Nitrogen Containing 2,3-Dihydroquinazolinone Compounds as Nav1.8 Inhibitors

1 .- 41 . (canceled)

42 . A compound of formula (I):

or a tautomer thereof, or a pharmaceutically acceptable salt thereof,

wherein:

Y is O or S;

X 1 is nitrogen or CR 1 ,

X 2 is nitrogen or CR 2 ,

X 3 is nitrogen or CR 3 , and

X 4 is nitrogen or CR 4 ,

provided at least one of X 2 , X 3 , and X 4 is nitrogen;

each of R 1 , R 2 , R 3 , and R 4 is independently hydrogen, halo, cyano, —NR a R b , —(C 1-6 )-alkyl, —(C 1-6 )-haloalkyl, —O—(C 1-6 )— alkyl, or —O—(C 1-6 )-haloalkyl;

ring B is phenyl, or a 5- or 6-membered heterocyclyl containing 1 or 2 nitrogen ring atoms;

each R 5 is independently halo, oxo, —OH, —NR a R b , —(C 1-6 )alkyl, —(C 1-6 )haloalkyl, —COOR a , —C(O)NR a R b , or —S(O) p R c ;

R 6 is hydrogen, —(C 1-6 )alkyl, —O—(C 1-6 )-alkyl, or —NR a R b ;

each R 7 is independently halo, —(C 1-6 )alkyl, —O—(C 1-6 )alkyl, or —O—(C 1-6 )-haloalkyl;

each of R a and R b is independently hydrogen, —(C 1-6 )alkyl, or —(C 1-6 )haloalkyl;

R c is hydrogen, —OH, —NR a R b , —(C 1-6 )-alkyl, or —(C 1-6 )-haloalkyl;

n is 0, 1, 2, or 3;

p is 0, 1, or 2; and

z is 0, 1, 2, or 3.

43 . The compound according to claim 42 which is a compound of formula (I-A):

or a tautomer thereof, or a pharmaceutically acceptable salt thereof,

wherein:

Y is O or S;

each of R 1 , R 2 , and R 3 is independently hydrogen, halo, cyano, —NR a R b , —(C 1-6 )-alkyl, —(C 1-6 )-haloalkyl, —O—(C 1-6 )— alkyl, or —O—(C 1-6 )-haloalkyl;

ring B is phenyl, or a 5- or 6-membered heterocyclyl containing 1 or 2 nitrogen ring atoms;

each R 5 is independently halo, oxo, —OH, —NR a R b , —(C 1-6 )alkyl, —(C 1-6 )haloalkyl, —COOR a , —C(O)NR a R b , or —S(O) p R c ;

R 6 is hydrogen, —(C 1-6 )alkyl, —O—(C 1-6 )-alkyl, or —NR a R b ;

each R 7 is independently halo, —(C 1-6 )alkyl, —O—(C 1-6 )alkyl, or —O—(C 1-6 )-haloalkyl;

each of R a and R b is independently hydrogen, —(C 1-6 )alkyl, or —(C 1-6 )haloalkyl;

R c is hydrogen, —OH, —NR a R b , —(C 1-6 )-alkyl, or —(C 1-6 )-haloalkyl;

n is 0, 1, 2, or 3;

p is 0, 1, or 2; and

z is 0, 1, 2, or 3.

44 . The compound according to claim 42 which is a compound of formula (I-B):

or a tautomer thereof, or a pharmaceutically acceptable salt thereof,

wherein:

Y is O or S;

each of R 1 , R 3 , and R 4 is independently hydrogen, halo, cyano, —NR a R b , —(C 1-6 )-alkyl, —(C 1-6 )-haloalkyl, —O—(C 1-6 )— alkyl, or —O—(C 1-6 )-haloalkyl;

ring B is phenyl, or a 5- or 6-membered heterocyclyl containing 1 or 2 nitrogen ring atoms;

each R 5 is independently halo, oxo, —OH, —NR a R b , —(C 1-6 )alkyl, —(C 1-6 )haloalkyl, —COOR a , —C(O)NR a R b , or —S(O) p R c ;

R 6 is hydrogen, —(C 1-6 )alkyl, —O—(C 1-6 )-alkyl, or —NR a R b ;

each R 7 is independently halo, —(C 1-6 )alkyl, —O—(C 1-6 )alkyl, or —O—(C 1-6 )-haloalkyl;

each of R a and R b is independently hydrogen, —(C 1-6 )alkyl, or —(C 1-6 )haloalkyl;

R c is hydrogen, —OH, —NR a R b , —(C 1-6 )-alkyl, or —(C 1-6 )-haloalkyl;

n is 0, 1, 2, or 3;

p is 0, 1, or 2; and

z is 0, 1, 2, or 3.

45 . The compound according to claim 42 which is a compound of formula (I-C):

or a or a tautomer thereof, or a pharmaceutically acceptable salt thereof,

wherein:

Y is O or S;

each of R 1 , R 2 , and R 4 is independently hydrogen, halo, cyano, —NR a R b , —(C 1-6 )-alkyl, —(C 1-6 )-haloalkyl, —O—(C 1-6 )— alkyl, or —O—(C 1-6 )-haloalkyl;

ring B is phenyl, or a 5- or 6-membered heterocyclyl containing 1 or 2 nitrogen ring atoms;

each R 5 is independently halo, oxo, —OH, —NR a R b , —(C 1-6 )alkyl, —(C 1-6 )haloalkyl, —COOR a , —C(O)NR a R b , or —S(O) p R c ;

R 6 is hydrogen, —(C 1-6 )alkyl, —O—(C 1-6 )-alkyl, or —NR a R b ;

each R 7 is independently halo, —(C 1-6 )alkyl, —O—(C 1-6 )alkyl, or —O—(C 1-6 )-haloalkyl;

each of R a and R b is independently hydrogen, —(C 1-6 )alkyl, or —(C 1-6 )haloalkyl;

R c is hydrogen, —OH, —NR a R b , —(C 1-6 )-alkyl, or —(C 1-6 )-haloalkyl;

n is 0, 1, 2, or 3;

p is 0, 1, or 2; and

z is 0, 1, 2, or 3.

46 . The compound according to claim 42 which is a compound of formula (I-D):

or a tautomer thereof, or a pharmaceutically acceptable salt thereof,

wherein:

Y is O or S;

each of R 2 and R 4 is independently hydrogen, halo, cyano, —NR a R b , —(C 1-6 )-alkyl, —(C 1-6 )-haloalkyl, —O—(C 1-6 )— alkyl, or —O—(C 1-6 )-haloalkyl;

ring B is phenyl, or a 5- or 6-membered heterocyclyl containing 1 or 2 nitrogen ring atoms;

each R 5 is independently halo, oxo, —OH, —NR a R b , —(C 1-6 )alkyl, —(C 1-6 )haloalkyl, —COOR a , —C(O)NR a R b , or —S(O) p R c ;

R 6 is hydrogen, —(C 1-6 )alkyl, —O—(C 1-6 )-alkyl, or —NR a R b ;

each R 7 is independently halo, —(C 1-6 )alkyl, —O—(C 1-6 )alkyl, or —O—(C 1-6 )-haloalkyl;

each of R a and R b is independently hydrogen, —(C 1-6 )alkyl, or —(C 1-6 )haloalkyl;

R c is hydrogen, —OH, —NR a R b , —(C 1-6 )-alkyl, or —(C 1-6 )-haloalkyl;

n is 0, 1, 2, or 3;

p is 0, 1, or 2; and

z is 0, 1, 2, or 3.

47 . The compound according to claim 42 which is a compound of formula (I-E):

or a tautomer thereof, or a pharmaceutically acceptable salt thereof,

wherein:

Y is O or S;

each of R 2 and R 3 is independently hydrogen, halo, cyano, —NR a R b , —(C 1-6 )-alkyl, —(C 1-6 )-haloalkyl, —O—(C 1-6 )— alkyl, or —O—(C 1-6 )-haloalkyl;

ring B is phenyl, or a 5- or 6-membered heterocyclyl containing 1 or 2 nitrogen ring atoms;

each R 5 is independently halo, oxo, —OH, —NR a R b , —(C 1-6 )alkyl, —(C 1-6 )haloalkyl, —COOR a , —C(O)NR a R b , or —S(O) p R c ;

R 6 is hydrogen, —(C 1-6 )alkyl, —O—(C 1-6 )-alkyl, or —NR a R b ;

each R 7 is independently halo, —(C 1-6 )alkyl, —O—(C 1-6 )alkyl, or —O—(C 1-6 )-haloalkyl;

each of R a and R b is independently hydrogen, —(C 1-6 )alkyl, or —(C 1-6 )haloalkyl;

R c is hydrogen, —OH, —NR a R b , —(C 1-6 )-alkyl, or —(C 1-6 )-haloalkyl;

n is 0, 1, 2, or 3;

p is 0, 1, or 2; and

z is 0, 1, 2, or 3.

48 . The compound according to claim 42 , wherein Y is O.

49 . The compound according to claim 42 , wherein

is:

50 . The compound according to claim 42 , wherein R 6 is —CH 3 , —CH 2 CH 3 , or —CH(CH 3 ) 2 .

51 . The compound according to claim 42 , wherein

is:

52 . A compound selected from the group consisting of:

1-(4-fluoro-2-methylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-7-(trifluoromethyl)-2,3-dihydropyrido[3,2-d]pyrimidin-4(1H)-one;

1-(3,4-difluoro-2-methylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-6-(trifluoromethyl)-2,3-dihydropyrido[3,4-d]pyrimidin-4(1H)-one;

1-(2-ethyl-3,4-difluorophenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-6-(trifluoromethyl)-2,3-dihydropyrido[3,4-d]pyrimidin-4(1H)-one;

1-(4-fluoro-2-methylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-7-(trifluoromethyl)-2,3-dihydropyrimido[4,5-d]pyrimidin-4(1H)-one;

6-chloro-1-(4-fluoro-2-isopropylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2,3-dihydropyrido[3,4-d]pyrimidin-4(1H)-one;

1-(4-fluoro-2-methylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-7-(trifluoromethyl)-2,3-dihydropyrido[4,3-d]pyrimidin-4(1H)-one;

1-(4-fluoro-2-isopropylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-6-(trifluoromethyl)-2,3-dihydropyrido[3,4-d]pyrimidin-4(1H)-one;

1-(4-fluoro-2-methylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-6-(trifluoromethyl)-2,3-dihydropyrido[3,4-d]pyrimidin-4(1H)-one;

6-Chloro-1-(4-fluoro-2-isopropylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2,3-dihydropyrido[3,2-d]pyrimidin-4(1H)-one;

1-(4-Fluoro-2-methylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2,3-dihydropyrido[3,4-d]pyrimidin-4(1H)-one;

1-(2-ethyl-4-fluorophenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-6-(trifluoromethyl)-2,3-dihydropyrido[3,4-d]pyrimidin-4(1H)-one;

1-(4-fluoro-2-methylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-7-(trifluoromethyl)-2,3-dihydropteridin-4(1H)-one;

1-(4-fluoro-2-methylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-6-(trifluoromethyl)-2,3-dihydropteridin-4(1H)-one;

6-chloro-1-(4-fluoro-2-methylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2,3-dihydropyrido[3,4-d]pyrimidin-4(1H)-one;

1-(2-methyl-4-(trifluoromethoxy)phenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-6-(trifluoromethyl)-2,3-dihydropyrido[3,4-d]pyrimidin-4(1H)-one;

1-(4-Fluoro-2-methylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-4-oxo-1,2,3,4-tetrahydropyrido[3,4-d]pyrimidine-6-carbonitrile;

7-chloro-1-(4-fluoro-2-methylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2,3-dihydropyrido[4,3-d]pyrimidin-4(1H)-one;

1-(4-fluoro-2-methylphenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-4-oxo-1,2,3,4-tetrahydropyrido[4,3-d]pyrimidine-7-carbonitrile;

1-(2-ethyl-4-fluorophenyl)-3-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-7-(trifluoromethyl)-2,3-dihydropyrido[4,3-d]pyrimidin-4(1H)-one;

3-(5-fluoro-2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-1-(2-methyl-4-(trifluoromethoxy)phenyl)-6-(trifluoromethyl)-2,3-dihydropyrido[3,4-d]pyrimidin-4(1H)-one;

3-(5-fluoro-2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-1-(4-fluoro-2-methylphenyl)-6-(trifluoromethyl)-2,3-dihydropyrido[3,4-d]pyrimidin-4(1H)-one; and

3-Methyl-4-(1-(2-methyl-4-(trifluoromethoxy)phenyl)-4-oxo-6-(trifluoromethyl)-1,4-dihydropyrido[3,4-d]pyrimidin-3(2H)-yl)pyridine 1-oxide,

or a tautomer thereof, or a pharmaceutically acceptable salt thereof.

53 . A pharmaceutical composition comprising a compound according to claim 42 or a tautomer thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

54 . A method of inhibiting a Na v 1.8 voltage-gated sodium channel in a subject in need thereof, the method comprising administering to the subject a compound according to claim 42 , or a tautomer thereof, or a pharmaceutically acceptable salt thereof.

55 . A method of treatment of pain or a pain-associated disease, disorder, or condition in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound according to claim 42 or a tautomer thereof, or a pharmaceutically acceptable salt thereof.

56 . A method of treatment of atrial fibrillation in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound according to claim 42 or a tautomer thereof, or a pharmaceutically acceptable salt thereof.

57 . A method of inhibiting a Na v 1.8 voltage-gated sodium channel in a subject in need thereof, the method comprising administering to the subject a pharmaceutical composition according to claim 53 .

58 . A method of treatment of pain or a pain-associated disease, disorder, or condition in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition according to claim 53 .

59 . A method of treatment of atrial fibrillation in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition according to claim 53 .