Geminal substituted quinuclidine amide compounds as agonists of α-7 nicotonic acetylcholine receptors

1. A geminal substituted quinuclidine amide compound represented by Formula (I):

wherein:

R 1 and R 2 independently represent a branched or unbranched C 1 -C 4 -alkyl radical; or the C(R 1 )(R 2 ) moiety forms a (3-4 membered)-carbocycle, wherein R 1 and R 2 taken together represent a C 2 -C 3 -alkyl di-radical; wherein the C 1 -C 4 -alkyl radical and the C 2 -C 3 -alkyl di-radical may be substituted with up to 4 radical substituents comprising: -D, —F, —Cl, —Br, —I, —CN, CH 3 , CH 2 CH 3 , ═O, —OR 3 , or —OCF 3 ;

R 3 independently represents —H; a branched or unbranched C 1 -C 4 -alkyl radical; C 3 -C 4 -cycloalkyl radical; wherein the C 1 -C 4 -alkyl radical and the C 3 -C 4 -cycloalkyl radical may be substituted with up to 4 radical substituents comprising: -D, —F, —Cl, —Br, —I, —CN, ═O, —OH, —OC 1 -C 4 -alkyl or —OCF 3 ; and

W represents a moiety represented by ring system M-I, M-II, M-III, M-IV, M-V, or M-VI:

wherein:

Z 1 , Z 2 , Z 3 , Z 4 , and Z 5 independently represent N or CR 4 ; with the proviso that no more than two of Z 1 , Z 2 , Z 3 , Z 4 , and Z 5 are N;

R 4 independently represents —H; -D; —F; —Cl; —Br; —I; —CN; —NO 2 ; —OR 5 ; —N(R 5 )(R 6 ); —SO 2 (CH 2 ) m R 5 ; —(CO)(CH 2 ) m R 5 ; —(CO)N(R 5 )(R 6 ); —OCF 3 ; a C 1 -C 6 -alkyl radical; a C 1 -C 6 -haloalkyl radical; a C 3 -C 6 -cycloalkyl radical; a (3-6 membered)-heterocycloalkyl radical; an aryl radical; or a heteroaryl radical; or when adjacent members of Z 1 , Z 2 , Z 3 , Z 4 , and Z 5 , is (CR 4 )(CR 4 ), the (CR 4 )(CR 4 ) may form a cycle such that the adjacent R 4 substitutents taken together represents a (3-6 membered)-heteroalkyl di-radical with at least one ring atom of the (3-6 membered)-heteroalkyl di-radical selected from the group consisting of oxygen, nitrogen, and sulfur, with the proviso that when the at least one ring atom is nitrogen, the nitrogen is substituted with —H, a branched or unbranched C 1 -C 4 -alkyl radical, a C 3 -C 4 -cycloalkyl radical, —(CO)-branched or unbranched C 1 -C 4 -alkyl, or —(SO 2 )-branched or unbranched C 1 -C 4 -alkyl, wherein the C 1 -C 4 -alkyl radical and the C 3 -C 4 -cycloalkyl radical may be substituted with up to 4 radical substituents comprising: -D, halogen, ═O, —OH, —OC 1 -C 4 -alkyl or —OCF 3 , and with the further proviso that when the at least one ring atom is sulfur, the sulfur may substituted with 0 or 2=O; wherein the C 1 -C 6 -alkyl radical, the (3-6 membered)-heterocycloalkyl radical, the aryl radical, the heteroaryl radical, and the alkyl portion of the (3-6 membered)-heteroalkyl di-radical, may be substituted with up to 4 radical substituents comprising: -D, —F, —Cl, —Br, —I, —CN, —NO 2 , —OR 5 , —(CH 2 ) m OR 5 , —N(R 5 )(R 6 ), —(CH 2 ) m N(R 5 )(R 6 ), —SO 2 (CH 2 ) m R 5 , —(CO)(CH 2 ) m R 5 , —(CO)N(R 5 )(R 6 ), —OCF 3 , a branched or unbranched C 1 -C 6 -alkyl radical, a C 3 -C 6 -cycloalkyl radical, a C 1 -C 6 -hydroxyalkyl radical, or a C 1 -C 6 -haloalkyl radical;

R 5 and R 6 independently represent —H; a branched or unbranched C 1 -C 6 -alkyl radical; a C 3 -C 6 -cycloalkyl radical; or the N(R 5 )(R 6 ) moiety forms a cycle, wherein R 5 and R 6 taken together represent a C 2 -C 6 -alkyl di-radical or a (3-6 membered)-heteroalkyl di-radical;

Z 6 , Z 7 , Z 8 , and Z 9 independently represent N or CR 7 ; with the proviso that no more than two of Z 6 , Z 7 , Z 8 , and Z 9 are N;

R 7 independently represents —H; -D; —F; —Cl; —Br; —I; —CN; —NO 2 ; —OR 8 ; —N(R 8 )(R 9 ); —SO 2 (CH 2 ) m R 8 ; —(CO)(CH 2 ) m R 8 ; —(CO)N(R 8 )(R 9 ); —OCF 3 ; a C 1 -C 6 -alkyl radical; a C 1 -C 6 -haloalkyl radical; a C 3 -C 6 -cycloalkyl radical; a (3-6 membered)-heterocycloalkyl radical; an aryl radical; a heteroaryl radical; or the bond directly attaching the W moiety with the carbonyl moiety; wherein the C 1 -C 6 -alkyl radical, the (3-6 membered)-heterocycloalkyl radical, the aryl radical, and the heteroaryl radical may be substituted with up to 4 radical substituents comprising: -D, —F, —Cl, —Br, —I, —CN, —NO 2 , —OR 8 , —(CH 2 ) m OR 8 , —N(R 8 )(R 9 ), —(CH 2 ) m N(R 8 )(R 9 ), —SO 2 (CH 2 ) m R 8 , —(CO)(CH 2 ) m R 8 , —(CO)N(R 8 )(R 9 ), —OCF 3 , a branched or unbranched C 1 -C 6 -alkyl radical, a C 3 -C 6 -cycloalkyl radical, a C 1 -C 6 -hydroxyalkyl radical, or a C 1 -C 6 -haloalkyl radical;

R 8 and R 9 independently represent —H; a branched or unbranched C 1 -C 6 -alkyl radical; a C 3 -C 6 -cycloalkyl radical; or the N(R 8 )(R 9 ) moiety forms a cycle, wherein R 8 and R 9 taken together represent a C 2 -C 6 -alkyl di-radical or a (3-6 membered)-heteroalkyl di-radical;

X 1 independently represents N or C;

A 1 , A 2 , A 3 and A 4 independently represent N; NR 10 ; N(CH 2 ) m R 10 ; O; S; or CR 11 ; with the proviso that only one A 1 , A 2 , A 3 and A 4 is NR 10 , O, or S; with the further proviso that when X 1 is N, then A 1 , A 2 , and A 3 independently represent N or CR 11 ;

R 10 independently represents —H; -D; —SO 2 (CH 2 ) m R 12 ; —(CO)(CH 2 ) m R 12 ; —(CO)N(R 12 )(R 13 ); a C 1 -C 6 -alkyl radical; a C 1 -C 6 -haloalkyl radical; a C 3 -C 6 -cycloalkyl radical; a (3-6 membered)-heterocycloalkyl radical; an aryl radical; or a heteroaryl radical; wherein the C 1 -C 6 -alkyl radical, the (3-6 membered)-heterocycloalkyl radical, the aryl radical, and the heteroaryl radical may be substituted with up to 4 radical substituents comprising: -D, —F, —Cl, —Br, —I, —CN, —NO 2 , —OR 12 , —(CH 2 ) m OR 12 , —N(R 12 )(R 13 ), —(CH 2 ) m N(R 12 )(R 13 ), —SO 2 (CH 2 ) m R 12 , —(CO)(CH 2 ) m R 13 , —(CO)N(R 12 )(R 13 ), —OCF 3 , a branched or unbranched C 1 -C 6 -alkyl radical, a C 3 -C 6 -cycloalkyl radical, a C 1 -C 6 -hydroxyalkyl radical, or a C 1 -C 6 -haloalkyl radical;

R 11 independently represents —H; -D; —F; —Cl; —Br; —I; —CN; —NO 2 ; —OR 12 ; —N(R 12 )(R 13 ); —SO 2 (CH 2 ) m R 12 ; —(CO)(CH 2 ) m R 12 ; —(CO)N(R 12 )(R 13 ); —OCF 3 ; a C 1 -C 6 -alkyl radical; a C 1 -C 6 -haloalkyl radical; a C 3 -C 6 -cycloalkyl radical; a (3-6 membered)-heterocycloalkyl radical; an aryl radical; or a heteroaryl radical; wherein the C 1 -C 6 -alkyl radical, the (3-6 membered)-heterocycloalkyl radical, the aryl radical, and the heteroaryl radical may be substituted with up to 4 radical substituents comprising: -D; —F; —Cl; —Br; —I; —CN; —NO 2 ; —OR 12 ; —(CH 2 ) m OR 12 ; —N(R 12 )(R 13 ); —(CH 2 ) m N(R 12 )(R 13 ); —SO 2 (CH 2 ) m R 12 ; —(CO)(CH 2 ) m R 12 ; —(CO)N(R 12 )(R 13 ); —OCF 3 ; a branched or unbranched C 1 -C 6 -alkyl radical, a C 3 -C 6 -cycloalkyl radical, or a C 1 -C 6 -haloalkyl radical;

R 12 and R 13 independently represent —H; a branched or unbranched C 1 -C 6 -alkyl radical; a C 3 -C 6 -cycloalkyl radical; or the N(R 12 )(R 13 ) moiety forms a cycle, wherein R 12 and R 13 taken together represent a C 2 -C 6 -alkyl di-radical or a (3-6 membered)-heteroalkyl di-radical;

X 2 independently represents N or C;

A 5 , A 6 , and A 7 independently represent N; NR 14 ; N(CH 2 ) m R 14 ; O; S; or CR 15 ; with the proviso that only one A 5 , A 6 , and A 7 is NR 14 , O, or S; with the further proviso that when X 2 is N, then A 5 , A 6 , and A 7 independently represent N or CR 15 ;

R 14 independently represents —H; -D; —(CH 2 ) m N(R 16 )(R 17 ); —SO 2 (CH 2 ) m R 16 ; —(CO)(CH 2 ) m R 16 ; —(CO)N(R 16 )(R 17 ); a C 1 -C 6 -alkyl radical; a C 1 -C 6 -haloalkyl radical; a C 3 -C 6 -cycloalkyl radical; a (3-6 membered)-heterocycloalkyl radical; an aryl radical; a heteroaryl radical; or the bond directly attaching the W moiety with the carbonyl moiety; wherein the C 1 -C 6 -alkyl radical, the (3-6 membered)-heterocycloalkyl radical, the aryl radical, and the heteroaryl radical may be substituted with up to 4 radical substituents comprising: -D, —F, —Cl, —Br, —I, —CN, —NO 2 , —OR 16 , —(CH 2 ) m OR 16 , —N(R 16 )(R 17 ), —(CH 2 ) m N(R 16 )(R 17 ), —SO 2 (CH 2 ) m R 16 , —(CO)(CH 2 ) m R 16 , —(CO)N(R 16 )(R 17 ), —OCF 3 , a branched or unbranched C 1 -C 6 -alkyl radical, a C 3 -C 6 -cycloalkyl radical, or a C 1 -C 6 -haloalkyl;

R 15 independently represents —H; -D; —F; —Cl; —Br; —I; —CN; —NO 2 ; —OR 16 ; —N(R 16 )(R 17 ); —SO 2 (CH 2 ) m R 16 ; —(CO)(CH 2 ) m R 16 ; —(CO)N(R 16 )(R 17 ); —OCF 3 ; a C 1 -C 6 -alkyl radical; a C 1 -C 6 -haloalkyl radical; a C 3 -C 6 -cycloalkyl radical; a (3-6 membered)-heterocycloalkyl radical; an aryl radical; a heteroaryl radical; or the bond directly attaching the W moiety with the carbonyl moiety; wherein the C 1 -C 6 -alkyl radical, the (3-6 membered)-heterocycloalkyl radical, the aryl radical, and the heteroaryl radical may be substituted with up to 4 radical substituents comprising: -D; —F; —Cl; —Br; —I; —CN; —NO 2 ; —OR 16 ; —(CH 2 ) m OR 16 ; —N(R 16 )(R 17 ); —(CH 2 ) m N(R 16 )(R 17 ); —SO 2 (CH 2 ) m R 16 ; —(CO)(CH 2 ) m R 16 ; —(CO)N(R 16 )(R 17 ); —OCF 3 ; a branched or unbranched C 1 -C 6 -alkyl radical, a C 3 -C 6 -cycloalkyl radical, or a C 1 -C 6 -haloalkyl radical;

R 16 and R 17 independently represent —H; a branched or unbranched C 1 -C 6 -alkyl radical; a C 3 -C 6 -cycloalkyl radical; or the N(R 16 )(R 17 ) moiety forms a cycle, wherein R 16 and R 17 taken together represent a C 2 -C 6 -alkyl di-radical or a (3-6 membered)-heteroalkyl di-radical;

G 1 , G 2 , G 3 , and G 4 independently represent C(R 18 )(R 18 ); N(R 19 ); —N(CH 2 ) m R 18 ; O; S; SO 2 ; or (C═O); with the proviso that no more than two of G 1 , G 2 , G 3 , and G 4 represent N(R 19 ); —N(CH 2 ) m R 18 , O; S; SO 2 ; or (C═O);

R 18 independently represents —H; -D; —F; —Cl; —Br; —I; —CN; —NO 2 ; —OR 19 ; —N(R 19 )(R 20 ); —SO 2 (CH 2 ) m R 19 ; —(CO)(CH 2 ) m R 19 ; —(CO)N(R 19 )(R 20 ); —OCF 3 ; a C 1 -C 6 -alkyl radical; a C 1 -C 6 -haloalkyl radical; a C 3 -C 6 -cycloalkyl radical; a (3-6 membered)-heterocycloalkyl radical; an aryl radical; or a heteroaryl radical; wherein the C 1 -C 6 -alkyl radical, the (3-6 membered)-heterocycloalkyl radical, the aryl radical, and the heteroaryl radical may be substituted with up to 4 radical substituents comprising: -D, —F, —Cl, —Br, —I, —CN, —NO 2 , —OR 19 , —(CH 2 ) m OR 19 , —N(R 19 )(R 20 ), —(CH 2 ) m N(R 19 )(R 20 ), —SO 2 (CH 2 ) m R 19 , —(CO)(CH 2 ) m R 19 , —(CO)N(R 19 )(R 20 ), —OCF 3 , a branched or unbranched C 1 -C 6 -alkyl radical, a C 3 -C 6 -cycloalkyl radical, or a C 1 -C 6 -haloalkyl radical; and

R 19 and R 20 independently represent —H; a branched or unbranched C 1 -C 6 -alkyl radical; a C 3 -C 6 -cycloalkyl radical; or the N(R 19 )(R 20 ) moiety forms a cycle, wherein R 19 and R 20 taken together represent a C 2 -C 6 -alkyl di-radical or a (3-6 membered)-heteroalkyl di-radical; or the C(R 19 )(R 20 ) moiety forms a cycle, wherein R 19 and R 20 taken together represent a C 2 -C 6 -alkyl di-radical or a (3-6 membered)-heteroalkyl di-radical;

m independently represents an integer from 1 to 6;

or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 , wherein W represents the moiety represented by the ring system M-II.

3. The compound of claim 2 , wherein M-II represents a moiety represented by ring system M-II-1:

wherein:

Z 6 , Z 8 , and Z 9 independently represent CR 7 ;

A 1 and A 2 independently represent N or CR 11 ; and

A 3 represents NR 10 ; O; or S.

4. The compound of claim 2 , wherein M-II represents a moiety represented by ring system M-II-2:

wherein:

Z 6 , Z 8 , and Z 9 independently represent CR 7 ;

A 1 and A 2 independently represent N or CR 11 ; and

A 3 represents NR 10 ; O; or S.

5. The compound of claim 2 , wherein M-II represents a moiety represented by ring system M-II-6:

wherein:

Z 6 and Z 9 independently represent CR 7 ;

A 1 and A 2 independently represent N or CR 11 ; and

A 3 represents NR 10 ; O; or S.

6. The compound of claim 2 , wherein the compound is selected from the group consisting of:

(R)—N-(2,2-dimethylquinuclidin-3-yl)benzofuran-5-carboxamide;

(R)—N-(1′-azaspiro[cyclopropane-1,2′-bicyclo[2.2.2]octan]-3′-yl)benzofuran-5-carboxamide;

(R)-2-chloro-N-(1′-azaspiro[cyclopropane-1,2′-bicyclo[2.2.2]octan]-3′-yl)benzofuran-5-carboxamide;

(R)—N-(1′-azaspiro[cyclopropane-1,2′-bicyclo[2.2.2]octan]-3′-yl)-1H-indole-6-carboxamide;

(R)—N-(1′-azaspiro[cyclopropane-1,2′-bicyclo[2.2.2]octan]-3′-yl)benzo[b]thiophene-6-carboxamide;

(R)-2-chloro-N-(1′-azaspiro[cyclopropane-1,2′-bicyclo[2.2.2]octan]-3′-yl)benzo[b]thiophene-6-carboxamide;

(R)—N-(2,2-dimethylquinuclidin-3-yl)furo[2,3-c]pyridine-5-carboxamide; and

(R)—N-(1′-azaspiro[cyclopropane-1,2′-bicyclo[2.2.2]octan]-3′-yl)furo[2,3-c]pyridine-5-carboxamide.

7. The compound of claim 1 , wherein W represents the moiety represented by the ring system M-IV.

8. The compound of claim 7 , wherein M-IV represents a moiety represented by one of the following:

wherein:

A 5 represents N or CR 15 ; and

A 7 represents NR 14 ; N(CH 2 ) m R 14 ; O; or S.

9. The compound of claim 7 , wherein the compound is selected from the group consisting of:

(R)—N-(2,2-dimethylquinuclidin-3-yl)benzo[b]thiophene-2-carboxamide;

(R)—N-(2,2-dimethylquinuclidin-3-yl)-7-fluoro-benzo[b]thiophene-2-carboxamide;

(R)-6-chloro-N-(2,2-dimethylquinuclidin-3-yl)benzo[b]thiophene-2-carboxamide;

(R)-7-chloro-N-(2,2-dimethylquinuclidin-3-yl)-6-methylbenzo[b]thiophene-2-carboxamide;

(R)—N-(2,2-dimethylquinuclidin-3-yl)-7-fluoro-6-methylbenzo[b]thiophene-2-carboxamide;

(R)—N-(1′-azaspiro[cyclopropane-1,2′-bicyclo[2.2.2]octan]-3′-yl)benzo[b]thiophene-2-carboxamide;

(R)-6-chloro-N-(1′-azaspiro[cyclopropane-1,2′-bicyclo[2.2.2]octan]-3′-yl)benzo[b]thiophene-2-carboxamide;

(R)-6-methyl-N-(1′-azaspiro[cyclopropane-1,2′-bicyclo[2.2.2]octan]-3′-yl)benzo[b]thiophene-2-carboxamide;

(R)-6-cyclopropyl-N-(1′-azaspiro[cyclopropane-1,2′-bicyclo[2.2.2]octan]-3′-yl)benzo[b]thiophene-2-carboxamide;

(R)-6-methoxy-N-(1′-azaspiro[cyclopropane-1,2′-bicyclo[2.2.2]octan]-3′-yl)benzo[b]thiophene-2-carboxamide;

(R)-6-bromo-N-(1′-azaspiro[cyclopropane-1,2′-bicyclo[2.2.2]octan]-3′-yl)benzo[b]thiophene-2-carboxamide;

(R)-7-fluoro-6-methyl-N-(1′-azaspiro[cyclopropane-1,2′-bicyclo[2.2.2]octan]-3′-yl)benzo[b]thiophene-2-carboxamide;

(R)-6,7-dichloro-N-(1′-azaspiro[cyclopropane-1,2′-bicyclo[2.2.2]octan]-3′-yl)benzo[b]thiophene-2-carboxamide;

(R)-6-chloro-7-fluoro-N-(1′-azaspiro[cyclopropane-1,2′-bicyclo[2.2.2]octan]-3′-yl)benzo[b]thiophene-2-carboxamide;

(R)-7-cyano-N-(1′-azaspiro[cyclopropane-1,2′-bicyclo[2.2.2]octan]-3′-yl)benzo[b]thiophene-2-carboxamide;

(R)-7-cyclopropyl-N-(1′-azaspiro[cyclopropane-1,2′-bicyclo[2.2.2]octan]-3′-yl)benzo[b]thiophene-2-carboxamide;

(R)—N-(1′-azaspiro[cyclopropane-1,2′-bicyclo[2.2.2]octan]-3′-yl)-7-(trifluoromethoxy)benzo[b]thiophene-2-carboxamide;

(R)-5-fluoro-6-methoxy-N-(1′-azaspiro[cyclopropane-1,2′-bicyclo[2.2.2]octan]-3′-yl)benzo[b]thiophene-2-carboxamide;

(R)-7-ethoxy-N-(1′-azaspiro[cyclopropane-1,2′-bicyclo[2.2.2]octan]-3′-yl)benzo[b]thiophene-2-carboxamide; and

(R)—N-(1′-azaspiro[cyclopropane-1,2′-bicyclo[2.2.2]octan]-3′-yl)-7-(2,2,2-trifluoroethoxy)benzo[b]thiophene-2-carboxamide.

10. The compound of claim 1 , wherein:

R 1 and R 2 independently represent an unbranched C 1 -alkyl radical and said compound is represented by Formula (II):

R 1 and R 2 taken together represent a C 2 -alkyl di-radical and said compound is represented by Formula (III):

11. A pharmaceutical composition, comprising:

i) the compound, or pharmaceutically acceptable salt thereof, of claim 1 ; and

ii) at least one pharmaceutically acceptable carrier, excipient or diluent.

12. A method of improving cognition of a patient in need thereof, comprising: administering to the patient the compound, or pharmaceutically acceptable salt thereof, of claim 1 .

13. The method of claim 12 , wherein the patient suffers from a cognitive impairment, suffers from a cognitive loss associated with a cognitive impairment, or suffers from one or more symptoms associated with a cognitive impairment.

14. The method of claim 13 , wherein the cognitive impairment comprises Limited Cognitive Impairment (LCI), Mild Cognitive Impairment (MCI), Alzheimer's disease, dementia of an Alzheimer's-type, schizophrenia, schizophreniform disorder, schizoaffective disorder, delusional disorder, positive symptoms of schizophrenia, negative symptoms of schizophrenia, or schizophrenia with dementia.

15. A method of treating or improving one or more symptoms associated with a cognitive disease and/or a cognitive impairment in a patient in need thereof, comprising: administering to the patient the compound, or pharmaceutically acceptable salt thereof, of claim 1 .