# US 10,370,366 B2 · Pyridazinone compounds and methods for the treatment of cystic fibrosis

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- Number: US 10,370,366 B2
- Document ID: US10370366B2
- Status: Granted
- Kind: B2
- Application number: 15/726,813
- Filed: 2017-10-06
- Published: 2018-04-05
- Granted: 2019-08-06
- Earliest claimed: 2013-03-13
- Assignees: Flatley Discovery Lab, LLC
- Applicants: Flatley Discovery Lab, LLC
- Inventors: Bridget M. Cole; Richard A. Nugent; Andrew Kolodziej; Karen Handley; Yevgen Barsukov
- Web page: https://patentgrep.com/patent/US10370366B2

## CPC

- C07D 413/12: linked by a chain containing hetero atoms as chain links
- A61K 31/38: having sulfur as a ring hetero atom
- A61K 31/4245: Oxadiazoles
- A61K 31/443: containing a five-membered ring with oxygen as a ring hetero atom
- A61K 31/47: Quinolines; Isoquinolines
- A61K 31/502: ortho- or peri-condensed with carbocyclic ring systems, e.g. cinnoline, phthalazine
- A61K 31/5025: ortho- or peri-condensed with heterocyclic ring systems
- A61K 31/506: not condensed and containing further heterocyclic rings
- A61K 31/519: ortho- or peri-condensed with heterocyclic rings
- A61K 31/5377: not condensed and containing further heterocyclic rings, e.g. timolol
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- 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 5/14: of the thyroid hormones, e.g. T3, T4
- A61P 5/18: of the parathyroid hormones
- A61P 7/02: Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
- A61P 11/00: Drugs for disorders of the respiratory system
- A61P 13/02: of urine or of the urinary tract, e.g. urine acidifiers
- 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 25/16: 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 37/00: Drugs for immunological or allergic disorders
- C07D 237/32: with oxygen atoms directly attached to carbon atoms of the nitrogen-containing ring
- C07D 401/04: directly linked by a ring-member-to-ring-member bond
- C07D 401/06: linked by a carbon chain containing only aliphatic carbon atoms
- C07D 401/12: linked by a chain containing hetero atoms as chain links
- C07D 401/14: containing three or more hetero rings
- C07D 403/04: directly linked by a ring-member-to-ring-member bond
- C07D 405/04: directly linked by a ring-member-to-ring-member bond
- C07D 405/12: linked by a chain containing hetero atoms as chain links
- C07D 405/14: containing three or more hetero rings
- C07D 413/14: containing three or more hetero rings
- C07D 417/14: containing three or more hetero rings
- C07D 487/04: Ortho-condensed systems
- C07D 495/14: Ortho-condensed systems
- C07D 498/04: Ortho-condensed systems
- C07D 519/00: Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
- 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

## Abstract

The invention relates to a compound of having the following formulae and methods of treating cystic fibrosis:

## Claims

### Claim 1

A compound of Formula II:
or a pharmaceutically acceptable salt thereof;
Wherein represents a single or double bond;
m is 0, 1, 2, 3 or 4;
d is 0, 1 or 2;
X10 is CH, CH2, S or O;
Cy1 is absent, an aryl, substituted aryl, carbocycle, substituted carbocycle, heterocyclyl, substituted heterocyclyl, heteroaryl, or substituted heteroaryl group having one, two or three rings;
Cy2 is an aryl, substituted aryl, carbocycle, substituted carbocycle, heterocyclyl, substituted heterocyclyl, heteroaryl, or substituted heteroaryl group having one, two or three rings;
A1 is absent, —[C(R100)(R101)]n—, —C(O)—, —C(S), —S(O)—, —C(O)N(R100)—, —S(O)2N(R100)—, —S(O)2—, —[C(R25)(R26)]n-, —[C(R25)(R26)]n-C═C—[C(R27)(R28)]p, or —[C(R25)(R26)]n-C≡C—[C(R27)(R28)]p, carbocycle, substituted carbocycle, heterocycle, substituted heterocycle, aromatic, substituted aromatic, heteroaromatic or substituted heteroaromatic; wherein n is 0, 1, 2, 3, 4, 5, 6 or 7;
wherein each R100 and R101 is hydrogen, deuterium, halogen, alkyl, substituted alkyl, heteroalkyl, substituted heteroalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aliphatic, substituted aliphatic, aryl and substituted aryl, —OR200, —SR200, —C(O)R200, —C(O)N(R200)2, —NC(O)R200, —S(O)2R200 wherein R200 is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl; alternatively two of R100 and R101 groups together with the atoms to which they are attached and any intervening atoms may form an additional optionally substituted, 3, 4, 5, 6 or 7 membered ring;
A2 is absent or —[C(R100)(R101)]n-, —C(O)—, —C(S)—, —S(O)—, —C(O)N(R100)—, —C(O)N(R100)(R101), N(R100)(R101), —S(O)2—, —S(O)2R100, —S(O)2N(R100)(R101),—[C(R25)(R26)]n-, —[C(R25)(R26)]n-C═C—[C(R27)(R28)]p, or —[C(R25)(R26)]n-C≡C—[C(R27)(R28)]p;
A3 is absent or —[C(R100)(R101)]n-, —C(O)—, —C(S)—, —S(O)—, —C(O)N(R100)—, —C(O)N(R100)(R101), N(R100)(R101), —S(O)2—, S(O)2R100, S(O)R100, S(O)2N(R100)(R101), —[C(R25)(R26)]n-, —[C(R25)(R26)]n-C═C—[C(R27)(R28)]p, or —[C(R25)(R26)]n-C≡C—[C(R27)(R28)]p;
A4 is absent or —[C(R25)(R26)]n-, —[C(R25)(R26)]n-C═C—[C(R27)(R28)]p, or —[C(R25)(R26)]n-C≡C—[C(R27)(R28)]p;
wherein each R25, R26, R27 and R28 is independently selected hydrogen, deuterium, halogen, alkyl, substituted alkyl, heteroalkyl, substituted heteroalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aliphatic, substituted aliphatic, aryl, substituted aryl, —OR100, —SR100, —NR100R101, —C(O)R100, —C(O)OR100, —C(O)NR100R101, —N(R100)C(O)R101, —S(O)2R100, —S(O)R100, —SR100, —S(O)2N(R100)R101, —CF3, —CN, —NO2, and —N3; alternatively two of R25, R26, R27 and R28 groups together with the atoms to which they are attached and any intervening atoms may form an additional optionally substituted, 3, 4, 5, 6 or 7 membered ring;
p is 0, 1, 2, 3, 4, 5, 6, or 7;
R2 is independently selected from hydrogen, deuterium, halogen, alkyl, substituted alkyl, cycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aliphatic, substituted aliphatic, aryl, substituted aryl, heterocyclyl, substituted heterocyclyl, heteroaryl, or substituted heteroaryl —OR100, —SR100, —NR100R101, —C(O)R100, —C(O)OR100, —C(O)NR100R101, —N(R100)C(O)R101, —S(O)2R100, —S(O)R100, —SR100, —S(O)2N(R100)R101, —CF3, —CN, —NO2, —N3;
alternatively two R2 together with the atoms to which they are attached may form an optionally substituted 3, 4, 5, 6 or 7 membered ring; and,
each R3 and R4 is independently selected from hydrogen, deuterium, halogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aliphatic, substituted aliphatic, aryl, substituted aryl, heterocyclyl, substituted heterocyclyl, heteroaryl, substituted heteroaryl, or —OR100, —SR100, —NR100R101, —C(O)R100, —C(O)OR100, —C(O)NR100R101, —N(R100)C(O)R101, —S(O)2R100, —S(O)R100, —SR100, —S(O)2N(R100)R101, —CF3, —CN, —NO2, —N3.

### Claim 2 (depends on 1)

The compound of claim 1, wherein Cy2 is selected from the group consisting of:
wherein q is 0, 1, 2, 3, 4 or 5;
each R102 is independently hydrogen, deuterium, halogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aliphatic, substituted aliphatic, carbocycle, substituted carbocycle, aryl, substituted aryl, —OR100, —SR100, —NR100R101, —C(O)R100, —C(O)OR100, —C(O)NR100R101, —N(R100)C(O)R101, —S(O)2R100, —S(O)R100, —SR100, —S(O)2N(R100)R101, —CF3, —CN, —NO2, —N3; alternatively two of R102 groups together with the atoms to which they are attached and any intervening atoms may form an additional optionally substituted 3, 4, 5, 6 or 7 membered ring.

### Claim 3 (depends on 1)

The compound of claim 1, wherein Cy1 is selected from the group consisting of:
wherein;
q is 0, 1, 2, 3, or 4;
each R102 is hydrogen, deuterium, halogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aliphatic, substituted aliphatic, carbocycle, substituted carbocycle, aryl, substituted aryl, —OR100, —SR100, —NR100R101, —C(O)R100, —C(O)OR100, —C(O)NR100R101, —N(R100)C(O)R101, —S(O)2R100, —S(O)R100, —SR100, —S(O)2N(R100)R101, —CF3, —CN, —NO2, —N3; alternatively two R102 groups together with the atoms to which they are attached and any intervening atoms form an additional optionally substituted 3, 4, 5, 6 or 7 membered ring; and
R103 is hydrogen, deuterium, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aliphatic, substituted aliphatic, aryl and substituted aryl.

### Claim 4 (depends on 1)

The compound of claim 1, wherein Cy1 is selected from the group consisting of:

### Claim 5 (depends on 1)

The compound of claim 1, wherein represents a double bond and d is 0.

### Claim 6 (depends on 1)

The compound of claim 1 represented by Formula IIA,
or a pharmaceutically acceptable salt thereof, wherein
t is 0, 1, 2 or 3;
R120 is selected from hydrogen, deuterium, halogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aliphatic, substituted aliphatic, aryl, substituted aryl, heterocyclyl, substituted heterocyclyl, heteroaryl, substituted heteroaryl, or —OR100, —SR100, —NR100R101, —C(O)R100, —C(O)OR100, —C(O)NR100R101, —N(R100)C(O)R101, —S(O)2R100, —S(O)R100, —SR100, —S(O)2N(R100)R101, —CF3, —CN, —NO2, —N3; and
each R121 is independently selected from hydrogen, deuterium, halogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aliphatic, substituted aliphatic, aryl, substituted aryl, heterocyclyl, substituted heterocyclyl, heteroaryl, substituted heteroaryl, —OR100, —SR100, —NR100R101, —C(O)R100, —C(O)OR100, —C(O)NR100R101, —N(R100)C(O)R101, —S(O)2R100, —S(O)R100, —SR100, —S(O)2N(R100)R101, —CF3, —CN, —NO2, and —N3.

### Claim 7 (depends on 1)

The compound of claim 1, wherein A1 is C(R100)(R101) and A2 is —C(O)N(R100)—.

### Claim 8 (depends on 6)

The compound of claim 6, wherein A4 is absent.

### Claim 9 (depends on 1)

The compound of claim 1, wherein A3 is absent, —[C(R100)(R101)]n—, —C(O)—, or —C(O)N(R100)—.

### Claim 10 (depends on 9)

The compound of claim 9, wherein A3 is absent.

### Claim 11 (depends on 1)

A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier or excipient.