# US 10,307,414 B2 · Pyridinyl and fused pyridinyl triazolone derivatives

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- Number: US 10,307,414 B2
- Document ID: US10307414B2
- Status: Granted
- Kind: B2
- Application number: 15/717,624
- Filed: 2017-09-27
- Published: 2018-01-18
- Granted: 2019-06-04
- Earliest claimed: 2013-03-11
- Assignees: Takeda Pharmaceutical Company Limited
- Applicants: Takeda Pharmaceutical Company Limited
- Inventors: John David Lawson; Mark Sabat; Nicholas Scorah; Christopher Smith; Phong H. Vu; Haixia Wang
- Web page: https://patentgrep.com/patent/US10307414B2

## CPC

- A61K 31/4725: containing further heterocyclic rings
- A61K 31/4375: the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
- A61K 31/4439: containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole (nicotine A61K31/465)
- A61K 31/519: ortho- or peri-condensed with heterocyclic rings
- A61P 35/02: specific for leukemia
- C07D 401/04: directly linked by a ring-member-to-ring-member bond
- C07D 401/14: containing three or more hetero rings
- C07D 403/14: containing three or more hetero rings
- C07D 471/04: Ortho-condensed systems
- 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
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## Abstract

Disclosed are compounds of Formula 1, or pharmaceutically acceptable salts thereof, wherein R1, R2, R3, and R4 are defined in the specification. This disclosure also relates to materials and methods for preparing compounds of Formula 1, to pharmaceutical compositions which contain them, and to their use for treating Type I hypersensitivity reactions, autoimmune diseases, inflammatory disorders, cancer, non-malignant proliferative disorders, and other conditions associated with BTK.

## Claims

### Claim 1

A method for inhibiting BTK in a subject, the method comprising administering to the subject a compound of Formula 1,
a tautomer thereof or a pharmaceutically acceptable salt of the compound or tautomer, wherein:
R1 is selected from hydrogen, halo, and C1-4 alkyl;
R2 and R3 are each independently selected from hydrogen, halo, and C1-6 alkyl, or R2 and R3, together with carbon atoms to which they are attached, form a benzene ring or a pyridine ring in which the benzene ring is optionally substituted with from one to four substituents independently selected from halo, —CN, —OR8, and C1-6 alkyl, and the pyridine ring is optionally substituted with from one to three substituents independently selected from halo, —CN, —OR8, and C1-6 alkyl;
R4 has the formula
in which indicates a point of attachment;
L is selected from —O—, —CH2O—, and —N(R4e)—;
R4a is selected from —CH2R5 and ethenyl optionally substituted with from one to three substituents independently selected from halo, cyano, and C1-6 alkyl optionally substituted with —N(R11)R12; and
(a) R4c is hydrogen, R4e is selected from hydrogen and C1-4 alkyl when L is —N(R4e)—, and R4b and R4d, together with a nitrogen atom and carbon atoms to which R4b, R4c, and R4d are respectively attached, form a pyrrolidine ring or a piperidine ring, each ring optionally substituted with from one to six substituents independently selected from halo, C1-4 alkyl, and C1-4 haloalkyl; or
(b) R4b is selected from hydrogen and C1-4 alkyl, R4d is hydrogen, L is —N(R4e)—, and R4c and R4e, together with the carbon atoms and a nitrogen atom to which R4c, R4d, and R4e are respectively attached, form a pyrrolidine ring or a piperidine ring, each ring optionally substituted with from one to six substituents independently selected from halo, C1-4 alkyl, and C1-4 haloalkyl; or
(c) R4d is hydrogen, R4e, is selected from hydrogen and C1-4 alkyl when L is —N(R4e)—, and R4b and R4c, together with the nitrogen and carbon atoms to which R4b and R4c are respectively attached, form pyrrolidine ring or a piperidine ring, each ring optionally substituted with from one to six substituents independently selected from halo, C1-4 alkyl, and C1-4 haloalkyl;
R5 is selected from hydrogen, halo, and C1-4 alkyl;
each R8 is independently selected from hydrogen and C1-6 alkyl; and
each R11 and R12 is independently selected from hydrogen and
C1-6 alkyl.

### Claim 2 (depends on 1)

The method according to claim 1, wherein the compound is (S)-3-(1-((1-acryloylpyrrolidin-3-yl)oxy)isoquinolin-3-yl)-1H-1,2,4-triazol-5(4H)-one, a tautomer thereof, or a pharmaceutically acceptable salt of the compound or tautomer.

### Claim 3 (depends on 1)

The method according to claim 1, wherein the compound is (S)-3-(1((1-acryloylpyrrolidin-3-yl)amino)isoquinolin-3-yl)-1H-1,2,4-triazol-5(4H)-one, a tautomer thereof, or a pharmaceutically acceptable salt of the compound or tautomer.

### Claim 4 (depends on 1)

The method according to claim 1, wherein the compound is (S)-3-(8-((1-acryloylpyrrolidin-3-yl)oxy)-1,7-naphthyridin-6-yl)-1H-1,2,4-triazol-5(4H)-one, a tautomer thereof, or a pharmaceutically acceptable salt of the compound or tautomer.

### Claim 5 (depends on 1)

The method according to claim 1, wherein the compound is (S)-3-(8-((1-acryloylpyrrolidin-3-yl)amino)-1,7-naphthyridin-6-yl)-1H-1,2,4 -triazol-5(4H)-one, a tautomer thereof, or a pharmaceutically acceptable salt of the compound or tautomer.

### Claim 6 (depends on 1)

The method according to claim 1, wherein the compound is (S)-3-(1-((1-acryloylpyrrolidin-3-yl)oxy)-8-fluoroisoquinolin-3-yl)-1H-1,2,4-triazol-5(4H)-one, a tautomer thereof, or a pharmaceutically acceptable salt of the compound or tautomer.

### Claim 7 (depends on 1)

The method according to claim 1, wherein the compound is (S)-3-(1-((1-acryloylpyrrolidin-3-yl)amino)-8-fluoroisoquinolin-3-yl)-1H-1,2,4-triazol-5(4H)-one, a tautomer thereof, or a pharmaceutically acceptable salt of the compound or tautomer.

### Claim 8 (depends on 1)

The method according to claim 1, wherein the compound is (S)-3-(1-((1-acryloylpyrrolidin-3-yl)oxy)-7-chloroisoquinolin-3-yl)-1H-1,2,4-triazol-5(4H)-one, a tautomer thereof, or a pharmaceutically acceptable salt of the compound or tautomer.

### Claim 9 (depends on 1)

The method according to claim 1, wherein the compound is (S)-3-(1-((1-acryloylpyrrolidin-3-yl)amino)-7-chloroisoquinolin-3-yl)-1H-1,2,4-triazol-5(4H)-one, a tautomer thereof, or a pharmaceutically acceptable salt of the compound or tautomer.

### Claim 10 (depends on 1)

The method according to claim 1, wherein the compound is (S)-3-(1-((1-acryloylpyrrolidin-3-yl)oxy)-8-chloroisoquinolin-3-yl)-1H-1,2,4-triazol-5(4H)-one, a tautomer thereof, or a pharmaceutically acceptable salt of the compound or tautomer.

### Claim 11 (depends on 1)

The method according to claim 1, wherein the compound is (S)-3-(1-((1-acryloylpyrrolidin-3-yl)amino)-8-chloroisoquinolin-3-yl)-1H-1,2,4-triazol-5(4H)-one, a tautomer thereof, or a pharmaceutically acceptable salt of the compound or tautomer.