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US 8,759,335 B2Granted
Modulators of ATP-binding cassette transporters
AssigneeVertex Pharmaceuticals Incorporated
InventorsSara Hadida Ruah, Peter Grootenhuis, Mark Miller, Matthew Hamilton
Life of this patent
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Abstract
The present invention relates to modulators of ATP-Binding Cassette (“ABC”) transporters or fragments thereof, including Cystic Fibrosis Transmembrane Conductance Regulator (“CFTR”), compositions thereof, and methods therewith. The present invention also relates to methods of treating ABC transporter mediated diseases using such modulators.
Claims86
A compound having formula I:
- or a pharmaceutically acceptable salt thereof, wherein:
- Ht is a 5-membered heteroaromatic ring containing 1-4 heteroatoms selected from O, S, or N, wherein Ht is optionally substituted with w occurrences of —WRW, wherein w is 0-4;
- RN is H or R;
- R is hydrogen or C1-6 aliphatic wherein up to two methylene units of R 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′—;
- ring A is a cyclopropyl ring, wherein ring A is optionally substituted with q occurrences of -QRQ;
- x is 2, wherein the two RxX form a fused benzodioxole ring;
- q is 0-4;
- each -Q-RQ, and —W—Rw is independently R′;
- R′ is independently R1, R2, R3, R4, or R5;
- R1 is oxo, R6 or ((C1-C4)aliphatic)n-Y;
- n is 0 or 1;
- Y is halo, CN, NO2, CF3, OCF3, OH, NH2, NHR6, N(R6)2, NR6R8, COOH, COOR6 or OR6;
- or
- two R1 on adjacent ring atoms, taken together, form 1,2-methylenedioxy or 1,2-ethylenedioxy;
- R2 is aliphatic, wherein each R2 optionally comprises up to 2 substituents independently selected from R1, R4, or R5;
- R3 is a cycloaliphatic, aryl, heterocyclic, or heteroaryl ring optionally comprising up to 3 substituents, independently selected from R1, R2, R4 or R5;
- R4 is OR5, OR6, OC(O)R6, OC(O)R5, OC(O)OR6, OC(O)OR5, OC(O)N(R6)2, OC(O)N(R5)2, OC(O)N(R6R5), SO2N(R6)2, SO2N(R5)2, SO2NR5R6, C(O)R5, C(O)OR5, C(O)R6, C(O)OR6, C(O)N(R6)2, C(O)N(R5)2, C(O)N(R5R6), C(O)N(OR6)R6, C(O)N(OR5)R6, C(O)N(OR6)R5, C(O)N(OR5)R5, C(NOR6)R6, C(NOR6)R5, C(NOR5)R6, C(NOR5)R5, N(R6)2, N(R5)2, N(R5R6), NR5C(O)R5, NR6C(O)R6, NR6C(O)R5, NR5C(O)R6, NR6C(O)OR6, NR5C(O)OR6, NR6C(O)OR5, NR5C(O)OR5, NR6C(O)N(R6)2, NR6C(O)NR5R6, NR6C(O)N(R5)2, NR5C(O)N(R6)2, NR5C(O)NR5R6, NR5C(O)N(R5)2, NR6SO2R6, NR6SO2R5, NR5SO2R6, NR5SO2R5, NR6SO2N(R6)2, NR6SO2NR5R6, NR6SO2N(R5)2, NR5SO2NR5R6, NR5SO2N(R5)2, N(OR6)R6, N(OR6)R5, N(OR5)R5, or N(OR5)R6;
- R5 is a cycloaliphatic, aryl, heterocyclic, or heteroaryl ring, optionally comprising up to 3 R1 substituents;
- R6 is H or aliphatic, wherein R6 optionally comprises a R7 substituent;
- R7 is a cycloaliphatic, aryl, heterocyclic, or heteroaryl ring, and each R7 optionally comprises up to 2 substituents independently chosen from H, (C1-C6)-straight or branched alkyl, (C2-6) straight or branched alkenyl or alkynyl, 1,2-methylenedioxy, 1,2-ethylenedioxy, or (CH2)n—Z;
- Z is selected from halo, CN, NO2, CF3, OCF3, OH, S-aliphatic, S(O)-aliphatic, SO2-aliphatic, NH2, NH-aliphatic, N(aliphatic)2, N(aliphatic)R8, NHR8, COOH, C(O)O(-aliphatic), or O-aliphatic;
- and
- R8 is an amino protecting group.
20 more elements
A compound having formula IIIB:
- wherein:
- m is 0;
- Ar is phenyl or a six-membered heteroaromatic ring;
- L is a bond, O, S, SO, SO2, C(O), NR′, C1-4 aliphatic, or CHRL;
- or
- RL is —OR′, —SR′, —SOR′, —SO2R′, or —N(R′)2;
- wherein ring A′ is a 3-7 membered monocyclic ring having 0-3 heteroatoms selected from O, S, or N, wherein ring A′ is optionally substituted with q occurrences of -QRQ;
- x is 0 wherein each -QRQ is independently R′;
- q is 0-5;
- R′ is independently R1, R2, R3, R4, or R5;
- R1 is oxo, R6 or ((C1-C4)aliphatic)n-Y;
- n is 0 or 1;
- Y is halo, CN, NO2, CF3, OCF3, OH, NH2, NHR6, N(R6)2, NR6R8, COOH, COOR6 or OR6;
- or
- two R1 on adjacent ring atoms, taken together, form 1,2-methylenedioxy or 1,2-ethylenedioxy;
- R2 is aliphatic, wherein each R2 optionally comprises up to 2 substituents independently selected from R1, R4, or R5;
- R3 is a cycloaliphatic, aryl, heterocyclic, or heteroaryl ring optionally comprising up to 3 substituents, independently selected from R1, R2, R4 or R5;
- R4 is OR5, OR6, OC(O)R6, OC(O)R5, OC(O)OR6, OC(O)OR5, OC(O)N(R6)2, OC(O)N(R5)2, OC(O)N(R6R5), SO2N(R6)2, SO2N(R5)2, SO2NR5R6, C(O)R5, C(O)OR5, C(O)R6, C(O)OR6, C(O)N(R6)2, C(O)N(R5)2, C(O)N(R5R6), C(O)N(OR6)R6, C(O)N(OR5)R6, C(O)N(OR6)R5, C(O)N(OR5)R5, C(NOR6)R6, C(NOR6)R5, C(NOR5)R6, C(NOR5)R5, N(R6)2, N(R5)2, N(R5R6), NR5C(O)R5, NR6C(O)R6, NR6C(O)R5, NR5C(O)R6, NR6C(O)OR6, NR5C(O)OR6, NR6C(O)OR5, NR5C(O)OR5, NR6C(O)N(R6)2, NR6C(O)NR5R6, NR6C(O)N(R5)2, NR5C(O)N(R6)2, NR5C(O)NR5R6, NR5C(O)N(R5)2, NR6SO2R6, NR6SO2R5, NR5SO2R6, NR5SO2R5, NR6SO2N(R6)2, NR6SO2NR5R6, NR6SO2N(R5)2, NR5SO2NR5R6, NR5SO2N(R5)2, N(OR6)R6, N(OR6)R5, N(OR5)R5, or N(OR5)R6;
- R5 is a cycloaliphatic, aryl, heterocyclic, or heteroaryl ring, optionally comprising up to 3 R1 substituents;
- R6 is H or aliphatic, wherein R6 optionally comprises a R7 substituent;
- R7 is a cycloaliphatic, aryl, heterocyclic, or heteroaryl ring, and each R7 optionally comprises up to 2 substituents independently chosen from H, (C1-C6)-straight or branched alkyl, (C2-6) straight or branched alkenyl or alkenyl, 1,2-methylenedioxy, 1,2-ethylenedioxy, or (CH2)n—Z;
- Z is selected from halo, CN, NO2, CF3, OCF3, OH, S-aliphatic, S(O)-aliphatic, SO2-aliphatic, NH2, NH-aliphatic, N(aliphatic)2, N(aliphatic)R8, NHR8, COOH, C(O)O(-aliphatic), or O-aliphatic;
- R8 is an amino protecting group;
- X9 is CH2 or CF2;
- z is 0-5;
- —ZRZ is independently R′;
- and
- Ht1 is a 5-membered heteroaromatic ring containing 1-4 heteroatoms selected from O, S, or N.
25 more elements
A compound having formula IVA-5′ or formula IVA-6′:
- wherein
- x is 2, wherein the two RxX form a fused benzodioxole ring;
- z is 0-5;
- —ZRZ is independently R′;
- R′ is R1, R2, R3, R4, or R5;
- R1 is oxo, R6 or ((C1-C4)aliphatic)n-Y;
- n is 0 or 1;
- Y is halo, CN, NO2, CF3, OCF3, OH, NH2, NHR6, N(R6)2, NR6R8, COOH, COOR6 or OR6;
- or
- two R1 on adjacent ring atoms, taken together, form 1,2-methylenedioxy or 1,2-ethylenedioxy;
- R2 is aliphatic, wherein each R2 optionally comprises up to 2 substituents independently selected from R1, R4, or R5;
- R3 is a cycloaliphatic, aryl, heterocyclic, or heteroaryl ring optionally comprising up to 3 substituents, independently selected from R1, R2, R4 or R5;
- R4 is OR5, OR6, OC(O)R6, OC(O)R5, OC(O)OR6, OC(O)OR5, OC(O)N(R6)2, OC(O)N(R5)2, OC(O)N(R6R5), SO2N(R6)2, SO2N(R5)2, SO2NR5R6, C(O)R5, C(O)OR5, C(O)R6, C(O)OR6, C(O)N(R6)2, C(O)N(R5)2, C(O)N(R5R6), C(O)N(OR6)R6, C(O)N(OR5)R6, C(O)N(OR6)R5, C(O)N(OR5)R5, C(NOR6)R6, C(NOR6)R5, C(NOR5)R6, C(NOR5)R5, N(R6)2, N(R5)2, N(R5R6), NR5C(O)R5, NR6C(O)R6, NR6C(O)R5, NR5C(O)R6, NR6C(O)OR6, NR5C(O)OR6, NR6C(O)OR5, NR5C(O)OR5, NR6C(O)N(R6)2, NR6C(O)NR5R6, NR6C(O)N(R5)2, NR5C(O)N(R6)2, NR5C(O)NR5R6, NR5C(O)N(R5)2, NR6SO2R6, NR6SO2R5, NR5SO2R6, NR5SO2R5, NR6SO2N(R6)2, NR6SO2NR5R6, NR6SO2N(R5)2, NR5SO2NR5R6, NR5SO2N(R5)2, N(OR6)R6, N(OR6)R5, N(OR5)R5, or N(OR5)R6;
- R5 is a cycloaliphatic, aryl, heterocyclic, or heteroaryl ring, optionally comprising up to 3 R1 substituents;
- R6 is H or aliphatic, wherein R6 optionally comprises a R7 substituent;
- R7 is a cycloaliphatic, aryl, heterocyclic, or heteroaryl ring, and each R7 optionally comprises up to 2 substituents independently chosen from H, (C1-C6)-straight or branched alkyl, (C2-6) straight or branched alkenyl or alkenyl, 1,2-methylenedioxy, 1,2-ethylenedioxy, or (CH2)n—Z;
- Z is selected from halo, CN, NO2, CF3, OCF3, OH, S-aliphatic, S(O)-aliphatic, SO2-aliphatic, NH2, NH-aliphatic, N(aliphatic)2, N(aliphatic)R8, NHR8, COOH, C(O)O(-aliphatic), or O-aliphatic;
- and
- R8 is an amino protecting group;
- X1 is O, S, or NR;
- R is hydrogen or C1-4 aliphatic;
- and
- each of X2 and X3 is independently selected from CH or N.
20 more elements
A compound having formula VA-1′, formula VA-2′, formula VA-3′, or formula VA-4′:
- wherein:
- x is 2, wherein the two RxX form a fused benzodioxole ring;
- each of RC, RD, and RE is independently hydrogen or C1-6 aliphatic optionally substituted with —OH, —O(C1-4aliphatic), —S(C1-4aliphatic), —CF3, —OCF3, —SCF3, halo, NH2, NHR, N(R)2, C(O)OH, C(O)O(C1-4aliphatic), NHC(O)(C1-4aliphatic), or a 3-7 membered heterocyclic ring containing up to 4 heteroatoms selected from O, N, or S, wherein said ring is optionally substituted with up to 2 substituents selected from oxo or (C1-4aliphatic)p-Y;
- p is 0 or 1;
- Y is halo, CN, NO2, CF3, OCF3, OR, SR, NH2, NHR, N(R)2, COOH, or COOR;
- R is hydrogen or C1-4 aliphatic;
- RAA and RBB, taken together with the nitrogen atom, is a 3-7 membered heterocyclic ring containing up to 4 heteroatoms selected from O, N, or S, wherein said ring is optionally substituted with up to 2 substituents selected from oxo or (C1-4aliphatic)p-Y;
- p is 0 or 1;
- Y is halo, CN, NO2, CF3, OCF3, OR, SR, NH2, NHR, N(R)2, COOH, or COOR;
- R is hydrogen or C1-4 aliphatic
- z is 0-5;
- —ZRZ is independently R′;
- R′ is R1, R2, R3, R4, or R5;
- R1 is oxo, R6 or ((C1-C4)aliphatic)n-Y;
- n is 0 or 1;
- Y is halo, CN, NO2, CF3, OCF3, OH, NH2, NHR6, N(R6)2, NR6R8, COOH, COOR6 or OR6;
- or
- two R1 on adjacent ring atoms, taken together, form 1,2-methylenedioxy or 1,2-ethylenedioxy;
- R2 is aliphatic, wherein each R2 optionally comprises up to 2 substituents independently selected from R1, R4, or R5;
- R3 is a cycloaliphatic, aryl, heterocyclic, or heteroaryl ring optionally comprising up to 3 substituents, independently selected from R1, R2, R4 or R5;
- R4 is OR5, OR6, OC(O)R6, OC(O)R5, OC(O)OR6, OC(O)OR5, OC(O)N(R6)2, OC(O)N(R5)2, OC(O)N(R6R5), SO2N(R6)2, SO2N(R5)2, SO2NR5R6, C(O)R5, C(O)OR5, C(O)R6, C(O)OR6, C(O)N(R6)2, C(O)N(R5)2, C(O)N(R5R6), C(O)N(OR6)R6, C(O)N(OR5)R6, C(O)N(OR6)R5, C(O)N(OR5)R5, C(NOR6)R6, C(NOR6)R5, C(NOR5)R6, C(NOR5)R5, N(R6)2, N(R5)2, N(R5R6), NR5C(O)R5, NR6C(O)R6, NR6C(O)R5, NR5C(O)R6, NR6C(O)OR6, NR5C(O)OR6, NR6C(O)OR5, NR5C(O)OR5, NR6C(O)N(R6)2, NR6C(O)NR5R6, NR6C(O)N(R5)2, NR5C(O)N(R6)2, NR5C(O)NR5R6, NR5C(O)N(R5)2, NR6SO2R6, NR6SO2R5, NR5SO2R6, NR5SO2R5, NR6SO2N(R6)2, NR6SO2NR5R6, NR6SO2N(R5)2, NR5SO2NR5R6, NR5SO2N(R5)2, N(OR6)R6, N(OR6)R5, N(OR5)R5, or N(OR5)R6;
- R5 is a cycloaliphatic, aryl, heterocyclic, or heteroaryl ring, optionally comprising up to 3 R1 substituents;
- R6 is H or aliphatic, wherein R6 optionally comprises a R7 substituent;
- R7 is a cycloaliphatic, aryl, heterocyclic, or heteroaryl ring, and each R7 optionally comprises up to 2 substituents independently chosen from H, (C1-C6)-straight or branched alkyl, (C2-6) straight or branched alkenyl or alkynyl, 1,2-methylenedioxy, 1,2-ethylenedioxy, or (CH2)n—Z;
- Z is selected from halo, CN, NO2, CF3, OCF3, OH, S-aliphatic, S(O)-aliphatic, SO2-aliphatic, NH2, NH-aliphatic, N(aliphatic)2, N(aliphatic)R8, NHR8, COOH, C(O)O(-aliphatic), or O-aliphatic;
- and
- R8 is an amino protecting group.
24 more elements
Dependencies are inferred from the claim text.