Pyran-spirocyclic piperidine amides as modulators of ion channels

1. A compound of formula I:

or a pharmaceutically acceptable salt thereof,

wherein, independently for each occurrence:

R 1 is an optionally substituted phenyl, pyridyl, thiazole, or pyrazole,

R 2 is C1-C6 alkyl, deuterated C1-C6 alkyl, C1-C6 alkoxy, C1-C6 fluoroalkyl, CF 3 , CHF 2 , or a straight chain, branched, or cyclic (C1-C8)-R 9 wherein up to two CH 2 units may be replaced with O, CO, S, SO, SO 2 , N, CF 2 , or NR 8 ;

R 3 is C1-C6 alkyl or halo;

R 8 is H, C1-C6 alkyl, C3-C8 cycloalkyl, CF 3 , or a straight chain, branched, or cyclic (C1-C8)-R 9 wherein up to two CH 2 units may be replaced with O, CO, S, SO, SO 2 , N, CF 2 , or NR, or 2 R 8 taken together with the atoms to which they are attached form a ring;

R 9 is H, CF 3 , CHF 2 , CH 2 F, CO 2 R, halo, OH, optionally substituted aryl, heteroaryl, C3-C8 cycloalkyl, heterocycloalkyl, N(R) 2 , NRCOR, CON(R) 2 , CN, or SO 2 R;

R is H, C1-C6 alkyl, optionally substituted aryl, heteroaryl, C3-C8 cycloalkyl, or heterocycloalkyl;

ring A is

wherein:

R 4 is H, C1-C6 alkyl, C1-C6 alkoxy, C3-C8 cycloalkyl halo, CN, OR 8 SO 2 R 8 SO 7 N(R 8 ) 2 , CHF 2 CF 3 OCF 3 OCHF 2 , R 9 , heterocycloalkyl, heterocycloalkoxy, aryl, heteroaryl, or a straight chain, branched, or cyclic (C1-C8)-R 9 wherein up to three CH 2 units may be replaced with O, CO, S, SO, SO 2 N, CF 2 , or NR 8 ;

R 5 is H, C1-C6 alkyl, C1-C6 alkoxy, C3-C8 cycloalkyl, halo, CN, OR 8 , SO 2 R 8 SO 7 N(R 8 ) 2 , CHF 2 CF 3 OCF 3 OCHF 2 , R 9 , heterocycloalkyl, heterocycloalkoxy, aryl, heteroaryl, or a straight chain, branched, or cyclic (C1-C8)-R 9 wherein up to three CH 2 units may be replaced with O, CO, S, SO, SO 2 N, CF 2 , or NR 8 ;

R 6 is H, C1-C6 alkyl, C1-C6 alkoxy, C3-C8 cycloalkyl, halo, CN, OR 8 , SO 2 R 8 , SO,N(R 8 ) 2 , CHF 2 CF 3 OCF 3 OCHF 2 , R 9 , heterocycloalkyl, heterocycloalkoxy, aryl, heteroaryl, or a straight chain, branched, or cyclic (C1-C8)-R 9 wherein up to three CH 2 units may be replaced with O, CO, S, SO, SO 2 N, CF 2 , or NR 8 ; or

two occurrences of R 4 and R 5 , or R 5 and R 6 together with the carbons to which they are attached form an optionally substituted ring comprising up to 2 heteroatoms; or

wherein:

R 4 is H, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, C1-C6 fluoroalkoxy, halo, CN, OH, OR 8 , N(R 8 ) 2 ,SO 2 R 8 , SO 2 N(R 8 ) 2 , CHF 2 , CF 3 , R 9 , heterocycloalkyl, or a straight chain, branched, or cyclic (C1-C8)-R 9 wherein up to three CH 2 units may be replaced with O, CO, S, SO, SO 2 N, CF 2 , or NR 8 ;

R 5 is H, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, C1-C6 fluoroalkoxy, halo, CN, OH, OR 8 , N(R 8 ) 2 , SO 2 R 8 , SO 2 N(R 8 ) 2 CHF 2 , CF 3 , R 9 , heterocycloalkyl, or a straight chain, branched, or cyclic (C1-C8)-R 9 wherein up to three CH 2 units may be replaced with O, CO, S, SO, SO 2 N, CF 2 , or NR 8 ;

R 6 is H, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, C1-C6 fluoroalkoxy, halo, CN, OH, OR 8 , N(R 8 ) 2 , SO 2 R 8 SO 2 N(R 8 ) 2 CHF 2 CF 3 , R 9 , heterocycloalkyl, or a straight chain, branched, or cyclic (C1-C8)-R 9 wherein up to three CH 2 units may be replaced with O, CO, S, SO, SO 2 N, CF 2 , or NR 8 ; or

two occurrences of R 4 and R 5 , or R 5 and R 6 together with the carbons to which they are attached form an optionally substituted ring comprising up to 2 heteroatoms;

n is 1 or 2; and

o is 0 or 1.

2. The compound of claim 1 , wherein R 2 is CH 2 CH 3 , OCH 3 , OCH 2 CH 3 , OCH 2 CH 2 CH 3 , OCH 2 CH 2 F, OCH 2 CH 2 OCH 3 , or OCH(CH 3 ) 2 .

3. The compound of claim 1 , wherein A is

wherein:

R 4 is H, C1-C6 alkyl, C1-C6 alkoxy, C3-C8 cycloalkyl, halo, CN, OR 8 , SO 2 R 8 , SO 2 N(R 8 ) 2 , CHF 2 , CF 3 , OCF 3 , OCHF 2 , R 9 , heterocycloalkyl, heterocycloalkoxy, aryl, heteroaryl, or a straight chain, branched, or cyclic (C1-C8)-R 9 wherein up to three CH 2 units may be replaced with O, CO, S, SO, SO 2 , N, CF 2 , or NR 8 ;

R 5 is H, C1-C6 alkyl, C1-C6 alkoxy, C3-C8 cycloalkyl, halo, CN, OR 8 , SO 2 R 8 , SO 2 N(R 8 ) 2 , CHF 2 , CF 3 , OCF 3 , OCHF 2 , R 9 , heterocycloalkyl, heterocycloalkoxy, aryl, heteroaryl, or a straight chain, branched, or cyclic (C1-C8)-R 9 wherein up to three CH 2 units may be replaced with O, CO, S, SO, SO 2 , N, CF 2 , or NR 8 ;

R 6 is H, C1-C6 alkyl, C1-C6 alkoxy, C3-C8 cycloalkyl, halo, CN, OR 8 , SO 2 R 8 , SO 2 N(R 8 ) 2 , CHF 2 , CF 3 , OCF 3 , OCHF 2 , R 9 , heterocycloalkyl, heterocycloalkoxy, aryl, heteroaryl, or a straight chain, branched, or cyclic (C1-C8)-R 9 wherein up to three CH 2 units may be replaced with O, CO, S, SO, SO 2 , N, CF 2 , or NR 8 ; or

two occurrences of R 4 and R 5 , or R 5 and R 6 together with the carbons to which they are attached form an optionally substituted ring comprising up to 2 heteroatoms.

4. The compound of claim 3 , wherein R 4 is H, CH 3 , OCH 3 , OCH 2 CH 3 , F, Cl, OCHF 2 , CHF 2 , CF 3 , CH 2 OCH 3 , OCH(CH 3 ) 2 , CH 2 OCH 3 , or

5. The compound of claim 3 , wherein R 5 is H, CH 3 , OCH 3 , OCH(CH 3 ) 2 , F, Cl, CF 3 , CN, or CH 2 OH.

6. The compound of claim 3 , wherein R 6 is H, F, Cl, CH 3 , CF 3 , CH 2 CH 3 , OCH 3 , OCH 2 CF 3 , OCH 2 CH 3 , OCH 2 CH 2 CH 3 , OCH 2 CH 2 CH(CH 3 ) 2 , OtBu, tBu, OCH(CH 3 ) 2 , OCH 2 CH(CH 3 ) 2 , OCH(CH 3 )CH 2 CH 3 , CH(OH)CH(CH 3 ) 2 , C(OH)(CH 3 )CH 2 CH 3 , OCH 2 C(CH 3 ) 2 OH, C(CH 3 ) 2 OH, CH 2 C(CH 3 ) 2 OH OCH 2 CH 2 OCH 3 , OCH 2 CH 2 OH, OCH 2 CH 2 CH 2 OH, SO 2 CH 3 , SO 2 CF 3 , SO 2 CH(CH 3 ) 2 , SO 2 CH 2 CH 3 , CH 2 OCH 2 CF 3 , CH 2 OCH 2 CH 2 CF 3 , OCHF 2 , OCH 2 CF(CH 3 ) 2 ,

7. The compound of claim 3 , wherein

is selected from:

8. The compound of claim 1 , wherein A is

wherein:

R 4 is H, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, C1-C6 fluoroalkoxy, halo, CN, OH, OR 8 , N(R 8 ) 2 , SO 2 R 8 , SO 2 N(R 8 ) 2 , CHF 2 , CF 3 , R 9 , heterocycloalkyl, or a straight chain, branched, or cyclic (C1-C8)-R 9 wherein up to three CH 2 units may be replaced with O, CO, S, SO, SO 2 , N, CF 2 , or NR 8 ;

R 5 is H, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, C1-C6 fluoroalkoxy, halo, CN, OH, OR 8 , N(R 8 ) 2 , SO 2 R 8 , SO 2 N(R 8 ) 2 , CHF 2 , CF 3 , R 9 , heterocycloalkyl, or a straight chain, branched, or cyclic (C1-C8)-R 9 wherein up to three CH 2 units may be replaced with 0, CO, S, SO, SO 2 , N, CF 2 , or NR 8 ;

R 6 is H, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, C1-C6 fluoroalkoxy, halo, CN, OH, OR 8 , N(R 8 ) 2 , SO 2 R 8 , SO 2 N(R 8 ) 2 , CHF 2 , CF 3 , R 9 , heterocycloalkyl, or a straight chain, branched, or cyclic (C1-C8)-R 9 wherein up to three CH 2 units may be replaced with 0, CO, S, SO, SO 2 , N, CF 2 , or NR 8 ; or

two occurrences of R 4 and R 5 , or R 5 and R 6 together with the carbons to which they are attached form an optionally substituted ring comprising up to 2 heteroatoms.

9. The compound of claim 8 , wherein R 4 is H, OCH 3 , OCH 2 CH 3 , OCH 2 CF 3 , N(CH 3 ) 2 , NH(CH 2 CH(CH 3 ) 2 ), or

10. The compound of claim 8 , wherein R 5 is H, CH 3 , OCH 3 , Cl, tBu, N(CH 3 ) 2 , or

11. The compound of claim 8 , wherein R 6 is H, CN, OCH 3 , OCH 2 CH 3 , OCH(CH 3 ) 2 , CF 3 , OCH 2 CF 3 ,

12. The compound of claim 8 , wherein A is selected from the following:

13. The compound of claim 1 , wherein the compound has formula IA:

wherein:

R 1 is as defined in claim 1 ;

R 2 is C1-C6 alkoxy or C1-C6 fluoroalkoxy;

R 5 is H, C1-C6 alkyl, C1-C6 alkoxy, C3-C8 cycloalkyl, halo, CN, OR 8 , SO 2 R 8 , SO 2 N(R 8 ) 2 , CHF 2 , CF 3 , OCF 3 , OCHF 2 , R 9 , heterocycloalkyl, heterocycloalkoxy, aryl, heteroaryl, or a straight chain, branched, or cyclic (C1-C8)-R 9 wherein up to three CH 2 units may be replaced with O, CO, S, SO, SO 2 , N, CF 2 , or NR 8 ;

R 6 is H, C1-C6 alkyl, C1-C6 alkoxy, C3-C8 cycloalkyl, halo, CN, OR 8 , SO 2 R 8 , SO 2 N(R 8 ) 2 , CHF 2 , CF 3 , OCF 3 , OCHF 2 , R 9 , heterocycloalkyl, heterocycloalkoxy, aryl, heteroaryl, or a straight chain, branched, or cyclic (C1-C8)-R 9 wherein up to three CH 2 units may be replaced with O, CO, S, SO, SO 2 , N, CF 2 , or NR 8 ; and

R 8 is H, C1-C6 alkyl, C3-C8 cycloalkyl, CF 3 , or a straight chain, branched, or cyclic (C1-C8)-R 9 wherein up to two CH 2 units may be replaced with O, CO, S, SO, SO 2 , N, CF 2 , or NR, or 2 R 8 taken together with the atoms to which they are attached form a ring.

14. The compound of claim 13 , wherein R 1 is

15. The compound of claim 13 , wherein R 2 is selected from OCH 3 , OCH 2 CH 3 , OCH 2 CH 2 CH 3 , OCH 2 CH 2 F, OCH 2 CH 2 OCH 3 , or OCH(CH 3 ) 2 .

16. The compound of claim 13 , wherein R 5 is H, CH 3 , OCH 3 , CF 3 , OCHF 2 , F, Cl, CN, or CH 2 OH.

17. The compound of claim 13 , wherein R 6 is H, Cl CH 2 CH 3 , tBu, OtBu, OCH 3 , OCH(CH 3 ) 2 , OCH 2 CH 2 (CH 3 ) 2 , OCH 2 CH 3 , OCH 2 CH 2 CH 3 , OCH 2 CH 2 CH(CH 3 ) 2 , OCH 2 CF(CH 3 ) 2 , CH 2 OCH 2 CH 2 CF 3 , OCH 2 CH 2 OH, CH 2 CH 2 CH 2 OH, OCHF 2 , OCH 2 CH 2 OCH 3 , OCH(CH 3 )CH 2 CH 3 , OCH 2 C(CH 3 ) 2 OH, C(CH 3 ) 2 0H, CH 2 C(CH 3 ) 2 OH,

18. The compound of claim 13 , wherein the

moiety is selected from:

19. A compound selected from the following table:

20. A pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable carrier.

21. A method of inhibiting a voltage-gated sodium ion channel in:

a patient; or

a biological sample;

comprising administering to the patient, or contacting the biological sample, with the compound of claim 1 .

22. The method of claim 21 , wherein the voltage-gated sodium ion channel is NaV 1.7.

23. A method of treating or lessening the severity in a subject of acute, chronic, neuropathic, or inflammatory pain, visceral pain, osteoarthritis pain, radicular pain, sciatica, back pain, head or neck pain, severe or intractable pain, nociceptive pain, breakthrough pain, postsurgical pain, or cancer pain, comprising administering an effective amount of a compound of claim 1 .