole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-[(4-fluorophenyl)thio]-1,3-thiazole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-[(2-chlorophenyl)thio]-1,3-thiazole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-[(3-chlorophenyl)thio]-1,3-thiazole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-[(4-chlorophenyl)thio]-1,3-thiazole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-phenoxy-1,3-thiazole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(2-fluorophenoxy)-1,3-thiazole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(3-fluorophenoxy)-1,3-thiazole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(4-fluorophenoxy)-1,3-thiazole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(2-chlorophenoxy)-1,3-thiazole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(3-chlorophenoxy)-1,3-thiazole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(4-chlorophenoxy)-1,3-thiazole-2-carboxamide;
N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl)]-5-thien-3-yl-1,3-thiazole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(2,4-difluorophenyl)-1,3-thiazole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(3,5-difluorophenyl)-1,3-thiazole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(2,4-dichlorophenyl)-1,3-thiazole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(3,5-dichlorophenyl)-1,3-thiazole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(2-bromophenyl)-1,3-thiazole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(3-bromophenyl)-1,3-thiazole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(2-cyanophenyl)-1,3-thiazole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(3-cyanophenyl)-1,3-thiazole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(4-cyanophenyl)-1,3-thiazole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(2-hydroxyphenyl)-1,3-thiazole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(3-hydroxyphenyl)-1,3-thiazol-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(4-hydroxyphenyl)-1,3-thiazole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(2-nitrophenyl)-1,3-thiazole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(4-nitrophenyl)-1,3-thiazole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(2-methylphenyl)-1,3-thiazole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(3-methylphenyl)-1,3-thiazole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(4-methylphenyl)-1,3-thiazole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(2-aminophenyl)-1,3-thiazole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(3-aminophenyl)-1,3-thiazole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(4-aminophenyl)-1,3-thiazole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-[(2-(acetylamino)phenyl]-1,3-thiazole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-[3-(acetylamino)phenyl]-1,3-thiazole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-[4-(acetylamino)phenyl]-1,3-thiazole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(pyridin-2-yl)-1,3-thiazole-2-carboxamaide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(pyridin-3-yl)-1,3-thiazole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(pyridin-4-yl)-1,3-thiazole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(3-fluoropyridin-2-yl)-1,3-thiazole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(4-fluoropyridin-2-yl)-1,3-thiazole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(5-fluoropyridin-2-yl)-1,3-thiazole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(6-fluoropyridin-2-yl)-1,3-thiazole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(2-fluoropyridin-3-yl)-1,3-thiazole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(4-fluoropyridin-3-yl)-1,3-thiazole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(5-fluoropyridin-3-yl)-1,3-thiazole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(6-fluoropyridin-3-yl)-1,3-thiazole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(2-fluoropyridin-4-yl)-1,3-thiazole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-[(2-methoxyphenyl)thio]-1,3-thiazole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-[(3-methoxyphenyl)thio]-1,3-thiazole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-[(4-methoxyphenyl)thio]-1,3-thiazole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-[(2-methylphenyl)thio]-1,3-thiazole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-[(3-methylphenyl)thio]-1,3-thiazole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-[(4-methylphenyl)thio]-1,3-thiazole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-([4-(acetylamino)phenyl]thio)-1,3-thiazole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-[(4-aminophenyl)thio]-1,3-thiazole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-[(4-hydroxyphenyl)thio]-1,3-thiazole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(2-methylphenoxy)-1,3-thiazole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(3-methylphenoxy)-1,3-thiazole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(4-methylphenoxy)-1,3-thiazole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(2-methoxyphenoxy)-1,3-thiazole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(3-methoxyphenoxy)-1,3-thiazole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(4-methoxyphenoxy)-1,3-thiazole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(4-hydroxyphenoxy)-1,3-thiazole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(4-aminophenoxy)-1,3-thiazole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-[4-(acetylamino)phenoxy]-1,3-thiazole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(2-fluorophenyl)-4-methyl-1,3-thiazole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(3-fluorophenyl)-4-methyl-1,3-thiazole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(2-chlorophenyl)-4-methyl-1,3-thiazole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(3-chlorophenyl)-4-methyl-1,3-thiazole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(2-methoxyphenyl)-4-methyl-1,3-thiazole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(3-methoxyphenyl)-4-methyl-1,3-thiazole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-4-methyl-5-thien-2-yl-1,3-thiazole-2-carboxamide,
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-4-methyl-5-phenyl-1,3-thiazole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-phenyl-1,3-thiazole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(4-bromophenyl)-1,3-thiazole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(3-nitrophenyl)-1,3-thiazole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(3-methoxyphenyl)-1,3-thiazole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(2-chlorophenyl)-1,3-thiazole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(4-fluorophenyl)-1,3-thiazole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(2-methoxyphenyl)-1,3-thiazole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(4-chlorophenyl)-1,3-thiazole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-methyl-1,3-thiazole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(3-chlorophenyl)-1,3-thiazole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(2-fluorophenyl)-1,3-thiazole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(3-fluorophenyl)-1,3-thiazole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-thien-2-yl-1,3-thiazole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-2-(phenylsulfanyl)-1,3-thiazole-5-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-2-[(4-chlorophenyl)-sulfanyl]-1,3-thiazole-5-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-2-phenoxy-1,3-thiazole-5-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-2-[(4-fluorophenyl)-sulfanyl]-1,3-thiazole-5-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-2-(methylsulfanyl)-1,3-thiazole-5-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-2-(4-chlorophenoxy)-1,3-thiazole-5-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-2,4-dimethyl-1,3-thiazole-5-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-2-(3-fluorophenyl)-1,3-thiazole-5-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-2-(4-fluorophenyl)-1,3-thiazole-5-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-2-(2-hydroxyphenyl)-1,3-thiazole-5-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-2-(4-methylphenyl)-1,3-thiazole-5-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-2-[4-(benzyloxy)phenyl]-1,3-thiazole-5-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-4-methyl-2-phenyl-1,3-thiazole-5-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-2-(4-chlorophenyl)-4-methyl-1,3-thiazole-5-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-4-methyl-2-pyridin-2-yl-1,3-thiazole-5-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-4-methyl-2-pyridin-4-yl-1,3-thiazole-5-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-2-(methylamino)-1,3-thiazole-5-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-2-(2,3-difluorophenyl)-1,3-thiazole-5-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-2-(2,4-difluorophenyl)-1,3-thiazole-5-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-2-(2,5-difluorophenyl)-1,3-thiazole-5-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-2-(2,6-difluorophenyl)-1,3-thiazole-5-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-2-(3,4-difluorophenyl)-1,3-thiazole-5-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-2-(3,5-difluorophenyl)-1,3-thiazole-5-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-2-(2-chlorophenyl)-1,3-thiazole-5-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-2-(3-chlorophenyl)-1,3-thiazole-5-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-2-(4-chlorophenyl)-1,3-thiazole-5-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-2-(2-bromophenyl)-1,3-thiazole-5-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-2-(3-bromophenyl)-1,3-thiazole-5-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-2-(4-bromophenyl)-1,3-thiazole-5-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-2-(2-cyanophenyl)-1,3-thiazole-5-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-2-(3-cyanophenyl)-1,3-thiazole-5-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-2-(4-cyanophenyl)-1,3-thiazole-5-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-2-(2-nitrophenyl)-1,3-thiazole-5-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-2-(3-nitrophenyl)-1,3-thiazole-5-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-2-(4-nitrophenyl)-1,3-thiazole-5-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-2-(2-methylphenyl)-1,3-thiazole-5-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-2-(3-methylphenyl)-1,3-thiazole-5-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-2-(2-aminophenyl)-1,3-thiazole-5-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-2-(3-aminophenyl)-1,3-thiazole-5-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-2-(4-aminophenyl)-1,3-thiazole-5-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-2-[2-(methylamino)phenyl]-1,3-thiazole-5-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-2-[3-(methylamino)phenyl]-1,3-thiazole-5-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-2-[4-(methylamino)phenyl]-1,3-thiazole-5-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-2-[2-(acetylamino)phenyl]-1,3-thiazole-5-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-2-[3-(acetylamino)phenyl]-1,3-thiazole-5-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-2-[4-(acetylamino)phenyl]-1,3-thiazole-5-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-2-(2-[(trifluoroacetyl)amino]phenyl)-1,3-thiazole-5-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-2-(3-[(trifluoroacetyl)amino]phenyl)-1,3-thiazole-5-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-2-(4-[(trifluoroacetyl)amino]phenyl)-1,3-thiazole-5-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-2-(2-[(methylsulfonyl)amino]phenyl)-1,3-thiazole-5-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-2-(3-[(methylsulfonyl)amino]phenyl)-1,3-thiazole-5-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-2-(4-[(methylsulfonyl)amino]phenyl)-1,3-thiazole-5-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-2-(3-hydroxyphenyl)-1,3-thiazole-5-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-2-(4-hydroxyphenyl)-1,3-thiazole-5-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-2-(2-methoxyphenyl)-1,3-thiazole-5-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-2-(3-methoxyphenyl)-1,3-thiazole-5-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-2-(4-methoxyphenyl)-1,3-thiazole-5-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-2-[2-(trifluoromethoxy)phenyl]-1,3-thiazole-5-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-2-[3-(trifluoromethoxy)phenyl]-1,3-thiazole-5-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-2-[4-(trifluoromethoxy)phenyl]-1,3-thiazole-5-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-2-pyridin-2-yl-1,3-thiazole-5-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-2-pyridin-3-yl-1,3-thiazole-5-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-2-pyridin-4-yl-1,3-thiazole-5-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-2-(6-fluoropyridin-2-yl)-1,3-thiazole-5-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-2-(5-fluoropyridin-2-yl)-1,3-thiazole-5-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-2-(4-fluoropyridin-2-yl)-1,3-thiazole-5-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-2-(3-fluoropyridin-2-yl)-1,3-thiazole-5-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-2-(2-fluoropyridin-2-yl)-1,3-thiazole-5-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-2-(6-fluoropyridin-3-yl)-1,3-thiazole-5-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-2-(5-fluoropyridin-3-yl)-1,3-thiazole-5-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-2-(4-fluoropyridin-3-yl)-1,3-thiazole-5-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-2-(2-fluoropyridin-3-yl)-1,3-thiazole-5-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-2-(2-fluoropyridin-4-yl)-1,3-thiazole-5-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-2-(3-fluoropyridin-4-yl)-1,3-thiazole-5-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(phenylsulfanyl)-1,3,4-thiadiazole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-phenoxy-1,3,4-thiadiazole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-[(4-chlorophenyl)-sulfanyl]-1,3,4-thiadiazole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(4-fluorophenoxy)-1,3,4-thiadiazole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(4-chlorophenoxy)-1,3,4-thiadiazole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-[(3-fluorophenyl)-sulfanyl]-1,3,4-thiadiazole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-[(2-chlorophenyl)-sulfanyl]-1,3,4-thiadiazole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-[(4-fluorophenyl)-sulfanyl]-1,3,4-thiadiazole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-[(3-chlorophenyl)-sulfanyl]-1,3,4-thiadiazole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-phenyl-1,3,4-oxadiazole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(methylthio)-1,3,4-oxadiazole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(3-chlorophenyl)-1,3-oxazole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(3-methoxyphenyl)-1,3-oxazole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(3-nitrophenyl)-1,3-oxazole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(4-methoxyphenyl)-1,3-oxazole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(2-nitrophenyl)-1,3-oxazole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(2-methoxyphenyl)-1,3-oxazole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(4-fluorophenyl)-1,3-oxazole-2carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(2-chlorophenyl)-1,3-oxazole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(3-cyanophenyl)-1,3-oxazole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(4-bromophenyl)-1,3-oxazole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-phenylsulfanyl-1,3-oxazole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(2-fluorophenylsulfanyl)-1,3-oxazole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(3-fluorophenylsulfanyl)-1,3-oxazole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(4-fluorophenylsulfanyl)-1,3-oxazole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(3,4-difluorophenylsulfanyl)-1,3-oxazole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(2,4-difluorophenylsulfanyl)-1,3-oxazole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(3,5-difluorophenylsulfanyl)-1,3-oxazole-2-carboxamaide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(2-chlorophenylsulfanyl)-1,3-oxazole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(3-chlorophenylsulfanyl)-1,3-oxazole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(4-chlorophenylsulfanyl)-1,3-oxazole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(3,4-dichlorophenylsulfanyl)-1,3-oxazole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(2,4-dichlorophenysulfanyl)-1,3-oxazole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(3,5-dichlorophenylsulfanyl)-1,3-oxazole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(2-fluorophenyl)-1,3-oxazole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(3-fluorophenyl)-1,3-oxazole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(3,4-difluorophenyl)-1,3-oxazole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(2,4-difluorophenyl)-1,3-oxazole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(3,5-difluorophenyl)-1,3-oxazole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(4-chlorophenyl)-1,3-oxazole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(3,4-dichlorophenyl)-1,3-oxazole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(2,4-dichlorophenyl)-1,3-oxazole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(3,5-dichlorophenyl)-1,3-oxazole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(2-bromophenyl)-1,3-oxazole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(3-bromophenyl)-1,3-oxazole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(2-cyanophenyl)-1,3-oxazole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(4-cyanophenyl)-1,3-oxazole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(2-hydroxyphenyl)-1,3-oxazole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(3-hydroxyphenyl)-1,3-oxazole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(4-hydroxyphenyl)-1,3-oxazole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(4-nitrophenyl)-1,3-oxazole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(2-methylphenyl)-1,3-oxazole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(3-methylphenyl)-1,3-oxazole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(4-methylphenyl)-1,3-oxazole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(2-methylaminophenyl)-1,3-oxazole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(3-methylaminophenyl)-1,3-oxazole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(4-methylaminophenyl)-1,3-oxazole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(2-aminophenyl)-1,3-oxazole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(3-aminophenyl)-1,3-oxazole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(4-aminophenyl)-1,3-oxazole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-[2-(acetylamino)phenyl]-1,3-oxazole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-[3-(acetylamino)phenyl]-1,3-oxazole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-[4-(acetylamino)phenyl]-1,3-oxazole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(pyridin-2-yl)-1,3-oxazole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(pyridin-3-yl)-1,3-oxazole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(pyridin-4-yl)-1,3-oxazole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(3-fluoropyridin-2-yl)-1,3-oxazole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(4-fluoropyridin-2-yl)-1,3-oxazole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(5-fluoropyridin-2-yl)-1,3-oxazole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(6-fluoropyridin-2-yl)-1,3-oxazole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(2-fluoropyridin-3-yl)-1,3-oxazole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(4-fluoropyridin-3-yl)-1,3-oxazole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(5-fluoropyridin-3-yl)-1,3-oxazole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(6-fluoropyridin-3-yl)-1,3-oxazole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(2-fluoropyridin-4-yl)-1,3-oxazole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(2-fluoropyridin-3-yl)-1,3-oxazole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-phenoxy-1,3-oxazole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(2-fluorophenoxy)-1,3-oxazole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(3-fluorophenoxy)-1,3-oxazole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(4-fluorophenoxy)-1,3-oxazole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(3,4-difluorophenoxy)-1,3-oxazole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(2,4-difluorophenoxy)-1,3-oxazole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(3,5-difluorophenoxy)-1,3-oxazole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-y]-5-(2-chlorophenoxy)-1,3-oxazole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(3-chlorophenoxy)-1,3-oxazole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(4-chlorophenoxy)-1,3-oxazole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(3,4-dichlorophenoxy)-1,3-oxazole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(2,4-dichlorophenoxy)-1,3-oxazole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(3,5-dichlorophenoxy)-1,3-oxazole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-2-phenyl-1,3-oxazole-5-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-1-methyl-5-phenyl-1H-pyrrole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-bromo-1-methyl-1H-pyrrole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-[2-(methylthio)phenyl]-1-methyl-1H-pyrrole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-[4-(methylthio)phenyl]-1-methyl-1H-pyrrole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-phenyl-1H-pyrrole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(2-fluorophenyl)-1-methyl-1H-pyrrole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(3-fluorophenyl)-1-methyl-1H-pyrrole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(4-fluorophenyl)-1-methyl-1H-pyrrole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(2,3-difluorophenyl)-1-methyl-1H-pyrrole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(2,4-difluorophenyl)-1-methyl-1H-pyrrole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(2,6-difluorophenyl)-1-methyl-1H-pyrrole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(3,4-difluorophenyl)-1-methyl-1H-pyrrole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(3,5-difluorophenyl)-1-methyl-1H-pyrrole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(2,4,6-trifluorophenyl)-1-methyl-1H-pyrrole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(2-chlorophenyl)-1-methyl-1H-pyrrole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(3-chlorophenyl)-1-methyl-1H-pyrrole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(4-chlorophenyl)-1-methyl-1H-pyrrole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(2,4-dichlorophenyl)-1-methyl-1H-pyrrole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(3,4-dichlorophenyl)-1-methyl-1H-pyrrole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(3,5-dichlorophenyl)-1-methyl-1H-pyrrole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(2-bromophenyl)-1-methyl-1H-pyrrole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(3-bromophenyl)-1-methyl-1H-pyrrole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(4-bromophenyl)-1-methyl-1H-pyrrole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(2-hydroxyphenyl)-1-methyl-1H-pyrrole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(3-hydroxyphenyl)-1-methyl-1H-pyrrole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(4-hydroxyphenyl)-1-methyl-1H-pyrrole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(2-methoxyphenyl)-1-methyl-1H-pyrrole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(3-methoxyphenyl)-1-methyl-1H-pyrrole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(4-methoxyphenyl)-1-methyl-1H-pyrrole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(2-methylphenyl)-1-methyl-1H-pyrrole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(3-methylphenyl)-1-methyl-1H-pyrrole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(4-methylphenyl)-1-methyl-1H-pyrrole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(2-methylaminophenyl)-1-methyl-1H-pyrrole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(3-methylaminophenyl)-1-methyl-1H-pyrrole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(4-methylaminophenyl)-1-methyl-1H-pyrrole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(2-nitrophenyl)-1-methyl-1H-pyrrole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(3-nitrophenyl)-1-methyl-1H-pyrrole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(4-nitrophenyl)-1-methyl-1H-pyrrole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(2-aminophenyl)-1-methyl-1H-pyrrole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(3-aminophenyl)-1-methyl-1H-pyrrole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(4-aminophenyl)-1-methyl-1H-pyrrole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-[2-(acetylamino)phenyl]-1-methyl-1H-pyrrole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-[3-(acetylamino)phenyl]-1-methyl-1H-pyrrole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-[4-(acetylamino)phenyl]-1-methyl-1H-pyrrole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(pyrid-2-yl)-1-methyl-1H-pyrrole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(pyrid-3-yl)-1-methyl-1H-pyrrole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(pyridin-4-yl)-1-methyl-1H-pyrrole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(3-fluoropyrid-2-yl)-1-methyl-1H-pyrrole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(4-fluoropyrid-2-yl)-1-methyl-1H-pyrrole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(5-fluoropyrid-2-yl)-1-methyl-1H-pyrrole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(6-fluoropyrid-2-yl)-1-methyl-1H-pyrrole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(2-fluoropyrid-3-yl)-1-methyl-1H-pyrrole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(4-fluoropyrid-3-yl)-1-methyl-1H-pyrrole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(5-fluoropyrid-3-yl)-1-methyl-1H-pyrrole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(6-fluoropyrid-3-yl)-1-methyl-1H-pyrrole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(2-fluoropyrid-4-yl)-1-methyl-1H-pyrrole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(3-fluoropyrid-4-yl)-1-methyl-1H-pyrrole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(2-cyanophenyl)-1-methyl-1H-pyrrole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(3-cyanophenyl)-1-methyl-1H-pyrrole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(4-cyanophenyl)-1-methyl-1H-pyrrole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(2-fluorophenyl)-1H-pyrrole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(3-fluorophenyl)-1H-pyrrole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(4-fluorophenyl)-1H-pyrrole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(3,5-difluorophenyl)-1H-pyrrole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(3,4-difluorophenyl)-1H-pyrrole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(2,4-difluorophenyl)-1H-pyrrole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(2-chlorophenyl)-1H-pyrrole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(3-chlorophenyl)-1H-pyrrole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(4-chlorophenyl)-1H-pyrrole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(3,5-dichlorophenyl)-1H-pyrrole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(3,4-dichlorophenyl)-1H-pyrrole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(2,4-dichlorophenyl)-1H-pyrrole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(2-bromophenyl)-1H-pyrrole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(3-bromophenyl)-1H-pyrrole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(4-bromophenyl)-1H-pyrrole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(2-hydroxyphenyl)-1H-pyrrole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(3-hydroxyphenyl)-1H-pyrrole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(4-hydroxyphenyl)-1H-pyrrole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(2-methoxyphenyl)-1H-pyrrole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(3-methoxyphenyl)-1H-pyrrole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(4-methoxyphenyl)-1H-pyrrole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(2-methylphenyl)-1H-pyrrole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(3-methylphenyl)-1H-pyrrole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(4-methylphenyl)-1H-pyrrole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(2-methylaminophenyl)-1H-pyrrole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(3-methylaminophenyl)-1H-pyrrole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(4-methylaminophenyl)-1H-pyrrole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(2-nitrophenyl)-1H-pyrrole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(3-nitrophenyl)-1H-pyrrole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(4-nitrophenyl)-1H-pyrrole-2-1-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(2-aminophenyl)-1H-pyrrole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(3-aminophenyl)-1H-pyrrole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(4-aminophenyl)-1H-pyrrole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-[2-(acetylamino)phenyl]-1H-pyrrole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-[3-(acetylamino)phenyl]-1H-pyrrole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-[4-(acetylamino)phenyl]-1H-pyrrole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(pyrid-2-yl)-1H-pyrrole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(pyrid-3-yl)-1H-pyrrole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(pyrid-4-yl)-1H-pyrrole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(3-fluoropyrid-2-yl)-1H-pyrrole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(4-fluoropyrid-2-yl)-1H-pyrrole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(5-fluoropyrid-2-yl)-1H-pyrrole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(6-fluoropyrid-2-yl)-1H-pyrrole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(2-fluoropyrid-3-yl)-1H-pyrrole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(4-fluoropyrid-3-yl)-1H-pyrrole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(5-fluoropyrid-3-yl)-1H-pyrrole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(6-fluoropyrid-3-yl)-1H-pyrrole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(2-fluoropyrid-4-yl)-1H-pyrrole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(3-fluoropyrid-4-yl)-1H-pyrrole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(2-cyanophenyl)-1H-pyrrole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(3-cyanophenyl)-1H-pyrrole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(4-cyanophenyl)-1H-pyrrole-2-carboxamide;
N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-3-phenyl-1,2,4-oxadiazole-5-carboxamide.
The compound of Formula I, where (b) is any one or more or combination of the following: 1,3-thiazole-4-yl, 1,3-oxazole-4-yl, 1H-1,2,4-triazole-3-yl, or isoxazole-3-yl, any of which is
optionally substituted on carbon (e.g., V or Y is independently CR5) with H, F, Cl, Br, I, 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, lactam heterocycloalkyl, aryl, xe2x80x94OR8, xe2x80x94SR8, xe2x80x94N(R8)2, xe2x80x94C(O)R8, xe2x80x94C(S)R8, xe2x80x94C(O)OR8, xe2x80x94C(O)N(R8)2, xe2x80x94NR8C(O)R8, xe2x80x94S(O)2N(R8)2, xe2x80x94OS(O)2R8, xe2x80x94S(O)2R8, xe2x80x94S(O)R8, xe2x80x94NR8S(O)2R8, xe2x80x94N(R8)C(O)N(R8)2, xe2x80x94CN, xe2x80x94NO2, R7, or R9; and
further optionally substituted on nitrogen (e.g., U is N-R3) with alkyl, cycloalkyl, heterocycloalkyl, halogenated alkyl, halogenated cycloalkyl, halogenated heterocycloalkyl, substituted alkyl, substituted cycloalkyl, substituted heterocycloalkyl, R7, R9, aryl, xe2x80x94C(O)-alkyl, xe2x80x94C(O)-cycloalkyl, xe2x80x94C(O)-heterocycloalkyl, xe2x80x94C(O)-halogenated alkyl, xe2x80x94C(O)-halogenated cycloalkyl, xe2x80x94C(O)-halogenated heterocycloalkyl, xe2x80x94C(O)-substituted alkyl, xe2x80x94C(O)-substituted cycloalkyl, xe2x80x94C(O)-substituted heterocycloalkyl, xe2x80x94C(O)xe2x80x94R7, xe2x80x94C(O)xe2x80x94R9, or xe2x80x94C(O)xe2x80x94aryl.
The compound of Formula I or formula Axe2x80x94Lxe2x80x94B, where the compound is any one or more or combination of the following as the free base or a pharmaceutically acceptable salt thereof: N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-2-pyridin-3-yl-1,3-thiazole-4-carboxamide; N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-2-phenyl-1,3-oxazole-4-carboxamide; N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-phenyl-1H-1,2,4-triazole-3-carboxamide; or N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-phenylisoxazole-3-carboxamide.
The present invention also includes a pharmaceutical composition comprising a compound of Formula I or formula Axe2x80x94Lxe2x80x94B or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient. The pharmaceutical composition is administered rectally, topically, orally, sublingually, or parenterally for a therapeutically effective interval. The pharmaceutical composition is administered to deliver a compound of the present invention in an amount of from about 0.001 to about 100 mg/kg of body weight of said mammal per day. The pharmaceutical composition is also administered to deliver a compound of the present invention in an amount of from about 0.1 to about 50 mg/kg of body weight of said mammal per day.
A pharmaceutical composition comprising a compound of Formula I or formula Axe2x80x94Lxe2x80x94B or a pharmaceutically acceptable salt thereof and an anti-psychotic agent. The pharmaceutical composition is administered to independently administer said compound and said agent rectally, topically, orally, sublingually, or parenterally for a therapeutically effective interval. The pharmaceutical composition is administered to deliver a compound of the present invention in an amount of from bout 0.001 to about 100 mg/kg of body weight of said mammal per day. The pharmaceutical composition is also administered to deliver a compound of the present invention in an amount of from about 0.1 to about 50 mg/kg of body weight of said mammal per day.
The present invention also includes a use of a compound according to Formula I or formula Axe2x80x94Lxe2x80x94B or pharmaceutically acceptable salt thereof for the preparation of a medicament for treating a disease or condition, wherein the mammal would receive symptomatic relief from the administration of a therapeutically effective amount of xcex17 nicotinic acetylcholine receptor agonist.
The present invention also includes a use of a compound according to Formula I or formula Axe2x80x94Lxe2x80x94B or pharmaceutically acceptable salt thereof for the preparation of a medicament for treating a disease or condition, wherein the mammal would receive symptomatic relief from the administration of a therapeutically effective amount of xcex17 nicotinic acetylcholine receptor agonist, wherein the disease, or condition is any one or more or combination of the following: cognitive and attention deficit symptoms of Alzheimer""s, neurodegeneration associated with diseases such as Alzheimer""s disease, pre-senile dementia (mild cognitive impairment), senile dementia, schizophrenia, psychosis, attention deficit disorder, attention deficit hyperactivity disorder, depression, anxiety, general anxiety disorder, post traumatic stress disorder, mood and affective disorders, amyotrophic lateral sclerosis, borderline personality disorder, traumatic brain injury, behavioral and cognitive problems in general and associated with brain tumors, AIDS dementia complex, dementia associated with Down""s syndrome, dementia associated with Lewy Bodies, Huntington""s disease, Parkinson""s disease, tardive dyskinesia, Pick""s disease, dysregulation of food intake including bulemia and anorexia nervosa, withdrawal symptoms associated with smoking cessation and dependant drug cessation, Gilles de la Tourette""s Syndrome, age-related macular degeneration, glaucoma, neurodegeneration associated with glaucoma, or symptoms associated with pain.
The present invention also includes a method for treating a disease or condition in a mammal in need thereof, wherein the mammal would receive symptomatic relief from the administration of an xcex17 nicotinic acetylcholine receptor agonist comprising administering to the mammal a therapeutically effective amount of a compound according to Formula I or formula Axe2x80x94Lxe2x80x94B or pharmaceutically acceptable salt thereof.
The present invention also includes a method for treating a disease or condition in a mammal in need thereof comprising administering to the mammal a therapeutically effective amount of a compound according to Formula I or formula Axe2x80x94Lxe2x80x94B or pharmaceutically acceptable salt thereof, wherein the disease or condition is any one or more or combination of the following: cognitive and attention deficit symptoms of Alzheimer""s, neurodegeneration associated with diseases such as Alzheimer""s disease, pre-senile dementia (mild cognitive impairment), senile dementia, schizophrenia, psychosis, attention deficit disorder, attention deficit hyperactivity disorder, depression, anxiety, general anxiety disorder, post traumatic stress disorder, mood and affective disorders, amyotrophic lateral sclerosis, borderline personality disorder, traumatic brain injury, behavioral and cognitive problems in general and associated with brain tumors, AIDS dementia complex, dementia associated with Down""s syndrome, dementia associated with Lewy Bodies, Huntington""s disease, Parkinson""s disease, tardive dyskinesia, Pick""s disease, dysregulation of food intake including bulemia and anorexia nervosa, withdrawal symptoms associated with smoking cessation and dependant drug cessation, Gilles de la Tourette""s Syndrome, age-related macular degeneration, glaucoma, neurodegeneration associated with glaucoma, or symptoms associated with pain.
The compounds of formula Axe2x80x94Lxe2x80x94B or Formula I have optically active centers on the 7-azabicyclo[2.2.1]heptane ring which can exhibit a number of stereochemical configurations. The terms exo and endo are stereochemical prefixes that describe the relative configuration of a substituent on a bridge (not a bridgehead) of a bicyclic system. If a substituent is oriented toward the larger of the other bridges, it is endo. If a substituent is oriented toward the smaller bridge it is exo. Depending on the substitution on the carbon atoms, the endo and exo orientations can give rise to different stereoisomers. For instance, when carbons 1 and 4 are substituted with hydrogen and carbon 2 is bonded to a nitrogen containing species, the endo orientation gives rise to the possibility of a pair of enantiomers: either the 1S, 2S, 4R isomer or its enantiomer, the 1R, 2R, 4S isomer. Likewise, the exo orientation gives rise to the possibility of another pair of stereoisomers which are diastereomeric and C-2 epimeric with respect to the endo isomers: either the 1R, 2S, 4S isomer or its enantiomer, the 1S, 2R, 4R isomer. The compounds of this invention exist in the exo orientation. For example, when R2=R4=H, the absolute stereochemistry is exo-(2R) for the compounds in Formula I.
Stereoselective syntheses and/or subjecting the reaction product to appropriate purification steps produces 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 compounds of the present invention have the exo orientation at the C-2 carbon and S configuration at the C-1 carbon and the R configuration at the C-2 and the C-4 carbons of the 7-azabicyclo[2.2.1]heptane ring. Unexpectedly, the inventive compounds exhibit much higher activity relative to compounds lacking the1S,2R, and 4R stereochemistry within the 7-azabicyclo[2.2.1]heptane ring system. For example, the ratio of activities for compounds having the1S,2R, and 4R configuration to other stereochemical configurations of the 7-azabicyclo[2.2.1]heptane ring system may be greater than about 100. Although it is desirable that the stereochemical purity be as high as possible, absolute purity is not required. For example, pharmaceutical compositions can include one or more compounds, each having an exo 2R configuration, or mixtures of compounds having exo 2R and other configurations. In mixtures of compounds, those species possessing stereochemical configurations other than exo 2R act as diluents and tend to lower the activity of the pharmaceutical composition. Typically, pharmaceutical compositions including mixtures of compounds possess a larger percentage of species having the exo 2R configuration relative to other configurations.
Further aspects and embodiments of the invention may become apparent to those skilled in the art from a review of the following detailed description, taken in conjunction with the examples and the appended claims. While the invention is susceptible of embodiments in various forms, described hereafter are specific embodiments of the invention with the understanding that the present disclosure is intended as illustrative, and is not intended to limit the invention to the specific embodiments described herein.
Surprisingly, we have found that compounds of the Formula I:
wherein the stereochemistry of the of the 7-azabicyclo[2.2.1]heptane ring is 1S,4R and the nitrogen substituent at the C-2 carbon has the exo orientation and is R;
X is O or S;
R1 is H, alkyl, halogenated alkyl, cycloalkyl, or aryl;
R2 is H, alkyl, halogenated alkyl, substituted alkyl, cycloalkyl, or aryl;
Alkyl is both straight- and branched-chain moieties having from 1-6 carbon atoms;
Substituted alkyl is an alkyl moiety having from 1-6 carbon atoms and having 0-3 substituents independently selected from F, Cl, Br, or I and further having 1 substituent selected from xe2x80x94OR10, xe2x80x94SR10, xe2x80x94S(O)2R10, xe2x80x94S(O)R10, xe2x80x94OS(O)2R10, xe2x80x94NR10R10, xe2x80x94C(O)R10, xe2x80x94C(S)R10, xe2x80x94C(O)OR10, xe2x80x94C(O)NR10R10, xe2x80x94CN, xe2x80x94NR10C(O)R10, xe2x80x94NR10C(O)NR10R10, xe2x80x94S(O)2NR10, R10, xe2x80x94NR10S(O)2R10, xe2x80x94NO2, R7, R9, or phenyl optionally substituted with 1-4 substituents independently selected from F, Cl, Br, I, R13, and R15;
Halogenated alkyl is an alkyl moiety having from 1-6 carbon atoms and having 1 to (2n+1) substituent(s) independently selected from F, Cl, 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 having 1-4 substituents independently selected from F, Cl, Br, I, or R13, or having 1 substituent selected from R15 and 0-3 substituents independently selected from F, Cl, Br, I, or R13;
Substituted naphthyl is a naphthalene moiety 1-4 substituents independently selected from F, Cl, Br, I, or R13, or having 1 substituent selected from R15 and 0-3 substituents independently selected from F, Cl, Br, I, or R13, where the substitution can be independently on either the same ring or different rings of said naphthalene moiety;
W is xe2x80x94Q, xe2x80x94Cxe2x95x90Cxe2x80x94Q, or xe2x80x94Cxe2x89xa1Cxe2x80x94Q;
Q is a cyclic heteroaromatic moiety where the heteroatoms can be from 1-3 atoms selected from oxygen, sulfur, or nitrogen of the following structures:
xe2x80x83wherein U is xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, or xe2x80x94N(R3)xe2x80x94;
V and Y are independently selected from xe2x95x90Nxe2x80x94, and xe2x95x90C(R5)xe2x80x94;
Z is xe2x95x90Nxe2x80x94, or xe2x95x90CHxe2x80x94;
R3 is H, alkyl, cycloalkyl, heterocycloalkyl, halogenated alkyl, halogenated cycloalkyl, halogenated heterocycloalkyl, substituted alkyl, substituted cycloalkyl, substituted heterocycloalkyl, R7, R9, aryl, xe2x80x94C(O)-alkyl, xe2x80x94C(O)-cycloalkyl, xe2x80x94C(O)-heterocycloalkyl, xe2x80x94C(O)-halogenated alkyl, xe2x80x94C(O)-halogenated cycloalkyl, xe2x80x94C(O)-halogenated heterocycloalkyl, xe2x80x94C(O)-substituted alkyl, xe2x80x94C(O)-substituted cycloalkyl, xe2x80x94C(O)-substituted heterocycloalkyl, xe2x80x94C(O)xe2x80x94R7, xe2x80x94C(O)xe2x80x94R9, or xe2x80x94C(O)-aryl;
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 (2nxe2x88x921) substituent(s) independently selected from F, Cl, 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, Cl, Br, or I, and further having 1 substituent selected from R7, R9, xe2x80x94OR10, xe2x80x94SR10, xe2x80x94S(O)R10, xe2x80x94S(O)2R10, xe2x80x94OS(O)2R10, xe2x80x94N(R10)2, xe2x80x94C(O)R10, xe2x80x94C(S)R10, xe2x80x94C(O)OR10, xe2x80x94C(O)N(R10)2, xe2x80x94CN, xe2x80x94NO2, xe2x80x94NR10C(O)R10, xe2x80x94NR10C(O)N(R10)2, xe2x80x94S(O)2N(R10)2, xe2x80x94NR10S(O)2R10, and phenyl optionally substituted with 1-4 substituents independently selected from F, Cl, Br, I, R13, and R15;
Alkynyl is straight- and branched-chained 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 (2nxe2x88x923) substituent(s) independently selected from F, Cl, 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, Cl, Br, or I, and further having 1 substituent selected from R7, R9, xe2x80x94OR10, xe2x80x94SR10, xe2x80x94S(O)2R10, xe2x80x94S(O)R10 xe2x80x94OS(O)2R10, xe2x80x94N(R10)2, xe2x80x94C(O)R10, xe2x80x94C(S)R10, xe2x80x94C(O)OR10, xe2x80x94C(O)N(R10)2, xe2x80x94CN, xe2x80x94NO2, xe2x80x94NR10C(O)R10, xe2x80x94NR10C(O)N(R10)2, xe2x80x94S(O)2N(R10)2, xe2x80x94NR10S(O)2R10, and phenyl optionally substituted with 1-4 substituents independently selected from F, Cl, Br, I, R13, and R15;
Halogenated cycloalkyl is a cyclic moiety having from 3-6 carbon atoms and having 1-4 substituents independently selected from F, Cl, Br, or I;
Substituted cycloalkyl is a cyclic moiety having from 3-6 carbon atoms and having 0-3 substituents independently selected from F, Cl, Br, or I, and further having 1 substituent selected from xe2x95x90O, xe2x95x90S, R7, R9, xe2x80x94OR10, xe2x80x94SR10, xe2x80x94S(O)R10, xe2x80x94S(O)2R10, xe2x80x94OS(O)2R10, xe2x80x94NR10R10, xe2x80x94C(O)R10, xe2x80x94C(S)R10, xe2x80x94C(O)OR10, xe2x80x94C(O)N(R10)2, xe2x80x94CN, xe2x80x94NO2, xe2x80x94NR10C(O)R10, xe2x80x94NR10C(O)N(R10)2, xe2x80x94S(O)2N(R10)2, xe2x80x94NR10S(O)2R10, and phenyl optionally substituted with 1-4 substituents independently selected from F, Cl, Br, I, R13, and R15;
Heterocycloalkyl is a cyclic moiety having 4-7 atoms with 1-2 atoms within the ring being xe2x80x94Sxe2x80x94, xe2x80x94N(R20)xe2x80x94, or xe2x80x94Oxe2x80x94;
Halogenated heterocycloalkyl is a cyclic moiety having from 4-7 atoms with 1-2 atoms within the ring being xe2x80x94Sxe2x80x94, xe2x80x94N(R20)xe2x80x94, or xe2x80x94Oxe2x80x94, and having 1-4 substituents independently selected from F, Cl, Br, or I;
Substituted heterocycloalkyl is a cyclic moiety having from 4-7 atoms with 1-2 atoms within the ring being xe2x80x94Sxe2x80x94, xe2x80x94N(R20)xe2x80x94, or xe2x80x94Oxe2x80x94 and having 0-3 substituents independently selected from F, Cl, Br, or I, and further having 1 substituent selected from xe2x95x90O, xe2x95x90S, xe2x80x94R7, xe2x80x94R9, xe2x80x94OR10, xe2x80x94SR10, xe2x80x94S(O)R10, xe2x80x94S(O)2R10, xe2x80x94OS(O)2R10, xe2x80x94N(R10)2, xe2x80x94C(O)R10, xe2x80x94C(S)R10, xe2x80x94C(O)OR10, xe2x80x94C(O)N(R10)2, xe2x80x94CN, xe2x80x94NO2, xe2x80x94NR10C(O)R10, xe2x80x94NR10C(O)N(R10)2, xe2x80x94S(O)2N(R10)2, xe2x80x94NR10S(O)2R10, and phenyl optionally substituted with 1-4 substituents independently selected from F, Cl, Br, I, R13, and R15;
Each R4 is independently H, alkyl, or substituted alkyl;
Each R5 is independently H, F, Cl, Br, I, 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, lactam heterocycloalkyl, aryl, xe2x80x94OR8, xe2x80x94SR8, xe2x80x94N(R8)2, xe2x80x94C(O)R8, xe2x80x94C(S)R8, xe2x80x94C(O)OR8, xe2x80x94C(O)N(R8)2, xe2x80x94NR8C(O)R8, xe2x80x94S(O)2N(R8)2, xe2x80x94OS(O)2R8, xe2x80x94S(O)2R8, xe2x80x94S(O)R8, xe2x80x94NR8S(O)2R8, xe2x80x94N(R8)C(O)N(R8)2, xe2x80x94CN, xe2x80x94NO2, R7, or R9;
Lactam heterocycloalkyl is a cyclic moiety having from 4-7 atoms with one atom being only nitrogen with the bond to the lactam heterocycloalkyl thru said atom being only nitrogen and having a xe2x95x90O on a carbon adjacent to said nitrogen, and having up to 1 additional ring atom being oxygen, sulfur, or nitrogen and further having 0-2 substituents selected from F, Cl, Br, I, or R18 where valency allows;
R6 is H, alkyl, an amino protecting group, or an alkyl group having 1-3 substituents selected from F, Cl, Br, I, xe2x80x94OH, xe2x80x94CN, xe2x80x94NH2, xe2x80x94NH(alkyl), or xe2x80x94N(alkyl)2;
R7 is 5-membered heteroaromatic mono-cyclic moieties containing within the ring 1-3 heteroatoms independently selected from the group consisting of xe2x95x90Nxe2x80x94, xe2x80x94N(R20)xe2x80x94, xe2x80x94Oxe2x80x94, and xe2x80x94Sxe2x80x94, and having 0-1 substituent selected from R17 and further having 0-3 substituents independently selected from F, Cl, Br, or I, or R7 is 9-membered fused-ring moieties having a 6-membered ring fused to a 5-membered ring including the formula
xe2x80x83wherein G1 is O, S or NR20,
xe2x80x83wherein G is C(R14) or N, and each G2 and G3 is independently selected from C(R14)2, C(R14), O, S, N, and N(R20), provided that both G2 and G3 are not simultaneously O or S, or
xe2x80x83wherein G is C(R14) or N, and each G2 and G3 is independently selected from C(R14)2, C(R14), O, S, N, and N(R20), each 9-membered bicyclic ring having 0-1 substituent selected from R17 and 0-3 substituents independently selected from F, Cl, Br, or I, wherein the R7 moiety attaches to other substituents as defined in formula I at any position on either ring as valency allows;
Each R8 is independently H, alkyl, halogenated alkyl, substituted alkyl, cycloalkyl, halogenated cycloalkyl, substituted cycloalkyl, heterocycloalkyl, halogenated heterocycloalkyl, substituted heterocycloalkyl, R7, R9, phenyl optionally substituted with 1-4 substituents independently selected from F, Cl, Br, I, R13, and R15, or naphthyl optionally substituted with 1-4 substituents independently selected from F, Cl, Br, I, R13, and R15;
R9 is 6-membered heteroaromatic mono-cyclic moieties containing within the ring 1-3 heteroatoms selected from xe2x95x90Nxe2x80x94and having 0-1 substituent selected from R17 and 0-3 substituent(s) independently selected from F, Cl, Br, or I, or R9 is 10-membered heteroaromatic bi-cyclic moieties containing within one or both rings 1-3 heteroatoms selected from xe2x95x90Nxe2x80x94, including, but not limited to, quinolinyl or isoquinolinyl, each 10-membered fused-ring moiety having 0-1 substituent selected from R17 and 0-3 substituent(s) independently selected from F, Cl, Br, or I, wherein the R9 moiety attaches to other substituents as defined in formula I at any position on either ring as valency allows;
Each R10 is independently H, alkyl, cycloalkyl, heterocycloalkyl, R7, R9, alkyl substituted with 1 substituent selected from R13, cycloalkyl substituted with 1 substituent selected from R13, heterocycloalkyl substituted with 1 substituent selected from R13, halogenated alkyl, halogenated cycloalkyl, halogenated heterocycloalkyl, or phenyl optionally substituted with 1-4 substituents independently selected from F, Cl, Br, I, R13, and R15;
Each R11 is independently H, alkyl, cycloalkyl, heterocycloalkyl, halogenated alkyl, halogenated cycloalkyl, or halogenated heterocycloalkyl;
R12 is alkyl, cycloalkyl, heterocycloalkyl, halogenated alkyl, halogenated cycloalkyl, halogenated heterocycloalkyl, substituted alkyl, substituted cycloalkyl, substituted heterocycloalkyl, xe2x80x94OR11, xe2x80x94SR11, xe2x80x94S(O)2R11, xe2x80x94S(O)R11, xe2x80x94OS(O)2R11, xe2x80x94N(R11)2, xe2x80x94C(O)R11, xe2x80x94C(S)R11, xe2x80x94C(O)OR11, xe2x80x94NO2, xe2x80x94C(O)N(R11)2, xe2x80x94CN, xe2x80x94NR11C(O)R11, xe2x80x94NR11C(O)N(R11)2, xe2x80x94S(O)2N(R11)2, or xe2x80x94NR11S(O)2R11;
R13 is xe2x80x94OR11, xe2x80x94SR11, xe2x80x94SOR11, xe2x80x94SO2R11, xe2x80x94OSO2R11, xe2x80x94N(R11)2, xe2x80x94C(O)R11, xe2x80x94C(O)OR11, xe2x80x94C(S)R11, xe2x80x94C(O)N(R11)2, xe2x80x94NO2xe2x80x94CN, xe2x80x94CF3, xe2x80x94NR11C(O)R11, xe2x80x94NR11C(O)N(R11)2, xe2x80x94S(O)2N(R11,)2, or xe2x80x94NR11S(O)2R11;
R14 is H or R19;
R15 is R7, R9, R9, or lactam heterocycloalkyl;
Each R16 is independently H, alkyl, cycloalkyl, halogenated alkyl, or halogenated cycloalkyl;
R17 is alkyl, cycloalkyl, or heterocycloalkyl, each optionally substituted with 1-4 substituents independently selected from F, Cl, Br, I, xe2x80x94NO2, xe2x80x94CN, xe2x80x94OR16, xe2x80x94SR16, xe2x80x94S(O)2R16, xe2x80x94S(O)R16, xe2x80x94OS(O)2R16, xe2x80x94N(R16)2, xe2x80x94C(O)R16, xe2x80x94C(S)R16, xe2x80x94C(O)OR16, xe2x80x94C(O)N(R16)2, xe2x80x94NR16C(O)R16, xe2x80x94NR16C(O)N(R16)2, xe2x80x94S(O)2N(R16)2, and xe2x80x94NR16S(O)2R16, and the cycloalkyl and heterocycloalkyl also being further optionally substituted with xe2x95x90O or xe2x95x90S;
R18 is alkyl, substituted alkyl, halogenated alkyl, xe2x80x94OR11, xe2x80x94CN, xe2x80x94NO2, xe2x80x94N(R10)2;
R19 is alkyl, cycloalkyl, heterocycloalkyl, phenyl, or naphthyl, each optionally substituted with 1-4 substituents independently selected from F, Cl, Br, I, xe2x80x94CN, xe2x80x94NO2, xe2x80x94OR16, xe2x80x94SR16, xe2x80x94S(O)2R16, xe2x80x94S(O)R16, xe2x80x94OS(O)2R16, xe2x80x94N(R16)2, xe2x80x94C(O)R16, xe2x80x94C(S)R16, xe2x80x94C(O)OR16, xe2x80x94C(O)N(R16)2, xe2x80x94NR16C(O)R16, xe2x80x94NR16C(O)N(R16)2, xe2x80x94S(O)2N(R16)2, or xe2x80x94NR16S(O)2R16, and the cycloalkyl and heterocycloalkyl also being further optionally substituted with xe2x95x90O or xe2x95x90S;
R20 is H, alkyl, halogenated alkyl, substituted alkyl, cycloalkyl, halogenated cycloalkyl, substituted cycloalkyl, phenyl, xe2x80x94SO2R8, or phenyl having 1 substituent selected from R12 and further having 0-3 substituents independently selected from F, Cl, Br, or I;
or pharmaceutical composition, pharmaceutically acceptable salt, racemic mixture, or pure enantiomer thereof useful to treat any one or more or combination of the following: cognitive and attention deficit symptoms of Alzheimer""s, neurodegeneration associated with diseases such as Alzheimer""s disease, pre-senile dementia (mild cognitive impairment), senile dementia, schizophrenia, psychosis, attention deficit disorder, attention deficit hyperactivity disorder, depression, anxiety, general anxiety disorder, post traumatic stress disorder, mood and affective disorders, amyotrophic lateral sclerosis, borderline personality disorder, traumatic brain injury, behavioral and cognitive problems in general and associated with brain tumors, AIDS dementia complex, dementia associated with Down""s syndrome, dementia associated with Lewy Bodies, Huntington""s disease, Parkinson""s disease, tardive dyskinesia, Pick""s disease, dysregulation of food intake including bulemia and anorexia nervosa, withdrawal symptoms associated with smoking cessation and dependant drug cessation, Gilles de la Tourette""s Syndrome, age-related macular degeneration, glaucoma, neurodegeneration associated with glaucoma, or symptoms associated with pain.
Another group of compounds of formula Axe2x80x94Lxe2x80x94B or Formula I includes any one or more or combination of the following compounds or a pharmaceutically acceptable salt or pharmaceutical composition thereof:
Abbreviations which are well known to one of ordinary skill in the art may be used (e.g., xe2x80x9cPhxe2x80x9d for phenyl, xe2x80x9cMexe2x80x9d for methyl, xe2x80x9cEtxe2x80x9d for ethyl, xe2x80x9chxe2x80x9d or xe2x80x9chrxe2x80x9d for hour or hours, min for minute or minutes, and xe2x80x9crtxe2x80x9d or xe2x80x9cRTxe2x80x9d for room temperature).
All temperatures are in degrees Centigrade.
Room temperature is within the range of 15-25 degrees Celsius.
AChR refers to acetylcholine receptor.
nAChR refers to nicotinic acetylcholine receptor.
Pre-senile dementia is also known as mild cognitive impairment.
5HT3R refers to the serotonin-type 3 receptor.
xcex1-btx refers to xcex1-bungarotoxin.
FLIPR refers to a device marketed by Molecular Devices, Inc. designed to precisely measure cellular fluorescence in a high throughput whole-cell assay. (Schroeder et. al., J. Biomolecular Screening, 1(2), p 75-80, 1996).
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 refers to dimethylsulfoxide.
DMF refers to N,N-dimethylformamide.
EtOAc refers to ethyl acetate.
TMS refers to tetramethylsilane.
TEA refers to triethylamine.
DIEA refers to N,N-diisopropylethylamine.
MLA refers to methyllycaconitine.
Ether refers to diethyl ether.
HATU refers to O-(7-azabenzotriazol-1-yl)xe2x80x94N,N,Nxe2x80x2, Nxe2x80x2-tetramethyluronium hexafluorophosphate.
CDI refers to carbonyl diimidazole.
NMO refers to N-methylmorpholinexe2x80x94N-oxide.
TPAP refers to tetrapropylammonium perruthenate.
Halogen is F, Cl, Br, or I.
Amino protecting group includes, but is not limited to, carbobenzyloxy (CBz), 1,1 dimethylcarbamate, tert butoxy carbonyl (BOC) and the like. Examples of other suitable amino protecting groups are known to person skilled in the art and can be found in xe2x80x9cProtective Groups in Organic synthesis,xe2x80x9d 3rd Edition, authored by Theodora Greene and Peter Wuts.
Acrylamide or acrylthioamide is a moiety having the general structure xe2x80x94N(H)C(X)Cxe2x95x90Cxe2x80x94, where X is O or S, respectively, so Axe2x80x94Lxe2x80x94B includes Axe2x80x94N(R1)C(X)xe2x80x94Cxe2x95x90Cxe2x80x94B.
Propiolamide or propiolthioamide is a moiety having the general structure xe2x80x94N(H)C(X)Cxe2x89xa1Cxe2x80x94, where X is O or S, respectively, so Axe2x80x94Lxe2x80x94B includes Axe2x80x94N(R1)C(X)xe2x80x94Cxe2x89xa1Cxe2x80x94B.
One of the most conventionally accepted ways of naming the compound pictured below is 5-(2-aminophenyl)-N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-thiophene-2-carboxamide, but for one ordinarily skilled in the art, the following name also describes the same compound, N-[(1S,2R,4R)-7-azabicyclo[2.2.1]hept-2-yl]-5-(2-aminophenyl)-thiophene-2-carboxamide. The two are used interchangeably in this patent.
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 Ci-j indicates a moiety of the integer xe2x80x9cixe2x80x9d to the integer xe2x80x9cjxe2x80x9d carbon atoms, inclusive. Thus, for example, C1-6 alkyl refers to alkyl of one to six carbon atoms.
Lower alkyl is both straight- and branched-chain moieties having 1-4 carbon atoms.
Halogenated lower alkyl is lower alkyl having 1 to (2n+1) substituent(s) independently selected from F, Cl, Br, or I where n is the maximum number of carbon atoms in the moiety.
Substituted lower alkyl is lower alkyl having 0-3 substituents independently selected from F, Cl, Br, or I and further having 1 substituent selected from R7, R9, xe2x80x94CN, xe2x80x94NO2, xe2x80x94OR10, xe2x80x94SR10, xe2x80x94S(O)R10, xe2x80x94S(O)2R10, xe2x80x94OS(O)2R10, xe2x80x94NR10R10, xe2x80x94C(O)R10, xe2x80x94C(O)OR10, xe2x80x94C(S)R10, xe2x80x94C(O)NR10R10, xe2x80x94NR10C(O)R10, xe2x80x94NR10C(O)NR10R10, xe2x80x94S(O)2NR10R10, xe2x80x94NR10S(O)2R10, or phenyl optionally substituted with 1-4 substituents independently selected from F, Cl, Br, I, R13, and R15.
Non-inclusive examples of heteroaryl compounds that fall within the definition of R7 and R9 include, but are not limited to, thienyl, benzothienyl, pyridyl, thiazolyl, quinolyl, pyrazinyl, pyrimidyl, imidazolyl, furanyl, benzofuranyl, benzothiazolyl, isothiazolyl, benzisothiazolyl, benzisoxazolyl, benzimidazolyl, indolyl, benzoxazolyl, pyrazolyl, triazolyl, tetrazolyl, isoxazolyl, oxazolyl, pyrrolyl, isoquinolinyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pydridazinyl, triazinyl, isoindolyl, purinyl, oxadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, quinazolinyl, quinoxalinyl, naphthridinyl, furopyridinyl, pyrrolopyridinyl, or thienopyridinyl. All isomeric forms of the non-inclusive named moieties are included, e.g., benzofuranyl includes 1-benzofuran-2-yl, 1-benzofuran-3-yl, 1-benzofuran-4-yl, 1-benzofuran-5-yl, 1-benzofuran-6-yl, 1-benzofuran-7-yl, 2-benzofuran-1-yl, 2-benzofuran-2-yl, 2-benzofuran-3-yl, 2-benzofuran-4-yl, or 2-benzofuran-5-yl. The non-inclusive examples of R7 and R9 may be substituted as allowed within the respective definition of R7 and R9 as valency allows. One of ordinary skill in the art can identify the allowed substitution by comparing the non-inclusive examples with the respective definitions of R7 and R9.
Non-inclusive examples of heterocycloalkyl include, but are not limited to, tetrahydrofurano, tetrahydropyrano, morpholino, pyrrolidino, piperidino, piperazine, azetidino, azetidinono, oxindolo, dihydroimidazolo, pyrrolidino, or isoxazolinyl.
Mammal denotes human and other mammals.
Brine refers to an aqueous saturated sodium chloride solution.
Equ means molar equivalents.
IR refers to infrared spectroscopy.
Lv refers to leaving groups within a molecule, including Cl, OH, or mixed anhydride.
NMR refers to nuclear (proton) magnetic resonance spectroscopy, chemical shifts are reported in ppm (xcex4) downfield from TMS.
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. EI refers to electron impact. ESI refers to electrospray ionization. CI refers to chemical ionization. FAB refers to fast atom bombardment.
Compounds of the present invention may be in the form of pharmaceutically acceptable salts. The term xe2x80x9cpharmaceutically acceptable saltsxe2x80x9d 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-dimethylaminoethanol, 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. 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 C1-6 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.
By the term xe2x80x9ceffective amountxe2x80x9d of a compound as provided herein is meant a nontoxic but sufficient amount of the compound(s) to provide the desired effect. As pointed out below, 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 xe2x80x9ceffective amount.xe2x80x9d However, an appropriate effective amount may be determined by one of ordinary skill in the art using only routine experimentation.
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 the present invention. The pharmaceutical compositions may contain active ingredient in the range of about 0.001 to 100 mg/kg/day for an adult, preferably in the range of about 0.1 to 50 mg/kg/day for an adult. A total daily dose of about 1 to 1000 mg of active ingredient may be appropriate for an adult. The daily dose can be administered in one to four doses per day.
In addition to the compound(s) of the present invention, the composition for therapeutic use may also comprise one or more non-toxic, pharmaceutically acceptable carrier materials or excipients. The term xe2x80x9ccarrierxe2x80x9d material or xe2x80x9cexcipientxe2x80x9d 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 hydroxypropylmethyl cellulose, or other methods known to those skilled in the art. For oral administration, 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.
In addition to the oral dosing, noted above, the 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. For parenteral administration, 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. These 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, EtOH, 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 (5HT3R) is a member of a superfamily of ligand-gated ion channels, which includes the muscle and neuronal nAChR, the glycine receptor, and the xcex3-aminobutyric acid type A receptor. Like the other members of this receptor superfamily, the 5HT3R exhibits a large degree of sequence homology with xcex17 nAChR but functionally the two ligand-gated ion channels are very different. For example, xcex17 nAChR is rapidly inactivated, is highly permeable to calcium and is activated by acetylcholine and nicotine. On the other hand, 5HT3R is inactivated slowly, is relatively impermeable to calcium and is activated by serotonin. These experiments suggest that the xcex17 nAChR and 5HT3R 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 5HT3R antagonist, has little activity at the xcex17 nAChR. The converse is also true. For example, GTS-21, a highly selective xcex17 nAChR agonist, has little activity at the 5HT3R.
xcex17 nAChR is a ligand-gated Ca++ channel formed by a homopentamer of xcex17 subunits. Previous studies have established that xcex1-bungarotoxin (xcex1-btx) binds selectively to this homopetameric, xcex17 nAChR subtype, and that xcex17 nAChR has a high affinity binding site for both xcex1-btx and methyllycaconitine (MLA). xcex17 nAChR is expressed at high levels in the hippocampus, ventral tegmental area and ascending cholinergic projections from nucleus basalis to thalamocortical areas. xcex17 nAChR agonists increase neurotransmitter release, and increase cognition, arousal, attention, learning and memory.
Data from human and animal pharmacological studies establish that nicotinic cholinergic neuronal pathways control many important aspects of cognitive function including attention, learning and memory (Levin, E. D., Psychopharmacology, 108:417-31, 1992; Levin, E. D. and Simon B. B., Psychopharmacology, 138:217-30, 1998). For example, it is well known that nicotine increases cognition and attention in humans. ABT-418, a compound that activates xcex14xcex22 and xcex17 nAChR, improves cognition and attention in clinical trials of Alzheimer""s disease and attention-deficit disorders (Potter, A. et. al., Psychopharmacology (Berl)., 142(4):334-42, March 1999; Wilens, T. E. et. al., Am. J. Psychiatry, 156(12):1931-7, December 1999). It is also clear that nicotine and selective but weak xcex17 nAChR agonists increase cognition and attention in rodents and non-human primates.
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. Pharmacological studies established that dopamine receptor antagonists are efficacious in treating the overt psychotic features (positive symptoms) of schizophrenia such as hallucinations and delusions. Clozapine, an xe2x80x9catypicalxe2x80x9d 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 drug 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. In this test, electroencepholographic (EEG) recordings of neuronal activity of the hippocampus are used to measure the subject""s response to a series of auditory xe2x80x9cclicksxe2x80x9d (Adler, L. E. et. al., Biol. Psychiatry, 46:8-18, 1999). Normal individuals respond to the first click with greater degree than to the second click. In general, schizophrenics and schizotypal patients respond to both clicks nearly the same (Cullum, C. M. et. al., Schizophr. Res., 10:131-41, 1993). These data reflect a schizophrenic""s inability to xe2x80x9cfilterxe2x80x9d or ignore unimportant information. The sensory gating deficit appears to be one of the key pathological features of this disease (Cadenhead, K. S. et. al., Am. J. Psychiatry, 157:55-9, 2000). Multiple studies show that nicotine normalizes the sensory deficit of schizophrenia (Adler, L. E. et. al., Am. J. Psychiatry, 150:1856-61, 1993). Pharmacological studies indicate that nicotine""s effect on sensory gating is via the xcex17 nAChR (Adler, L. E. et. al., Schizophr. Bull., 24:189-202, 1998). Indeed, the biochemical data indicate that schizophrenics have 50% fewer of xcex17 nAChR receptors in the hippocampus, thus giving a rationale to partial loss of xcex17 nAChR functionality (Freedman, R. et. al., Biol. Psychiatry, 38:22-33, 1995). Interestingly, genetic data indicate that a polymorphism in the promoter region of the xcex17 nAChR gene is strongly associated with the sensory gating deficit in schizophrenia (Freedman, R. et. al., Proc. Nat""l Acad. Sci. USA, 94(2):587-92, 1997; Myles-Worsley, M. et. al., Am. J. Med. Genet, 88(5):544-50, 1999). To date, no mutation in the coding region of the xcex17 nAChR has been identified. Thus, schizophrenics express the same xcex17 nAChR as non-schizophrenics.
Selective xcex17 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 xcex17 nAChR and 5HT3R. To conduct such an assay, one uses cell lines that expressed functional forms of the xcex17 nAChR using the xcex17/5-HT3 channel as the drug target and cell lines that expressed functional 5HT3R. In both cases, the ligand-gated ion channel was expressed in SH-EP1 cells. Both ion channels can produce robust signal in the FLIPR assay.
The compounds of the present invention are xcex17 nAChR agonists and may be used to treat a wide variety of diseases. For example, they may be used in treating schizophrenia, or psychosis.
Schizophrenia is a disease having multiple aspects. Currently available 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. Thus, there is a need for a drug to treat the cognitive and attention deficits associated with schizophrenia. Similarly, there is a need for a drug to treat the cognitive and attention deficits associated with 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. In the past, the term psychosis has been applied to many conditions that do not meet the stricter definition given above. For example, mood disorders were named as psychoses.
There are a variety of antipsychotic drugs. The conventional antipsychotic drugs include Chlorpromazine, Fluphenazine, Haloperidol, Loxapine, Mesoridazine, Molindone, Perphenazine, Pimozide, Thioridazine, Thiothixene, and Trifluoperazine. These drugs all have an affinity for the dopamine 2 receptor.
These conventional antipsychotic drugs have several side effects, including sedation, weight gain, tremors, elevated prolactin levels, akathisia (motor restlessness), dystonia and muscle stiffness. These drugs may also cause tardive dyskinesia. Unfortunately, only about 70% of patients with schizophrenia respond to conventional antipsychotic drugs. For these patients, atypical antipsychotic drugs are available.
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 drugs have a lower risk of producing tardive dyskinesia. Finally these atypical antipsychotic drugs cause little or no elevation of prolactin. Unfortunately, these drugs are not free of side effects. Although these drugs each produce different side effects, as a group the side effects include: agranulocytosis; increased risk of seizures, weight gain, somnolence, dizziness, tachycardia, decreased ejaculatory volume, and mild prolongation of QTc interval.
In a combination therapy to treat multiple symptoms of diseases such as schizophrenia, the compounds of the present invention and the anti-psychotic drugs can be administered simultaneously or at separate intervals. When administered simultaneously the compounds of the present invention and the anti-psychotic drugs can be incorporated into a single pharmaceutical composition, e.g., a pharmaceutical combination therapy composition. Alternatively, two separate compositions, i.e., one containing compounds of the present invention and the other containing anti-psychotic drugs, can be administered simultaneously. Examples of anti-psychotic drugs, in addition to those listed above, include, but are not limited to, Thorazine, Mellaril, Trilafon, Navane, Stelazine, Permitil, Prolixin, Risperdal, Zyprexa, Seroquel, ZELDOX, Acetophenazine, Carphenazine, Chlorprothixene, Droperidol, Loxapine, Mesoridazine, Molindone, Ondansetron, Pimozide, Prochlorperazine, and Promazine.
A pharmaceutical combination therapy composition can include therapeutically effective amounts of the compounds of the present invention, noted above, and a therapeutically effective amount of anti-psychotic drugs (also called anti-psychotic agents). These compositions may be formulated with common excipients, diluents or carriers, and compressed into tablets, or formulated elixirs or solutions for convenient oral administration or administered by intramuscular intravenous routes. The compounds can be administered rectally, topically, orally, sublingually, or parenterally and maybe formulated as sustained relief dosage forms and the like.
When separately administered, therapeutically effective amounts of compositions containing compounds of the present invention and anti-psychotic drugs are administered on a different schedule. One may be administered before the other as long as the time between the two administrations falls within a therapeutically effective interval. A therapeutically effective interval is a period of time beginning when one of either (a) the compounds of the present invention, or (b) the anti-psychotic drugs is administered to a human and ending at the limit of the beneficial effect in the treatment of schizophrenia or psychosis of the combination of (a) and (b). The methods of administration of the compounds of the present invention and the anti-psychotic drugs may vary. Thus, either agent or both agents may be administered rectally, topically, orally, sublingually, or parenterally.
As discussed, the compounds of the present invention are xcex17 nAChR agonists. Therefore, as another aspect of the present invention, the compounds of the present invention may be used to treat a variety of diseases including cognitive and attention deficit symptoms of Alzheimer""s, neurodegeneration associated with diseases such as Alzheimer""s disease, pre-senile dementia (also known as mild cognitive impairment), and senile dementia.
Alzheimer""s disease has many aspects, including cognitive and attention deficits. Currently, these deficits are treated with cholinesterase inhibitors. These inhibitors slow the break down of acetylcholine, and thereby provide a general nonspecific increase in the activity of the cholinergic nervous system. Since the drugs are nonspecific, they have a wide variety of side effects. Thus, there is a need for a drug that stimulates a portion of the cholinergic pathways and thereby provides improvement in the cognitive and attention deficits associated with Alzheimer""s disease without the side effects created by nonspecific stimulation of the cholinergic pathways.
Neurodegeneration is a common problem associated with diseases such as Alzheimer""s disease. While the current drugs treat some of the symptoms of this disease, they do not control the underlying pathology of the disease. Accordingly, it would be desirable to provide a drug that can slow the progress of Alzheimer""s disease.
Pre-senile dementia (mild cognitive impairment) concerns memory impairment rather than attention deficit problems and otherwise unimpaired cognitive functioning. Mild cognitive impairment is distinguished from senile dementia in that mild cognitive impairment involves a more persistent and troublesome problem of memory loss for the age of the patient. There currently is no medication specifically identified for treatment of mild cognitive impairment, due somewhat to the newness of identifying the disease. Therefore, there is a need for a drug to treat the memory problems associated with mild cognitive impairment.
Senile dementia is not a single disease state. However, the conditions classified under this name frequently include cognitive and attention deficits. Generally, these deficits are not treated. Accordingly, there is a need for a drug that provides improvement in the cognitive and attention deficits associated with senile dementia.
As discussed, the compounds of the present invention are xcex17 nAChR agonists. Therefore, yet other diseases to be treated with compounds of the present invention include treating the cognitive and attention deficits as well as the neurodegeneration associated with any one or more or combination of the following: attention deficit disorder, attention deficit hyperactivity disorder, depression, anxiety, general anxiety disorder, post traumatic stress disorder, mood and affective disorders, amyotrophic lateral sclerosis, borderline personality disorder, traumatic brain injury, behavioral and cognitive problems associated with brain tumors, AIDS dementia complex, dementia associated with Down""s syndrome, dementia associated with Lewy Bodies, Huntington""s disease, Parkinson""s disease, tardive dyskinesia, Pick""s disease, dysregulation of food intake including bulemia and anorexia nervosa, withdrawal symptoms associated with smoking cessation and dependant drug cessation, Gilles de la Tourette""s Syndrome, age-related macular degeneration, glaucoma, neurodegeneration associated with glaucoma, or symptoms associated with pain.
Attention deficit disorder is generally treated with methylphenidate, an amphetamine-like molecule that has some potential for abuse. Accordingly, it would be desirable to provide a drug that treats attention deficit disorder while having fewer side effects than the currently used drug.
Attention deficit hyperactivity disorder, otherwise known as ADHD, is a neurobehavioral disorder affecting 3-5% of all American children. ADHD concerns cognitive alone or both cognitive and behavioral actions by interfering with a person""s ability to stay on a task and to exercise age-appropriate inhibition. Several types of ADHD exist: a predominantly inattentive subtype, a predominantly hyperactive impulsive subtype, and a combined subtype. Treatment may include medications such as methylphenidate, dextroamphetamine, or pemoline, which act to decrease impulsivity and hyperactivity and to increase attention. No xe2x80x9ccurexe2x80x9d for ADHD currently exists. Children with the disorder seldom outgrow it; therefore, there is a need for appropriate medicaments.
Depression is a mood disorder of varying lengths of normally several months to more than two years and of varying degrees of feelings involving sadness, despair, and discouragement. The heterocyclic antidepressants (HCA""s) are currently the largest class of antidepressants, but monoamine oxidase inhibitors (MAOI""s) are used in particular types of depression. Common side effects from HCA""s are sedation and weight gain. In elderly patients with organic brain disease, the side effects from HCA""s can also include seizures and behavioral symptoms. The main side effects from using MAOI""s occur from dietary and drug interactions. Therefore, agents with fewer side effects would be useful.
Anxiety disorders (disorders with prominent anxiety or phobic avoidance), represent an area of umet medical needs in the treatment of psychiatric illness. See Diagnostic and Statistical Manual of Mental Disorders, IV (1994), pp 393-394, for various disease forms of anxiety.
General anxiety disorder (GAD) occurs when a person worries about things such as family, health, or work when there is no reason to worry and is unable not to worry. About 3 to 4% of the U.S. population has GAD during the course of a year. GAD most often strikes people in childhood or adolescence, but can begin in adulthood, too. It affects women more often than men. Currently, treatment involves cognitive-behavioral therapy, relaxation techniques, and biofeedback to control muscle tension and medications such as benzodiazepines, imipramine, and buspirone. These drugs are effective but all have side-effect liabilities. Therefore, there is a need of a pharmaceutical agent to address the symptoms with fewer side effects.
Anxiety also includes post-traumatic stress disorder (PTSD), which is a form of anxiety triggered by memories of a traumatic event that directly affected the patient or that the patient may have witnessed. The disorder commonly affects survivors of traumatic events including sexual assault, physical assault, war, torture, natural disasters, an automobile accident, an airplane crash, a hostage situation, or a death camp. The affliction also can affect rescue workers at an airplane crash or a mass shooting, someone who witnessed a tragic accident or someone who has unexpectedly lost a loved one. Treatment for PTSD includes cognitive-behavioral therapy, group psychotherapy, and medications such as Clonazepam, Lorazepam and selective serotonin-reuptake inhibitors such as Fluoxetine, Sertraline, Paroxetine, Citalopram and Fluvoxamine. These medications help control anxiety as well as depression. Various forms of exposure therapy (such as systemic desensitization and imaginal flooding) have all been used with PTSD patients. Exposure treatment for PTSD involves repeated reliving of the trauma, under controlled conditions, with the aim of facilitating the processing of the trauma. Therefore, there is a need for better pharmaceutical agents to treat post traumatic stress disorder.
Mood and affective disorders fall within a large group of diseases, including monopolar depression and bi-polar mood disorder. These diseases are treated with three major classes of compounds. The first group is the heterocyclic antidepressant (HCA""s). This group includes the well-known tricyclic antidepressants. The second group of compounds used to treat mood disorders is the monoamine oxidase inhibitors (MAOI""s) that are used in particular types of diseases. The third drug is lithium. Common side effects from HCA""s are sedation and weight gain. In elderly patients with organic brain disease, the side effects of HCA""s can also include seizures and behavioral symptoms. The main side effects from using MAOI""s occur from dietary and drug interactions. Benign side effects from the use of lithium include, but are not limited to, weight gain, nausea, diarrhea, polyuria, polydipsia, and tremor. Toxic side effects from lithium can include persistent headache, mental confusion, and may reach seizures and cardiac arrhythmias. Therefore, agents with less side effects or interactions with food or other medications would be useful.
Borderline personality disorder, although not as well known as bipolar disorder, is more common. People having borderline personality disorder suffer from a disorder of emotion regulation. Pharmaceutical agents are used to treat specific symptoms, such as depression or thinking distortions.
Acquired immune deficiency syndrome (AIDS) results from an infection with the human immunodeficiency virus (HIV). This virus attacks selected cells and impairs the proper function of the immune, nervous, and other systems. HIV infection can cause other problems such as, but not limited to, difficulties in thinking, otherwise known as AIDS dementia complex. Therefore, there is a need to drugs to relieve the confusion and mental decline of persons with AIDS.
Amyotrophic lateral sclerosis, also known as Lou Gehrig""s disease, belongs to a class of disorders known as motor neuron diseases wherein specific nerve cells in the brain and spinal cord gradually degenerate to negatively affect the control of voluntary movement. Currently, there is no cure for amyotrophic lateral sclerosis although patients may receive treatment from some of their symptoms and although Riluzole has been shown to prolong the survival of patients. Therefore, there is a need for a pharmaceutical agent to treat this disease.
Traumatic brain injury occurs when the brain is damaged from a sudden physical assault on the head. Symptoms of the traumatic brain injury include confusion and other cognitive problems. Therefore, there is a need to address the symptoms of confusion and other cognitive problems.
Brain tumors are abnormal growths of tissue found inside of the skull. Symptoms of brain tumors include behavioral and cognitive problems. Surgery, radiation, and chemotherapy are used to treat the tumor, but other agents are necessary to address associated symptoms. Therefore, there is a need to address the symptoms of behavioral and cognitive problems.
Persons with Down""s syndrome have in all or at least some of their cells an extra, critical portion of the number 21 chromosome. Adults who have Down""s syndrome are known to be at risk for Alzheimer-type dementia. Currently, there is no proven treatment for Down""s syndrome. Therefore, there is a need to address the dementia associated with Down""s syndrome.
Genetically programmed degeneration of neurons in certain areas of the brain cause Huntington""s disease. Early symptoms of Huntington""s disease include mood swings, or trouble learning new things or remembering a fact. Most drugs used to treat the symptoms of Huntington""s disease have side effects such as fatigue, restlessness, or hyperexcitability. Currently, there is no treatment to stop or reverse the progression of Huntington""s disease. Therefore, there is a need of a pharmaceutical agent to address the symptoms with fewer side effects.
Dementia with Lewy Bodies is a neurodegenerative disorder involving abnormal structures known as Lewy bodies found in certain areas of the brain. Symptoms of dementia with Lewy bodies include, but are not limited to, fluctuating cognitive impairment with episodic delirium. Currently, treatment concerns addressing the parkinsonian and psychiatric symptoms. However, medicine to control tremors or loss of muscle movement may actually accentuate the underlying disease of dementia with Lewy bodies. Therefore, there is a need of a pharmaceutical agent to treat dementia with Lewy bodies.
Parkinson""s disease is a neurological disorder characterized by tremor, hypokinesia, and muscular rigidity. Currently, there is no treatment to stop the progression of the disease. Therefore, there is a need of a pharmaceutical agent to address Parkinson""s.
Tardive dyskinesia is associated with the use of conventional antipsychotic drugs. This disease is characterized by involuntary movements most often manifested by puckering of the lips and tongue and/or writhing of the arms or legs. The incidence of tardive dyskinesia is about 5% per year of drug exposure among patients taking conventional antipsychotic drugs. In about 2% of persons with the disease, tardive dyskinesia is severely disfiguring. Currently, there is no generalized treatment for tardive dyskinesia. Furthermore, the removal of the effect-causing drugs is not always an option due to underlying problems. Therefore, there is a need for a pharmaceutical agent to address the symptoms of tardive dyskinesia.
Pick""s disease results from a slowly progressive deterioration of social skills and changes in personality with the resulting symptoms being impairment of intellect, memory, and language. Common symptoms include memory loss, lack of spontaneity, difficulty in thinking or concentrating, and speech disturbances. Currently, there is no specific treatment or cure for Pick""s disease but some symptoms can be treated with cholinergic and serotonin-boosting antidepressants. In addition, antipsychotic medications may alleviate symptoms in FTD patients who are experiencing delusions or hallucinations. Therefore, there is a need for a pharmaceutical agent to treat the progressive deterioration of social skills and changes in personality and to address the symptoms with fewer side effects.
Dysregulation of food intake associated with eating disease, including bulemia nervosa and anorexia nervosa, involve neurophysiological pathways. Anorexia nervosa is hard to treat due to patients not entering or remaining in after entering programs. Currently, there is no effective treatment for persons suffering from severe anorexia nervosa. Cognitive behavioral therapy has helped patients suffering from bulemia nervosa; however, the response rate is only about 50% and current treatment does not adequately address emotional regulation. Therefore, there is a need for pharmaceutical agents to address neurophysiological problems underlying diseases of dysregulation of food intake.
Cigarette smoking has been recognized as a major public health problem for a long time. However, in spite of the public awareness of health hazard, the smoking habit remains extraordinarily persistent and difficult to break. There are many treatment methods available, and yet people continue to smoke. Administration of nicotine transdermally, or in a chewing gum base is common treatments. However, nicotine has a large number of actions in the body, and thus can have many side effects. It is clear that there is both a need and a demand of long standing for a convenient and relatively easy method for aiding smokers in reducing or eliminating cigarette consumption. A drug that could selectively stimulate only certain of the nicotinic receptors would be useful in smoke cessation programs.
Smoke cessation programs may involve oral dosing of the drug of choice. The drug may be in the form of tablets. However, it is preferred to administer the daily dose over the waking hours, by administration of a series of incremental doses during the day. The preferred method of such administration is a slowly dissolving lozenge, troche, or chewing gum, in which the drug is dispersed. Another drug in treating nicotine addiction is Zyban. This is not a nicotine replacement, as are the gum and patch. Rather, this works on other areas of the brain, and its effectiveness is to help control nicotine craving or thoughts about cigarette use in people trying to quit. Zyban is not very effective and effective drugs are needed to assist smokers in their desire to stop smoking. These drugs may be administered transdermally through the use of skin patches. In certain cases, the drugs may be administered by subcutaneous injection, especially if sustained release formulations are used.
Drug use and dependence is a complex phenomenon, which cannot be encapsulated within a single definition. Different drugs have different effects, and therefore different types of dependence. Drug dependence has two basic causes, that is, tolerance and physical dependence. Tolerance exists when the user must take progressively larger doses to produce the effect originally achieved with smaller doses. Physical dependence exists when the user has developed a state of physiologic adaptation to a drug, and there is a withdrawal (abstinence) syndrome when the drug is no longer taken. A withdrawal syndrome can occur either when the drug is discontinued or when an antagonist displaces the drug from its binding site on cell receptors, thereby counteracting its effect. Drug dependence does not always require physical dependence.
In addition drug dependence often involves psychological dependence, that is, a feeling of pleasure or satisfaction when taking the drug. These feelings lead the user to repeat the drug experience or to avoid the displeasure of being deprived of the drug. Drugs that produce strong physical dependence, such as nicotine, heroin and alcohol are often abused, and the pattern of dependence is difficult to break. Drugs that produce dependence act on the CNS and generally reduce anxiety and tension; produce elation, euphoria, or other pleasurable mood changes; provide the user feelings of increased mental and physical ability; or alter sensory perception in some pleasurable manner. Among the drugs that are commonly abused are ethyl alcohol, opioids, anxiolytics, hypnotics, cannabis (marijuana), cocaine, amphetamines, and hallucinogens. The current treatment for drug-addicted people often involves a combination of behavioral therapies and medications. Medications, such as methadone or LAAM (levo-alpha-acetyl-methadol), are effective in suppressing the withdrawal symptoms and drug craving associated with narcotic addiction, thus reducing illicit drug use and improving the chances of the individual remaining in treatment. The primary medically assisted withdrawal method for narcotic addiction is to switch the patient to a comparable drug that produces milder withdrawal symptoms, and then gradually taper off the substitute medication. The medication used most often is methadone, taken orally once a day. Patients are started on the lowest dose that prevents the more severe signs of withdrawal and then the dose is gradually reduced. Substitutes can be used also for withdrawal from sedatives. Patients can be switched to long-acting sedatives, such as diazepam or phenobarbital, which are then gradually reduced.
Gilles de la Tourette""s Syndrome is an inherited neurological disorder. The disorder is characterized by uncontrollable vocal sounds called tics and involuntary movements. The symptoms generally manifest in an individual before the person is 18 years of age. The movement disorder may begin with simple tics that progress to multiple complex tics, including respiratory and vocal ones. Vocal tics may begin as grunting or barking noises and evolve into compulsive utterances. Coprolalia (involuntary scatologic utterances) occurs in 50% of patients. Severe tics and coprolalia may be physically and socially disabling. Tics tend to be more complex than myoclonus, but less flowing than choreic movements, from which they must be differentiated. The patient may voluntarily suppress them for seconds or minutes.
Currently simple tics are often treated with benzodiazepines. For simple and complex tics, Clonidine may be used. Long-term use of Clonidine does not cause tardive dyskinesia; its limiting adverse effect is hypotension. In more severe cases, antipsychotics, such as Haloperidol may be required, but side effects of dysphoria, parkinsonism, akathisia, and tardive dyskinesia may limit use of such antipsychotics. There is a need for safe and effective methods for treating this syndrome.
Age-related macular degeneration (AMD) is a common eye disease of the macula which is a tiny area in the retina that helps produce sharp, central vision required for xe2x80x9cstraight aheadxe2x80x9d activities that include reading and driving. Persons with AMD lose their clear, central vision. AMD takes two forms: wet and dry. In dry AMD, there is a slow breakdown of light-sensing cells in the macula. There currently is no cure for dry AMD. In wet AMD, new, fragile blood vessels growing beneath the macula as dry AMD worsens and these vessels often leak blood and fluid to cause rapid damage to the macula quickly leading to the loss of central vision. Laser surgery can treat some cases of wet AMD. Therefore, there is a need of a pharmaceutical agent to address AMD.
Glaucoma is within a group of diseases occurs from an increase in intraocular pressure causing pathological changes in the optical disk and negatively affects the field of vision. Medicaments to treat glaucoma either decrease the amount of fluid entering the eye or increase drainage of fluids from the eye in order to decrease intraocular pressure. However, current drugs have drawbacks such as not working over time or causing side effects so the eye-care professional has to either prescribe other drugs or modify the prescription of the drug being used. There is a need for safe and effective methods for treating problems manifesting into glaucoma.
Ischemic periods in glaucoma cause release of excitotoxic amino acids and stimulate inducible form of nitric oxide synthase (iNOS) leading to neurodegeneration. Alpha 7 nicotinic agonists may stimulate the release of inhibitory amino acids such as GABA which will dampen hyperexcitablity. Alpha 7 nicotinic agonists are also directly neuroprotective on neuronal cell bodies. Thus alpha 7 nicotinic agonists have the potential to be neuroprotective in glaucoma.
Persons afflicted with pain often have what is referred to as the xe2x80x9cterrible triadxe2x80x9d of suffering from the pain, resulting in sleeplessness and sadness, all of which are hard on the afflicted individual and that individual""s family. Pain can manifest itself in various forms, including, but not limited to, headaches of all severity, back pain, neurogenic, and pain from other ailments such as arthritis and cancer from its existence or from therapy to irradicate it. Pain can be either chronic (persistent pain for months or years) or acute (short-lived, immediate pain to inform the person of possible injury and need of treatment). Persons suffering from pain respond differently to individual therapies with varying degrees of success. There is a need for safe and effective methods for treating pain.
Finally, the compounds of the present invention may be used in combination therapy with typical and atypical anti-psychotic drugs (also called an anti-psychotic agent). 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.
Compounds of Formula I can be prepared as shown in Scheme 1. Starting materials can be prepared by procedures described below or by procedures that would be well known to one of ordinary skill in organic chemistry. The variables used in Scheme 1 are defined below or as in the claims. The key step in the preparation of this class of compounds is the coupling of exo-tert-butyl (1S,2R,4R)-(+)-2-amino-7-azabicyclo[2.2.1]heptane-7-carboxylate (Example 1) with the requisite acid chloride (Lv=Cl), mixed anhydride (e.g., Lv=diphenyl phosphoryl, bis(2-oxo-3-oxazolidinyl)phosphinyl, or acyloxy of the general formula of Oxe2x80x94C(O)xe2x80x94RLv, where RLv includes phenyl or t-butyl), ester (e.g., Lv=alkyl, aryl, or electron deficient aryl), or carboxylic acid (Lv=OH) in the presence of an activating agent. Suitable activating reagents are well known in the art, for examples see Kiso, Y., Yajima, H. xe2x80x9cPeptidesxe2x80x9d pp. 39-91, San Diego, Calif., Academic Press, (1995), and include, but are not limited to, agents such as carbodiimides, phosphonium and uronium salts (such as uronium salt HATU).
Preferably, tert-butyl (1S,2R,4R)-(+)-2-amino-7-azabicyclo[2.2.1]heptane-7-carboxylate can be coupled to the acid in the presence of an appropriate base, such as DIEA, and a uronium salt, such as HATU, in an aprotic medium, such as DMF, to give the desired amides. Alternatively, the acid is converted into a mixed anhydride by treatment with bis (2-oxo-3-oxazolidinyl) phosphinic chloride in the presence of TEA with CH2Cl2 or CHCl3 as the solvent. The resulting anhydride solution is directly reacted with tert-butyl (1S,2R,4R)-(+)-2-amino-7-azabicyclo[2.2.1]heptane-7-carboxylate added neat or using CH2Cl2 or CHCl3 as solvent. Furthermore, condensation of the amine with an ester (Wxe2x80x94C(O)xe2x80x94O-alkyl or Wxe2x80x94C(O)xe2x80x94O-(electron-deficient aryl)) in an alcoholic solvent such as ethanol at an elevated temperature will yield desired amides.
Treatment of the carboxamide with a sulfurating agent such as Lawesson""s Reagent (2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide) in, for instance, dioxane at an appropriate temperature provides the corresponding thioamide, e.g., X in formula I is S. See Lawesson et. al. in Bull. Soc. Chim. Belg., 229 (1978)), or P4S10 (see Chem. Rev., 45 (1961). Alternatively, one can react a dithiocarboxylic ester with the corresponding azbicyclo moiety to form the same thioamide.
There are various methods for the construction of the optionally substituted 7-azabicyclo[2.2.1]heptane ring system. For example, the independent work of Trudell (R4=H, Zhang, C., Trudell, M. L., J. Org. Chem., 61, 7189-7191, 1996), and Schultz (R4=Me, Schultz, A. G., Shen, M. S., Tetrahedron Lett., 22, 3347-3350, 1981) describes the utility of a Diels-Alder approach toward preparing this ring system with functionality suitable for further elaboration to the desired 2-amino-7-aza-bicyclo[2.2.1]heptane (Scheme 2). For instance, Trudell reports (Zhang, C., Trudell, M. L., Tetrahedron, 54, 8349-8354, 1998) that Diels-Alder adduct 1a (where R6=methylcarbamate, R4=H, and Lv=Br) could readily be functionalized at C-3 via reaction with organocopper species to introduce the substituent R2 in 2a,b. Likewise, hydrogenolysis of adduct 1a,b or 2a,b followed by isomerization of the endo products as described by Singh (Singh, S., Basmadjian, G. P., Tetrahedron Lett., 38, 6829-6830, 1997) could provide access to the required exo acid 3a-d. Treatment of 3 with diphenylphosphoryl azide in the presence of a tertiary amine base (e.g., Et3N) in a suitable solvent such as toluene, followed by warming of the intermediate acylazide in the presence of a suitable alcohol (e.g., benzyl alcohol) would effect the well-known Curtius rearrangement to provide a differentially protected bis carbamate which could be cleaved under typical hydrogenolysis conditions (e.g., 10% Pd/C, EtOH, H2, ambient to 50 psi) to give the desired amine 4. Alternatively, the differentially protected bis carbamate might provide an attractive point of intervention for the chromatographic resolution of the individual 2-exo isomers prior to cleavage to amine 4.
In the case where R6=tert-butyloxycarbonyl, deprotection of the 7-aza group can be conveniently accomplished under acidic conditions in a suitable solvent such as methanol. After deprotection, the secondary amine may be functionalized with alkyl and substituted alkyl via reductive amination or alkylative procedures.
It will be apparent to those skilled in the art that the requisite carboxylic acids can be obtained through synthesis via literature procedures or through the slight modification thereof.

Preparation of methyl-3-bromo-propiolate:
Methyl propiolate (52 ml, 0.583 mol) is combined with recrystallized N-bromo-succinimide (120 g, 0.674 mol) in 1,700 ml acetone under nitrogen. The solution is treated with silver nitrate (9.9 g, 0.0583 mol) neat in a single lot and the reaction is stirred 6 h at RT. The acetone is removed under reduced pressure (25xc2x0 C., bath temperature) to provide a gray slurry. The slurry is washed with 2xc3x97200 ml hexane, the gray solid is removed by filtration, and the filtrate is concentrated in vacuo to provide 95 g of a pale yellow oily residue. The crude material is distilled via short path under reduced pressure (65xc2x0 C., about 25 mm Hg) into a dry ice/acetone cooled receiver to give 83.7 g (88%) of methyl-3-bromo-propiolate as a pale yellow oil. Anal. calc3 d for C4H3BrO2: C, 29.48; H, 1.86. Found: C, 29.09; H, 1.97.
Preparation of 7-tert-butyl 2-methyl 3-bromo-7-azabicyclo[2.2.1]hepta-2,5-diene-2,7-dicarboxylate.
Methyl-3-bromo-propiolate (83.7 g, 0.513 mol) is added to N-t-butyloxy-pyrrole (430 ml, 2.57 mol) under nitrogen. The dark mixture is warmed in a 90xc2x0 C. bath for 30 h, is cooled, and the bulk of the excess N-t-butyloxy-pyrrole is removed in vacuo using a dry ice/acetone condenser. The dark oily residue is chromatographed over 1 kg silica gel (230-400 mesh) eluting with 0-15% EtOAc/hexane. The appropriate fractions are combined and concentrated to afford 97 g (57%) of 7-tert-butyl 2-methyl 3-bromo-7-azabicyclo[2.2.1]hepta-2,5-diene-2,7-dicarboxylate as a dark yellow oil. HRMS (FAB) calc""d for C13H16BrNO4+H: 330.0341, found 330.0335 (M+H)+.
Preparation of (+/xe2x88x92) endo-7-tert-butyl 2-methyl 7-azabicyclo[2.2.1]heptane-2,7-dicarboxylate.
7-tert-Butyl 2-methyl 3-bromo-7-azabicyclo[2.2.1]hepta-2,5-diene-2,7-dicarboxylate (97 g, 0.294 mol) is added to 10% Pd/C (6.8g) in 900 ml absolute EtOH in a PARR bottle. The suspension is diluted with a solution of NaHCO3 (25 g, 0.301 mol) in 250 ml water and the mixture is hydrogenated at 50 PSI for 2.5 h. The catalyst is removed by filtration, is washed with fresh EtOH, and the filtrate is concentrated in vacuo to give a residue. The residue is partitioned between 1xc3x97200 ml saturated NaHCO3 and CH2Cl2 (4xc3x97100 ml). The combined organic layer is dried over 1:1 anhydrous K2CO3/anhydrous MgSO4 and concentrated in vacuo to afford 72.8 g (98%) of (+/xe2x88x92) endo-7-tert-butyl 2-methyl 7-azabicyclo[2.2.1]heptane-2,7-dicarboxylate. MS (EI) for C14H22O4, m/z: 255 (M)+.
Preparation of (+/xe2x88x92) exo-7-(tert-butoxycarbonyl)-7-azabicyclo[2.2.1]heptane-2-carboxylic acid.
(+/xe2x88x92)Endo-7-tert-butyl 2-methyl 7-azabicyclo[2.2.1]heptane-2,7-dicarboxylate (72.8 g, 0.285 mol) is dissolved in 1000 ml dry MeOH in a dried flask under nitrogen. The solution is treated with solid NaOMe (38.5 g, 0.713 mol) neat, in a single lot and the reaction is warmed to reflux for 4h. The mixture is cooled to 0xc2x0 C., is treated with 400 ml water, and the reaction is stirred 1 h as it warms to RT. The mixture is concentrated in vacuo to about 400 ml and the pH of the aqueous residue is adjusted to 4.5 with 12N HCl. The precipitate is collected and dried. The tan, slightly tacky solid is washed with 2xc3x97100 ml 60% ether in hexane and is dried to provide 47 g (68%) of (+/xe2x88x92) exo-7-(tert-butoxycarbonyl)-7-azabicyclo[2.2.1]heptane-2-carboxylic acid as an off-white powder. HRMS (FAB) calc""d for C12H19NO4+H: 242.1392, found 242.1390 (M+H)+.
Preparation of (+/xe2x88x92) exo-tert-butyl 2-{[(benzyloxy)carbonyl]amino}-7-azabicyclo[2.2.1]heptane-7-carboxylate.
(+/xe2x88x92)Exo-7-(tert-butoxycarbonyl)-7-azabicyclo[2.2.1]heptane-2-carboxylic acid (103.9 g, 0.430 mol) is combined with TEA (60 ml, 0.430 mol) in 1200 ml dry toluene in a dry flask under nitrogen. The solution is treated drop-wise with diphenylphosphoryl azide (92.8 ml, 0.430 mol), and is allowed to stir for 20 min at RT. The mixture is treated with benzyl alcohol (47.9 ml, 0.463 mol), and the reaction is stirred overnight at 55xc2x0 C. The mixture is cooled, is extracted successively with 2xc3x97500 ml 5% citric acid, 2xc3x97500 ml water, 2xc3x97500 ml saturated sodium bicarbonate, and 500 ml saturated NaCl. The organic layer is dried over anhydrous MgSO4 and concentrated in vacuo to an amber oil. The crude material is chromatographed over 900 g silica gel (230-400 mesh), eluting with 10-30% EtOAc/hexane. The appropriate fractions are combined and concentrated to give 106 g (71%) of (+/xe2x88x92) exo-tert-butyl 2-{[(benzyloxy)carbonyl]amino }-7-azabicyclo[2.2.1]heptane-7-carboxylate as a pale oil. 1H NMR (CDCl3) xcex4 1.29-1.60, 1.44, 1.62-2.01, 3.76-3.88, 4.10, 4.24, 5.10, 7.36 ppm.
Preparation of (+/xe2x88x92) exo-tert-butyl 2-amino-7-azabicyclo[2.2.1]heptane-7-carboxylate.
(+/xe2x88x92) Exo-tert-Butyl 2-{[(benzyloxy)carbonyl]amino}-7-azabicyclo[2.2.1]heptane-7-carboxylate (1.5 g, 4.33 mmol) is combined with 10% Pd/C (150 mg) in 40 ml EtOH in a 250 ml Parr shaker bottle. The mixture is hydrogenated at 50 PSI for 1.5 h. The catalyst is removed by filtration and the filtrate is concentrated in vacuo. The crude material is chromatographed over 30 g silica gel (230-400 mesh), eluting with 7% MeOH/CH2Cl2+1% conc. NH4OH. The appropriate fractions are combined and concentrated to provide 606 mg (66%) of (+/xe2x88x92) exo-tert-butyl 2-amino-7-azabicyclo[2.2.1]heptane-7-carboxylate. HRMS (FAB) calcd for C11H20N2O2+H: 213.1603, found 213.1580 (M+H)+. This racemic mixture will be referenced as (+/xe2x88x92)-7-aza-[2.2.1]-Amine.
Resolution of racemic carboxylate mixture:
The isolated (+/xe2x88x92) exo-tert-butyl 2-{[(benzyloxy)carbonyl]amino}-7-azabicyclo[2.2.1]heptane-7-carboxylate is resolved via preparative chiral HPLC (50xc3x97500 mm Chiralcel OJ column, 30 deg. C, 70 m/min. 10/90 (v/v) isopropanol/heptane). The resolution affords 40 g of tert-butyl (1S,2R,4R)-(+)-2{[(benzyloxy)carbonyl]amino}-7-azabicyclo[2.2.1]heptane-7-carboxylate and 42 g of tert-butyl-(1R,2S,4S)(xe2x88x92)-2{[(benzyloxy)carbonyl]amino}-7-azabicyclo[2.2.1]heptane-7-carboxylate.
The 2R enantiomer is triturated with 40 ml ether followed by 40 ml hexane (to remove lingering diastereo and enantiomeric impurities) and is dried to afford 30 g (56%) of purified tert-butyl (1S,2R,4R)-(+)-2{[(benzyloxy)carbonyl]amino}-7-azabicyclo[2.2.1]heptane-7-carboxylate with 99% enantiomeric excess. MS (EI) for C)19H26N2O4, m/z: 346 (M)+. [xcex1]25D=22, (c 0.42, chloroform).
The 2S enantiomer is triturated with 40 ml ether followed by 40 ml hexane to give 35 g (66%) of purified tert-butyl (1R,2S,4S)-(xe2x88x92)-2{[(benzyloxy)carbonyl]amino}-7-azabicyclo[2.2.1]heptane-7-carboxylate with 99% enantiomeric excess. MS (EI) for C19H26N2O4, m/z: 346 (M)+. [xcex1]25D=xe2x88x9223, (c 0.39, chloroform).
Preparation of tert-butyl-(1S,2R,4R)-(+)-2-amino-7-azabicyclo[2.2.1]heptane-7-carboxylate ((2R)-7-aza-[2.2.1]-Amine).
tert-Butyl (1S,2R,4R)-(+)-2{[(benzyloxy)carbonyl]amlno}-7-azabicyclo[2.2.1]heptane-7-carboxylate (9.5 g, 27.4 mmol) is combined with 950 mg 10% Pd/C in 75 ml absolute EtOH in a 500 ml Parr bottle. The reaction mixture is hydrogenated at 50 PSI for 3h, the catalyst is removed by filtration, and the filter cake is washed with MeOH. The filtrate is concentrated in vacuo to give 6.4 g of a residue. The crude material is chromatographed over 200 g silica gel (230-400 mesh) eluting with 7% CH3OH/CHCl3 containing 1% conc. NH4OH. The appropriate fractions are combined and concentrated to give 5.61 g (96%) of tert-butyl-(1S,2R,4R)-(+)-2-amino-7-azabicyclo[2.2.1]heptane-7-carboxylate as a pale oil. MS (EI) for C11H20N2O2, m/z: 212 (M)+. [xcex1]25D=9, (c 0.67, CHCl3). This wil referenced as (2R)-7-aza-[2.2.1]-Amine.
Preferably, when Q is furan, oxazole, oxadiazole, pyrrole, 5-thiazole, thiophene, or triazole, the acid is activated with a uronium salt, preferably HATU (see J. Am. Chem. Soc., 4397 (1993)), in the presence of a base such as DIEA in DMF, and reacted directly with (2R)-7-aza-[2.2.1]-Amine to afford the desired amides. In the case where Q is a 2-thiazole, or 2-oxazole, the amide bond is formed by the reaction of the amine and ester (Lv=OEt) in an alcoholic solvent (see Liebigs Ann. Chem., 1216-1231 (1980)).
It will be apparent to those skilled in the art that the requisite carboxylic acids can be obtained commercially or can be synthesized by known procedures. Certain thiophene acids can be synthesized from the corresponding aldehydes by oxidation with NaClO2 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. The reaction works best if heated at reflux in THF/water for 24 hours.
Other thiophene acids are synthesized from the corresponding esters by base catalyzed hydrolysis. Typical hydrolysis procedures are well known in the art. Preferably, 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.
Furan examples are prepared in a convergent means by a direct palladium catalyzed Suzuki coupling N-[(2R)-7-azabicyclo[2.2.2]hept-2-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.
The 1,3-oxazole-2-carboxylate intermediates can be prepared by the method described in J. Pharm. Sci. Japan 305-7, (1956).

Substituted-heteroaryl-7-aza[2.2.1]bicycloheptanes for the treatment of disease

Abstract: wherein R1, R2, R4, R6, X, and W are defined herein. These compounds may be in the form of pharmaceutical salts or compositions, may be in pure enantiomeric form or racemic mixtures, and are useful in pharmaceuticals used to treat diseases or conditions in which xcex17 is known to be involved.