Modulators of ATP-binding cassette transporters

• US 9,550,761 B2
• Filed: 08/21/2013
• Issued: 01/24/2017
• Est. Priority Date: 01/30/2004
• Status: Active Grant

• Current Assignee: Vertex Pharmaceuticals Incorporated
• Original Assignee: Vertex Pharmaceuticals Incorporated
• Inventors: Hadida-Ruah, Sara Sabina, Grootenhuis, Peter Diederik Jan, Miller, Mark Thomas, Hamilton, Matthew
• Primary Examiner(s): Yoo, Sun Jae
• Application Number:
  US13/972,151
• Publication Number:
  US 20140080825A1
• Time in Patent Office: 1,252 Days
• US Class Current: 1/1
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 1/12 Antidiarrhoeals
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• CPC Class Codes: A61P 3/00 Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 3/06 Antihyperlipidemics
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: C07D 231/40 Acylated on said nitrogen atom
• CPC Class Codes: C07D 233/88 Nitrogen atoms, e.g. allantoin
• CPC Class Codes: C07D 263/48 Nitrogen atoms not forming part of a nitro radical
• CPC Class Codes: C07D 271/113 with oxygen, sulfur or nitrogen atoms, directly attached to ring carbon atoms, the nitrogen atoms not forming part of a nitro radical
• CPC Class Codes: C07D 277/46 by carboxylic acids, or sulfur or nitrogen analogues thereof
• CPC Class Codes: C07D 277/54 Nitrogen and either oxygen or sulfur atoms
• CPC Class Codes: C07D 277/82 Nitrogen atoms
• CPC Class Codes: C07D 285/135 Nitrogen atoms
• CPC Class Codes: C07D 405/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 407/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 409/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 409/14 : containing three or more hetero rings
• CPC Class Codes: C07D 413/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 417/04 : directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 417/06 : linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 417/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 417/14 : containing three or more hetero rings
• CPC Class Codes: C07D 493/10 : Spiro-condensed systems

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.

Claims

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

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 Ht₁ is a thiazolyl ring, wherein Ht is optionally substituted with up to three substituents.

5. The method of claim 1, wherein X₉ is CH₂.

6. The method of claim 1, wherein X₉ is CF₂.

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

CH₂—

.

8. The method of claim 1, wherein L is —

CH—

R^L, wherein R^L is —

OH, —

NHR^D, or NR^AAR^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_1-4aliphatic), 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_1-4alkyl), 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 substituents selected from oxo, (C_1-4 aliphatic), (C_1-4 aliphatic)-Y, wherein Y is halo, —

OH, or —

O(C_1-4 alkyl).

19. The method of claim 8, wherein R^D is selected from C_1-6 alkyl optionally substituted with —

OH or —

O(C_1-4alkyl).

20. The method of claim 8, wherein one of R^AA and R^BB is C1-C4 alkyl, and the other of R^AA and R^BB is selected from C1-C4 alkyl, C2-C4 alkenyl, C3-C6 cycloalkyl, (C3-C6 cycloalkyl)-C1-C4 alkyl, wherein said alkyl, alkenyl, or cycloalkenyl has up to 2 substituents selected from OH or —

O(C1-C4 alkyl).

21. The method of claim 8, wherein R^AA and R^BB, taken together with the nitrogen atom, forms a ring selected from pyrrolidinyl, piperidinyl, or morpholinyl, wherein said ring is optionally substituted with up to two substituents selected from hydroxy, C1-C4 alkyl, C2-C4 alkenyl, COOH, acetoxy, acetyl, hydroxymethyl, methoxymethyl, hydroxyethyl, methoxyethyl, allyl, ethylenedioxy, or C(O)NH₂.

22. The method of claim 8, wherein said compound has formula VB-3-i:

23. The method of claim 22, wherein R^AA and R^BB taken together is 3-acetoxy-pyrrolidin-1-yl, 2-methoxymethyl-pyrrolidin-1-yl, 2-hydroxymethyl-pyrrolidin-1-yl, (2-carboxypyrrolidin-1-yl), pyrrolidin-1-yl, 2-aminocarbonyl-pyrrolidin-1-yl, or 3-hydroxy-pyrrolidin-1-yl.

24. The method of claim 22, wherein R^AA is hydrogen, and R^BB is —

CH(C1-C6 alkyl)-CH₂OH.

25. The method of claim 24, wherein said alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, or isobutyl.

26. The method of claim 24, wherein said R^BB is (R)—

CH(C1-C6 alkyl)-CH₂OH or R^BB is (S)—

CH(C1-C6 alkyl)-CH₂OH.

27. The method of claim 1, wherein the compound selected from the following table:

28. The method of claim 1, wherein XR^X is hydrogen.

29. The method of claim 1, where

in ZR^Z is selected from halo, CF₃, OCF₃, C1-C4 alkoxy, methylenedioxy, or difluoromethylenedioxy.

30. The method of claim 1, wherein z is 1-3.

31. The method of claim 1, wherein the compound is