Pyrimidines useful as modulators of voltage-gated ion channels

1. A method of treating or lessening the severity of a disease, disorder, or condition selected from arthritis, migraine, cluster headaches, osteoarthritis pain, head pain or neck pain, comprising the step of administering to said patient an effective amount of a compound of formula I:

or a pharmaceutically acceptable salt thereof, wherein:

R Z is —C(O)R 3 ;

R 1 and R 2 are each hydrogen; or

both R 1 and R 2 are R 2 independently selected from methyl, ethyl, cyclopropyl, n-propyl, propenyl, cyclobutyl, (CO)OCH 2 CH 3 , (CH 2 ) 2 OCH 3 , CH 2 (CO)OCH 2 CH 3 , CH 2 (CO)OCH 3 , CH(CH 3 )CH 2 CH 3 , or t-butyl, or n-butyl; or

R 1 and R 2 , taken together with the nitrogen atom to which they are bound, form an R 1 and R 2 , taken together with the nitrogen atom to which they are bound, form ring bb, dd, ee, ff, or gg;

wherein z is 0-4;

ring A is a phenyl optionally substituted at one or more carbon atoms with 0-5 occurrences of —R 7 ;

R 3 is selected from —CF 2 H, —CF 3 , —CHCl 2 , —CHBr 2 , CH 2 CN, —CH 2 OR′, —CH 2 SR′, —CH 2 N(R′) 2 , —N(R′) 2 , —(CH 2 ) 2 N(R′) 2 , —(CH 2 ) 2 OR′, —(CH 2 ) 2 SR′, —COR′, —CON(R′) 2 , or —S(O) 2 N(R′) 2 or an optionally substituted group selected from C 2-8 aliphatic, C 6-10 aryl, aryl(C 1-6 )alkyl, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having 3-10 ring atoms;

R 4 is selected from hydrogen, halogen, CN, NO 2 , or an optionally substituted group selected from C 1-6 alkyl, aryl, aryl(C 1-6 )alkyl, —N(R′) 2 , —CH 2 N(R′) 2 , OR′, —CH 2 OR′, SR′, —CH 2 SR′, COOR′, —NRCOR′, —(CH 2 ) 2 N(R′) 2 , —(CH 2 ) 2 OR′, —(CH 2 ) 2 SR′, —COR′, —CON(R′) 2 , or —S(O) 2 N(R′) 2 ;

each occurrence of R 5 is independently selected from halogen, CN, NO 2 , or an optionally substituted group selected from C 1-6 alkyl, aryl, aryl(C 1-6 )alkyl, —N(R′) 2 , —CH 2 N(R′) 2 , OR′, —CH 2 OR′, SR′, —CH 2 SR′, COOR′, —NRCOR′, —NRC(O)OR′, —(CH 2 ) 2 N(R′) 2 , —(CH 2 ) 2 OR′, —(CH 2 ) 2 SR′, —COR′, —CON(R′) 2 , or —S(O) 2 N(R 3 ) 2 ;

each occurrence of R 7 is independently selected from halogen, CN, NO 2 , or an optionally substituted group selected from C 1-6 alkyl, aryl, aryl(C 1-6 )alkyl, —N(R′) 2 , —CH 2 N(R′) 2 , OR′, —CH 2 OR′, SR′, —CH 2 SR′, COOR′, —NRCOR′, —(CH 2 ) 2 N(R′) 2 , —(CH 2 ) 2 OR′, —(CH 2 ) 2 SR′, —COR′, —CON(R′) 2 , or —S(O) 2 N(R′) 2 ;

wherein each occurrence of R is independently selected from hydrogen or an optionally substituted C 1-6 aliphatic group; and each occurrence of R′ is independently selected from hydrogen or an optionally substituted group selected from C 1-8 aliphatic, C 6-10 aryl, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having 3-10 ring atoms, or wherein R and R′ taken together with the atom(s) to which they are bound, or two occurrences of R′ taken together with the atom(s) to which they are bound, form a 5-8 membered cycloalkyl, heterocyclyl, aryl, or heteroaryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; and

each occurrence of R 6 or R 8 is independently R′, —COR′, —CO 2 (C 1-6 aliphatic), —CON(R′) 2 , or —SO 2 R′.

2. The method according to claim 1 , wherein the disease, condition, or disorder is implicated in the activation or hyperactivity of voltage-gated sodium channels.

3. The method according to claim 2 , wherein the disease, condition, or disorder is implicated in the activation or hyperactivity of voltage-gated calcium channels.

4. The method according to claim 1 , wherein the disease, condition, or disorder is head pain or neck pain.

5. The method according to claim 1 , wherein R 6 is hydrogen, or an optionally substituted group selected from C 1-6 alkyl, aryl, aryl(C 1-6 )alkyl, —N(R′) 2 , —CH 2 N(R′) 2 , —CH 2 OR′, —CH 2 SR′, —(CH 2 ) 2 N(R′) 2 , —(CH 2 ) 2 OR′, —(CH 2 ) 2 SR′, —COR′, —CON(R′) 2 , or —S(O) 2 N(R′) 2 .

6. The method according to claim 1 , wherein R 3 is —CF 2 H, —CF 3 , —CHCl 2 , —CHBr 2 , CH 2 CN, —CH 2 OR′, —CH 2 SR′, or —CH 2 N(R′) 2 .

7. The method according to claim 1 , wherein each R 8 is independently selected from hydrogen, or an optionally substituted group selected from C 1-6 alkyl, aryl, aryl(C 1-6 )alkyl, —N(R′) 2 , —CH 2 N(R′) 2 , —CH 2 OR′, —CH 2 SR′, —(CH 2 ) 2 N(R′) 2 , —(CH 2 ) 2 OR′, —(CH 2 ) 2 SR′, —COR′, —CON(R′) 2 , or —S(O) 2 N(R′) 2 .

8. The method according to claim 1 , further comprising a pharmaceutically acceptable carrier, vehicle, or diluent, and optionally an additional therapeutic agent.

9. The method according to claim 1 , wherein said compound is selected from:

Cmpd

#

Compound

1

8

13

17

18

35

41

44

48

53

60

67

68

80

81

99

125

126

144

146

152

153

156

193

212

230

232

234