Chemical Compounds Useful for Inhibiting Nav1.8 Voltage-Gated Sodium Channels and Treating Nav1.8 Mediated Diseases

1 .- 41 . (canceled)

42 . A compound of formula (I):

or a pharmaceutically acceptable salt thereof,

wherein:

X 1 is N or CH;

R 1 is —P(O)(OH) 2 ;

R 2 is hydrogen, -(C 1-6 )alkyl, —NR a R b , halo, or -(C 1-6 )haloalkyl;

each of 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;

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

R 6 is hydrogen or -(C 1-6 )alkyl;

R 7 is hydrogen, -(C 1-6 )alkyl, halo, or -(C 1-6 )haloalkyl;

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

n is 0, 1, or 2.

43 . The compound according to claim 42 , wherein X 1 is N.

44 . The compound according to claim 42 , wherein X 1 is CH.

45 . The compound according to claim 42 , wherein R 2 is -(C 1-6 )alkyl.

46 . The compound according to claim 42 , wherein each of R 3 and R 4 is independently hydrogen, halo, or -(C 1-6 )haloalkyl.

47 . The compound according to claim 46 , wherein each of R 3 and R 4 is hydrogen, —Cl, or —CF 3 .

48 . The compound according to claim 42 , wherein one of R 3 and R 4 is hydrogen and the other of R 3 and R 4 is halo or -(C 1-6 )haloalkyl.

49 . The compound according to claim 48 , wherein one of R 3 and R 4 is hydrogen and the other of R 3 and R 4 is —Cl or —CF 3 .

50 . The compound according to claim 42 , wherein each R 5 is independently halo or —O(C 1-6 )haloalkyl.

51 . The compound according to claim 50 , wherein each R 5 is independently —F or —OCF 3 .

52 . The compound according to claim 42 , wherein R 6 is -(C 1-6 )alkyl.

53 . The compound according to claim 52 , wherein R 6 is —CH 3 , —CH 2 CH 3 , or —CH(CH 3 ) 2 .

54 . The compound according to claim 42 , wherein:

X 1 is N;

R 1 is —PO(OH) 2 ;

R 2 is —CH 3 ;

one of R 3 and R 4 is hydrogen and the other of R 3 and R 4 is halo or -(C 1-6 )haloalkyl;

R 5 is halo or —O(C 1-6 )haloalkyl;

R 6 is -(C 1-6 )alkyl;

R 7 is hydrogen; and

n is 1.

55 . The compound according to claim 42 , being a pharmaceutically acceptable salt of the compound of formula (I), wherein:

R 1 is —P(O)(OH)O − M + , —PO(O − ) 2 ·2M + , or —PO(O − ) 2 ·D 2+ ;

each M + is independently a pharmaceutically acceptable monovalent cation; and

D 2+ is a pharmaceutically acceptable divalent cation.

56 . A compound selected from the group consisting of:

(5-(1-(4-Fluoro-2-methylphenyl)-4-oxo-6-(trifluoromethyl)-1,4-dihydroquinazolin-3(2H)-yl)-6-methyl-2-oxopyridin-1(2H)-yl)methyl dihydrogen phosphate;

(5-(1-(4-fluoro-2-methylphenyl)-4-oxo-7-(trifluoromethyl)-1,4-dihydroquinazolin-3(2H)-yl)-6-methyl-2-oxopyridin-1(2H)-yl)methyl dihydrogen phosphate;

(5-(6-chloro-1-(4-fluoro-2-methylphenyl)-4-oxo-1,4-dihydroquinazolin-3(2H)-yl)-6-methyl-2-oxopyridin-1(2H)-yl)methyl dihydrogen phosphate; and

(6-methyl-5-(1-(2-methyl-4-(trifluoromethoxy)phenyl)-4-oxo-6-(trifluoromethyl)-1,4-dihydropyrido[2,3-d]pyrimidin-3(2H)-yl)-2-oxopyridin-1(2H)-yl)methyl dihydrogen phosphate,

or a pharmaceutically acceptable salt thereof.

57 . A pharmaceutical composition comprising a compound as defined in claim 42 , and a pharmaceutically acceptable excipient.

58 . The pharmaceutical composition according to claim 57 , formulated for intravenous administration.

59 . 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 or pharmaceutically acceptable salt thereof or tautomer thereof according to claim 42 or a pharmaceutically acceptable salt thereof.

60 . 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 pharmaceutically acceptable salt thereof.

61 . The method according to claim 60 , wherein the pain is acute pain or chronic pain.

62 . The method according to claim 60 , wherein the pain or pain-associated disease, disorder, or condition is pain caused by trauma; pain caused by iatrogenic medical or dental procedures; or pre-operative or post-operative associated pain.

63 . The method according to claim 60 , wherein the pain or pain-associated disease, disorder, or condition is neuropathic pain, nociceptive pain, inflammatory pain, musculoskeletal pain, visceral pain, or idiopathic pain.

64 . The method according to claim 60 , wherein the pain or pain-associated disease, disorder or condition is neuropathic pain or chronic neuropathic pain selected from small fiber neuropathy, small fiber-mediated diabetic neuropathy, idiopathic small fiber neuropathy, painful diabetic neuropathy or polyneuropathy.

65 . The method according to claim 60 , wherein the pain or pain associated disease, disorder, or condition is inflammatory pain selected from osteoarthritis, chronic osteoarthritis pain, or chronic inflammatory demyelinating polyneuropathy.

66 . 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 pharmaceutically acceptable salt thereof.

67 . The method according to claim 60 , wherein the subject is human.

68 . The method according to claim 66 , wherein the subject is human.