5- or 6-substituted benzofuran-2-carboxamide compounds and methods for using them

Patent metadata

Field	Value
Publication number	US-9409884-B2
Application number	US-201314376098-A
Country	US
Kind code	B2
Filing date	Jan 31, 2013
Priority date	Feb 1, 2012
Publication date	Aug 9, 2016
Grant date	Aug 9, 2016

Abstract

The disclosure relates particularly to certain carboxamide, sulfonamide and amine compounds and pharmaceutical compositions thereof, and to methods of treating and ameliorating disorders and conditions related to the adiponectin pathway, sphingolipid metabolism, oxidative stress, mitochondrial dysfunction, free radical damage and metabolic inefficiency, among others. In certain embodiments, the compounds have the structures (I-1), (2-I) and (3-I)

in which the variables are as described herein.

First claim

What is claimed is:

1. A compound having the structural formula

wherein
R 1 is H, —(C 1 -C 4 alkyl), —C(O)—(C 1 -C 4 alkyl) or —C(O)O—(C 1 -C 4 alkyl);
G is a bond, —CH 2 —, —C(O)—, —CH(CH 3 )—, —O— or —S(O) 2 —;
each R 15 is independently selected from —(C 1 -C 3 alkyl), —(C 1 -C 3 haloalkyl), —(C 0 -C 3 alkyl)-L-R 7 , —(C 0 -C 3 alkyl)-NR 8 R 9 , —(C 0 -C 3 alkyl)-OR 10 , —(C 0 -C 3 alkyl)-C(O)R 10 , —(C 0 -C 3 alkyl)-S(O) 0-2 R 10 , -halogen, —NO 2 and —CN, and two R 15 on the same carbon optionally combine to form oxo; and
v is 0, 1, 2, 3 or 4;
R 17 is phenyl optionally substituted with 0, 1, 2 or 3 substituents independently selected from —(C 1 -C 3 alkyl), —(C 1 -C 3 haloalkyl), —(C 0 -C 3 alkyl)-L-R 7 , —(C 0 -C 3 alkyl)-NR 8 R 9 , —(C 0 -C 3 alkyl)-OR 10 , —(C 0 -C 3 alkyl)-C(O)R 10 , —(C 0 -C 3 alkyl)-S(O) 0-2 R 10 , -halogen, —SF 5 , —NO 2 and —CN;
R 3 is a substituent on a benzo carbon of the benzofuran ring system, which substituent is independently selected from —(C 1 -C 3 alkyl), —(C 1 -C 3 haloalkyl), —(C 0 -C 3 alkyl)-L-R 7 , —(C 0 -C 3 alkyl)-NR 8 R 9 , —(C 0 -C 3 alkyl)-OR 10 , —(C 0 -C 3 alkyl)-C(O)R 10 , —(C 0 -C 6 alkyl)-S(O) 0-2 R 10 , -halogen, —NO 2 and —CN;
R 14 is selected from —(C 1 -C 3 alkyl), —(C 1 -C 3 haloalkyl), —(C 0 -C 3 alkyl)-L-R 7 , —(C 0 -C 3 alkyl)-NR 8 R 9 , —(C 0 -C 3 alkyl)-OR 10 , —(C 0 -C 3 alkyl)-C(O)R 10 , —(C 0 -C 3 alkyl)-S(O) 0-2 R 10 , -halogen, —NO 2 and —CN;
Q is —CH 2 —; a single bond; —S(O) 2 —; —C(O)—; —O— or —CH(CH 3 )—;
the ring system denoted by “A” is phenyl;
each R 5 is independently selected from —(C 1 -C 3 alkyl), —(C 1 -C 3 haloalkyl), —(C 0 -C 3 alkyl)-L-R 7 , —(C 0 -C 3 alkyl)-NR 8 R 9 , —(C 0 -C 3 alkyl)-OR 10 , —(C 0 -C 3 alkyl)-C(O)R 10 , —(C 0 -C 3 alkyl)-S(O) 0-2 R 10 , -halogen, —NO 2 and —CN; and
y is 0, 1, 2, 3 or 4;
in which
each L is independently selected from —NR 9 C(O)O—, —OC(O)NR 9 —, —NR 9 C(O)—NR 9 —, —NR 9 C(O)S—, —SC(O)NR 9 —, —NR 9 C(O)—, —C(O)—NR 9 —, —NR 9 C(S)O—, —OC(S)NR 9 —, —NR 9 C(S)—NR 9 —, —NR 9 C(S)S—, —SC(S)NR 9 —, —C(S)NR 9 —, —SC(O)NR 9 —, —NR 9 C(S)—, —S(O) 0-2 —, —C(O)O, —OC(O)—, —C(S)O—, —OC(S)—, —C(O)S—, —SC(O)—, —C(S)S—, —SC(S)—, —OC(O)O—, —SC(O)O—, —OC(O)S—, —SC(S)O—, —OC(S)S—, —NR 9 C(NR 2 )NR 9 —, —NR 9 SO 2 —, —SO 2 NR 9 — and —NR 9 SO 2 NR 9 —,
each R 7 , R 8 and R 10 is independently selected from H, —(C 1 -C 2 alkyl), —(C 1 -C 2 haloalkyl), —(C 0 -C 2 alkyl)-L-(C 0 -C 2 alkyl), —(C 0 -C 2 alkyl)-NR 9 —(C 0 -C 2 alkyl), —(C 0 -C 2 alkyl)-O—(C 0 -C 2 alkyl), —(C 0 -C 2 alkyl)-C(O)—(C 0 -C 2 alkyl) and —(C 0 -C 2 alkyl)-S(O) 0-2 —(C 0 -C 2 alkyl), and
each R 9 is independently selected from —H, —(C 1 -C 4 alkyl) and —C(O)O—(C 1 -C 4 alkyl),

or a pharmaceutically-acceptable salt thereof.

2. A compound according to claim 1 , wherein the

moiety is

wherein y3 is 0, 1, 2 or 3, and each R 36 is independently selected from halo, cyano, —(C 1 -C 3 haloalkyl), —O—(C 1 -C 2 haloalkyl), —(C 1 -C 3 alkyl), —O—(C 1 -C 2 alkyl), —C(O)—(C 0 -C 2 alkyl), —C(O)O—(C 0 -C 2 alkyl), —C(O)N(C 0 -C 4 alkyl)(C 0 -C 2 alkyl), —S(O) 2 (C 1 -C 2 alkyl), —SF 5 , and NO 2 .

3. A compound according to claim 1 , having the structural formula

4. A compound according to claim 1 , having the formula

in which R 25 is selected from halo, cyano, —(C 1 -C 3 haloalkyl), —O—(C 1 -C 2 haloalkyl), —(C 1 -C 3 alkyl), —O—(C 1 -C 2 alkyl), —C(O)—(C 0 -C 2 alkyl), —C(O)O—(C 0 -C 2 alkyl), —C(O)N(C 0 -C 4 alkyl)(C 0 -C 2 alkyl), and NO 2 .

5. A compound according to claim 1 , wherein R 1 is H.

6. A compound according to claim 1 , wherein (R 3 ) 0-1 is (R 3 ) 0 .

7. A compound according to claim 1 , wherein v is 0.

8. A compound according to claim 1 , wherein (R 14 ) 0-1 is (R 14 ) 0 .

9. A compound according to claim 1 , wherein F (0-1) is F (0) .

10. A compound according to claim 1 , wherein (R 3 ) 0-1 is (R 3 ) 0 , (R 14 ) 0-1 is (R 14 ) 0 , and v is 0.

11. A compound according to claim 10 , having the structural formula

12. A compound according to claim 4 , having the structural formula

13. A compound according to claim 1 , having the structural formula

14. A compound according to claim 1 , wherein Q is —CH 2 —; a single bond; —S(O) 2 —; —C(O)—; or —CH(CH 3 )—.

15. A compound according to claim 1 , selected from
5-(4-(4-fluorobenzoyl)piperidine-1-carbonyl)-N-(1-(pyridin-4-ylmethyl)piperidin-4-yl)benzofuran-2-carboxamide;
N-(1-(4-cyanobenzyl)piperidin-4-yl)-5-(4-(4-fluorobenzoyl)piperidine-1-carbonyl)benzofuran-2-carboxamide;
N-(6-(4-cyanophenoxy)pyridin-3-yl)-5-(4-(4-fluorobenzoyl)piperidine-1-carbonyl)benzofuran-2-carboxamide;
5-(4-(4-fluorophenoxy)piperidine-1-carbonyl)-N-(1-(pyridin-4-ylmethyl)piperidin-4-yl)benzofuran-2-carboxamide;
N-(1-(4-cyanobenzyl)piperidin-4-yl)-5-(4-(4-fluorophenoxy)piperidine-1-carbonyl)benzofuran-2-carboxamide;
5-(4-(4-fluorophenoxy)piperidine-1-carbonyl)-N-(6-(4-fluorophenoxy)pyridin-3-yl)benzofuran-2-carboxamide;
N-(1-(4-methoxybenzyl)piperidin-4-yl)-5-(4-(4-(trifluoromethyl)phenoxy)piperidine-1-carbonyl)benzofuran-2-carboxamide;
N-(6-(4-fluorophenoxy)pyridin-3-yl)-5-(4-(4-(trifluoromethyl)phenoxy)piperidine-1-carbonyl)benzofuran-2-carboxamide;
N-(1-(4-cyanobenzyl)piperidin-4-yl)-5-(4-(4-(trifluoromethyl)phenoxy)piperidine-1-carbonyl)benzofuran-2-carboxamide;
N-(1-(4-methoxybenzyl)piperidin-4-yl)-5-(4-(4-(methylsulfonyl)phenoxy)piperidine-1-carbonyl)benzofuran-2-carboxamide;
5-(4-(4-(methylsulfonyl)phenoxy)piperidine-1-carbonyl)-N-(1-(4-(trifluoromethoxy)benzyl)piperidin-4-yl)benzofuran-2-carboxamide;
N-(1-(4-cyanobenzyl)piperidin-4-yl)-5-((3,4-trans)-3-fluoro-4-(4-(methylsulfonyl)phenoxy)piperidine-1-carbonyl)benzofuran-2-carboxamide;
5-((3,4-trans)-3-fluoro-4-(4-(methylsulfonyl)phenoxy)piperidine-1-carbonyl)-N-(1-(4-methoxybenzyl)piperidin-4-yl)benzofuran-2-carboxamide;
5-((3,4-trans)-3-fluoro-4-(4-(methylsulfonyl)phenoxy)piperidine-1-carbonyl)-N-(1-(4-(trifluoromethoxy)benzyl)piperidin-4-yl)benzofuran-2-carboxamide;
N-(1-(4-cyanobenzyl)piperidin-4-yl)-5-(4-(4-fluorophenylsulfonyl)piperidine-1-carbonyl)benzofuran-2-carboxamide;
N-(1-(4-cyanobenzyl)piperidin-4-yl)-5-(4-(4-(trifluoromethylsulfonyl)phenoxy)piperidine-1-carbonyl)benzofuran-2-carboxamide;
N-(1-(4-cyanobenzyl)piperidin-4-yl)-5-(4-(4-(4-methoxyphenyl)-1H-pyrazol-1-yl)piperidine-1-carbonyl)benzofuran-2-carboxamide;
5-(4-(4-(methylsulfonyl)phenoxy)piperidine-1-carbonyl)-N-(1-(4-(trifluoromethoxy)benzyl)piperidin-4-yl)benzofuran-2-carboxamide;
N-(1-(4-(trifluoromethoxy)benzyl)piperidin-4-yl)-5-(4-(4-(trifluoromethylsulfonyl)phenoxy)piperidine-1-carbonyl)benzofuran-2-carboxamide;
N-(1-(3-fluoro-4-methoxybenzyl)piperidin-4-yl)-5-(4-(4-(trifluoromethylsulfonyl)phenoxy)piperidin

Assignees

• Rigel Pharmaceuticals Inc

Inventors

• Goff Dane
• Payan Donald
• Carroll David
• Shaw Simon
• Yasumichi Hitoshi

Classifications

• A61K31/4709

  Non-condensed quinolines and containing further heterocyclic rings · CPC title

• C07D211/58

  attached in position 4 · CPC title

• A61K31/454

  containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone · CPC title

• A61K31/4545

  containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine · CPC title

• C07D409/14

  containing three or more hetero rings · CPC title