US 8,101,767 B2Granted

Modulators of ATP-binding cassette transporters

AssigneeVertex Pharmaceuticals Incorporated

InventorsSara Hadida Ruah, Anna Hazlewood, Peter D. J. Grootenhuis, Fredrick Van Goor, Ashvani Singh, Jinglan Zhou, Jason McCartney

Life of this patent

Estimating the term…

Abstract

The present invention relates to modulators of ATP-Binding Cassette (“ABC”) transporters or fragments thereof, including Cystic Fibrosis Transmembrane Conductance Regulator, compositions thereof, and methods therewith. The present invention also relates to methods of treating ABC transporter mediated diseases using such modulators.

Claims8

Dependent claims

A compound of formula V-B-5:

wherein:
ring A2 is a phenyl or a 5-6 membered heteroaryl ring, wherein ring A2 and the phenyl ring fused thereto together have up 4 substituents independently selected from WRW;
and
W is a bond or is an optionally substituted C1-C6 alkylidene chain wherein up to two methylene units of W are optionally and independently replaced by —CO—, —CS—, —COCO—, —CONR′—, —CONR′NR′—, —CO2—, —OCO—, —NR′CO2—, —O—, —NR′CONR′—, —OCONR′—, —NR′NR′, —NR′NR′CO—, —NR′CO—, —S—, —SO, —SO2—, —NR′—, —SO2NR′—, NR′SO2—, —NR′SO2NR′—;
RW is independently R′, halo, NO2, CN, CF3 , or OCF3;
X is a bond or is an optionally substituted C1-C6 alkylidene chain wherein up to two methylene units of X are optionally and independently replaced by —CO—, —CS—, —COCO—,—CONR′—, —CONR′NR′—, —CO2—, —OCO—, —NR′CO2—, —O—, —NR′CONR′—, —OCONR′—, —NR′NR′, —NR′NR′CO—, —NR′CO—, —S—, —SO, —SO2—,—NR′—, —SO2NR′—, NR′SO2—, or —NR′SO2NR′—;
RX is independently R′, halo, NO2, CN, CF3, or OCF3;
R′ is independently selected from hydrogen or an optionally substituted group selected from a C1-C8 aliphatic group a 3-8-membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-12 membered saturated, partially unsaturated, or fully unsaturated bicyclic ring system having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
or two occurrences of R′ are taken together with the atom(s) to which they are bound to form an optionally substituted 3-12 membered saturated, partially unsaturated, or fully unsaturated monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
and
m is 0-4.

8 more elements

A compound selected from:

Cmpd
No.
Name
1
N-[5-(5-chloro-2-methoxy-phenyl)-1H-indol-6-yl]-4-oxo-1H-quinoline-3-carboxamide
22
4-Oxo-1,4-dihydro-quinoline-3-carboxylic acid N-(1′,2′-dihydrospiro[cyclopropane-1,3′-
[3H]indol]-6′-yl)-amide
27
N-[1-[2-[methyl-(2-methylaminoacetyl)-amino]acetyl]-1H-indol-6-yl]-4-oxo-1H-
quinoline-3-carboxamide
32
N-(5-chloro-1H-indol-6-yl)-4-oxo-1H-quinoline-3-carboxamide
33
N-(1H-indol-6-yl)-4-oxo-1H-quinoline-3-carboxamide
37
N-(1H-indol-7-yl)-4-oxo-1H-quinoline-3-carboxamide
44
N-(2-methylbenzothiazol-5-yl)-4-oxo-1H-quinoline-3-carboxamide
51
6-[(4-methyl-1-piperidyl)sulfonyl]-4-oxo-N-(5-tert-butyl-1H-indol-6-yl)-1H-quinoline-
3-carboxamide
54
4-oxo-N-(8-thia-7,9-diazabicyclo[4.3.0]nona-2,4,6,9-tetraen-5-yl)-1H-quinoline-3-
carboxamide
64
4-oxo-N-(2-oxo-1,3-dihydrobenzoimidazol-5-yl)-1H-quinoline-3-carboxamide
65
4-oxo-N-[5-(3-pyridyl)-1H-indol-6-yl]-1H-quinoline-3-carboxamide
66
N-(2,2-difluorobenzo[1,3]dioxol-5-yl)-4-oxo-1H-quinoline-3-carboxamide
67
6-ethyl-4-hydroxy-N-(1H-indol-6-yl)quinoline-3-carboxamide
73
4-oxo-N-(2-phenyl-3H-benzoimidazol-5-yl)-1H-quinoline-3-carboxamide
77
N-(5-fluoro-1H-indol-6-yl)-4-oxo-1H-quinoline-3-carboxamide
96
N-[3-(cyanomethyl)-1H-indol-6-yl]-4-oxo-1H-quinoline-3-carboxamide
100
N-(1H-indol-4-yl)-4-oxo-1H-quinoline-3-carboxamide
104
N-(2-methyl-1H-indol-6-yl)-4-oxo-1H-quinoline-3-carboxamide
105
1,4-dihydro-N-(3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-4-oxoquinoline-3-
carboxamide
107
7-[(4-oxo-1H-quinolin-3-yl)carbonylamino]-1,2,3,4-tetrahydroisoquinoline-2-carboxylic
acid tert-butyl ester
108
4,4-dimethyl-7-[(4-oxo-1H-quinoline-3-yl)carbonylamino]-1,2,3,4-tetrahydroquinoline-
1-carboxylic acid tert-butyl ester
112
6-ethoxy-4-hydroxy-N-(1H-indol-6-yl)quinoline-3-carboxamide
113
N-(3-methyl-1H-indol-6-yl)-4-oxo-1H-quinoline-3-carboxamide
116
5-hydroxy-N-(1H-indol-6-yl)-4-oxo-1H-quinoline-3-carboxamide
124
6-fluoro-4-oxo-N-(5-tert-butyl-1H-indol-6-yl)-1H-quinoline-3-carboxamide
130
4-hydroxy-N-(1H-indol-6-yl)-5,7-bis(trifluoromethyl)quinoline-3-carboxamide
145
6-[(4-oxo-1H-quinolin-3-yl)carbonylamino]-1H-indole-4-carboxylic acid ethyl ester
146
4-oxo-N-(1,7,9-triazabicyclo[4.3.0]nona-2,4,6,8-tetraen-5-yl)-1H-quinoline-3-
carboxamide
148
4-oxo-N-[5-(1-piperidylcarbonyl)-1H-indol-6-yl]-1H-quinoline-3-carboxamide
152
4-oxo-N-(2-oxo-3H-benzooxazol-6-yl)-1H-quinoline-3-carboxamide
158
4-oxo-N-(5-phenyl-1H-indol-6-yl)-1H-quinoline-3-carboxamide
169
N-(1-methyl-1H-indol-6-yl)-4-oxo-1H-quinoline-3-carboxamide
175
4-Oxo-1,4-dihydro-quinoline-3-carboxylic acid N-(1′-Acetyl-1′,2′-
dihydrospiro[cyclopropane-1,3′-3H-indol]-6′-yl)-amide
183
7-[(4-oxo-1H-quinolin-3-yl)carbonylamino]-1,2,3,4-tetrahydroquinoline-1-carboxylic
acid tert-butyl ester
184
N-(1H-indol-6-yl)-4-oxo-2-(trifluoromethyl)-1H-quinoline-3-carboxamide
186
N-(3-cyclopentyl-1H-indol-6-yl)-4-oxo-1H-quinoline-3-carboxamide
187
N-(1-acetyl-1H-indol-6-yl)-4-oxo-1H-quinoline-3-carboxamide
188
6-[(4-oxo-1H-quinolin-3-yl)carbonylamino]-1H-indole-5-carboxylic acid ethyl ester
191
4-oxo-N-(5-quinolyl)-1H-quinoline-3-carboxamide
203
N-(1-benzyl-1H-indol-6-yl)-4-oxo-1H-quinoline-3-carboxamide
204
N-(4,4-dimethylchroman-7-yl)-4-oxo-1H-quinoline-3-carboxamide
207
2-[6-[(4-oxo-1H-quinolin-3-yl)carbonylamino]-1H-indol-3-yl]acetic acid ethyl ester
216
N-(3H-benzoimidazol-2-yl)-4-oxo-1H-quinoline-3-carboxamide
217
N-(1H-indazol-5-yl)-4-oxo-1H-quinoline-3-carboxamide
230
N-(2-methyl-1H-indol-5-yl)-4-oxo-1H-quinoline-3-carboxamide
233
N-(1-acetylindolin-6-yl)-4-oxo-1H-quinoline-3-carboxamide
234
4-oxo-N-[5-(trifluoromethyl)-1H-indol-6-yl]-1H-quinoline-3-carboxamide
237
N-[5-(2-methoxyphenyl)-1H-indol-6-yl]-4-oxo-1H-quinoline-3-carboxamide
238
7′-[(4-oxo-1H-quinolin-3-ylcarbonyl)amino]-spiro[piperidine-4,4′(1′H)-quinoline], 2′,3′-
dihydro-carboxylic acid tert-butyl ester
241
4-oxo-N-(8-quinolyl)-1H-quinoline-3-carboxamide
244
4-oxo-N-(6,7,8,9-tetrahydro-5H-carbazol-2-yl)-1H-quinoline-3-carboxamide
254
6-fluoro-N-(5-fluoro-1H-indol-6-yl)-4-oxo-1H-quinoline-3-carboxamide
256
N-(1H-benzotriazol-5-yl)-4-oxo-1H-quinoline-3-carboxamide
258
N-indolin-6-yl-4-oxo-1H-quinoline-3-carboxamide
259
4-oxo-N-(3-sec-butyl-1H-indol-6-yl)-1H-quinoline-3-carboxamide
262
1,4-dihydro-N-(3,4-dihydro-3-oxo-2H-benzo[b][1,4]thiazin-6-yl)-4-oxoquinoline-3-
carboxamide
270
N-(2-cyano-1H-indol-6-yl)-4-oxo-1H-quinoline-3-carboxamide
274
4-oxo-6-pyrrolidin-1-ylsulfonyl-N-(5-tert-butyl-1H-indol-6-yl)-1H-quinoline-3-
carboxamide
280
4-oxo-N-(6-quinolyl)-1H-quinoline-3-carboxamide
284
N-(1H-indazol-6-yl)-4-oxo-1H-quinoline-3-carboxamide
294
N-(1H-indol-5-yl)-4-oxo-1H-quinoline-3-carboxamide
299
4-oxo-N-(1,2,3,4-tetrahydroquinolin-7-yl)-1H-quinoline-3-carboxamide
300
N-(4,4-dimethyl-1,2,3,4-tetrahydroquinolin-7-yl)-4-oxo-1H-quinoline-3-carboxamide
303
N-(2-acetyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-oxo-1H-quinoline-3-carboxamide
320
4-oxo-N-(2-tert-butyl-1H-indol-6-yl)-1H-quinoline-3-carboxamide
327
N-[5-(2-ethoxyphenyl)-1H-indol-6-yl]-4-oxo-1H-quinoline-3-carboxamide
329
N-[2-(o-tolyl)benzooxazol-5-yl]-4-oxo-1H-quinoline-3-carboxamide
334
7′-[(4-oxo-1H-quinolin-3-ylcarbonyl)amino]-spiro[piperidine-4,4′(1′H)-1-acetyl-
quinoline], 2′,3′-dihydro-carboxylic acid tert-butyl ester
338
N-(3-methyl-1H-indol-4-yl)-4-oxo-1H-quinoline-3-carboxamide
339
N-(3-cyano-1H-indol-6-yl)-4-oxo-1H-quinoline-3-carboxamide
342
N-[5-(4-isopropylphenyl)-1H-indol-6-yl]-4-oxo-1H-quinoline-3-carboxamide
343
N-[5-(isobutylcarbamoyl)-1H-indol-6-yl]-4-oxo-1H-quinoline-3-carboxamide
345
6-fluoro-4-hydroxy-N-(1H-indol-6-yl)quinoline-3-carboxamide
347
N-[5-[4-(2-dimethylaminoethylcarbamoyl)phenyl]-1H-indol-6-yl]-4-oxo-1H-quinoline-
3-carboxamide
351
N-(5-ethyl-1H-indol-6-yl)-4-oxo-1H-quinoline-3-carboxamide
352
2-[6-[(4-oxo-1H-quinolin-3-yl)carbonylamino]-1H-indol-3-yl]ethylaminoformic acid
tert-butyl ester
357
N-(3-isopropyl-1H-indol-6-yl)-4-oxo-1H-quinoline-3-carboxamide
358
6-chloro-4-hydroxy-N-(1H-indol-6-yl)quinoline-3-carboxamide
364
N-(2-methyl-8-quinolyl)-4-oxo-1H-quinoline-3-carboxamide
374
4-hydroxy-N-(1H-indol-6-yl)-2-methylsulfanyl-quinoline-3-carboxamide
376
4-oxo-N-(2-phenylbenzooxazol-5-yl)-1H-quinoline-3-carboxamide
377
6,8-difluoro-4-hydroxy-N-(1H-indol-6-yl)quinoline-3-carboxamide
381
4-oxo-N-(5-tert-butyl-1H-indol-6-yl)-1H-quinoline-3-carboxamide
383
N-(3-ethyl-1H-indol-6-yl)-4-oxo-1H-quinoline-3-carboxamide
386
N-(3,3-dimethylindolin-6-yl)-4-oxo-1H-quinoline-3-carboxamide
404
N-[5-(2,6-dimethoxyphenyl)-1H-indol-6-yl]-4-oxo-1H-quinoline-3-carboxamide
406
6-[(4-fluorophenyl)-methyl-sulfamoyl]-4-oxo-N-(5-tert-butyl-1H-indol-6-yl)-1H-
quinoline-3-carboxamide
412
6-[(4-oxo-1H-quinolin-3-yl)carbonylamino]-1H-indole-7-carboxylic acid ethyl ester
414
N-(3H-benzoimidazol-5-yl)-4-oxo-1H-quinoline-3-carboxamide
423
N-[3-(2-ethoxyethyl)-1H-indol-6-yl]-4-oxo-1H-quinoline-3-carboxamide
427
5-[(4-oxo-1H-quinolin-3-yl)carbonylamino]-1,2,3,4-tetrahydroisoquinoline-2-carboxylic
acid tert-butyl ester
437
N-benzo[1,3]dioxol-5-yl-4-oxo-1H-quinoline-3-carboxamide
443
4-oxo-N-quinoxalin-6-yl-1H-quinoline-3-carboxamide
446
N-(1,1-dioxobenzothiophen-6-yl)-4-oxo-1H-quinoline-3-carboxamide
467
N-(2,3-dihydrobenzofuran-5-yl)-4-oxo-1H-quinoline-3-carboxamide
474
N-(3-methyl-2-oxo-3H-benzooxazol-5-yl)-4-oxo-1H-quinoline-3-carboxamide
478
4-oxo-N-(3-tert-butyl-1H-indol-6-yl)-1H-quinoline-3-carboxamide
479
N-(1H-indol-6-yl)-5-methoxy-4-oxo-1H-quinoline-3-carboxamide.

214 more elements

Dependencies are inferred from the claim text.

Facts

Application: 12/351,401Filed 9 Jan 2009 · continuation
Priority: 24 Jun 2004
Published: US 2009/0227797 A110 Sep 2009
Granted: 24 Jan 2012
Term ends: Not estimatedThe source records don’t support an estimate.

Classification119 codes

C07D 471/10
In which the condensed system contains two hetero rings: spiro-condensed systems
A61K 8/4926
With one nitrogen as the only hetero atom: having six membered rings
A61K 31/04
Medicinal preparations containing organic active ingredients: nitro compounds
A61K 31/136
Having aromatic rings , e.g. ketamine, nortriptyline: having the amino group directly attached to the aromatic ring, e.g. benzeneamine

Family

Application60/582,676Us provisional application · filed 24 Jun 2004
Application60/630,127Us provisional application · filed 22 Nov 2004
Application60/635,674Us provisional application · filed 13 Dec 2004
Application60/658,219Us provisional application · filed 3 Mar 2005
Application60/661,311Us provisional application · filed 11 Mar 2005
Application11/165,818Parent of this continuation · filed 24 Jun 2005
US 2009/0227797 A1Pre-grant publication · published 10 Sep 2009
US 7,495,103 B2Parent of this continuation
US 2006/0074075 A1Published application
US 8,101,767 B2This patent

From the US filing history. Foreign family members aren’t listed.

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Abstract

A compound of formula V-B-5:

wherein:
ring A2 is a phenyl or a 5-6 membered heteroaryl ring, wherein ring A2 and the phenyl ring fused thereto together have up 4 substituents independently selected from WRW;
and
W is a bond or is an optionally substituted C1-C6 alkylidene chain wherein up to two methylene units of W are optionally and independently replaced by —CO—, —CS—, —COCO—, —CONR′—, —CONR′NR′—, —CO2—, —OCO—, —NR′CO2—, —O—, —NR′CONR′—, —OCONR′—, —NR′NR′, —NR′NR′CO—, —NR′CO—, —S—, —SO, —SO2—, —NR′—, —SO2NR′—, NR′SO2—, —NR′SO2NR′—;
RW is independently R′, halo, NO2, CN, CF3 , or OCF3;
X is a bond or is an optionally substituted C1-C6 alkylidene chain wherein up to two methylene units of X are optionally and independently replaced by —CO—, —CS—, —COCO—,—CONR′—, —CONR′NR′—, —CO2—, —OCO—, —NR′CO2—, —O—, —NR′CONR′—, —OCONR′—, —NR′NR′, —NR′NR′CO—, —NR′CO—, —S—, —SO, —SO2—,—NR′—, —SO2NR′—, NR′SO2—, or —NR′SO2NR′—;
RX is independently R′, halo, NO2, CN, CF3, or OCF3;
R′ is independently selected from hydrogen or an optionally substituted group selected from a C1-C8 aliphatic group a 3-8-membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-12 membered saturated, partially unsaturated, or fully unsaturated bicyclic ring system having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
or two occurrences of R′ are taken together with the atom(s) to which they are bound to form an optionally substituted 3-12 membered saturated, partially unsaturated, or fully unsaturated monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
and
m is 0-4.

8 more elements

Facts

Application

12/351,401Filed 9 Jan 2009 · continuation

Priority

24 Jun 2004

Published

US 2009/0227797 A110 Sep 2009

Granted

24 Jan 2012

Term ends

Not estimatedThe source records don’t support an estimate.

Classification119 codes

C07D 471/10
In which the condensed system contains two hetero rings: spiro-condensed systems
A61K 8/4926
With one nitrogen as the only hetero atom: having six membered rings
A61K 31/04
Medicinal preparations containing organic active ingredients: nitro compounds
A61K 31/136
Having aromatic rings , e.g. ketamine, nortriptyline: having the amino group directly attached to the aromatic ring, e.g. benzeneamine

Family

Application60/582,676Us provisional application · filed 24 Jun 2004

Application60/630,127Us provisional application · filed 22 Nov 2004

Application60/635,674Us provisional application · filed 13 Dec 2004

Application60/658,219Us provisional application · filed 3 Mar 2005

Application60/661,311Us provisional application · filed 11 Mar 2005

Application11/165,818Parent of this continuation · filed 24 Jun 2005

US 2009/0227797 A1Pre-grant publication · published 10 Sep 2009

US 7,495,103 B2Parent of this continuation

US 2006/0074075 A1Published application

US 8,101,767 B2This patent

From the US filing history. Foreign family members aren’t listed.