Pyrido[3, 4-d]pyrimidine derivative and pharmaceutically acceptable salt thereof

Patent metadata

Field	Value
Publication number	US-11084814-B2
Application number	US-201716463458-A
Country	US
Kind code	B2
Filing date	Nov 27, 2017
Priority date	Nov 28, 2016
Publication date	Aug 10, 2021
Grant date	Aug 10, 2021

Abstract

The purpose of the present invention is to provide a compound that has excellent CDK4/6 inhibitory activity. The present invention is a compound represented by formula (I) or a pharmaceutically acceptable salt of the compound.

First claim

The invention claimed is:

1. A compound represented by formula (I):

wherein in the formula,
R 1 represents C 3-12 cycloalkyl, C 4-12 cycloalkenyl, 4- to 12-membered heterocyclyl, C 6-10 aryl, or 5- to 10-membered heteroaryl, wherein each heteroatom-containing group represented by R 1 contains one to four heteroatoms independently selected from oxygen, sulfur, and nitrogen atoms,
R 1 is optionally substituted with one to six substituents selected from the group consisting of a halogen atom, ═O, —OH, —CN, —COOH, —COOR 6 , —R 7 , C 3-6 cycloalkyl substituted with [zero to two —OH groups, zero to two C 1-8 alkoxy groups, and zero to six fluorine atoms], 3- to 10-membered heterocyclyl substituted with [zero to two —OH groups, zero to two C 1-8 alkoxy groups, and zero to six fluorine atoms], C 1-8 acyl substituted with [zero to two —OH groups, zero to two C 1-8 alkoxy groups, and zero to six fluorine atoms], and C 1-8 alkoxy substituted with [zero to two —OH groups, zero to two C 1-8 alkoxy groups, and zero to six fluorine atoms];
R 6 and R 7 each independently represent C 1-6 alkyl substituted with [zero to two —OH groups, zero to two C 1-8 alkoxy groups, and zero to six fluorine atoms];
R 2 represents C 1-8 alkyl, C 3-8 cycloalkyl, 4- to 6-membered heterocyclyl, C 1-8 acyl, —COOR 8 , or —CONR 9 R 10 , wherein each of C 1-8 alkyl represented by R 2 is substituted independently with zero to one —OH group, zero to two C 1-8 alkoxy groups substituted with [zero to one —OH group, zero to one C 1-4 alkoxy group, and zero to three fluorine atoms], and zero to five fluorine atoms; each of C 3-8 cycloalkyl represented by R 2 is independently substituted with zero to one —OH group, zero to two C 1-8 alkoxy groups substituted with [zero to one —OH group, zero to one C 1-4 alkoxy group, and zero to three fluorine atoms], zero to one hydroxymethyl group, and zero to five fluorine atoms; provided that R 2 is neither an unsubstituted C 1-8 alkyl, nor an unsubstituted C 3-8 cycloalkyl, nor trifluoromethyl group;
each of R 8 , R 9 , and R 10 independently represents a hydrogen atom or C 1-8 alkyl;
each 4- to 6-membered heterocyclyl represented by R 2 is optionally substituted with one to four substituents selected from the group consisting of a fluorine atom, —OH group, C 1-4 alkyl groups, and C 1-4 alkoxy groups;
each of C 1-8 acyl group, —COOR 8 , and —CONR 9 R 10 represented by R 2 is optionally substituted independently with one to four substituents selected from the group consisting of a fluorine atom, —OH group, and C 1-4 alkoxy groups;
R 9 and R 10 of —CONR 9 R 10 represented by R 2 are optionally bonded via a single bond or —O— to form a ring including the nitrogen atom bonded to R 9 and R 10 ;
each heterocyclyl group represented by R 2 contains one oxygen atom as a heteroatom in the case of a 4- or 5-membered ring, and one to two oxygen atoms as heteroatoms in the case of a 6-membered ring;
R 3 represents a hydrogen atom, C 1-8 alkyl, or a halogen atom;
X represents CR 11 or a nitrogen atom;
R 11 represents a hydrogen atom, C 1-6 alkyl, or C 3-6 cycloalkyl;
R 4 is represented by -A 1 -A 2 -A 3 ;
A 1 represents a single bond or C 1-8 alkylene;
one to two sp 3 carbon atoms at any positions of A 1 are optionally replaced independently with one to two structures selected from the group consisting of [—O—, —NR 14 —, —C(═O)—, —C(═O)—O—, —O—C(═O)—, —O—C(═O)—O—, —C(═O)—NR 15 —, —O—C(═O)—NR 16 —, —NR 17 —C(═O)—, —NR 18 —C(═O)—O—, —NR 19 —C(═O)—NR 20 —, —S(═O) p —, —S(═O) 2 —NR 21 —, —NR 22 —S(═O) 2 —, and —NR 23 —S(═O) 2 —NR 24 —], provided that no structure selected from —O—O—, —O—NR 14 —, —NR 14 —O—, —O—CH 2 —O—, —O—CH 2 —NR 14 —, and —NR 14 —CH 2 —O— is formed in the case of replacement of two sp 3 carbon atoms;
A 2 represents a single bond, C 1-7 alkylene, C 3-12 cycloalkylene, C 3-12 cycloalkylidene, 4-to 12-membered heterocyclylene, 4- to 12-membered heterocyclylidene, C 6-10 arylene, or 5- to 10-membered heteroarylene;
A 3 represents a halogen, —CN, —NO 2 , —R 25 , —OR 26 , —NR 27 R 28 , —C(═O)R 29 , —C(═O)—OR 30 , —O—C(═O)R 31 , —O—C(═O)—NR 32 R 33 , —C(═O)—NR 34 R 35 , —NR 36 —C(═O)R 37 , —NR 38 —C(═O)—OR 39 , —S(═O) 2 —R 40 , —S(═O) 2 —NR 41 R 42 , or —NR 43 —S(═O) 2 R 44 ; provided that A 3 represents —R 25 if the terminal of A 1 on the side of A 2 is a structure selected from the group consisting of [—O—, —NR 14 —, —C(═O)—, —C(═O)—O—, —O—C(═O)—, —O—C(═O)—O—, —C(═O)—NR 15 —, —O—C(═O)—NR 16 —, —NR 17 —C(═O)—, —NR 18 —C(═O)—O—, —NR 19 —C(═O)—NR 20 —, —S(═O) p —, —S(═O) 2 —NR 21 —, —NR 22 —S(═O) 2 —, and —NR 23 —S(═O) 2 —NR 24 —] and A 2 is a single bond;
each of R 14 , R 32 , R 34 , R 36 , R 38 , R 41 , and R 43 independently represents a hydrogen atom, C 1-8 alkyl, C 1-8 acyl, C 1-8 alkylsulfonyl, 4- to 12-membered heterocyclyl, C 3-12 cycloalkyl, C 6-10 aryl, 5- to 10-membered heteroaryl, (4- to 12-membered heterocyclyl)C 1-3 alkyl, (C 3-12 cycloalkyl)C 1-3 alkyl, (C 6-10 aryl)C 1-3 alkyl, or (5- to 10-membered heteroaryl)C 1-3 alkyl;
each of R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 , R 23 , R 24 , R 25 , R 26 , R 27 , R 28 , R 29 , R 30 , R 31 , R 33 , R 35 , R 37 , R 39 , R 40 , R 42 , and R 44 independently represents a hydrogen atom, C 1-8 alkyl, 12-membered heterocyclyl, C 3-12 cycloalkyl, C 6-10 aryl, 5- to 10-membered heteroaryl, (4- to 12-membered heterocyclyl)C 1-3 alkyl, (C 3-12 cycloalkyl)C 1-3 alkyl, (C 6-10 aryl)C 1-3 alkyl, or (5- to 10-membered heteroaryl)C 1-3 alkyl;
each of A 1 , A 2 , A 3 , and each of R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 , R 23 , R 24 , R 25 , R 26 , R 27 , R 28 , R 29 , R 30 , R 31 , R 32 , R 33 , R 34 , R 35 , R 36 , R 37 , R 38 , R 39 , R 40 , R 41 , R 42 , R 43 , and R 44 contained in A 1 and A 3 are optionally substituted independently with one to four substituents selected from the group consisting of —OH, ═O, —COOH, —SO 3 H, —PO 3 H 2 , —CN, —NO 2 , a halogen, C 1-8 alkyl substituted with [zero to two —OH groups, zero to two —OR 45 groups, and zero to six fluorine atoms], C 3-12 cycloalkyl substituted with [zero to two —OH groups, zero to two —OR 46 groups, and zero to six fluorine atoms], C 1-8 alkoxy substituted with [zero to two —OH groups, zero to two —OR 47 groups, and zero to six fluorine atoms], and 4- to 12-membered heterocyclyl substituted with [zero to two —OH groups, zero to two —OR 49 groups, and zero to six fluorine atoms];
each of R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 , R 23 , R 24 , R 25 , R 26 , R 27 , R 28 , R 29 , R 30 , R 31 , R 32 , R 33 , R 34 , R 35 , R 36 , R 37 , R 38 , R 39 , R 40 , R 41 , R 42 , R 43 , and R 44 are optionally bonded in A 1 , in A 3 , [between A 1 and A 2 ], [between A 1 and A 3 ], or [between A 2 and A 3 ] via [a single bond, —O—, —NR 50 —, or —S(═O) p —] to form a ring;
R 11 is optionally bonded with [A 1 , A 2 , or A 3 ] via [a single bond, —O—, —NR 51 —, or —S(═O) p —] to form a ring;
R 45 , R 46 , R 47 , R 49 , R 50 , and R 51 each independently represents a hydrogen atom, or C 1-4 alkyl substituted with [zero to one —OH group and zero to six fluorine atoms];
p represents an integer of zero to two; and
each of the heterocyclyl, heteroaryl, (heterocyclyl)alkyl, and (heteroaryl)alkyl represented by A 1 and A 3 and the heterocyclylene, heterocyclylidene, and heteroarylene represented by A 2 contains one to four heteroatoms independently selected from oxygen, sulfur, and nitrogen atoms,
or a pharmaceutically acceptable salt thereof.

Assignees

• Teijin Pharma Ltd

Inventors

• Mizuno Tsuyoshi
• Shimada Tomohiro
• Unoki Gen
• Maruyama Akinobu
• Sasaki Kosuke
• Yokosaka Takuya
• Takahashi Hiroshi
• Horie Kyohei
• Sakai Yuri

Classifications

• C07D471/04 Primary

  Ortho-condensed systems · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P19/02

  for joint disorders, e.g. arthritis, arthrosis · CPC title

• A61P11/00

  Drugs for disorders of the respiratory system · CPC title

• A61P9/10

  for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis · CPC title