What we claim is:
1. A method of leak detection in a closed vapor handling system of an automotive vehicle, wherein an engine is shut off, comprising:
obtaining a start temperature and start pressure;
providing an evaluation temperature;
calculating a temperature differential between the start temperature and the evaluation temperature;
incrementing a time counter if the temperature differential is greater than a temperature control value;
computing a pressure differential between the start pressure and an evaluation pressure; and comparing the time counter to a time control value if the pressure differential is not greater than a pressure control value.
2. The method of claim 1 further comprising:
closing a shut off valve.
3. The method of claim 1 further comprising:
providing a pressure sensing element.
4. The method of claim 3 wherein the providing comprises:
using a differential tank pressure sensor that supplies differential pressure.
5. The method of claim 3 wherein the providing comprises:
using a switch that moves at a given relative vacuum.
6. The method of claim 3 wherein the providing comprises:
using a pair of switches that move at different relative vacuums having a low vacuum threshold.
7. The method of claim 1 further comprising:
providing a temperature sensing element.
8. The method of claim 7 wherein the providing comprises:
using a temperature sensor.
9. The method of claim 7 wherein the providing comprises:
using a transducer that supplies differential temperature.
10. The method of claim 7 wherein the providing comprises:
using a model based on induction air temperature and engine coolant temperature with a statistical treatment.
11. The method of claim 1 further comprising:
setting the time counter to zero if the temperature differential is less than or equal to the temperature control value.
12. The method of claim 1 further comprising:
determining whether the engine is off.
13. The method of claim 1 further comprising:
providing an engine management system to receive pressure and temperature signals from a pressure sensing element and a temperature sensing element.
14. The method of claim 1 wherein the comparing comprises:
determining a leak condition if the time counter is greater than the time control value.
15. The method of claim 14 wherein the determining comprises:
detecting a leak of about 0.5 millimeter.
16. The method of claim 14 wherein the determining comprises:
detecting a leak of about 1 millimeter.
17. The method of claim 14 wherein the computing comprises:
determining a no leak condition if the pressure differential is greater than the pressure control value.
18. The method of claim 1 further comprising:
comparing the temperature differential to the temperature control value; and
comparing the pressure differential to the pressure control value.
19. The method of claim 1 further comprising:
providing a vacuum detection component having a temperature sensing element, a pressure sensing element and a control valve.
20. A method of leak detection in a closed vapor handling system of an automotive vehicle, wherein an engine is shut off, comprising:
determining whether the engine is off;
closing a shut off valve;
providing a pressure sensing element, a temperature sensing element, and an engine management system to receive pressure and temperature signals from the pressure sensing element and temperature sensing element;
obtaining a start temperature and start pressure;
providing an evaluation temperature;
calculating a temperature differential between the start temperature and the evaluation temperature;
comparing the temperature differential to a temperature control value;
incrementing a time counter if the temperature differential is greater than the temperature control value;
setting the time counter to zero if the temperature differential is less than or equal to the temperature control value;
computing a pressure differential between the start pressure and an evaluation pressure;
comparing the pressure differential to a pressure control value; and
comparing the time counter to a time control value if the pressure differential is not greater than the pressure control value.
21. An automotive evaporative leak detection system comprising:
a pressure sensing element;
a temperature sensing element; and
a processor operatively coupled to the pressure sensing element and the temperature sensing element and receiving, respectively, pressure and temperature signals therefrom;
wherein the processor calculates a temperature differential between a start temperature and an evaluation temperature, increments a time counter, computes a pressure differential between a start pressure and an evaluation pressure, and compares a time counter to the time control value.
22. The system of claim 21 wherein the pressure sensing element is in fluid communication with fuel tank vapor.
23. The system of claim 21 wherein the temperature sensing element is in thermal contact with fuel tank vapor.
24. The system of claim 21 wherein the processor is in communication with the pressure sensing element and the temperature sensing element.
25. The system of claim 21 wherein the processor compares the temperature differential to a temperature control value and compares the pressure differential to a pressure control value.
26. The system of claim 21 wherein the temperature sensing element comprises a temperature sensor mounted on a fuel tank.
27. The system of claim 21 wherein the pressure sensing element comprises a switch that moves at a given relative vacuum.
28. The system of claim 21 wherein the pressure sensing element comprises a pair of switches that move at different relative vacuums having a low vacuum threshold.
29. The system of claim 21 wherein the pressure sensing element comprises a differential tank pressure sensor located on a conduit between a fuel tank and a canister.
30. The system of claim 21 wherein the temperature sensing element comprises a transducer that supplies differential temperature.
31. The system of claim 21 wherein the temperature sensing element comprises a model based on induction air temperature and engine coolant temperature with a statistical treatment.
32. The system of claim 21 wherein the temperature sensing element and pressure sensing element are located within a vacuum detection component, having a shut off valve, operatively coupled to the processor.
33. The system of claim 21 further comprising:
a fuel tank communicating with an engine, the temperature sensing element mounted on the fuel tank;
a canister communicating with the fuel tank, the engine and an atmosphere, the pressure sensing element located between the fuel tank and the canister;
a shut off valve operatively coupled to the processor and located between the canister and the atmosphere; and
a control valve operatively coupled to the processor and located between the canister and the engine;
wherein the processor opens and closes the shut off valve and the control valve.
34. An automotive evaporative leak detection system comprising:
a differential tank pressure sensor located on a conduit between a fuel tank and a canister, the canister communicating with an engine and an atmosphere, the fuel tank communicating with the engine;
a temperature sensor mounted on the fuel tank;
a shut off valve located between the canister and the atmosphere;
a control valve located between the canister and the engine; and
a processor operatively coupled to the shut off valve, the control valve, the pressure sensor and the temperature sensor, the processor receiving pressure and temperature signals from the pressure and temperature sensors, respectively;
wherein the processor opens and closes the shut off valve and control valve, calculates a temperature differential between a start temperature and an evaluation temperature, increments a time counter, computes a pressure differential between a start pressure and an evaluation pressure, and compares the time counter to a time control value.
The claims below are in addition to those above.
All refrences to claim(s) which appear below refer to the numbering after this setence.
What is claimed:
1. A compound of the Formula I:
58
wherein X is O, or S;
Each R1 is H, alkyl, cycloalkyl, halogenated alkyl, substituted phenyl, or substituted naphthyl;
Azabicyclo is
59
R0 is H, lower alkyl, substituted lower alkyl, or halogenated lower alkyl;
Each R2 is independently alkyl, cycloalkyl, substituted phenyl, or substituted naphthyl, or R2 is absent provided that k2, k5, or k6 is 0;
k2 is 0 or 1;
k5 and k6 are independently 0, 1, or 2;
R2-3 is H, alkyl, halogenated alkyl, substituted alkyl, F, Cl, Br, or I;
W0 is a bicyclic moiety and is
60
W is C(H) where
VZY is selected from OC(R3)N, OC(R5)2N(R4), OC(R5)2S, ONC(R5), OC(R5)(R8)O, OC(R5)2O, C(R5)2OC(R5)2, SC(R3)N, SC(R5)2N(R4), SNC(R5), NC(R3)O, NC(R3)S, NC(R3)N(R4), N(R4)NC(R5), N(R4)C(R5)2O, N(R4)C(R5)2S, N(R4)C(R5)2N(R4), C(R5)2ON(R4), C(R5)2SC(R5)2, C(R5)2N(R4)C(R5)2, C(R5)2N(R4)O, C(R5)2N(R4)S, C(R5)NO, C(R5)NS, C(R5)NN(R4), C(R5)(R17)C(R3)(R17)C(R5)(R17), or C(R5)2C(R3)(R5)C(R5)2;
W is N where
VZY is selected from OC(R3)N, OC(R5)2N(R4), OC(R5)2S, ONC(R5) OC(R5)2O, SC(R3)N, SC(R5)2N(R4), SNC(R5), NC(R3)O, NC(R3)S, NC(R3)N(R4), N(R4)NC(R3), N(R4)C(R5)2O, N(R4)C(R5)2S, N(R4)C(R5)2N(R4), C(R5)2ON(R4), C(R5)2N(R4)O, C(R5)2N(R4)S, C(R5)NO, C(R5)NS, C(R3)NN(R4), C(R5)C(R3)O, C(R5)C(R3)S, C(R5)C(R5)N(R4), C(R5)C(R5)C(R5)2, or C(R5)2C(R3)(R5)C(R5)2;
W1, W2, W3, and W4 are each independently N or C(R21), provided that no more than two of W1, W2, W3, and W4 are N and further provided when more than two of W1, W2, W3, and W4 are C(R21) that no more than two R21 are other than H;
J is N(R23), S, or O;
Q is N(R19), O, or S;
Each R3 is independently H, F, Cl, Br, I, alkyl, halogenated alkyl, substituted alkyl, cycloalkyl, lactam heterocycloalkyl, phenoxy, substituted phenoxy, R7, R9, N(R4)-aryl, N(R4)-halogenated phenyl, N(R4)-halogenated naphthyl, O-halogenated phenyl, O-substituted phenyl, O-halogenated naphthyl, O-substituted naphthyl, S-halogenated phenyl, S-substituted phenyl, S-halogenated naphthyl, S-substituted naphthyl, or alkyl substituted on the carbon with R15 where said carbon is determined by counting the longest carbon chain of the alkyl moiety with the C-1 carbon being the carbon attached to the bicyclic moiety W0 and the carbon being the carbon furthest, e.g., separated by the greatest number of carbon atoms in the chain, from said C-1 carbon;
Each R4 is H, or alkyl;
Each R5 is independently H, F, alkyl, substituted alkyl, halogenated alkyl, alkenyl, substituted alkenyl, halogenated alkenyl, alkynyl, substituted alkynyl, halogenated alkynyl, cycloalkyl, C(O)NH2, CO2R1, or aryl;
R6 is H, F, Br, I, Cl, CN, CF3, OR16, SR16, or N(R16)2;
R7 is 5-membered heteroaromatic mono-cyclic moieties containing within the ring 1-3 heteroatoms independently selected from the group consisting of O, N, N(R19), and S, and having 0-1 substituent selected from R20 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 and having the formula
61
wherein A1 is O, S, or NR19,
wherein A is CR18 or N, A2 and A3 are independently selected from CR18, C(R18)2, O, S, N, or NR19, provided that both A2 and A3 are not simultaneously O, simultaneously S, or simultaneously O and S, or
62
wherein A2 and A3 are independently selected from CR18, C(R18)2, O, S, N, or NR19, and A is CR18 or N, each 9-membered fused-ring moiety having 0-1 substituent selected from R20 and further having 0-3 substituent(s) independently selected from F, Cl, Br, or I, and having a bond directly or indirectly attached to the core molecule where valency allows in either the 6-membered or the 5-membered ring of the fused-ring moiety;
Each R8 is independently F, alkyl, substituted alkyl, halogenated alkyl, alkenyl, substituted alkenyl, halogenated alkenyl, alkynyl, substituted alkynyl, halogenated alkynyl, cycloalkyl, C(O)NH2, CO2R1, or aryl;
R9 is 6-membered heteroaromatic mono-cyclic moieties containing within the ring 1-3 heteroatoms selected from N and having 0-1 substituent selected from R20 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 N, including, but not limited to, quinolinyl or isoquinolinyl, each 10-membered fused-ring moiety having 0-1 substituent selected from R20 and 0-3 substituent(s) independently selected from F, Cl, Br, or I and having a bond directly or indirectly attached to the core molecule where valency allows;
Each R10 is independently H, alkyl, cycloalkyl, heterocycloalkyl, 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, phenyl, or substituted phenyl;
Each R11 is independently H, alkyl, cycloalkyl, heterocycloalkyl, halogenated alkyl, halogenated cycloalkyl, or halogenated heterocycloalkyl;
R13 is OR11, SR11, N(R11)2, C(O)R11, C(O)NR11R11, CN, CF3, NR11C(O)R11, S(O)2N(R11)2, NR11S(O)2R11, or NO2;
R15 is aryl, R7, or R9;
R16 is H, alkyl, substituted alkyl, cycloalkyl, halogenated alkyl, substituted phenyl, or substituted naphthyl;
One of R17 is H, alkyl, substituted alkyl, halogenated alkyl, alkenyl, substituted alkenyl, halogenated alkenyl, alkynyl, substituted alkynyl, halogenated alkynyl, CN, F, Br, Cl, I, OR1, C(O)NH2, NHR1, SR1, CO2R1, aryl, R7, or R9, and each of the other two R17 is independently alkyl, substituted alkyl, halogenated alkyl, alkenyl, substituted alkenyl, halogenated alkenyl, alkynyl, substituted alkynyl, halogenated alkynyl, CN, F, Br, Cl, I, OR1, C(O)NH2, NHR1, SR1, CO2R1, aryl, R7, or R9;
Each R18 is independently selected from H, alkyl, cycloalkyl, heterocycloalkyl, halogenated alkyl, halogenated cycloalkyl, halogenated heterocycloalkyl, substituted alkyl, substituted cycloalkyl, substituted heterocycloalkyl, OR11, SR11, NR11R11, C(O)R11, NO2, C(O)N(R11)2, CN, NR11C(O)R11, S(O)2N(R11)2, F, Cl, Br, or I, NR11S(O)2R11, or a bond directly or indirectly attached to the core molecule, provided that there is only one said bond to the core molecule within the 9-membered fused-ring moiety, further provided that the fused-ring moiety has 0-1 substituent selected from alkyl, cycloalkyl, heterocycloalkyl, halogenated alkyl, halogenated cycloalkyl, halogenated heterocycloalkyl, substituted alkyl, substituted cycloalkyl, substituted heterocycloalkyl, OR11, SR11, NR11R11, C(O)R11, NO2, C(O)NR11R11, CN, NR11C(O)R11, S(O)2NR11R11, or NR11S(O)2R11, and further provided that the fused-ring moiety has 0-3 substituent(s) selected from F, Cl, Br, or I;
R19 is H, alkyl, halogenated alkyl, substituted alkyl, cycloalkyl, halogenated cycloalkyl, substituted cycloalkyl, phenyl, or phenyl having 1 substituent selected from R20 and further having 0-3 substituents independently selected from F, Cl, Br, or I;
R20 is alkyl, cycloalkyl, heterocycloalkyl, halogenated alkyl, halogenated cycloalkyl, halogenated heterocycloalkyl, OR11, SR11, NR11R11, C(O)R11, C(O)NR11R11, CN, NR11C(O)R11, S(O)2NR11R11, NR11S(O)2R11, NO2, alkyl substituted with 1-4 substituent(s) independently selected from F, Cl, Br, I, or R13, cycloalkyl substituted with 1-4 substituent(s) independently selected from F, Cl, Br, I, or R13, or heterocycloalkyl substituted with 1-4 substituent(s) independently selected from F, Cl, Br, I, or R13;
R2 is H, F, Cl, Br, I, alkyl, substituted alkyl, halogenated alkyl, cycloalkyl, CN, NR22R22, OR22, or SR22;
Each R22 is independently H, alkyl, substituted alkyl, cycloalkyl, halogenated alkyl, substituted cycloalkyl, heterocycloalkyl, or substituted heterocycloalkyl;
R23 is alkyl, halogenated alkyl, substituted alkyl, cycloalkyl, halogenated cycloalkyl, substituted cycloalkyl, heterocycloalkyl, halogenated heterocycloalkyl, substituted heterocycloalkyl, substituted phenyl, naphthyl, substituted naphthyl, R7, or R9;
or a pharmaceutically acceptable salt thereof.
2. The compound of claim 1, wherein X is O.
3. The compound of claim 2, wherein R1 is H, alkyl, or cycloalkyl.
4. The compound of claim 3, wherein W0 is (a).
5. The compound of claim 4, wherein (a) is 1,3-oxazolo4,5-cpyridin-6-yl, 1,3-oxazolo5,4-cpyridin-6-yl, 1,3-dioxolo4,5-cpyridin-6-yl, 1,3-benzoxazol-5-yl, 1,3-benzoxazol-6-yl, 1,2-benzisothiazol-5-yl, 1,2-benzisothiazol-6-yl, 1,3-thiazolo4,5-cpyridin-6-yl, 1,3-thiazolo5,4-cpyridin-6-yl, 1,3-benzothiazol-5-yl, 1,3-benzothiazol-6-yl, 1,3-benzodioxol-5-yl, 1H-benzimidazole-5-yl, 1H-indazol-5-yl, 1H-indazol-6-yl, or indan-5-yl, any of which is optionally substituted with lower cycloalkyl or lower alkyl optionally substituted with to 4 halogens, and further optionally substituted with up to 1 substituent selected from OR10, N(R10)2, C(O)NR10R10, CN, NR10C(O)R10, NR10S(O)2R10, wherein each R10 is independently selected from lower alkyl or halogenated lower alkyl.
6. The compound of claim 5, wherein Azabicyclo is I, II, V, or VI.
7. The compound of claim 6, wherein each k2, k5, and k6 is independently 0 or 1.
8. The compound of claim 7, wherein R2 is alkyl, or R2 is absent provided that Azabicyclo is II, V or VI and further provided that k2, k5, and k6 are 0.
9. The compound of claim 8, wherein R1 is H or lower alkyl, and wherein R2 is lower alkyl or is absent provided that k2, k5, or k6 is 0.
10. The compound of claim 9, wherein the compound is
N-(exo-4(S)-1-azabicyclo2.2.1hept-3-yl)-1,3-benzoxazole-5-carboxamide;
N-(exo-4(S)-1-azabicyclo2.2.1hept-3-yl)-1,3-benzothiazole-6-carboxamide;
N-(exo-4S)-1-azabicyclo2.2.1hept-3-yl-indane-5-carboxamide;
N-(exo-4(S)-1-azabicyclo2.2.1hept-3-yl)-1,3-benzodioxole-5-carboxamide;
N-(exo-4S)-1-azabicyclo2.2.1hept-3-yl-1H-indazole-5-carboxamide;
N-(exo-4S)-1-azabicyclo2.2.1hept-3-yl-1H-indazole-6-carboxamide;
N-(exo-4S)-1-azabicyclo2.2.1hept-3-yl-1,3-dioxolo4,5-cpyridine-6-carboxamide;
N-(3R,5R)-1-azabicyclo3.2.1oct-3-yl-1,3-benzothiazole-6-carboxamide; or a pharmaceutically acceptable salt thereof, provided that the compound is the pure enantiomer or racemic mixture thereof.
11. The compound of claim 9, wherein the compound is
N-(1-(6-methyl)-azabicyclo2.2.2oct-3-yl)-1,3-benzoxazole-5-carboxamide;
N-(1-(6-methyl)-azabicyclo2.2.2oct-3-yl)-2-methyl-1,3-benzoxazole-5-carboxamide;
N-(1-(6-methyl)-azabicyclo2.2.2oct-3-yl)-1,3-benzoxazole-6-carboxamide;
N-(1-(6-methyl)-azabicyclo2.2.2oct-3-yl)-2-methyl-1,3-benzoxazole-6-carboxamide;
N-(1-(6-methyl)-azabicyclo2.2.2oct-3-yl)-1,3-benzothiazole-6-carboxamide;
N-(1-(6-methyl)-azabicyclo2.2.2oct-3-yl)indane-5-carboxamide;
N-(1-(6-methyl)-azabicyclo2.2.2oct-3-yl)-1,3-benzodioxole-5-carboxamide;
N-(1-(6-methyl)-azabicyclo2.2.2oct-3-yl)-1,3-oxazolo5,4-cpyridine-6-carboxamide;
N-(1-(6-methyl)-azabicyclo2.2.2oct-3-yl)-1H-indazole-5-carboxamide;
N-(1-(6-methyl)-azabicyclo2.2.2oct-3-yl)-1H-indazole-6-carboxamide;
N-(1-(6-methyl)-azabicyclo2.2.2oct-3-yl)-1,3-dioxolo4,5-cpyridine-6-carboxamide;
N-(exo-4(S)-1-azabicyclo2.2.1hept-3-yl)-2-methyl-1,3-benzoxazole-5-carboxamide;
N-(exo-4(S)-1-azabicyclo2.2.1hept-3-yl)-1,3-benzoxazole-6-carboxamide;
N-(exo-4(S)-1-azabicyclo2.2.1hept-3-yl)-2-methyl-1,3-benzoxazole-6-carboxamide;
N-exo-4(S)-1-azabicyclo2.2.1hept-3-yl-1,3-oxazolo5,4-cpyridine-6-carboxamide;
N-(exo-4(S)-1-(6-methyl)-azabicyclo2.2.1hept-3-yl)-1,3-benzoxazole-5-carboxamide;
N-(exo-4(S)-1-(6-methyl)-azabicyclo2.2.1hept-3-yl)-2-methyl-1,3-benzoxazole-5-carboxamide;
N-(exo-4(S)-1-(6-methyl)-azabicyclo2.2.1hept-3-yl)-1,3-benzoxazole-6-carboxamide;
N-(exo-4(S)-1-(6-methyl)-azabicyclo2.2.1hept-3-yl)-2-methyl-1,3-benzoxazole-6-carboxamide;
N-(exo-4(S)-1-(6-methyl)-azabicyclo2.2.1hept-3-yl)-1,3-benzothiazole-6-carboxamide;
N-(exo-4(S)-1-(6-methyl)-azabicyclo2.2.1hept-3-yl)indane-5-carboxamide;
N-(exo-4(S)-1-(6-methyl)-azabicyclo2.2.1hept-3-yl)-1,3-benzodioxole-5-carboxamide;
N-(exo-4(S)-1-(6-methyl)-azabicyclo2.2.1hept-3-yl)-1,3-oxazolo5,4-cpyridine-6-carboxamide;
N-(exo-4(S)-1-(6-methyl)-azabicyclo2.2.1hept-3-yl)-1H-indazole-5-carboxamide;
N-(exo-4(S)-1-(6-methyl)-azabicyclo2.2.1hept-3-yl)-1H-indazole-6-carboxamide;
N-(exo-4(S)-1-(6-methyl)-azabicyclo2.2.1hept-3-yl)-1,3-dioxolo4,5-cpyridine-6-carboxamide;
N-(3R,5R)-1-azabicyclo3.2.1oct-3-yl-1,3-benzoxazole-5-carboxamide;
N-(3R,5R)-1-azabicyclo3.2.1oct-3-yl-2-methyl-1,3-benzoxazole-5-carboxamide;
N-(3R,5R)-1-azabicyclo3.2.1oct-3-yl-1,3-benzoxazole-6-carboxamide;
N-(3R,5R)-1-azabicyclo3.2.1oct-3-yl-2-methyl-1,3-benzoxazole-6-carboxamide;
N-(3R,5R)-1-azabicyclo3.2.1oct-3-ylindane-5-carboxamide;
N-(3R,5R)-1-azabicyclo3.2.1oct-3-yl-1,3-benzodioxole-5-carboxamide;
N-(3R,5R)-1-azabicyclo3.2.1oct-3-yl-1,3-oxazolo5,4-cpyridine-6-carboxamide;
N-(3R,5R)-1-azabicyclo3.2.1oct-3-yl-1H-indazole-5-carboxamide;
N-(3R,5R)-1-azabicyclo3.2.1oct-3-yl-1H-indazole-6-carboxamide;
N-(3R,5R)-1-azabicyclo3.2.1oct-3-yl-1,3-dioxolo4,5-cpyridine-6-carboxamide;
N-((3R)-1-azabicyclo3.2.2nonan-3-yl)-1,3-benzoxazole-5-carboxamide;
N-((3R)-1-azabicyclo3.2.2nonan-3-yl)-1,3-benzothiazole-6-carboxamide;
N-((3R)-1-azabicyclo3.2.2nonan-3-yl)indane-5-carboxamide;
N-((3R)-1-azabicyclo3.2.2nonan-3-yl)-1,3-benzodioxole-5-carboxamide;
N-(3R)-1-azabicyclo3.2.2nonan-3-yl-1H-indazole-6-carboxamide;
N-(3R)-1-azabicyclo3.2.2nonan-3-yl-1,3-dioxolo4,5-cpyridine-6-carboxamide;
or a pharmaceutically acceptable salt thereof, provided that the compound is the pure enantiomer or racemic mixture thereof.
12. The compound of claim 9, wherein the compound is
N-exo-4(S)-1-azabicyclo2.2.1hept-3-yl-1,2-benzisothiazole-6-carboxamide;
N-exo-4(S)-1-azabicyclo2.2.1hept-3-yl-1,2-benzisothiazole-5-carboxamide;
N-(3R,5R)-1-azabicyclo3.2.1oct-3-yl-1H-indazole-5-carboxamide;
N-(3R,5R)-1-azabicyclo3.2.1oct-3-yl-3-methyl-1H-indazole-6-carboxamide;
N-(3R,5R)-1-azabicyclo3.2.1oct-3-yl-3-methyl-1H-indazole-5-carboxamide;
N-(3R,5R)-1-azabicyclo3.2.1oct-3-yl-3-ethyl-1H-indazole-6-carboxamide;
N-(3R,5R)-1-azabicyclo3.2.1oct-3-yl-3-ethyl-1H-indazole-5-carboxamide;
N-(3R,5R)-1-azabicyclo3.2.1oct-3-yl-1,2-benzisothiazole-6-carboxamide;
N-(3R,5R)-1-azabicyclo3.2.1oct-3-yl-1,2-benzisothiazole-5-carboxamide;
N-(3R,5R)-1-azabicyclo3.2.1oct-3-yl-3-ethyl-1,2-benzisothiazole-6-carboxamide;
N-(3R,5R)-1-azabicyclo3.2.1oct-3-yl-3-ethyl-1,2-benzisothiazole-5-carboxamide;
N-(3R,5R)-1-azabicyclo3.2.1oct-3-yl-3-methyl-1,2-benzisothiazole-6-carboxamide;
N-(3R,5R)-1-azabicyclo3.2.1oct-3-yl-3-methyl-1,2-benzisothiazole-5-carboxamide;
N-(3R,5R)-1-azabicyclo3.2.1oct-3-yl-2-cyclopropyl-1,3-benzoxazole-6-carboxamide;
N-(3R,5R)-1-azabicyclo3.2.1oct-3-yl-2-cyclopropyl-1,3-benzoxazole-5-carboxamide;
N-(3R,5R)-1-azabicyclo3.2.1oct-3-yl-2-cyclopropyl-1,3-benzothiazole-6-carboxamide;
N-(3R,5R)-1-azabicyclo3.2.1oct-3-yl-2-cyclopropyl-1,3-benzothiazole-5-carboxamide;
N-(3R,5R)-1-azabicyclo3.2.1oct-3-yl-2-methyl-1,3-benzothiazole-6-carboxamide;
N-(3R,5R)-1-azabicyclo3.2.1oct-3-yl-2-methyl-1,3-benzothiazole-5-carboxamide;
N-(3R,5R)-1-azabicyclo3.2.1oct-3-yl-2-ethyl-1,3-benzothiazole-6-carboxamide;
N-(3R,5R)-1-azabicyclo3.2.1oct-3-yl-2-ethyl-1,3-benzothiazole-5-carboxamide;
N-(3R,5R)-1-azabicyclo3.2.1oct-3-yl-2-methyl-1,3-benzodioxole-5-carboxamide;
N-(3R,5R)-1-azabicyclo3.2.1oct-3-yl-2-ethyl-1,3-benzodioxole-5-carboxamide;
N-(3R,5R)-1-azabicyclo3.2.1oct-3-yl-2,2-dimethyl-1,3-benzodioxole-5-carboxamide;
N-(3R,5R)-1-azabicyclo3.2.1oct-3-yl-1H-benzimidazole-5-carboxamide;
N-(3R,5R)-1-azabicyclo3.2.1oct-3-yl-1,3-thiazolo5,4-cpyridine-6-carboxamide;
N-(3R,5R)-1-azabicyclo3.2.1oct-3-yl-1,3-thiazolo4,5-cpyridine-6-carboxamide;
N-(3R,5R)-1-azabicyclo3.2.1oct-3-yl-1,3-dioxolo4,5-cpyridine-6-carboxamide;
N-(3R,5R)-1-azabicyclo3.2.1oct-3-yl-1,3-oxazolo4,5-cpyridine-6-carboxamide;
or a pharmaceutically acceptable salt thereof, provided that the compound is the pure enantiomer or racemic mixture thereof.
13. The compound of claim 5, wherein Azabicyclo is III, or IV.
14. The compound of claim 13, wherein R2-3 is H, or alkyl.
15. The compound of claim 14, wherein the compound is
N-(2-azabicyclo2.2.1hept-5-yl)-1,3-benzoxazole-5-carboxamide;
N-(2-azabicyclo2.2.1hept-5-yl)-2-methyl-1,3-benzoxazole-5-carboxamide;
N-(2-azabicyclo2.2.1hept-5-yl)-1,3-benzoxazole-6-carboxamide;
N-(2-azabicyclo2.2.1hept-5-yl)-2-methyl-1,3-benzoxazole-6-carboxamide;
N-(2-azabicyclo2.2.1hept-5-yl)-1,3-benzothiazole-6-carboxamide;
N-(2-azabicyclo2.2.1hept-5-yl)indane-5-carboxamide;
N-(2-azabicyclo2.2.1hept-5-yl)-1,3-benzodioxole-5-carboxamide;
N-(2-azabicyclo2.2.1hept-5-yl)-1,3-oxazolo5,4-cpyridine-6-carboxamide;
N-(2-azabicyclo2.2.1hept-5-yl)-1H-indazole-5-carboxamide;
N-(2-azabicyclo2.2.1hept-5-yl)-1H-indazole-6-carboxamide;
N-(2-azabicyclo2.2.1hept-5-yl)-1,3-dioxolo4,5-cpyridine-6-carboxamide;
N-(2-azabicyclo2.2.1hept-6-yl))-1,3-benzoxazole-5-carboxamide;
N-(2-azabicyclo2.2.1hept-6-yl))-2-methyl-1,3-benzoxazole-5-carboxamide;
N-(2-azabicyclo2.2.1hept-6-yl))-1,3-benzoxazole-6-carboxamide;
N-(2-azabicyclo2.2.1hept-6-yl))-2-methyl-1,3-benzoxazole-6-carboxamide;
N-(2-azabicyclo2.2.1hept-6-yl))-1,3-benzothiazole-6-carboxamide;
N-(2-azabicyclo2.2.1hept-6-yl))indane-5-carboxamide;
N-(2-azabicyclo2.2.1hept-6-yl))-1,3-benzodioxole-5-carboxamide;
N-(2-azabicyclo2.2.1hept-6-yl))-1,3-oxazolo5,4-cpyridine-6-carboxamide;
N-(2-azabicyclo2.2.1hept-6-yl))-1H-indazole-5-carboxamide;
N-(2-azabicyclo2.2.1hept-6-yl))-1H-indazole-6-carboxamide;
N-(2-azabicyclo2.2.1hept-6-yl))-1,3-dioxolo4,5-pyridine-6-carboxamide; or a pharmaceutically acceptable salt thereof.
16. The compound of claim 3, wherein W0 is (b).
17. The compound of claim 16, wherein (b) is 2-benzoisothiophen-5-yl, 2H-isoindole-5-yl, or 2-benzofuran-5-yl, any of which is optionally substituted with lower cycloalkyl or lower alkyl optionally substituted with to 4 halogens, and further optionally substituted with up to 1 substituent selected from OR10, N(R10)2, C(O)NR10R10, CN, NR10C(O)R10, NR10S(O)2R10, wherein each R10 is independently selected from lower alkyl or halogenated lower alkyl.
18. The compound of claim 17, wherein Azabicyclo is I, II, V, or VI.
19. The compound of claim 18, wherein each k2, k5, and k6 is independently 0 or 1.
20. The compound of claim 19, wherein R2 is alkyl, or R2 is absent provided that Azabicyclo is II, V or VI and further provided that k2, k5, and k6 are 0.
21. The compound of claim 20, wherein R11 is H or lower alkyl, and wherein R2 is lower alkyl or is absent provided that k2, k5, or k6 is 0.
22. The compound of claim 21, wherein the compound is
N-(1-(6-methyl)-azabicyclo2.2.2oct-3-yl)-2-benzoisothiophene-5-benzamide;
N-exo-4(S)-1-azabicyclo2.2.1hept-3-yl-2-benzoisothiophene-5-benzamide;
N-(exo-4(S)-1-(6-methyl)-azabicyclo2.2.1hept-3-yl)-2-benzoisothiophene-5-benzamide;
N-(3R,5R)-1-azabicyclo3.2.1oct-3-yl-2-benzoisothiophene-5-benzamide;
N-exo-4(S)-1-azabicyclo2.2.1hept-3-yl-2-benzofuran-5-carboxamide;
N-exo-4(S)-1-azabicyclo2.2.1hept-3-yl-2H-isoindole-5-carboxamide;
N-(3R,5R)-1-azabicyclo3.2.1oct-3-yl-2-benzofuran-5-carboxamide;
N-(3R,5R)-1-azabicyclo3.2.1oct-3-yl-2H-isoindole-5-carboxamide; or a pharmaceutically acceptable salt thereof, provided that the compound is the pure enantiomer or racemic mixture thereof.
23. The compound of claim 17, wherein Azabicyclo is III, or IV.
24. The compound of claim 23, wherein R2-3 is H, or alkyl.
25. The compound of claim 24, wherein the compound is
N-(2-azabicyclo2.2.1hept-5-yl)-2-benzoisothiophene-5-benzamide;
N-(2-azabicyclo2.2.1hept-6-yl))-2-benzoisothiophene-5-benzamide; or a pharmaceutically acceptable salt thereof.
26. The compound of claim 3, wherein W0 is (c).
27. The compound of claim 26, wherein (c) is 1,3-benzothiazol-2-yl, or 1H-imidazo4,5-cpyridin-6-yl, either of which is optionally substituted with lower alkyl, lower substituted alkyl, or lower halogenated alkyl.
28. The compound of claim 27, wherein Azabicyclo is I, II, V, or VI.
29. The compound of claim 28, wherein each k2, k5, and k6 is independently 0 or 1.
30. The compound of claim 29, wherein R2 is alkyl, or R2 is absent provided that Azabicyclo is II, V or VI and further provided that k2, k5, and k6 are 0.
31. The compound of claim 30, wherein R1 is H or lower alkyl, and wherein R2 is lower alkyl or is absent provided that k2, k5, or k6 is 0.
32. The compound of claim 31, wherein the compound is
N-(1-(6-methyl)-azabicyclo2.2.2oct-3-yl)-1,3-benzothiazole-2-carboxamide;
N-exo-4(S)-1-azabicyclo2.2.1hept-3-yl-1,3-benzothiazole-2-carboxamide;
N-(exo-4(S)-1-(6-methyl)-azabicyclo2.2.1hept-3-yl)-1,3-benzothiazole-2-carboxamide;
N-(3R,5R)-1-azabicyclo3.2.1oct-3-yl-1,3-benzothiazole-2-carboxamide;
N-(3R,5R)-1-azabicyclo3.2.1oct-3-yl-1H-imidazo4,5-cpyridine-6-carboxamide;
N-(3R)-1-azabicyclo3.2.2nonan-3-yl-1,3-benzothiazole-2-carboxamide; or a pharmaceutically acceptable salt thereof, provided that the compound is the pure enantiomer or racemic mixture thereof.
33. The compound of claim 27, wherein Azabicyclo is III, or IV.
34. The compound of claim 33, wherein R2-3 is H, or alkyl.
35. The compound of claim 34, wherein the compound is
N-(2-azabicyclo2.2.1hept-5-yl)-1,3-benzothiazole-2-carboxamide;
N-(2-azabicyclo2.2.1hept-6-yl))-1,3-benzothiazole-2-carboxamide; or a pharmaceutically acceptable salt thereof.
36. A pharmaceutical composition comprising a compound according to claim 1, an anti-psychotic agent, and a pharmaceutically acceptable excipient.
37. The pharmaceutical composition according to claim 36, wherein said compound and said agent are to be independently administered rectally, topically, orally, sublingually, or parenterally for a therapeutically effective interval.
38. The pharmaceutical composition according to claim 36, wherein said compound is administered in an amount of from about 0.001 to about 100 mgkg of body weight of said mammal per day.
39. The pharmaceutical composition according to claim 36, wherein said compound is administered in an amount of from about 0.1 to about 50 mgkg of body weight of said mammal per day.
40. The pharmaceutical composition according to claim 36, comprising a compound according to claim 1 and a pharmaceutically acceptable excipient.
41. The pharmaceutical composition according to claim 40, wherein said compound is administered rectally, topically, orally, sublingually, or parenterally for a therapeutically effective interval.
42. The pharmaceutical composition according to claim 40, wherein said compound is administered in an amount of from about 0.001 to about 100 mgkg of body weight of said mammal per day.
43. The pharmaceutical composition according to claim 40, wherein said compound is administered in an amount of from about 0.1 to about 50 mgkg of body weight of said mammal per day.
44. 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 7 nicotinic acetylcholine receptor agonist comprising administering to the mammal a therapeutically effective amount of a compound according to claim 1.
45. The method according to claim 44, wherein the disease or condition is cognitive and attention deficit symptoms of Alzheimer’s, neurodegeneration associated with diseases such as Alzheimer’s disease, pre-senile dementia (mild cognitive impairment), or senile dementia.
46. The method according to claim 44, wherein the disease or condition is schizophrenia or psychosis.
47. The method of claim 46, wherein the mammal would receive symptomatic relief from the administration of a therapeutically effective amount of 7 nicotinic acetylcholine receptor agonist and an anti-psychotic agent for a therapeutically effective interval.
48. The method according to claim 44, wherein the disease or condition is depression, or anxiety and general anxiety disorders and post traumatic stress disorder.
49. The method according to claim 44, wherein the disease or condition is attention deficit disorder, or attention deficit hyperactivity disorder.
50. The method according to claim 44, wherein the disease or condition is 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.