Modulators of ATP-binding cassette transporters

Patent metadata

Field	Value
Publication number	US-9550761-B2
Application number	US-201313972151-A
Country	US
Kind code	B2
Filing date	Aug 21, 2013
Priority date	Jan 30, 2004
Publication date	Jan 24, 2017
Grant date	Jan 24, 2017

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.

First claim

The invention claimed is:

1. A method of treating dry-eye disease in a patient, comprising the step of administering to said patient a compound having formula IIIB:

wherein:
X 9 is CH 2 , CF 2 , CH 2 —CH 2 , or CF 2 —CF 2 ;
m is 0 to 4;
Ht 1 is a 5-membered heteroaromatic ring containing 1-4 heteroatoms selected from O, S, N, or NH;
x, q, and z is independently 0-5;
Q-R Q , X—R X and Z—R Z each is independently R′;
L is a bond, O, S, SO, SO 2 , C(O), NR′, C 1-4 aliphatic, or CHR L ;
R L is —OR′, —SR′, —SOR′, —SO 2 R′, or —N(R′) 2 ; or
L is

wherein ring A′ is a 3-7 membered monocyclic ring having 0-3 heteroatoms selected from O, S, N, or NH, wherein ring A′ is optionally substituted with q occurrences of -QR Q ;
Ar is phenyl or a six-membered heteroaromatic ring;
R′ is independently selected from hydrogen or an optionally substituted group selected from a C 1 -C 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; or
R′ is independently R 1 , R 2 , R 3 , R 4 , or R 5 ;
R 1 is oxo, R 6 or ((C1-C4)aliphatic) n - Y; or two R 1 on adjacent ring atoms, taken together, form 1,2-methylenedioxy, 1,2-difluoromethylenedioxy, 1,2-ethylenedioxy, or 1,2-tetrafluoroethylenedioxy;
n is 0 or 1;
Y is halo, CN, NO 2 , CF 3 , OCF 3 , OH, SR 6 , S(O)R 6 , SO 2 R 6 NH 2 , NHR 6 , N(R 6 ) 2 , NR 6 R 8 , COOH, COOR 6 or OR 6 ;
R 2 is aliphatic, wherein each R 2 optionally comprises up to 2 substituents independently selected from R 1 , R 4 , or R 5 ;
R 3 is a cycloaliphatic, aryl, heterocyclic, or heteroaryl ring optionally comprising up to 3 substituents, independently selected from R 1 , R 2 , R 4 or R 5 ;
R 4 is OR 5 , OR 6 , OC(O)R 6 , OC(O)R 5 , OC(O)OR 6 , OC(O)OR 5 , OC(O)N(R 6 ) 2 , OC(O)N(R 5 ) 2 , OC(O)N(R 6 R 5 ), SR 6 , SR 5 , S(O)R 6 , S(O)R 5 , SO 2 R 6 , SO 2 R 5 , SO 2 N(R 6 ) 2 , SO 2 N(R 5 ) 2 , SO 2 NR 5 R 6 , SO 3 R 6 , SO 3 R 5 , C(O)R 5 , C(O)OR 5 , C(O)R 6 , C(O)OR 6 , C(O)N(R 6 ) 2 , C(O)N(R 5 ) 2 , C(O)N(R 5 R 6 ), C(O)N(OR 6 )R 6 , C(O)N(OR 5 )R 6 , C(O)N(OR 6 )R 5 , C(O)N(OR 5 )R 5 , C(NOR 6 )R 6 , C(NOR 6 )R 5 , C(NOR 5 )R 6 , C(NOR 5 )R 5 , N(R 6 ) 2 , N(R 5 ) 2 , N(R 5 R 6 ), NR 5 C(O)R 5 , NR 6 C(O)R 6 , NR 6 C(O)R 5 , NR 5 C(O)R 6 , NR 6 C(O)OR 6 , NR 5 C(O)OR 6 , NR 6 C(O)OR 5 , NR 5 C(O)OR 5 , NR 6 C(O)N(R 6 ) 2 , NR 6 C(O)NR 5 R 6 , NR 6 C(O)N(R 5 ) 2 , NR 5 C(O)N(R 6 ) 2 , NR 5 C(O)NR 5 R 6 , NR 5 C(O)N(R 5 ) 2 , NR 6 SO 2 R 6 , NR 6 SO 2 R 5 , NR 5 SO 2 R 6 , NR 5 SO 2 R 5 , NR 6 SO 2 N(R 6 ) 2 , NR 6 SO 2 NR 5 R 6 , NR 6 SO 2 N(R 5 ) 2 , NR 5 SO 2 N(R 6 ) 2 , NR 5 SO 2 NR 5 R 6 , NR 5 SO 2 N(R 5 ) 2 , N(OR 6 )R 6 , N(OR 6 )R 5 , N(OR 5 )R 5 , or N(OR 5 )R 6 ;
R 5 is a cycloaliphatic, aryl, heterocyclic, or heteroaryl ring, optionally comprising up to 3 R 1 substituents;
R 6 is H or aliphatic, wherein R 6 optionally comprises a R 7 substituent;
R 7 is a cycloaliphatic, aryl, heterocyclic, or heteroaryl ring, and each R 7 optionally comprises up to 2 substituents independently chosen from H, (C1-C6)-straight or branched alkyl, (C 2 -C 6 ) straight or branched alkenyl or alkenyl, 1,2-methylenedioxy, 1,2-ethylenedioxy, or (CH 2 ) n —Z′;
Z′ is selected from halo, CN, NO 2 , CF 3 , OCF 3 , OH, S-aliphatic, S(O)-aliphatic, SO 2 -aliphatic, NH 2 , NH-aliphatic, N(aliphatic) 2 , N(aliphatic)R 8 , NHR 8 , COOH, C(O)O(-aliphatic), or O-aliphatic; and
R 8 is an amino protecting group.

2. The method of claim 1 , wherein two R′ in N(R′) 2 taken together with the nitrogen atom, form an optionally substituted 3-7 membered heterocyclic ring containing up to 4 heteroatoms selected from O, N, or S.

3. The method of claim 1 , wherein m is 0.

4. The method of claim 1 , wherein Ht 1 is a thiazolyl ring, wherein Ht is optionally substituted with up to three substituents.

5. The method of claim 1 , wherein X 9 is CH 2 .

6. The method of claim 1 , wherein X 9 is CF 2 .

7. The method of claim 1 , wherein L is —CH 2 —.

8. The method of claim 1 , wherein L is —CH—R L , wherein R L is —OH, —NHR D , or NR AA R BB ; wherein
each of R AA , R BB , and R D is independently hydrogen, C1-C6 aliphatic, C3-C7 cycloalkyl, (C3-C7-cycloalkyl)-C1-C6 aliphatic, (C3-C7-cycloalkenyl)-C1-C6-aliphatic, 3-7-membered heterocyclyl, (3-7-membered heterocyclyl)-C1-C6-aliphatic, 3-6 membered heteroaryl, (3-6-membered heteroaryl)-C1-C6 aliphatic, wherein said aliphatic, cycloalkyl, cycloalkenyl, heterocyclyl, or heteroaryl is optionally substituted with up to three substituents selected from OH, —O(C 1-4 aliphatic), or (C1-C4 aliphatic) p -Y; wherein
p is 0 or 1;
Y is OR or NHC(O)R;
R is hydrogen or C 1-4 aliphatic; or
R AA and R BB , taken together with the nitrogen atom, is a 3-7 membered heterocyclic ring containing up to 4 heteroatoms selected from O, wherein said ring is optionally substituted with up to 2 substituents selected from oxo or (C1-C4 aliphatic) p -Y; and
wherein up to two methylene groups in any said aliphatic above are optionally and independently replaced with O, C(O), or NH.

9. The method of claim 8 , wherein R D is hydrogen.

10. The method of claim 8 , wherein R D is optionally substituted C1-C6 aliphatic.

11. The method of claim 8 , wherein R D is selected from an optionally substituted C3-C6 cycloalkyl or cycloalkenyl ring, or (C3-C6 cycloalkyl or cycloalkenyl ring) -C1-C6 aliphatic.

12. The method of claim 8 , wherein R D is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenylethyl or cyclohexylmethyl.

13. The method of claim 8 , wherein R D is selected from optionally substituted 3-7 membered heterocyclyl or (3-7 membered heterocyclyl)-C1-C6 aliphatic, wherein said heterocyclyl contains up to 2 heteroatoms selected from O, S, or N.

14. The method of claim 8 , wherein R D is selected from (N-methyl-pyrrolidin-2-yl)-ethyl, pyrrolidin-1-yl-ethyl, tetrahydrofuran-2-yl-methyl, morpholin-4-yl-ethyl, or morpholin-4-yl-propyl.

15. The method of claim 8 , wherein R D is selected from optionally substituted 5-6 membered heteroaryl or (5-6-membered heteroaryl)-C1-C6 aliphatic, wherein said heteroaryl contains up to 2 heteroatoms selected from O, S, or N.

16. The method of claim 8 , wherein R D is selected from imidazolylpropyl, furanylmethyl, or pyridinylethyl.

17. The method of claim 8 , wherein R D is selected from C 1-4 alkyl optionally substituted with —OH, —O(C 1-4 alkyl), NH(C 1-4 alkyl), or N(C 1-4 alkyl) 2 .

18. The method of claim 8 , wherein R D is selected from C 1-4 alkyl optionally substituted with 5-6 membered heterocyclic ring containing up to 2 heteroatoms selected from O, N, or S, wherein said ring is optionally substituted with up to 2 substi

Assignees

• Vertex Pharma

Inventors

• Hadida-Ruah Sara Sabina
• Grootenhuis Peter Diederik Jan
• Miller Mark Thomas
• Hamilton Matthew

Classifications

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P3/06

  Antihyperlipidemics · CPC title

• A61P3/00

  Drugs for disorders of the metabolism (of the blood or the extracellular fluid A61P7/00) · CPC title