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

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.

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]-4-yl)-2-methoxyphenyl)amino)pyrimidin-4-yl)amino)phenyl)methanesulfonamide;   <15> N-(2-((2-((4-(1-acetylpiperidin-4-yl)-2-methoxyphenyl)amino)-5-chloropyrimidin-4-yl)amino)phenyl)methanesulfonamide;   <16> N-(2-((2-((4-([1,4′-bipiperidin]-4-yl)-2-methoxyphenyl)amino)-5-chloropyrimidin-4-yl)amino)phenyl)methanesulfonamide;   <17> N-(2-((5-chloro-2-((2-methoxy-4-(1′-methyl-[1,4′-bipiperidin]-4-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)methanesulfonamide;   <18> N-(2-((2-((4-(1′-acetyl-[1,4′-bipiperidin]-4-yl)-2-methoxyphenyl)amino)-5-chloropyrimidin-4-yl)amino)phenyl)methanesulfonamide;   <19> N-(2-((2-((4-(4-(4-acetylpiperazin-1-yl)piperidin-1-yl)-2-methoxyphenyl)amino)-5-chloropyrimidin-4-yl)amino)phenyl)methanesulfonamide;   <20> tert-butyl 4-(1-(4-((5-chloro-4-((2-(methylsulfonamido)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazine-1-carboxylate;   <21> N-(2-((5-chloro-2-((2-methoxy-4-(4-(piperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)methanesulfonamide;   <22> N-(2-((5-chloro-2-((4-(4-(4-(2-hydroxyethyl)piperazin-1-yl)piperidin-1-yl)-2-methoxyphenyl)amino)pyrimidin-4-yl)amino)phenyl)methanesulfonamide;   <23> N-(2-((5-chloro-2-((2-methoxy-4-(piperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)methanesulfonamide;   <24> N-(2-((2-((4-(4-(1-acetylpiperidin-4-yl)piperazin-1-yl)-2-methoxyphenyl)amino)-5-chloropyrimidin-4-yl)amino)phenyl)methanesulfonamide;   <25> N-(2-((5-chloro-2-((2-methoxy-4-(4-(1-methylpiperidin-4-yl)piperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)methanesulfonamide;   <26> tert-butyl 4-(4-(4-((5-chloro-4-((2-(methylsulfonamido)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazin-1-yl)piperidine-1-carboxylate;   <27> N-(2-((5-chloro-2-((2-methoxy-4-(4-(piperidin-4-yl)piperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)methanesulfonamide;   <28> N-(2-((5-chloro-2-((2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)methanesulfonamide;   <29> 4-(4-((5-chloro-4-((2-(sulfamoylamino)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazine;   <30> 4-(4-((5-bromo-4-((2-(sulfamoylamino)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazine;   <31> N-(2-((2-((2-methoxy-4-(piperazin-4-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)phenyl)methanesulfonamide;   <32> N-(2-((5-chloro-2-((2-methoxy-4-morpholinophenyl)amino)pyrimidin-4-yl)amino)phenyl)methanesulfonamide;   <33> N-(2-((5-chloro-2-((4-(4-((3R,5S)-3,5-dimethylpiperazin-1-yl)piperidin-1-yl)-2-methoxyphenyl)amino)pyrimidin-4-yl)amino)phenyl)methanesulfonamide;   <34> N-(2-((5-chloro-2-((2-methoxy-4-(4-morpholinopiperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)methanesulfonamide;   <35> N-(2-((5-chloro-2-((2-methoxy-4-(4-(pyrrolidin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)methanesulfonamide;   <36> (N-(2-((5-chloro-2-((4-(4-(dimethylamino)piperidin-1-yl)-2-methoxyphenyl)amino)pyrimidin-4-yl)amino)phenyl)sulfamoyl)carbamate;   <37> (N-(2-((5-chloro-2-((2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)sulfamoyl)carbamate;   <38> N-(2-((2-((4-(4-aminopiperidin-1-yl)-2-methoxyphenyl)amino)-5-chloropyrimidin-4-yl)amino)phenyl)methanesulfonamide;   <39> N-(1-(4-((5-chloro-4-((2-(methylsulfonamido)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)acetamide;   <40> N-(2-((5-chloro-2-((2-methoxy-4-(4-(methylamino)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)methanesulfonamide;   <41> N-(2-((5-chloro-2-((4-(4-((2-hydroxyethyl)amino)piperidin-1-yl)-2-methoxyphenyl)amino)pyrimidin-4-yl)amino)phenyl)methanesulfonamide;   <42> N-(2-((5-chloro-2-((2-methoxy-4-(4-((2-methoxyethyl)amino)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)methanesulfonamide; and   <43> N-(2-((5-chloro-2-((4-(4-((2-(dimethylamino)ethyl)amino)piperidin-1-yl)-2-methoxyphenyl)amino)pyrimidin-4-yl)amino)phenyl)methanesulfonamide.   
     
     
         12 . (canceled) 
     
     
         13 . (canceled) 
     
     
         14 . The method of  claim 1 , wherein one or more of an EGFR (epidermal growth factor receptor) mutation, FLT3, and FLT3 mutation are inhibited. 
     
     
         15 . The method of  claim 14 , wherein the EGFR mutation is one or more selected from the group consisting of EGFR del19, EGFR del19/T790M, EGFR del19/T790M/C 797 S, EGFR L858R, EGFR L858R/T790MS, and EGFR L858R/T790M/C 797 S. 
     
     
         16 . The method of  claim 14 , wherein characterized in that the FLT3 mutation is one or more selected from the group consisting of FLT3(D835H), FLT3(D835V), FLT3(D835Y), FLT3(ITD), FLT3(ITD,D835V), FLT3(ITD,F691L), FLT3(K663Q), FLT3(N 841 I), and FLT3(R834Q). 
     
     
         17 . The method of  claim 1 , wherein characterized in that the cancer has a mutation expressed on one or more selected from the group consisting of EGFR, ALK, FAK, FLT3, JAK3, KIT, and PLK4. 
     
     
         18 . The method of  claim 1 , characterized in that the cancer is one or more selected from the group consisting of pseudomyxoma, intrahepatic cholangiocarcinoma, hepatoblastoma, liver cancer, thyroid cancer, colon cancer, testis cancer, myelodysplastic syndrome, glioblastoma, oral cancer, lip cancer, mycosis fungoides, acute myeloid leukemia, acute lymphocytic leukemia, basal cell carcinoma, epithelial ovarian cancer, ovarian seminoma, male breast cancer, brain cancer, pituitary adenoma, multiple myeloma, gallbladder cancer, cholangiocarcinoma, colorectal cancer, chronic myeloid leukemia, chronic lymphocytic leukemia, retinoblastoma, choroidal melanoma, ampullar of vater cancer, bladder cancer, peritoneal cancer, parathyroid cancer, adrenal cancer, nasal and paranasal cavity cancer, non-small cell lung cancer, tongue cancer, astrocytoma, small cell lung cancer, pediatric brain cancer, pediatric lymphoma, pediatric leukemia, small intestine cancer, meningioma, esophageal cancer, glioma, renal pelvis cancer, renal cancer, heart cancer, duodenal cancer, malignant soft tissue cancer, malignant bone cancer, malignant lymphoma, malignant mesothelioma, malignant melanoma, eye cancer, vulvar cancer, ureteral cancer, urethral cancer, cancer of unknown primary site, gastric lymphoma, gastric cancer, gastric carcinoid, gastrointestinal stromal tumor, Wilms' tumor, breast cancer, sarcoma, penile cancer, pharyngeal cancer, gestational choriocarcinoma, cervical cancer, endometrial cancer, uterine sarcoma, prostate cancer, metastatic bone cancer, metastatic brain cancer, mediastinal cancer, rectal cancer, rectal carcinoid, vaginal cancer, spinal cancer, vestibular schwannoma, pancreatic cancer, salivary gland cancer, Kaposi's sarcoma, Paget's disease, tonsillar cancer, squamous cell cancer, adenocarcinoma of lung, lung cancer, squamous cell lung cancer, skin cancer, anal cancer, rhabdomyosarcoma, laryngeal cancer, pleura cancer, hematologic malignancy, and thymic cancer. 
     
     
         19 . The method of  claim 1 , further comprising administering an anticancer agent in combination with the compound of Formula 1. 
     
     
         20 . (canceled) 
     
     
         21 . The method of  claim 19 , wherein the anticancer agent is cetuximab. 
     
     
         22 . The method of  claim 21 , wherein the compound of Formula 1 is:
 N-(2-((5-chloro-2-((2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)methanesulfonamide; or   N-(2-((5-chloro-2-((4-(4-(dimethylamino)piperidin-1-yl)-2-methoxyphenyl)amino)pyrimidin-4-yl)amino)phenyl)methanesulfonamide.