Pyridone derivatives having tetrahydropyranylmethyl groups

Patent metadata

Field	Value
Publication number	US-11208403-B2
Application number	US-201916575177-A
Country	US
Kind code	B2
Filing date	Sep 18, 2019
Priority date	Jul 7, 2014
Publication date	Dec 28, 2021
Grant date	Dec 28, 2021

Abstract

The present disclosure provides novel compounds or salts thereof, or crystals of the compounds or the salts, which inhibit Axl and are useful in the treatment of a disease caused by hyperfunction of Axl, the treatment of a disease associated with hyperfunction of Axl, and/or the treatment of a disease involving hyperfunction of Axl.The present disclosure provides pyridone derivatives having a tetrahydropyranylmethyl group represented by the following formula (I) having various substituents, or salts thereof, or crystals of the compounds or the salts, wherein R1, R2, R3, R4, R5, W, X, Y, and Z are each as defined in the specification:

First claim

The invention claimed is:

1. A method of inhibiting Axl in a cell, comprising contacting the cell with an effective amount of a compound of formula (I):

or a pharmaceutically acceptable salt thereof, or a solvate of the compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein
W, X, and Y are each independently C—H, C—F, or C—Cl,
Z is C—H, C—F, C—Cl, C-C 1 -C 6 alkyl group, or C-C 1 -C 6 alkoxy group,
R 1 is formula (II-1):

Q is C—H, or C—F,
T is C—H,
U is a nitrogen atom,
R 6 is a halogen atom, a C 1 -C 6 alkyl group, a C 3 -C 6 cycloalkyl group, a cyano group, or a trifluoromethoxy group,
R 2 is a hydrogen atom, a halogen atom, a C 1 -C 6 alkyl group, a C 1 -C 6 alkoxy group, or a cyano group,
R 3 is a hydrogen atom or a C 1 -C 6 alkyl group,
R 4 is a hydrogen atom, a halogen atom, or a C 1 -C 6 alkyl group,
R 5 is a group of formula (III-1)

R 8 and R 12 are each independently a hydrogen atom or a deuterium atom,
R 9 is a hydrogen atom, a halogen atom, or a C 1 -C 6 alkoxy group,
R 10 is 1,4-dioxan-2-ylmethoxy, and
R 11 is a hydrogen atom, a C 1 -C 6 alkoxy group, or a deuterium- substituted C 1 -C 6 alkoxy group.

2. The method of claim 1 , wherein the cell is a lung cancer cell or a non-small cell lung cancer cell.

3. A method of treating cancer in a patient in need thereof, comprising administering to the patient an effective amount of a compound of formula (I):

or a pharmaceutically acceptable salt thereof, or a solvate of the compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein
W, X, and Y are each independently C—H, C—F, or C—Cl,
Z is C—H, C—F, C—Cl, C-C 1 -C 6 alkyl group, or C-C 1 -C 6 alkoxy group,
R 1 is formula (II-1)

Q is C—H, or C—F,
T is C—H,
U is a nitrogen atom,
R 6 is a halogen atom, a C 1 -C 6 alkyl group, a C 3 -C 6 cycloalkyl group, a cyano group, or a trifluoromethoxy group,
R 2 is a hydrogen atom, a halogen atom, a C 1 -C 6 alkyl group, a C 1 -C 6 alkoxy group, or a cyano group,
R 3 is a hydrogen atom or a C 1 -C 6 alkyl group,
R 4 is a hydrogen atom, a halogen atom, or a C 1 -C 6 alkyl group,
R 5 is a group of formula (III-1)

R 8 and R 12 are each independently a hydrogen atom or a deuterium atom,
R 9 is a hydrogen atom, a halogen atom, or a C 1 -C 6 alkoxy group,
R 10 is 1,4-dioxan-2-ylmethoxy,
R 11 is a hydrogen atom, a C 1 -C 6 alkoxy group, or a deuterium- substituted C 1 -C 6 alkoxy group, and
the cancer is lung cancer.

4. The method of claim 3 , wherein the cancer is non-small cell lung cancer, lung cancer in which Axl is overexpressed, or lung cancer having an EGFR mutation.

5. A method of inhibiting tumor growth in a patient having a tumor in a lung, wherein the tumor overexpresses Axl, comprising administering to the patient an effective amount of a compound of formula (I):

or a pharmaceutically acceptable salt thereof, or a solvate of the compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein
W, X, and Y are each independently C—H, C—F, or C—Cl,
Z is C—H, C—F, C—Cl, C-C 1 -C 6 alkyl group, or C-C 1 -C 6 alkoxy group,
R 1 is formula (II-1)

Q is C—H, or C—F,
T is C—H,
U is a nitrogen atom,
R 6 is a halogen atom, a C 1 -C 6 alkyl group, a C 3 -C 6 cycloalkyl group, a cyano group, or a trifluoromethoxy group,
R 2 is a hydrogen atom, a halogen atom, a C 1 -C 6 alkyl group, a C 1 -C 6 alkoxy group, or a cyano group,
R 3 is a hydrogen atom or a C 1 -C 6 alkyl group,
R 4 is a hydrogen atom, a halogen atom, or a C 1 -C 6 alkyl group,
R 5 is a group of formula (III-1)

R 8 and R 12 are each independently a hydrogen atom or a deuterium atom,
R 9 is a hydrogen atom, a halogen atom, or a C 1 -C 6 alkoxy group,
R 10 is 1,4-dioxan-2-ylmethoxy, and
R 11 is a hydrogen atom, a C 1 -C 6 alkoxy group, or a deuterium- substituted C 1 -C 6 alkoxy group.

6. A method of inhibiting or overcoming resistance of a cancer to an epidermal growth factor tyrosine kinase inhibitor (EGFR- TKI) in a patient in need thereof, comprising administering to the patient an effective amount of a compound of formula (I):

or a pharmaceutically acceptable salt thereof, or a solvate of the compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein
W, X, and Y are each independently C—H, C—F, or C—Cl,
Z is C—H, C—F, C—Cl, C-C 1 -C 6 alkyl group, or C-C 1 -C 6 alkoxy group,
R 1 is formula (II-1)

Q is C—H, or C—F,
T is C—H,
U is a nitrogen atom,
R 6 is a halogen atom, a C 1 -C 6 alkyl group, a C 3 -C 6 cycloalkyl group, a cyano group, or a trifluoromethoxy group,
R 2 is a hydrogen atom, a halogen atom, a C 1 -C 6 alkyl group, a C 1 -C 6 alkoxy group, or a cyano group,
R 3 is a hydrogen atom or a C 1 -C 6 alkyl group,
R 4 is a hydrogen atom, a halogen atom, or a C 1 -C 6 alkyl group,
R 5 is a group of formula (III-1)

R 8 and R 12 are each independently a hydrogen atom or a deuterium atom,
R 9 is a hydrogen atom, a halogen atom, or a C 1 -C 6 alkoxy group,
R 10 is 1,4-dioxan-2-ylmethoxy,
R 11 is a hydrogen atom, a C 1 -C 6 alkoxy group, or a deuterium- substituted C 1 -C 6 alkoxy group, and
the cancer is lung cancer.

7. The method of claim 6 , wherein the compound of formula (I) is administered to a patient having non-small cell lung cancer, lung cancer in which Axl is overexpressed, or lung cancer having an EGFR mutation.

8. The method of claim 1 , wherein the compound is a solvate of N-[4-(2-amino-5-{4-[(2R)-1,4-dioxan-2-ylmethoxy]-3-methoxyphenyl}pyridin-3-yl)-3-fluorophenyl]-5-methyl-4′-oxo-1′-(tetrahydro-2H-pyran-4-ylmethyl)-1′,4′-dihydro-2,3′-bipyridine-5′-carboxamide represented by the following formula:

or a pharmaceutically acceptable salt thereof.

9. The method of claim 8 , wherein the compound is a hydrate of N-[4-(2-amino-5-{4-[(2R)-1,4-dioxan-2-ylmethoxy]-3-methoxyphenyl}pyridin-3-yl)-3-fluorophenyl]-5-methyl-4′-oxo-1′-(

Assignees

• Daiichi Sankyo Co Ltd

Inventors

• Haginoya Noriyasu
• Suzuki Takashi
• Hayakawa Miho
• Ota Masahiro
• Tsukada Tomoharu
• Kobayashi Katsuhiro
• Ando Yosuke
• Jimbo Takeshi
• Nakamura Koichi

Classifications

• C07D409/14 Primary

  containing three or more hetero rings · CPC title

• A61K31/444

  containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone · CPC title

• C07C309/04

  containing only one sulfo group · CPC title

• C07D405/14 Primary

  containing three or more hetero rings · CPC title

• A61P19/08

  for bone diseases, e.g. rachitism, Paget's disease · CPC title