IP Library › Granted Patent US 10,385,070

Granted Patent B2

US 10,385,070 · App. 13/398,184 · Granted Aug 20, 2019

Chroman-spirocyclic piperidine amides as modulators of ion channels

Inventors: Sara Sabina Hadida-Ruah (La Jolla, CA); Mark Thomas Miller (San Diego, CA); Edward Adam Kallel (Escondido, CA); Brian Richard Bear (Oceanside, CA); Vijayalaksmi Arumugam (San Marcos, CA); Michael Paul Deninno (San Diego, CA); Jinglan Zhou (San Diego, CA); Johnny Uy (San Diego, CA); Bryan A. Frieman (La Jolla, CA)

Assignee: VERTEX PHARMACEUTICALS INCORPORATED

C07D519/00 C07D491/107 C07D491/20 C07D495/10 C07D498/08

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Quick Facts

Patent No.: US 10,385,070
App. No.: 13/398,184
Granted: Aug 20, 2019
Kind: B2

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USPTO Patent Center↗ Full Patent PDF↗

Abstract

The invention relates to chroman spirocyclic piperidine amide derivatives useful as inhibitors of ion channels. The invention also provides pharmaceutically acceptable compositions comprising the compounds of the invention and methods of using the compositions in the treatment of various disorders.

Claims (231)

1. A compound of formula I:

or a pharmaceutically acceptable salt thereof,

wherein, independently for each occurrence:

W is CR 1 ;

a dashed circle denotes unsaturation;

R 1 is H or halo;

R 2 is C1-C6 alkoxy, halo, CN, OR 7 , N(R 7 ) 2 , NR 7 SO 2 R 7 , SO 2 R 7 , SR 7 , SOR 7 , CO 2 R 7 , NR 7 COR 7 , NR 7 CO 2 R 7 , CON(R 7 ) 2 , SO 2 N(R 7 ) 2 , CF 3 , OCF 3 , OCHF 2 , CH 2 OCHF 2 , CH 2 OCH 2 CHF 2 , C3-C8 cycloalkyl, or heterocycloalkyl, a straight chain or branched (C1-C8)-H wherein up to two CH 2 units are replaced with O, CO, S, SO, SO 2 or NR 7 ;

R 7 is C1-C6 alkyl or fluoroalkyl, or C3-C8 cycloalkyl, or 2 R 7 taken together with the atoms to which they are attached form a ring;

R 8 is H, CF 3 , CO 2 R 7 , OH, an optionally substituted aryl, heteroaryl, C3-C8 cycloalkyl, heterocycloalkyl, N(R 7 ) 2 , NR 7 COR 7 , CON(R 7 ) 2 , CN, or SO 2 R 7 ;

A is aryl optionally substituted with one or more of C1-C6 alkyl, C3-C8 cycloalkoxy, C1-C6 alkoxy, halo, OR 7 , NR 7 SO 2 R 7 , SOR 7 , SR 7 , NR 7 CO 2 R 7 , SO 2 N(R 7 ) 2 , OCF 3 , OCHF 2 , R 8 , heterocycloalkoxy, a straight chain (C1-C8)-R 8 , or branched or cyclic (C3-C8)-R 8 wherein up to three CH 2 units of the straight chain (C1-C8)-R 8 and branched or cyclic (C3-C8)-R 8 may be replaced with O, S, SO, SO 2 , or NR 7 ; or wherein two adjacent groups on the aryl ring form a heterocyclic ring comprising up to 2 heteroatoms and which is optionally substituted with a methyl group;

X is O;

n is 1 or 2; and

o is 0.

2. The compound of claim 1 , wherein all W's are CH.

3. The compound of claim 1 , wherein R 1 is halo.

4. The compound of claim 1 , wherein R 1 is F.

5. The compound of claim 1 , wherein R 2 is C1-C6 alkoxy, OR 7 , or N(R 7 ) 2 .

6. The compound of claim 1 , wherein R 2 is OCH 3 , CH 2 OCHF 2 , CH 2 OCH 3 , OCH 2 CH 3 , CH 3 , CH(CH 3 ) 2 , OCH(CH 3 ) 2 , CH 2 OCH 2 CH 3 , CH(CH 3 )OCH 3 , CH 2 SCH 3 ,

OCH 2 CH 2 SO 2 CH 3 , NHCH(CH 3 ) 2 , OtBu,

7. The compound of claim 1 , wherein A is

wherein:

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

R 5 is H, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, C3-C8 cycloalkoxy, halo, CN, OH, OR 7 , N(R 7 ) 2 , NR 7 SO 2 R 7 , SO 2 R 7 , SOR 7 , SR 7 , CO 2 R 7 , NR 7 COR 7 , NR 7 CO 2 R 7 , CON(R 7 ) 2 , SO 2 N(R 7 ) 2 , CF 3 , OCF 3 , OCHF 2 , heterocycloalkyl, heterocycloalkoxy, an optionally substituted aryl, heteroaryl, a straight chain (C1-C8)-R 8 , or branched or cyclic (C3-C8)-R 8 wherein up to three CH 2 units of the straight chain (C1-C8)-R 8 and branched or cyclic (C3-C8)-R 8 may be replaced with O, CO, S, SO, SO 2 , or NR 7 ;

R 6 is H, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, halo, CN, OH, OR 7 , N(R 7 ) 2 , NR 7 SO 2 R 7 , SO 2 R 7 , SOR 7 , SR 7 , CO 2 R 7 , NR 7 COR 7 , NR 7 CO 2 R 7 , CON(R 7 ) 2 , SO 2 N(R 7 ) 2 , CF 3 , OCF 3 , OCHF 2 , heterocycloalkyl, heterocycloalkoxy, an optionally substituted aryl, heteroaryl, a straight chain (C1-C8)-R 8 , branched, or cyclic (C3-C8)-R 8 wherein up to three CH 2 units of the straight chain (C1-C8)-R 8 and branched or cyclic (C3-C8)-R 8 may be replaced with O, CO, S, SO, SO 2 , or NR 7 ; 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.

8. The compound of claim 7 , wherein R 4 is H, C1-C6 alkyl, C1-C6 alkoxy, halo, CN, OH, CHF 2 , CF 3 , OCHF 2 , OCF 3 , a straight chain (C1-C8)-R 8 , or branched or cyclic (C3-C8)-R 8 wherein up to three CH 2 units of the straight chain (C1-C8)-R 8 and branched or cyclic (C3-C8)-R 8 may be replaced with O, CO, S, SO, SO 2 , or NR 7 .

9. The compound of claim 7 , wherein R 4 is H, OCH 3 , OCHF 2 , OCF 3 , F, CH 3 , or CH 2 OCH 3 .

10. The compound of claim 7 , wherein R 5 is H, C1-C6 alkyl, C1-C6 alkoxy, CN, a straight chain (C1-C8)-R 8 , branched, or cyclic (C3-C8)-R 8 wherein up to three CH 2 units of the straight chain (C1-C8)-R 8 and branched or cyclic (C3-C8)-R 8 may be replaced with O, CO, S, SO, SO 2 , or NR 7 .

11. The compound of claim 7 , wherein R 5 is H, F, CH 3 , OCH 3 , CH 2 OH, OH, CH 2 NH 2 , CH 2 NHCH 3 , CH 2 N(CH 3 ) 2 , or CN.

12. The compound of claim 7 , wherein R 6 is H, C1-C6 alkyl, C1-C6 alkoxy, SO 2 R 7 , SO 2 N(R 7 ) 2 , a straight chain (C1-C8)-R 8 , or branched or cyclic (C3-C8)-R 8 , wherein up to three CH 2 units of the straight chain (C1-C8)-R 8 and branched or cyclic (C3-C8)-R 8 may be replaced with O, S, SO, SO 2 , or NR 7 .

13. The compound of claim 7 , wherein R 6 is H, OCH 3 , OH, OCH(CH 3 ) 2 ,

C(CH 3 ) 2 OH,

SO 2 CH 3 , OCH 2 CH 2 OH, OCH 2 CH 2 CH 2 OH, SO 2 CH 3 , SO 2 CH 2 CH 3 , SO 2 CF 3 , SO 2 CH(CH 3 ) 2 , SO 2 tBu,

SO 2 NHCH(CH 3 ) 2 , tBu, OCHF 2 , CH 2 CH 3 , OCH 2 CH 3 ,

14. The compound of claim 7 , wherein

is selected from:

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

or a pharmaceutically acceptable salt thereof,

wherein, independently for each occurrence:

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

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

R 6 is H, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, halo, CN, OH, OR 7 , N(R 7 ) 2 , NR 7 SO 2 R 7 , SO 2 R 7 , SOR 7 , SR 7 , CO 2 R 7 , NR 7 COR 7 , NR 7 CO 2 R 7 , CON(R 7 ) 2 , SO 2 N(R 7 ) 2 , CF 3 , OCF 3 , OCHF 2 , heterocycloalkyl, heterocycloalkoxy, aryl, heteroaryl, a straight chain (C1-C8)-R 8 , or branched or cyclic (C3-C8)-R 8 wherein up to three CH 2 units of the straight chain (C1-C8)-R 8 and branched or cyclic (C3-C8)-R 8 may be replaced with O, S, SO, SO 2 , or NR 7 ; 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; and

n is 1 or 2.

16. The compound of claim 15 , wherein R 1 is halo.

17. The compound of claim 15 , wherein R 1 is F.

18. The compound of claim 15 , wherein R 2 is C1-C6 alkoxy, N(R 7 ) 2 , a straight chain or branched (C1-C8)-H wherein up to two CH 2 units are replaced with O, S, SO, SO 2 or NR 7 .

19. The compound of claim 15 , wherein R 2 is OCH 3 , CH 2 OCH 3 , OCH 2 CH 3 , CH 3 , CH(CH 3 ) 2 , OCH(CH 3 ) 2 , CH 2 OCH(CH 3 ) 2 , CH 2 OCHF 2 , CH 2 OCH 2 CH 3 , CH(CH 3 )OCH 3 ,

CH 2 SCH 3 , OCH 2 CH 2 SO 2 CH 3 , NHCH(CH 3 ) 2 , OtBu,

or OCH 2 CH 2 N(C 2 H 5 ) 2 , OCH 2 Ph.

20. The compound of claim 15 , wherein R 4 is H, C1-C6 alkyl, C1-C6 alkoxy, halo, CN, OH, OR 7 , CHF 2 , CF 3 , OCHF 2 , OCF 3 , a straight chain (C1-C8)-R 8 , or branched or cyclic (C3-C8)-R 8 wherein up to three CH 2 units of the straight chain (C1-C8)-R 8 and branched or cyclic (C3-C8)-R 8 may be replaced with O, S, SO, SO 2 , or NR 7 .

21. The compound of claim 15 , wherein R 4 is H, OCH 3 , OCHF 2 , OCF 3 , F, CH 3 , or CH 3 .

22. The compound of claim 15 , wherein R 5 is H, C1-C6 alkyl, C1-C6 alkoxy, CN, a straight chain (C1-C8)-R 8 , or branched or cyclic (C3-C8)-R 8 wherein up to three CH 2 units of the straight chain (C1-C8)-R 8 and branched or cyclic (C3-C8)-R 8 may be replaced with O, S, SO, SO 2 , or NR 7 .

23. The compound of claim 15 , wherein R 5 is H, CH 3 , OCH 3 , CH 2 OH, F, OH, CH 2 NH 2 , CH 2 NHCH 3 , CH 2 N(CH 3 ) 2 , or CN.

24. The compound of claim 15 , wherein R 6 is H, C1-C6 alkyl, C1-C6 alkoxy, SO 2 R 7 , SO 2 N(R 7 ) 2 , a straight chain (C1-C8)-R 8 , or branched or cyclic (C3-C8)-R 8 , wherein up to three CH 2 units of the straight chain (C1-C8)-R 8 and branched or cyclic (C3-C8)-R 8 may be replaced with O, S, SO, SO 2 , or NR 7 .

25. The compound of claim 15 , wherein R 6 is H, OH, OCH 3 , OCH(CH 3 ) 2 , OCH 2 CH 2 OH, OCH 2 CH 2 CH 2 OH,

SO 2 CH 3 , SO 2 CH 2 CH 3 , SO 2 CF 3 , SO 2 CH(CH 3 ) 2 , SO 2 tBu, SO 2 CHF 2 , tBu,

OCHF 2 , CH 2 CH 3 , OCH 2 CH 3 ,

26. The compound of claim 15 , wherein n is 1.

27. The compound of claim 15 , wherein

is selected from:

28. A compound having formula IB:

or a pharmaceutically acceptable salt thereof,

wherein, independently for each occurrence:

n is 0, 1, or 2;

o is zero;

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

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

R 6 is H, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, halo, CN, OH, OR 7 , N(R 7 ) 2 , NR 7 SO 2 R 7 , SO 2 R 7 , SOR 7 , SR 7 , CO 2 R 7 , NR 7 COR 7 , NR 7 CO 2 R 7 , CON(R 7 ) 2 , SO 2 N(R 7 ) 2 , CF 3 , OCF 3 , OCHF 2 , heterocycloalkyl, heterocycloalkoxy, aryl, heteroaryl, a straight chain (C1-C8)-R 8 , or branched or cyclic (C3-C8)-R 8 wherein up to three CH 2 units of the straight chain (C1-C8)-R 8 and branched or cyclic (C3-C8)-R 8 may be replaced with O, S, SO, SO 2 , or NR 7 ;

R 7 is C1-C6 alkyl or fluoroalkyl, or C3-C8 cycloalkyl, or 2 R 7 taken together with the atoms to which they are attached form a ring;

R 8 is H, CF 3 , CO 2 R 7 , OH, an optionally substituted aryl, heteroaryl, C3-C8 cycloalkyl, heterocycloalkyl, N(R 7 ) 2 , NR 7 COR 7 , CON(R 7 ) 2 , CN, or SO 2 R 7 ; 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.

29. The compound of claim 28 , wherein R 2 is C1-C6 alkoxy.

30. The compound of claim 28 , wherein R 2 is OCH 3 , OC 2 H 5 , or OCH(CH 3 ) 2 .

31. The compound of claim 28 , wherein R 4 is H, C1-C6 alkyl, C1-C6 alkoxy.

32. The compound of claim 28 , wherein R 4 is H or OCHF 2 .

33. The compound of claim 28 , wherein R 5 is H, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, a straight chain (C1-C8)-R 8 , or branched or cyclic (C3-C8)-R 8 wherein up to three CH 2 units of the straight chain (C1-C8)-R 8 and branched or cyclic (C3-C8)-R 8 may be replaced with O, S, SO, SO 2 , or NR 7 .

34. The compound of claim 28 , wherein R 5 is H, CH 3 or OCH 3 .

35. The compound of claim 28 , wherein R 6 is H, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, a straight chain (C1-C8)-R 8 , or branched or cyclic (C3-C8)-R 8 wherein up to three CH 2 units of the straight chain (C1-C8)-R 8 and branched or cyclic (C3-C8)-R 8 may be replaced with O, S, SO, SO 2 , or NR 7 .

36. The compound of claim 28 , wherein R 6 is OCH(CH 3 ) 2 .

37. The compound of claim 28 , wherein n is 1.

38. The compound of claim 28 , wherein o is 0.

39. The compound of claim 28 , wherein

is selected from:

40. A compound selected from the following table:

100

104

105

106

108

110

112

113

114

115

116

117

118

119

120

121

122

123

125

126

127

128

130

131

133

134

135

136

137

138

140

141

142

143

144

145

146

147

148

149

150

151

152

153

154

155

156

157

158

160

161

163

164

165

166

167

168

169

170

171

172

173

177

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

42. 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 .

43. The method of claim 42 , wherein the voltage-gated sodium ion channel is NaV 1.7.

Assignments (3)

RELEASE OF SECURITY INTEREST Recorded Oct 14, 2016

From: MACQUARIE US TRADING LLC

To: VERTEX PHARMACEUTICALS INCORPORATED; VERTEX PHARMACEUTICALS (SAN DIEGO) LLC

Reel/Frame 040357/0001 →

SECURITY INTEREST Recorded Jul 10, 2014

From: VERTEX PHARMACEUTICALS INCORPORATED; VERTEX PHARMACEUTICALS (SAN DIEGO) LLC

To: MACQUARIE US TRADING LLC

Reel/Frame 033292/0311 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jul 23, 2013

From: HADIDA-RUAH, SARA SABINA; MILLER, MARK THOMAS; KALLEL, EDWARD ADAM; BEAR, BRIAN RICHARD; ARUMUGAM, VIJAYALAKSMI; DENINNO, MICHAEL PAUL; ZHOU, JINGLAN; UY, JOHNNY; FRIEMAN, BRYAN A.; VERTEX PHARMACEUTICALS(SAN DIEGO)

To: VERTEX PHARMACEUTICALS INCORPORATED

Reel/Frame 030858/0064 →

Continuity (3)

Provisional Application 61444250 · Feb 18, 2011

Provisional Application 61540121 · Sep 28, 2011

Related Publication 20120245136A1 · Sep 27, 2012