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Details for Patent: 8,101,767

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Details for Patent: 8,101,767

Title:Modulators of ATP-binding cassette transporters
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.
Inventor(s): Ruah; Sara Hadida (La Jolla, CA), Hazlewood; Anna (San Diego, CA), Grootenhuis; Peter D. J. (San Diego, CA), Van Goor; Fredrick (San Diego, CA), Singh; Ashvani (San Diego, CA), Zhou; Jinglan (San Diego, CA), McCartney; Jason (Cardiff-by-the-Sea, CA)
Assignee: Vertex Pharmaceuticals Incorporated (Cambridge, MA)
Filing Date:Jan 09, 2009
Application Number:12/351,401
Claims:1. A compound of formula V-B-5: ##STR00245## wherein: ring A.sub.2 is a phenyl or a 5-6 membered heteroaryl ring, wherein ring A.sub.2 and the phenyl ring fused thereto together have up 4 substituents independently selected from WR.sup.W; and W is a bond or is an optionally substituted C.sub.1-C.sub.6 alkylidene chain wherein up to two methylene units of W are optionally and independently replaced by --CO--, --CS--, --COCO--, --CONR'--, --CONR'NR'--, --CO.sub.2--, --OCO--, --NR'CO.sub.2--, --O--, --NR'CONR'--, --OCONR'--, --NR'NR', --NR'NR'CO--, --NR'CO--, --S--, --SO, --SO.sub.2--, --NR'--, --SO.sub.2NR'--, NR'SO.sub.2--, --NR'SO.sub.2NR'--; R.sup.W is independently R', halo, NO.sub.2, CN, CF.sub.3 , or OCF.sub.3; X is a bond or is an optionally substituted C.sub.1-C.sub.6 alkylidene chain wherein up to two methylene units of X are optionally and independently replaced by --CO--, --CS--, --COCO--,--CONR'--, --CONR'NR'--, --CO.sub.2--, --OCO--, --NR'CO.sub.2--, --O--, --NR'CONR'--, --OCONR'--, --NR'NR', --NR'NR'CO--, --NR'CO--, --S--, --SO, --SO.sub.2--,--NR'--, --SO.sub.2NR'--, NR'SO.sub.2--, or --NR'SO.sub.2NR'--; R.sup.X is independently R', halo, NO.sub.2, CN, CF.sub.3, or OCF.sub.3; R' is independently selected from hydrogen or an optionally substituted group selected from a C.sub.1-C.sub.8 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.

2. The compound according to claim 1, wherein ring A.sub.2 is selected from: ##STR00246## wherein said ring is optionally substituted.

3. The compound according to claim 1, wherein said compound has formula V-B-5-a: ##STR00247## wherein: G.sub.4 is hydrogen, halo, CN, CF.sub.3, CHF.sub.2, CH.sub.2F, optionally substituted C1-C6 aliphatic, aryl-C1-C6 alkyl, or a phenyl, wherein G.sub.4 is optionally substituted with up to 4 WR.sup.W substituents; wherein up to two methylene units of said C1-C6 aliphatic or C1-C6 alkyl is optionally replaced with --CO--, --CONR'--, --CO.sub.2--, --OCO--, --NR'CO.sub.2--, --O--, --NR'CONR'--, --OCONR'--, --NR'CO--, --S--, --NR'--, --SO.sub.2NR'--, NR'SO.sub.2--, or --NR'SO.sub.2NR'--; G.sub.5 is hydrogen or an optionally substituted C1-C6 aliphatic; wherein said indole ring system is further optionally substituted with up to 3 substituents independently selected from WR.sup.W.

4. The compound according to claim 3, wherein G.sub.4 is hydrogen, and G.sub.5 is C1-C6 aliphatic, wherein said aliphatic is optionally substituted with C1-C6 alkyl, halo, cyano, or CF.sub.3, and wherein up to two methylene units of said C1-C6 aliphatic or C1-C6 alkyl is optionally replaced with --CO--, --CONR'--, --CO.sub.2--, --OCO--, --NR'CO.sub.2--, --O--, --NR'CONR'--, --OCONR'--, --NR'CO--, --S--, --NR'--, --SO.sub.2NR'--, NR'SO.sub.2--, or --NR'SO.sub.2NR'--.

5. The compound according to claim 3, wherein G.sub.4 is hydrogen, and G.sub.5 is cyano, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, t-butyl, cyanomethyl, methoxyethyl, CH.sub.2C(O)OMe, (CH.sub.2).sub.2--NHC(O)O-tert-But, or cyclopentyl.

6. The compound according to claim 3, wherein G.sub.5 is hydrogen, and G.sub.4 is halo, C1-C6 aliphatic or phenyl, wherein said aliphatic or phenyl is optionally substituted with C1-C6 alkyl, halo, cyano, or CF.sub.3, wherein up to two methylene units of said C1-C6 aliphatic or C1-C6 alkyl is optionally replaced with --CO--, --CONR'--, --CO.sub.2--, --OCO--, --NR'CO.sub.2--, --O--, --NR'CONR'--, --OCONR'--, --NR'CO--, --S--, --NR'--, --SO.sub.2NR'--, NR'SO.sub.2--, or --NR'SO.sub.2NR'--.

7. The compound according to claim 3, wherein G.sub.5 is hydrogen, and G.sub.4 is halo, ethoxycarbonyl, t-butyl, 2-methoxyphenyl, 2-ethoxyphenyl, (4-C(O)NH(CH.sub.2).sub.2--NMe.sub.2)-phenyl, 2-methoxy-4-chloro-phenyl, pyridine-3-yl, 4-isopropylphenyl, 2,6-dimethoxyphenyl, sec-butylaminocarbonyl, ethyl, t-butyl, or piperidin-1-ylcarbonyl.

8. A compound selected from: TABLE-US-00016 Cmpd No. Name 1 N-[5-(5-chloro-2-methoxy-phenyl)-1H-indol-6-yl]-4-oxo-1H-quinoline-3-car- boxamide 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-ox- o-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-qu- inoline-3- carboxamide 64 4-oxo-N-(2-oxo-1,3-dihydrobenzoimidazol-5-yl)-1H-quinoline-3-carboxamid- e 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-tetrahydroisoquinoli- ne-2-carboxylic acid tert-butyl ester 108 4,4-dimethyl-7-[(4-oxo-1H-quinoline-3-yl)carbonylamino]-1,2,3,4-tetrah- ydroquinoline- 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-carboxami- de 130 4-hydroxy-N-(1H-indol-6-yl)-5,7-bis(trifluoromethyl)quinoline-3-carbox- amide 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-quino- line-3- carboxamide 148 4-oxo-N-[5-(1-piperidylcarbonyl)-1H-indol-6-yl]-1H-quinoline-3-carboxa- mide 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-carboxami- de 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-oxoqu- inoline-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-quin- oline-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-c- arboxamide 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-carboxami- de 343 N-[5-(isobutylcarbamoyl)-1H-indol-6-yl]-4-oxo-1H-quinoline-3-carboxami- de 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]ethylaminof- ormic 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-carboxa- mide 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-tetrahydroisoquinoli- ne-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-carboxamid- e 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.
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