NITROGEN CONTAINING CONDENSED 2,3-DIHYDROQUINAZOLINONE COMPOUNDS AS NAV1.8 INHIBITORS

1 . A compound of formula (I-a):

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 no more than two of X 1 , X 2 , X 3 , and X 4 are nitrogen;

ring A is:

 wherein represents a covalent bond to the nitrogen atom of the bicyclic ring core of formula (I-a) and represents a covalent bond to L of formula (I-a);

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

X 5 is N or CR 5 ;

each of R 5 and R 5a is independently hydrogen, halo, or —(C 1 -C 6 )alkyl;

each of R 6 , R 7 and R 8 is independently hydrogen, halo, cyano, hydroxy, —(C 1 -C 6 )alkyl, —(C 1 -C 6 )alkoxy, halo(C 1 -C 6 )alkyl-, or halo(C 1 -C 6 )alkoxy-;

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

each of R 15 and R 16 is independently hydrogen or deuterium; and

L is (C 3 -C 6 )alkenylene, —NHCH 2 CH 2 NHCH 2 —, —NHCH 2 CH 2 OCH 2 —, a divalent linker of formula (L-ia), or a divalent linker of formula (L-iia):

wherein:

each of X 8 and X 9 is independently —CR 9 R 10 —, wherein each of R 9 and R 10 is independently hydrogen or —(C 1 -C 3 )alkyl;

R d is hydrogen or —(C 1 -C 3 )alkyl;

r is 1, 2, 3, or 4;

s is 1, 2, 3, or 4;

the sum of r and s is 2, 3, 4, or 5; and

represents a covalent bond to ring A of formula (I-a) and represents a covalent bond to the phenyl ring of formula (I-a);

wherein:

X 6 is —NR c — or —CH 2 —;

X 7 is —CR 11 R 12 —, —O— or —NH 2 —, wherein each of R 11 and R 12 is independently hydrogen or —(C 1 -C 3 )alkyl, provided that when X 7 is —NH 2 —, X 6 is —CH 2 —;

each X 10 is independently —CR 13 R 14 —, wherein each of R 13 and R 14 is independently hydrogen or —(C 1 -C 3 )alkyl;

R c is hydrogen or —(C 1 -C 3 )alkyl;

q is 1, 2, 3, or 4;

and

represents a covalent bond to ring A of formula (I-a) and represents a covalent bond to the phenyl ring of formula (I-a).

2 . The compound according to claim 1 , which is a compound of formula (II):

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

wherein:

Y is O or S;

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

R 5 is hydrogen, halo, or —(C 1 -C 6 )alkyl;

each of R 6 , R 7 and R 8 is independently hydrogen, halo, —(C 1 -C 6 )alkyl, —(C 1 -C 6 )alkoxy, halo(C 1 -C 6 )alkyl-, or halo(C 1 -C 6 )alkoxy-;

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

L is (C 3 -C 6 )alkenylene, a divalent linker of formula (L-i), or a divalent linker of formula (L-ii):

wherein:

r is 1, 2, 3, or 4;

s is 1, 2, 3, or 4;

the sum of r and s is 2, 3, 4, or 5; and

represents a covalent bond to the pyridone ring of formula (II) and represents a covalent bond to the phenyl ring of formula (II);

wherein:

X 6 is —NR c — or —CH 2 —;

X 7 is —CH 2 —, —O— or —NH 2 —, provided that when X 7 is —NH 2 —, X 6 is —CH 2 —;

R c is hydrogen or —(C 1 -C 3 )alkyl;

q is 1, 2, 3, or 4; and

represents a covalent bond to the pyridone ring of formula (II) and represents a covalent bond to the phenyl ring of formula (II).

3 . The compound according to claim 1 , which is a compound of formula (III):

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 -C 6 )alkyl, —(C 1 -C 6 )alkoxy, halo(C 1 -C 6 )alkyl-, or halo(C 1 -C 6 )alkoxy-;

R 5 is hydrogen, halo, or —(C 1 -C 6 )alkyl;

each of R 6 , R 7 and R 8 is independently hydrogen, halo, —(C 1 -C 6 )alkyl, —(C 1 -C 6 )alkoxy, halo(C 1 -C 6 )alkyl-, or halo(C 1 -C 6 )alkoxy-;

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

L is (C 3 -C 6 )alkenylene, a divalent linker of formula (L-i), or a divalent linker of formula (L-ii):

wherein:

r is 1, 2, 3, or 4;

s is 1, 2, 3, or 4;

the sum of r and s is 2, 3, 4, or 5; and

represents a covalent bond to the pyridone ring of formula (III) and represents a covalent bond to the phenyl ring of formula (III);

wherein:

X 6 is —NR c — or —CH 2 —;

X 7 is —CH 2 —, —O— or —NH 2 —, provided that when X 7 is —NH 2 —, X 6 is —CH 2 —;

R c is hydrogen or —(C 1 -C 3 )alkyl;

q is 1, 2, 3, or 4; and

represents a covalent bond to the pyridone ring of formula (III) and represents a covalent bond to the phenyl ring of formula (III).

4 . The compound according to claim 1 , which is a compound of formula (IV):

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 -C 6 )alkyl, —(C 1 -C 6 )alkoxy, halo(C 1 -C 6 )alkyl-, or halo(C 1 -C 6 )alkoxy-;

R 5 is hydrogen, halo, or —(C 1 -C 6 )alkyl;

each of R 6 , R 7 and R 8 is independently hydrogen, halo, —(C 1 -C 6 )alkyl, —(C 1 -C 6 )alkoxy, halo(C 1 -C 6 )alkyl-, or halo(C 1 -C 6 )alkoxy-;

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

L is (C 3 -C 6 )alkenylene, a divalent linker of formula (L-i), or a divalent linker of formula (L-ii):

wherein:

r is 1, 2, 3, or 4;

s is 1, 2, 3, or 4;

the sum of r and s is 2, 3, 4, or 5; and

represents a covalent bond to the pyridone ring of formula (IV) and represents a covalent bond to the phenyl ring of formula (IV),

wherein:

X 6 is —NR c — or —CH 2 —;

X 7 is —CH 2 —, —O— or —NH 2 —, provided that when X 7 is —NH 2 —, X 6 is —CH 2 —;

R c is hydrogen or —(C 1 -C 3 )alkyl;

q is 1, 2, 3, or 4; and

represents a covalent bond to the pyridone ring of formula (IV) and represents a covalent bond to the phenyl ring of formula (IV).

5 . The compound according to claim 1 , which is a compound of formula (V):

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

wherein:

Y is O or S;

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

R 5 is hydrogen, halo, or —(C 1 -C 6 )alkyl;

each of R 6 , R 7 and R 8 is independently hydrogen, halo, —(C 1 -C 6 )alkyl, —(C 1 -C 6 )alkoxy, halo(C 1 -C 6 )alkyl-, or halo(C 1 -C 6 )alkoxy-;

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

L is (C 3 -C 6 )alkenylene, a divalent linker of formula (L-i), or a divalent linker of formula (L-ii):

wherein:

r is 1, 2, 3, or 4;

s is 1, 2, 3, or 4;

the sum of r and s is 2, 3, 4, or 5; and

represent a covalent bond to the pyridone ring of formula (V) and represents a covalent bond to the phenyl ring of formula (V);

wherein:

X 6 is —NR c — or —CH 2 —;

X 7 is —CH 2 —, —O— or —NH 2 —, provided that when X 7 is —NH 2 —, X 6 is —CH 2 —;

R c is hydrogen or —(C 1 -C 3 )alkyl;

q is 1, 2, 3, or 4; and

represents a covalent bond to the pyridone ring of formula (V) and represents a covalent bond to the phenyl ring of formula (V).

6 . The compound, or tautomer thereof or pharmaceutically acceptable salt thereof according to claim 1 , wherein Y is O.

7 . The compound, or tautomer thereof or pharmaceutically acceptable salt thereof according to claim 1 , wherein L is (C 3 -C 6 )alkenylene selected from the group consisting of: *—CH═CH—CH 2 —**, *—CH 2 —CH═CH—CH 2 —**, *—CH 2 CH 2 —CH═CH—CH 2 —**, and *—CH 2 —CH═CH—CH 2 CH 2 CH 2 —**, wherein “*” represents a covalent bond to the ring A or pyridone ring of formulas (Ia)-(V) and “**” represents a covalent bond to the phenyl ring of formulas (Ia)-(V).

8 . The compound, or tautomer thereof or pharmaceutically acceptable salt thereof according to claim 1 , wherein L is a divalent linker of formula (L-i):

wherein:

r is 1, 2, 3, or 4;

s is 1, 2, 3, or 4;

the sum of r and s is 2, 3, 4, or 5; and

represents a covalent bond to the ring A or pyridone ring of formulas (Ia)-(V) and represents a covalent bond to the phenyl ring of formulas (Ia)-(V).

9 . The compound, or tautomer thereof or pharmaceutically acceptable salt thereof according to claim 8 , wherein L is a divalent linker of formula (L-i) selected from the group consisting of:

wherein represents a covalent bond to the ring A or pyridone group of formulas (Ia)-(V) and represents a covalent bond to the phenyl ring of formulas (Ia)-(V).

10 . The compound, or tautomer thereof or pharmaceutically acceptable salt thereof according to claim 1 , wherein L is a divalent linker of formula (L-ii):

wherein:

X 6 is —NR c — or —CH 2 —;

X 7 is —CH 2 —, —O— or —NH 2 —, provided that when X 7 is —NH 2 —, X 6 is —CH 2 —;

R c is hydrogen or —(C 1 -C 3 )alkyl;

q is 1, 2, 3, or 4; and

represents a covalent bond to the ring A or pyridone ring of formulas (Ia)-(V) and represents a covalent bond to the phenyl ring of formulas (Ia)-(V); wherein L is a divalent linker of formula (T-ii) selected from the group consisting of

11 . The compound, or tautomer thereof or pharmaceutically acceptable salt thereof according to claim 10 , wherein X 6 is —NR c — and X 7 is CH 2 .

12 . The compound, or tautomer thereof or pharmaceutically acceptable salt thereof according to claim 10 , wherein L is a divalent linker of formula (L-ii) selected from the group consisting of:

—CH 2 CH 2 CH 2 CH 2 —, —CH 2 CH 2 CH 2 CH 2 CH 2 — and —CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 —, wherein represents a covalent bond to the ring A or pyridone ring of formulas (Ia)-(V) and represents a covalent bond to the phenyl ring of formulas (Ia)-(V).

13 . The compound, or tautomer thereof or pharmaceutically acceptable salt thereof according to claim 1 , wherein L is a divalent linker of formula (L-ii) selected from the group consisting of:

wherein represents a covalent bond to the ring A or pyridone ring of formulas (Ia)-(V) and represents a covalent bond to the phenyl ring of formulas (Ia)-(V).

14 . The compound, or tautomer thereof or pharmaceutically acceptable salt thereof according to claim 1 , wherein L is a divalent linker selected from the group consisting of

wherein represents a covalent bond to the ring A or pyridone ring of formulas (Ia)-(V) and represents a covalent bond to the phenyl ring of formulas (Ia)-(V).

15 . A compound selected from the group consisting of:

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

16 . A compound selected from the group consisting of:

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

17 . A pharmaceutical composition comprising the compound, or tautomer thereof or pharmaceutically acceptable salt thereof according to claim 1 , and a pharmaceutically acceptable excipient.

18 . A method of treatment of pain or a pain-associated disease in a human in need thereof, the method comprising administering to the human a compound according to claim 1 , or a tautomer thereof, or a pharmaceutically acceptable salt thereof.

19 . A method of treatment of atrial fibrillation in a human in need thereof, the method comprising administering to the human a compound according to claim 1 , or a tautomer thereof, or a pharmaceutically acceptable salt thereof.

20 - 25 . (canceled)

26 . A method of treatment of a Na v 1.8-mediated disease, disorder, or condition in a human in need thereof, the method comprising administering a therapeutically effective amount of a compound according to claim 1 , or a pharmaceutically acceptable salt thereof.

27 . A method of treatment of a Na v 1.8-mediated disease, disorder, or condition in a human in need thereof, the method comprising administering to the human the pharmaceutical composition according to claim 17 .

28 . A method of treatment of pain or a pain-associated disease in a human in need thereof, the method comprising administering to the human the pharmaceutical composition according to claim 17 .

29 . A method of treatment of atrial fibrillation in a human in need thereof, the method comprising administering to the human-the pharmaceutical composition according to claim 17 .