IP Library › Granted Patent US 8,153,635

Granted Patent B2

US 8,153,635 · App. 12/204,600 · Granted Apr 10, 2012

Compounds and compositions as modulators of GPR119 activity

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Patent No.: US 8,153,635
App. No.: 12/204,600
Granted: Apr 10, 2012
Kind: B2

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Abstract

The invention provides compounds of Formula I: wherein A, L, m, q, Q, R 1 , R 2 , R 3 , R 4 and R 5 are defined in the Summary of the Invention. The invention further provides for pharmaceutical compositions comprising such compounds and methods of using such compounds to treat or prevent diseases or disorders associated with the activity of GPR119.

Claims (187)

1. A compound of Formula I:

or a pharmaceutically acceptable salt thereof; in which:

Q is a divalent radical selected from C 6-10 aryl, C 3-10 heteroaryl, C 3-8 cycloalkyl and C 3-8 heterocycloalkyl; wherein said aryl, heteroaryl, cycloalkyl or heterocycloalkyl of Q is optionally substituted with up to 3 radicals independently selected from halo, C 1-6 alkyl, halo-substituted-C 1-6 alkyk C 1-6 alkoxy, halo-substituted-C 1-6 alkoxy, —C(O)R 20 and —C(O)OR 20 ;

wherein R 20 is selected from hydrogen and C 1-6 alkyl;

ring A can have one ring carbon replaced by a —C(O)—;

L is selected from C 1-6 alkylene, C 2-6 alkenylene, —(CH 2 ) n O—, —OC(O)(CH 2 ) n —, —C(O)O(CH 2 ) n —, —NR 26 (CH 2 ) n — and —O(CH 2 ) n —; wherein

R 26 is selected from hydrogen and C 1-6 alkyl;

n is selected from 0, 1, 2, 3, 4 and 5;

any alkyl of L can be optionally substituted with 1 to 3 radicals independently selected from halo, C 1-6 alkyl, halo-substituted-C 1-6 alkyl, C 1-6 alkoxy, halo-substituted-C 1-6 alkoxy, —C(O)R 22 and —C(O)OR 22 ; wherein R 22 is selected from hydrogen and C 1-6 alkyl;

m is selected from 0, 1, 2, 3 and 4;

q is selected from 0, 1, 2, 3 and 4;

R 1 is selected from —X 1 S(O) 0-2 X 2 R 6a , —X 1 S(O) 0-2 X 2 OR 6a , —X 1 S(O) 0-2 X 2 C(O)R 6a , —X 1 S(O) 0-2 X 2 C(O)OR 6a , —X 1 S(O) 0-2 X 2 OC(O)R 6a and —X 1 S(O) 0-2 NR 6a R 6b ; wherein

X 1 is selected from a bond, O, NR 7a and C 1-4 alkylene; wherein R 7a is selected from hydrogen and C 1-6 alkyl;

X 2 is selected from a bond and C 1-4 alkylene;

R 6a is selected from hydrogen, halo, C 1-6 alkyl, C 2-6 alkenyl, C 6-10 aryl, C 3-10 heteroaryl, C 3-8 heterocycloalkyl and C 3-8 cycloalkyl; wherein said aryl, heteroaryl, cycloalkyl and heterocycloalkyl of R 6a is optionally substituted with 1 to 3 radicals independently selected from hydroxyl, halo, C 1-6 alkyl, halo-substituted-C 1-6 alkyl, hydroxyl-substituted-C 1-6 alkyl, cyano-substituted-C 1-6 alkyl, C 1-6 alkoxy, halo-substituted-C 1-6 alkoxy and C 6-10 aryl-C 1-4 alkoxy; and

R 6b is selected from hydrogen and C 1-6 alkyl;

R 2 and R 3 are independently selected from hydrogen, halo, hydroxyl, C 1-6 alkyl, halo-substituted-C 1-6 alkyl, hydroxyl-substituted-C 1-6 alkyl, C 1-6 alkoxy, halo-substituted-C 1-6 alkoxy, —C(O)R 23 , and —C(O)OR 23 , wherein R 23 is selected from hydrogen and C 1-6 alkyl;

R 4 is selected from R 8 and —C(O)OR 8 ; wherein R 8 is selected from C 1-6 alkyl, C 6-10 aryl, C 3-10 heteroaryl, C 3-8 cycloalkyl and C 3-8 heterocycloalkyl; wherein said aryl, heteroaryl, cycloalkyl or heterocycloalkyl of R 8 is optionally substituted with 1 to 3 radicals independently selected from halo, C 1-6 alkyl, C 3-8 cycloalkyl, C 3-8 heterocycloalkyl, halo-substituted-C 1-6 alkyl, hydroxyl-substituted-C 1-6 alkyl, C 1-6 alkoxy and halo-substituted-C 1-6 alkoxy; and

R 5 is selected from hydrogen, C 1-6 alkyl, halo-substituted-C 1-6 alkyl, hydroxyl-substituted-C 1-6 alkyl, C 1-6 alkoxy and halo-substituted-C 1-6 alkoxy.

2. The compound of claim 1 of Formula Ia:

in which:

Q is a divalent radical selected from C 6-10 aryl and C 3-10 heteroaryl; wherein said aryl and heteroaryl of Q is optionally substituted with up to 3 radicals independently selected from halo, C 1-6 alkyl, halo-substituted-C 1-6 alkyl, C 1-6 alkoxy, halo-substituted-C 1-6 alkoxy, —C(O)R 20 and —C(O)OR 20 ; wherein R 20 is selected from hydrogen and C 1-6 alkyl.

3. The compound of claim 2 in which Q is a divalent radical selected from phenyl, pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, 1,2,4-oxadiazolyl, and thiazolyl; wherein said phenyl, pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl and thiazolyl of Q is optionally substituted with up to 3 radicals independently selected from halo, C 1-6 alkyl, C 1-6 alkoxy, halo-substituted-C 1-6 alkyl, —C(O)OR 20 and —C(O)R 20 ; wherein R 20 is selected from hydrogen and C 1-6 alkyl.

4. The compound of claim 3 in which:

L is selected from —O(CH 2 ) 0-4 —, —(CH═CH)—, —OC(O)—, —NH(CH 2 ) 0-4 —, —NCH 3 (CH 2 ) 0-4 — and —(CH 2 ) 1-4 —.

5. The compound of claim 4 in which:

R 1 is selected from —S(O) 0-2 X 2 R 6a , —S(O) 0-2 X 2 OR 6a , —S(O) 0-2 X 2 C(O)OR 6a , —S(O) 0-2 X 2 OC(O)R 6a and —S(O) 0-2 NR 6a R 6b ; wherein

X 2 is selected from a bond and C 1-4 alkylene;

R 6a is selected from hydrogen, halo, methyl, ethyl, propyl, isopropyl, ethenyl, pyridinyl, pyrrolidinyl, piperidinyl, morpholino, isoxazolyl, tetrazolyl, phenyl and imidazolyl; wherein said piperidinyl, pyridinyl, pyrrolidinyl, morpholino, isoxazolyl, tetrazolyl, phenyl or imidazolyl of R 6a is optionally substituted with 1 to 3 radicals independently selected from hydroxy, halo, C 1-6 alkyl and benzoxy; and

R 6b is selected from hydrogen, methyl and ethyl.

6. The compound of claim 5 in which:

R 4 is selected from R 8 and —C(O)OR 8 ; wherein R 8 is selected from isopropyl, cyclopropyl, t-butyl, 1,2,4-oxadiazolyl, pyrimidinyl, pyridinyl, pyridazinyl, tetrahydro-2H-pyranyl, tetrahydrofuranyl, oxetanyl, 2H-tetrazolyl and thiazolyl; wherein said cyclopropyl, 1,2,4-oxadiazolyl, pyrimidinyl, pyridinyl, pyridazinyl, tetrahydro-2H-pyranyl, tetrahydrofuranyl, oxetanyl, 2H-tetrazolyl or thiazolyl of R 8 is optionally substituted with 1 to 3 radicals independently selected from halo, trifluoromethyl, isopropyl, t-butyl, methyl, ethyl and cyclopropyl; and

R 5 is selected from hydrogen and methoxy.

7. The compound of claim 1 selected from:

1-Methylcyclopropyl 4-((5-(4-(methylsulfonyl)piperazin-1-yl)pyrazin-2-yloxy)methyl)piperidine-1-carboxylate;

Isopropyl 4-((4-((4-methanesulfonylpiperazin)-1-yl)phenoxy)methyl)piperidine-1-carboxylate;

Isopropyl 4-(2-(4-(4-(methylsulfonyl)piperazin-1-yl)phenoxy)ethyl)piperidine-1-carboxylate;

Isopropyl 4-(3-(4-(4-(methylsulfonyl)piperazin-1-yl)phenoxy)propyl)piperidine-1-carboxylate;

Isopropyl 4-(4-(4-(4-(methylsulfonyl)piperazin-1-yl)phenoxy)butyl)piperidine-1-carboxylate;

Isopropyl 4-((6-(4-(methylsulfonyl)piperazin-1-yl)pyridin-3-yloxy)methyl)piperidine-1-carboxylate;

tert-Butyl 4-((6-(4-(methylsulfonyl)piperazin-1-yl)pyridin-3-yloxy)methyl)piperidine-1-carboxylate;

Isopropyl 4-((5-(4-(methylsulfonyl)piperazin-1-yl)pyrazin-2-yloxy)methyl)piperidine-1-carboxylate;

tert-Butyl 4-((5-(4-(methylsulfonyl)piperazin-1-yl)pyrazin-2-yloxy)methyl)piperidine-1-carboxylate;

3-Cyclopropyl-5-(4-((5-(4-(methylsulfonyl)piperazin-1-yl)pyrazin-2-yloxy)methyl)piperidin-1-yl)-1,2,4-oxadiazole;

5-Cyclopropyl-3-(4-((5-(4-(methylsulfonyl)piperazin-1-yl)pyrazin-2-yloxy)methyl)piperidin-1-yl)-1,2,4-oxadiazole;

2-(4-(Methylsulfonyl)piperazin-1-yl)-5-((1-(5-(trifluoromethyl)pyridin-2-yl)piperidin-4-yl)methoxy)pyrazine;

5-Isopropyl-3-(4-((5-(4-(methylsulfonyl)piperazin-1-yl)pyrazin-2-yloxy)methyl)piperidin-1-yl)-1,2,4-oxadiazole;

Tetrahydro-2H-pyran-4-yl 4-((5-(4-(methylsulfonyl)piperazin-1-yl)pyrazin-2-yloxy)methyl)piperidine-1-carboxylate;

(S)-Tetrahydrofuran-3-yl 4-((5-(4-(methylsulfonyl)piperazin-1-yl)pyrazin-2-yloxy)methyl)piperidine-1-carboxylate;

(R)-Tetrahydrofuran-3-yl 4-((5-(4-(methyl sulfonyl)piperazin-1-yl)pyrazin-2-yloxy)methyl)piperidine-1-carboxylate;

2-Isopropyl-5-(4-((5-(4-(methylsulfonyl)piperazin-1-yl)pyrazin-2-yloxy)methyl)piperidin-1-yl)thiazole;

2-((1-(2-Methyl-2H-tetrazol-5-yl)piperidin-4-yl)methoxy)-5-(4-(methylsulfonyl)piperazin-1-yl)pyrazine;

Oxetan-3-yl 4-((5-(4-(methylsulfonyl)piperazin-1-yl)pyrazin-2-yloxy)methyl)piperidine-1-carboxylate;

Isopropyl 4-((5-(4-(methylsulfonyl)piperazin-1-yl)pyridin-2-yloxy)methyl)piperidine-1-carboxylate;

Isopropyl 4-((6-(4-(methyl sulfonyl)piperazin-1-yl)pyridazin-3-yloxy)methyl)piperidine-1-carboxylate;

Isopropyl 4-((5-(4-(methylsulfonyl)piperazin-1-yl)pyrimidin-2-yloxy)methyl)piperidine-1-carboxylate;

(E)-Isopropyl 4-(2-(6-(4-(methylsulfonyl)piperazin-1-yl)pyridin-3-yl)vinyl)piperidine-1-carboxylate;

Isopropyl 4-(2-(6-(4-(methylsulfonyl)piperazin-1-yl)pyridin-3-yl)ethyl)piperidine-1-carboxylate;

(E)-Isopropyl 4-(2-(2-(4-(methylsulfonyl)piperazin-1-yl)pyrimidin-5-yl)vinyl)piperidine-1-carboxylate;

5-Ethyl-2-(4-((6-(4-(methylsulfonyl)piperazin-1-yl)pyridin-3-yloxy)methyl)piperidin-1-yl)pyrimidine;

1-(Methylsulfonyl)-4-(5-((1-(5-(trifluoromethyl)pyridin-2-yl)piperidin-4-yl)methoxy)pyridin-2-yl)piperazine;

5-Ethyl-2-(4-((5-(4-(methylsulfonyl)piperazin-1-yl)pyrazin-2-yloxy)methyl)piperidin-1-yl)pyrimidine;

2-((1-(5-Methylpyridin-2-yl)piperidin-4-yl)methoxy)-5-(4-(methylsulfonyl)piperazin-1-yl)pyrazine;

1-Methylcyclopropyl 4-((5-(4-(methylsulfonyl)piperazin-1-yl)pyridin-2-yloxy)methyl)piperidine-1-carboxylate;

5-Ethyl-2-(4-((5-(4-(methylsulfonyl)piperazin-1-yl)pyridin-2-yloxy)methyl)piperidin-1-yl)pyrimidine;

3-Isopropyl-5-(4-((5-(4-(methylsulfonyl)piperazin-1-yl)pyrazin-2-yloxy)methyl)piperidin-1-yl)-1,2,4-oxadiazole;

3-Isopropyl-5-(4-((5-(4-(methylsulfonyl)piperazin-1-yl)pyridin-2-yloxy)methyl)piperidin-1-yl)-1,2,4-oxadiazole;

1-Methylcyclopropyl 4-((6-(4-(methylsulfonyl)piperazin-1-yl)pyridin-3-yloxy)methyl)piperidine-1-carboxylate;

5-Isopropyl-3-(4-((6-(4-(methylsulfonyl)piperazin-1-yl)pyridin-3-yloxy)methyl)piperidin-1-yl)-1,2,4-oxadiazole;

2-((1-(5-Fluoropyridin-2-yl)piperidin-4-yl)methoxy)-5-(4-(methylsulfonyl)piperazin-1-yl)pyrazine;

3-Isopropyl-5-(4-((6-(4-(methylsulfonyl)piperazin-1-yl)pyridin-3-yloxy)methyl)piperidin-1-yl)-1,2,4-oxadiazole;

tert-Butyl 4-(2-(3-(4-(methylsulfonyl)piperazin-1-yl)-1,2,4-oxadiazol-5-yl)ethyl)piperidine-1-carboxylate;

tert-Butyl 4-(3-(3-(4-(methylsulfonyl)piperazin-1-yl)-1,2,4-oxadiazol-5-yl)propyl)piperidine-1-carboxylate;

5-(3-(1-(5-Ethylpyrimidin-2-yl)piperidin-4-yl)propyl)-3-(4-(methylsulfonyl)piperazin-1-yl)-1,2,4-oxadiazole;

Isopropyl 4-(3-(3-(4-(methylsulfonyl)piperazin-1-yl)-1,2,4-oxadiazol-5-yl)propyl)piperidine-1-carboxylate;

3-Isopropyl-5-(4-(2-(5-(4-(methylsulfonyl)piperazin-1-yl)thiazol-2-yl)ethyl)piperidin-1-yl)-1,2,4-oxadiazole;

1-Methylcyclopropyl 4-methoxy-4-((5-(4-(methylsulfonyl)piperazin-1-yl)pyrazin-2-yloxy)methyl)piperidine-1-carboxylate;

1-Methylcyclopropyl 4-((6-formyl-5-(4-(methylsulfonyl)piperazin-1-yl)pyrazin-2-yloxy)methyl)piperidine-1-carboxylate;

1-Methylcyclopropyl 4-((6-chloro-5-(4-(methylsulfonyl)piperazin-1-yl)pyrazin-2-yloxy)methyl)piperidine-1-carboxylate;

1-Methylcyclopropyl 4-((5-(4-(3-methoxy-3-oxopropylsulfonyl)piperazin-1-yl)pyrazin-2-yloxy)methyl)piperidine-1-carboxylate;

3-(4-(5-((1-((1-Methylcyclopropoxy)carbonyl)-piperidin-4-yl)methoxy)pyrazin-2-yl)piperazin-1-ylsulfonyl)propanoic acid;

1-Methylcyclopropyl 4-((5-(4-(3-(1H-tetrazol-5-yl)propylsulfonyl)piperazin-1-yl)pyrazin-2-yloxy)methyl)piperidine-1-carboxylate;

1-Methylcyclopropyl 4-((5-(4-(vinylsulfonyl)piperazin-1-yl)pyrazin-2-yloxy)methyl)piperidine-1-carboxylate;

1-Methylcyclopropyl 4-((5-(4-(2-(piperidin-1-yl)ethylsulfonyl)piperazin-1-yl)pyrazin-2-yloxy)methyl)piperidine-1-carboxylate;

1-Methylcyclopropyl 4-((5-(4-(2-morpholinoethylsulfonyl)piperazin-1-yl)pyrazin-2-yloxy)methyl)piperidine-1-carboxylate;

tert-Butyl 4-((5-(4-(3-chloropropylsulfonyl)piperazin-1-yl)pyrazin-2-yloxy)methyl)piperidine-1-carboxylate;

tert-Butyl 4-((5-(4-(3-acetoxypropylsulfonyl)piperazin-1-yl)pyrazin-2-yloxy)methyl)piperidine-1-carboxylate;

1-Methylcyclopropyl 4-((5-(4-(2-ethoxyethylsulfonyl)piperazin-1-yl)pyrazin-2-yloxy)methyl)piperidine-1-carboxylate;

1-Methylcyclopropyl 4-((5-(4-(3-(pyrrolidin-1-yl)propylsulfonyl)piperazin-1-yl)pyrazin-2-yloxy)methyl)piperidine-1-carboxylate;

1-Methylcyclopropyl 4-((5-(4-(3-(2-methyl-1H-imidazol-1-yl)propylsulfonyl)piperazin-1-yl)pyrazin-2-yloxy)methyl)piperidine-1-carboxylate;

1-Methylcyclopropyl 4-((5-(4-(propylsulfonyl)piperazin-1-yl)pyrazin-2-yloxy)methyl)piperidine-1-carboxylate;

1-Methylcyclopropyl 4-((5-(4-(ethylsulfonyl)piperazin-1-yl)pyrazin-2-yloxy)methyl)piperidine-1-carboxylate;

1-Methylcyclopropyl 4-((5-(4-(isopropylsulfonyl)piperazin-1-yl)pyrazin-2-yloxy)methyl)piperidine-1-carboxylate;

1-Methylcyclopropyl 4-((5-(4-(isobutylsulfonyl)piperazin-1-yl)pyrazin-2-yloxy)methyl)piperidine-1-carboxylate;

1-Methylcyclopropyl 4-((5-(4-(sec-butylsulfonyl)piperazin-1-yl)pyrazin-2-yloxy)methyl)piperidine-1-carboxylate;

1-Methylcyclopropyl 4-((5-(4-(2-(pyridin-3-yl)ethylsulfonyl)piperazin-1-yl)pyrazin-2-yloxy)methyl)piperidine-1-carboxylate;

1-Methylcyclopropyl 4-((5-(4-(2-(pyridin-4-yl)ethylsulfonyl)piperazin-1-yl)pyrazin-2-yloxy)methyl)piperidine-1-carboxylate;

1-Methylcyclopropyl 4-((5-(4-sulfamoylpiperazin-1-yl)pyrazin-2-yloxy)methyl)piperidine-1-carboxylate;

tert-Butyl 4-((5-(4-(morpholinosulfonyl)piperazin-1-yl)pyrazin-2-yloxy)methyl)piperidine-1-carboxylate;

1-Methylcyclopropyl 4-((6-(4-(ethylsulfonyl)piperazin-1-yl)pyridin-3-yloxy)methyl)piperidine-1-carboxylate;

tert-Butyl 4-((5-(4-(methylsulfonyl)-2-oxopiperazin-1-yl)pyrazin-2-yloxy)methyl)piperidine-1-carboxylate;

1-Methylcyclopropyl 4-((5-(4-(methylsulfonyl)-2-oxopiperazin-1-yl)pyrazin-2-yloxy)methyl)piperidine-1-carboxylate;

1-Methylcyclopropyl 4-((5-(2-oxo-4-(propylsulfonyl)piperazin-1-yl)pyrazin-2-yloxy)methyl)piperidine-1-carboxylate;

1-Methylcyclopropyl 4-((5-(4-(isopropylsulfonyl)-2-oxopiperazin-1-yl)pyrazin-2-yloxy)methyl)piperidine-1-carboxylate;

1-Methylcyclopropyl 4-((6-(2-oxo-4-(propylsulfonyl)piperazin-1-yl)pyridin-3-yloxy)methyl)piperidine-1-carboxylate;

1-Methylcyclopropyl 4-((6-(4-(isopropylsulfonyl)-2-oxopiperazin-1-yl)pyridin-3-yloxy)methyl)piperidine-1-carboxylate;

1-(5-((1-(5-Ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)pyrazin-2-yl)-4-(methylsulfonyl)piperazin-2-one;

1-(5-((1-(5-Ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)pyridin-2-yl)-4-(methylsulfonyl)piperazin-2-one;

1-Methylcyclopropyl 4-({[5-(2-oxo-4-{[2-(pyrrolidin-1-yl)ethane]sulfonyl}piperazin-1-yl)pyrazin-2-yl]oxy}methyl)piperidine-1-carboxylate;

1-Methylcyclopropyl 4-({[5-(4-{[2-(morpholin-4-yl)ethane]sulfonyl}-2-oxopiperazin-1-yl)pyrazin-2-yl]oxy}methyl)piperidine-1-carboxylate;

1-Methylcyclopropyl 4-{[(5-{4-[1-(2-methylpropyl)pyrrolidine-3-sulfonyl]-2-oxopiperazin-1-yl}pyrazin-2-yl)oxy]methyl}piperidine-1-carboxylate;

1-Methylcyclopropyl 4-({[5-(2-oxo-4-{[3-(1H-pyrazol-1-yl)propane]sulfonyl}piperazin-1-yl)pyrazin-2-yl]oxy}methyl)piperidine-1-carboxylate;

1-Methylcyclopropyl 4-[({5-[2-oxo-4-(pyrrolidine-3-sulfonyl)piperazin-1-yl]pyrazin-2-yl}oxy)methyl]piperidine-1-carboxylate;

1-Methylcyclopropyl 4-({[5-(4-{[(1-methylpyrrolidin-3-yl)methane]sulfonyl}-2-oxopiperazin-1-yl)pyrazin-2-yl]oxy}methyl)piperidine-1-carboxylate;

1-Methylcyclopropyl 4-({[5-(4-{[2-(azetidin-1-yl)ethane]sulfonyl}-2-oxopiperazin-1-yl)pyrazin-2-yl]oxy}methyl)piperidine-1-carboxylate;

1-Methylcyclopropyl 4-({[5-(2-oxo-4-{[2-(1H-pyrazol-1-yl)ethane]sulfonyl}piperazin-1-yl)pyrazin-2-yl]oxy}methyl)piperidine-1-carboxylate;

1-Methylcyclopropyl 4-[({5-[4-(1-methylpyrrolidine-3-sulfonyl)-2-oxopiperazin-1-yl]pyrazin-2-yl}oxy)methyl]piperidine-1-carboxylate;

1-Methylcyclopropyl 4-({[5-(4-{[2-(3,3-difluoroazetidin-1-yl)ethane]sulfonyl}-2-oxopiperazin-1-yl)pyrazin-2-yl]oxy}methyl)piperidine-1-carboxylate;

1-Methylcyclopropyl 4-[({5-[4-(azetidine-3-sulfonyl)-2-oxopiperazin-1-yl]pyrazin-2-yl}oxy)methyl]piperidine-1-carboxylate;

1-Methylcyclopropyl 4-({[5-(4-{[3-(3,3-difluoroazetidin-1-yl)propane]sulfonyl}-2-oxopiperazin-1-yl)pyrazin-2-yl]oxy}methyl)piperidine-1-carboxylate;

1-Methylcyclopropyl 4-({[5-(4-{[3-(azetidin-1-yl)propane]sulfonyl}-2-oxopiperazin-1-yl)pyrazin-2-yl]oxy}methyl)piperidine-1-carboxylate;

1-Methylcyclopropyl 4-{[(5-{2-oxo-4-[(3S)-pyrrolidine-3-sulfonyl]piperazin-1-yl}pyrazin-2-yl)oxy]methyl}piperidine-1-carboxylate;

1-Methylcyclopropyl 4-{[(5-{4-[(3S)-1-methylpyrrolidine-3-sulfonyl]piperazin-1-yl}pyrazin-2-yl)oxy]methyl}piperidine-1-carboxylate;

1-Methylcyclopropyl 4-{[(5-{4-[(3R)-1-methylpyrrolidine-3-sulfonyl]piperazin-1-yl}pyrazin-2-yl)oxy]methyl}piperidine-1-carboxylate;

1-Methylcyclopropyl 4-{[(5-{4-[(3S)-pyrrolidine-3-sulfonyl]piperazin-1-yl}pyrazin-2-yl)oxy]methyl}piperidine-1-carboxylate;

1-Methylcyclopropyl 4-{[(5-{4-[(3R)-pyrrolidine-3-sulfonyl]piperazin-1-yl}pyrazin-2-yl)oxy]methyl}piperidine-1-carboxylate;

1-Methylcyclopropyl 4-{[(5-[4-(azetidine-3-sulfonyl)piperazin-1-yl]pyrazin-2-yl}oxy)methyl]piperidine-1-carboxylate;

1-Methylcyclopropyl 4-{[(5-{2-oxo-4-[(pyrrolidin-3-ylmethane)sulfonyl]piperazin-1-yl}pyrazin-2-yl)oxy]methyl}piperidine-1-carboxylate;

1-Methylcyclopropyl 4-[({5-[4-(1-hydroxy-2-methylpropane-2-sulfonyl)piperazin-1-yl]pyrazin-2-yl}oxy)methyl]piperidine-1-carboxylate;

1-Methylcyclopropyl 4-{[(5-{4-[(2-hydroxyethane)sulfonyl]piperazin-1-yl}pyrazin-2-yl)oxy]methyl}piperidine-1-carboxylate;

1-Methylcyclopropyl 4-{[(5-{4-[(azetidin-3-ylmethane)sulfonyl]piperazin-1-yl}pyrazin-2-yl)oxy]methyl}piperidine-1-carboxylate;

1-Methylcyclopropyl 4-({[5-(4-{[(1-methylpyrrolidin-2-yl)methane]sulfonyl}-2-oxopiperazin-1-yl)pyrazin-2-yl]oxy}methyl)piperidine-1-carboxylate;

1-Methylcyclopropyl 4-{[(5-{2-oxo-4-[(3R)-pyrrolidine-3-sulfonyl]piperazin-1-yl}pyrazin-2-yl)oxy]methyl}piperidine-1-carboxylate;

1-Methylcyclopropyl 4-[({5-[4-(1-methylazetidine-3-sulfonyl)piperazin-1-yl]pyrazin-2-yl}oxy)methyl]piperidine-1-carboxylate;

1-Methylcyclopropyl 4-[({5-[4-(1-methylazetidine-3-sulfonyl)-2-oxopiperazin-1-yl]pyrazin-2-yl}oxy)methyl]piperidine-1-carboxylate;

1-Methylcyclopropyl 4-({[5-(4-{[(1-methylazetidin-3-yl)methane]sulfonyl}-2-oxopiperazin-1-yl)pyrazin-2-yl]oxy}methyl)piperidine-1-carboxylate;

1-Methylcyclopropyl 4-({[5-(4-{[(1-methylazetidin-3-yl)methane]sulfonyl}piperazin-1-yl)pyrazin-2-yl]oxy}methyl)piperidine-1-carboxylate;

1-Methylcyclopropyl 4-[({5-[4-({3-[(3S,4S)-3,4-dihydroxypyrrolidin-1-yl]propane}sulfonyl)-2-oxopiperazin-1-yl]pyrazin-2-yl}oxy)methyl]piperidine-1-carboxylate;

1-Methylcyclopropyl 4-[({5-[4-({2-[(3S,4S)-3,4-dihydroxypyrrolidin-1-yl]ethane}sulfonyl)-2-oxopiperazin-1-yl]pyrazin-2-yl}oxy)methyl]piperidine-1-carboxylate;

1-Methylcyclopropyl 4-{[(5-{4-[(azetidin-3-ylmethane)sulfonyl]-2-oxopiperazin-1-yl}pyrazin-2-yl)oxy]methyl}piperidine-1-carboxylate;

1-Methylcyclopropyl 4-{[(5-{2-oxo-4-[(pyrrolidin-2-ylmethane)sulfonyl]piperazin-1-yl}pyrazin-2-yl)oxy]methyl}piperidine-1-carboxylate;

1-Methylcyclopropyl 4-({[5-(2-oxo-4-{[3-(pyrrolidin-1-yl)propane]sulfonyl}piperazin-1-yl)pyrazin-2-yl]oxy}methyl)piperidine-1-carboxylate;

1-Methylcyclopropyl 4-({[5-(4-{[3-(morpholin-4-yl)propane]sulfonyl}-2-oxopiperazin-1-yl)pyrazin-2-yl]oxy}methyl)piperidine-1-carboxylate;

1-Methylcyclopropyl 4-({[5-(4-{[(3-methyloxetan-3-yl)methane]sulfonyl}piperazin-1-yl)pyrazin-2-yl]oxy}methyl)piperidine-1-carboxylate;

1-Methylcyclopropyl 4-({[5-(4-{[3-(acetyloxy)propane]sulfonyl}-2-oxopiperazin-1-yl)pyrazin-2-yl]oxy}methyl)piperidine-1-carboxylate;

1-Methylcyclopropyl 4-{[(5-{4-[(3-chloropropane)sulfonyl]-2-oxopiperazin-1-yl}pyrazin-2-yl)oxy]methyl}piperidine-1-carboxylate;

1-Methylcyclopropyl 4-{[(5-{4-[(3-hydroxypropane)sulfonyl]-2-oxopiperazin-1-yl}pyrazin-2-yl)oxy]methyl}piperidine-1-carboxylate;

1-Methylcyclopropyl 4-{[(5-{2-oxo-4-[(3R)-oxolane-3-sulfonyl]piperazin-1-yl}pyrazin-2-yl)oxy]methyl}piperidine-1-carboxylate;

1-Methylcyclopropyl 4-{[(5-{2-oxo-4-[(3S)-oxolane-3-sulfonyl]piperazin-1-yl}pyrazin-2-yl)oxy]methyl}piperidine-1-carboxylate;

1-Methylcyclopropyl 4-({[5-(4-{[(1-hydroxycyclopropyl)methane]sulfonyl}piperazin-1-yl)pyrazin-2-yl]oxy}methyl)piperidine-1-carboxylate;

1-Methylcyclopropyl 4-({[5-(4-{[2-(1-hydroxycyclopropyl)ethane]sulfonyl}piperazin-1-yl)pyrazin-2-yl]oxy}methyl)piperidine-1-carboxylate;

1-Methylcyclopropyl 4-[({5-[4-({[1-(benzyloxy)cyclopropyl]methane}sulfonyl)piperazin-1-yl]pyrazin-2-yl}oxy)methyl]piperidine-1-carboxylate;

1-Methylcyclopropyl 4-({[5-(4-{[2-(1-hydroxycyclopropyl)ethane]sulfonyl}-2-oxopiperazin-1-yl)pyrazin-2-yl]oxy}methyl)piperidine-1-carboxylate;

1-Methylcyclopropyl (3S,4S)-3-hydroxy-4-{[(6-{4-[(2-methylpropane)sulfonyl]piperazin-1-yl}pyridin-3-yl)oxy]methyl}piperidine-1-carboxylate;

1-Methylcyclopropyl 4-{[(6-{4-[(2-hydroxy-2-methylpropane)sulfonyl]piperazin-1-yl}pyridin-3-yl)oxy]methyl}piperidine-1-carboxylate;

1-Methylcyclopropyl (3S,4R)-3-methoxy-4-{[(6-{4-[(2-methylpropane)sulfonyl]piperazin-1-yl}pyridin-3-yl)oxy]methyl}piperidine-1-carboxylate;

1-Methylcyclopropyl 4-({[5-(4-{[3-(3,3-difluoroazetidin-1-yl)propane]sulfonyl}piperazin-1-yl)pyrazin-2-yl]oxy}methyl)piperidine-1-carboxylate;

1-Methylcyclopropyl 4-({[5-(4-{[3-(azetidin-1-yl)propane]sulfonyl}piperazin-1-yl)pyrazin-2-yl]oxy}methyl)piperidine-1-carboxylate;

1-Methylcyclopropyl 4-{[(5-{4-[(3-methoxypropane)sulfonyl]piperazin-1-yl}pyrazin-2-yl)oxy]methyl}piperidine-1-carboxylate;

1-Methylcyclopropyl 4-{[(6-{4-[(3-chloropropane)sulfonyl]-2-oxopiperazin-1-yl}pyridin-3-yl)oxy]methyl}piperidine-1-carboxylate;

1-Methylcyclopropyl 4-({[5-(4-{[2-(azetidin-1-yl)ethane]sulfonyl}piperazin-1-yl)pyrazin-2-yl]oxy}methyl)piperidine-1-carboxylate;

1-Methylcyclopropyl 4-({[6-(4-{[3-(azetidin-1-yl)propane]sulfonyl}piperazin-1-yl)pyridin-3-yl]oxy}methyl)piperidine-1-carboxylate;

1-Methylcyclopropyl 4-[({5-[4-(pyrrolidine-3-sulfonyl)piperazin-1-yl]pyrazin-2-yl}oxy)methyl]piperidine-1-carboxylate;

1-Methylcyclopropyl 4-({[5-(4-{[2-(3,3-difluoroazetidin-1-yl)ethane]sulfonyl}piperazin-1-yl)pyrazin-2-yl]oxy}methyl)piperidine-1-carboxylate;

1-Methylcyclopropyl 4-{[6-{4-[(3-hydroxypropane)sulfonyl]-2-oxopiperazin-1-yl}pyridin-3-yl)oxy]methyl}piperidine-1-carboxylate;

1-Methylcyclopropyl 4-({[6-(4-{[3-(azetidin-1-yl)propane]sulfonyl}-2-oxopiperazin-1-yl)pyridin-3-yl]oxy}methyl)piperidine-1-carboxylate;

1-Methylcyclopropyl 4-[2,6-difluoro-4-(4-methanesulfonyl-2-oxopiperazin-1-yl)phenoxymethyl]piperidine-1-carboxylate; and

1-Methylcyclopropyl 4-[({5-[4-(oxetane-3-sulfonyl)-2-oxopiperazin-1-yl]pyrazin-2-yl}oxy)methyl]piperidine-1-carboxylate.

8. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 in combination with a pharmaceutically acceptable excipient.

9. A compound of the formula: