IP Library › Granted Patent US 8,916,565

Granted Patent B2

US 8,916,565 · App. 13/364,586 · Granted Dec 23, 2014

Pyrrolopyrazine-spirocyclic piperidine amides as modulators of ion channels

Inventors: Sara Sabina Hadida Ruah (La Jolla, CA); Edward Adam Kallel (Escondido, CA); Mark Thomas Miller (San Diego, CA); Vijayalaksmi Arumugam (San Marcos, CA); Jason McCartney (Cardiff by the Sea, CA); Corey Anderson (San Diego, CA); Peter Diederik Jan Grootenhuis (San Diego, CA); Licong Jiang (San Diego, CA)

Assignee: Vertex Pharmaceuticals Incorporated

C07D471/20 C07D519/00

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Quick Facts

Patent No.: US 8,916,565
App. No.: 13/364,586
Granted: Dec 23, 2014
Kind: B2

External Links

USPTO Patent Center↗ Full Patent PDF↗

Abstract

The invention relates to pyrrolopyrazine-spirocyclic piperidine amide compounds of formula (I) useful as inhibitors of ion channels: wherein R 1 , R 2 , R 3 , R 4 , A, m, n, and o are as defined in the description. 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 (959)

1. A compound of formula I:

or a pharmaceutically acceptable salt thereof,

wherein, independently for each occurrence:

R 1 is H, C1-C8 alkyl, C3-C8 cycloalkyl, halo, CN, NR 8 SO 2 R 8 , SO 2 R 8 , SR 8 , SOR 8 , NR 8 COR 8 , NR 8 CO 2 R 8 , CON(R 8 ) 2 , SO 2 N(R 8 ) 2 , CF 3 , heterocycloalkyl, or a straight chain, branched, or cyclic (C3-C8)-R 9 wherein up to two CH 2 units may be replaced with O, CO, S, SO, SO 2 or NR 8 , or two R 1 taken together form an oxo group;

R 2 is H, C1-C8 alkyl, halo, C1-C8 haloalkyl, CN, OH, SO 2 R 8 , SR 8 , SOR 8 , COR 8 , CO 2 R 8 , CON(R 8 ) 2 , SO 2 N(R 8 ) 2 , CF 3 , CHF 2 , or a straight chain, branched, or cyclic (C3-C8)-R 9 wherein up to two CH 2 units may be replaced with O, CO, S, SO, SO 2 , CF 2 , or NR 8 ;

R 3 is H, C1-C8 alkyl, C3-C8 cycloalkyl, CO 2 R 8 , COR 8 , COH, CON(R 8 ) 2 , CF 3 , CH 2 CF 3 , CH 2 CHF 2 , or a straight chain, branched, or cyclic (C3-C8)-R 9 wherein up to two CH 2 units may be replaced with O, CO, S, SO, SO 2 or NR 8 ;

R 4 is H, C1-C8 alkyl, halo, C3-C8 cycloalkyl, wherein up to two CH 2 units may be replaced by O, CO, S, SO, SO 2 , or NR 8 , or 2 R 4 taken together form a fused 3 to 7 membered cycloalkyl ring;

R 8 is H, C1-C8 alkyl, CF 3 , C3-C8 cycloalkyl, fluoroalkyl, aryl, heteroaryl, or a straight chain, branched, or cyclic (C3-C8)-R 9 wherein up to two CH 2 units may be replaced with O, CO, S, SO, SO 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 , CO 2 R, OH, aryl, heteroaryl, C3-C8 cycloalkyl, heterocycloalkyl, N(R) 2 , NRCOR, CON(R) 2 , CN, halo, or SO 2 R;

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

A is an aryl optionally substituted with one or more of C1-C8 alkyl, C3-C8 cycloalkyl, C1-C8 alkoxy, C3-C8 cycloalkoxy, halo, CN, OH, OR 8 , N(R 8 ) 2 , NR 8 SO 2 R 8 , OSO 2 R 8 , SO 2 R 8 , SOR 8 , SR 8 , CO 2 R 8 , NR 8 COR 8 , NR 8 CO 2 R 8 , CON(R 8 ) 2 , 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 (C3-C8)-(R 9 ) p wherein p is 1 or 2 and wherein up to three CH 2 units may be replaced with O, CO, S, SO, SO 2 , or NR 8 ;

or wherein two adjacent substituents on A together with the carbons to which they are attached form a ring comprising up to 2 heteroatoms;

m is 0, 1, 2, 3, or 4;

n is 0, 1, 2, or 3; and

o is 0, 1, 2, 3, or 4.

2. The compound of claim 1 , wherein A is

wherein:

R 5 is H, C1-C8 alkyl, C3-C8 cycloalkyl, C1-C8 alkoxy, halo, CN, OH, OR 8 , N(R 8 ) 2 , NR 8 SO 2 R 8 , SO 2 R 8 , SOR 8 , SR 8 , CO 2 R 8 , NR 8 COR 8 , NR 8 CO 2 R 8 , CON(R 8 ) 2 , 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 (C3-C8)-R 9 wherein up to three CH 2 units may be replaced with O, CO, S, SO, SO 2 , or NR 8 ;

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

R 7 is H, C1-C8 alkyl, C3-C8 cycloalkyl, C1-C8 alkoxy, halo, CN, OH, OR 8 , N(R 8 ) 2 , NR 8 SO 2 R 8 , SO 2 R 8 , OSO 2 R 8 , SOR 8 , SR 8 , CO 2 R 8 , NR 8 COR 8 , NR 8 CO 2 R 8 , CON(R 8 ) 2 , SO 2 N(R 8 ) 2 , CF 3 , OCF 3 , OCHF 2 , R 9 , heterocycloalkyl, heterocycloalkoxy, aryl, heteroaryl, or a straight chain, branched, or cyclic (C3-C8)-(R 9 ) p , wherein p is 1 or 2 and wherein up to three CH 2 units may be replaced with O, CO, S, SO, SO 2 , or NR 8 ; or

two occurrences of R 5 and R 6 , or R 6 and R 7 are both C1-C8 alkyl and together with the carbons to which they are attached form an optionally substituted ring comprising up to 2 heteroatoms.

3. The compound of claim 2 , wherein R 5 is H, C1-C8 alkyl, C1-C8 alkoxy, halo, OCF 3 , OCHF 2 , R 9 , or a straight chain, branched, or cyclic (C3-C8)-R 9 wherein up to three CH 2 units may be replaced with O, CO, S, SO, SO 2 , or NR 7 .

4. The compound of claim 2 , wherein R 5 is H, CH 3 , OCH 3 , OCF 3 , OPh, Ph, OCHF 2 , or F.

5. The compound of claim 2 , wherein R 6 is H, C1-C8 alkyl, C1-C8 alkoxy, halo, R 9 , or a straight chain, branched, or cyclic (C3-C8)-R 9 wherein up to three CH 2 units may be replaced with O, CO, S, SO, SO 2 , or NR 8 .

6. The compound of claim 2 , wherein R 6 is H, CH 3 , OCH 3 , OCH 2 CH 3 , OCH 2 CH 2 CH 3 , OCH(CH 3 ) 2 , CF 3 , CN, Ph, SO 2 CH 3 , OH, CH(CH 3 ) 2 , OCH 2 CH 2 CH 2 CH 3 , F, Cl, or CH 2 OH.

7. The compound of claim 2 , wherein R 7 is H, C1-C8 alkyl, C1-C8 alkoxy, SO 2 R 8 , OSO 2 R 8 , SO 2 N(R 8 ) 2 , R 9 , OCHF 2 , OCF 3 , or a straight chain, branched, or cyclic (C3-C8)-(R 9 ) p , wherein p is 1 or 2 and wherein up to three CH 2 units may be replaced with O, CO, S, SO, SO 2 , or NR 8 .

8. The compound of claim 2 , wherein R 7 is H, CH 3 , CH 2 CH 3 , tBu, Cl, F, OH, C(═CH 2 )CH 3 , OC(═CH 2 )CH 3 , OCH 3 , OCH 2 CH 2 CH 2 CH 3 , CH 2 OH, OCH 2 CH 2 OH, OCH 2 CH 2 CH 2 OH, OtBu, OCH(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, CH(OH)CH(CH 3 ) 2 , C(CH 3 ) 2 CH 2 OH, OCH 2 CH 2 CH(CH 3 ) 2 , OCH 2 CH 2 CH 3 , OCH(CH 3 ) 2 , OCH 2 CH 2 OCH 3 ,

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

SO 2 NH(CH 3 ), SO 2 NH(CH(CH 3 ) 2 ), SO 2 NH(CH 2 CH 3 ), SO 2 NH(CH(CH 3 ) 2 ), SO 2 N(CH 3 ) 2 ,

OPh, Ph,

OCH 2 CH 2 OCH 3 , CH(CH 3 ) 2 , SO 2 N(CH 2 CH 2 CH 3 ) 2 , CH 2 CH 2 CH 2 CH 3 , CH 2 CH 2 CH 3 , OCH 2 CH 2 CH 2 CH 3 , CH 2 OPh,

OCH 2 Ph, CH 2 CH 2 CH 2 CH 2 CH 3 , OCH 2 CH 3 , OCH 2 CH(CH 3 ) 2 , CH 2 Ph,

CCCH 2 OCH 3 , SO 2 CHF 2 , OCF 3 ,

OCHF 2 ,

CH 2 CH(CH 3 ) 2 , OCH 2 tBu,

OCH 2 CF 3 ,

CH 2 OCH 2 CH 2 CF 3 , CH 2 OCH 2 CF 3 , SO 2 CF 3 , C(CH 3 ) 2 CH 2 CH 3 , C(CH 2 CH 3 ) 3 , CH(OCH 2 CF 3 ) 2 ,

CF 3 , OCH 2 C(CH 3 ) 2 F,

CH(OH)CH 2 OCH 2 CF 3 , CH(OCH 2 CF 3 )CH 2 OH, OSO 2 CF 3 ,

or OCH 2 CH 2 OCF 3 .

9. The compound of claim 2 , wherein

is:

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

wherein:

R 3 is H, C1-C8 alkyl, CO 2 R 8 , COR 8 , COH, CON(R 8 ) 2 , CF 3 , or a straight chain, branched, or cyclic (C3-C8)-R 9 wherein up to two CH 2 units may be replaced with CF 2 , O, CO, S, SO, SO 2 or NR 8 ;

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

11. The compound of claim 10 , wherein R 2 is H, COCF 3 , COtBu, Cl, COCH 3 , CF 2 CF 3 , CH 2 CF 3 , CF 3 , CN, Br, COCH(CH 3 ) 2 , COCH 2 CH 3 , CH(OH)CF 3 , SO 2 CH 3 ,

COPh,

12. The compound of claim 10 , wherein R 3 is H, CH 3 , CH 2 CH 3 , CH 2 CH 2 OCH 3 , CH 2 CH 2 OH, CH 2 CO 2 CH 2 CH 3 , CH 2 CON(CH 3 ) 2 , CH 2 CONH 2 , CH 2 CN, benzyl, cyclobutyl, CH 2 CH(CH 2 ) 2 , CH(CH 2 ) 2 , CH 2 CF 3 , CH 2 CHF 2 , COCH 3 , COCH 2 CH 3 , CO 2 CH 3 , CO 2 CH 2 CH 3 , COH, CONH(CH 3 ) 2 , or CONHCH 3 .

13. The compound of claim 10 , wherein R 6 is H, CH 3 , OCH 3 , OCH 2 CH 3 , OCH 2 CH 2 CH 3 , OCH(CH 3 ) 2 , CF 3 , CN, Ph, SO 2 CH 3 , OH, CH(CH 3 ) 2 , OCH 2 CH 2 CH 2 CH 3 , F, Cl, or CH 2 OH.

14. The compound of claim 10 , wherein R 7 is H, CH 3 , CH 2 CH 3 , tBu, Cl, F, OH, C(═CH 2 )CH 3 , OC(═CH 2 )CH 3 , OCH 3 , OCH 2 CH 2 CH 2 CH 3 , CH 2 OH, OCH 2 CH 2 OH, OCH 2 CH 2 CH 2 OH, OtBu, OCH(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, CH(OH)CH(CH 3 ) 2 , C(CH 3 ) 2 CH 2 OH, OCH 2 CH 2 CH(CH 3 ) 2 , OCH 2 CH 2 CH 3 , OCH(CH 3 ) 2 , OCH 2 CH 2 OCH 3 ,

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

SO 2 NH(CH 3 ),), SO 2 NH(CH(CH 3 ) 2 ), SO 2 NH(CH 2 CH 3 ), SO 2 NH(CH(CH 3 ) 2 ), SO 2 N(CH 3 ) 2 ,

OPh, Ph,

OCH 2 CH 2 OCH 3 , CH(CH 3 ) 2 , SO 2 N(CH 2 CH 2 CH 3 ) 2 , CH 2 CH 2 CH 2 CH 3 , CH 2 CH 2 CH 3 , OCH 2 CH 2 CH 2 CH 3 , CH 2 OPh,

OCH 2 Ph, CH 2 CH 2 CH 2 CH 2 CH 3 , OCH 2 CH 3 , OCH 2 CH 2 CH 2 CH 3 , CH 2 Ph

CCCH 2 OCH 3 , SO 2 CHF 2 ,OCF 3 ,

OCHF 2 ,

CH 2 CH(CH 3 ) 2 , OCH 2 tBu,

OCH 2 CF 3 ,

CH 2 OCH 2 CH 2 CF 3 , CH 2 OCH 2 CF 3 , SO 2 CF 3 , C(CH 3 ) 2 CH 2 CH 3 , C(CH 2 CH 3 ) 3 , CH(OCH 2 CF 3 ) 2 ,

CF 3 , OCH 2 C(CH 3 ) 2 F,

CH(OH)CH 2 OCH 2 CF 3 , CH(OCH 2 CF 3 ) CH 2 OH, OSO 2 CF 3 ,

or OCH 2 CH 2 OCF 3 .

15. The compound of claim 10 , wherein the

moiety is:

16. The compound of claim 1 , wherein, independently for each occurrence:

R 1 is H, C1-C6 alkyl, C3-C8 cycloalkyl, halo, CN, NR 8 SO 2 R 8 , SO 2 R 8 , SR 8 , SOR 8 , NR 8 COR 8 , NR 8 CO 2 R 8 , CON(R 8 ) 2 , SO 2 N(R 8 ) 2 , CF 3 , heterocycloalkyl, or a straight chain, branched, or cyclic (C3-C8)-R 9 wherein up to two CH 2 units may be replaced with O, CO, S, SO, SO 2 or NR 8 , or two R 1 taken together form an oxo group, or a 3 to 7 membered fused cycloalkyl ring, or a 3 to 7 membered spirocyclic ring;

R 2 is H, C1-C6 alkyl, C1-C6 haloalkyl, CN, OH, SO 2 R 8 , SR 8 , SOR 8 , CO 2 R 8 , CON(R 8 ) 2 , SO 2 N(R 8 ) 2 , CF 3 , CHF 2 , or a straight chain, branched, or cyclic (C3-C8)-R 9 wherein up to two CH 2 units may be replaced with O, CO, S, SO, SO 2 , CF 2 , or NR 8 ;

R 3 is H, C1-C6 alkyl, C3-C8 cycloalkyl, CO 2 R 8 , COR 8 , COH, CON(R 8 ) 2 , CF 3 , CH 2 CF 3 , CH 2 CHF 2 , or a straight chain, branched, or cyclic (C3-C8)-R 9 wherein up to two CH 2 units may be replaced with O, CO, S, SO, SO 2 or NR 8 ;

R 4 is H, C1-C6 alkyl, halo, C3-C8 cycloalkyl, wherein up to two CH 2 units may be replaced by O, CO, S, SO, SO 2 , or NR 8 , or 2 R 4 taken together form a fused 3 to 7 membered cycloalkyl ring;

R 8 is H, C1-C6 alkyl, CF 3 , C3-C8 cycloalkyl, or a straight chain, branched, or cyclic (C3-C8)-R 9 wherein up to two CH 2 units may be replaced with O, CO, S, SO, SO 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 , CO 2 R, OH, aryl, heteroaryl, C3-C8 cycloalkyl, heterocycloalkyl, N(R) 2 , NRCOR, CON(R) 2 , CN, or SO 2 R;

R is H, C1-C6 alkyl, aryl, heteroaryl, C3-C8 cycloalkyl, or heterocycloalkyl.

17. The compound of claim 1 , wherein R 1 is C1-C8 alkyl or two R 1 taken together with the atoms to which they are attached form a 3 to 7 membered fused cycloalkyl or spirocyclic ring.

18. The compound of claim 1 , wherein R 1 is CH 3 or two R 1 taken together form a fused cyclohexyl ring.

19. The compound claim 1 , wherein R 2 is H, C1-C8 alkyl, halo, CF 3 , CN, COR 8 , CON(R 8 ) 2 , or a straight chain, branched, or cyclic (C3-C8)-R 9 wherein up to two CH 2 units may be replaced with O, CO, S, SO, SO 2 , CF 2 , or NR 8 .

20. The compound of claim 1 , wherein R 2 is COCF 3 , COtBu, Cl, COCH 3 , CF 2 CF 3 , CH 2 CF 3 , CF 3 , CN, Br, COCH(CH 3 ) 2 , COCH 2 CH 3 , CH(OH)CF 3 , SO 2 CH 3 ,

COPh,

21. The compound of claim 1 , wherein R 3 is H, C1-C8 alkyl, CO 2 R 8 , COR 8 , COH, CON(R 8 ) 2 or a straight chain, branched, or cyclic (C3-C8)-R 9 wherein up to two CH 2 units may be replaced with O, CO, S, SO, SO 2 or NR 8 .

22. The compound of claim 1 , wherein R 3 is H, CH 3 , CH 2 CH 3 , CH 2 CH 2 OCH 3 , CH 2 CH 2 OH, CH 2 CO 2 CH 2 CH 3 , CH 2 CON(CH 3 ) 2 , CH 2 CONH 2 , CH 2 CN, benzyl, cyclobutyl, CH 2 CH(CH 2 ) 2 , CH(CH 2 ) 2 , CH 2 CF 3 , CH 2 CHF 2 , COCH 3 , COCH 2 CH 3 , CO 2 CH 3 , CO 2 CH 2 CH 3 , COH, CONH(CH 3 ) 2 , or CONHCH 3 .

23. The compound of claim 1 , wherein R 4 is H, halo, or C1-C8 alkyl.

24. The compound of claim 1 , wherein R 4 is H, F, or CH 3 .

25. The compound of claim 1 , wherein m is 0, 1, or 2.

26. The compound of claim 1 , wherein n is 0, 1, or 2.

27. The compound of claim 1 , wherein o is 0 or 1.

28. The compound of claim 1 , wherein the compound is selected from the following table:

100

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

30. 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 .

31. The method of claim 30 , wherein the voltage-gated sodium ion channel is NaV 1.7.

32. A compound of formula I:

or a pharmaceutically acceptable salt thereof,

wherein, independently for each occurrence:

R 4 is H, C1-C6 alkyl, halo, C3-C8 cycloalkyl, wherein up to two CH 2 units may be replaced by O, CO, S, SO, SO 2 , or NR 8 , or 2 R 4 taken together form a fused 3 to 7 membered cycloalkyl ring;

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

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

A is an aryl optionally substituted with one or more of C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, C3-C8 cycloalkoxy halo, CN, OH, OR 8 , N(R 8 ) 2 , NR 8 SO 2 R 8 , SO 2 R 8 , SOR 8 , SR 8 , CO 2 R 8 , NR 8 COR 8 , NR 8 CO 2 R 8 , CON(R 8 ) 2 , 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 (C3-C8)-R 9 wherein up to three CH 2 units may be replaced with O, CO, S, SO, SO 2 , or NR 8 ;

or wherein two substituents on A together with the carbon atoms to which they are attached form a ring comprising up to 2 heteroatoms;

m is 0, 1, 2, 3, or 4;

n is 0, 1, 2, or 3; and

o is 0, 1, 2, 3, or 4.

33. The compound of claim 32 , wherein the compound has formula IA:

wherein:

R 2 is C1-C6 alkyl, C1-C6 haloalkyl, CN, OH, SO 2 R 8 , SR 8 , SOR 8 , CO 2 R 8 , CON(R 8 ) 2 , SO 2 N(R 8 ) 2 , CF 3 , CHF 2 , or a straight chain, branched, or cyclic (C3-C8)-R 9 wherein up to two CH 2 units may be replaced with O, CO, S, SO, SO 2 , CF 2 , or NR 8 ;

R 3 is H, C1-C6 alkyl, CO 2 R 8 , COR 8 , COH, CON(R 8 ) 2 , 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 or NR 8 ;

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

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

34. The compound of claim 32 , wherein the

moiety is selected from:

35. The compound of claim 32 , wherein the compound is selected from the following table:

100

102

103

104

105

106

107

108

109

113

114

116

117

118

119

120

121

122

123

124

125

126

127

128

129

130

132

133

135

136

137

138

139

140

141

142

143

144

145

148

149

150

151

152

153

155

156

157

158

159

161

162

164

165

166

167

168

169

170

171

172

173

177

179

180

181

182

184

186

187

188

190

191

192

193

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 Sep 18, 2013

From: HADIDA-RUAH, SARA SABINA; KALLEL, EDWARD ADAM; MILLER, MARK THOMAS; ARUMUGAM, VIJAYALAKSMI; MCCARTNEY, JASON; ANDERSON, COREY; GROOTENHUIS, PETER DIEDERIK JAN; JIANG, LICONG; VERTEX PHARMACEUTICALS(SAN DIEGO)

To: VERTEX PHARMACEUTICALS INCORPORATED

Reel/Frame 031230/0176 →

Continuity (4)

Provisional Application 61438685 · Feb 2, 2011

Provisional Application 61440987 · Feb 9, 2011

Provisional Application 61495538 · Jun 10, 2011

Related Publication 20120196869A1 · Aug 2, 2012