4-(2-amino-tetrahydronaphthalenyl)pyrimidine derivative, preparation method therefor, and pharmaceutical composition for preventing or treating cancer, containing same as active ingredient

Patent metadata

Field	Value
Publication number	US-10369149-B2
Application number	US-201515567224-A
Country	US
Kind code	B2
Filing date	Dec 30, 2015
Priority date	Apr 22, 2015
Publication date	Aug 6, 2019
Grant date	Aug 6, 2019

Abstract

The present invention relates to a 4-(2-amino-tetrahydronaphthaleneyl)pyrimidine derivative, a preparation method thereof, and a pharmaceutical composition for the prevention or treatment of cancer comprising the same as an active ingredient. The 4-(2-amino-tetrahydronaphthaleneyl)pyrimidine derivative, the optical isomer thereof, or the pharmaceutically acceptable salt thereof of the present invention is very effective in suppressing anaplastic lymphoma kinase (ALK) activity and as a result it can improve the effectiveness of treatment on cancer cells having anaplastic lymphoma kinase (ALK) fusion proteins such as EML4-ALK and NPM-ALK, so that it can be effectively used as a pharmaceutical composition for preventing or treating cancer.

First claim

What is claimed is:

1. A compound represented by formula 1 or a pharmaceutically acceptable salt of the same:

In the formula 1,
R 1a , R 1b , R 2a and R 2b are independently hydrogen or C 1-5 straight or branched alkyl, and R 1a and R 1b or R 2a and R 2b can form oxo group (═O);
indicates either single bond or double bond;
when is single bond,
X is —OH or —NR 3 R 4 , wherein, R 3 and R 4 are independently hydrogen, C 1-5 straight or branched alkyl, —(C═NH)—R 5 , or —(C═O)(CH 2 ) n R 5 , wherein, R 5 is hydrogen, methyl, —OH, —N(CH 3 ) 2 , —NH 2 , or trihalomethyl, and n is an integer of 0-3,
R 3 and R 4 can form 5-8 membered unsubstituted or substituted heterocycloalkyl containing one or more hetero atoms selected from the group consisting of N, O, and S along with the nitrogen atoms conjugated to the same;
when is double bond,
X is ═O, ═N—OH or ═N—NR 6 R 7 , wherein, R 6 and R 7 are independently hydrogen, C 1-5 straight or branched alkyl, —(C═O)R 8 or —(C═NH)R 8 , wherein, R 8 is methyl, —NH 2 or C 1-5 straight or branched alkoxy,
R 6 and R 7 can form 5-8 membered unsubstituted or substituted heterocycloalkyl containing one or more hetero atoms selected from the group consisting of N, O, and S along with the nitrogen atoms conjugated to the same, and the substituted heterocycloalkyl can be substituted with —(C═O)CF 3 or C 1-5 straight or branched alkyl.

2. The compound represented by formula 1 or the pharmaceutically acceptable salt of the same according to claim 1 , wherein:
R 1a , R 1b , R 2a and R 2b are independently hydrogen or C 1-3 straight or branched alkyl, and R 1a and R 1b can form oxo group (═O);
indicates either single bond or double bond;
when is single bond,
X is —OH or —NR 3 R 4 , wherein, R 3 and R 4 are independently hydrogen, C 1-3 straight or branched alkyl, —(C═NH)—R 5 , or —(C═O)(CH 2 ) n R 5 , wherein, R 5 is hydrogen, methyl, —OH, —N(CH 3 ) 2 , or —CF 3 , and n is an integer of 0-1,
R 3 and R 4 can form 6 membered unsubstituted or substituted heterocycloalkyl containing one or more hetero atoms selected from the group consisting of N and O along with the nitrogen atoms conjugated to the same, and the substituted heterocycloalkyl can be substituted with —(C═O)CF 3 ;
when is double bond,
X is ═O, ═N—OH or ═N—NR 6 R 7 , wherein, R 6 and R 7 are independently hydrogen, C 1-3 straight or branched alkyl, —(C═O)R 8 or —(C═NH)R 8 , wherein, R 8 is methyl, —NH 2 or C 1-3 straight or branched alkoxy,
R 6 and R 7 can form 6 membered unsubstituted or substituted heterocycloalkyl containing one or more hetero atoms selected from the group consisting of N and O along with the nitrogen atoms conjugated to the same, and the substituted heterocycloalkyl can be substituted with —(C═O)CF 3 or C 1-3 straight or branched alkyl.

3. The compound represented by formula 1 or the pharmaceutically acceptable salt of the same according to claim 1 , wherein:
R 1a , R 1b , R 2a and R 2b are independently hydrogen or methyl, and R 1a and R 1b can form oxo group (═O);
indicates either single bond or double bond;
when is single bond,

when is double bond,

4. The compound represented by formula 1 or the pharmaceutically acceptable salt of the same according to claim 1 , wherein the compound represented by formula 1 is selected from the group consisting of the following compounds:
(1) 5-chloro-N4-(2-(isopropylsulfonyl)phenyl)-N2-(3-methoxy-6-morpholino-5,6,7,8-tetrahydronaphthalene-2-yl)pyrimidine-2,4-diamine;
(2) 5-chloro-N4-(2-(isopropylsulfonyl)phenyl)-N2-(3-methoxy-6-(piperazine-1-yl)-5,6,7,8-tetrahydronaphthalene-2-yl)pyrimidine-2,4-diamine;
(3) 7-(5-chloro-4-(2-(isopropylsulfonyl)phenylamino)pyrimidine-2-ylamino)-6-methoxy-2-morpholino-3,4-dihydronaphthalene-1(2H)-one;
(4) N-(6-(5-chloro-4-(2-(isopropylsulfonyl)phenylamino)pyrimidine-2-ylamino)-7-methoxy-1,1-dimethyl-1,2,3,4-tetrahydronaphthalene-2-yl)-2,2,2-trifluoroacetamide;
(5) 6-(5-chloro-4-(2-(isopropylsulfonyl)phenylamino)pyrimidine-2-ylamino)-7-methoxy-1,1-dimethyl-3,4-dihydronaphthalene-2(1H)-one;
(6) 7-(5-chloro-4-(2-(isopropylsulfonyl)phenylamino)pyrimidine-2-ylamino)-6-methoxy-1,1-dimethyl-3,4-dihydronaphthalene-2(1H)-one;
(7) N-(7-(5-chloro-4-(2-(isopropylsulfonyl)phenylamino)pyrimidine-2-ylamino)-6-methoxy-1,1-dimethyl-1,2,3,4-tetrahydronaphthalene-2-yl)-2,2,2-trifluoroacetamide;
(8) (E)-6-(5-chloro-4-(2-(isopropylsulfonyl)phenylamino)pyrimidine-2-ylamino)-7-methoxy-1,1-dimethyl-3,4-dihydronaphthalene-2(1H)-one oxime;
(9) (E)-N′-(6-(5-chloro-4-(2-(isopropylsulfonyl)phenylamino)pyrimidine-2-ylamino)-7-methoxy-1,1-dimethyl-3,4-dihydronaphthalene-2(1H)-yladene)acetohydrazide;
(10) (E)-2-(6-(5-chloro-4-(2-(isopropylsulfonyl)phenylamino)pyrimidine-2-ylamino)-7-methoxy-1,1-dimethyl-3,4-dihydronaphthalene-2(1H)-yladene)hydrazinecarboxamide;
(11) (E)-2-(6-(5-chloro-4-(2-(isopropylsulfonyl)phenylamino)pyrimidine-2-ylamino)-7-methoxy-1,1-dimethyl-3,4-dihydronaphthalene-2(1H)-yladene)hydrazinecarboxamideamide;
(12) (E)-tert-butyl 2-(6-(5-chloro-4-(2-(isopropylsulfonyl)phenylamino)pyrimidine-2-ylamino)-7-methoxy-1,1-dimethyl-3,4-dihydronaphthalene-2(1H)-yladene)hydrazinecarboxylate;
(13) (E)-5-chloro-N2-(6-hydrazono-3-methoxy-5,5-dimethyl-5,6,7,8-tetrahydronaphthalene-2-yl)-N4-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4-diamine hydrochloride;
(14) (E)-5-chloro-N4-(2-(isopropylsulfonyl)phenyl)-N2-(3-methoxy-5,5-dimethyl-6-(4-methylpiperazine-1-ylimino)-5,6,7,8-tetrahydronaphthalene-2-yl)pyrimidine-2,4-diamine;
(15) (E)-5-chloro-N4-(2-(isopropylsulfonyl)phenyl)-N2-(3-methoxy-5,5-dimethyl-6-(morpholinoimino)-5,6,7,8-tetrahydronaphthalene-2-yl)pyrimidine-2,4-diamine;
(16) (E)-7-(5-chloro-4-(2-(isopropylsulfonyl)phenylamino)pyrimidine-2-ylamino)-6-methoxy-1,1-dimethyl-3,4-dihydronaphthalene-2(1H)-one oxime;
(17) (E)-5-chloro-N4-(2-(isopropylsulfonyl)phenyl)-N2-(3-methoxy-8,8-dimethyl-7-(morpholinoimino)-5,6,7,8-tetrahydronaphthalene-2-yl)pyrimidine-2,4-diamine;
(18) (E)-2-(7-(5-chloro-4-(2-(isopropylsulfonyl)phenylamino)pyrimidine-2-ylamino)-6-methoxy-1,1-dimethyl-3,4-dihydronaphthalene-2(1H)-yladene)hydrazinecarboxamideamide;
(19) (E)-5-chloro-N4-(2-(isopropylsulfonyl)phenyl)-N2-(3-methoxy-8,8-dimethyl-7-(4-methylpiperazine-1-ylimino)-5,6,7,8-tetrahydronaphthalene-2-yl)pyrimidine-2,4-diamine;
(20) (E)-N′-(7-(5-chloro-4-(2-(isopropyl sulfonyl)phenylamino)pyrimidine-2-ylamino)-6-methoxy-1,1-dimethyl-3,4-dihydronaphthalene-2(1H)-yladene)acetohydrazide;
(21) (E)-2-(7-(5-chloro-4-(2-(isopropylsulfonyl)phenylamino)pyrimidine-2-ylamino)-6-methoxy-1,1-dimethyl-3,4-dihydronaphthalene-2(1H)-yladene)hydrazinecarboxamide;
(22) N2-(6-amino-3-methoxy-5,5-dimethyl-5,6,7,8-tetrahydronaphthalene-2-yl)-5-chloro-N4-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4-diamine;
(23) N2-(7-amino-3-methoxy-8,8-dimethyl-5,6,7,8-tetrahydronaphthalene-2-yl)-5-chloro-N4-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4-diamine;
(24) 6-(5-chloro-4-(2-(isopropylsulfonyl)phenylamino)pyrimidine-2-ylamino)-7-methoxy-1,1-dimethyl-1,2,3,4-tetrahydronaphthalene-2-ol;
(25) 7-(5-chloro-4-(2-(isopropylsulfonyl)phenylamino)pyrimidine-2-ylamino)-6-methoxy-1,1-dimethyl-1,2,3,4-tetrahydronaphthalene-2-ol;
(26) N-(6-(5-chloro-4-(2-(isopropylsulfonyl)phenylamino)pyrimidine-2-ylamino)-7-methoxy-1,1-dimethyl-1,2,3,4-tetrahydronaphthalene-2-yl)-2-hydroxyacetamide;
(27) N-(6-(5-chloro-4-(2-(isopropylsulfonyl)phenylamino)pyrimidine-2-ylamino)

Assignees

• Korea Res Inst Chemical Tech

Inventors

• Hwang Jong Yeon
• Kim Hyoung Rae
• Ha Jae Du
• Cho Sung Yun
• Jung Hee Jung
• Kim Pilho
• Yun Chang Soo
• Lee Chong Ock
• Park Chi Hoon
• Chae Chong Hak
• Ahn Sunjoo

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• C07B2200/07

  Optical isomers · CPC title

• C07C13/48

  Completely or partially hydrogenated naphthalenes · CPC title

• C07B43/04

  of amino groups · CPC title

• C07D239/48

  Two nitrogen atoms · CPC title