US2016221945A1PendingUtilityA1
Substituted heterocyclic sulfonamide compounds useful as trpa1 modulators
Est. expiryOct 11, 2033(~7.2 yrs left)· nominal 20-yr term from priority
Inventors:Huifen ChenYanyan ChuSteven DoAnthony A. EstradaBaihua HuAleksandr KolesnikovXingyu LinJoseph P. LyssikatosDaniel ShoreVishal VermaLan WangGuosheng WuPo-Wai Yuen
A61P 43/00A61P 25/02A61P 29/00A61P 29/02A61P 25/04A61P 27/16A61P 11/08A61P 1/00A61P 17/04A61P 11/06A61P 11/14A61P 13/02A61P 25/00A61P 11/00A61P 19/02A61P 1/04A61K 31/4155C07D 401/12C07D 451/02C07D 207/48C07D 491/048C07D 403/12C07D 417/12C07D 403/14C07D 401/14A61K 31/506C07D 405/14A61K 31/4025C07D 417/14
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Claims
Abstract
The invention is concerned with the compounds of formula I or II: and salts thereof. In addition, the present invention relates to methods of manufacturing and methods of using the compounds of formula I or II as well as pharmaceutical compositions containing such compounds. The compounds may be useful in treating diseases and conditions mediated by TRPA1, such as pain.
Claims
exact text as granted — not AI-modifiedWe claim:
1 . A compound of formula II:
wherein:
(1) A is
B is B 1 and R 5 is R 5a ; or
(2) A is
B is B 2 and R 5 is R 5b ; or
(3) A is
B is B 3 and R 5 is R 5a ; or
(4) A is
B is B 4 and R 5 is R 5a ; or
(5) A is
B is B 1 and R 5 is R 5a ; or
(6) A is
B is B 5 and R 5 is R 5a ; or
(7) A is
B is B 3 and R 5 is R 5a ;
B is B 1 , B 2 , B 3 , B 4 , or B 5 ;
B 1 is a 5-membered heteroaryl comprising 2 or 3 nitrogen atoms in the ring or a 6-membered heteroaryl, wherein any 5-membered heteroaryl or 6-membered heteroaryl of B′ is optionally substituted with one or more groups independently selected from halogen, (C 1 -C 6 )alkyl, —O(C 1 -C 6 )alkyl and (C 3 -C 7 )cycloalkyl;
B 2 is a pyridinyl, wherein any pyridinyl of B 2 is optionally substituted with one or more groups independently selected from halogen, (C 1 -C 6 )alkyl, —O(C 1 -C 6 )alkyl, —O(C 1 -C 6 )alkyl-O(C 1 -C 6 )alkyl, (C 3 -C 7 )cycloalkyl, (C 1 -C 6 )haloalkyl, —CN, and 6-membered heteroaryl, wherein any 6-membered heteroaryl is optionally substituted with one or more (C 1 -C 6 )alkyl or (C 1 -C 6 )haloalkyl;
B 3 is a 5-membered heteroaryl comprising 2 or 3 nitrogen atoms in the ring or a 6-membered heteroaryl comprising 2 nitrogen atoms in the ring, wherein any 5-membered heteroaryl or 6-membered heteroaryl of B 3 is optionally substituted with one or more groups independently selected from halogen, (C 1 -C 6 )alkyl, —O(C 1 -C 6 )alkyl, (C 3 -C 7 )cycloalkyl, —CN, and NR 6 2 , and wherein when B 3 is pyrimidinyl which is attached to the remainder of Formula II at the 4 and 6 positions of the pyrimidinyl, then R 5a is not pyrrolidinyl or substituted pyrrolidinyl;
B 4 is a 5-membered heteroaryl, 6-membered heteroaryl, or phenyl, wherein any 5-membered heteroaryl, 6-membered heteroaryl, or phenyl of B 4 is optionally substituted with one or more groups independently selected from halogen, —CN, (C 1 -C 6 )alkyl, —O(C 1 -C 6 )alkyl and (C 3 -C 7 )cycloalkyl;
B 5 is a phenyl optionally substituted with one or more groups independently selected from —CN, halogen, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, —O(C 1 -C 6 )alkyl, and —O(C 1 -C 6 )haloalkyl;
R 1 is a phenyl, 5-membered heteroaryl or 6-membered heteroaryl, wherein any phenyl, 5-membered heteroaryl or 6-membered heteroaryl of R 1 is optionally substituted with one or more groups independently selected from halogen, —CN, (C 1 -C 6 )alkyl and (C 1 -C 6 )haloalkyl;
R 2 is halogen, (C 1 -C 6 )alkyl or CN, wherein any (C 1 -C 6 )alkyl of R 2 is optionally substituted with one or more groups independently selected from halogen, —OH and —O(C 1 -C 6 )alkyl;
each R 3a is independently selected from H, halogen and (C 1 -C 6 )alkyl;
one R 3b group is halogen, —CN, or (C 1 -C 6 )alkyl and the remaining R 3b groups are independently selected from H, (C 1 -C 6 )alkyl and (C 1 -C 6 )haloalkyl;
one R 3b′ group is halogen, (C 1 -C 6 )alkyl, —CN, or (C 1 -C 6 )haloalkyl and the remaining R 3b′ groups are independently selected from H, (C 1 -C 6 )alkyl and (C 1 -C 6 )haloalkyl;
two R 3c groups attached to different non-adjacent carbon atoms or adjacent carbon atoms are combined to form a (C 1 -C 4 )alkyl linker or a (C 1 -C 2 )alkyl-O—(C 1 -C 2 )alkyl linker, wherein the (C 1 -C 4 )alkyl linker or (C 1 -C 2 )alkyl-O—(C 1 -C 2 )alkyl linker is optionally substituted with one or more groups independently selected from halogen and (C 1 -C 6 )alkyl, and the remaining R 3c groups are independently selected from H, halogen and (C 1 -C 6 )alkyl;
each R 3d group is independently selected from H, halogen, (C 1 -C 6 )alkyl, and —CN, wherein any (C 1 -C 6 )alkyl of R 3d is optionally substituted with one or more groups independently selected from halogen, —OH and —O(C 1 -C 6 )alkyl;
one R 3e group is halogen, —CN or (C 1 -C 6 )alkyl and the remaining R 3e groups are independently selected from H, (C 1 -C 6 )alkyl and (C 1 -C 6 )haloalkyl;
two R 3f groups attached to the same carbon atom are combined to form a (C 2 -C 4 )alkyl linker, wherein the (C 2 -C 4 )alkyl linker is optionally substituted with one or more groups independently selected from halogen and (C 1 -C 6 )alkyl, and the remaining R 3f groups are independently selected from H, halogen and (C 1 -C 6 )alkyl;
R 4 is H, (C 1 -C 6 )alkyl or (C 1 -C 6 )haloalkyl;
R 5 is R 5a or R 5b ;
R 5a is a phenyl, 5-membered heteroaryl, 6-membered heteroaryl, 4, 5, 6 or 7-membered heterocycle or (C 3 -C 8 )cycloalkyl, wherein any phenyl, 5-membered heteroaryl, 6-membered heteroaryl, 4, 5, 6 or 7-membered heterocycle or (C 3 -C 8 )cycloalkyl of R 5a is optionally substituted with one or more groups independently selected from halogen, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, —CN, (C 3 -C 7 )cycloalkyl, —O(C 1 -C 6 )alkyl, —O(C 1 -C 6 )alkyl-O(C 1 -C 6 )alkyl, —O(C 1 -C 6 )haloalkyl, —S(C 1 -C 6 )alkyl, —S(C 1 -C 6 )haloalkyl, oxo and —O—(C 1 -C 2 )alkyl-O— optionally substituted with one or more halogen, which —O—(C 1 -C 2 )alkyl-O— group is bonded to two adjacent carbon atoms of any phenyl, 5-membered heteroaryl, 6-membered heteroaryl, 4, 5, 6 or 7-membered heterocycle or (C 3 -C 8 )cycloalkyl of R 5a ;
R 5b is a phenyl, 5-membered heteroaryl, 6-membered heteroaryl or 4, 5, 6, 7 or 8-membered heterocycle, wherein any phenyl, 5-membered heteroaryl, 6-membered heteroaryl or 4, 6, 7 or 8-membered heterocycle of R 5b is optionally substituted with one or more groups independently selected from halogen, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, —CN, (C 3 -C 7 )cycloalkyl optionally substituted with one or more halogen, —O(C 1 -C 6 )alkyl, —O(C 1 -C 6 )haloalkyl, —OH, —S(C 1 -C 6 )alkyl, —S(C 1 -C 6 )haloalkyl, and NR 6 2 , and wherein any 5-membered heterocycle of R 5b is substituted with one or more groups independently selected from halogen, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, —CN, (C 3 -C 7 )cycloalkyl, —O(C 1 -C 6 )alkyl, —O(C 1 -C 6 )haloalkyl, —S(C 1 -C 6 )alkyl and —S(C 1 -C 6 )haloalkyl; and
each R 6 is independently H or (C 1 -C 6 )alkyl;
or a salt thereof.
2 . The compound of claim 1 , wherein:
(1) A is
B is B 1 and R 5 is R 5a ; or
(2) A is
B is B 2 and R 5 is R 5b ; or
(3) A is
B is B 3 and R 5 is R 5a ; or
(4) A is
B is B 4 and R 5 is R 5a ; or
(5) A is
B is B 1 and R 5 is R 5a ; or
(6) A is
B is B 5 and R 5 is R 5a ; or
(7) A is
B is B 3 and R 5 is R 5a .
3 . The compound of claim 1 or claim 2 , wherein each R 3a is independently H or F.
4 . The compound of claim 1 or claim 2 , wherein one R 3a is F and the remaining R 3a groups are H.
5 . The compound of claim 1 or claim 2 , wherein each R 3a is H.
6 . The compound of any one of claims 1 - 5 , wherein R 2 is (C 1 -C 6 )alkyl or CN, wherein any (C 1 -C 6 )alkyl of R 2 is optionally substituted with one or more groups independently selected from halogen, —OH and —O(C 1 -C 6 )alkyl.
7 . The compound of any one of claims 1 - 5 , wherein R 2 is —CH 3 , —CH 2 OH, —CHF 2 , —CH 2 OCH 3 or CN.
8 . The compound of any one of claims 1 - 5 , wherein R 2 is —CH 3 .
9 . The compound of any one of claims 1 - 8 , wherein B 1 is a pyrazolyl, triazolyl, pyridinyl or pyrimidinyl, wherein any pyrazolyl, triazolyl, pyridinyl or pyrimidinyl of B 1 is optionally substituted with one or more groups independently selected from halogen, (C 1 -C 6 )alkyl, —O(C 1 -C 6 )alkyl and (C 3 -C 7 )cycloalkyl.
10 . The compound of any one of claims 1 - 8 , wherein B 1 is a pyridinyl or pyrimidinyl wherein any pyridinyl or pyrimidinyl of B 1 is optionally substituted with one or more groups independently selected from halogen, (C 1 -C 6 )alkyl, —O(C 1 -C 6 )alkyl and (C 3 -C 7 )cycloalkyl.
11 . The compound of any one of claims 1 - 8 , wherein B 1 is:
wherein each R Z1 is independently selected from H, halogen, (C 1 -C 6 )alkyl, —O(C 1 -C 6 )alkyl and (C 3 -C 7 )cycloalkyl.
12 . The compound of any one of claims 1 - 8 , wherein B 1 is:
wherein each R Z1 is independently selected from H, halogen, (C 1 -C 6 )alkyl, —O(C 1 -C 6 )alkyl and (C 3 -C 7 )cycloalkyl.
13 . The compound of any one of claims 1 - 8 , wherein B 1 is a pyrazolyl or a triazolyl, wherein any pyrazolyl or triazolyl of B 1 is optionally substituted with one or more groups independently selected from halogen, (C 1 -C 6 )alkyl, —O(C 1 -C 6 )alkyl and (C 3 -C 7 )cycloalkyl.
14 . The compound of any one of claims 1 - 8 , wherein B 1 is a pyrazolyl, wherein any pyrazolyl of B 1 is optionally substituted with one or more groups independently selected from halogen, (C 1 -C 6 )alkyl, —O(C 1 -C 6 )alkyl and (C 3 -C 7 )cycloalkyl.
15 . The compound of any one of claims 1 - 8 , wherein B 1 is:
wherein each R Z1 is independently selected from H, halogen, (C 1 -C 6 )alkyl, —O(C 1 -C 6 )alkyl and (C 3 -C 7 )cycloalkyl.
16 . The compound of any one of claims 1 - 15 , wherein one R 3b group is F and the remaining R 3b groups are H, and one R 3b′ group is F and the remaining R 3b′ groups are H.
17 . The compound of any one of claims 2 - 15 , wherein
(1) the A group
B is B 2 and R 5 is R 5b ;
(2) the A group
B is B 3 and R 5 is R 5a ; and
(3) the A group
B is B 5 and R 5 is R 5a .
18 . The compound of any one of claims 1 - 17 , wherein B 2 is pyridinyl, wherein any pyridinyl of B 2 is optionally substituted with one or more groups independently selected from halogen, (C 1 -C 6 )alkyl, —O(C 1 -C 6 )alkyl, —O(C 1 -C 6 )alkyl-O(C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, —CN, and 6-membered heteroaryl, wherein any 6-membered heteroaryl is optionally substituted with one or more (C 1 -C 6 )alkyl or (C 1 -C 6 )haloalkyl.
19 . The compound of any one of claims 1 - 17 , wherein B 2 is:
wherein each R Z1 is independently selected from H, halogen, (C 1 -C 6 )alkyl, —O(C 1 -C 6 )alkyl, —O(C 1 -C 6 )alkyl-O(C 1 -C 6 )alkyl, (C 3 -C 7 )cycloalkyl, (C 1 -C 6 )haloalkyl, —CN, and 6-membered heteroaryl, wherein any 6-membered heteroaryl is optionally substituted with (C 1 -C 6 )alkyl or (C 1 -C 6 )haloalkyl.
20 . The compound of any one of claims 1 - 19 , wherein B 3 is pyrazolyl, triazolyl or pyrimidinyl, wherein any pyrazolyl, triazolyl or pyrimidinyl of B 3 is optionally substituted with one or more groups independently selected from halogen, (C 1 -C 6 )alkyl, —O(C 1 -C 6 )alkyl, (C 3 -C 7 )cycloalkyl, —CN, and NR 6 2 .
21 . The compound of any one of claims 1 - 19 , wherein B 3 is a pyrimidinyl, wherein any pyrimidinyl of B 3 is optionally substituted with one or more groups independently selected from halogen, (C 1 -C 6 )alkyl, —O(C 1 -C 6 )alkyl, (C 3 -C 7 )cycloalkyl, —CN, and NR 6 2 .
22 . The compound of any one of claims 1 - 19 wherein B 3 is:
wherein each R Z1 is independently selected from hydrogen, halogen, (C 1 -C 6 )alkyl, —O(C 1 -C 6 )alkyl, (C 3 -C 7 )cycloalkyl, —CN, and NR 6 2 .
23 . The compound of any one of claims 1 - 19 , wherein B 3 is a pyrazolyl or a triazolyl, wherein any pyrazolyl or triazolyl of B 3 is optionally substituted with one or more groups independently selected from halogen, (C 1 -C 6 )alkyl, —O(C 1 -C 6 )alkyl and (C 3 -C 7 )cycloalkyl.
24 . The compound of any one of claims 1 - 19 , wherein B 3 is a pyrazolyl, wherein any pyrazolyl of B 3 is optionally substituted with one or more groups independently selected from halogen, (C 1 -C 6 )alkyl, —O(C 1 -C 6 )alkyl and (C 3 -C 7 )cycloalkyl.
25 . The compound of any one of claims 1 - 19 , wherein B 3 is:
wherein each R Z1 is independently selected from H, halogen, (C 1 -C 6 )alkyl, —O(C 1 -C 6 )alkyl and (C 3 -C 7 )cycloalkyl.
26 . The compound of any one of claims 1 - 25 , wherein two R 3c groups attached to different non-adjacent carbon atoms or adjacent carbon atoms are combined to form a —CH 2 , —CH 2 CH 2 — or a —CH 2 OCH 2 — linker, wherein the —CH 2 —, —CH 2 CH 2 — or a —CH 2 OCH 2 — linker is optionally substituted with one or more independent halogen groups and the remaining R 3c groups are each H.
27 . The compound of any one of claims 2 - 25 , wherein the
A group
B is B 4 and R 5 is R 5a .
28 . The compound of any one of claims 1 - 27 , wherein B 4 is a pyrazolyl, triazolyl, pyridinyl, pyrimidinyl, or phenyl wherein any pyrazolyl, triazolyl, pyridinyl, pyrimidinyl, or phenyl of B 4 is optionally substituted with one or more groups independently selected from halogen, —CN, (C 1 -C 6 )alkyl, —O(C 1 -C 6 )alkyl and (C 3 -C 7 )cycloalkyl.
29 . The compound of any one of claims 1 - 27 , wherein B 4 is a pyrimidinyl, wherein any pyrimidinyl of B 4 is optionally substituted with one or more groups independently selected from halogen, —CN, (C 1 -C 6 )alkyl, —O(C 1 -C 6 )alkyl and (C 3 -C 7 )cycloalkyl.
30 . The compound of any one of claims 1 - 27 , wherein B 4 is:
wherein each R Z1 is independently selected from hydrogen, halogen, —CN, (C 1 -C 6 )alkyl, —O(C 1 -C 6 )alkyl and (C 3 -C 7 )cycloalkyl.
31 . The compound of any one of claims 1 - 30 wherein one R 3d group is halogen or (C 1 -C 6 )alkyl and the remaining R 3d groups are H.
32 . The compound of any one of claims 1 - 30 wherein one R 3d group is methyl and the remaining R 3d groups are H.
33 . The compound of any one of claims 2 - 30 , wherein the
A group
B is B 1 and R 5 is R 5a .
34 . The compound of any one of claim 11 , 12 , 15 , 19 , 22 , 25 or 30 , wherein each R Z1 is independently selected from H, halogen, (C 1 -C 6 )alkyl, and (C 3 -C 7 )cycloalkyl.
35 . The compound of any one of claim 11 , 12 , 15 , 19 , 22 , 25 or 30 , wherein each R Z1 is independently selected from H, fluoro, chloro, methyl, trifluoromethyl, —O(CH 3 ), —CN, 2-(trifluoromethyl)pyrimidin-5-yl, 2-(trifluoromethyl)pyrinin-5-yl, —NH(CH 3 ), 2-methoxyethoxy, and cyclopropyl.
36 . The compound of any one of claim 12 , 22 or 30 , wherein each R Z1 is H.
37 . The compound of any one of claims 1 - 36 , wherein R 4 is H.
38 . The compound of any one of claims 1 - 37 , wherein R 1 is a phenyl or thiophenyl, wherein any phenyl or thiophenyl of R 1 is optionally substituted with one or more groups independently selected from halogen, —CN, (C 1 -C 6 )alkyl and (C 1 -C 6 )haloalkyl.
39 . The compound of any one of claims 1 - 37 , wherein R 1 is a phenyl or thiophenyl, wherein any phenyl or thiophenyl of R 1 is optionally substituted with one or more groups independently selected from halogen and —CN.
40 . The compound of any one of claims 1 - 37 , wherein R 1 is a phenyl or thiophenyl, wherein any phenyl or thiophenyl of R 1 is optionally substituted with one or more groups independently selected from fluoro, chloro and —CN.
41 . The compound of any one of claims 1 - 37 , wherein R 1 is 4-fluorophenyl, 3-fluorophenyl, 4-cyanophenyl, 2-chlorothiophen-5-yl, 3,4,-difluorophenyl or 3-fluoropyridin-5-yl.
42 . The compound of any one of claims 1 - 41 , wherein R 5a is phenyl, 6-membered heteroaryl, 6-membered heterocycle or (C 6 )cycloalkyl, wherein any phenyl, 6-membered heteroaryl, 6-membered heterocycle or (C 6 )cycloalkyl of R 5a is optionally substituted with one or more groups independently selected from halogen, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, —CN, (C 3 -C 7 )cycloalkyl, —O(C 1 -C 6 )alkyl, —O(C 1 -C 6 )alkyl-O(C 1 -C 6 )alkyl, —O(C 1 -C 6 )haloalkyl, —S(C 1 -C 6 )alkyl, —S(C 1 -C 6 )haloalkyl, oxo, and —O—(C 1 -C 2 )alkyl-O— optionally substituted with one or more halogen; and R 5b is phenyl, 6-membered heteroaryl or 6-membered heterocycle, wherein any phenyl, 6-membered heteroaryl or 6-membered heterocycle of R 5b is optionally substituted with one or more groups independently selected from halogen, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, —CN, (C 3 -C 7 )cycloalkyl optionally substituted with one or more halogen, —O(C 1 -C 6 )alkyl, —O(C 1 -C 6 )haloalkyl, —OH, —S(C 1 -C 6 )alkyl, —S(C 1 -C 6 )haloalkyl, and NR 6 2 .
43 . The compound of any one of claims 1 - 41 , wherein R 5a is phenyl, 6-membered heteroaryl, 6-membered heterocycle or (C 6 )cycloalkyl, wherein any phenyl, 6-membered heteroaryl, 6-membered heterocycle or (C 6 )cycloalkyl of R 5a is optionally substituted with one or more groups independently selected from (C 1 -C 6 )haloalkyl, (C 3 -C 7 )cycloalkyl, —O(C 1 -C 6 )haloalkyl and —S(C 1 -C 6 )haloalkyl; and R 5b is phenyl, 6-membered heteroaryl or 6-membered heterocycle, wherein any phenyl, 6-membered heteroaryl or 6-membered heterocycle of R 5b is optionally substituted with one or more groups independently selected from (C 1 -C 6 )haloalkyl, (C 3 -C 7 )cycloalkyl, —O(C 1 -C 6 )haloalkyl and —S(C 1 -C 6 )haloalkyl.
44 . The compound of any one of claims 1 - 41 , wherein R 5a is phenyl, pyridinyl, piperidinyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrazolyl, thiazolyl, cyclohexenyl, cyclohexanyl, or bicyclo[2.2.2]octanyl wherein any phenyl, pyridinyl, piperidinyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrazolyl, thiazolyl, cyclohexenyl, cyclohexanyl, or bicyclo[2.2.2]octanyl of R 5a is optionally substituted with one or more groups independently selected from halogen, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, —CN, (C 3 -C 7 )cycloalkyl, —O(C 1 -C 6 )alkyl, —O(C 1 -C 6 )alkyl-O(C 1 -C 6 )alkyl, —O(C 1 -C 6 )haloalkyl, —S(C 1 -C 6 )alkyl, —S(C 1 -C 6 )haloalkyl, oxo, and —O—(C 1 -C 2 )alkyl-O— optionally substituted with one or more halogen; and R 5b is phenyl, pyridinyl, piperidinyl, pyrimidinyl, pyridazinyl, pyrazinyl, 6-azaspiro[2.5]octan-6-yl, or 8-azabicyclo[3.2.1]octan-8-yl, wherein any phenyl, pyridinyl, piperidinyl, pyrimidinyl, pyridazinyl, pyrazinyl, 6-azaspiro[2.5]octan-6-yl, or 8-azabicyclo[3.2.1]octan-8-yl of R 5b is optionally substituted with one or more groups independently selected from halogen, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, —CN, (C 3 -C 7 )cycloalkyl optionally substituted with one or more halogen, —O(C 1 -C 6 )alkyl, —O(C 1 -C 6 )haloalkyl, —OH, —S(C 1 -C 6 )alkyl, —S(C 1 -C 6 )haloalkyl, and NR 6 2 .
45 . The compound of any one of claims 1 - 41 , wherein R 5a is phenyl, pyridinyl, piperidinyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrazolyl, thiazolyl, cyclohexenyl, cyclohexanyl, or bicyclo[2.2.2]octanyl wherein any phenyl, pyridinyl, piperidinyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrazolyl, thiazolyl, cyclohexenyl, cyclohexanyl, or bicyclo[2.2.2]octanyl of R 5a is optionally substituted with one or more groups independently selected from —F, —CHF 2 , —CF 3 , —SCF 3 , —OCHF 2 , —OCF 3 , oxo, —O—CF 2 —O—, —OCH 2 CH 2 OCH 3 , cyclopropyl, or spirocyclopropyl; and R 5b is phenyl, pyridinyl, piperidinyl, pyrimidinyl, pyridazinyl, pyrazinyl, 6-azaspiro[2.5]octan-6-yl, or 8-azabicyclo[3.2.1]octan-8-yl, wherein any phenyl, pyridinyl, piperidinyl, pyrimidinyl, pyridazinyl, pyrazinyl, 6-azaspiro[2.5]octan-6-yl, or 8-azabicyclo[3.2.1]octan-8-yl of R 5b is optionally substituted with one or more groups independently selected from —F, —CHF 2 , —CF 3 , —SCF 3 , —OCH 3 , —OCHF 2 , —OCF 3 , —OH, —NH 2 , —NHCH 3 , cyclopropyl, or 2,2-difluoro-spirocyclopropyl.
46 . The compound of any one of claims 1 - 41 , wherein R 5a or R 5b is phenyl, pyridinyl, pyrimidinyl, pyridazinyl, or pyrazinyl wherein any phenyl, pyridinyl pyrimidinyl, pyridazinyl, or pyrazinyl of R 5a or R 5b is optionally substituted with one or more groups independently selected from halogen, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, —CN, (C 3 -C 7 )cycloalkyl, —O(C 1 -C 6 )alkyl, —O(C 1 -C 6 )haloalkyl, —S(C 1 -C 6 )alkyl and —S(C 1 -C 6 )haloalkyl.
47 . The compound of any one of claims 1 - 41 , wherein R 5a or R 5b is phenyl, pyridinyl, pyrimidinyl, pyridazinyl, or pyrazinyl wherein any phenyl, pyridinyl pyrimidinyl, pyridazinyl, or pyrazinyl of R 5a or R 5b is optionally substituted with one or more groups independently selected from (C 1 -C 6 )haloalkyl, (C 3 -C 7 )cycloalkyl, —O(C 1 -C 6 )haloalkyl and —S(C 1 -C 6 )haloalkyl.
48 . The compound of any one of claims 1 - 41 , wherein R 5a or R 5b is phenyl, pyridinyl, pyrimidinyl, pyridazinyl, or pyrazinyl wherein any phenyl, pyridinyl pyrimidinyl, pyridazinyl, or pyrazinyl of R 5a or R 5b is optionally substituted with one or more groups independently selected from —F, —CF 3 , —SCF 3 , —OCF 3 or cyclopropyl.
49 . The compound of any one of claims 1 - 41 , wherein R 5a is
50 . The compound of any one of claims 1 - 41 , wherein R 5b is
51 . The compound according to claim 1 , which is:
52 . The compound according to claim 1 , which is:
or a salt thereof.
53 . The compound of claim 2 , wherein
(1) the A group
B is B 2 and R 5 is R 5b ;
(2) the A group
B is B 3 and R 5 is R 5a ; and
(3) the A group
B is B 5 and R 5 is R 5a .
54 . The compound of claim 2 , wherein
(1) the A group
B is B 2 and R 5 is R 5b ;
(2) the A group
B is B 3 and R 5 is R 5a ; and
(3) the A group
B is B 5 and R 5 is R 5a .
55 . The compound of claim 2 , wherein
(1) the A group
B is B 2 and R 5 is R 5b ;
(2) the A group
B is B 3 and R 5 is R 5a ; and
(3) the A group
B is B 5 and R 5 is R 5a .
56 . The compound of claim 2 , wherein
(1) the A group
B is B 2 and R 5 is R 5b ;
(2) the A group
B is B 3 and R 5 is R 5a ; and
(3) the A group
B is B 5 and R 5 is R 5a .
57 . The compound of claim 2 , wherein
(1) the A group
B is B 2 and R 5 is R 5b ;
(2) the A group
B is B 3 and R 5 is R 5a ; and
(3) the A group
B is B 5 and R 5 is R 5a .
58 . The compound of claim 2 , wherein
(1) the A group
B is B 2 and R 5 is R 5b ;
(2) the A group
B is B 3 and R 5 is R 5a ; and
(3) the A group
B is B 5 and R 5 is R 5a .
59 . The compound of claim 1 , wherein
(1) the A group
B is B 2 and R 5 is R 5b ;
(2) the A group
B is B 3 and R 5 is R 5a ; and
(3) the A group
B is B 5 and R 5 is R 5a .
60 . The compound of claim 2 , wherein
(1) the A group
B is B 2 and R 5 is R 5b ;
(2) the A group
B is B 3 and R 5 is R 5a ; and
(3) the A group
B is B 5 and R 5 is R 5a .
61 . The compound of claim 2 , wherein:
(1) the A group
B is B 2 and R 5 is R 5b ;
(2) the A group
B is B 3 and R 5 is R 5a ; and
(3) the A group
B is B 5 and R 5 is R 5a .
62 . The compound of any one of claims 53 - 61 , wherein:
B 2 is pyridinyl, wherein any pyridinyl of B 2 is optionally substituted with one or more groups independently selected from halogen, (C 1 -C 6 )alkyl, —O(C 1 -C 6 )alkyl, —O(C 1 -C 6 )alkyl-O(C 1 -C 6 )alkyl, (C 3 -C 7 )cycloalkyl, (C 1 -C 6 )haloalkyl, —CN, and 6-membered heteroaryl, wherein any 6-membered heteroaryl is optionally substituted with one or more (C 1 -C 6 )alkyl or (C 1 -C 6 )haloalkyl; B 3 is a pyrimidinyl, wherein any pyrimidinyl of B 3 is optionally substituted with one or more groups independently selected from halogen, (C 1 -C 6 )alkyl, —O(C 1 -C 6 )alkyl, (C 3 -C 7 )cycloalkyl, —CN, and NR 6 2 ; B 5 is a phenyl optionally substituted with one or more groups independently selected from —CN, halogen, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, —O(C 1 -C 6 )alkyl, and —O(C 1 -C 6 )haloalkyl; R 5a is phenyl, pyridinyl, piperidinyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrazolyl, thiazolyl, cyclohexenyl, cyclohexanyl, or bicyclo[2.2.2]octanyl wherein any phenyl, pyridinyl, piperidinyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrazolyl, thiazolyl, cyclohexenyl, cyclohexanyl, or bicyclo[2.2.2]octanyl of R 5a is optionally substituted with one or more groups independently selected from halogen, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, —CN, (C 3 -C 7 )cycloalkyl, —O(C 1 -C 6 )alkyl, —O(C 1 -C 6 )alkyl-O(C 1 -C 6 )alkyl, —O(C 1 -C 6 )haloalkyl, —S(C 1 -C 6 )alkyl, —S(C 1 -C 6 )haloalkyl, oxo, and —O—(C 1 -C 2 )alkyl-O— optionally substituted with one or more halogen; R 5b is phenyl, pyridinyl, piperidinyl, pyrimidinyl, pyridazinyl, pyrazinyl, 6-azaspiro[2.5]octan-6-yl, or 8-azabicyclo[3.2.1]octan-8-yl, wherein any phenyl, pyridinyl, piperidinyl, pyrimidinyl, pyridazinyl, pyrazinyl, 6-azaspiro[2.5]octan-6-yl, or 8-azabicyclo[3.2.1]octan-8-yl of R 5b is optionally substituted with one or more groups independently selected from halogen, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, —CN, (C 3 -C 7 )cycloalkyl optionally substituted with one or more halogen, —O(C 1 -C 6 )alkyl, —O(C 1 -C 6 )haloalkyl, —OH, —S(C 1 -C 6 )alkyl, —S(C 1 -C 6 )haloalkyl, and NR 6 2 ; R 1 is a phenyl or thiophenyl, wherein any phenyl or thiophenyl of R 1 is optionally substituted with one or more groups independently selected from fluoro, chloro and —CN; and R 4 is H.
63 . The compound of any one of claims 53 - 62 , wherein R 5a is
64 . The compound of any one of claims 53 - 62 , wherein R 5b is
65 . The compound of claim 1 , wherein the
A grout B is B 3 and R 5 is R 5a .
66 . The compound of claim 65 , wherein:
B 3 is a pyrimidinyl, wherein any pyrimidinyl of B 3 is optionally substituted with one or more groups independently selected from halogen, (C 1 -C 6 )alkyl, —O(C 1 -C 6 )alkyl, (C 3 -C 7 )cycloalkyl, —CN, and NR 6 2 ; and R 5a is phenyl, pyridinyl, piperidinyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrazolyl, thiazolyl, cyclohexenyl, cyclohexanyl, or bicyclo[2.2.2]octanyl wherein any phenyl, pyridinyl, piperidinyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrazolyl, thiazolyl, cyclohexenyl, cyclohexanyl, or bicyclo[2.2.2]octanyl of R 5a is optionally substituted with one or more groups independently selected from halogen, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, —CN, (C 3 -C 7 )cycloalkyl, —O(C 1 -C 6 )alkyl, —O(C 1 -C 6 )alkyl-O(C 1 -C 6 )alkyl, —O(C 1 -C 6 )haloalkyl, —S(C 1 -C 6 )alkyl, —S(C 1 -C 6 )haloalkyl, oxo, and —O—(C 1 -C 2 )alkyl-O— optionally substituted with one or more halogen.
67 . The compound of claim 66 , wherein R 5a is
68 . A pharmaceutical composition, comprising a compound of Formula II as described in any one of claims 1 - 67 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent or excipient.
69 . A compound of Formula II as described in any one of claims 1 - 67 or a pharmaceutically acceptable salt thereof for use in medical therapy.
70 . A compound of Formula II as described in any one of claims 1 - 67 or a pharmaceutically acceptable salt thereof for the treatment or prophylaxis of a respiratory disorder.
71 . The use of a compound of Formula II as described in any one of claims 1 - 67 or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the treatment or prophylaxis of a respiratory disorder.
72 . A method for treating a respiratory disorder in a mammal comprising, administering a compound of Formula II as described in any one of claims 1 - 67 or a pharmaceutically acceptable salt thereof to the mammal.
73 . A compound of Formula II as described in any one of claims 1 - 67 or a pharmaceutically acceptable salt thereof for modulating TRPA1 activity.
74 . A compound of Formula II as described in any one of claims 1 - 67 or a pharmaceutically acceptable salt thereof for the treatment or prophylaxis of a disease or condition mediated by TRPA1 activity.
75 . The compound of claim 74 wherein the disease or condition is pain, itch, an inflammatory disorder, an inner ear disorder, fever or another disorder of thermoregulation, tracheobronchial or diaphragmatic dysfunction, a gastrointestinal or urinary tract disorder, chronic obstructive pulmonary disease, incontinence, or a disorder associated with reduced blood flow to the CNS or CNS hypoxia.
76 . The compound of claim 74 wherein the disease or condition is pain, arthritis, itch, cough, asthma, inflammatory bowel disease, or an inner ear disorder.
77 . The use of a compound of Formula II as described in any one of claims 1 - 67 or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the treatment or prophylaxis of a disease or condition that is mediated by TRPA1 activity.
78 . The use of claim 77 wherein the disease or condition is pain, itch, an inflammatory disorder, an inner ear disorder, fever or another disorder of thermoregulation, tracheobronchial or diaphragmatic dysfunction, a gastrointestinal or urinary tract disorder, chronic obstructive pulmonary disease, incontinence, or a disorder associated with reduced blood flow to the CNS or CNS hypoxia.
79 . The use of claim 77 wherein the disease or condition is pain, arthritis, itch, cough, asthma, inflammatory bowel disease, or an inner ear disorder.
80 . A method for modulating TRPA1 activity, comprising contacting TRPA1 with a compound of Formula II as described in any one of claims 1 - 67 or a salt thereof.
81 . A method for treating a disease or condition mediated by TRPA1 activity in a mammal, comprising administering a compound of Formula II as described in any one of claims 1 - 67 or a pharmaceutically acceptable salt thereof to the mammal.
82 . The method of claim 81 wherein the disease or condition is pain, itch, an inflammatory disorder, an inner ear disorder, fever or another disorder of thermoregulation, tracheobronchial or diaphragmatic dysfunction, a gastrointestinal or urinary tract disorder, chronic obstructive pulmonary disease, incontinence, or a disorder associated with reduced blood flow to the CNS or CNS hypoxia.
83 . The method of claim 81 wherein the disease or condition is pain, arthritis, itch, cough, asthma, inflammatory bowel disease, or an inner ear disorder.
84 . The compound of claim 1 wherein the salt of the compound of Formula II is a pharmaceutically acceptable salt of the compound of Formula II.Join the waitlist — get patent alerts
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