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

Patent metadata

Field	Value
Publication number	US-10124004-B2
Application number	US-201615577802-A
Country	US
Kind code	B2
Filing date	May 27, 2016
Priority date	May 29, 2015
Publication date	Nov 13, 2018
Grant date	Nov 13, 2018

Abstract

The purpose of the present invention is to provide a compound having an excellent CDK4/6 inhibiting activity. The present invention is a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof.

First claim

The invention claimed is:

1. A compound represented by Formula (I) or a pharmaceutically acceptable salt thereof:

[where
L represents —NR 5 —, —O—, or —S—;
R 5 represents a hydrogen atom or a C 1-6 alkyl group substituted with zero to two —OH groups, zero to two C 1-8 alkoxy groups, and zero to six fluorine atoms;
R 1 represents a C 1-8 alkyl, C 3-12 cycloalkyl, (C 3-12 cycloalkyl)-C 1-6 alkyl, 4- to 12-membered heterocyclyl, (4- to 12-membered heterocyclyl)-C 1-6 alkyl, C 6-10 aryl, (C 6-10 aryl)-C 1-6 alkyl, 5- to 10-membered heteroaryl, (5- to 10-membered heteroaryl)-C 1-6 alkyl, C 1-8 alkylsulfonyl, or C 1-8 acyl group;
each of the heteroatom-containing groups represented by R 1 contains one to four heteroatoms 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 , a C 3-6 cycloalkyl group substituted with zero to two —OH groups, zero to two C 1-8 alkoxy groups, and zero to six fluorine atoms, a 3- to 10-membered heterocyclyl group substituted with zero to two —OH groups, zero to two C 1-8 alkoxy groups, and zero to six fluorine atoms, a C 1-8 acyl group substituted with zero to two —OH groups, zero to two C 1-8 alkoxy groups, and zero to six fluorine atoms, and a C 1-8 alkoxy group 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 a C 1-6 alkyl group substituted with zero to two —OH groups, zero to two C 1-8 alkoxy groups, and zero to six fluorine atoms;
R 2 represents a C 1-8 alkyl, C 3-8 cycloalkyl, 4- to 6-membered heterocyclyl, or C 1-8 acyl group, —COOR 8 , or —CONR 9 R 10 ;
each of the C 1-8 alkyl and C 3-8 cycloalkyl groups represented by R 2 is substituted with zero or one —OH group, zero to two C 1-8 alkoxy groups substituted with zero or one —OH group, zero or one C 1-4 alkoxy group, and zero to three fluorine atoms, and zero to five fluorine atoms;
R 2 is neither an unsubstituted C 1-8 alkyl, nor unsubstituted C 3-8 cycloalkyl, nor trifluoromethyl group;
R 8 , R 9 , and R 10 each independently represent a hydrogen atom or a C 1-8 alkyl group;
the 4- to 6-membered heterocyclyl group represented by R 2 is optionally substituted with one to four substituents selected from the group consisting of a fluorine atom, —OH, and C 1-4 alkyl and C 1-4 alkoxy groups;
each of the C 1-8 acyl group, —COOR 8 , and —CONR 9 R 10 represented by R 2 is optionally substituted with one to four substituents selected from the group consisting of a fluorine atom, —OH, and a C 1-4 alkoxy group;
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 ;
the heterocyclyl group represented by R 2 having a 4- or 5-membered ring contains one oxygen heteroatom, and the heterocyclyl group having a 6-membered ring contains one or two oxygen heteroatoms;
R 3 represents a hydrogen atom, a C 1-8 alkyl group, or a halogen atom;
X represents CR 11 or a nitrogen atom;
Y represents CR 12 or a nitrogen atom;
Z represents CR 13 or a nitrogen atom;
R 11 to R 13 each independently represent a hydrogen, fluorine, or chlorine atom or a C 1-6 alkyl or C 1-6 alkoxy group;
R 4 represents -A 1 -A 2 -A 3 ;
A 1 represents a single bond or a C 1-8 alkylene, C 2-8 alkenylene, or C 2-8 alkynylene group;
one or two sp 3 carbon atoms at any positions of A 1 are optionally replaced with one or 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 5 —, —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 structure of —O—O—, —O—NR 14 —, —NR 14 —O—, —O—CH 2 —O—, —O—CH 2 —NR 14 —, or —NR 14 —CH 2 —O— is not formed in the case of replacement of two sp 3 carbon atoms;
A 2 represents a single bond or a 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 group;
A 3 represents a halogen atom, —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 ;
A 3 represents —R 25 , if the A 1 end on the A 2 side has 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;
R 14 , R 32 , R 34 , R 36 , R 38 , R 41 , and R 43 each independently represent a hydrogen atom or a 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 group;
R 15 to R 31 , R 33 , R 35 , R 37 , R 39 , R 40 , R 42 , and R 44 each independently represent a hydrogen atom or a C 1-8 alkyl, 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 group;
A 1 , A 2 , A 3 , and R 14 to R 44 in A 1 , A 2 , and A 3 are each optionally substituted with one to four substituents selected from the group consisting of —OH, ═O, —COOH, —SO 3 H, —PO 3 H, —CN, —NO 2 , a halogen atom, a C 1-8 alkyl group substituted with zero to two —OH groups, zero to two —OR 45 groups, and zero to six fluorine atoms, a C 3-12 cycloalkyl group substituted with zero to two —OH groups, zero to two —OR 46 groups, and zero to six fluorine atoms, a C 1-8 alkoxy group substituted with zero to two —OH groups, zero to two —OR 47 groups, and zero to six fluorine atoms, and a 4- to 12-membered heterocyclyl group substituted with zero to two —OH groups, zero to two —OR 49 groups, and zero to six fluorine atoms;
R 14 to R 44 are optionally bonded in A 1 , A 2 , or A 3 or 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 or R 13 is optionally bonded to A 1 , A 2 , or A 3 via a single bond, —O—, —NR 51 —, or —S(═O) p — to form a ring;
R 45 to R 51 each represent a hydrogen atom or a C 1-4 alkyl group substituted with zero or one —OH group and zero to six fluorine atoms;
p represents an integer of 0 to 2; and
each of the heteroatom-containing groups represented by A 1 , A 2 , and A 3 contains one to four heteroatoms selected from oxygen, sulfur, and nitrogen atoms].

2. The compound or pharmaceutically acceptable salt thereof according to claim 1 , wherein L represents —NH—.

3. The compound or pharmaceutically acceptable salt thereof according to claim 1 , wherein R 1 represents a C 1-8 alkyl, C 3-12 cycloalkyl, (C 3-12 cycloalkyl)-C 1-6 alkyl, 4- to 12-membered heterocyclyl, or (4- to 12-membered heter

Assignees

• Teijin Pharma Ltd

Inventors

• Mizuno Tsuyoshi
• Shimada Tomohiro
• Unoki Gen
• Ebisawa Masaru
• Takeuchi Susumu
• Minamizono Kunio
• Sasaki Kosuke
• Yokosaka Takuya
• Igarashi Junji
• Maruyama Akinobu
• Takahashi Hiroshi
• Horie Kyohei
• Sakai Yuri

Classifications

• C07D519/00

  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 · 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

• A61P19/02

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

• A61K31/519 Primary

  ortho- or peri-condensed with heterocyclic rings · CPC title

• A61K31/541

  Non-condensed thiazines containing further heterocyclic rings · CPC title