Calcium channel inhibitors

1. A compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein:

X is O or CH 2 ;

Y is CR 1 R 2 , NR 3 , C(═O), C(═O)NH, or NH(C═O);

Z is C(═O)OR Z1 , or C(═O)NR Z2 R Z3 ;

n is 0, 1, 2, or 3;

R N is H or an optionally substituted C 1-4 alkyl;

R 1 is H or an optionally substituted C 1-4 alkyl;

R 2 is H or an optionally substituted C 1-4 alkyl; or

R 1 and R 2 in combination form a C 2-4 alkylene group which, together with the carbon atom to they are attached, form a 3-6-membered optionally substituted cycloalkyl ring;

R 3 is H or an optionally substituted C 1-4 alkyl;

R Z1 is methyl;

R Z2 is H or an optionally substituted C 1-4 alkyl;

R Z3 is H or an optionally substituted C 1-4 alkyl; or

R Z2 and R Z3 in combination with the nitrogen atom to which they are attached form an optionally substituted 4-6 membered heterocycloalkyl ring; and

Ar is optionally substituted C 6-10 aryl, or a 5-10 membered optionally substituted heteroaryl; wherein each substituted C 1-4 alkyl is substituted by 1, 2, 3, 4 or 5 substituents, each independently selected from halo, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 haloalkyl, C 1-4 alkoxy, OH, CN, NO 2 , amino, C 1-4 alkylamino, di(C 1-4 alkyl)amino, oxo, optionally substituted C 3-10 cycloalkyl, optionally substituted C 6-10 aryl, optionally substituted 4-10 membered heterocycloalkyl, and optionally substituted 5-10 membered heteroaryl; each substituted cycloalkyl and heterocycloalkyl is substituted by 1, 2, 3, 4 or 5 substituents, each independently selected from halo, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 haloalkyl, C 1-4 alkoxy, OH, CN, NO 2 , amino, C 1-4 alkylamino, di(C 1-4 alkyl)amino and oxo; and each substituted aryl and heteroaryl is substituted by 1, 2, 3, 4, or 5 substituents, each independently selected from halo, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 haloalkyl, C 1-4 alkoxy, OH, CN, NO 2 , amino, C 1-4 alkylamino, and di(C 1-4 alkyl)amino;

wherein when Ar is a 5-10 membered optionally substituted heteroaryl,

R 1 and R 2 are each an optionally substituted C 1-4 alkyl, or

R 1 and R 2 in combination form a C 2-4 alkylene group which, together with the carbon atom to they are attached, form a 3-6-membered optionally substituted cycloalkyl ring, or

R Z2 is H or an unsubstituted C 1-4 alkyl and R Z3 is methyl, N,N-dimethylaminoethyl, N,N-diethylaminoethyl, methoxyethyl, pyrrolidinylethyl, 2-(N,N-dimethylamino)ethyl, 2-(N,N-diethylamino)ethyl, 2-methoxyethyl, or 2-(pyrrolidin-1-yl)ethyl, or

R Z2 and R Z3 in combination with the nitrogen atom to which they are attached form an optionally substituted 4-6 membered heterocycloalkyl ring.

2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Y is CR 1 R 2 .

3. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R N is an optionally substituted C 1-4 alkyl, and wherein said optionally substituted C 1-4 alkyl is methyl or ethyl.

4. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 and R 2 are each H.

5. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 and R 2 are each an optionally substituted C 1-4 alkyl, and wherein said optionally substituted C 1-4 alkyl is methyl.

6. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 and R 2 in combination form a C 2-4 alkylene group which, together with the carbon atom to they are attached, form a 3-6-membered optionally substituted cycloalkyl ring, and wherein said optionally substituted cycloalkyl ring is an unsubstituted cyclopropyl ring.

7. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3 is an optionally substituted C 1-4 alkyl, and wherein said optionally substituted C 1-4 alkyl is an unsubstituted C 1-4 alkyl.

8. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Z is C(═O)NR Z2 R Z3 , wherein R Z2 is methyl, and wherein R Z3 is methyl, N,N-dimethylaminoethyl, N,N-diethylaminoethyl, methoxyethyl, pyrrolidinylethyl, 2-(N,N-dimethylamino)ethyl, 2-(N,N-diethylamino)ethyl, 2-methoxyethyl, or 2-(pyrrolidin-1-yl)ethyl.

9. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R Z2 and R Z3 in combination with the nitrogen atom to which they are attached form an optionally substituted 4-6 membered heterocycloalkyl ring, and wherein said is a morpholinyl ring.

10. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Ar is an optionally substituted aryl, and wherein said optionally substituted aryl is a phenyl or a naphthyl.

11. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Ar is a 5-10 membered heteroaryl optionally substituted heteroaryl, and wherein said optionally substituted heteroaryl is substituted by 1, 2, 3, or 4 groups independently selected from chloro, methyl, methoxy, and trifluoromethyl.

12. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Ar is:

13. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:

X is O or CH 2 ;

Y is CR 1 R 2 ;

Z is C(═O)OR Z1 , or C(═O)NR Z2 R Z3 ;

R N is an unsubstituted C 1-4 alkyl;

R 1 is H or unsubstituted C 1-4 alkyl;

R 2 is H or unsubstituted C 1-4 alkyl; or

R 1 and R 2 in combination form a C 2-4 alkylene group which, together with the carbon atom to they are attached, form a 3-6-membered optionally substituted cycloalkyl ring;

n is 0, 1, 2, or 3;

R Z1 is methyl;

R Z2 is H or an unsubstituted C 1-4 alkyl;

R Z3 is an optionally substituted C 1-4 alkyl; or

R Z2 and R Z3 in combination with the nitrogen atom to which they are attached form an optionally substituted 4-6 membered heterocycloalkyl ring; and

Ar is optionally substituted phenyl, optionally substituted naphthyl, or a 5-10 membered optionally substituted heteroaryl.

14. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:

X is O or CH 2 ;

Y is CR 1 R 2 ;

Z is C(═O)OR Z1 , or C(═O)NR Z2 R Z3 ;

R N is an unsubstituted C 1-4 alkyl;

R 1 is H or unsubstituted C 1-4 alkyl;

R 2 is H or unsubstituted C 1-4 alkyl; or

R 1 and R 2 in combination form a C 2-4 alkylene group which, together with the carbon atom to they are attached, form a 3-6-membered optionally substituted cycloalkyl ring;

n is 1;

R Z1 is methyl;

R Z2 is H or an unsubstituted C 1-4 alkyl;

R Z3 is methyl, N,N-dimethylaminoethyl, N,N-diethylaminoethyl, methoxyethyl, pyrrolidinylethyl, 2-(N,N-dimethylamino)ethyl, 2-(N,N-diethylamino)ethyl, 2-methoxyethyl, or 2-(pyrrolidin-1-yl)ethyl, or R Z2 and R Z3 in combination with the nitrogen atom to which they are attached form an optionally substituted 4-6 membered heterocycloalkyl ring; and

Ar is a 5-10 membered optionally substituted heteroaryl.

15. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:

X is O or CH 2 ;

Y is CR 1 R 2 ;

Z is C(═O)OR Z1 , or C(═O)NR Z2 R Z3 ;

R N is an unsubstituted C 1-4 alkyl;

R 1 is H or methyl;

R 2 is H or methyl; or

R 1 and R 2 in combination form an ethylene group which, together with the carbon atom to they are attached, form a cyclopropyl ring;

n is 1;

R Z1 is methyl;

R Z2 is H or an unsubstituted C 1-4 alkyl;

R Z3 is methyl, N,N-dimethylaminoethyl, N,N-diethylaminoethyl, methoxyethyl, pyrrolidinylethyl, 2-(N,N-dimethylamino)ethyl, 2-(N,N-diethylamino)ethyl, 2-methoxyethyl, or 2-(pyrrolidin-1-yl)ethyl, or R Z2 and R Z3 in combination with the nitrogen atom to which they are attached form an optionally substituted 4-6 membered heterocycloalkyl ring; and

Ar is a 5-10 membered heteroaryl optionally substituted by 1, 2, 3, or 4 groups independently selected from halo, C 1-4 alkyl, C 1-4 haloalkyl, and C 1-4 alkoxy.

16. The compound of claim 1 , wherein the compound of Formula I is selected from the group consisting of:

a compound of Formula II:

or a pharmaceutically acceptable salt thereof, a compound of Formula III:

or a pharmaceutically acceptable salt thereof;

a compound of Formula IV:

or a pharmaceutically acceptable salt thereof, wherein each R A r is independently selected from H, halo, C 1-4 alkyl, C 1-4 haloalkyl, and C 1-4 alkoxy;

a compound of Formula V:

or a pharmaceutically acceptable salt thereof, wherein each R A r is independently selected from H, halo, C 1-4 alkyl, C 1-4 haloalkyl, and C 1-4 alkoxy; and

a compound of Formula I-a, I-b, II-a, II-b, III-a, III-b, IV-a, IV-b, V-a, or V-b:

or a pharmaceutically acceptable salt thereof, wherein each R A r is independently selected from H, halo, C 1-4 alkyl, C 1-4 haloalkyl, and C 1-4 alkoxy.

17. The compound of claim 1 , wherein the compound is selected from: 2-(2-((3-(1H-benzo[d]imidazol-2-yl)propyl)(methyl)amino)ethyl)-6-fluoro-1-isopropyl-1,2,3,4-tetrahydronaphthalen-2-yl methylcarbamate;

2-(2-((3-(1H-benzo[d]imidazol-2-yl)propyl)(methyl)amino)ethyl)-6-fluoro-1-isopropyl-1,2,3,4-tetrahydronaphthalen-2-yl methylcarbonate;

2-(2-((3-(4,7-dimethyl-1H-benzo[d]imidazol-2-yl)propyl)(methyl)amino)ethyl)-6-fluoro-1-isopropyl-1,2,3,4-tetrahydronaphthalen-2-yl methylcarbamate;

2-(2-((3-(4,7-dimethyl-1H-benzo[d]imidazol-2-yl)propyl)(methyl)amino)ethyl)-6-fluoro-1-isopropyl-1,2,3,4-tetrahydronaphthalen-2-yl (2-(dimethylamino)ethyl)carbamate;

2-(2-((3-(4,7-dimethoxy-1H-benzo[d]imidazol-2-yl)propyl)(methyl)amino)ethyl)-6-fluoro-1-isopropyl-1,2,3,4-tetrahydronaphthalen-2-yl methylcarbamate;

2-(2-((3-(4,7-dimethoxy-1H-benzo[d]imidazol-2-yl)propyl)(methyl)amino)ethyl)-6-fluoro-1-isopropyl-1,2,3,4-tetrahydronaphthalen-2-yl (2-methoxyethyl)carbamate;

2-(2-((3-(7-chloro-4-methoxy-1H-benzo [d]imidazol-2-yl)propyl)(methyl)amino)ethyl)-6-fluoro-1-isopropyl-1,2,3,4-tetrahydronaphthalen-2-yl dimethylcarbamate;

2-(2-((3-(4, 6-bi s(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)propyl)(methyl)amino)ethyl)-6-fluoro-1-isopropyl-1,2,3,4-tetrahydronaphthalen-2-yl morpholine-4-carboxylate;

2-(2-((3-(1H-benzo[d]imidazol-2-yl)-3-methylbutyl)(methyl)amino)ethyl)-6-fluoro-1-isopropyl-1,2,3,4-tetrahydronaphthalen-2-yl morpholine-4-carboxylate;

2-(2-((3-(1H-benzo[d]imidazol-2-yl)-3-methylbutyl)(methyl)amino)ethyl)-6-fluoro-1-isopropyl-1,2,3,4-tetrahydronaphthalen-2-yl methylcarbamate;

2-(2-((3-(1H-benzo[d]imidazol-2-yl)-3-methylbutyl)(methyl)amino)ethyl)-6-fluoro-1-isopropyl-1,2,3,4-tetrahydronaphthalen-2-yl (2-(dimethylamino)ethyl)carbamate;

2-(2-((3-(1H-benzo[d]imidazol-2-yl)-3-methylbutyl)(methyl)amino)ethyl)-6-fluoro-1-isopropyl-1,2, 3,4-tetrahydronaphthalen-2-yl (2-methoxyethyl)carbamate;

2-(2-((3-(1H-benzo[d]imidazol-2-yl)-3-methylbutyl)(methyl)amino)ethyl)-6-fluoro-1-isopropyl-1,2,3,4-tetrahydronaphthalen-2-yl (2-(pyrrolidin-1-yl)ethyl)carbamate;

2-(2-((3-(1H-benzo[d]imidazol-2-yl)-3-methylbutyl)(methyl)amino)ethyl)-6-fluoro-1-isopropyl-1,2,3,4-tetrahydronaphthalen-2-yl (2-(diethylamino)ethyl)carbamate;

2-(2-((3-(4, 7-dimethyl-1H-benzo[d]imidazol-2-yl)propyl)(methyl)amino)ethyl)-6-fluoro-1-isopropyl-1,2,3,4-tetrahydronaphthalen-2-yl morpholine-4-carboxylate;

2-(2-((3-(4, 7-dimethyl-1H-benzo[d]imidazol-2-yl)propyl)(methyl)amino)ethyl)-6-fluoro-1-isopropyl-1,2,3,4-tetrahydronaphthalen-2-yl dimethylcarbamate;

2-(2-((4-((2-amino-3, 6-dimethy 1 pheny 1)amino)-4-oxobuty 1)(ethy 1)amino)ethy 1)-6-fluoro-1-isopropyl-1,2,3,4-tetrahydronaphthalen-2-yl morpholine-4-carboxylate;

2-(2-((2-(1-(1H-benzo[d]imidazol-2-yl)cyclopropyl)ethyl)(methyl)amino)ethyl)-6-fluoro-1-isopropyl-1,2,3,4-tetrahydronaphthalen-2-yl morpholine-4-carboxylate;

3-(24(3-(1H-benzo[d]imidazol-2-yl)propyl)(methyl)amino)ethyl)-7-fluoro-4 isopropylchroman-3-yl methylcarbamate;

3-(24(3-(4, 7-dimethyl-1H-benzo[d]imidazol-2-yl)propyl)(methyl)amino)ethyl)-7-fluoro-4-isopropylchroman-3-yl methylcarbamate;

(1S,2S)-2-(2-((3-(1H-benzo[d]imidazol-2-yl)propyl)(methyl)amino)ethyl)-6-fluoro-1-isopropyl-1,2,3,4-tetrahydronaphthalen-2-yl methylcarbamate;

(1S,2S)-2-(2-((3-(1H-benzo[d]imidazol-2-yl)propyl)(methyl)amino)ethyl)-6-fluoro-1-isopropyl-1,2,3,4-tetrahydronaphthalen-2-yl methylcarbonate;

(1S,2S)-2-(2-((3-(4,7-dimethyl-1H-benzo[d]imidazol-2-yl)propyl)(methyl)amino)ethyl)-6-fluoro-1-isopropyl-1,2,3,4-tetrahydronaphthalen-2-yl methylcarbamate;

(1S,2S)-2-(2-((3-(4,7-dimethyl-1H-benzo[d]imidazol-2-yl)propyl)(methyl)amino)ethyl)-6-fluoro-1-isopropyl-1,2,3,4-tetrahydronaphthalen-2-yl (2-(dimethylamino)ethyl)carbamate;

(1S,2S)-2-(2-((3-(4,7-dimethoxy-1H-benzo[d]imidazol-2-yl)propyl)(methyl)amino)ethyl)-6-fluoro-1-isopropyl-1,2,3,4-tetrahydronaphthalen-2-yl methylcarbamate;

(1S,2S)-2-(2-((3-(4,7-dimethoxy-1H-benzo[d]imidazol-2-yl)propyl)(methyl)amino)ethyl)-6-fluoro-1-isopropyl-1,2,3,4-tetrahydronaphthalen-2-yl (2-methoxyethyl)carbamate;

(1S,2S)-2-(2-((3-(7-chloro-4-methoxy-1H-benzo [d]imidazol-2-yl)propyl)(methyl)amino)ethyl)-6-fluoro-1-isopropyl-1,2,3,4-tetrahydronaphthalen-2-yl dimethylcarbamate;

(1S,2S)-2-(2-((3-(4,6-bis(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)propyl)(methyl)amino)ethyl)-6-fluoro-1-isopropyl-1,2,3,4-tetrahydronaphthalen-2-yl morpholine-4-carboxylate;

(1S,2S)-2-(2-((3-(1H-benzo[d]imidazol-2-yl)-3-methylbutyl)(methyl)amino)ethyl)-6-fluoro-1-isopropyl-1,2,3,4-tetrahydronaphthalen-2-yl morpholine-4-carboxylate;

(1S,2S)-2-(2-((3-(1H-benzo[d]imidazol-2-yl)-3-methylbutyl)(methyl)amino)ethyl)-6-fluoro-1-isopropyl-1,2,3,4-tetrahydronaphthalen-2-yl methylcarbamate;

(1S,2S)-2-(2-((3-(1H-benzo[d]imidazol-2-yl)-3-methylbutyl)(methyl)amino)ethyl)-6-fluoro-1-isopropyl-1,2,3,4-tetrahydronaphthalen-2-yl (2-(dimethylamino)ethyl)carbamate;

(1S,2S)-2-(2-((3-(1H-benzo[d]imidazol-2-yl)-3-methylbutyl)(methyl)amino)ethyl)-6-fluoro-1-isopropyl-1,2,3,4-tetrahydronaphthalen-2-yl (2-methoxyethyl)carbamate;

(1S,2S)-2-(2-((3-(1H-benzo[d]imidazol-2-yl)-3-methylbutyl)(methyl)amino)ethyl)-6-fluoro-1-isopropyl-1,2,3,4-tetrahydronaphthalen-2-yl (2-(pyrrolidin-1-yl)ethyl)carbamate;

(1S,2S)-2-(2-((3-(1H-benzo[d]imidazol-2-yl)-3-methylbutyl)(methyl)amino)ethyl)-6-fluoro-1-isopropyl-1,2,3,4-tetrahydronaphthalen-2-yl (2-(diethylamino)ethyl)carbamate;

(1S,2S)-2-(2-((3-(4,7-dimethyl-1H-benzo[d]imidazol-2-yl)propyl)(methyl)amino)ethyl)-6-fluoro-1-isopropyl-1,2,3,4-tetrahydronaphthalen-2-yl morpholine-4-carboxylate;

(1S,2S)-2-(2-((3-(4,7-dimethyl-1H-benzo[d]imidazol-2-yl)propyl)(methyl)amino)ethyl)-6-fluoro-1-isopropyl-1,2,3,4-tetrahydronaphthalen-2-yl dimethylcarbamate;

(1R,2R)-2-(2-((3-(4,7-dimethyl-1H-benzo[d]imidazol-2-yl)propyl)(methyl)amino)ethyl)-6-fluoro-1-isopropyl-1,2,3,4-tetrahydronaphthalen-2-yl morpholine-4-carboxylate;

(1S,2S)-2-(2-((4-((2-amino-3,6-dimethylphenyl)amino)-4-oxobutyl)(ethyl)amino)ethyl)-6-fluoro-1-isopropyl-1,2,3,4-tetrahydronaphthalen-2-yl morpholine-4-carboxylate;

(1S,2S)-2-(24(2-(1-(1H-benzo[d]imidazol-2-yl)cyclopropyl)ethyl)(methyl)amino)ethyl)-6-fluoro-1-isopropyl-1,2,3,4-tetrahydronaphthalen-2-yl morpholine-4-carboxylate;

(3S,4S)-3-(24(3-(1H-benzo[d]imidazol-2-yl)propyl)(methyl)amino)ethyl)-7-fluoro-4-isopropylchroman-3-yl methylcarbamate;

(3R,4S)-3-(24(3-(1H-benzo[d]imidazol-2-yl)propyl)(methyl)amino)ethyl)-7-fluoro-4-isopropylchroman-3-yl methylcarbamate;

(3 S,4S)-3-(2-((3-(4,7-dimethyl-1H-benzo[d]imidazol-2-yl)propyl)(methyl)amino)ethyl)-7-fluoro-4-isopropylchroman-3-yl methylcarbamate; and

(3R,4S)-3-(24(3-(4, 7-dimethyl-1H-benzo[d]imidazol-2-yl)propyl)(methyl)amino)ethyl)-7-fluoro-4-isopropyl chroman-3-yl methylcarbamate;

or a pharmaceutically acceptable salt thereof.

18. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

19. A method of ameliorating a seizure disorder or epilepsy, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof.

20. The compound of claim 1 having the formula

or a pharmaceutically acceptable salt thereof.

21. The method of claim 19 wherein the compound has the formula

or a pharmaceutically acceptable salt thereof.