Heteroaryl derivatives as CFTR modulators

• US 9,751,890 B2
• Filed: 10/19/2016
• Issued: 09/05/2017
• Est. Priority Date: 02/28/2008
• Status: Active Grant

• Current Assignee: Vertex Pharmaceuticals Incorporated
• Original Assignee: Vertex Pharmaceuticals Incorporated
• Inventors: Hadida Ruah, Sara, Miller, Mark, Zhou, Jinglan, Bear, Brian
• Primary Examiner(s): RAO, DEEPAK R
• Application Number:
  US15/297,983
• Publication Number:
  US 20170107225A1
• Time in Patent Office: 321 Days
• Field of Search: 544238, 51425201
• CPC Class Codes: A61K 31/443 containing a five-membered ring with oxygen as a ring hetero atom
• CPC Class Codes: A61K 31/497 containing further heterocyclic rings
• CPC Class Codes: A61K 31/501 not condensed and containing further heterocyclic rings
• CPC Class Codes: A61K 31/506 not condensed and containing further heterocyclic rings
• CPC Class Codes: A61K 31/513 having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
• CPC Class Codes: A61K 31/519 ortho- or peri-condensed with heterocyclic rings
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 1/02 Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
• 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 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 19/00 Drugs for skeletal disorders
• CPC Class Codes: A61P 19/08 for bone diseases, e.g. rachitism, Paget's disease
• CPC Class Codes: A61P 21/00 Drugs for disorders of the muscular or neuromuscular system
• CPC Class Codes: A61P 21/04 for myasthenia gravis
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/14 for treating abnormal movements, e.g. chorea, dyskinesia
• CPC Class Codes: A61P 25/16 Anti-Parkinson drugs
• 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 27/04 : Artificial tears; Irrigation solutions
• CPC Class Codes: A61P 29/00 : Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• 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 31/00 : Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 35/00 : Antineoplastic agents
• CPC Class Codes: A61P 37/06 : Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 5/00 : Drugs for disorders of the endocrine system
• CPC Class Codes: A61P 5/02 : of the hypothalamic hormones, e.g. TRH, GnRH, CRH, GRH, somatostatin
• CPC Class Codes: A61P 5/14 : of the thyroid hormones, e.g. T3, T4
• CPC Class Codes: A61P 5/16 : for decreasing, blocking or antagonising the activity of the thyroid hormones
• CPC Class Codes: A61P 7/00 : Drugs for disorders of the blood or the extracellular fluid
• CPC Class Codes: A61P 7/02 : Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
• CPC Class Codes: A61P 7/04 : Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
• CPC Class Codes: A61P 7/10 : Antioedematous agents; Diuretics
• CPC Class Codes: A61P 7/12 : Antidiuretics, e.g. drugs for diabetes insipidus ADH A61P5/10
• CPC Class Codes: A61P 9/00 : Drugs for disorders of the cardiovascular system
• CPC Class Codes: C07D 213/75 : Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
• CPC Class Codes: C07D 239/42 : One nitrogen atom nitro radicals C07D239/30
• CPC Class Codes: C07D 241/20 : Nitrogen atoms nitro radicals C07D241/16
• CPC Class Codes: C07D 405/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 405/14 : containing three or more hetero rings
• CPC Class Codes: C07D 491/048 : the oxygen-containing ring being five-membered
• CPC Class Codes: G01N 2333/705 : Assays involving receptors, cell surface antigens or cell surface determinants
• CPC Class Codes: G01N 2333/914 : Hydrolases (3)
• CPC Class Codes: G01N 2500/10 : involving cells
• CPC Class Codes: G01N 2570/00 : Omics, e.g. proteomics, glycomics or lipidomics; Methods of analysis focusing on the entire complement of classes of biological molecules or subsets thereof, i.e. focusing on proteomes, glycomes or lipidomes
• CPC Class Codes: G01N 33/5008 : for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics
• CPC Class Codes: G01N 33/6872 : Intracellular protein regulatory factors and their receptors, e.g. including ion channels

Abstract

The present invention relates to modulators of ATP-Binding Cassette (“ABC”) transporters or fragments thereof, including Cystic Fibrosis Transmembrane Conductance Regulator (“CFTC”), compositions thereof, and methods therewith. The present invention also relates to methods of treating ABC transporter mediated diseases using such modulators.

Claims

1. A compound of formula I:

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein A is

3. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein A is

4. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein J is CH₂.

5. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein J is CF₂.

6. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R^N is H.

7. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein W is —

CH₂—

, —

NH—

, —

O—

, or —

SO₂—

.

8. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R^w is H, OH, —

CH₂OH, methoxy, or trifluoromethoxy.

9. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R^w is aryl, heteroaryl, or heterocycloalkyl.

10. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R^w is alkoxy.

11. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R^w is cyclohexyl, phenyl, pyridyl, or pyridone.

12. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R^w is an unsaturated heterocycloalkyl.

13. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R^w is —

(C1-C6)alkylidene-N(R)₂ or —

(C1-C6)alkylidene-OH.

14. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein Ar¹ is substituted with at least one —

W—

R^w selected from;

—

CH₃, —

OMe,

16. A pharmaceutical composition comprising

(i) a compound of claim 1, or a pharmaceutically acceptable salt thereof;

and

(ii) a pharmaceutically acceptable carrier.

17. The composition of claim 16, further comprising an additional agent selected from a mucolytic agent, bronchodialator, an anti-biotic, an anti-infective agent, an anti-inflammatory agent, CFTR corrector, and a nutritional agent.

15. A compound selected from