Compounds and compositions as modulators of GPR119 activity

1. A compound of Formula I:

or the pharmaceutically acceptable salts thereof;

in which:

Q is a divalent radical selected from C 6-10 aryl, C 1-10 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 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;

R 21 is selected from hydrogen, cyano, C 1-6 alkyl and —C(O)OR 25 ; wherein R 25 is selected from hydrogen and C 1-6 alkyl;

ring A can have up to 2 ring carbons replaced with a group selected from —C(O)—, —C(S)— and —C(═NOR 30 )— and can be partially unsaturated with up to 2 double bonds; wherein R 30 is selected from hydrogen and C 1-6 alkyl;

L is selected from C 1-6 alkylene, C 2-6 alkenylene, —(CH 2 ) 1-5 O—, —OC(O)(CH 2 ) n —, —C(O)O(CH 2 ) n —, —NR 26 (CH 2 ) n — and —O(CH 2 ) 1-5 —; wherein

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

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

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(C) 0-2 X 2 C(C)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 1-10 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 hydroxy, halo, C 1-6 alkyl, halo-substituted-C 1-6 alkyl, hydroxy-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;

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

R 2 and R 3 are independently selected from hydrogen, halo, hydroxy, C 1-6 alkyl, halo-substituted-C 1-6 alkyl, hydroxy-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 1-10 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, hydroxy-substituted-C 1-6 alkyl, C 1-6 alkoxy and halo-substituted-C 1-6 alkoxy;

R 5 is selected from hydrogen, C 1-6 alkyl, halo-substituted-C 1-6 alkyl, hydroxy-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:

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 ) 1-4 —, —(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 —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)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 and O;

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

R 6a is selected from hydrogen, halo, cyano, 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:

Isopropyl 4-((4-(1-methanesulfonylpiperidin-4-yl)phenoxy)methyl)piperidine-1-carboxylate,

isopropyl 4-(4-(1-(methylsulfonyl)piperidin-4-yl)phenoxy)piperidine-1-carboxylate,

isopropyl 4-(2-(4-(1-(methylsulfonyl)piperidin-4-yl)phenoxy)ethyl)piperidine-1-carboxylate,

isopropyl 4-(3-(4-(1-(methylsulfonyl)piperidin-4-yl)phenoxy)propyl)piperidine-1-carboxylate,

isopropyl 4-(4-(4-(1-(methylsulfonyl)piperidin-4-yl)phenoxy)butyl)piperidine-1-carboxylate,

1-Methylcyclopropyl 4-((4-(1-(methylsulfonyl)piperidin-4-yl)phenoxy)methyl)piperidine-1-carboxylate,

2-(4-((4-(1-(methylsulfonyl)piperidin-4-yl)phenoxy)methyl)piperidin-1-yl)-5-(trifluoromethyl)pyridine,

5-isopropyl-3-(4-((4-(1-(methylsulfonyl)piperidin-4-yl)phenoxy)methyl)piperidin-1-yl)-1,2,4-oxadiazole,

3-chloro-2-(4-((4-(1-(methylsulfonyl)piperidin-4-yl)phenoxy)methyl)piperidin-1-yl)-5-(trifluoromethyl)pyridine,

5-chloro-2-(4-((4-(1-(methylsulfonyl)piperidin-4-yl)phenoxy)methyl)piperidin-1-yl)pyridine,

3-chloro-6-(4-((4-(1-(methylsulfonyl)piperidin-4-yl)phenoxy)methyl)piperidin-1-yl)pyridazine,

5-bromo-2-(4-((4-(1-(methylsulfonyl)piperidin-4-yl)phenoxy)methyl)piperidin-1-yl)pyrimidine,

5-ethyl-2-(4-((4-(1-(methylsulfonyl)piperidin-4-yl)phenoxy)methyl)piperidin-1-yl)pyrimidine,

5-fluoro-2-(4-((4-(1-(methylsulfonyl)piperidin-4-yl)phenoxy)methyl)piperidin-1-yl)pyridine,

3-isopropyl-5-(4-((4-(1-(methylsulfonyl)piperidin-4-yl)phenoxy)methyl)piperidin-1-yl)-1,2,4-oxadiazole,

3-tert-butyl-6-(4-((4-(1-(methylsulfonyl)piperidin-4-yl)phenoxy)methyl)piperidin-1-yl)pyridazine,

5-fluoro-2-(4-((4-(1-(methylsulfonyl)piperidin-4-yl)phenoxy)methyl)piperidin-1-yl)pyrimidine,

2-(4-((2-bromo-4-(1-(methylsulfonyl)piperidin-4-yl)phenoxy)methyl)piperidin-1-yl)-5-fluoropyrimidine,

tert-Butyl 4-((2,6-difluoro-4-(1-(methylsulfonyl)piperidin-4-yl)phenoxy)methyl)piperidine-1-carboxylate;

tert-butyl 4-((2-methyl-4-(1-(methylsulfonyl)piperidin-4-yl)phenoxy)methyl)piperidine-1-carboxylate;

tert-butyl 4-((3-methoxy-4-(1-(methylsulfonyl)piperidin-4-yl)phenoxy)methyl)piperidine-1-carboxylate;

tert-butyl 4-((2,6-dimethyl-4-(1-(methylsulfonyl)piperidin-4-yl)phenoxy)methyl)piperidine-1-carboxylate;

tert-butyl 4-((2,5-dimethyl-4-(1-(methylsulfonyl)piperidin-4-yl)phenoxy)methyl)piperidine-1-carboxylate;

tert-butyl 4-((2-(methoxycarbonyl)-4-(1-(methylsulfonyl)piperidin-4-yl)phenoxy)methyl)piperidine-1-carboxylate;

tert-butyl 4-((2-chloro-4-(1-(methylsulfonyl)piperidin-4-yl)phenoxy)methyl)piperidine-1-carboxylate;

tert-butyl 4-((3-methyl-4-(1-(methylsulfonyl)piperidin-4-yl)phenoxy)methyl)piperidine-1-carboxylate;

tert-butyl 4-((2,3-dimethyl-4-(1-(methylsulfonyl)piperidin-4-yl)phenoxy)methyl)piperidine-1-carboxylate;

tert-butyl 4-((2-fluoro-4-(1-(methylsulfonyl)piperidin-4-yl)phenoxy)methyl)piperidine-1-carboxylate;

tert-butyl 4-((4-(1-(methylsulfonyl)piperidin-4-yl)-2-(trifluoromethyl)phenoxy)methyl)piperidine-1-carboxylate;

2-(4-((2,6-Difluoro-4-(1-(methylsulfonyl)piperidin-4-yl)phenoxy)methyl)piperidin -1-yl)-5-ethylpyrimidine;

1-Methylcyclopropyl 4-((2,6-difluoro-4-(1-(methylsulfonyl)piperidin-4-yl)phenoxy)methyl)piperidine-1-carboxylate;

3-(4-(4-((1-(5-Ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)-3,5-difluorophenyl)piperidin-1-ylsulfonyl)propyl acetate;

1-Methylcyclopropyl 4-((4-(1-(3-acetoxypropylsulfonyl)piperidin-4-yl)-2,6-difluorophenoxy)methyl)piperidine-1-carboxylate;

3-(4-(4-((1-(5-Ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)-3,5-difluorophenyl)piperidin-1-ylsulfonyl)propan-1-ol;

1-Methylcyclopropyl 4-((2,6-difluoro-4-(1-(3-hydroxypropylsulfonyl)piperidin-4-yl)phenoxy)methyl)piperidine-1-carboxylate;

Isopropyl 4-((5-(1,2,3,6-tetrahydro-1-methanesulfonylpyridin-4-yl)pyrazin-2-yloxy)methyl)piperidine-1-carboxylate;

1-Methylcyclopropyl 4-((6-(1,2,3,6-tetrahydro-1-methanesulfonylpyridin-4-yl)pyridin-3-yloxy)methyl)piperidine-1-carboxylate;

2-((1-(5-Ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)-5-(1-methanesulfonylpiperidin-4-yl)pyrazine;

2-(4-((6-(1-Methanesulfonylpiperidin-4-yl)pyridin-3-yloxy)methyl)piperidin-1-yl)-5-ethylpyrimidine;

3-((1-(5-Ethylpyrimidin-2-yl)piperidin-4-yl)methoxy)-6-(1-methanesulfonylpiperidin-4-yl)pyridazine;

2-(4-((5-(1-Methanesulfonylpiperidin-4-yl)pyridin-2-yloxy)methyl)piperidin-1-yl)-5-ethylpyrimidine;

N-((1-(5-Ethylpyrimidin-2-yl)piperidin-4-yl)methyl)-4-(1-(methylsulfonyl)piperidin-4-yl)aniline;

N-((1-(5-Ethylpyrimidin-2-yl)piperidin-4-yl)methyl)-N-methyl-4-(1-(methylsulfonyl)piperidin-4-yl)aniline;

4-(4-((1-(5-fluoropyrimidin-2-yl)piperidin-4-yl)methoxy)phenyl)-1-(methylsulfonyl)piperidine-4-carboxylic acid;

propan-2-yl 4-{3-[3-(1-methanesulfonylpiperidin-4-yl)phenoxy]propyl}piperidine-1-carboxylate;

propan-2-yl 4-{2-[3-(1-methanesulfonylpiperidin-4-yl)phenoxy]ethyl}piperidine-1-carboxylate; and

propan-2-yl 4-[3-(1-methanesulfonylpiperidin-4-yl)phenoxymethyl]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.