Claims for Patent: 8,598,181

Summary for Patent: 8,598,181

Title:	Modulators of ATP-binding cassette transporters
Abstract:	Compounds of the present invention and pharmaceutically acceptable compositions thereof, are useful as modulators of ATP-Binding Cassette ("ABC") transporters or fragments thereof, including Cystic Fibrosis Transmembrane Conductance Regulator ("CFTR"). The present invention also relates to methods of treating ABC transporter mediated diseases using compounds of the present invention.
Inventor(s):	Hadida Ruah; Sara S. (La Jolla, CA), Grootenhuis; Peter D. J. (San Diego, CA), Van Goor; Fredrick (San Diego, CA), Zhou; Jinglan (San Diego, CA), Bear; Brian (Oceanside, CA), Miller; Mark T. (San Diego, CA), McCartney; Jason (Cardiff by the Sea, CA), Numa; Mehdi Michel Jamel (San Diego, CA), Yang; Xiaoqing (San Diego, CA)
Assignee:	Vertex Pharmaceuticals Incorporated (Cambridge, MA)
Application Number:	12/829,879
Patent Claims:	1. A method of modulating ABC transporter activity comprising the step of contacting said ABC transporter with a compound of the formula: ##STR00788## or a pharmaceutically acceptable salt thereof, wherein R.sub.1 is --Z.sup.AR.sub.4, wherein each Z.sup.A is independently a bond or an optionally substituted branched or straight C.sub.1-6 aliphatic chain wherein up to two carbon units of Z.sup.A are optionally and independently replaced by --CO--, --CS--, --CONR.sup.A--, --CONR.sup.ANR.sup.A--, --CO.sub.2--, --OCO--, --NR.sup.ACO.sub.2--, --O--, --NR.sup.ACONR.sup.A--, --OCONR.sup.A--, --NR.sup.ANR.sup.A--, --NR.sup.ACO--, --S--, --SO--, --SO.sub.2--, --NR.sup.A--, --SO.sub.2NR.sup.A--, --NR.sup.ASO.sub.2--, or --NR.sup.ASO.sub.2NR.sup.A--, Each R.sub.4 is independently R.sup.A, halo, --OH, --NH.sub.2, --NO.sub.2, --CN, or --OCF.sub.3, Each R.sup.A is independently hydrogen, an optionally substituted aliphatic, an optionally substituted cycloaliphatic, an optionally substituted heterocycloaliphatic, an optionally substituted aryl, or an optionally substituted heteroaryl; Each R.sub.2 is independently --Z.sup.BR.sub.5, wherein each Z.sup.B is independently a bond or an optionally substituted branched or straight C.sub.1-6 aliphatic chain wherein up to two carbon units of Z.sup.B are optionally and independently replaced by --CO--, --CS--, --CONR.sup.B--, --CONR.sup.BNR.sup.B--, --CO.sub.2--, --OCO--, --NR.sup.BCO.sub.2--, --O--, --NR.sup.BCONR.sup.B--, --OCONR.sup.B--, --NR.sup.BNR.sup.B--, --NR.sup.BCO--, --S--, --SO--, --SO.sub.2--, --NR.sup.B--, --SO.sub.2NR.sup.B--, --NR.sup.BSO.sub.2--, or --NR.sup.BSO.sub.2NR.sup.B--, Each R.sub.5 is independently R.sup.B, halo, --OH, --NH.sub.2, --NO.sub.2, --CN, --CF.sub.3, or --OCF.sub.3, Each R.sup.B is independently hydrogen, an optionally substituted aliphatic, an optionally substituted cycloaliphatic, an optionally substituted heterocycloaliphatic, an optionally substituted aryl, or an optionally substituted heteroaryl, Or, any two adjacent R.sub.2 groups together with the atoms to which they are attached form an optionally substituted carbocycle or an optionally substituted heterocycle; Ring A is an optionally substituted 3-7 membered monocyclic ring having 0-3 heteroatoms selected from N, O, and S; Ring B is a group having formula Ia: ##STR00789## or a pharmaceutically acceptable salt thereof, wherein p is 0-2, Each R.sub.3 and R'.sub.3 is independently --Z.sup.CR.sub.6, where each Z.sup.C is independently a bond or an optionally substituted branched or straight C.sub.1-6 aliphatic chain wherein up to two carbon units of Z.sup.C are optionally and independently replaced by --CO--, --CS--, --CONR.sup.C--, --CONR.sup.CNR.sup.C--, --CO.sub.2--, --OCO--, --NR.sup.CCO.sub.2--, --O--, --NR.sup.CCONR.sup.C--, --OCONR.sup.C--, --NR.sup.CNR.sup.C--, --NR.sup.CCO--, --S--, --SO--, --SO.sub.2--, --NR.sup.C--, --SO.sub.2NR.sup.C--, --NR.sup.CSO.sub.2--, or --NR.sup.CSO.sub.2NR.sup.C--, Each R.sub.6 is independently R.sup.C, halo, --OH, --NH.sub.2, --NO.sub.2, --CN, or --OCF.sub.3, Each R.sup.C is independently hydrogen, an optionally substituted aliphatic, an optionally substituted cycloaliphatic, an optionally substituted heterocycloaliphatic, an optionally substituted aryl, or an optionally substituted heteroaryl, Or, any two adjacent R.sub.3 groups together with the atoms to which they are attached form an optionally substituted heterocycle; and n is 1-3. 2. The method of claim 1, wherein the ABC transporter is CFTR. 3. A method of treating or lessening the severity of a disease in a patient, wherein said disease is selected from cystic fibrosis, hereditary emphysema, COPD, or dry-eye disease, said method comprising the step of administering to said patient an effective amount of a compound of the formula: ##STR00790## or a pharmaceutically acceptable salt thereof, wherein R.sub.1 is --Z.sup.AR.sub.4, wherein each Z.sup.A is independently a bond or an optionally substituted branched or straight C.sub.1-6 aliphatic chain wherein up to two carbon units of Z.sup.A are optionally and independently replaced by --CO--, --CS--, --CONR.sup.A--, --CONR.sup.ANR.sup.A--, --CO.sub.2--, --OCO--, --NR.sup.ACO.sub.2--, --O--, --NR.sup.ACONR.sup.A--, --OCONR.sup.A--, --NR.sup.ANR.sup.A--, --NR.sup.ACO--, --S--, --SO--, --SO.sub.2--, --NR.sup.A--, --SO.sub.2NR.sup.A--, --NR.sup.ASO.sub.2--, or --NR.sup.ASO.sub.2NR.sup.A--, Each R.sub.4 is independently R.sup.A, halo, --OH, --NH.sub.2, --NO.sub.2, --CN, or --OCF.sub.3, Each R.sup.A is independently hydrogen, an optionally substituted aliphatic, an optionally substituted cycloaliphatic, an optionally substituted heterocycloaliphatic, an optionally substituted aryl, or an optionally substituted heteroaryl; Each R.sub.2 is independently --Z.sup.BR.sub.5, wherein each Z.sup.B is independently a bond or an optionally substituted branched or straight C.sub.1-6 aliphatic chain wherein up to two carbon units of Z.sup.B are optionally and independently replaced by --CO--, --CS--, --CONR.sup.B--, --CONR.sup.BNR.sup.B--, --CO.sub.2--, --NR.sup.BCO.sub.2--, --O--, --NR.sup.BCONR.sup.B--, --OCONR.sup.B--, --NR.sup.BNR.sup.B--, --NR.sup.BCO--, --S--, --SO--, --SO.sub.2--, --NR.sup.B--, --SO.sub.2NR.sup.8--, --NR.sup.BSO.sub.2--, or --NR.sup.BSO.sub.2NR.sup.B--, Each R.sub.5 is independently R.sup.B, halo, --OH, --NH.sub.2, --NO.sub.2, --CN, --CF.sub.3, or --OCF.sub.3, Each R.sup.B is independently hydrogen, an optionally substituted aliphatic, an optionally substituted cycloaliphatic, an optionally substituted heterocycloaliphatic, an optionally substituted aryl, or an optionally substituted heteroaryl, Or, any two adjacent R.sub.2 groups together with the atoms to which they are attached form an optionally substituted carbocycle or an optionally substituted heterocycle; Ring A is an optionally substituted 3-7 membered monocyclic ring having 0-3 heteroatoms selected from N, O, and S; Ring B is a group having formula Ia: ##STR00791## or a pharmaceutically acceptable salt thereof, wherein p is 0-2, Each R.sub.3 and R'.sub.3 is independently --Z.sup.CR.sub.6, where each Z.sup.C is independently a bond or an optionally substituted branched or straight C.sub.1-6 aliphatic chain wherein up to two carbon units of Z.sup.C are optionally and independently replaced by --CO--, --CS--, --CONR.sup.C--, --CONR.sup.CNR.sup.C--, --CO.sub.2--, --OCO--, --NR.sup.CCO.sub.2--, --O--, --NR.sup.CCONR.sup.C--, --OCONR.sup.C--, --NR.sup.CNR.sup.C--, --NR.sup.CCO--, --S--, --SO--, --SO.sub.2--, --NR.sup.C--, --SO.sub.2NR.sup.C--, --NR.sup.CSO.sub.2--, or --NR.sup.CSO.sub.2NR.sup.C--, Each R.sub.6 is independently R.sup.C, halo, --OH, --NH.sub.2, --NO.sub.2, --CN, or --OCF.sub.3, Each R.sup.C is independently hydrogen, an optionally substituted aliphatic, an optionally substituted cycloaliphatic, an optionally substituted heterocycloaliphatic, an optionally substituted aryl, or an optionally substituted heteroaryl, Or, any two adjacent R.sub.3 groups together with the atoms to which they are attached form an optionally substituted heterocycle; and n is 1-3. 4. The method of claim 3, wherein: R.sub.1 is --Z.sup.AR.sub.4, wherein each Z.sup.A is independently a bond or an optionally substituted branched or straight C.sub.1-6 aliphatic chain wherein up to two carbon units of Z.sup.A are optionally and independently replaced by --CO--, --CS--, --CONR.sup.A--, --CONR.sup.ANR.sup.A--, --CO.sub.2--, --OCO--, --NR.sup.ACO.sub.2--, --O--, --NR.sup.ACONR.sup.A--, --OCONR.sup.A--, --NR.sup.ANR.sup.A--, --NR.sup.ACO--, --S--, --SO--, --SO.sub.2--, --NR.sup.A--, --SO.sub.2NR.sup.A--, --NR.sup.ASO.sub.2--, or --NR.sup.ASO.sub.2NR.sup.A--; Each R.sub.4 is independently R.sup.A, halo, --OH, --NH.sub.2, --NO.sub.2, --CN, or --OCF.sub.3; Each R.sup.A is independently hydrogen, an optionally substituted aliphatic, an optionally substituted cycloaliphatic, or an optionally substituted aryl; n is 2 and the two R.sub.2 are adjacent to each other and together with the atoms to which they are attached form ##STR00792## Ring A is an optionally substituted 3-7 membered monocyclic ring; Ring B is a group of the formula ##STR00793## or a pharmaceutically acceptable salt thereof, wherein p is 0-2; Each R.sub.3 and R'.sub.3 is independently --Z.sup.CR.sub.6, where each Z.sup.C is independently a bond or an optionally substituted branched or straight C.sub.1-6 aliphatic chain wherein up to two carbon units of Z.sup.C are optionally and independently replaced by --CO--, --CS--, --CONR.sup.C--, --CONR.sup.CNR.sup.C--, --CO.sub.2--, --OCO--, --NR.sup.CCO.sub.2--, --O--, --NR.sup.CCONR.sup.C--, --OCONR.sup.C--, --NR.sup.CNR.sup.C--, --NR.sup.CCO--, --S--, --SO--, --SO.sub.2--, --NR.sup.C--, --SO.sub.2NR.sup.C--, --NR.sup.CSO.sub.2--, or --NR.sup.CSO.sub.2NR.sup.C--; Each R.sub.6 is independently R.sup.C, halo, --OH, --NH.sub.2, --NO.sub.2, --CN, or --OCF.sub.3; and Each R.sup.C is independently hydrogen, an optionally substituted aliphatic, an optionally substituted cycloaliphatic, or an optionally substituted aryl; Or, any two adjacent R.sub.3 groups together with the atoms to which they are attached form an optionally substituted heterocycle. 5. The method of claim 4, wherein R.sub.1 is --Z.sup.AR.sub.4, Z.sup.A is a bond, and R.sub.4 is hydrogen. 6. The method of claim 4, wherein ring A is a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl, each of which is optionally substituted with 1-3 of halo, hydroxy, C.sub.1-5 aliphatic, or combinations thereof. 7. The method of claim 4, wherein ring A is an optionally substituted 3-7 membered monocyclic heterocycloaliphatic. 8. The method claim 4, wherein ring A is one selected from ##STR00794## wherein Each R.sub.9 is independently --Z.sup.ER.sub.10, wherein each Z.sup.E is independently a bond or an optionally substituted branched or straight C.sub.1-6 aliphatic chain wherein up to two carbon units of Z.sup.E are optionally and independently replaced by --CO--, --CS--, --CONR.sup.E--, CO.sub.2--, --OCO--, --NR.sup.ECO.sub.2--, --O--, --NR.sup.ECONR.sup.E--, --OCONR.sup.E--, --NR.sup.ENR.sup.E--, --NR.sup.ECO--, --S--, --SO--, --SO.sub.2--, --NR.sup.E--, --SO.sub.2NR.sup.E--, --NR.sup.ESO.sub.2--, or --NR.sup.ESO.sub.2NR.sup.E--; Each R.sub.10 is independently R.sup.E, --OH, --NH.sub.2, --NO.sub.2, --CN, --CF.sub.3, oxo, or --OCF.sub.3, Each R.sup.E is independently hydrogen, an optionally substituted cycloaliphatic, an optionally substituted heterocycloaliphatic, an optionally substituted aryl, or an optionally substituted heteroaryl; and q is 0-5. 9. The method of claim 4, wherein R'.sub.3 is H. 10. The method of claim 4, wherein one of R.sub.3 or R'.sub.3 is an optionally substituted acyl group. 11. The method of claim 4, wherein one of R.sub.3 or R'.sub.3 is an (alkoxy)carbonyl optionally substituted with 1-3 of halo, hydroxy, or combinations thereof. 12. The method of claim 4, wherein one of R.sub.3 or R'.sub.3 is an (aliphatic)carbonyl optionally substituted with 1-3 of halo, hydroxy, or combinations thereof. 13. The method of claim 4, wherein one of R.sub.3 or R'.sub.3 is a (cycloaliphatic)carbonyl or a (heterocycloaliphatic)carbonyl, each is optionally substituted with 1-3 of aliphatic, halo, hydroxy, nitro, cyano, or combinations thereof. 14. The method claim 13, wherein one of R.sub.3 or R'.sub.3 is (piperidine-1-yl,)carbonyl, (pyrrolidine-1-yl)carbonyl, (morpholine-4-yl)carbonyl, (piperazine-1-yl)carbonyl, (cyclopropyl)carbonyl, (cyclobutyl)carbonyl, (cyclopentyl)carbonyl, (cyclohexyl)carbonyl, or (cycloheptyl)carbonyl, each of which is each of which is optionally substituted with 1-3 of halo, hydroxy, cyano, nitro, aliphatic, or combinations thereof. 15. The method of claim 4, wherein R.sub.3 is optionally substituted (aliphatic)amido that is attached to the 2 or 3 position on the indole ring of formula Ia. 16. The method of claim 15, wherein R.sub.3 is (N,N-dimethyl(amino))carbonyl, (methyl(amino))carbonyl, (ethyl(amino))carbonyl, (propyl(amino))carbonyl, (prop-2-yl(amino))carbonyl, (dimethyl(but-2-yl(amino)))carbonyl, (tertbutyl(amino))carbonyl, (butyl(amino))carbonyl, each of which is optionally substituted with 1-3 of halo, hydroxy, cycloaliphatic, heterocycloaliphatic, aryl, heteroaryl, or combinations thereof. 17. The method of claim 4, wherein R'.sub.3 is ##STR00795## wherein R.sub.31 is H or a C.sub.1-2 aliphatic that is optionally substituted with 1-3 of halo, --OH, or combinations thereof, R.sub.32 is -L-R.sub.33, wherein L is a bond, --CH.sub.2--, --CH.sub.2O--, --CH.sub.2NHS(O).sub.2--, --CH.sub.2C(O)--, --CH.sub.2NHC(O)--, or --CH.sub.2NH--, and R.sub.33 is hydrogen, or C.sub.1-2 aliphatic, cycloaliphatic, heterocycloaliphatic, or heteroaryl, each of which is optionally substitututed with 1 of --OH, --NH.sub.2, or --CN. 18. The method of claim 4, wherein R'.sub.3 is independently selected from one of the following: --H, --CH.sub.3, --CH.sub.2CH.sub.3, --C(O)CH.sub.3, --CH.sub.2CH.sub.2OH, --C(O)OCH.sub.3, ##STR00796## ##STR00797## ##STR00798## 19. The method of claim 3, wherein the compound is: ##STR00799## ##STR00800## ##STR00801## ##STR00802## ##STR00803## ##STR00804## ##STR00805## ##STR00806## ##STR00807## ##STR00808## ##STR00809## ##STR00810## ##STR00811## ##STR00812## ##STR00813## ##STR00814## ##STR00815## ##STR00816## ##STR00817## ##STR00818## ##STR00819## ##STR00820## ##STR00821## ##STR00822## ##STR00823## ##STR00824## ##STR00825## ##STR00826## ##STR00827## ##STR00828## ##STR00829## ##STR00830## ##STR00831## ##STR00832## ##STR00833## ##STR00834## ##STR00835## ##STR00836## ##STR00837## ##STR00838## ##STR00839## ##STR00840## ##STR00841## ##STR00842## ##STR00843## ##STR00844## ##STR00845## ##STR00846## ##STR00847## ##STR00848## ##STR00849## ##STR00850##