RU2006107211A

RU2006107211A - COMPOSITIONS USEFUL AS INHIBITORS OF POTENTIAL DEPENDENT SODIUM CHANNELS

Info

Publication number: RU2006107211A
Application number: RU2006107211/04A
Authority: RU
Inventors: Хесус Э. ГОНСАЛЕС III (US); Хесус Э. ГОНСАЛЕС III; Андреас П. ТЕРМИН (US); Андреас П. ТЕРМИН; Эстер МАРТИНБОРО (US); Эстер МАРТИНБОРО; Николе ЦИММЕРМАН (US); Николе ЦИММЕРМАН
Original assignee: Вертекс Фармасьютикалз Инкорпорейтед (Us); Вертекс Фармасьютикалз Инкорпорейтед
Priority date: 2003-08-08
Filing date: 2004-08-09
Publication date: 2007-09-20

Abstract

1. Соединение формулы I-Aв которойкаждый Rнезависимо представляет собой водород или C-алифатическую группу, необязательно содержащую до 2 заместителей, выбранных из R, Rили R;Xпредставляет собой O, S или NR;p равно 0 или 1;Rпредставляет собой H или R;Xпредставляет собой C-алифатическую группу, необязательно содержащую до 2 заместителей, независимо выбранных из R, Rили R;Z выбирают изT представляет собой 8-14-членное ароматическое или неароматическое бициклическое или трициклическое кольцо, содержащее 0-5 гетероатомов, выбранных из O, S, N, NH, S(O) или SO;где каждый из Z и T необязательно содержит до 4 заместителей, независимо выбранных из R, R, R, Rили R;где соединенное с сульфонилом фениленовое кольцо необязательно содержит до 3 заместителей, выбранных из Rи R;Rпредставляет собой оксо, =NN(R), =NN(R), =NN(RR), Rили (CH)-Y;n равно 0, 1 или 2;Y представляет собой галоген, CN, NO, CF, OCF, OH, SR, S(O)R, SOR, NH, NHR, N(R), NRR, COOH, COORили OR; илидва Rу смежных кольцевых атомов образуют вместе 1,2-дифторметилендиокси, 1,2-диметилметилендиокси, 1,2-метилендиокси или 1,2-этилендиокси;Rявляется алифатической группой, где каждый Rнеобязательно содержит до 2 заместителей, независимо выбранных из R, Rили R;Rпредставляет собой циклоалифатическое, арильное, гетероциклическое или гетероарильное кольцо, которое необязательно содержит до 3 заместителей, независимо выбранных из R, R, Rили R;Rпредставляет собой OR, OR, OC(O)R, OC(O)R, OC(O)OR, OC(O)OR, OC(O)N(R), OC(O)N(R), OC(O)N(RR), OP(O)(OR), OP(O)(OR), OP(O)(OR)(OR), SR, SR, S(O)R, S(O)R, SOR, SOR, SON(R), SON(R), SONRR, SOR, SOR, C(O)R, C(O)OR, C(O)R, C(O)OR, C(O)N(R), C(O)N(R), C(O)N(RR), C(O)N(OR)R, C(O)N(OR)R, C(O)N(OR)R, C(O)N(OR)R, C(NOR)R, C(NOR)R, C(NOR)R, C(NOR)R, N(R), N(R), N(RR), NRC(O)R, NRC(O)R, NRC(O)R, NRC(O)OR, NRC(O)OR, NRC(O)OR, NRC(O)OR, NRC(O)N(R), NRC(O)NRR, NRC(O)N(R), NRC(O)N(R), NRC(O)NRR, NRC(O)N(R), NRSOR, NRSOR, NRSOR, NRSON(R), NRSONRR, NRSON(R), NRSONRR, NRSON(R), N(OR)R, N(OR)R, 1. A compound of formula I-A in which each R is independently hydrogen or a C-aliphatic group, optionally containing up to 2 substituents selected from R, R or R; X is O, S or NR; p is 0 or 1; R is H or R ; X is a C-aliphatic group, optionally containing up to 2 substituents independently selected from R, R or R; Z is selected from T is an 8-14 membered aromatic or non-aromatic bicyclic or tricyclic ring containing 0-5 heteroatoms selected from O, S, N, NH, S (O) or SO; where each from Z and T optionally contains up to 4 substituents independently selected from R, R, R, R or R; where the phenylene ring joined to the sulfonyl optionally contains up to 3 substituents selected from R and R; R is oxo, = NN (R), = NN (R), = NN (RR), R or (CH) -Y; n is 0, 1 or 2; Y is halogen, CN, NO, CF, OCF, OH, SR, S (O) R, SOR NH, NHR, N (R), NRR, COOH, COOR or OR; or two Ru of adjacent ring atoms together form 1,2-difluoromethylenedioxy, 1,2-dimethylmethylenedioxy, 1,2-methylenedioxy or 1,2-ethylenedioxy; R is an aliphatic group where each R optionally contains up to 2 substituents independently selected from R, R or R ; R is a cycloaliphatic, aryl, heterocyclic or heteroaryl ring, which optionally contains up to 3 substituents independently selected from R, R, R or R; R is OR, OR, OC (O) R, OC (O) R, OC (O ) OR, OC (O) OR, OC (O) N (R), OC (O) N (R), OC (O) N (RR), OP (O) (OR), OP (O) (OR ), OP (O) (OR) (OR), SR, SR, S (O) R, S (O) R, SOR, SOR, SON (R), SON (R), SON RR, SOR, SOR, C (O) R, C (O) OR, C (O) R, C (O) OR, C (O) N (R), C (O) N (R), C ( O) N (RR), C (O) N (OR) R, C (O) N (OR) R, C (O) N (OR) R, C (O) N (OR) R, C (NOR ) R, C (NOR) R, C (NOR) R, C (NOR) R, N (R), N (R), N (RR), NRC (O) R, NRC (O) R, NRC ( O) R, NRC (O) OR, NRC (O) OR, NRC (O) OR, NRC (O) OR, NRC (O) N (R), NRC (O) NRR, NRC (O) N (R ), NRC (O) N (R), NRC (O) NRR, NRC (O) N (R), NRSOR, NRSOR, NRSOR, NRSON (R), NRSONRR, NRSON (R), NRSONRR, NRSON (R) , N (OR) R, N (OR) R,

Claims

1. The compound of formula I-A

wherein

each R ^N independently represents hydrogen or a C _1-4 aliphatic group, optionally containing up to 2 substituents selected from R ¹ , R ⁴ or R ⁵ ;

X ₁ represents O, S or NR ^X ;

p is 0 or 1;

R ^X represents H or R ² ;

X ₂ represents a C _1-3 aliphatic group, optionally containing up to 2 substituents independently selected from R ¹ , R ⁴ or R ⁵ ;

Z choose from

T represents an 8-14 membered aromatic or non-aromatic bicyclic or tricyclic ring containing 0-5 heteroatoms selected from O, S, N, NH, S (O) or SO ₂ ;

where each of Z and T optionally contains up to 4 substituents independently selected from R ¹ , R ² , R ³ , R ⁴ or R ⁵ ;

wherein the phenylene ring joined to sulfonyl optionally contains up to 3 substituents selected from R ¹ and R ² ;

R ¹ represents oxo, = NN (R ⁶ ) ₂ , = NN (R ⁷ ) ₂ , = NN (R ⁶ R ⁷ ), R ⁶ or (CH ₂ ) _n —Y;

n is 0, 1 or 2;

Y represents halogen, CN, NO ₂ , CF ₃ , OCF ₃ , OH, SR ⁶ , S (O) R ⁶ , SO ₂ R ⁶ , NH ₂ , NHR ⁶ , N (R ⁶ ) ₂ , NR ⁶ R ⁸ , COOH, COOR ⁶ or OR ⁶ ; or

two R ¹ at adjacent ring atoms together form 1,2-difluoromethylenedioxy, 1,2-dimethylmethylenedioxy, 1,2-methylenedioxy or 1,2-ethylenedioxy;

R ² is an aliphatic group, where each R ² optionally contains up to 2 substituents independently selected from R ¹ , R ⁴ or R ⁵ ;

R ³ represents a cycloaliphatic, aryl, heterocyclic or heteroaryl ring, which optionally contains up to 3 substituents independently selected from R ¹ , R ² , R ⁴ or R ⁵ ;

R ⁴ represents OR ⁵ , OR ⁶ , OC (O) R ⁶ , OC (O) R ⁵ , OC (O) OR ⁶ , OC (O) OR ⁵ , OC (O) N (R ⁶ ) ₂ , OC (O) N (R ⁵ ) ₂ , OC (O) N (R ⁶ R ⁵ ), OP (O) (OR ⁶ ) ₂ , OP (O) (OR ⁵ ) ₂ , OP (O) (OR ⁶ ) (OR ⁵ ), SR ⁶ , SR ⁵ , S (O) R ⁶ , S (O) R ⁵ , SO ₂ R ⁶ , SO ₂ R ⁵ , SO ₂ N (R ⁶ ) ₂ , SO ₂ N (R ⁵ ) ₂ , SO ₂ NR ⁵ R ⁶ , SO ₃ R ⁶ , SO ₃ R ⁵ , C (O) R ⁵ , C (O) OR ⁵ , C (O) R ⁶ , C (O) OR ⁶ , C ( O) N (R ⁶ ) ₂ , C (O) N (R ⁵ ) ₂ , C (O) N (R ⁵ R ⁶ ), C (O) N (OR ⁶ ) R ⁶ , C (O) N ( OR ⁵ ) R ⁶ , C (O) N (OR ⁶ ) R ⁵ , C (O) N (OR ⁵ ) R ⁵ , C (NOR ⁶ ) R ⁶ , C (NOR ⁶ ) R ⁵ , C (NOR ⁵ ) R ⁶ , C (NOR ⁵ ) R ⁵ , N (R ⁶ ) ₂ , N (R ⁵ ) ₂ , N (R ⁵ R ⁶ ), NR ⁵ C (O) R ⁵ , NR ⁶ C (O) R ⁶ , NR ⁶ C (O) R ⁵ , NR ⁶ C (O) OR ⁶ , NR ⁵ C (O) OR ⁶ , NR ⁶ C (O) OR ⁵ , NR ⁵ C (O) OR ⁵ , NR ⁶ C (O) N (R ⁶ ) ₂ , NR ⁶ C (O) NR ⁵ R ⁶ , NR ⁶ C (O) N (R ⁵ ) ₂ , NR ⁵ C (O) N (R ⁶ ) ₂ , NR ⁵ C (O) NR ⁵ R ⁶ , NR ⁵ C (O) N (R ⁵ ) ₂ , NR ⁶ SO ₂ R ⁶ , NR ⁶ SO ₂ R ⁵ , NR ⁵ SO ₂ R ⁵ , NR ⁶ SO ₂ N (R ⁶ ) ₂ , NR ⁶ SO ₂ NR ⁵ R ⁶ , NR ⁶ SO ₂ N (R ⁵ ) ₂ , NR ⁵ SO ₂ NR ⁵ R ⁶ , NR ⁵ SO ₂ N (R ⁵ ) ₂ , N (OR ⁶ ) R ⁶ , N ( OR ⁶ ) R ⁵ , N (OR ⁵ ) R ⁵ , N (OR ⁵ ) R ⁶ , P (O) (OR ⁶ ) N (R ⁶ ) ₂ , P (O) (OR ⁶ ) N (R ⁵ R ⁶ ), P (O) (OR ⁶ ) N (R ⁵ ) ₂ , P (O) (OR ⁵ ) N (R ⁵ R ⁶ ), P (O) (OR ⁵ ) N (R ⁶ ) ₂ , P (O) (OR ⁵ ) N (R ⁵ ) ₂ , P (O) (OR ⁶ ) ₂ , P (O) (OR ⁵ ) ₂ or P (O) (OR ⁶ ) (OR ⁵ );

R ⁵ represents a cycloaliphatic, aryl, heterocyclic or heteroaryl ring, which optionally contains up to 3 substituents R ¹ ;

R ⁶ represents H or an aliphatic group, wherein R ^{6 is} optionally substituted with R ⁷ ;

R ⁷ represents a cycloaliphatic, aryl, heterocyclic or heteroaryl ring, and each R ⁷ optionally contains up to 2 substituents independently selected from H, an aliphatic group or (CH ₂ ) _n -Z ';

Z 'is selected from halogen, CN, NO ₂ , C (halogen) ₃ , CH (halogen) ₂ , CH ₂ (halogen), -OC (halogen) ₃ , -OCH (halogen) ₂ , -OCH ₂ (halogen), OH, S-aliphatic group, S (O) -aliphatic group, SO ₂ -aliphatic group, NH ₂ , NH-aliphatic group, N (aliphatic group) ₂ , N (aliphatic group) R ⁸ , COOH, C (O) O (aliphatic group) or O-aliphatic group; and

R ⁸ represents an amino protecting group

provided that

a) if both R ^N are hydrogen and T is isoindol-1,3-dion-2-yl, optionally containing up to 4 halogen atoms as substituents, then Z is not pyridyl, thiazol-2-yl, 4- (4-methoxyphenyl) thiazol-2-yl, 2-ethyl-1,3,4-thiadiazol-5-yl, optionally substituted with pyrimidin-2-yl, 5-methylisoxazolyl, 3,4-dimethylisoxazolyl or 2-methylisoxazolyl;

b) if both R ^N are hydrogen and T is

optionally containing up to 4 halogen atoms as substituents, where R ^mm is phenyl optionally substituted with C _1-4 alkyl or hydrogen, Z is not optionally substituted with pyrimidin-2-yl, 2-pyridyl or thiazol-2-yl;

c) if both R ^N are hydrogen, X ₂ is —CH ₂ -, p is 1, X ₁ is S, and T is

then Z is not 3,4-dimethylisoxazolyl, pyrimidin-2-yl, thiazol-2-yl or 4,6-dimethylpyrimidin-2-yl;

c) if both R ^N are hydrogen, X ₂ is —CH ₂ -, and X ₁ is S, or X ₂ is CH = CH and X _{1 is} absent and T is optionally substituted

where Y 'represents O, S or NH, then Z is not pyrimidinyl optionally containing up to 2 methyl or methoxy groups, 2-pyridyl, thiazol-2-yl, 2-methoxypyrazin-3-yl, 3-chloropyridazin- as substituents 6-yl, 3,4-dimethylisoxazolyl or 2-ethyl-1,3,4-thiadiazol-5-yl;

d) if both R ^N are hydrogen, X ₂ is —CH ₂ —CH ₂ -, X _{1 is} absent, and T is

then Z is not thiazol-2-yl, 2,6-dimethylpyrimidin-4-yl or 3,4-dimethylisoxazol-5-yl;

e) if both R ^N are hydrogen, X ₂ is —CH ₂ -, X ₁ is O or S, and T is

where Y ² represents O or CH ₂ , then Z is not thiazol-2-yl, or 4,6-dimethylpyrimidin-2-yl, or pyrimidin-2-yl;

f) if both R ^N are hydrogen, X ₂ is —CH ₂ -, X ₁ is O, T is

where R ⁿⁿ is hydrogen or halogen, then Z is not thiazol-2-yl, 4-methylpyrimidin-2-yl, 4,6-dimethylpyrimidin-2-yl, pyrimidin-2-yl or 5-methylisoxazol-3-yl ;

g) if both R ^N are hydrogen, X ₂ is —CH ₂ -, X _{1 is} absent, T is 1,4-dihydroquinoxaline-2,3-dion-4-yl, then Z is not 5-methylisoxazole- 3-yl, thiazol-2-yl, 4,6-dimethylpyrimidin-2-yl, pyrimidin-2-yl or 2-pyridyl;

h) if both R ^N are hydrogen, X ₂ is —CH ₂ -, X _{1 is} absent, and T is 2,3-dihydrophthalazin-1,4-dion-2-yl, then Z is not pyridyl, thiazole -2-yl or optionally substituted pyrimidin-2-yl;

i) if both R ^N are hydrogen, X ₂ is —CH ₂ -, X _{1 is} absent, and T is adamantyl or halogenadamantyl, then Z is not 3,4-dimethylisoxazol-5-yl, thiazol-2-yl or 4-methylpyrimidin-2-yl;

j) excluded are the compounds shown in table A and table B, where R ^N represents hydrogen.

2. The compound according to claim 1, in which Z is selected from

where Z contains up to 2 substituents selected from R ¹ , R ² or R ⁵ .

3. The compound according to claim 2, in which Z is selected from

4. The compound according to claim 3, in which Z represents i-a.

5. The compound according to claim 2, in which Z is selected from

6. The compound according to claim 2, in which Z is selected from

7. The compound according to claim 2, in which Z is selected from

8. The compound according to claim 2, in which Z is selected from

9. The compound according to claim 2, in which Z is selected from

10. The compound according to claim 2, in which Z is selected from

11. The compound according to claim 1, in which R ⁶ represents hydrogen.

12. The compound according to claim 1, in which R ⁶ represents a C _1-4 -alkyl.

13. The compound according to claim 1, in which X ₂ choose from -CH ₂ -, -CH ₂ -CH ₂ -, - (CH ₂ ) ₃ -, -C (Me) ₂ -, -CH (Me) -, -C (Me) = CH-, -CH = CH-, -CH (Ph) -, -CH ₂ -CH (Me) -, -CH (Et) -, -CH (i-Pr) - or cyclopropylene.

14. The compound according to claim 1, in which p is 1, and X ₁ represents O.

15. The compound according to claim 1, in which p is 1, and X ₁ represents S.

16. The compound according to claim 1, in which T represents naphthyl, tetralin or decalin, optionally containing up to 3 substituents independently selected from halogen, cyano, trifluoromethyl, OH, C _1-4 alkyl, C _2-4 alkenyl, C _1-4 alkoxy, trifluoromethoxy, C (O) NH ₂ , NH ₂ , NH (C _1-4 alkyl), N (C _1-4 alkyl) ₂ , NHC (O) C _1-4 alkyl , 1-pyrrolidinyl, 1-piperidinyl, 1-morpholinyl or C (O) C _1-4 alkyl.

17. The compound of claim 16, wherein T is optionally substituted naphthyl.

18. The compound according to claim 1, in which T is selected from

or

where T optionally contains up to 3 substituents independently selected from halogen, cyano, trifluoromethyl, OH, C _1-4 alkyl, C _2-4 alkenyl, C _1-4 alkoxy, trifluoromethoxy, C (O) NH ₂ , NH ₂ , NH (C _1-4 alkyl), N (C _1-4 alkyl) ₂ , NHC (O) C _1-4 alkyl or C (O) C _1-4 alkyl.

19. The compound according to claim 1, in which T is selected from

or

20. The compound according to claim 1, in which p is 1.

21. The compound according to claim 1, in which p is 0.

22. The compound according to claim 2, in which Z is selected from

23. The compound of claim 22, wherein Z is selected from ii-a or ii-b.

24. The compound according to claim 1 of the formula

or

.

25. The compound of formula III

or its pharmaceutically acceptable salt, where

Z ^N is a 5-7 membered monocyclic, unsaturated or aromatic, heterocyclic ring containing up to 4 heteroatoms independently selected from O, N, NH, S, SO or SO ₂ ;

T ^N is a 3-14 membered monocyclic, bicyclic or tricyclic, saturated, unsaturated or aromatic ring system containing up to 5 heteroatoms independently selected from O, N, NH, S, SO or SO ₂ ;

where attached to the sulfonyl phenylene ring optionally contains up to 3 substituents selected from R ¹ and R ² ;

where each Z ^N and T ^N independently and optionally contains up to 4 substituents independently selected from R ¹ , R ² , R ³ , R ⁴ or R ⁵ ;

n is 0, 1 or 2;

two R ¹ at adjacent ring atoms together form 1,2-methylenedioxy or 1,2-ethylenedioxy;

Z 'is selected from halogen, CN, NO ₂ , C (halogen) ₃ , CH (halogen) ₂ , CH ₂ (halogen), -OC (halogen) ₃ , -OCH (halogen) ₂ , -OCH ₂ (halogen), OH, S-aliphatic group, S (O) -aliphatic group, SO ₂ -aliphatic group, NH ₂ , NH-aliphatic group, N (aliphatic group) ₂ , N (aliphatic group) R ⁸ , COOH, C (O) O (aliphatic group) or O-aliphatic group;

provided that

a) if both R ^N are hydrogen, then T ^{N is} not

(i) 1,3-dionisoindol-2-yl, 1,3-dionisoindol-2-yl containing up to 4 halogen atoms as a substituent;

(ii)

where R ^m represent methyl or phenyl, optionally containing up to 4 halogen atoms as a substituent;

(iii)

where W represent O or S, and R ^o represent phenyl or substituted phenyl;

(iv) 4-methyl-1,4-dihydroquinoxalin-1-yl;

(v)

and additionally provided that

b) if both R ^N are hydrogen, the following compounds are excluded:

26. The compound of claim 25, wherein Z ^{N is} selected from

or

27. The compound of claim 26, wherein Z ^{N is} selected from

or

.

28. The compound according to item 27, in which Z ^N represents the formula ia.

29. The compound of claim 26, wherein Z ^{N is} selected from

or

.

30. The compound of claim 26, wherein Z ^{N is} selected from

or

.

31. The compound of claim 26, wherein Z ^{N is} selected from

or

32. The compound of claim 26, wherein Z ^{N is} selected from

or

33. The compound of claim 26, wherein Z ^{N is} selected from

or

.

34. The compound of claim 26, wherein Z ^{N is} selected from

or

35. The compound of claim 25, wherein each R ^N is hydrogen.

36. The compound according to claim 1, in which each R ^N represents an unsubstituted C _1-4 -alkyl.

37. The compound of claim 25, wherein X _{2 is} selected from —CH ₂ -, —CH ₂ —CH ₂ -, - (CH ₂ ) ₃ -, —CH (Me) -, —C (Me) = CH- , -CH = CH-, -CH (Ph) -, -CH ₂ -CH (Me) -, -C (Me) ₂ -, -CH (Et) -, -CH (i-Pr) - or cyclopropylene.

38. The compound of claim 37, wherein X _{2 is} selected from —CH ₂ -, —CH (Me) -, —CH ₂ —CH ₂ -, or - (CH ₂ ) ₃ -.

39. The compound of claim 38, wherein X ₂ is —CH ₂ -.

40. The compound of claim 25, wherein T ^N is an optionally substituted 5-6 membered monocyclic ring.

41. The compound of claim 40, wherein T ^{N is} selected from 1-pyrrolyl, 2,3-dihydro-1H-pyrrol-1-yl, 1-pyrazolyl, 1-imidazolyl, 1-pyrrolidinyl, 1,2,3, 4-tetrahydropyrid-1-yl, 1,2,3,6-tetrahydropyrid-1-yl, 1-piperidinyl, 1-piperazinyl, 1-morpholinyl, 1-azepinyl or 1-azepanyl, wherein said ring optionally contains up to 3 substituents .

42. The compound of paragraph 41, T ^{N is} fused to a phenyl ring.

43. The compound according to paragraph 41 or 42, wherein said substituents are independently selected from halogen, cyano, trifluoromethyl, OH, C _1-4 alkyl, C _2-4 alkenyl, C _1-4 alkoxy, trifluoromethoxy, C ( O) NH ₂ , NH ₂ , NH (C _1-4 alkyl), N (C _1-4 alkyl) ₂ , NHC (O) C _1-4 alkyl or C (O) C _1-4 alkyl .

44. The compound of formula IV

;

or a pharmaceutically acceptable salt thereof;

wherein

Z ^M represents a 5-7 membered monocyclic, unsaturated or aromatic, heterocyclic ring containing up to 4 heteroatoms independently selected from O, N, NH, S, SO or SO ₂ ;

T ^M is an 8-14 membered aromatic or non-aromatic bicyclic or tricyclic ring containing 0-5 heteroatoms selected from O, S, N, NH, S (O) or SO ₂ ;

where each Z ^M and T ^M independently and optionally contains up to 4 substituents independently selected from R ¹ , R ² , R ³ , R ⁴ or R ⁵ ;

n is 0, 1 or 2;

provided that

(a) if Z is optionally substituted pyrimidinyl or thiazolyl, both R ⁶ is hydrogen, and X ₁ is NH, then T is not optionally substituted adamantyl;

(b) if Z is optionally substituted pyridyl, pyrimidinyl, isoxazolyl or thiazolyl, both R ⁶ are hydrogen, and X ₁ is NH, then T is not

optionally containing up to 2 halogen atoms;

(c) if both R ⁶ is hydrogen and X ₁ is NH, then T is not 1-naphthyl, 2-naphthyl or 7-hydroxynaphth-1-yl;

(d) if Z is pyrimidinyl, 5-methylisoxazolyl or pyridyl, both R ⁶ are hydrogen and X ₁ is NH, then T is not substituted purinyl; and

(e) if Z is thiazol-2-yl, both R ⁶ are hydrogen, and X ₁ is NH, then T is not substituted with 3H-isobenzofuran-1-one-7-yl.

45. The compound of claim 44, wherein Z ^{M is} selected from

or

.

46. The compound of claim 45, wherein Z ^{M is} selected from

or

47. The compound according to item 46, in which Z ^M represents the formula ia.

48. The compound of claim 44, wherein Z ^{M is} selected from

or

49. The compound of claim 44, wherein Z ^{M is} selected from

or

50. The compound of claim 45, wherein Z ^{M is} selected from

or

51. The compound of claim 45, wherein Z ^{M is} selected from

or

52. The compound of claim 45, wherein Z ^{M is} selected from

or

53. The compound of claim 45, wherein Z ^{M is} selected from

or

54. The compound of claim 44, wherein each R ^N is hydrogen.

55. The compound of claim 44, wherein each R ^N is unsubstituted C _1-4 alkyl.

56. The compound of claim 44, wherein Z ^M is an optionally substituted 5-6 membered monocyclic ring.

57. The compound of claim 44, wherein X ₁ is NH.

58. The compound of claim 44, wherein X ₁ is O.

59. The compound of claim 44, wherein T ^M is phenyl or naphthyl, optionally containing up to 3 substituents independently selected from halo, cyano, trifluoromethyl, OH, C _1-4 alkyl, C _2-4 alkenyl, C _1-4- alkoxy, trifluoromethoxy, C (O) NH ₂ , NH ₂ , NH (C _1-4 -alkyl), N (C _1-4 -alkyl) ₂ , NHC (O) C _1-4 -alkyl, 1-pyrrolidinyl, 1-piperidinyl, 1-morpholinyl or C (O) C _1-4 alkyl.

60. The compound of claim 44, wherein T ^{M is} selected from

or

61. The compound of claim 44, wherein T is selected from

or

62. The compound of formula (V)

T ₁ --L ₁₁ -A - L ₂₂ -Z; in which T ₁ represents an 8-14 membered aromatic or unsubstituted bicyclic or tricyclic ring containing 0-5 heteroatoms selected from O, S, N, NH, S (O) or SO ₂ ;

L ₁₁ represents - (X ₁ ) _p - (CHR ¹ ) _r - (X ₂ ) -R _y ; where p is 0 or 1;

r is 0 or 1;

X ₁ represents O, S or NR _x , where R _x represents H or R ² ;

X ₂ represents R ² ;

R _y represents —C (O) —NR ² -;

L ₂₂ represents OC (O), C (O) O, S (O), SO ₂ , N (R ⁵ ) SO ₂ , N (R ⁶ ) SO ₂ , SO ₂ N (R ⁵ ), SO ₂ N (R ⁶ ), C (O) N (R ⁵ ), C (O) N (R ⁶ ), NR ⁵ C (O), NR ⁶ C (O), C (NOR ⁵ ) R ⁶ , C (NOR ⁵ ) R ⁶ , C (NOR ⁶ ) R ⁵ , C (NOR ⁶ ) R ⁶ , N (R ⁵ ), N (R ⁶ ), NR ⁵ C (O) O, NR ⁶ C (O) O, OC (O) NR ⁵ , OC (O) NR ⁶ , NR ⁵ C (O) N (R ⁵ ), NR ⁵ C (O) N (R ⁶ ), NR ⁶ C (O) N (R ⁵ ), NR ⁶ C (O) N (R ⁶ ), NR ⁵ SO ₂ N (R ⁵ ), NR ⁵ SO ₂ N (R ⁶ ), NR ⁶ SO ₂ N (R ⁵ ), NR ⁶ SO ₂ N (R ⁶ ) , N (OR ⁵ ) or N (OR ⁶ );

A is a 5-7 membered monocyclic aromatic ring containing 0-4 heteroatoms;

Z represents 2-thiazolyl;

where each T, A and Z optionally contains up to 4 suitable substituents independently selected from R ¹ , R ² , R ³ , R ⁴ or R ⁵ ;

n is 0, 1 or 2;

R ⁸ represents an amino protecting group;

provided that

(i) if

L ₂₂ represents SO ₂ , N (R ⁵ ) SO ₂ , N (R ⁶ ) SO ₂ , SO ₂ N (R ⁵ ), SO ₂ N (R ⁶ ), C (O) N (R ⁵ ), C (O) N (R ⁶ ), NR ⁵ C (O) or NR ⁶ C (O);

A is an optionally substituted 5-6 membered monocyclic aromatic ring with 0-4 heteroatoms independently selected from N, S or O;

X ₂ is optionally substituted methylene or ethylene;

T ₁ is an optionally substituted fused aromatic bicyclic ring system containing 0-4 heteroatoms independently selected from N, O or S;

then r is 1;

(ii) if

p is 1;

X ₂ is optionally substituted methylene, ethylene or propylene;

then X _{1 is} not O or S;

(iii) if

L ₁₁ represents —O — CH ₂ —C (O) —NH—;

A represents phenylene;

L ₂₂ represents —S (O) ₂ —NH—;

then T _{1 is} not any of the following groups:

(iv) if

L ₁₁ represents —S — CH ₂ —C (O) —NH—;

A represents phenylene;

L ₂₂ represents —S (O) ₂ —NH—;

then T _{1 is} not any of the following groups

or

where B is hydrogen, methyl, n-propyl, isopropyl, allyl, benzyl or phenylethyl.

63. The compound of claim 62, wherein T ₁ is an 8-14 membered aromatic or non-aromatic bicyclic or tricyclic ring containing 0 heteroatoms.

64. The compound of claim 63, wherein T ₁ is naphthyl, anthracenyl, tetralinyl or decalinyl.

65. The compound of claim 63, wherein T ₁ is an 8-14 membered aromatic or non-aromatic bicyclic or tricyclic ring containing up to 5 heteroatoms.

66. The compound of claim 65, wherein T ₁ is an 8-14 membered aromatic bicyclic ring containing up to 5 heteroatoms.

67. The compound of claim 65, wherein T ₁ is an 8-14 membered non-aromatic bicyclic ring containing up to 5 heteroatoms.

68. The compound of claim 66, wherein T _{1 is} selected from quinolinyl, isoquinolinyl, benzofuranyl, benzothiophenyl, quinolinyl, isoquinolinyl, benzofuranyl, benzothiophenyl, indolisinyl, indolyl, isoindolyl, indolinyl, indazolyl, benzinyl azinazyl azinazyl azinazyl azinazyl azinazyl azinazyl azinazyl azinazyl azinazinyl quinazolinyl, quinoxaline, naphthylirinyl or pteridinyl.

69. The compound of claim 66, wherein T ₁ is an 8-14 membered non-aromatic tricyclic ring containing up to 5 heteroatoms.

70. The compound of claim 65, wherein T ₁ is an 8-14 membered aromatic tricyclic ring containing up to 5 heteroatoms.

71. The compound of claim 65, wherein T _{1 is} selected from dibenzofuranyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl or carbazolyl.

72. The compound of claim 62, wherein A is phenyl.

73. The compound of claim 62, wherein A is a 5-6 membered monocyclic aromatic ring containing 1-4 heteroatoms.

74. The compound of claim 73, wherein A is a 5-6 membered monocyclic aromatic ring containing 1-3 heteroatoms.

75. The compound of claim 74, wherein A is selected from thiazolyl, isothiazolyl, thiadiazolyl, thiophenyl, furanyl, oxazolyl, isoxazolyl, oxadiazolyl, triazolyl, imidazolyla, pyrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl.

76. A pharmaceutical composition comprising a compound according to any one of claims 1 to 75 and a pharmaceutically acceptable excipient or carrier.

77. A method of inhibiting the activity of one or more of Na _V 1.1, Na _V 1.2, Na _V 1.3, Na _V 1.4, Na _V 1.5, Na _V 1.6, Na _V 1.7, Na _V 1.8, Na _V 1.9 or Ca _V 2.2

(a) in a patient; or

(b) in a biological sample;

comprising administering to said patient or interacting with said biological sample of a compound of formula I

(I);

or a pharmaceutically acceptable derivative thereof;

in which L ₁ represents - (X ₁ ) _p - (X ₂ ) _q -R _y -;

Where:

X ₁ represents O, S or NR _X ;

p is 0 or 1;

q is 0 or 1;

R _x represents H or R ² ;

X ₂ represents R ² ;

R _y represents —C (O) —NR ² -; or

L ₂ and R _{y are} independently selected from OC (O), C (O) O, S (O), SO ₂ , N (R ⁵ ) SO ₂ , N (R ⁶ ) SO ₂ , SO ₂ N (R ⁵ ) , SO ₂ N (R ⁶ ), C (O) N (R ⁵ ), C (O) N (R ⁶ ), NR ⁵ C (O), NR ⁶ C (O), C (NOR ⁵ ) R ⁶ , C (NOR ⁵ ) R ⁶ , C (NOR ⁶ ) R ⁵ , C (NOR ⁶ ) R ⁶ , N (R ⁵ ), N (R ⁶ ), NR ⁵ C (O) O, NR ⁶ C (O ) O, OC (O) NR ⁵ , OC (O) NR ⁶ , NR ⁵ C (O) N (R ⁵ ), NR ⁵ C (O) N (R ⁶ ), NR ⁶ C (O) N (R ⁵ ), NR ⁶ C (O) N (R ⁶ ), NR ⁵ SO ₂ N (R ⁵ ), NR ⁵ SO ₂ N (R ⁶ ), NR ⁶ SO ₂ N (R ⁵ ), NR ⁶ SO ₂ N (R ⁶ ), N (OR ⁵ ) or N (OR ⁶ );

Z represents hydrogen, a cycloaliphatic, heterocyclic, aryl or heteroaryl ring;

T represents an aliphatic group, a cycloaliphatic, aryl, heteroaryl or heterocyclic ring;

A represents an aryl or heteroaryl ring;

in which each of T, A and Z optionally contains up to 4 suitable substituents independently selected from R ¹ , R ² , R ³ , R ⁴ or R ⁵ ;

n is 0, 1 or 2;

R ⁸ represents an amino protecting group.

78. The method according to p, in which p is 0, and q is 0.

79. The method according to p, in which p is 0, and q is 1.

80. The method according to p, in which p is 1, and q is 1.

81. The method according to p, in which X ₁ represents O or NR _X.

82. The method of claim 80, wherein X ₁ is NR _X ; and R _X represents H.

83. The method according to p, in which X ₂ is a straight or branched (C ₁ -C ₆ ) alkyl or (C ₂ -C ₆ ) alkenyl or alkynyl, optionally containing up to 2 substituents independently selected from R ¹ and R ⁵ .

84. The method of claim 80, wherein X ₂ is straight or branched (C ₁ -C ₆ ) alkyl, optionally containing up to 2 substituents independently selected from R ¹ and R ⁵ .

85. The method according to claim 1, in which R _y represents a linear or branched (C ₁ -C ₆ ) alkyl or (C ₂ -C ₆ ) alkenyl or alkynyl, optionally containing up to 2 substituents independently selected from R ¹ and R ⁵ .

86. The method according to p, in which Z represents aryl or heteroaryl.

87. The method of claim 85, wherein Z is phenyl or naphthyl.

88. The method of claim 85, wherein Z is heteroaryl.

89. The method of Claim 87, wherein Z is selected from thiazolyl, isothiazolyl, thiadiazolyl, thienyl, furanyl, oxazolyl, isoxazolyl, oxadiazolyl, triazolyl, imidazolyl, pyrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl pyrrolazinyl.

90. The method according to p, in which A represents aryl.

91. The method of claim 89, wherein A is phenyl or naphthyl.

92. The method according to p, in which A is a monocyclic aromatic ring containing from 1 to 3 heteroatoms selected from O, S or NH.

93. The method of claim 77, wherein A is pyridyl, pyrazyl, triazinyl, furanyl, pyrrolyl, thiophenyl, oxazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, imidazolyl, triazolyl, thiadiazolyl or pyrimidinyl.

94. The method of claim 77, wherein A is a bicyclic or tricyclic ring system with at least one aromatic ring, wherein said ring system contains 1-5 heteroatoms selected from O, S or NH.

95. The method according to p. 93, in which A is quinolinyl, isoquinolinyl, benzofuranyl, benzothiophenyl, indolisinyl, indolyl, isoindolyl, indolinyl, indazolyl, benzimidazolyl, benzothiazolyl, purinyl, cinnolinyl, phthalazine, quininofininyl, quininosinyl vinyl , carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, anthracenyl, fluorenyl, dibenzofuranyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl or phenoxazinyl.

96. The method according to p, in which T is an aliphatic or cycloaliphatic group.

97. The method of claim 95, wherein T is straight or branched (C ₁ -C ₆ ) alkyl.

98. The method of claim 95, wherein T is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl or adamantyl.

99. The method according to p, in which T represents an aryl or heteroaryl ring.

100. The method of claim 98, wherein T is phenyl, naphthyl, anthracenyl, thiophenyl, benzothiophenyl, pyridyl, furanyl, benzofuranyl, oxazolyl, quinolinyl, phenyl, naphthyl, anthracenyl, thiophenyl, benzothiophenyl, pyridyl, furanyl, benzofuranyl , quinolinyl, pyrrolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, pyridazinyl, pyrimidinyl, indolizinyl, benzolindinolin, indolizinyl, benzolindinolin, indolizinolinazole, benzolindinolindinolindinolindinolindinolindinolin , quinoxalinyl, naphthyridinyl, pteridinyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl or carbazolyl.

101. The method according to p, in which T is a heterocyclic ring.

102. The method according to p, in which T is tetrahydrofuranyl, pyrrolidinyl, piperidinyl, morpholinyl, dithianil, thiomorpholinyl, piperazinyl, quinuclidinyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, imidiolinodiolinodiolinodiolinodiolinodiolinodiolinodiolinodiolinodiolinol , dioxanyl, piperazinyl or tritianil.

103. The method according to p, in which R ¹ represents oxo.

104. The method according to p, in which R ¹ represents R ⁶ or (CH ₂ ) _n -Y.

105. The method according to p, in which R ¹ represents (CH ₂ ) _n -Y, where n is 0.

106. The method according to p. 77 or 103, in which R ² represents a linear or branched (C ₁ -C ₆ ) alkyl or (C ₂ -C ₆ ) alkenyl or alkynyl, optionally containing up to 2 substituents R ¹ .

107. The method according to p, in which

Z represents thiazol-2-yl;

A represents phenyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, triazinyl or tetrazinyl;

L ₁ represents - (X ₁ ) _p - (X ₂ ) _q —R _y -;

where X ₁ represents O, S or NR _X ;

p is 0 or 1;

q is 0 or 1;

R _X represents H or R ² ;

X ₂ represents R ² ;

R _y represents —C (O) —NR ² -; and

L ₂ represents SO ₂ N (R ⁵ ) or SO ₂ N (R ⁶ ).

108. The method of claim 77, wherein said compound has formula I-A, formula IIA-i, formula IIB-i, formula IIC-i, formula IID-i, formula III, formula IV, or formula V.

109. A method of treating or alleviating the severity of a disease, disorder or condition selected from acute, chronic, neuropathic pain or inflammatory pain, arthritis, migraine, histamine headache, trigeminal neuralgia, herpetic neuralgia, general neuralgia, epilepsy or epileptic conditions, neurodegenerative disorders, mental disorders such as anxiety and depression, myotonia, arrhythmias, motor disorders, neuroendocrine disorders, ataxia, multiple sclerosis, irritable syndrome bowel, urinary incontinence, visceral pain, pain with osteoarthritis, postherpetic neuralgia, diabetic neuropathy, radicular pain, sciatica, back pain, headache or neck pain, severe or indomitable pain, nociceptive pain, severe pain, postoperative pain, stroke, bipolar disorder or cancer pain, comprising administering to said patient an effective amount of a compound of formula I.

110. The method according to p, in which said compound corresponds to any one of claims 1-77.

111. The method according to p, in which the disease, disorder or condition is associated with the activation or hyperactivity of voltage-dependent sodium channels.

112. The method of claim 108, wherein the disease, disorder, or condition is associated with activation or hyperactivity of voltage-gated calcium channels.

113. The method according to p. 111, in which the disease, disorder or condition is an acute, chronic, neuropathic pain, inflammatory pain or inflammatory sharp pain.

114. The method according to p, in which the disease, disorder or condition is a radicular pain, sciatica, back pain, headache, neck pain or neuropathy.

115. The method of claim 108, wherein the disease, disorder, or condition is severe or indomitable pain, acute pain, postoperative pain, back pain, or cancer pain.

116. The method according to p. 77 or 108, in which said compound is selected from figure 1.