US2016221974A1PendingUtilityA1
Sodium channel modulators for the treatment of pain and diabetes
Est. expirySep 10, 2033(~7.2 yrs left)· nominal 20-yr term from priority
Inventors:Olga BabichTina GaryantesRobert Zhiyong LuoDavid PallingSrinivasan P. VenkatachalanYanlin Wang-Fischer
C07D 277/52A61P 29/00A61P 25/04A61K 31/426A61P 3/10A61P 43/00C07D 487/04C07D 285/08C07D 471/04C07D 417/12A61K 9/0021A61K 31/433A61K 9/0019
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Claims
Abstract
Provided herein are sodium channel modulating Compounds, in particular NaV1.7 modulating compounds of Formula I or compounds of Formula I′: In particular, provided herein are processes for the preparation of, intermediates used in the preparation of, pharmaceutical compositions comprising, and therapeutic methods comprising administering such compounds. In particular, provided herein are compounds for the treatment of pain and diabetes.
Claims
exact text as granted — not AI-modifiedWhat is claimed is:
1 . A compound of Formula (I),
or a pharmaceutically acceptable salt, or a stereoisomeric or tautomeric form thereof, wherein:
Z is —O— or —S—;
Y is —X—C(═O)NR 4 R 5 , —(CH 2 ) 3 —NR 9 R 10 , or 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-(2-yl or 3-yl);
X is (C 6 -C 10 )aryl or 5- or 6-membered heteroaryl;
R 1 is a partially unsaturated or aromatic 5- or 6-membered heterocycle;
R 2 is independently at each occurrence —F, —Cl, —Br, —CH 3 or —CN;
R 3 is independently at each occurrence —H, —F, —Cl, —Br, —CF 3 , —OCF 3 , —CN, (C 1 -C 12 )alkyl, or (C 1 -C 12 )alkoxy;
R 4 and R 5 are each independently H, (C 1 -C 9 )alkyl, (C 4 -C 12 )cycloalkyl, or R 4 and R 5 together form a 5- to 7-membered heterocycloalkyl ring; with the proviso that:
R 4 and R 5 are not both H; and
at least one of R 4 and R 5 independently or said heterocycloalkyl ring formed by R 4 and R 5 together is substituted with 1 or 2 substituents selected from the group consisting of —CO 2 H, —CO 2 R 6 , —CN, —OH, —CONR 7 R 8 , and —NR 7 R 8 ; wherein:
R 6 is (C 1 -C 12 )alkyl;
R 7 and R 8 are each independently H, (C 1 -C 12 )alkyl, or R 7 and R 8 together form a 4- to 7-membered heterocycloalkyl ring;
R 9 is (C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl, pyrazolyl or pyridinyl; wherein R 9 is optionally further substituted with 1 or 2 substituents selected from the group consisting of —COOH, —COOR 11 , —CONR 11 R 12 , —SO 2 R 11 , —SO 2 NR 11 R 12 , —OH, —CN, —OR 11 , and —NR 11 R 12 ; wherein R 11 and R 12 may form a 6 membered heterocycloalkyl ring
R 10 is R 11 , —COR 11 , —COOR 11 , —SO 2 R 11 , 5-methyl-2-oxo-1,3-dioxol-4-yl,
—COO—CH(CH 3 )OCOCH(CH 3 ) 2 ; or R 9 and R 10 together form a piperazinone or a 4- to 8-membered heterocycloalkyl ring, wherein said heterocycloalkyl ring is substituted with 1 or 2 substituents selected from the group consisting of —COOH, —COOR 11 , —CH 2 —COOR 11 , —OH, —NH 2 , —CN, and (C 1 -C 8 )alkoxy;
R 11 and R 12 are independently H or (C 1 -C 6 )alkyl, optionally substituted with 4- to 8-membered heterocycloalkyl ring; and
m and n are each independently 1, 2, 3, or 4.
2 . A compound of Formula (I′),
or a pharmaceutically acceptable salt, or a stereoisomeric or tautomeric form thereof, wherein:
Z is —O— or —S—;
Y is —X—C(═O)NR 4 R 5 , —(CH 2 ) 3 —NR 9 R 10 , or 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-(2-yl or 3-yl);
X is (C 6 -C 10 )aryl or 5- or 6-membered heteroaryl;
R 1 is a partially unsaturated or aromatic 5- or 6-membered heterocycle;
R 2 is independently at each occurrence —F, —Cl, —Br, —CH 3 or —CN;
R 3 is independently at each occurrence —H, —F, —Cl, —Br, —CF 3 , —OCF 3 , —CN, (C 1 -C 12 )alkyl, or (C 1 -C 12 )alkoxy;
R 4 and R 5 are each independently H, (C 1 -C 9 )alkyl, (C 4 -C 12 )cycloalkyl, or R 4 and R 5 together form a 5- to 7-membered heterocycloalkyl ring; with the proviso that:
R 4 and R 5 are not both H; and
at least one of R 4 and R 5 independently or said heterocycloalkyl ring formed by R 4 and R 5 together is substituted with 1 or 2 substituents selected from the group consisting of —CO 2 H, —CO 2 R 6 , —CN, —OH, —CONR 7 R 8 , and —NR 7 R 8 ; wherein:
R 6 is (C 1 -C 12 )alkyl;
R 7 and R 8 are each independently H, (C 1 -C 12 )alkyl, or R 7 and R 8 together form a 4- to 7-membered heterocycloalkyl ring;
R 9 is (C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl, pyrazolyl or pyridinyl; wherein R 9 is optionally further substituted with 1 or 2 substituents selected from the group consisting of —COOH, —COOR 11 , —CONR 11 R 12 , —SO 2 R 11 , —SO 2 NR 11 R 12 , —OH, —CN, —OR 11 , and —NR 11 R 12 ; wherein R 11 and R 12 may form a 6 membered heterocycloalkyl ring
R 10 is R 11 , (C 3 -C 6 )alkynyl, (C 3 -C 6 )alkenyl, —COR 11 , —COOR 11 , —SO 2 R 11 , 5-methyl-2-oxo-1,3-dioxol-4-yl,
—COO—CH(CH 3 )OCOCH(CH 3 ) 2 ; or R 9 and R 10 together form a piperazinone or a 4- to 8-membered heterocycloalkyl ring, wherein said heterocycloalkyl ring is substituted with 1 or 2 substituents selected from the group consisting of —COOH, —COOR 11 , —CH 2 —COOR 11 , —OH, —NH 2 , —CN, and (C 1 -C 8 )alkoxy; or R 9 and R 10 together form a unsubstituted 4- to 8-membered heterocycloalkyl ring, wherein said heterocycloalkyl ring is fused with a 5-membered heteroaryl; and
R 11 and R 12 are independently H or (C 1 -C 6 )alkyl, optionally substituted with 4- to 8-membered heterocycloalkyl ring; and
m and n are each independently 1, 2, 3, or 4.
3 . The compound of any of claims 1 or 2 , wherein Y is —(CH 2 ) 3 —NR 9 R 10 .
4 . The compound of claim 3 , wherein R 1 is an aromatic 5- or 6-membered heterocycle, with 1-3 heteroatoms independently selected from the group consisting of N, O, and S.
5 . The compound of any of claims 3 or 4 , wherein R 1 is pyridyl or pyrimidinyl.
6 . The compound of any of claims 3 or 4 , wherein R 1 is an aromatic 5-membered heterocycle with 1 or 2 nitrogen atoms and optionally 1 or 2 sulphur atoms.
7 . The compound of any of claims 3 or 4 , or 6 wherein R 1 is thiazolyl, isothiazolyl, or thiadiazolyl.
8 . The compound of any of claims 3 , 4 , 6 , or 7 , wherein R 1 is thiazolyl.
9 . The compound of any of claims 3 , 4 , 6 , 7 , or 8 , wherein R 1 is thiazol-4-yl.
10 . The compound of any of claims 3 , 4 , 6 , or 7 , wherein R 1 is 1,2,4-thiadiazol-5-yl.
11 . The compound of any of claims 3 - 10 , wherein R 2 is independently at each occurrence —F or —Cl.
12 . The compound of any of claims 3 - 11 , wherein n is 1, 2, or 3.
13 . The compound of any of claims 3 - 12 , wherein n is 2.
14 . The compound of any of claims 3 - 13 , wherein Z is —O—.
15 . The compound of any of claims 3 - 14 , wherein R 3 is independently at each occurrence —H, —F, —Cl, or —Br.
16 . The compound of any of claims 3 - 15 , wherein R 3 is —H or —Cl.
17 . The compound of any of claims 3 - 16 , wherein R 3 is —Cl.
18 . The compound of any of claims 3 - 17 , wherein m is 1, 2, or 3.
19 . The compound of any of claims 3 - 18 , wherein m is 1.
20 . The compound of any of claims 3 - 19 , wherein R 9 is (C 1 -C 6 )alkyl; wherein R 9 is optionally further substituted with 1 or 2 substituents selected from the group consisting of —COOH, —COOMe, —CONH 2 , and —NH 2 .
21 . The compound of any of claims 3 - 20 , wherein R 9 is methyl or ethyl.
22 . The compound of any of claims 3 - 21 , wherein R 9 is further substituted with —COOH.
23 . The compound of any of claims 3 - 22 , wherein R 10 is —H, —COMe, —COOEt.
24 . The compound of any of claims 3 - 22 , wherein R 10 is —H or —COMe.
25 . The compound of any of claims 3 - 24 , wherein R 10 is —H.
26 . The compound of any of claims 3 - 19 , wherein R 10 is H and R 9 is (C 1 -C 6 )alkyl, wherein R 9 is further substituted with —CONR 11 R 12 , wherein R 11 and R 12 are independently H or (C 1 -C 6 )alkyl.
27 . The compound of claim 26 , wherein the R 9 is further substituted with —CONH 2 .
28 . The compound of claim 27 , wherein the R 9 is methyl.
29 . The compound of any of claims 3 - 19 , wherein R 9 and R 10 together form a 4 to 8 membered heterocycloalkyl ring, wherein said heterocycloalkyl ring is substituted with 1 or 2 groups selected from the group consisting of —COOH, —COOMe, —COOEt, —CH 2 —COOH, and —NH 2 .
30 . The compound of any of claims 3 - 19 , wherein R 9 and R 10 together form a 4 to 8 membered heterocycloalkyl ring, wherein said heterocycloalkyl ring is substituted with 1 or 2 groups selected from the group consisting of —COOH, —CH 2 —COOH, and —NH 2 .
31 . The compound of any of claims 3 - 19 , wherein R 9 and R 10 together form a piperidine substituted with 1 or 2 groups selected from the group consisting of —COOH, —COOMe, —COOEt, —CH 2 —COOH, —CH 2 —COOMe, —CH 2 —COOEt, and —NH 2 .
32 . The compound of any of claims 3 - 19 , wherein R 9 and R 10 together form a piperidine substituted with 1 or 2 groups selected from the group consisting of —COOH, —CH 2 —COOH, and —NH 2 .
33 . The compound of any of claims 1 or 2 , wherein Y is —X—C(═O)NR 4 R 5 .
34 . The compound of claim 33 , wherein R 1 is an aromatic 5- or 6-membered heterocycle, with 1-3 heteroatoms independently selected from the group consisting of N, O, and S.
35 . The compound of any of claims 33 or 34 , wherein R 1 is pyridyl or pyrimidinyl.
36 . The compound of any of claims 33 or 34 , wherein R 1 is an aromatic 5-membered heterocycle with 1 or 2 nitrogen atoms and optionally 1 or 2 sulphur atoms.
37 . The compound of any of claims 33 , 34 , or 36 wherein R 1 is thiazolyl, isothiazolyl, or thiadiazolyl.
38 . The compound of any of claims 33 , 34 , 36 , or 37 , wherein R 1 is thiazolyl.
39 . The compound of any of claims 33 , 34 , 36 , or 37 , wherein R 1 is 1,2,4-thiadiazol-5-yl.
40 . The compound of any of claims 33 - 39 , wherein R 2 is independently at each occurrence —F or —Cl.
41 . The compound of any of claims 33 - 40 , wherein n is 1, 2, or 3.
42 . The compound of any of claims 33 - 41 , wherein n is 2.
43 . The compound of any of claims 33 - 42 , wherein Z is —O—.
44 . The compound of any of claims 33 - 43 , wherein R 3 is independently at each occurrence H, —F, —Cl, or —Br.
45 . The compound of any of claims 33 - 44 , wherein R 3 is —H or —Cl.
46 . The compound of any of claims 33 - 45 , wherein R 3 is —Cl.
47 . The compound of any of claims 33 - 46 , wherein m is 1, 2, or 3.
48 . The compound of any of claims 33 - 47 , wherein m is 1.
49 . The compound of any of claims 33 - 48 , wherein X is 5- or 6-membered heteroaryl.
50 . The compound of any of claims 33 - 49 , wherein X is pyridyl or pyrimidinyl.
51 . The compound of any of claims 33 - 50 , wherein X is pyridyl.
52 . The compound of any of claims 33 - 51 , wherein R 4 is H and R 5 is (C 1 -C 9 )alkyl.
53 . The compound of any of claims 33 - 52 , wherein R 5 is methyl or ethyl, substituted with 1 or 2 substituents selected from the group consisting of —CO 2 H, —CO 2 R 6 , and —CONR 7 R 8 .
54 . The compound of any of claims 33 - 53 , wherein R 6 is (C 1 -C 6 )alkyl.
55 . The compound of any of claims 33 - 53 , wherein R 5 is methyl or ethyl, substituted with —CO 2 H.
56 . The compound of any of claims 1 or 2 , wherein Y is 4,5,6,7-tetrahydropyrazolo[1,5-c]pyrimidine-(2-yl or 3-yl).
57 . The compound of claim 56 , wherein Y is 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-yl.
58 . The compound of any of claims 56 or 57 , wherein R 1 is an aromatic 5- or 6-membered heterocycle, with 1-3 heteroatoms independently selected from the group consisting of N, O, and S.
59 . The compound of any of claims 56 - 58 , wherein R 1 is pyridyl or pyrimidinyl.
60 . The compound of any of claims 56 - 58 , wherein R 1 is an aromatic 5-membered heterocycle with 1 or 2 nitrogen atoms and optionally 1 or 2 sulphur atoms.
61 . The compound of any of claims 56 - 58 , or 60 wherein R 1 is thiazolyl, isothiazolyl, or thiadiazolyl.
62 . The compound of any of claims 56 - 58 , 60 , or 61 , wherein R 1 is thiazolyl.
63 . The compound of any of claims 56 - 58 , 60 , or 61 , wherein R 1 is 1,2,4-thiadiazol-5-yl.
64 . The compound of any of claims 56 - 63 , wherein R 2 is independently at each occurrence —F or —Cl.
65 . The compound of any of claims 56 - 64 , wherein n is 1, 2, or 3.
66 . The compound of any of claims 56 - 65 , wherein n is 2.
67 . The compound of any of claims 56 - 66 , wherein Z is —O—.
68 . The compound of any of claims 56 - 67 , wherein R 3 is independently at each occurrence H, —F, —Cl, or —Br.
69 . The compound of any of claims 56 - 68 , wherein R 3 is —H or —Cl.
70 . The compound of any of claims 56 - 69 , wherein R 3 is —Cl.
71 . The compound of any of claims 56 - 70 , wherein m is 1, 2, or 3.
72 . The compound of any of claims 56 - 71 , wherein m is 1.
73 . The compound of any of claims 1 or 2 , wherein the compound is
3-(4-(2-(4-(N-(1,2,4-thiadiazol-5-yl)sulfamoyl)-2-chloro-5-fluorophenoxy)-5-chlorophenyl)picolinamido)propanoic acid,
2-(4-(2-(4-(N-(1,2,4-thiadiazol-5-yl)sulfamoyl)-2-chloro-5-fluorophenoxy)-5-chlorophenyl)picolinamido)acetic acid,
5-(4-(2-(4-(N-(1,2,4-thiadiazol-5-yl)sulfamoyl)-2-chloro-5-fluorophenoxy)-5-chlorophenyl)picolinamido)pentanoic acid,
4-(4-(2-(4-(N-(1,2,4-thiadiazol-5-yl)sulfamoyl)-2-chloro-5-fluorophenoxy)-5-chlorophenyl)picolinamido)butanoic acid,
2-(4-(2-(4-(N-(1,2,4-thiadiazol-5-yl)sulfamoyl)-2-chloro-5-fluorophenoxy)-5-chlorophenyl)picolinamido)propanoic acid,
(R)-2-(4-(2-(4-(N-(1,2,4-thiadiazol-5-yl)sulfamoyl)-2-chloro-5-fluorophenoxy)-5-chlorophenyl)picolinamido)propanoic acid,
2-(6-(2-(4-(N-(1,2,4-thiadiazol-5-yl)sulfamoyl)-2-chloro-5-fluorophenoxy)-5-chlorophenyl)picolinamido)acetic acid,
(S)-2-(4-(2-(4-(N-(1,2,4-thiadiazol-5-yl)sulfamoyl)-2-chloro-5-fluorophenoxy)-5-chlorophenyl)picolinamido)propanoic acid,
3-(4-(2-(4-(N-(1,2,4-thiadiazol-5-yl)sulfamoyl)-2-cyanophenoxy)-5-chlorophenyl)picolinamido)propanoic acid,
3-(4-(2-(4-(N-(1,2,4-thiadiazol-5-yl)sulfamoyl)-2,5-difluorophenoxy)-5-chlorophenyl)picolinamido)propanoic acid,
2-((3-(5-chloro-2-(2-chloro-5-fluoro-4-(N-(thiazol-4-yl)sulfamoyl)phenoxy)phenyl)propyl)amino)acetic acid,
3-((3-(2-(4-(N-(1,2,4-thiadiazol-5-yl)sulfamoyl)-2-chloro-5-fluorophenoxy)-5-chlorophenyl)propyl)amino)propanoic acid,
2-((3-(5-chloro-2-(2-chloro-5-fluoro-4-(N-(thiazol-2-yl)sulfamoyl)phenoxy)phenyl)propyl)amino)acetic acid,
1-(3-(5-chloro-2-(2-chloro-5-fluoro-4-(N-(thiazol-4-yl)sulfamoyl)phenoxy)phenyl)propyl)piperidine-4-carboxylic acid,
3-((3-(5-chloro-2-(2-chloro-5-fluoro-4-(N-(thiazol-4-yl)sulfamoyl)phenoxy)phenyl)propyl)amino)propanoic acid,
4-amino-1-(3-(5-chloro-2-(2-chloro-5-fluoro-4-(N-(thiazol-4-yl)sulfamoyl)phenoxy)phenyl)propyl)piperidine-4-carboxylic acid,
2-amino-4-((3-(5-chloro-2-(2-chloro-5-fluoro-4-(N-(thiazol-4-yl)sulfamoyl)phenoxy)phenyl)propyl)amino)butanoic acid,
2-((3-(5-chloro-2-(2,5-difluoro-4-(N-(thiazol-2-yl)sulfamoyl)phenoxy)phenyl)propyl)amino)acetic acid,
1-(3-(5-chloro-2-(2-chloro-5-fluoro-4-(N-(thiazol-4-yl)sulfamoyl)phenoxy)phenyl)propyl)piperidine-3-carboxylic acid,
2-((3-(2-(4-(N-(1,2,4-thiadiazol-5-yl)sulfamoyl)-2-chloro-5-fluorophenoxy)phenyl)propyl)amino)acetic acid,
2-((3-(5-chloro-2-(2,5-difluoro-4-(N-(thiazol-4-yl)sulfamoyl)phenoxy)phenyl)propyl)amino)acetic acid,
3-((3-(5-chloro-2-(2,5-difluoro-4-(N-(thiazol-4-yl)sulfamoyl)phenoxy)phenyl)propyl)amino)propanoic acid,
3-((3-(5-chloro-2-(2-cyano-4-(N-(thiazol-4-yl)sulfamoyl)phenoxy)phenyl)propyl)amino)propanoic acid,
methyl 2-((3-(5-chloro-2-(2-chloro-5-fluoro-4-(N-(thiazol-4-yl)sulfamoyl)phenoxy)phenyl)propyl)amino)acetate,
3-((3-(2-(2-chloro-5-fluoro-4-(N-(thiazol-4-yl)sulfamoyl)phenoxy)-5-fluorophenyl)propyl)amino)propanoic acid,
3-((3-(5-chloro-2-(2-chloro-5-fluoro-4-(N-(thiazol-4-yl)sulfamoyl)phenoxy)phenyl)propyl)amino)propanamide,
2-(N-(3-(5-chloro-2-(2-chloro-5-fluoro-4-(N-(thiazol-4-yl)sulfamoyl)phenoxy)phenyl)propyl)acetamido)acetic acid,
2-(1-(3-(2-(4-(N-(1,2,4-thiadiazol-5-yl)sulfamoyl)-2-chloro-5-fluorophenoxy)-5-chlorophenyl)propyl)piperidin-4-yl)acetic acid,
3-((3-(5-chloro-2-(2-chloro-5-fluoro-4-(N-(thiazol-2-yl)sulfamoyl)phenoxy)phenyl)propyl)amino)propanoic acid,
2-((3-(5-chloro-2-(2-chloro-5-fluoro-4-(N-(thiazol-4-yl)sulfamoyl)phenoxy)phenyl)propyl)amino)-N-methylacetamide,
5-chloro-4-(4-chloro-2-(3-((2-(methylsulfonyl)ethyl)amino)propyl)phenoxy)-2-fluoro-N-(thiazol-4-yl)benzenesulfonamide,
1-(3-(2-(4-(N-(1,2,4-thiadiazol-5-yl)sulfamoyl)-2-chloro-5-fluorophenoxy)-5-chlorophenyl)propyl)piperidine-4-carboxylic acid,
5-chloro-4-(4-chloro-2-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-3-yl)phenoxy)-2-fluoro-N-(thiazol-4-yl)benzenesulfonamide,
2-((3-(5-chloro-2-(2-chloro-5-fluoro-4-(N-(thiazol-2-yl)sulfamoyl)phenoxy)phenyl)propyl)(ethoxycarbonyl)amino)acetic acid,
ethyl 2-((3-(5-chloro-2-(2-chloro-5-fluoro-4-(N-(thiazol-2-yl)sulfamoyl)phenoxy)phenyl)propyl)amino)acetate,
4-(2-(3-((1H-pyrazol-4-yl)amino)propyl)-4-chlorophenoxy)-5-chloro-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide,
3-((3-(5-chloro-2-(2,5-difluoro-4-(N-(thiazol-2-yl)sulfamoyl)phenoxy)phenyl)propyl)amino)propanoic acid,
5-chloro-4-(4-chloro-2-(3-((2-(methylsulfonyl)ethyl)amino)propyl)phenoxy)-2-fluoro-N-(thiazol-4-yl)benzenesulfonamide,
4-(2-(3-((1H-pyrazol-3-yl)amino)propyl)-4-chlorophenoxy)-5-chloro-2-fluoro-N-(thiazol-4-yl)benzenesulfonamide,
2-((3-(5-chloro-2-(2-chloro-5-fluoro-4-(N-(thiazol-4-yl)sulfamoyl)phenoxy)phenyl)propyl)amino)-N-methylacetamide,
2-((3-(5-chloro-2-(2-chloro-5-fluoro-4-(N-(thiazol-4-yl)sulfamoyl)phenoxy)phenyl)propyl)(methyl)amino)acetic acid,
5-chloro-4-(4-chloro-2-(3-(6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)propyl)phenoxy)-2-fluoro-N-(thiazol-4-yl)benzenesulfonamide,
2-((3-(5-chloro-2-(2-chloro-5-fluoro-4-(N-(thiazol-4-yl)sulfamoyl)phenoxy)phenyl)propyl)amino)acetamide,
isopentyl 2-((3-(5-chloro-2-(2-chloro-5-fluoro-4-(N-(thiazol-2-yl)sulfamoyl)phenoxy)phenyl)propyl)amino)acetate,
isopropyl 2-((3-(5-chloro-2-(2-chloro-5-fluoro-4-(N-(thiazol-2-yl)sulfamoyl)phenoxy)phenyl)propyl)amino)acetate,
methyl 2-((3-(5-chloro-2-(2-chloro-5-fluoro-4-(N-(thiazol-4-yl)sulfamoyl)phenoxy)phenyl)propyl)(methyl)amino)acetate,
2-((3-(5-chloro-2-(2-chloro-5-fluoro-4-(N-(thiazol-2-yl)sulfamoyl)phenoxy)phenyl)propyl)((pentyloxy)carbonyl)amino)acetic acid,
2-((3-(5-chloro-2-(2-chloro-5-fluoro-4-(N-(thiazol-2-yl)sulfamoyl)phenoxy)phenyl)propyl)(prop-2-yn-1-yl)amino)acetic acid,
5-chloro-4-(4-chloro-2-(3-(5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)propyl)phenoxy)-2-fluoro-N-(thiazol-4-yl)benzenesulfonamide,
5-chloro-2-fluoro-4-(2-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-3-yl)phenoxy)-N-(thiazol-2-yl)benzenesulfonamide,
5-chloro-4-(4-chloro-2-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-3-yl)phenoxy)-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide,
5-chloro-2-fluoro-4-(2-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-3-yl)phenoxy)-N-(thiazol-4-yl)benzenesulfonamide,
5-chloro-4-(4-chloro-2-(3-((2-(methylsulfonyl)ethyl)amino)propyl)phenoxy)-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide,
2-((3-(2-(2-chloro-5-fluoro-4-(N-(thiazol-4-yl)sulfamoyl)phenoxy)phenyl)propyl)amino)acetamide,
2-((3-(5-chloro-2-(2-chloro-5-fluoro-4-(N-(thiazol-4-yl)sulfamoyl)phenoxy)phenyl)propyl)(prop-2-yn-1-yl)amino)acetic acid,
2-(allyl(3-(5-chloro-2-(2-chloro-5-fluoro-4-(N-(thiazol-2-yl)sulfamoyl)phenoxy)phenyl)propyl)amino)acetic acid,
2-((3-(5-chloro-2-(2-chloro-5-fluoro-4-(N-(thiazol-2-yl)sulfamoyl)phenoxy)phenyl)propyl)amino)acetamide,
2-(but-2-yn-1-yl(3-(5-chloro-2-(2-chloro-5-fluoro-4-(N-(thiazol-2-yl)sulfamoyl)phenoxy)phenyl)propyl)amino)acetic acid,
2-((3-(5-chloro-2-(2-chloro-5-fluoro-4-(N-(thiazol-2-yl)sulfamoyl)phenoxy)phenyl)propyl)(propyl)amino)acetic acid,
3-((3-(5-chloro-2-(2-chloro-5-fluoro-4-(N-(thiazol-2-yl)sulfamoyl)phenoxy)phenyl)propyl)(prop-2-yn-1-yl)amino)propanoic acid,
2-((3-(5-chloro-2-(2,5-difluoro-4-(N-(thiazol-2-yl)sulfamoyl)phenoxy)phenyl)propyl)(prop-2-yn-1-yl)amino)acetic acid,
ethyl 2-((3-(5-chloro-2-(2-chloro-5-fluoro-4-(N-(thiazol-2-yl)sulfamoyl)phenoxy)phenyl)propyl)(methyl)amino)acetate, or
2-((3-(5-chloro-2-(2,5-difluoro-4-(N-(thiazol-4-yl)sulfamoyl)phenoxy)phenyl)propyl)amino)acetamide;
or a pharmaceutically acceptable salt, or a stereoisomeric or tautomeric form thereof.
74 . The compound of any of claims 1 , 2 , or 73 , wherein the compound is
2-(4-(2-(4-(N-(1,2,4-thiadiazol-5-yl)sulfamoyl)-2-chloro-5-fluorophenoxy)-5-chlorophenyl)picolinamido)acetic acid, 3-(4-(2-(4-(N-(1,2,4-thiadiazol-5-yl)sulfamoyl)-2-chloro-5-fluorophenoxy)-5-chlorophenyl)picolinamido)propanoic acid, 2-(4-(2-(4-(N-(1,2,4-thiadiazol-5-yl)sulfamoyl)-2-chloro-5-fluorophenoxy)-5-chlorophenyl)picolinamido)propanoic acid, 3-((3-(2-(4-(N-(1,2,4-thiadiazol-5-yl)sulfamoyl)-2-chloro-5-fluorophenoxy)-5-chlorophenyl)propyl)amino)propanoic acid, 2-((3-(5-chloro-2-(2-chloro-5-fluoro-4-(N-(thiazol-4-yl)sulfamoyl)phenoxy)phenyl)propyl)amino)acetamide, 2-((3-(5-chloro-2-(2-chloro-5-fluoro-4-(N-(thiazol-2-yl)sulfamoyl)phenoxy)phenyl)propyl)((pentyloxy)carbonyl)amino)acetic acid, or 2-((3-(5-chloro-2-(2-chloro-5-fluoro-4-(N-(thiazol-2-yl)sulfamoyl)phenoxy)phenyl)propyl)(prop-2-yn-1-yl)amino)acetic acid; or a pharmaceutically acceptable salt, or a stereoisomeric or tautomeric form thereof.
75 . The compound of any of claims 1 , 2 , or 73 , wherein the compound is
3-((3-(5-chloro-2-(2-chloro-5-fluoro-4-(N-(thiazol-4-yl)sulfamoyl)phenoxy)phenyl)propyl)amino)propanoic acid, 2-((3-(5-chloro-2-(2-chloro-5-fluoro-4-(N-(thiazol-4-yl)sulfamoyl)phenoxy)phenyl)propyl)amino)acetamide, 2-((3-(5-chloro-2-(2-chloro-5-fluoro-4-(N-(thiazol-2-yl)sulfamoyl)phenoxy)phenyl)propyl)(prop-2-yn-1-yl)amino)acetic acid, 2-((3-(5-chloro-2-(2-chloro-5-fluoro-4-(N-(thiazol-4-yl)sulfamoyl)phenoxy)phenyl)propyl)(prop-2-yn-1-yl)amino)acetic acid, 2-((3-(5-chloro-2-(2-chloro-5-fluoro-4-(N-(thiazol-2-yl)sulfamoyl)phenoxy)phenyl)propyl)amino)acetamide, 2-((3-(5-chloro-2-(2-chloro-5-fluoro-4-(N-(thiazol-2-yl)sulfamoyl)phenoxy)phenyl)propyl)(propyl)amino)acetic acid, 2-((3-(5-chloro-2-(2,5-difluoro-4-(N-(thiazol-2-yl)sulfamoyl)phenoxy)phenyl)propyl)(prop-2-yn-1-yl)amino)acetic acid, or 2-((3-(5-chloro-2-(2,5-difluoro-4-(N-(thiazol-4-yl)sulfamoyl)phenoxy)phenyl)propyl)amino)acetamide; or a pharmaceutically acceptable salt, or a stereoisomeric or tautomeric form thereof.
76 . A method for treating neuropathic pain comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (I) or a compound of Formula (I′), or a pharmaceutically acceptable salt, solvate or tautomeric form thereof.
77 . A method for treating pain comprising use of a compound of Formula (I) or of a compound of Formula (I′), as a voltage-gated sodium channel inhibitor.
78 . The method of claim 77 , wherein the pain is neuropathic, nociceptive or inflammatory pain.
79 . The method of claim 77 , wherein the voltage-gated sodium channel is NaV1.7.
80 . A pharmaceutical composition comprising a compound of any one of claims 1 to 75 and a pharmaceutically acceptable carrier.
81 . The composition of claim 80 , wherein the composition is suitable for topical, oral, subcutaneous, or intravenous administration.
82 . A method for prevention or treatment of pain in a subject, wherein the method comprises administering to the subject in need of such prevention or treatment a therapeutically effective amount of a compound of any one of claims 1 to 75 .
83 . The method of claim 82 , wherein the therapeutically effective amount is effective to alleviate pain in a subject, wherein the compound of any one of claims 1 to 75 shows a reduction in pain response in the Formalin Assay in phase 1 or phase 2, or both, at a dose between 0.1 mg/kg and 1,000 mg/kg, at a dose between 0.5 mg/kg and 100 mg/kg, or at a dose between 1 mg/kg to 50 mg/kg.
84 . The method of claim 82 , wherein the pain is nociceptive pain, such as that resulting from physical trauma (e.g., a cut or contusion of the skin; or a chemical or thermal burn), osteoarthritis, rheumatoid arthritis or tendonitis; myofascial pain; neuropathic pain, such as that associated with stroke, diabetic neuropathy, luetic neuropathy, postherpetic neuralgia, trigeminal neuralgia, fibromyalgia, or painful neuropathy induced iatrogenically by drugs; or mixed pain (i.e., pain with both nociceptive and neuropathic components); visceral pain; headache pain (e.g., migraine headache pain); CRPS; CRPS type I; CRPS type II; RSD; reflex neurovascular dystrophy; reflex dystrophy; sympathetically maintained pain syndrome; causalgia; Sudeck atrophy of bone; algoneurodystrophy; shoulder hand syndrome; post-traumatic dystrophy; autonomic dysfunction; autoimmune-related pain; inflammation-related pain; cancer-related pain; phantom limb pain; chronic fatigue syndrome; post-operative pain; spinal cord injury pain; central post-stroke pain; radiculopathy; sensitivity to temperature, light touch or color change to the skin (allodynia); pain from hyperthermic or hypothermic conditions; and other painful conditions (e.g., diabetic neuropathy, luetic neuropathy, postherpetic neuralgia, trigeminal neuralgia); chronic pain; acute pain; pain from neuromas, pain or itch associated with channelopathies (e.g., small fiber neuralgia, IEM or Raynodes); or itch from various origins (e.g., allergic itch).
85 . A method for modulating the activity of a voltage-gated sodium channel, wherein the method comprises contacting a cell that expresses the voltage-gated sodium channel with a compound of any one of claims 1 to 75 .
86 . The method of claim 85 , wherein the voltage-gated sodium channel is NaV1.7.
87 . The method of claim 85 , wherein the method results in inhibition of the voltage-gated sodium channel.
88 . A method for treating or preventing prediabetes comprising administering to a subject in need thereof a therapeutically effective amount of a compound of any one of claims 1 to 75 , or a pharmaceutically acceptable salt, solvate or tautomeric form thereof.
89 . A method for treating or preventing diabetes comprising administering to a subject in need thereof a therapeutically effective amount of a compound of any one of claims 1 to 75 , or a pharmaceutically acceptable salt, solvate or tautomeric form thereof.
90 . A method for maintaining or lowering blood or plasma glucose in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1 to 75 , or a pharmaceutically acceptable salt, solvate or tautomeric form thereof.
91 . A method for maintaining or lowering blood or plasma glycated hemoglobin in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1 to 75 , or a pharmaceutically acceptable salt, solvate or tautomeric form thereof.
92 . The method of any one of claims 90 or 91 , wherein the subject has prediabetes.
93 . The method of any one of claims 90 or 91 , wherein the subject has diabetes.
94 . The method of any one of claims 89 or 93 , wherein diabetes is gestational diabetes, type-1 diabetes, type-2 diabetes, or latent autoimmune diabetes of adults.
95 . The method of claim 94 , wherein diabetes is gestational diabetes.
96 . The method of claim 94 , wherein diabetes is type-1 diabetes.
97 . The method of claim 94 , wherein diabetes is type-2 diabetes.
98 . The method of claim 97 , wherein type-2 diabetes is hyperinsulinemic Type 2 diabetes.
99 . The method of claim 94 , wherein diabetes is latent autoimmune diabetes of adults.
100 . The method of any one of claims 88 or 92 , wherein the prediabetes is caused by or accompanied by obesity.
101 . The method of any one of claims 89 or, wherein the diabetes is caused by or accompanied by obesity.
102 . The method of any one of claims 89 or 93 , wherein the subject has not been previously treated for prediabetes.
103 . The method of any one of claims 89 or 93 , wherein the subject has not been previously treated for diabetes.Cited by (0)
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