N2,n4-diphenylpyrimidine-2,4-diamine derivative, method for preparing same, and pharmaceutical composition containing same as active ingredient for prevention or treatment of cancer

Patent metadata

Field	Value
Publication number	US-2022249482-A1
Application number	US-202217675917-A
Country	US
Kind code	A1
Filing date	Feb 18, 2022
Priority date	Jun 13, 2017
Publication date	Aug 11, 2022
Grant date	—

Abstract

The present invention relates to a N2,N4-diphenylpyrimidin-2,4-diamine derivative, a method for preparing the same, and a pharmaceutical composition for the prevention or treatment of cancer, containing the same as an active ingredient. The derivative shows a relatively weak EGFR activity inhibitory effect on wild-type EGFR, a high inhibitory ability on EGFR mutation, and a high inhibitory ability on even FLT3 and FLT3 mutation, and thus, can be effectively used for the treatment of cancer with EGFR mutation or cancer with FLT3 or a mutation thereof, and the derivative shows a synergy effect at the time of combination administration, and thus can be effectively used for the treatment of combination administration.

First claim

1 . A method of treating or preventing cancer, comprising administering to a subject in need thereof a compound represented by Formula 1:

in which,
R 1 is CH 3 or NH 2 ,
R 2 is hydrogen, halogen, methoxy, or methyl unsubstituted or substituted with one or more halogens;
R 3 is hydrogen, halogen, or straight or branched C 1-6 alkyl;
R 4 is straight or branched C 1-6 alkyl; and

is an unsubstituted or substituted 5- to 7-membered heterocycloalkyl comprising one or more heteroatoms selected from the group consisting of N, O, and S, wherein the substituted heterocycloalkyl may be substituted with one or more substituents selected from the group consisting of straight or branched C 1-3 alkyl, straight or branched hydroxyC 1-3 alkyl, acetyl, —NR a R b , morpholinyl, pyrrolidinyl, and unsubstituted or substituted piperidinyl or piperazinyl, wherein R a and R b are independently hydrogen, straight or branched C 1-3 alkyl, acetyl, straight or branched hydroxyC 1-3 alkyl, straight or branched C 1-3 alkoxyC 1-2 alkyl, or straight or branched diC 1-3 alkylaminoC 1-2 alkyl, and the substituted piperidinyl or piperazinyl may be substituted with one or more substituents selected from the group consisting of straight or branched C 1-3 alkyl, straight or branched hydroxyC 1-3 alkyl, acetyl, and straight or branched C 1-5 alkoxycarbonyl,
an optical isomer thereof or a pharmaceutically acceptable salt thereof.

2 . The method of claim 1 , characterized in that R 1 is CH 3 .

3 . The method of claim 1 , characterized in that R 1 is NH 2 .

4 . The method of claim 1 , characterized in that
R 2 is hydrogen, F, Cl, Br, methoxy, or methyl unsubstituted or substituted with one or more fluoro; R 3 is hydrogen, F, Cl, or straight or branched C 1-3 alkyl; and R 4 is straight or branched C 1-3 alkyl.

5 . The method of claim 1 , characterized in that
R 2 is hydrogen, Cl, Br, methyl, CF 3 , or methoxy; R 3 is hydrogen or methyl; and R 4 is methyl.

6 . The method of claim 1 , characterized in that

is an unsubstituted or substituted 5- or 6-membered heterocycloalkyl comprising one or more heteroatoms selected from the group consisting of N, O, and S, wherein the substituted heterocycloalkyl may be substituted with one or more substituents selected from the group consisting of methyl, hydroxyethyl, acetyl, —NR a R b , morpholinyl, pyrrolidinyl, and unsubstituted or substituted piperidinyl or piperazinyl, wherein R a and R b are independently hydrogen, straight or branched C 1-3 alkyl, acetyl, straight or branched hydroxyC 1-3 alkyl, straight or branched C 1-3 alkoxyC 1-2 alkyl, or straight or branched diC 1-3 alkylaminoC 1-2 alkyl, and the substituted piperidinyl or piperazinyl may be substituted with one or more substituents selected from the group consisting of methyl, ethyl, hydroxymethyl, hydroxyethyl, acetyl, and tert-butoxycarbonyl.

7 . The method of claim 1 , characterized in that

is an unsubstituted or substituted 5- or 6-membered heterocycloalkyl comprising one or more heteroatoms selected from the group consisting of N and O, wherein the substituted heterocycloalkyl may be substituted with one or more substituents selected from the group consisting of methyl, hydroxyethyl, acetyl, —NR a R b , morpholinyl, pyrrolidinyl, and unsubstituted or substituted piperidinyl or piperazinyl, wherein R a and R b are independently hydrogen, methyl, acetyl, hydroxyethyl, —(CH 2 ) 2 OCH 3 , or —(CH 2 ) 2 N(CH 3 ) 2 , and the substituted piperidinyl or piperazinyl may be substituted with one or more substituents selected from the group consisting of methyl, hydroxyethyl, acetyl, and tert-butoxycarbonyl.

8 . The method of claim 1 , characterized in that

wherein A 1 is CH or N, and A 2 is NH, O, CH—R 5 , or N—R 5 , with the proviso that if A 1 is CH, then A 2 is not CH—R 5 , wherein R 5 is independently hydrogen, methyl, hydroxyethyl, acetyl, —NR a R b , morpholinyl, pyrrolidinyl,

wherein R a and R b are independently hydrogen, methyl, acetyl, hydroxyethyl, —(CH 2 ) 2 OCH 3 , or —(CH 2 ) 2 N(CH 3 ) 2 , and R c and R d are independently hydrogen, methyl, or ethyl, and R 6 is independently hydrogen, methyl, hydroxyethyl, acetyl, or tert-butoxycarbonyl.

9 . The method of claim 1 , characterized in that

wherein R 5 is independently hydrogen, methyl, hydroxyethyl, acetyl, —NH 2 , —NH(CH 3 ), —NH(C═O)CH 3 , —NH(CH 2 ) 2 OH, —NH(CH 2 ) 2 OCH 3 , —NH(CH 2 ) 2 N(CH 3 ) 2 , —N(CH 3 ) 2 , morpholinyl, pyrrolidinyl,

wherein R c and R d are independently hydrogen or methyl, and R 6 is independently hydrogen, methyl, hydroxyethyl, acetyl, or tert-butoxycarbonyl.

10 . The method of claim 1 , characterized in that

wherein R 5 is independently —NH(CH 3 ) or

wherein R c and R d are independently hydrogen, and R 6 is methyl.

11 . The method of claim 1 , characterized in that the compound represented by Formula 1 is any one selected from the group consisting of the following compounds:
<1> N-(2-((5-chloro-2-((2-methoxy-4-(piperidin-4-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)methanesulfonamide; <2> N-(2-((5-chloro-2-((2-methoxy-5-methyl-4-(piperidin-4-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)methanesulfonamide; <3> N-(2-((5-bromo-2-((2-methoxy-4-(piperidin-4-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)methanesulfonamide; <4> N-(2-((5-methoxy-2-((2-methoxy-4-(piperidin-4-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)methanesulfonamide; <5> N-(2-((2-((2-methoxy-4-(piperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)phenyl)methanesulfonamide; <6> 4-(4-((5-chloro-4-((2-(sulfamoylamino)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidine; <7> 4-(4-((5-bromo-4-((2-(sulfamoylamino)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidine; <8> N-(2-((2-((2-methoxy-4-(piperidin-4-yl)phenyl)amino))-5-methylpyrimidin-4-ylamino)phenyl)methanesulfonamide; <9> N-(2-((2-((2-methoxy-4-(piperidin-4-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)methanesulfonamide; <10> N-(2-((5-chloro-2-((2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)methanesulfonamide; <11> N-(2-((5-chloro-2-((4-(4-(dimethylamino)piperidin-1-yl)-2-methoxyphenyl)amino)pyrimidin-4-yl)amino)phenyl)methanesulfonamide; <12> N-(2-((5-chloro-2-((2-methoxy-4-(1-methylpiperidin-4-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)methanesulfonamide; <13> N-(2-((5-chloro-2-((4-(1-(2-hydroxyethyl)piperidin-4-yl)-2-methoxyphenyl)amino)pyrimidin-4-yl)amino)phenyl)methanesulfonamide; <14> N-(2-((5-chloro-2-((4-(1′-(2-hydroxyethyl)[1,4′-bipiperidin

Assignees

• Korea Res Inst Chemical Tech

Inventors

• Lee Kwangho
• Shin Inji
• Choi Gildon
• Chae Chong Hak
• Choe Hyeon Jeong
• Jung Myoung Eun
• Jeon Byeong Uk
• Cho Byoung Chul
• Park Chae Won
• Kim Hwan
• Duggirala Krishna Babu

Classifications

• A61K31/18

  Sulfonamides (compounds containing a para-N-benzene-sulfonyl-N- group A61K31/63) · CPC title

• A23V2002/00

  Food compositions, function of food ingredients or processes for food or foodstuffs · CPC title

• A61P35/00 Primary

  Antineoplastic agents · CPC title

• C07D401/12 Primary

  linked by a chain containing hetero atoms as chain links · CPC title

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title