# US 9,751,890 B2 · Heteroaryl derivatives as CFTR modulators

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- Number: US 9,751,890 B2
- Document ID: US9751890B2
- Status: Granted
- Kind: B2
- Application number: 15/297,983
- Filed: 2016-10-19
- Published: 2017-04-20
- Granted: 2017-09-05
- Earliest claimed: 2008-02-28
- Assignees: Vertex Pharmaceuticals Incorporated
- Applicants: Vertex Pharmaceuticals Incorporated
- Inventors: Sara Hadida Ruah; Mark Miller; Jinglan Zhou; Brian Bear
- Web page: https://patentgrep.com/patent/US9751890B2

## CPC

- C07D 491/048: the oxygen-containing ring being five-membered
- A61K 31/443: containing a five-membered ring with oxygen as a ring hetero atom
- A61K 31/497: containing further heterocyclic rings
- A61K 31/501: not condensed and containing further heterocyclic rings
- A61K 31/506: not condensed and containing further heterocyclic rings
- A61K 31/513: having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
- A61K 31/519: ortho- or peri-condensed with heterocyclic rings
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 1/02: Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
- A61P 3/00: Drugs for disorders of the metabolism (of the blood or the extracellular fluid A61P7/00)
- A61P 3/06: Antihyperlipidemics
- A61P 3/10: for hyperglycaemia, e.g. antidiabetics
- A61P 5/00: Drugs for disorders of the endocrine system
- A61P 5/02: of the hypothalamic hormones, e.g. TRH, GnRH, CRH, GRH, somatostatin
- A61P 5/14: of the thyroid hormones, e.g. T3, T4
- A61P 5/16: for decreasing, blocking or antagonising the activity of the thyroid hormones
- A61P 7/00: Drugs for disorders of the blood or the extracellular fluid
- A61P 7/02: Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
- A61P 7/04: Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
- A61P 7/10: Antioedematous agents; Diuretics
- A61P 7/12: Antidiuretics, e.g. drugs for diabetes insipidus (ADH A61P5/10)
- A61P 9/00: Drugs for disorders of the cardiovascular system
- A61P 11/00: Drugs for disorders of the respiratory system
- A61P 13/12: of the kidneys
- A61P 17/00: Drugs for dermatological disorders
- A61P 19/00: Drugs for skeletal disorders
- A61P 19/08: for bone diseases, e.g. rachitism, Paget's disease
- A61P 21/00: Drugs for disorders of the muscular or neuromuscular system
- A61P 21/04: for myasthenia gravis
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 25/14: for treating abnormal movements, e.g. chorea, dyskinesia
- A61P 25/16: Anti-Parkinson drugs
- 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
- A61P 27/02: Ophthalmic agents
- A61P 27/04: Artificial tears; Irrigation solutions
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 31/00: Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P 35/00: Antineoplastic agents
- A61P 37/06: Immunosuppressants, e.g. drugs for graft rejection
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D 213/75: Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
- C07D 239/42: One nitrogen atom (nitro radicals C07D239/30)
- C07D 241/20: Nitrogen atoms (nitro radicals C07D241/16)
- C07D 405/12: linked by a chain containing hetero atoms as chain links
- C07D 405/14: containing three or more hetero rings
- G01N 33/5008: {for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics}
- G01N 33/6872: {Intracellular protein regulatory factors and their receptors, e.g. including ion channels}
- G01N 2333/705: Assays involving receptors, cell surface antigens or cell surface determinants
- G01N 2333/914: Hydrolases (3)
- G01N 2500/10: involving cells
- 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
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- G01N: INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES (measuring or testing apparatus or processes other than immunoassay, involving enzymes or microorganisms C12M, C12Q)

## 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

### Claim 1

A compound of formula I:
or a pharmaceutically acceptable salt thereof, wherein:
Ar1 is
Ar1 is optionally substituted with w occurrences of —W—RW; wherein
each W is independently an optionally substituted (C1-C6) alkylidene chain wherein up to two methylene units of W are independently replaced by —CO—, —O—, —S—, —SO2—, or —NR′—;
each R′ is independently H, alkyl, aryl, heteroaryl, aralkyl, cycloalkyl, or heterocycloalkyl; and
each RW is independently H, halo, CN, NO2, NH2, CF3, OCF3, OH, alkoxy, or an optionally substituted aliphatic, cycloaliphatic, heterocyclic, aryl, or heteroaryl, wherein, when substituted, Rw is substituted with up to two R2;
each R2 is halo, CN, NO2, CF3, OCF3, OR, —(C1-C6)alkylidene-OH, —(C1-C6)alkylidene-N(R)2, OC(O)R, OC(O)N(R)2, SR, S(O)R, SO2R, SO2N(R)2, SO3R, C(O)R, CO2R, C(O)N(R)2, N(R)2, NRC(O)R, NRCO2R, NRC(O)N(R)2, NRSO2R, B(OR)2, or NRSO2N(R)2;
each R is independently H, alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl;
RN is H, alkyl, aryl, heteroaryl, aralkyl, cycloalkyl, or heterocycloalkyl,
A is an optionally substituted 3-7 membered monocyclic ring;
B is optionally fused to a 5-7 membered ring selected from cycloaliphatic, aryl, heterocyclic, and heteroaryl;
J is selected from CH2, CF2, C(CH3)2, C(O),
C(Phenyl)2, B(OH), and CH(OEt); and
w is independently an integer from 0 to 5 inclusive.

### Claim 2 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein A is
wherein R3 is selected from alkyl, alkaryl, aryl, and heteroaryl; and q is an integer from 0 to 4 inclusive.

### Claim 3 (depends on 1)

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

### Claim 4 (depends on 1)

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

### Claim 5 (depends on 1)

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

### Claim 6 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein RN is H.

### Claim 7 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein W is —CH2—, —NH—, —O—, or —SO2—.

### Claim 8 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein Rw is H, OH, —CH2OH, methoxy, or trifluoromethoxy.

### Claim 9 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein Rw is aryl, heteroaryl, or heterocycloalkyl.

### Claim 10 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein Rw is alkoxy.

### Claim 11 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein Rw is cyclohexyl, phenyl, pyridyl, or pyridone.

### Claim 12 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein Rw is an unsaturated heterocycloalkyl.

### Claim 13 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein Rw is —(C1-C6)alkylidene-N(R)2 or —(C1-C6)alkylidene-OH.

### Claim 14 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein Ar1 is substituted with at least one —W—Rw selected from:
—CH3, —OMe,

### Claim 15

A compound selected from
or a pharmaceutically acceptable salt thereof.

### Claim 16 (depends on 1)

A pharmaceutical composition comprising
(i) a compound of claim 1, or a pharmaceutically acceptable salt thereof; and
(ii) a pharmaceutically acceptable carrier.

### Claim 17 (depends on 16)

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.