# US 9,750,719 B2 · Tetrazole compounds as calcium channel blockers

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- Number: US 9,750,719 B2
- Document ID: US9750719B2
- Status: Granted
- Kind: B2
- Application number: 14/802,982
- Filed: 2015-07-17
- Published: 2016-01-21
- Granted: 2017-09-05
- Earliest claimed: 2010-07-09
- Assignees: Convergence Pharmaceuticals Limited
- Applicants: Convergence Pharmaceuticals Limited
- Inventors: Paul Beswick; Robert James Gleave; Shuji Hachisu; Sadie Vile; Nicolas Bertheleme; Simon E. Ward
- Web page: https://patentgrep.com/patent/US9750719B2

## CPC

- A61K 31/41: having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K 31/435: having six-membered rings with one nitrogen as the only ring hetero atom
- A61K 31/4439: containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole (nicotine A61K31/465)
- A61K 31/496: Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
- A61K 31/4985: Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
- A61K 31/5377: not condensed and containing further heterocyclic rings, e.g. timolol
- A61K 31/5386: spiro-condensed or forming part of bridged ring systems
- A61K 31/541: Non-condensed thiazines containing further heterocyclic rings
- A61K 31/551: having two nitrogen atoms, e.g. dilazep
- A61P 23/00: Anaesthetics
- A61P 25/04: Centrally acting analgesics, e.g. opioids
- C07D 257/04: Five-membered rings
- C07D 257/06: with nitrogen atoms directly attached to the ring carbon atom
- C07D 401/14: containing three or more hetero rings
- C07D 403/06: linked by a carbon chain containing only aliphatic carbon atoms
- C07D 413/06: linked by a carbon chain containing only aliphatic carbon atoms
- C07D 417/06: linked by a carbon chain containing only aliphatic carbon atoms
- C07D 471/04: Ortho-condensed systems
- C07D 471/10: Spiro-condensed systems
- C07D 487/04: Ortho-condensed systems
- C07D 487/08: Bridged systems
- C07D 491/08: Bridged systems
- C07D 513/04: Ortho-condensed systems
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## Abstract

The present invention relates to novel tetrazole compounds; to processes for their preparation; to pharmaceutical compositions containing the compounds; and to the use of the compounds in therapy to treat diseases for which blocking the Cav2.2 calcium channels is beneficial. Formula (I) wherein A is: (II) or (III) wherein A is

## Claims

### Claim 1

A method for inhibiting CaV2.2 in a human or other mammal in need thereof comprising administering to said human or mammal a therapeutically effective amount of a compound or pharmaceutically acceptable salt according to the compound of Formula I:
wherein
A is
R1 is hydrogen, methyl or chloro;
R2 is hydrogen, trifluoromethyl, trifluoromethoxy, chloro or cyano;
R3 is hydrogen, cyano, trifluoromethyl, trifluoromethoxy, difluoromethoxy, chloro, bromo, —S—CH3, —SO2—C1-3alkyl or —SF5;
R4 is hydrogen, trifluoromethyl, trifluoromethoxy, chloro or cyano;
R5 is hydrogen, methyl or chloro;
wherein at least one of R1, R2, R3, R4 or R5 is a group other than hydrogen;
X is —CH2—, —CH2—CH2—or —CH(CH3)—;
wherein when R1 is methyl, R5 is hydrogen or chloro, and when R5 is methyl, R1 is hydrogen or chloro;
wherein when R2 is chloro, R4 is hydrogen, trifluoromethyl, trifluoromethoxy or cyano, and when R4 is chloro, R2 is hydrogen, trifluoromethyl, trifluoromethoxy or cyano;
R6 is hydrogen and R7 is C1-5 alkyl or C3-6cycloalkyl; or R6 and R7 together with the nitrogen atom to which they are attached form a saturated ring system B, where B is selected from
a) a 4 to 7 membered monocyclic heterocyclic ring,
b) a 5 to 10 membered fused bicyclic ring system;
c) a bridged 4 to 7 membered monocyclic heterocyclic ring system; and
d) a 7 to 11 membered spiro ring system;
which ring system B is unsubstituted or substituted with 1 to 3 substituents independently selected from halogen, oxo, C1-3alkyl, cyano, —SO2—C1-3alkyl, C1-3haloalkyl and —CO—C1-3alkyl.

### Claim 2 (depends on 1)

The method according to claim 1 wherein said compound or pharmaceutically acceptable salt is selected from the group consisting of 4-{[1-(4-chlorophenyl)-1H-tetrazol-5-yl]methyl}morpholine, 4-({1-[3-(trifluoromethyl)phenyl]-1H-tetrazol-5-yl}methyl)morpholine hydrochloride, 4-({1-[3-(trifluoromethyl)phenyl]-1H-tetrazol-5-yl}methyl)morpholine, 4-{[1-(3,4-dichlorophenyl)-1H-tetrazol-5-yl]methyl}morpholine, 1-{[1-(4-chlorophenyl)-1H-tetrazol-5-yl]methyl}-4-(methylsulfonyl)piperazine, 1-{[1-(4-chlorophenyl)-1H-tetrazol-5-yl]methyl}-4-(propylsulfonyl)piperazine; 1-{[1-(3,4-dichlorophenyl)-1H-tetrazol-5-yl]methyl}piperidine; 1-{[1-(4-chlorophenyl)-1H-tetrazol-5-yl]methyl}-4-methylpiperidine; 1-}[1-(4-chlorophenyl)-1H-tetrazol-5-yl]methyl}piperidine; 1-{[1-(4-chlorophenyl)-1H-tetrazol-5-yl]methyl-4-(ethylsulfonyl)piperazine; 1-{[1-(4-chlorophenyl)-1H-tetrazol-5-yl]methyl}-2-methylpiperidine; 1-{[1-(4-chlorophenyl)-1H-tetrazol-5-yl]methyl}piperazine; 1-(4-chlorophenyl)-5-(1-pyrrolidinylmethyl)-1H-tetrazole; 1-{[1-(4-chlorophenyl)-1H-tetrazol-5-yl]methyl}-4-methylpiperazine; and 1-{[1-(4-chlorophenyl)-1H-tetrazol-5-yl]methyl}hexahydro-1H-azepine.

### Claim 3 (depends on 1)

The method according to claim 1 wherein the compound or pharmaceutically acceptable salt is of the formula (1a):
wherein
R1 is hydrogen, methyl or chloro;
R2 is hydrogen or trifluoromethyl;
R3 is hydrogen, cyano, trifluoromethyl, trifluoromethoxy or chloro;
R4 is hydrogen or trifluoromethyl;
R5 is hydrogen, methyl or chloro;
X is —CH2—or —CH2—CH2;
wherein when R1 is methyl, R5 is hydrogen or chloro, and when R5 is methyl, R1 is hydrogen or chloro;
R6 is hydrogen and R7 is C1-3alkyl; or R6 and R7 together with the nitrogen atom to which they are attached form a 5 to 6 membered heterocyclyl ring or 2,8-diazaspiro[4.5]decan-1-one group either of which is unsubstituted or substituted with 1 or 2 substituents independently selected from halogen, oxo and C1-3alkyl; with the proviso that the compound is not 4-{[1-(4-chlorophenyl)-1H-tetrazol-5-yl]methyl}morpholine, 4-({1-[3-(trifluoromethyl)phenyl]-1H-tetrazol-5-yl}methyl)morpholine hydrochloride or 4-({1[3-(trifluoromethyl)phenyl]-1H-tetrazol-5-yl}methyl)morpholine.

### Claim 4 (depends on 1)

The method according to claim 1 wherein R6 is hydrogen and R7 is C1-5alkyl or C3-6cycloalkyl; or R6 and R7 together with the nitrogen atom to which they are attached forms a saturated ring system B, where B is selected from
a) a 4 to 7 membered monocyclic heterocyclic ring,
b) a 5 to 10 membered fused bicyclic ring system;
c) a bridged 4 to 7 membered monocyclic heterocyclic ring system; and
d) a 7 to 11 membered spiro ring system; which ring system B is unsubstituted or substituted with 1 to 3 substituents independently selected from halogen, oxo, C1-3alkyl, cyano, —SO2—C1-3alkyl and C1-3haloalkyl.

### Claim 5 (depends on 1)

The method according to claim 1 wherein R6 and R7 together with the nitrogen atom to which they are attached forms a saturated ring system B, where B is selected from
a) a 4 to 7 membered monocyclic heterocyclic ring,
b) a 5 to 10 membered fused bicyclic ring system;
c) a bridged 4 to 7 membered monocyclic heterocyclic ring system; and
d) a 7 to 11 membered spiro ring system;
which ring system B is unsubstituted or substituted with 1 to 3 substituents independently selected from halogen, oxo, C1-3alkyl, cyano, —SO2—C1-3alkyl and C1-3haloalkyl.

### Claim 6 (depends on 1)

The method according to claim 1 wherein R6 and R7 together with the nitrogen atom to which they are attached form a saturated ring system B, where B is selected from
a) a 4 to 7 membered monocyclic heterocyclic ring,
b) a 5 to 10 membered fused bicyclic ring system; and
c) a bridged 4 to 7 membered monocyclic heterocyclic ring system;
which ring system B is unsubstituted or substituted with 1 to 3 substituents independently selected from halogen, oxo, C1-3alkyl, cyano, —SO2—C1-3alkyl and C1-3haloalkyl.

### Claim 7 (depends on 1)

The method according to claim 1 wherein R6 and R7 together with the nitrogen atom to which they are attached form a saturated ring system B, where B is selected from
a) a 4 to 7 membered monocyclic heterocyclic ring selected from
pyrrolidine ring,
morpholine ring,
thiomorpholine ring,
piperazine ring, and
azetidine ring,
b) a 5 to 10 membered fused bicyclic ring system selected from
octahydropyrrolo[1,2-a]pyrazine group,
hexahydro-2H-isothiazolo[2,3-a]pyrazine group, and
octahydro-pyrido[1,2-a]pyrazine group,
c) a bridged 4 to 7 membered monocyclic heterocyclic ring system selected from
2-oxa-5-azabicyclo[2.2.1]heptane group, and
2,5-diazabicyclo[2.2.1]heptane group;
which ring system B is unsubstituted or substituted with 1 to 3 substituents independently selected from halogen, oxo, C1-3alkyl, cyano, —SO2—C1-3alkyl and C1-3haloalkyl.

### Claim 8 (depends on 1)

The method according to claim 1 wherein R6 and R7 together with the nitrogen atom to which they are attached form a saturated ring system B, where B is selected from
a) a 4 to 7 membered monocyclic heterocyclic ring selected from
pyrrolidine ring,
morpholine ring, and
piperazine ring,
c) a bridged 4 to 7 membered monocyclic heterocyclic ring system selected from
2-oxa-5-azabicyclo[2.2.1]heptane group, and
2,5-diazabicyclo[2.2.1]heptane group;
which ring system B is unsubstituted or substituted with 1 to 3 substituents independently selected from halogen, oxo, C1-3alkyl, cyano, —SO2—C1-3alkyl and C1-3haloalkyl.

### Claim 9 (depends on 1)

The method according to claim 1, wherein R6 and R7 together with the nitrogen atom to which they are attached form a saturated ring system B, where B is selected from
a) a 4 to 7 membered monocyclic heterocyclic ring selected from
pyrrolidine ring,
morphonline ring, and
piperazine ring,
c) a bridged 4 to 7 membered monocyclic heterocyclic ring system selected from
2-oxa-5-azabicyclo[2.2.1]heptane group, and
2,5-diazabicyclo[2.2.1]heptane group;
which ring system B is unsubstituted or substituted with 1 to 3 substituents independently selected from fluoro, oxo, methyl, ethyl, propyl, cyano, —SO2—CH3, —SO2—(CH2)CH3, —SO2—(CH2)2CH3 and trifluoromethyl.

### Claim 10 (depends on 1)

The method according to claim 1, wherein R1 is hydrogen or methyl.

### Claim 11 (depends on 1)

The method according to claim 1, wherein R2 is hydrogen, trifluoromethyl or chloro.

### Claim 12 (depends on 1)

The method according to claim 1, wherein R3 is hydrogen, trifluoromethyl or cyano.

### Claim 13 (depends on 1)

The method according to claim 1, wherein R5 is hydrogen or methyl.

### Claim 14 (depends on 1)

The method according to claim 1, wherein R3 is trifluoromethyl and R1, R2, R4 and R5 are hydrogen.

### Claim 15 (depends on 1)

The method according to claim 1, wherein R2 is trifluoromethyl and R1, R3, R4 and R5 are hydrogen.

### Claim 16 (depends on 1)

The method according to claim 1, wherein R3 is cyano and R1, R2, R4 and R5 are hydrogen.

### Claim 17 (depends on 1)

The method according to claim 1, wherein X is —CH2—.

### Claim 18 (depends on 1)

The method according to claim 1, wherein a compound or pharmaceutically acceptable salt is selected from the group consisting of compounds 1 to 100:
1 5-[(3,3-Difluoro-1-pyrrolidinyl)methyl]-1-[4-(trifluoromethy)phenyl]-1H-tetrazole
2 (cis)-2,6-Dimethyl-4-({1-[4-(trifluoromethyl)phenyl[-1H-tetrazol-5-yl}methyl)morpholine
3 (cis)-2,6-Dimethyl-4-({1-[3-(trifluoromethyl)phenyl[-1H-tetrazol-5-yl}methyl)morpholine
4 4-({1-[4(Trifluoromethyl)phenyl]-1H-tetrarol-5-yl}methyl)morpholine
5 4-({1-[2-Chloro-4-(trifluoromethy)phenyl]-1H-tetrazol-5-yl}methyl)morpholine
6 5-[2-(3,3-Difluoro-1-pyrrolidinyl)ethyl]-1-[4-(trifluoromethyl)phenyl]1H-tetrazole
7 5-(1-Pyrrolidinylmethyl)-1-[4-(trifluoromethyl)phenyl]-1H-tetrazole
8 N-({1-[4(Trifluoromethyl)phenyl]-1H-tetrazol-5-yl}methyl)-2-propanamine
9 4-(2-{1-[4(Trifluoromethyl)phenyl]1H-tetrazol-5-yl}ethyl)morpholine hydrochloride
10 4-{[1-(2,4-Dichlorophenyl)-1H-tetrazol-5-yl]methyl}morpholine
11 (cis)-4-(5-{[2,6-Dimethyl-4-morpholinyl]methyl}-1H-tetrazol-1-yl)benzonitrile
12 8-({1-[3-(Trifluoromethyl)phenyl]-1H-tetrazol-5-yl)methyl)-2,8-diazaspiro[4.5]decan-1-one
13 (cis)-4-{[1-(4-Chlorophenyl)-1H-tetrazol-5-yl]methyl }-2,6-dimethylmorplioline
14 4[(1-{4-[(Trifluoromethyl)oxy]phenyl}-1H-tetrazol-5-yl)methyl]morpholine
15 4-({1-[3-(Trifluoromethyl)phenyl[-1H-tetrazol-5-yl}methyl)thiomorpholine 1,1-dioxide
16 (cis)-2,6-Dimethyl-4-[4-(trifluoromethyl)phenyl]-1H-tetrazol-5-yl}ethyl)morpholine
17 4-{5-[(3,3-Difluoro-1-pyrrolidinyl)methyl-]-1 H-tetrazol-1-yl}benzonitrile
18 1-(4Chlorophenyl)-5-[(3,3-difluoro-1-pyrrolidinyl)methyl]-1H-tetrazole
19 4-({1-[3-(Trifluoromethyl)phenyl-]1H-tetrazol-5-yl})methyl)morpholine
19a 4-({1-[3-(trifitioromethyl)phenyl-]-1H-tetrazol-5-yl}methyl)morpholine hydrochloride salt
20 4-{[1-(4-Chlorophenyl)-1H-tetrazol-5-yl]methyl}morpholine
21 4-{[1-(3,4- Dichlorophenyl)-1H-tetrazol-5-yl]methyl}morpholine
22 1-{[1-(4-Chlorophenyl)-1H-tetrazol-5-yl]methyl}-4-(methylsulfonyl)piperazine
23 1-{[1-(4-Chlorophenyl)-1H-tetrazol-5-yl]methyl}-4propysulfonyl)piperazine
24 1-({1-[3(Trifluromethyl)phenyl]-1H-tetrazol-5-yl}methyl)-3-pyrrolidinecarbonitrile hydrochloride
25 (3R)-3-Methyl-4-({1-[3-(trifluoromethyl)phenyl]-1H-tetrazol-5-yl}methyl)morpholine hydrochloride
26 (cis)-2,6-Dimethyl-4-({1-[4-(methylthio)phenyl]-1H-tetrazol-5-yl}methyl)morpholine
27 4-(5-{[cis-2,6-Dimethyl-4-morpholinyl]methyl}-1H- tetrazol-1-yl)-3-methylbenzonitrile hydrochloride
28 (3R)-3-Methyl-4-({1-[4-(trifluoromethyl)phenyl]-1H-tetrazol-5-yl}methyl)morpholine hydrochloride
29 3,3-Dimethyl-4-({1-[3-trifluoromethyl)phenyl]-1H-tetrazol-5-yl}methyl)morpholine
30 4-(5-{]cis-2,6-Dimethyl-4-morpholinyl]methyl}-1H- tetrazol-1-yl)-2-(trifluoromethyl)benzonitrile
31 1-Methyl-4-({1-[4-(trifluoromethyl)phenyl]-1H-tetrazol-5-yl}methyl)piperazine dihydrochloride
32 3-Methyl-4-({1-[3-(trifluoromethyl)phenyl]-1H- tetrazol-5-yl)}methyl)-2-piperazinone
33 1,3-Dimethyl-4-({1-[3(trifluoromethyl)phenyl[-1H-tetrazol-5-yl}methyl)-2-piperazinone
34 4-[5-(4-Morpholinylmethyl)-1H-tetrazol-1-yl]-2(trifluoromethyl)benzonitrile hydrochloride
35 3-Methyl-1-(1-methylethyl)-4-({1-[3-(trifluoromethyl)phenyl]-1H-tetrazol-5-yl}methyl)-2-piperazinone
36 4-({1-[3-(Trifluoromethyl)phenyl]-1H-tetrazol-5-yl}methyl)-2-piperazinone
37 4-(5-{[(cis)-2,5Dimethyl-1-pyrrolidinyl]methyl}-1H-tetrazol-1-yl)benzonitrile
38 4-({1-[5-(Trifluoromethyl)-2-pyridinyl]-1H-tetrazol-5-yl}methyl)morpholine
39 (3S)-3-Methyl-4-({1-[4(trifluoromethyl)phenyl]-1H-tetrazol-5-yl}methyl)morpholine hydrochloride
40 4-(1-{1-4-Trifluoromethyl)phenyl]-1H-tetrazol-5-yl}ethyl)morpholine
41 4-(5-{[(3R)-3-Methyl-4-morpholinyl]methyl}-1H-tetrazol-1-yl)-2-(trifluoromethyl)benzonitrile
42 (3R)-3-Methyl-4-({1-[5(trifluoromethyl)-2-pyridinyl]-1H-tetrazol-5-yl}methyl)morpholine
43 (1S,4S)-5-({1-[4-(Trifluoromethyl)phenyl]-1H-tetrazol-5-yl}methyl)-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride
44 4-{5-[(1S,4S)-2-Oxa-5-azabicyclo[2.2.1]hept-5-ylmethyl]-1H-tetrazol-1-yl}-2-(trifluoromethyl)benzonitrile
45 1,2,2-Trimethyl-4-({1-[3-(trifluoromethyl)phenyl]-1H-tetrazol-5-yl}methyl)piperazine hydrochloride
46 1({1-[4-(Trifluoromethy)phenyl]-1H-tetrazol-5-yl}methyl)piperazine
47 1-(Ethylsulfonyl)-4-({1-[4-(trifluoromethyl)phenyl-1H-tetrazol-5-yl}methyl)piperazine
48 1-(Ethylsulfonyl)-4-({1-[3-(trifluoromethyl)phenyl]-1H-tetrazol-5-yl}methyl)piperazine
49 4-(5-{[(2S)-2-(Trifluoromethyl)-1-pyrrolidinyl]methyl}-1H-tetrazol-1-yl)benzonitrile
50 (1S,4S)-2-({1-[4-Trifluoromethyl)phenyl]-1H-tetrazol-5-yl}methyl)-2,5-diazabicyclo[2.2.1]heptane
51 (1S,4S)-2-(1-Methylethyl)-5-({1-[4-(trifluoromethyl)phenyl]-1H-tetrazol-5-yl}methyl)-2,5-diazabicyclo[2.2.1]heptane hydrochloride
52 (3R)-1-Ethyl-3-methyl-4-(trifluoromethy)phenyl[-1H-tetrazol-5-yl}methyl)-2-piperazinone
53 4-{5-[(3,3-Dimethyl-4-morpholinyl)methyl]-1H-tetrazol-1-yl}benzonitrile
54 (3R)-4-[(1-{4-[(Difluoromethyl)oxy]phenyl}-1H-tetrazol-5-yl)methyl}-3-methylmorpholine hydrochloride
55 (cis)-4-{[1-(4Bromo-2-methylphenyl)-1H-tetrazol-5-yl]methyl}-2,6-dimethylmorpholine hydrochloride
56 4-[5-(1-Pyrrolidinylmethyl)-1H-tetrazol-1-yl)benzonitrile hydrochloride
57 cis-4-{[1-(4-Bromo-2-chlorophenyl)-1H-tetrazol-5-yl[methyl}-2,6-dimethylmorpholine hydrochloride
58 (1S,4S)-5-({1-[5-(Trifluoromethyl)-2- pyridinyl[-1H-tetrazol-5-}methyl)-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride
59 3-(5-{[(cis)-2,6-Dimethyl-4-morpholinyl]methyl}-1H-tetrazol-1-yl)benzonitrile hydrochloride
60 4-{5-[(Cyclohexylamino)methyl]-1H-tetrazol-1-yl}benzonitrile hydrochloride
61 4-(5-{[(1-Ethylpropyl)amino]methyl}-1H-tetrazol-1-yl)benzonitrile hydrochloride
62 N-({1-[3-(Trifluoromethyl)phenyl]-1H-tetrazol-5}methyl)cyclopentanamine hydrochloride
63 N-({1-[3-(Trifluoromethyl)phenyl]-1H-tetrazol-5-yl}methyl)-3-pentanamine hydrochloride
64 (cis)-3,5-dimethyl-4({1-[3-(Trifluoromethyl)phenyl]-1H-tetrazol-5-yl}methyl)morpholine hydrochloride
65 N-({1-[3-(Trifluoromethyl)phenyl]-1H-tetrazol-5-yl}methyl)cyclohexanamine hydrochloride
66 cis-1,2,6-Trimethyl-4-({1-[3-(trifluoromethyl)phenyl]-1H-tetrazol-5-yl}methyl)piperazine formate salt
67 1,2-Dimethyl-4-({1-[3-(trifluoromethyl)phenyl]-1H-tetrazole-5-yl}methyl)piperazine dihydrochloride
68 5-(1-Azetidinylmethyl)-1-[4-(trifluoromethyl)phenyl]-1H-tetrazole hydrochloride
69 4-(5-{[(2S)-2-Methyl-1pyrrolidinyl]methyl}-1H-tetrazol-1-yl)benzonitrile
70 2-({1-[4-(Trifluoromethyl)phenyl]-1H-tetrazol-5-yl}methyl)octahydropyrrolo[1,2-a]{pyrazine dihydrochloride
71 1-(Methylsulfonyl)-4-({1-[4-(trifluoromethyl)phenyl]-1H-tetrazol-5-yl}methyl)piperazine
72 1(Methylsulfonyl)-4-({1-[3-(trifluoromethyl)phenyl]-1H-tetrazol-5-yl}methyl)piperazine
73 4-(5-{[(2R)-2-(Trifluoromethyl)-1-pyrrolidinyl]methyl}-1H-tetrazol-1-yl)benzonitrile
74 2-({1-[4-(Trifluoromethyl)phenyl]-1H-tetrazol-5-yl}methyl)hexahydropyrrolo[1,2-a]pyrazin-6(2H)-one
75 5-(1-Azetidinylmethyl)-1-[3-(trifluoromethyl)phenyl]-1H-tetrazole
76 (8aR)-2-({1-[4-(Trifluoromethyl)phenyl]-1H-tetrazol-5-yl}methyl)octahydropyrrolo[1,2-a]pyrazine
77 8a-(Fluoromethyl)-2-({1-[4-(Trifluoromethyl)phenyl]-1H-tetrazol-5-yl}methyl)octahydropyrrolo[1,2-a]pyrazine
78 5-({1-[4-(Trifluoromethyl)phenyl]-1H-tetrazol-5-yl}methyl)hexahydro-2H-isothiazolo[2,3-a]pyrazine 1,1-dioxide
79 5-({1-[3-(Trifluoromethyl)phenyl]-1H-tetrazol-5-yl}methyl)hexahydro-2H-isothiazolo[2,3-a]pyrazine 1,1-dioxide
80 2-({1-[4-(Trifluoromethyl)phenyl]-1H-tetrazol-5-yl}methyl)octahydro-2H-pyrido[1,2-a]pyrazine
81 4-{5-[(3,4-Dimethyl-1-piperazinyl)methyl]-1H-tetrazol-1-yl}benzonitrile dichydrochloride
82 4-(5-{[4-(1-Methylethyl)-1piperazinyl]methyl}-1H-tetrazol-1-yl)benzonitrile dichydrochloride
83 4-{5-[(4-Methyl-1-piperazinyl)methyl]-1-yl}benzonitrile hydrochloride
84 1-Ethyl-3-methyl-4-({1-[3-(trifluoromethyl)phenyl]-1H-tetrazol-5-yl}methyl)-2-piperazinone
85 1-Methyl-4-({1-[3-(trifluoromethyl)phenyl]-1H-tetrazol-5-yl}methyl)-2-piperazinone
86 1-Ethyl-4-({1-[3-(trifluoromethyl)phenyl]-1H-tetrazol-5-yl}methyl)-2-piperazinone
87 1-(1-Methylethyl)-4-({1-[3-trifluoromethyl)phenyl]-1H-tetrazol-5-yl}methyl)-2-piperazinone
88 (3S)-3-Methyl-1-(-1-methylethyl)-4-({(trifluoromethyl)phenyl]-1H-tetrazol-5-yl}methyl)-2-piperazinone
89 (3R)-1,3-Dimethyl-4-({1-[4-trifluoromethyl)phenyl]-1H-tetrazol-5-yl}methyl)-2-piperazinone
90 (3R)-3-Methyl-1-(1-methylethyl)-4-({1-[4-(trifluoromethyl)phenyl]-1H-tetrazol-5-yl}methyl)-2-piperazinone
91 1-Ethyl-2,2-dimethyl-4-({1-[3-(trifluoromethyl)phenyl]-1H-tetrazol-5-yl}methyl)piperazine hydrochloride
92 (2R)-4-Ethyl-2methyl-1-({1-[3-(trifluoromethyl)phenyl]-1H-tetrazol-5-yl}methyl)piperazine hydrochloride
93 (2R)-2,4-Dimethyl-1-({1-[3-(trifluoromethyl)phenyl]-1H-tetrazol-5-yl}methyl)piperazine hydrochloride
94 (2R)-2-Methyl-4-(1-methylethyl)-1-({1-[3-(trifluoromethyl)phenyl]-1H-tetrazol-5-yl}methyl)piperazine hydrochloride
95 1-Ethyl-4-({1-[4-(trifluoromethyl)phenyl]-1H-tetrazol-5-yl}methyl)piperazine hydrochloride
96 1-(1-Methylethyl)-4-({1-[4-(trifluoromethyl)phenyl]-1H-tetrazol-5-yl}methyl)piperazine
97 (1S,4S)-2-Ethyl-5-({1-[4-(trifluoromethyl)phenyl]-1H-tetrazol-5-yl}methyl)-2,5-diazabicyclo[2.2.1]heptane hydrochloride
98 (1S,4S)-2-Methyl-5-({1-[4-((trifluoromethyl)phenyl]-1H-tetrazol -5-yl}methyl)-2,5-diazabicyclo[2.2.1]heptane hydrochloride
99 3,3-Dimethyl-1-({1-[4-(trifluorornethyl)phenyl]-1H-tetrazol-5-yl}methyl)piperazine dihydrochloride
100 3-Methyl-1-({1-[4-(trifluorornethyl)phenyl]-1H-tetrazol-5-yl}methyl)piperazine dihydrochloride
and a pharmaceutically acceptable salt thereof.