WO2021177721A1 - Kras 돌연변이 및 활성화된 ron이 존재하는 암의 예방 또는 치료용 약학 조성물 - Google Patents
Kras 돌연변이 및 활성화된 ron이 존재하는 암의 예방 또는 치료용 약학 조성물 Download PDFInfo
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- WO2021177721A1 WO2021177721A1 PCT/KR2021/002622 KR2021002622W WO2021177721A1 WO 2021177721 A1 WO2021177721 A1 WO 2021177721A1 KR 2021002622 W KR2021002622 W KR 2021002622W WO 2021177721 A1 WO2021177721 A1 WO 2021177721A1
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- oxo
- oxy
- fluorophenyl
- phenyl
- carboxamide
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Definitions
- the present invention relates to a pharmaceutical composition for preventing or treating cancer applicable to cancer patients having cancer cells in which KRAS mutations and activated RON are present.
- the KRAS (V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog) gene is one of several genes involved in the development of non-small cell lung cancer, colorectal cancer, and pancreatic cancer. is considered important. Specifically, considering whether the KRAS gene is mutated, it is known to significantly improve the drug response and survival period of cancer patients.
- RON recepteur d'origine nantais
- MSP macrophage-stimulating protein
- Non-Patent Document 1 Targeting Receptor Kinases in Colorectal Cancer, Cancers (2019), 11, 433-456.
- Non-Patent Document 2 Comprehensive review of targeted therapy for colorectal cancer, Sig Transduct Target Ther (2020), 5, 22-51
- Non-Patent Document 3 New Strategies for Treatment of KRAS Mutant Metastatic Colorectal Cancer, Clin Cancer Res ., (2010), 16, 2921-2926.
- An object of the present invention is to provide a pharmaceutical composition for preventing or treating cancer in which KRAS mutations and activated RON exist.
- the present invention is a pharmaceutical composition for the prevention or treatment of cancer in which KRAS mutation and activated RON are present, comprising a compound represented by the following formula 1 or 2 or a pharmaceutically acceptable salt thereof as an active ingredient
- the KRAS mutation provides a pharmaceutical composition, wherein the amino acid residue glycine at the 13th position in the amino acid sequence of SEQ ID NO: 1 is substituted with another amino acid or the amino acid residue glycine at the 12th position is substituted with another amino acid.
- R 1 to R 7 , and X are as defined in the detailed description below.
- R 1 to R 6 , L and X are as defined in the detailed description to be described later.
- the pharmaceutical composition according to the present invention is applicable to cancer patients carrying KRAS mutations and activated RON.
- the pharmaceutical composition has excellent apoptosis inducing ability against cancer cells having KRAS G13 mutation or KRAS G12 mutation and RON mutation ( ⁇ 155, ⁇ 160, ⁇ 165) or tyrosine phosphorylated RON (pTyr-RON). It can be used as an anticancer agent representing
- Example 1 is a KRAS mutation (G12V or G13D), a result of confirming the apoptosis inducing efficacy of the compound of Example 1 and the positive control 1 in a colon cancer cell line having an activated RON.
- Figure 2 shows the cell death rate after each treatment of the compound of Example 1, positive control 1, positive control 2 or positive control 3 in SW620 cell line (KRAS G12V / mRON ⁇ 155).
- Example 4 is a result of treatment of the compound of Example 1 in various colorectal cancer patient-derived cell lines, comparing the efficacy of inducing apoptosis according to whether KRAS mutation and RON activation.
- Example 5 shows the change in tumor volume in the course of orally administering the compound of Example 1 to a mouse model implanted with the SW620 cell line for 4 weeks.
- FIG. 6 shows the tumor growth inhibition rate by measuring the tumor weight after orally administering the compound of Example 1 to a mouse model transplanted with the SW620 cell line for 4 weeks.
- Example 7 is a result of confirming the expression change of proteins through immunohistochemistry after orally administering the compound of Example 1 to a mouse model transplanted with the SW620 cell line for 4 weeks.
- Example 8 is a result of oral administration of the compounds of Example 1, positive control 1, and positive control 2 to a mouse model implanted with an HCT8 cell line (KRAS G13D/pTyr-wtRON) for 4 weeks, respectively, showing the difference in the relative tumor volume will be.
- HCT8 cell line KRAS G13D/pTyr-wtRON
- Example 10 is a result of analyzing the effect of treatment with the compound of Example 1 on apoptosis rate after overexpressing ⁇ -catenin in SW620 cell line.
- Example 11 is a result of confirming the change in the expression of each protein by the Western blot method when the compound of Example 1 is treated after overexpressing ⁇ -catenin in the SW620 cell line.
- Example 12 shows the change in tumor volume during the course of orally administering the compound of Example 1 to an animal transplanted with HCT15 (KRAS G13D/mRON ⁇ 160) cell line for 4 weeks.
- Example 13 is an analysis of expression changes of pTyr-mRON, mRON, cleaved caspase 3, and Cyclin D1 in tumor tissues after the compound of Example 1 was orally administered to animals transplanted with HCT15 cell line for 4 weeks.
- One aspect of the present invention provides a pharmaceutical composition for preventing or treating cancer in which KRAS mutation and activated RON exist, comprising a compound represented by Formula 1 or 2 or a pharmaceutically acceptable salt thereof as an active ingredient, wherein the KRAS The mutation is a KRAS mutation and activated RON, characterized in that the amino acid residue glycine at the 13th position in the amino acid sequence of SEQ ID NO: 1 is substituted with another amino acid or the amino acid residue glycine at the 12th position is substituted with another amino acid. , It provides a pharmaceutical composition for the prevention or treatment of cancer.
- KRAS is also called K-Ras, and is a factor constituting a part of RAS/MAPK, a cell signaling pathway that regulates cell growth, cell maturation and apoptosis.
- the mutated form of KRAS is found in various solid cancers such as non-small cell lung cancer, colorectal cancer, and pancreatic cancer.
- the KRAS may have the amino acid sequence of SEQ ID NO: 1.
- KRAS mutation may be one in which some amino acids of KRAS are substituted, deleted, or inserted.
- the KRAS mutation may be one in which the 12th amino acid or the 13th amino acid of SEQ ID NO: 1 is substituted with another amino acid.
- the KRAS mutation may be one in which the glycine at the 12th position is substituted with any one selected from the group consisting of aspartic acid, valine, cysteine and histidine.
- the KRAS mutation may be one in which glycine at the 13th position is substituted with any one selected from the group consisting of aspartic acid, valine and arginine.
- the KRAS mutation may be characterized in that the amino acid residue glycine at the 13th position is substituted with aspartic acid or the amino acid residue glycine at the 12th position is substituted with valine or histidine.
- activated RON may be understood as a concept including everything that can confirm that RON is an active type in all expression levels, such as DNA level, mRNA level, protein level, and the like.
- phosphorylation on the RON protein for example, phosphorylation on the kinase domain of the RON protein, may be present in an activated form, and may be in an active form induced in the presence of a ligand such as MSP.
- a ligand such as MSP.
- it may include a splicing variant or mutation of the RON gene as a form that is always activated even without a ligand.
- the activated RON may be characterized as a splicing variant of the RON gene or a phosphorylated RON protein with tyrosine.
- the splicing variant of the RON gene may be one or more selected from the group consisting of exons 5, 6 and 11 deleted by splicing. Specifically, it may be mRON ⁇ 155 in which exons 5, 6 and 11 are deleted, mRON ⁇ 160 in which exons 5 and 6 are deleted, or RON ⁇ 165 in which exon 11 is deleted.
- the cDNA of mRON ⁇ 155 may have the nucleotide sequence of SEQ ID NO: 2
- the cDNA of mRON ⁇ 160 may have the nucleotide sequence of SEQ ID NO: 3
- the cDNA of RON ⁇ 165 may have the nucleotide sequence of SEQ ID NO: 4.
- the cancer may be selected from the group consisting of breast cancer, lung cancer, stomach cancer, prostate cancer, uterine cancer, ovarian cancer, kidney cancer, pancreatic cancer, liver cancer, colorectal cancer, skin cancer, head and neck cancer, and thyroid cancer. , but is not limited thereto.
- Another aspect of the present invention provides the use of a compound represented by Formula 1 or 2, or a pharmaceutically acceptable salt thereof, for the prevention or treatment of cancer in which KRAS mutations and activated RON exist.
- Another aspect of the present invention provides the use of a compound represented by Formula 1 or 2, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for preventing or treating cancer in which KRAS mutations and activated RON exist.
- Another aspect of the present invention is to prevent or treat cancer in which KRAS mutations and activated RON exist, including administering to a subject in need of a compound represented by Formula 1 or 2 or a pharmaceutically acceptable salt thereof provides a way to
- the individual has a G13D, G13V, G13R, G12V, G12D, G12C or G12H mutation in KRAS, comprising the steps of determining whether the activated RON; And KRAS mutation and activated RON comprising the step of administering an anticancer agent comprising a compound represented by Formula 1 or 2 or a pharmaceutically acceptable salt thereof to an individual having a KRAS mutation with an activated RON as an active ingredient
- an anticancer agent comprising a compound represented by Formula 1 or 2 or a pharmaceutically acceptable salt thereof to an individual having a KRAS mutation with an activated RON as an active ingredient
- Another aspect of the present invention comprises the steps of identifying a mutation and activated RON of KRAS in an individual; And in the amino acid sequence of SEQ ID NO: 1, when a KRAS mutation in which the amino acid residue glycine at the 13th position is substituted with another amino acid or the amino acid residue glycine at the 12th position is substituted with another amino acid and activated RON are found, it is represented by Formula 1 or 2 It provides a method of providing information on an anti-cancer therapeutic agent, comprising the step of providing information that a compound or a pharmaceutically acceptable salt thereof is suitable for anti-cancer treatment of the subject.
- prevention refers to any action that inhibits or delays the occurrence, spread, and recurrence of the disease by administration of the compound
- treatment means that the symptoms of the disease are improved or beneficially changed by administration of the compound means any action.
- subject or individual means monkeys, cows, horses, sheep, pigs, chickens, turkeys, quails, cats, including humans (patients) who have or may develop a disease related to cancer related to the KRAS mutation. , refers to all animals such as dogs, mice, mice, rabbits, and guinea pigs, and may specifically refer to mammals. In addition, the subject or individual may refer to a biological sample.
- administration means providing a predetermined substance to a subject in need thereof by any suitable method, and the administration route of the compound of the present invention is administered through any general route as long as it can reach the target tissue.
- the compound of Formula 1 used in the present invention is represented as follows.
- R 1 and R 2 are each independently H, halogen, C 1-10 alkoxy, or C 1-10 haloalkyl;
- R 3 and R 4 are each independently H, halogen, C 1-10 alkyl, or C 1-10 alkoxy;
- R 5 is H, halogen, or C 1-10 alkyl
- R 6 and R 7 together with the N atom to which they are attached form a 4-10 membered heterocycle, or R 6 is —C 2 H 4 —O-CH 3 and R 7 is H, methyl or t-moiety oxycarbonyl;
- the heterocycle has or does not further have 1 or 2 heteroatoms selected from the group consisting of N, O and S in addition to the N atom to which R 6 and R 7 are bonded, and the heterocycle is halogen and C 1-6 It is unsubstituted or substituted with one or more selected from alkyl.
- the C 1-10 alkyl may include C 1-6 alkyl, C 1-3 alkyl, C 3-10 alkyl, C 3-6 alkyl, C 6-10 alkyl, and the like.
- the C 1-10 alkoxy may include C 1-6 alkoxy, C 1-3 alkoxy, C 3-10 alkoxy, C 3-6 alkoxy, C 6-10 alkoxy, and the like.
- the 4 to 10 membered heterocycle may include a 4 to 7 membered heterocycle, a 4 to 6 membered heterocycle, a 5 to 7 membered heterocycle, a 5 or 6 membered heterocycle, and the like.
- R 1 and R 2 may each independently be H, halogen, methoxy, or —CF 3 . wherein halogen may be F, Cl, Br or I.
- R 3 and R 4 may each independently be H, halogen, methyl, methoxy, or ethoxy. wherein halogen may be F, Cl, Br or I.
- R 4 may be halogen, methyl, methoxy, or ethoxy. wherein halogen may be F, Cl, Br or I.
- R 5 may be H or halogen. wherein halogen may be F, Cl, Br or I.
- R 6 And R 7 Together with the N atom to which they are bonded to form; wherein R a and R b are each independently C 1-3 alkylene; A is -N(-R 9 )- or -O-, and R 9 may be C 1-6 alkyl.
- R 6 and R 7 together with the N atom to which they are attached are azetidinyl, diazetidinyl, pyrrolidinyl, pyrrolyl, imidazolidinyl, imidazolyl, pyrazolidinyl, pyrazolyl, oxazolyl Diinyl, oxazolyl, isoxazolidinyl, isoxazolyl, thiazolidinyl, thiazolyl, isothiazolidinyl, isothiazolyl, piperidinyl, pyridinyl, piperazinyl, diazinyl, morpholino, thiomo Polyno, azepanyl, diazepanyl, or C 1-6 alkyl substituted thereto may form a heterocycle group.
- R a and R b may each independently be -CH 2 -, -C 2 H 4 - or -C 3 H 6 -.
- R 9 may be methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, n-pentyl, i-pentyl, t-pentyl, sec-pentyl, neopentyl, hexyl, etc. have.
- R 1 and R 2 are each independently H, halogen, methoxy, or —CF 3 ;
- R 3 and R 4 are each independently H, halogen, methyl, methoxy, or ethoxy;
- R 5 is H or halogen;
- R 6 is —C 2 H 4 —O-CH 3 ,
- R 7 is H, methyl or t-butoxycarbonyl, or R 6 and R 7 combine with each other to form morpholino or methylpiperazinyl can do.
- halogen may be F, Cl, Br or I.
- the compound of Formula 1 may be represented by Formula 1a below.
- R 1 to R 7 are as defined in Formula 1 above.
- R 1 and R 2 may each independently be H, halogen, or —CF 3 .
- R 3 and R 4 may each independently be H, halogen, methyl, methoxy, or ethoxy, wherein R 3 and R 4 are not H at the same time.
- R 5 may be H or halogen.
- R 1 and R 2 are each independently H, halogen, or —CF 3 ;
- R 3 and R 4 are each independently H, halogen, methyl, methoxy, or ethoxy;
- R 5 is H or halogen;
- R 6 may be —C 2 H 4 —O-CH 3 , and
- R 7 may be H, methyl or t-butoxycarbonyl.
- the compound of Formula 1 may be represented by Formula 1b below.
- R 1 to R 7 are as defined in Formula 1 above.
- R 1 and R 2 may each independently be H, halogen, or —CF 3 .
- R 4 may be halogen, methyl, methoxy, or ethoxy.
- R 5 may be H or halogen.
- R 1 and R 2 are each independently H, halogen, or —CF 3 ;
- R 4 is halogen, methyl, methoxy, or ethoxy;
- R 5 is H or halogen;
- R 6 is —C 2 H 4 —O—CH 3 ;
- R 7 may be H, methyl or t-butoxycarbonyl.
- the compound of Formula 1 may be represented by Formula 1c below.
- R 1 to R 5 are as defined in Formula 1; R a and R b are each independently C 1-3 alkylene; A is -N(-R 9 )- or -O-, and R 9 may be C 1-6 alkyl.
- R 1 and R 2 may each independently be H, halogen, or —CF 3 .
- R 3 and R 4 may each independently be H, halogen, methyl, methoxy, or ethoxy, wherein R 3 and R 4 are not H at the same time.
- R 5 may be H or halogen.
- R a and R b together with N and A to which they are attached may form morpholino or methylpiperazinyl.
- the compound of Formula 1 may be represented by Formula 1d below.
- R 1 to R 5 are as defined in Formula 1; R a and R b are each independently C 1-3 alkylene; A is -N(-R 9 )- or -O-, and R 9 may be C 1-6 alkyl.
- R 1 and R 2 may each independently be H, halogen, or —CF 3 .
- R 4 may be halogen, methyl, methoxy, or ethoxy.
- R 5 may be H or halogen.
- R a and R b together with N and A to which they are attached may form morpholino or methylpiperazinyl.
- the compound represented by Formula 1 is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
- the compound of Formula 1 used in the composition according to the present invention can be prepared by the method disclosed in Korean Patent Application Laid-Open No. 2019-0106802, and other known methods and/or various methods based on the technology in the field of organic synthesis can be manufactured by Based on the above methods, various derivatives can be synthesized using an appropriate synthesis method according to the type of the substituent.
- the compound of Formula 2 used in the present invention is represented as follows.
- L is -NH- or -CH 2 -
- R 1 to R 4 are each independently hydrogen, halogen, hydroxy, cyano, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 2-4 alkenyl, C 2-4 alkyl nyl, C 3-7 cycloalkyl, C 6-10 aryl, 5-9 membered heteroaryl or 3-9 membered heterocycloalkyl;
- X is O, S, -CH(-Rx)- or -N(-Rx)-,
- Rx is hydrogen, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl , C 6-10 aryl, C 6-10 aryl-C 1-4 alkyl, or 3 to 9 membered heterocycloalkyl;
- A is a 3- to 12-membered heterocycle
- R 5 and R 6 are each independently hydrogen, nitro, amino, halogen, hydroxy, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, amino-C 1-6 alkoxy, aminocarbonyl, C 1-6 alkylaminocarbonyl, diC 1-6 alkylaminocarbonyl, C 1-6 alkylcarbonylamino, C 1-6 alkylamino, C 1-6 alkyl-amino-C 1-6 alkoxy, C 6-10 aryl, C 6-10 aryl-C 1-4 alkyl, or 5 to 9 membered heteroaryl;
- R 5 and R 6 are each independently C 1-6 alkyl; C 1-6 alkoxy-C 1-6 alkylamino, C 1-6 alkyl or C 1-6 alkylamino-C substituted with any one of 3-9 membered cycloalkyl and 3-9 membered heterocycloalkyl 1-6 alkyl; 3- to 9-membered cycloalkyl; or unsubstituted or substituted with 3 to 9 membered heterocycloalkyl,
- Said cycloalkyl or heterocycloalkyl is halogen, oxo, cyano, hydroxy, hydroxy-C 1-6 alkyl, amino, diC 1-6 alkylamino, C 1-6 alkyl, C 1-6 alkoxy, and with or without one or more substituents selected from the group consisting of C 1-6 alkoxy-C 1-6 alkyl,
- heterocycle, heteroaryl and heterocycloalkyl each independently include one or more heteroatoms selected from the group consisting of N, O and S.
- the C 1-6 alkyl may include C 1-3 alkyl, C 3-6 alkyl, and the like.
- the C 1-6 alkoxy may include C 1-3 alkoxy, C 3-6 alkoxy, and the like.
- the 3- to 12-membered heterocycle includes a 4- to 12-membered heterocycle, a 4 to 10-membered heterocycle, a 4 or 7-membered heterocycle, a 7- to 12-membered heterocycle, and the like. can do.
- the heterocycle may include an aromatic ring or a non-aromatic ring, and as an example, the 3- to 12-membered heterocycle may include one or more aromatic rings.
- the heterocycle is quinoline, quinazoline, pyridine, pyrimidine, thienopyridine, pyrrolopyridine, pyrazolopyridine, imidazopyridine, pyrrolopyrimidine, dihydropyrrolopyrimidine, furopyridine, pyra zolopyrimidine, purine, indazole, azetidine, diazetidine, pyrrolidine, pyrrole, imidazolidine, imidazole, pyrazolidine, pyrazole, oxazolidine, oxazole, isoxazolidine, isoxane sazole, thiazolidine, thiazole, isothiazolidine, isothiazole, piperidine, pyridine, piperazine, diazine, morpholine, thiomorpholine, azepan, diazepan, and the like.
- R 1 to R 4 may each independently be hydrogen, C 1-4 haloalkyl, or halogen. wherein halogen may be F, Cl, Br or I. Specifically, R 1 may be hydrogen, trifluoromethyl, or fluoro, R 2 may be hydrogen, R 3 may be fluoro, and R 4 may be hydrogen.
- X may be O or -CH(-Rx)-, and Rx may be hydrogen or C 1-6 alkyl.
- A may be quinoline or thienopyridine.
- the thienopyridine is or It may be represented by the structural formula of
- the pyrrolopyridine is or It may be represented by the structural formula of
- the pyrrolopyrimidine is or It may be represented by the structural formula of
- the dihydropyrrolopyrimidine is or It may be represented by the structural formula of
- the pyrazolopyridine is or It may be represented by the structural formula of
- the pyrazolopyrimidine is or It may be represented by the structural formula of
- the imidazopyridine is or It may be represented by the structural formula of
- the furopyridine is or It may be represented by the structural formula of
- the purine is or It may be represented by the structural formula of
- R 5 and R 6 are each independently hydrogen, amino, halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, amino -C 1-6 alkoxy, aminocarbonyl, C 1-6 alkylaminocarbonyl, diC 1-6 alkylcarbonylamino, C 1-6 alkylcarbonylamino, C 1-6 alkylamino, C 1-6 alkyl-amino-C 1-6 alkoxy, or 5 to 9 membered heteroaryl, wherein R 5 and R 6 are each independently C 1-6 alkyl; C 1-6 alkoxy -C 1-6 alkyl-amino, 3-to 9-membered cycloalkyl and 3-to 9 heterocycloalkyl source of any one of the substituted C 1-6 alkyl or C 1-6 alkyl-amino -C 1-6 alkyl; 3- to 9-membered cycloalkyl; or 3 to 9 membere
- the heteroaryl is pyridinyl, imidazolyl, or pyrazolyl
- the heterocycloalkyl is azetidinyl, pyrrolidinyl, tetrahydropyranyl, morpholino, morpholinyl, dioxidothiomorphol no, piperazinyl, piperidinyl, or oxetanyl, wherein the cycloalkyl can be cyclobutyl, cyclopentyl, or cyclohexyl.
- heteroaryl or heterocycloalkyl includes one or more N atoms
- any one of them may be substituted at the N atom position, but is not particularly limited.
- R 1 and R 2 are hydrogen, C 1-4 haloalkyl, or halogen
- R 3 and R 4 are hydrogen or halogen
- X is O or —CH(- Rx)-
- Rx is hydrogen or C 1-4 alkyl
- A is quinoline, thienopyridine
- R 5 and R 6 are each independently hydrogen, amino, halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, amino-C 1-6 alkoxy, aminocarbonyl, C 1-6 alkylaminocarbonyl, diC 1-6 alkylcarbonylamino, C 1-6 alkylcarbonyl amino, C 1-6 alkylamino, C 1-6 alkyl-amino-C 1-6 alkoxy, or 5-9 membered heteroaryl, wherein R 5 and R 6 are each independently C 1-6 alkyl; C 1-6 alkoxy -C 1-6 alkyl-amino, 3-to 9-
- R 5 and R 6 are each independently hydrogen, nitro, amino, halogen, hydroxy, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 1 -6 alkoxy, amino, -C 1-6 alkoxy, aminocarbonyl, C 1-6 alkylamino-carbonyl, di-C 1-6 alkylamino-carbonyl, C 1-6 alkylcarbonylamino, C 1-6 alkylamino , C 1-6 alkyl-amino-C 1-6 alkoxy, C 6-10 aryl, C 6-10 aryl-C 1-4 alkyl, or 5-9 membered heteroaryl, said amino, said alkyl,
- the alkoxy, the aryl and the heteroaryl are each independently C 1-6 alkyl; C 1-6 alkoxy-C 1-6 alkylamino, C 1-6 alkyl or C 1-6 alkylamino-C substituted with any one of 3-9 membered cycloalky
- R 5 and R 6 may not be C 6-10 aryl, C 6-10 aryl-C 1-4 alkyl, or 5- to 9-membered heteroaryl at the same time.
- R 5 and R 6 are simultaneously C 1-6 alkyl or C 1 substituted with any one of 3 to 9 membered cycloalkyl and 3 to 9 membered heterocycloalkyl.
- -6 alkylamino-C 1-6 alkyl; 3- to 9-membered cycloalkyl; or 3 to 9 membered heterocycloalkyl may not be substituted.
- R 5 when R 5 includes a ring such as aryl or heteroaryl, R 6 may not include these rings at the same time. Also, when R 5 is substituted with a group including a ring such as cycloalkyl or heterocycloalkyl, R 6 may not be simultaneously substituted with a group including a ring.
- R 5 is C 6-10 aryl, C 6-10 aryl-C 1-4 alkyl, or 5 to 9 membered heteroaryl
- R 6 is hydrogen, nitro, amino, halogen, hydroxy , cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, amino-C 1-6 alkoxy, aminocarbonyl, C 1-6 alkylaminocarbonyl, diC 1-6 alkyl aminocarbonyl, C 1-6 alkylcarbonylamino, C 1-6 alkylamino, or C 1-6 alkyl-amino-C 1-6 alkoxy.
- R 5 is C 1-6 alkyl; Or C 1-6 alkoxy -C 1-6 alkyl, 3-to 9 circle of cycloalkyl and 3-to 9-membered heterocycloalkyl of any one of the substituted C 1-6 alkyl or C 1-6 alkyl-amino- It may be unsubstituted or substituted with C 1-6 alkyl.
- R 6 is a 3- to 9-membered cycloalkyl; Or it may be unsubstituted or substituted with 3 to 9 membered heterocycloalkyl.
- cycloalkyl or heterocycloalkyl is halogen, oxo, cyano, hydroxy, hydroxy-C 1-6 alkyl, amino, diC 1-6 alkylamino, C 1-6 alkyl, C 1-6 alkoxy, and C 1-6 alkoxy-C 1-6 alkyl with or without one or more substituents selected from the group consisting of, wherein the heteroaryl and the heterocycloalkyl are each independently selected from the group consisting of N, O and S It may contain one or more heteroatoms.
- the compound of Formula 2 may be represented by Formula 2a below.
- B is a 5- or 6-membered aromatic heterocycle containing 1 or 2 N atoms
- R 7 is C 1-6 alkyl; Or C 1-6 alkoxy -C 1-6 alkyl, 3-to 9 circle of cycloalkyl and 3-to 9-membered heterocycloalkyl of any one of the substituted C 1-6 alkyl or C 1-6 alkyl-amino- C 1-6 alkyl;
- Said cycloalkyl or heterocycloalkyl is halogen, oxo, cyano, hydroxy, hydroxy-C 1-6 alkyl, amino, diC 1-6 alkylamino, C 1-6 alkyl, C 1-6 alkoxy, and with or without one or more substituents selected from the group consisting of C 1-6 alkoxy-C 1-6 alkyl,
- the heterocycloalkyl includes 1 to 4 heteroatoms selected from the group consisting of N, O and S.
- the compound of Formula 2 may be represented by Formula 2b below.
- R 5 and R 6 are each independently hydrogen, amino, halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, amino-C 1-6 alkoxy, aminocarbonyl, C 1-6 alkylaminocarbonyl, diC 1-6 alkylcarbonylamino, C 1-6 alkylcarbonylamino, C 1-6 alkylamino, or C 1-6 alkyl-amino-C 1-6 alkoxy;
- R 5 and R 6 are each independently 3 to 9 membered cycloalkyl; or unsubstituted or substituted with 3 to 9 membered heterocycloalkyl,
- Said cycloalkyl or heterocycloalkyl is halogen, oxo, cyano, hydroxy, hydroxy-C 1-6 alkyl, amino, diC 1-6 alkylamino, C 1-6 alkyl, C 1-6 alkoxy, and with or without one or more substituents selected from the group consisting of C 1-6 alkoxy-C 1-6 alkyl,
- the heterocycloalkyl includes 1 to 4 heteroatoms selected from the group consisting of N, O and S.
- the compound represented by Formula 2 is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
- the compound of Formula 2 used in the composition according to the present invention can be prepared by the method disclosed in Korean Patent Application Laid-Open No. 2021-0015730, and other known methods and/or various methods based on the technology in the field of organic synthesis. can be manufactured by Based on the above methods, various derivatives can be synthesized using an appropriate synthesis method according to the type of the substituent.
- the compound included as an active ingredient in the pharmaceutical composition of the present invention may be represented by Formula 3 below. That is, the pharmaceutical composition according to the present invention may include a compound represented by the following Chemical Formula 3 or a pharmaceutically acceptable salt thereof.
- X is hydrogen or halogen
- Y is hydrogen or halogen
- R 1 and R 2 are each independently hydrogen or C 1-10 alkoxy, or linked to each other to form a 5- to 10-membered heterocycloalkyl having a heteroatom O;
- R is 5-7 membered heteroaryl with 1 or 2 heteroatoms N;
- R 3 is hydrogen or —(CH 2 ) n —R 4 ;
- n is an integer from 0 to 10;
- R 4 is a 5- to 10-membered heterocycle having 1 or 2 heteroatoms selected from the group consisting of N, O and S.
- X and Y may each be hydrogen or fluoro.
- R 1 and R 2 are each independently hydrogen, methyl, methoxy, or ethoxy and are not hydrogen at the same time, or are linked to each other and have a heteroatom O from 5 to 10 members of heterocycloalkyl.
- R may be a 5- to 6-membered heteroaryl having one or two heteroatoms N.
- R 3 is hydrogen or —(CH 2 )nR 4 , wherein n is an integer from 0 to 4, and R 4 is a 6-membered group having N and O heteroatoms. It may be a heterocycle.
- X and Y are fluoro; R 1 and R 2 are each independently ethoxy or hydrogen and at the same time not hydrogen, or 5 membered heterocycloalkyl linked to each other having a heteroatom O; R is pyridine or imidazole; R 3 is hydrogen or —(CH 2 )—R 4 ; R 4 may be a 6 membered heterocycle having heteroatoms of N and O.
- the compound of Formula 3 may be prepared by the method disclosed in Korean Patent Publication No. 2019-0106802 or No. 2021-0015730, and by various methods based on other known methods and/or techniques in the field of organic synthesis. can be manufactured. Based on the above methods, various derivatives can be synthesized using an appropriate synthesis method according to the type of the substituent.
- halogen means F, Cl, Br or I, unless otherwise stated.
- alkyl unless otherwise specified, means a linear or branched saturated hydrocarbon moiety.
- C 1-10 alkyl refers to alkyl having a backbone of 1 to 10 carbons. Specifically, C 1-10 alkyl is methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, n-pentyl, i-pentyl, t-pentyl, sec-pentyl, neopentyl , hexyl, heptyl, octyl, nonyl, decyl, and the like.
- haloalkyl means an alkyl substituted with one or more halogens. Specifically, haloalkyl may be an alkyl in which two or more halogens of the same kind are substituted or two or more kinds of halogens are substituted.
- alkoxy means a group having the formula -O-alkyl, wherein the alkyl group as defined above is attached to the parent compound through an oxygen atom.
- the alkyl portion of the alkoxy group has 1 to 20 carbon atoms (ie, C 1-20 alkoxy), 1 to 12 carbon atoms (ie, C 1-12 alkoxy), or 1 to 6 carbon atoms (ie, C 1 ). -6 alkoxy).
- suitable alkoxy groups include methoxy (-O-CH 3 or -OMe), ethoxy (-OCH 2 CH 3 or -OEt), t-butoxy (-OC(CH 3 ) 3 or -O-tBu) etc.
- aryl means an aromatic hydrocarbon radical derived by the removal of one hydrogen atom from a carbon atom constituting a parent aromatic ring system.
- an aryl group can have 6 to 20 carbon atoms, 6 to 14 carbon atoms, or 6 to 10 carbon atoms.
- cycloalkyl refers to a saturated monocycle or polycycle containing only carbon atoms in the ring. Cycloalkyl can have 3 to 7 carbon atoms as a monocycle, 7 to 12 carbon atoms as a bicyclo, and up to about 20 carbon atoms as a polycyclo.
- heterocycle means an aromatic or non-aromatic ring having one or more heteroatoms, and may be saturated or unsaturated, and may be monocyclic or polycyclic.
- a 4 to 10 membered heterocycle means a heterocycle having a backbone of 4 to 10 atoms in total including heteroatoms and carbon atoms.
- a 4- to 10-membered heterocycle is azetidine, diazetidine, pyrrolidine, pyrrole, imidazolidine, imidazole, pyrazolidine, pyrazole, oxazolidine, oxazole, isoxazolidine, isoxazole, thiazolidine, thiazole, isothiazolidine, isothiazole, piperidine, pyridine, piperazine, diazine, morpholine, thiomorpholine, azepane, diazepane, and the like.
- heterocycle is described as a substituent in the present specification, it may be used as a term encompassing "heteroaryl” and "heterocycloalkyl”.
- heteroaryl refers to an aromatic heterocyclyl having one or more heteroatoms in the ring.
- Non-limiting examples of heteroaryl include pyridinyl, pyrrolyl, oxazolyl, indolyl, isoindolyl, purinyl, furanyl, thienyl, benzofuranyl, benzothiophenyl, carbazolyl, imidazolyl, thia zolyl, isoxazolyl, pyrazolyl, isothiazolyl, quinolyl, isoquinolyl, pyridazyl, pyrimidyl, pyrazyl, which may have one or more substituents on the ring; and the like.
- heterocycloalkyl refers to a non-aromatic heterocyclyl having one or more heteroatoms in the ring.
- a heterocycloalkyl may have one or more carbon-carbon double bonds or carbon-heteroatom double bonds in the ring to the extent that the ring is not aromatic due to the presence of the double bond.
- heterocycloalkyl examples include azetidinyl, aziridinyl, pyrrolidinyl, piperidinyl, piperazinyl, homopiperazinyl, morpholino, thiomorpholino, tetrahydrofuranyl, tetrahydrothio furanyl, tetrahydropyranyl, pyranyl (which may have one or more substituents on the ring), and the like.
- heteroatom means an atom other than carbon (C), and specifically may be a nitrogen (N), oxygen (O) or sulfur (S) atom.
- the aforementioned heteroaryl and heterocycloalkyl include one or more heteroatoms, and may include, for example, 1, 1-2, 1-3, or 1-4 heteroatoms.
- substitution refers to the replacement of a hydrogen atom in a molecular structure with a substituent such that the compound is chemically stable from such substitution without exceeding the valence on the designated atom.
- group A is substituted with substituent B or "group A has substituent B” means that a hydrogen atom bonded to an atom such as carbon constituting the backbone of group A is replaced with substituent B, and the group It may mean that A and the substituent B form a covalent bond.
- the pharmaceutical composition of the present invention contains, as an active ingredient, the compound represented by Formula 1 or 2, or a pharmaceutically acceptable salt thereof, in an amount of about 0.1% to about 90% by weight, specifically about 0.5% by weight, based on the total weight of the composition. It may be contained in an amount of from about 75% by weight to about 75% by weight, more specifically from about 1% to about 50% by weight.
- the pharmaceutical composition of the present invention may include conventional and non-toxic pharmaceutically acceptable additives formulated into a formulation according to a conventional method.
- the pharmaceutical composition may further include a pharmaceutically acceptable carrier, diluent or excipient.
- additives used in the composition of the present invention include sweetening agents, binders, solvents, solubilizing agents, wetting agents, emulsifying agents, isotonic agents, absorbents, disintegrating agents, antioxidants, preservatives, lubricants, glidants, fillers, flavoring agents, and the like.
- the additive may include lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, glycine, silica, talc, stearic acid, stearin, magnesium stearate, magnesium aluminosilicate, starch, gelatin, gum tragacanth, alginic acid, sodium alginate, methylcellulose, sodium carboxymethylcellulose, agar, water, ethanol, polyethylene glycol, polyvinylpyrrolidone, sodium chloride, calcium chloride, orange essence, strawberry essence, vanilla flavor, and the like.
- composition of the present invention may be formulated in various formulation forms for oral administration (eg, tablets, pills, powders, capsules, syrups or emulsions) or parenteral administration (eg, intramuscular, intravenous or subcutaneous injection).
- oral administration eg, tablets, pills, powders, capsules, syrups or emulsions
- parenteral administration eg, intramuscular, intravenous or subcutaneous injection.
- the composition of the present invention may be formulated as a formulation for oral administration.
- the additives used at this time include cellulose, calcium silicate, corn starch, lactose, sucrose, dextrose, calcium phosphate, stearic acid, magnesium stearate, calcium stearate, gelatin, talc, surfactant, suspending agent, emulsifier, diluent, etc. may be included.
- solid preparations for oral administration include tablets, pills, powders, granules, capsules, and the like, and such solid preparations include at least one excipient in the composition, for example, starch, calcium carbonate, sucrose, lactose. , gelatin, etc. may be mixed and formulated.
- excipients for example, starch, calcium carbonate, sucrose, lactose. , gelatin, etc.
- lubricants such as magnesium stearate and talc may be used.
- liquid formulations for oral administration may be exemplified by suspensions, emulsions, syrups, etc., and various excipients, for example, wetting agents, sweeteners, fragrances, preservatives, etc. in addition to water and liquid paraffin, which are commonly used simple diluents. may be included.
- formulations for parenteral administration include sterile aqueous solutions, non-aqueous solutions, suspensions, emulsions, lyophilized formulations and suppositories.
- Non-aqueous solvents and suspending agents include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate.
- the suppositories are Witepsol, Macrogol, and Tween61. Cacao butter, laurin fat, glycerogelatin, etc. may be used.
- the injection may contain conventional additives such as solubilizers, isotonic agents, suspending agents, emulsifiers, stabilizers, preservatives, and the like.
- a compound or composition of the present invention may be administered to a patient in a therapeutically or pharmaceutically effective amount.
- terapéuticaally effective amount refers to an amount of a compound or composition effective to prevent or treat a target disease, which is sufficient to treat the disease at a reasonable benefit/risk ratio applicable to medical treatment, and It means an amount that does not cause side effects.
- the level of the effective amount may be determined by the patient's health status, disease type, severity, drug activity, drug sensitivity, administration method, administration time, administration route and excretion rate, treatment period, combination or factors including drugs used concurrently and It may be determined according to factors well known in the medical field.
- the compounds or compositions of the present invention may be administered as separate therapeutic agents or in combination with other therapeutic agents, may be administered sequentially or simultaneously with conventional therapeutic agents, and may be administered singly or in multiples. Taking all of the above factors into consideration, it is important to administer an amount that can obtain the maximum effect with the minimum amount of side effects or without side effects, which can be easily determined by those skilled in the art.
- the effective amount of the compound in the composition of the present invention may vary depending on the age, sex, and weight of the patient, and in general, from about 0.1 mg to about 1,000 mg, or from about 5 mg to about 200 mg per kg of body weight daily or It can be administered every other day or divided into 1 to 3 times a day.
- the scope of the present invention is not limited thereto, since it may increase or decrease depending on the route of administration, the severity of the disease, sex, weight, age, and the like.
- the compound or composition of the present invention is administered for tumor therapy in combination with chemotherapy, radiation therapy, immunotherapy, hormone therapy, bone marrow transplantation, stem cell replacement therapy, other biological therapy, surgical intervention or a combination thereof.
- a compound or composition of the present invention can be used as an adjuvant therapy in combination with other long-term treatment strategies, or to maintain the patient's condition after tumor regression or chemopreventive therapy in critically ill patients.
- the pharmaceutical composition of the present invention may further include one or more active ingredients, and the additional active ingredients include anti-proliferative compounds such as aromatase inhibitors, anti-estrogens, topoisomerase I inhibitors, and topoisomerase. II inhibitors, microtubule active compounds, alkylating compounds, histone deacetylase inhibitors, compounds inducing cell differentiation processes, cyclooxygenase inhibitors, MMP inhibitors, mTOR inhibitors, anti-neoplastics, anti-metabolites, platinum compounds , compounds targeting/reducing protein or lipid kinase activity, anti-angiogenic compounds, compounds targeting, reducing or inhibiting the activity of protein or lipid phosphatase, gonadorelin agonists, anti-androgens, methionine aminopeptidase Inhibitors, bisphosphonates, biological response modifiers, anti-proliferative antibodies, heparanase inhibitors, inhibitors of Ras tumorigenic isoforms, telomerase inhibitors
- the additional active ingredient may be a known anticancer agent.
- the anticancer agent are DNA alkylating agents, mechloethamine, chlorambucil, phenylalanine, mustard, cyclophosphamide, ipo spamid (ifosfamide), carmustine (BCNU), lomustine (CCNU), streptozotocin, busulfan, thiotepa, cisplatin and carboplatin (carboplatin);
- anti-cancer antibiotics dactinomycin (actinomycin D), doxorubicin (adriamycin), daunorubicin, idarubicin, mitoxantrone, plicama plicamycin, mitomycin C and bleomycin; and plant alkaloids vincristine, vinblastine, paclitaxel, docetaxel, etoposide, teniposide, topotecan and irinotecan and the like.
- Example 1 4-ethoxy-N-[3-fluoro-4-( ⁇ 2-[5-(morpholinomethyl)pyridin-2-yl]thieno[3,2-b]pyridine-7 -yl ⁇ oxy)phenyl]-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide hydrochloride
- the title compound was synthesized by the method described in Example 31 of Korean Patent Application Laid-Open No. 2019-0106802.
- the title compound was synthesized by the method described in Example 1 of Korean Patent Application Laid-Open No. 2019-0106802.
- the title compound was synthesized by the method described in Example 34 of Korean Patent Application Laid-Open No. 2019-0106802.
- the title compound was synthesized by the method described in Example 8 of Korean Patent Application Laid-Open No. 2021-0015730.
- the title compound was synthesized by the method described in Example 78 of Korean Patent Application Laid-Open No. 2021-0015730.
- the title compound was synthesized by the method described in Example 88 of Korean Patent Application Laid-Open No. 2021-0015730.
- N- ⁇ 4-[(2-amino-3-chloro-4-pyridinyl)oxy]-3-fluorophenyl ⁇ which is compound 1 disclosed in US Patent No. 8,536,200 B2 -4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydro-3-pyridinecarboxamide was used, which is a well-known RON inhibitor, BMS-777607.
- N-(4- ⁇ [6,7-bis(methyloxy)quinolin-4-yl]oxy ⁇ phenyl)-N which is compound 1 disclosed in PCT International Publication WO 2014/165786 A1 '-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide was used, which is a well-known anticancer drug cabozantinib.
- DMSO Dimethylsulfoxide
- Example 1 To compare the cytotoxicity of the compounds of Example 1, Example 2, Example 3, Example 4, Example 5, Example 6 and positive control 1 to colon cancer cell lines, an MTS assay was performed and , the apoptosis rate for colon cancer cell lines was analyzed to compare the anticancer activity.
- MTS assay was performed by seeding 1,000 each colorectal cancer cell line per well in a 96-well plate, and 24 hours later, in 100 ⁇ l of 10% FBS-RPMI medium (Welgene) at various concentrations (0.000001 ⁇ M to 10 ⁇ M) per well. of Examples 1 to 6 and the compounds of positive control 1 were treated. Then, after culturing the cells for 72 hours, 20 ⁇ l of MTS solution (Promega) was added, followed by incubation for 2 hours, and absorbance was measured at 490 nm.
- FBS-RPMI medium Welgene
- MTS solution Promega
- Examples 1 to 6 and positive control 1 using GraphPad Prism TM 5 The cytotoxicity was analyzed by deriving the IC 50 for the compound of The compounds of Examples 1 to 6 showed high efficacy in most cell lines except for SNUC2A, which was inactive in RON. Among them, it was confirmed that the compound of Example 4 showed high efficacy in cell lines (HCT8 and DLD-1) expressing most mRON or activated RON (pTyr-wtRON) except for SW620. On the other hand, the compound of the positive control 1 showed a high IC 50 value in most cell lines, confirming that the reactivity to the drug was low.
- each of the colorectal cancer cell lines SNU-C2A, HCT8, T84, SW620 was inoculated into a 60 mm plate by 3x10 5 each. After preparation, incubated for 24 hours. After 24 hours, Example 1 and positive control 1 were treated at 1 ⁇ M and incubated for 48 hours.
- SW620 cell line was prepared by inoculating 3x10 5 each on a 60 mm plate, and then cultured for 24 hours. After 24 hours, Example 1, positive control 1, positive control 2, and positive control 3 were each treated with 1 ⁇ M.
- the SNUC2A cell line inactive in RON did not show reactivity to the compound of Example 1, and it was confirmed that the compound of the positive control 1 had little reactivity even in T84 and SW620 cell lines harboring the RON mutation. In addition, it was confirmed that the SW620 cell line was treated with the compound of Example 1 to show a high apoptosis rate. On the other hand, as shown in FIG. 2 , it was confirmed that the SW620 cell line treated with the compounds of the positive control 1, the positive control 2, or the positive control 3 did not induce apoptosis.
- RNA was extracted from a cell line derived from a colorectal cancer patient using a Trizol reagent the reverse transcriptase process was performed. PCR was performed using a primer capable of confirming the RON mutation of the reverse transcribed sample, and each band was sequenced to determine whether the mutation was present.
- the base sequence of the primer used is as follows.
- the human colorectal cancer patient-derived cell line SW620 KRAS G12V/mRON ⁇ 155 5 ⁇ 10 6 cells/mice was subcutaneously (100 ⁇ l) on the right ventral side of the mouse. injected. When the tumor size reached about 100 mm 3 , the compound of Example 1 was orally administered. Once a day, the drug was administered for 4 weeks, and the tumor size and body weight of the mice were measured twice a week. After the drug administration was completed, the experimental animals were euthanized, the tumors were excised, and the weights were measured for comparative analysis.
- Part of the extracted tumor tissue was fixed in 10% formalin, and a paraffin block was prepared and then sliced. Staining of the slides was carried out through immunochemical staining, and a part of the extracted tumor tissue was lysed and the expression change of each protein was confirmed by Western blot analysis.
- the tumor growth inhibition rate after administration of the compound of Example 1 in the SW620 cell line (KRAS G12V/mRON ⁇ 155) transplanted animal model is shown in Table 5 below.
- Human beta-catenin pcDNA3.1 a vector in which an empty vector and ⁇ -catenin DNA (X87838.1, GENE ID: 1499) were introduced into the human colorectal cancer patient-derived cell line SW620 (KRAS G12V/mRON ⁇ 155) ( Plasmid #16828, Addgene) was treated with the compound of Example 1 after each transfection, and when 48 hours had elapsed, all cells were collected and trypan blue exclusion assay was used. to compare and analyze the apoptosis induction efficacy. As such, after overexpressing ⁇ -catenin in the SW620 cell line, the apoptosis-inducing efficacy was observed by treatment with the compound of Example 1, and as shown in FIG. 10 , it was confirmed that the apoptosis-inducing efficacy was reduced.
- ⁇ -catenin, p-ERK, ERK, c-myc, Cyclin D1 pTyr- using a sample treated with the compound of Example 1 after overexpressing ⁇ -catenin in the SW620 cell line as described above, by Western blot method. Expression of mRON, mRON, and cleaved caspase 3 was confirmed. As a result, as shown in FIG. 11 , the expression of pTyr-mRON was reduced by the compound of Example 1 regardless of ⁇ -catenin, and p-ERK, c-myc, and Cyclin D1 were transfected with an empty vector. It was decreased in the cell line, but it was confirmed that it increased again when ⁇ -catenin was overexpressed.
- the human colon cancer-derived cell line HCT15 KRAS G13D/mRON ⁇ 160 5 ⁇ 10 6 cells/mice was subcutaneously (100 ⁇ l) on the right ventral side of the mouse. injected.
- the tumor size reached about 100 mm 3
- the compound of Example 1 was orally administered.
- the drug was administered for 4 weeks, and the tumor size and body weight of the mice were measured twice a week.
- FIG. 12 it was confirmed that a high tumor growth inhibitory effect was exhibited in the group administered with the compound of Example 1.
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Abstract
본 발명은 KRAS 돌연변이 및 활성화된 RON이 존재하는 암의 예방 또는 치료용 약학 조성물에 관한 것이다. 구체적으로, 상기 약학 조성물은 KRAS G13 돌연변이 또는 KRAS G12 돌연변이 및 RON 돌연변이 또는 티로신이 인산화된 RON을 보유하는 암 세포에 대한 우수한 세포 사멸 유도능을 나타내는 항암제로서 활용될 수 있다.
Description
본 발명은 KRAS 돌연변이 및 활성화된 RON이 존재하는 암 세포를 보유하고 있는 암 환자에 적용 가능한 암 예방 또는 치료용 약학 조성물에 관한 것이다.
KRAS(V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog) 유전자는 비소세포 폐암, 대장암, 췌장암 등의 발생에 연관된 여러 유전자 중 하나이며, 세툭시맙(cetuximab)과 같은 항암제의 효과 여부를 판단하는데 중요하게 고려되고 있다. 구체적으로 KRAS 유전자의 돌연변이 여부를 고려하여 암 환자의 약물의 반응 및 생존 기간을 의미 있게 개선시키는 것으로 알려져 있다.
한편, RON(recepteur d'origine nantais)은 c-MET 계열에 속하는 단백질 수용체로서, 간에서 분비되며 대식세포의 작용을 조절하는 혈청 단백질(macrophage-stimulating protein; MSP)의 수용체이다. RON의 활성 여부는 종양의 발생, 진행 및 전이에 중요한 역할을 한다. 특히, 대장암 및 유방암에서 과발현 또는 과활성되면 종양의 침윤 및 전이를 유도하고 세포사멸을 억제하는데 기여하는 것으로 보고되고 있다. 이러한 RON의 비정상적인 활성을 특이적으로 억제할 수 있는 물질은 RON과 관련된 여러 질환, 특히 대장암과 같은 종양을 효과적으로 치료할 수 있다.
따라서, KRAS 돌연변이 및 비정상적으로 활성화된 RON을 보유하고 있는 암 환자의 암 세포를 특이적으로 사멸할 수 있는 물질에 관한 연구가 최근 지속적으로 활발하게 전개되고 있다.
[선행기술문헌]
(비특허문헌1) Targeting Receptor Kinases in Colorectal Cancer, Cancers (2019), 11, 433-456.
(비특허문헌2) Comprehensive review of targeted therapy for colorectal cancer, Sig Transduct Target Ther (2020), 5, 22-51
(비특허문헌3) New Strategies for Treatment of KRAS Mutant Metastatic Colorectal Cancer, Clin Cancer Res., (2010), 16, 2921-2926.
본 발명자들은 KRAS 돌연변이 및 비정상적으로 활성화된 RON을 보유하고 있는 암 환자에 적용 가능한 암 예방 또는 치료용 약학 조성물을 개발하기 위해 노력한 결과, 특정 구조를 가지는 화합물들이 KRAS 돌연변이 및 활성화된 RON을 보유하고 있는 암 세포에 대하여 우수한 세포 사멸 효과를 나타내는 것을 확인하여 본 발명을 완성하였다.
본 발명의 과제는, KRAS 돌연변이 및 활성화된 RON이 존재하는 암의 예방 또는 치료용 약학 조성물을 제공하는 것이다.
상기 목적을 달성하기 위하여, 본 발명은 하기 화학식 1 또는 2로 표시되는 화합물 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 포함하는 KRAS 돌연변이 및 활성화된 RON이 존재하는 암의 예방 또는 치료용 약학 조성물로서, 상기 KRAS 돌연변이는 서열번호 1의 아미노산 서열에서 13번째 위치의 아미노산 잔기 글리신이 다른 아미노산으로 치환되거나 12번째 위치의 아미노산 잔기 글리신이 다른 아미노산으로 치환된 것인, 약학 조성물을 제공한다.
[화학식 1]
상기 화학식 1에서, R1 내지 R7, 및 X는 후술하는 구체적인 설명에서 정의한 바와 같다.
[화학식 2]
상기 화학식 2에서, R1 내지 R6, L 및 X는 후술하는 구체적인 설명에서 정의한 바와 같다.
본 발명에 따른 약학 조성물은 KRAS 돌연변이 및 활성화된 RON을 보유하고 있는 암 환자에 적용 가능하다. 구체적으로, 상기 약학 조성물은 KRAS G13 돌연변이 또는 KRAS G12 돌연변이 및 RON 돌연변이(△155, △160, △165) 또는 티로신이 인산화된 RON(pTyr-RON)을 보유하는 암 세포에 대한 우수한 세포 사멸 유도능을 나타내는 항암제로서 활용될 수 있다.
도 1은 KRAS 돌연변이(G12V 또는 G13D)가 있고, 활성화된 RON을 가진 대장암 세포주에서 실시예 1 및 양성 대조군 1의 화합물의 세포 사멸 유도 효능을 확인한 결과이다.
도 2는 SW620 세포주(KRAS G12V/mRON △155)에 실시예 1, 양성 대조군 1, 양성 대조군 2 또는 양성 대조군 3의 화합물을 각각 처리한 후 세포 사멸율을 나타낸 것이다.
도 3은 다양한 대장암 환자 유래 세포주에서 면역형광 염색(immunofluorescence staining)을 통해 pTyr-RON의 발현을 확인한 결과이다.
도 4는 다양한 대장암 환자 유래 세포주에 실시예 1의 화합물을 처리하여, KRAS 돌연변이 및 RON 활성화 여부에 따른 세포 사멸 유도 효능을 비교한 결과이다.
도 5는 SW620 세포주를 이식한 마우스 모델에 실시예 1의 화합물을 경구로 4주 동안 투여하는 과정에서 종양 부피의 변화를 나타낸 것이다.
도 6은 SW620 세포주를 이식한 마우스 모델에 실시예 1의 화합물을 경구로 4주 동안 투여한 후, 종양 무게를 측정하여 종양 성장 억제율을 나타낸 것이다.
도 7은 SW620 세포주를 이식한 마우스 모델에 실시예 1의 화합물을 경구로 4주 동안 투여한 후에 단백질들의 발현 변화를 면역화학 염색(immunohistochemistry)을 통하여 확인한 결과이다.
도 8은 HCT8 세포주(KRAS G13D/pTyr-wtRON)를 이식한 마우스 모델에 실시예 1, 양성 대조군 1 및 양성 대조군 2의 화합물을 각각 경구로 4주 동안 투여한 결과, 상대적인 종양 부피의 차이를 나타낸 것이다.
도 9는 HCT8 세포주를 이식한 동물에 실시예 1, 양성 대조군 1 및 양성 대조군 2의 화합물을 각각 경구로 4주 동안 투여한 후 종양 조직에서 pTyr-mRON, mRON, cleaved caspase 3, Cyclin D1의 발현 변화를 분석한 결과이다.
도 10은 SW620 세포주에 β-카테닌(β-catenin)을 과발현시킨 후, 실시예 1의 화합물을 처리하여 세포 사멸율에 미치는 영향을 분석한 결과이다.
도 11은 SW620 세포주에 β-카테닌을 과발현시킨 후, 실시예 1의 화합물을 처리하였을 때 각각의 단백질 발현의 변화를 웨스턴 블럿의 방법으로 확인한 결과이다.
도 12는 HCT15(KRAS G13D/mRON △160) 세포주를 이식한 동물에 실시예 1의 화합물을 경구로 4주 동안 투여하는 과정에서 종양 부피의 변화를 나타낸 것이다.
도 13은 HCT15 세포주를 이식한 동물에 실시예 1의 화합물을 경구로 4주 동안 투여한 후 종양 조직에서 pTyr-mRON, mRON, cleaved caspase 3, Cyclin D1의 발현 변화를 분석한 것이다.
이하 본 발명을 보다 구체적으로 설명한다.
본 발명은 일 측면은, 화학식 1 또는 2로 표시되는 화합물 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 포함하는 KRAS 돌연변이 및 활성화된 RON이 존재하는 암의 예방 또는 치료용 약학 조성물로서, 상기 KRAS 돌연변이는 서열번호 1의 아미노산 서열에서 13번째 위치의 아미노산 잔기 글리신이 다른 아미노산으로 치환되거나 12번째 위치의 아미노산 잔기 글리신이 다른 아미노산으로 치환된 것을 특징으로 하는 KRAS 돌연변이 및 활성화된 RON이 존재하는 것인, 암의 예방 또는 치료용 약학 조성물을 제공한다.
본 명세서에서 사용된 용어 "KRAS"는 K-Ras라고도 불리우며, 세포 성장, 세포 성숙 및 세포 사멸을 조절하는 세포 신호 전달 경로인 RAS/MAPK의 일부를 구성하는 인자이다. 상기 KRAS가 돌연변이된 형태는 비소세포 폐암, 대장암, 췌장암 등 다양한 고형암에서 발견된다. 이때, 상기 KRAS는 서열번호 1의 아미노산 서열을 가질 수 있다.
본 명세서에서 사용된 용어 "KRAS 돌연변이"는 KRAS의 일부 아미노산이 치환, 결실 또는 삽입되어 있는 것일 수 있다. 예를 들어, 상기 KRAS 돌연변이는 서열번호 1의 12번째 아미노산 또는 13번째 아미노산이 다른 아미노산으로 치환된 것일 수 있다. 구체적으로, 상기 KRAS 돌연변이는 12번째 위치의 글리신이 아스파르트산, 발린, 시스테인 및 히스티딘으로 이루어진 군에서 선택되는 어느 하나로 치환된 것일 수 있다. 또는, 상기 KRAS 돌연변이는 13번째 위치의 글리신이 아스파르트산, 발린 및 아르기닌으로 이루어진 군에서 선택되는 어느 하나로 치환된 것일 수 있다. 보다 구체적으로, 상기 KRAS 돌연변이는 13번째 위치의 아미노산 잔기 글리신이 아스파트르산으로 치환되거나 12번째 위치의 아미노산 잔기 글리신이 발린 또는 히스티딘으로 치환된 것을 특징으로 할 수 있다.
본 명세서에서 사용된 용어 "활성화된 RON"은 DNA 레벨, mRNA 레벨, 단백질 레벨 등 모든 발현 레벨에 있어 RON이 활성형임을 확인할 수 있는 모든 것을 포함하는 개념으로 이해될 수 있다. 구체적으로, RON 단백질에 인산화, 예를 들어 RON 단백질의 키나제 도메인에 인산화가 되어 있어 활성화된 형태로 존재하는 것일 수 있으며, MSP와 같은 리간드의 존재 하에 활성형으로 유도된 형태일 수 있다. 또한, 리간드 없이도 항상 활성화되어 있는 형태로서 RON 유전자의 스플라이싱 변이체(splicing variant) 또는 돌연변이를 포함할 수 있다.
이때, 상기 활성화된 RON은 RON 유전자의 스플라이싱 변이체이거나 티로신이 인산화된 RON 단백질인 것을 특징으로 할 수 있다. 이때, 상기 RON 유전자의 스플라이싱 변이체는 엑손(Exon) 5, 6 및 11로 이루어진 군으로부터 선택된 하나 이상이 스플라이싱에 의해서 결손된 것일 수 있다. 구체적으로, 엑손 5, 6 및 11이 결손된 mRONΔ155, 엑손 5 및 6이 결손된 mRONΔ160 또는 엑손 11이 결손된 RONΔ165일 수 있다. 또한, mRONΔ155의 cDNA는 서열번호 2의 염기서열, mRONΔ160의 cDNA는 서열번호 3의 염기서열, RONΔ165의 cDNA는 서열번호 4의 염기서열을 가질 수 있다.
본 발명에 있어서, 상기 암은 유방암, 폐암, 위암, 전립선암, 자궁암, 난소암, 신장암, 췌장암, 간암, 대장암, 피부암, 두경부암 및 갑상선암으로 이루어진 군에서 선택되는 것을 특징으로 할 수 있으나, 이에 제한되는 것은 아니다.
본 발명의 다른 측면은, 화학식 1 또는 2로 표시되는 화합물 또는 이의 약학적으로 허용 가능한 염의, KRAS 돌연변이 및 활성화된 RON이 존재하는 암의 예방 또는 치료를 위한 용도를 제공한다.
본 발명의 또 다른 측면은, 화학식 1 또는 2로 표시되는 화합물 또는 이의 약학적으로 허용 가능한 염의, KRAS 돌연변이 및 활성화된 RON이 존재하는 암의 예방 또는 치료용 약제의 제조를 위한 용도를 제공한다.
본 발명의 또 다른 측면은, 화학식 1 또는 2로 표시되는 화합물 또는 이의 약학적으로 허용 가능한 염을 필요로 하는 대상에 투여하는 것을 포함하는, KRAS 돌연변이 및 활성화된 RON이 존재하는 암을 예방 또는 치료하는 방법을 제공한다.
본 발명은 또 다른 측면은, 개체가 KRAS에서 G13D, G13V, G13R, G12V, G12D, G12C 또는 G12H 돌연변이를 가지며, 활성화된 RON을 가지고 있는지 확인하는 단계; 및 활성화된 RON을 가지고 KRAS 돌연변이를 가지는 개체에 상기 화학식 1 또는 2로 표시되는 화합물 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 포함하는 항암제를 투여하는 단계를 포함하는 KRAS 돌연변이 및 활성화된 RON을 보유한 암 환자를 치료하는 방법을 제공한다.
본 발명의 또 다른 측면은, 개체에서 KRAS의 돌연변이 및 활성화된 RON을 확인하는 단계; 및 서열번호 1의 아미노산 서열에서 13번째 위치의 아미노산 잔기 글리신이 다른 아미노산으로 치환되거나 12번째 위치의 아미노산 잔기 글리신이 다른 아미노산으로 치환된 KRAS 돌연변이 및 활성화된 RON이 발견되면 화학식 1 또는 2로 표시되는 화합물 또는 이의 약학적으로 허용 가능한 염이 상기 개체의 항암 치료에 적합하다는 정보를 제공하는 단계를 포함하는, 항암 치료제에 대한 정보를 제공하는 방법을 제공한다.
본 명세서에서 "예방"이란 상기 화합물의 투여로 상기 질환의 발생, 확산 및 재발을 저해시키거나 지연시키는 모든 행위를 의미하고, "치료"는 상기 화합물의 투여로 상기 질환의 증세가 호전되거나 이롭게 변경되는 모든 행위를 의미한다.
또한, "대상" 또는 "개체"란, 상기 KRAS 돌연변이와 관련된 암과 관련된 질환이 발병하였거나 발병할 수 있는 인간(환자)을 포함한 원숭이, 소, 말, 양, 돼지, 닭, 칠면조, 메추라기, 고양이, 개, 마우스, 쥐, 토끼, 기니아 피그 등의 모든 동물을 의미하며, 구체적으로 포유류를 의미할 수 있다. 또한, 상기 대상 또는 개체는 생체 시료(biological sample)를 의미할 수도 있다.
또한, "투여"란, 임의의 적절한 방법으로 이를 필요로 하는 대상에게 소정의 물질을 제공하는 것을 의미하며, 본 발명의 화합물의 투여 경로는 목적 조직에 도달할 수 있는 한 어떠한 일반적인 경로를 통하여 투여될 수 있다.
본 발명에서 사용되는 화학식 1의 화합물은 아래와 같이 표시된다.
[화학식 1]
상기 화학식 1에서,
R1 및 R2는 각각 독립적으로 H, 할로겐, C1-10알콕시, 또는 C1-10할로알킬이고;
X는 -C(-R3)= 또는 -N=이고;
R3 및 R4는 각각 독립적으로 H, 할로겐, C1-10알킬, 또는 C1-10알콕시이고;
R5는 H, 할로겐, 또는 C1-10알킬이고;
R6 및 R7은 이들이 결합된 N 원자와 함께 4 내지 10원의 헤테로사이클을 형성하거나, 또는 R6는 -C2H4-O-CH3이고, R7은 H, 메틸 또는 t-부톡시카보닐이고;
상기 헤테로사이클은 R6과 R7이 결합된 N 원자 이외에도 N, O 및 S로 이루어진 군으로부터 선택되는 1 또는 2개의 헤테로원자를 더 갖거나 갖지 않으며, 또한 상기 헤테로사이클은 할로겐 및 C1-6알킬 중에서 선택되는 하나 이상으로 치환되거나 비치환된다.
상기 C1-10알킬은 C1-6알킬, C1-3알킬, C3-10알킬, C3-6알킬, C6-10알킬 등을 포함할 수 있다. 또한, 상기 C1-10알콕시는 C1-6알콕시, C1-3알콕시, C3-10알콕시, C3-6알콕시, C6-10알콕시 등을 포함할 수 있다. 또한, 상기 4 내지 10원의 헤테로사이클은 4 내지 7원의 헤테로사이클, 4 내지 6원의 헤테로사이클, 5 내지 7원의 헤테로사이클, 5 또는 6원의 헤테로사이클 등을 포함할 수 있다.
일 구현예에 따르면, 상기 화학식 1에서, R1 및 R2는 각각 독립적으로 H, 할로겐, 메톡시, 또는 -CF3일 수 있다. 여기서 할로겐은 F, Cl, Br 또는 I일 수 있다.
다른 구현예에 따르면, 상기 화학식 1에서, R3 및 R4는 각각 독립적으로 H, 할로겐, 메틸, 메톡시, 또는 에톡시일 수 있다. 여기서 할로겐은 F, Cl, Br 또는 I일 수 있다.
또 다른 구현예에 따르면, 상기 화학식 1에서, X는 -C(-R3)=이고; R3 및 R4는 각각 독립적으로 H, 할로겐, 메틸, 메톡시, 또는 에톡시이며, 이때 R3 및 R4는 동시에 H가 아니다.
또 다른 구현예에 따르면, 상기 화학식 1에서, X는 -N=이고; R4는 할로겐, 메틸, 메톡시, 또는 에톡시일 수 있다. 여기서 할로겐은 F, Cl, Br 또는 I일 수 있다.
또 다른 구현예에 따르면, 상기 화학식 1에서, R5는 H 또는 할로겐일 수 있다. 여기서 할로겐은 F, Cl, Br 또는 I일 수 있다.
또 다른 구현예에 따르면, 상기 화학식 1에서, R6과 R7은 이들이 결합된 N 원자와 함께 를 형성하고; 여기서 Ra 및 Rb는 각각 독립적으로 C1-3알킬렌이고; A는 -N(-R9)- 또는 -O-이고, R9는 C1-6알킬일 수 있다. 구체적인 예로서, R6과 R7은 이들이 결합된 N 원자와 함께 아제티딘일, 디아제티딘일, 피롤리딘일, 피롤릴, 이미다졸리딘일, 이미다졸릴, 피라졸리딘일, 피라졸릴, 옥사졸리딘일, 옥사졸릴, 이속사졸리딘일, 이속사졸릴, 티아졸리딘일, 티아졸릴, 이소티아졸리딘일, 이소티아졸릴, 피페리딘일, 피리딘일, 피페라진일, 디아진일, 모폴리노, 티오모폴리노, 아제판일, 디아제판일, 또는 이들에 C1-6알킬이 치환된 헤테로사이클 그룹을 형성할 수 있다. 또한, Ra 및 Rb는 각각 독립적으로 -CH2-, -C2H4- 또는 -C3H6-일 수 있다. 또한 R9는 메틸, 에틸, n-프로필, i-프로필, n-부틸, i-부틸, t-부틸, n-펜틸, i-펜틸, t-펜틸, sec-펜틸, 네오펜틸, 헥실 등일 수 있다.
또 다른 구현예에 따르면, 상기 화학식 1에서, R1 및 R2는 각각 독립적으로 H, 할로겐, 메톡시, 또는 -CF3이고; R3 및 R4는 각각 독립적으로 H, 할로겐, 메틸, 메톡시, 또는 에톡시이고; R5는 H 또는 할로겐이고; R6는 -C2H4-O-CH3이고, R7은 H, 메틸 또는 t-부톡시카보닐이거나, 또는 R6과 R7은 서로 결합하여 모폴리노 또는 메틸피페라진일을 형성할 수 있다. 여기서 할로겐은 F, Cl, Br 또는 I일 수 있다.
구체적인 일례에 따르면, 상기 화학식 1의 화합물은 하기 화학식 1a로 표시될 수 있다.
[화학식 1a]
상기 화학식 1a에서 R1 내지 R7은 상기 화학식 1에서 정의한 바와 같다.
구체적으로, 상기 화학식 1a에서, R1 및 R2는 각각 독립적으로 H, 할로겐, 또는 -CF3일 수 있다. 또한, R3 및 R4는 각각 독립적으로 H, 할로겐, 메틸, 메톡시, 또는 에톡시일 수 있으며, 이때 R3 및 R4는 동시에 H가 아니다. 또한, R5는 H 또는 할로겐일 수 있다.
보다 구체적으로, 상기 화학식 1a에서, R1 및 R2는 각각 독립적으로 H, 할로겐, 또는 -CF3이고; R3 및 R4는 각각 독립적으로 H, 할로겐, 메틸, 메톡시, 또는 에톡시이고; R5는 H 또는 할로겐이고; R6는 -C2H4-O-CH3이고, R7은 H, 메틸 또는 t-부톡시카보닐일 수 있다.
구체적인 다른 예에 따르면, 상기 화학식 1의 화합물은 하기 화학식 1b로 표시될 수 있다.
[화학식 1b]
상기 화학식 1b에서 R1 내지 R7은 상기 화학식 1에서 정의한 바와 같다.
구체적으로, 상기 화학식 1b에서, R1 및 R2는 각각 독립적으로 H, 할로겐, 또는 -CF3일 수 있다. 또한, R4는 할로겐, 메틸, 메톡시, 또는 에톡시일 수 있다. 또한, R5는 H 또는 할로겐일 수 있다.
보다 구체적으로, 상기 화학식 1b에서, R1 및 R2는 각각 독립적으로 H, 할로겐, 또는 -CF3이고; R4는 할로겐, 메틸, 메톡시, 또는 에톡시이고; R5는 H 또는 할로겐이고; R6는 -C2H4-O-CH3이고; R7은 H, 메틸 또는 t-부톡시카보닐일 수 있다.
구체적인 또 다른 예에 따르면, 상기 화학식 1의 화합물은 하기 화학식 1c로 표시될 수 있다.
[화학식 1c]
상기 화학식 1c에서 R1 내지 R5은 상기 화학식 1에서 정의한 바와 같고; Ra 및 Rb는 각각 독립적으로 C1-3알킬렌이고; A는 -N(-R9)- 또는 -O-이고, R9는 C1-6알킬일 수 있다.
구체적으로, 상기 화학식 1c에서, R1 및 R2는 각각 독립적으로 H, 할로겐, 또는 -CF3일 수 있다. 또한, R3 및 R4는 각각 독립적으로 H, 할로겐, 메틸, 메톡시, 또는 에톡시일 수 있으며, 이때 R3 및 R4는 동시에 H가 아니다. 또한, R5는 H 또는 할로겐일 수 있다. 또한, Ra 및 Rb는 이들이 결합된 N 및 A와 함께 모폴리노 또는 메틸피페라진일을 형성할 수 있다.
구체적인 또 다른 예에 따르면, 상기 화학식 1의 화합물은 하기 화학식 1d로 표시될 수 있다.
[화학식 1d]
상기 화학식 1d에서 R1 내지 R5은 상기 화학식 1에서 정의한 바와 같고; Ra 및 Rb는 각각 독립적으로 C1-3알킬렌이고; A는 -N(-R9)- 또는 -O-이고, R9는 C1-6알킬일 수 있다.
구체적으로, 상기 화학식 1d에서, R1 및 R2는 각각 독립적으로 H, 할로겐, 또는 -CF3일 수 있다. 또한, R4는 할로겐, 메틸, 메톡시, 또는 에톡시일 수 있다. 또한, R5는 H 또는 할로겐일 수 있다. 또한, Ra 및 Rb는 이들이 결합된 N 및 A와 함께 모폴리노 또는 메틸피페라진일을 형성할 수 있다.
상기 화학식 1로 표시되는 화합물의 구체적인 예는 아래와 같다:
a1) 4-에톡시-N-(3-플루오로-4-{[2-(5-{[(2-메톡시에틸)아미노]메틸}피리딘-2-일)티에노[3,2-b]피리딘-7-일]옥시}페닐)-2-옥소-1-페닐-1,2-디히드로피리딘-3-카르복스아미드;
a2) N-(3-플루오로-4-{[2-(5-{[(2-메톡시에틸)아미노]메틸}피리딘-2-일)티에노[3,2-b]피리딘-7-일]옥시}페닐)-1-(4-플루오로페닐)-4-메톡시-2-옥소-1,2-디히드로피리딘-3-카르복스아미드;
a3) N-(3-플루오로-4-{[2-(5-{[(2-메톡시에틸)아미노]메틸}피리딘-2-일)티에노[3,2-b]피리딘-7-일]옥시}페닐)-4-메톡시-2-옥소-1-페닐-1,2-디히드로피리딘-3-카르복스아미드;
a4) N-(3-플루오로-4-{[2-(5-{[(2-메톡시에틸)아미노]메틸}피리딘-2-일)티에노[3,2-b]피리딘-7-일]옥시}페닐)-1-(4-플루오로페닐)-2-옥소-1,2-디히드로피리딘-3-카르복스아미드;
a5) N-(3-플루오로-4-{[2-(5-{[(2-메톡시에틸)아미노]메틸}피리딘-2-일)티에노[3,2-b]피리딘-7-일]옥시}페닐)-2-옥소-1-페닐-1,2-디히드로피리딘-3-카르복스아미드;
a6) t-부틸 {[6-(7-{4-[4-에톡시-1-(4-플루오로페닐)-2-옥소-1,2-디히드로피리딘-3-카르복스아미도]-2-플루오로페녹시}티에노[3,2-b]피리딘-2-일)피리딘-3-일]메틸}(2-메톡시에틸)카바메이트;
a7) 4-에톡시-N-(3-플루오로-4-{[2-(5-{[(2-메톡시에틸)아미노]메틸}피리딘-2-일)티에노[3,2-b]피리딘-7-일]옥시}페닐)-1-(4-플루오로페닐)-2-옥소-1,2-디히드로피리딘-3-카르복스아미드;
a8) 1-(4-클로로페닐)-4-에톡시-N-(3-플루오로-4-{[2-(5-{[(2-메톡시에틸)아미노]메틸}피리딘-2-일)티에노[3,2-b]피리딘-7-일]옥시}페닐)-2-옥소-1,2-디히드로피리딘-3-카르복스아미드;
a9) N-(3-클로로-4-{[2-(5-{[(2-메톡시에틸)아미노]메틸}피리딘-2-일)티에노[3,2-b]피리딘-7-일]옥시}페닐)-1-(4-플루오로페닐)-4-메톡시-2-옥소-1,2-디히드로피리딘-3-카르복스아미드;
a10) N-(2-클로로-4-{[-2-(5-{[(2-메톡시에틸)아미노]메틸}피리딘-2-일)티에노[3,2-b]피리딘-7-일]옥시}페닐)-1-(4-플루오로페닐)-4-메톡시-2-옥소-1,2-디히드로피리딘-3-카르복스아미드;
a11) 1-(4-플루오로페닐)-4-메톡시-N-(4-{[2-(5-{[(2-메톡시에틸)아미노]메틸}피리딘-2-일)티에노[3,2-b]피리딘-7-일)옥시)페닐)-2-옥소-1,2-디히드로피리딘-3-카르복스아미드;
a12) 4-에톡시-N-(3-플루오로-4-{[2-(5-{[(2-메톡시에틸)아미노]메틸}피리딘-2-일)티에노[3,2-b]피리딘-7-일]옥시}페닐)-2-옥소-1-(4-(트리플루오로메틸)페닐)-1,2-디히드로피리딘-3-카르복스아미드;
a13) 1-(4-클로로페닐)-N-(3-플루오로-4-{[2-(5-{[(2-메톡시에틸)아미노]메틸}피리딘-2-일)티에노[3,2-b]피리딘-7-일]옥시}페닐)-4-메톡시-2-옥소-1,2-디히드로피리딘-3-카르복스아미드;
a14) 4-에톡시-N-(3-플루오로-4-{[2-(5-{[(2-메톡시에틸)아미노]메틸}피리딘-2-일)티에노[3,2-b]피리딘-7-일]옥시}페닐)-1-(3-플루오로페닐)-2-옥소-1,2-디히드로피리딘-3-카르복스아미드;
a15) 4-에톡시-N-(3-플루오로-4-{[2-(5-{[(2-메톡시에틸)아미노]메틸}피리딘-2-일)티에노[3,2-b]피리딘-7-일]옥시}페닐)-1-(4-메톡시페닐)-2-옥소-1,2-디히드로피리딘-3-카르복스아미드;
a16) 4-에톡시-N-(3-플루오로-4-{[2-(5-{[(2-메톡시에틸)아미노]메틸}피리딘-2-일)티에노[3,2-b]피리딘-7-일]옥시}페닐)-1-(3-메톡시페닐)-2-옥소-1,2-디히드로피리딘-3-카르복스아미드;
a17) N-(3-플루오로-4-{[2-(5-{[(2-메톡시에틸)아미노]메틸}피리딘-2-일)티에노[3,2-b]피리딘-7-일]옥시}페닐)-2-(4-플루오로페닐)-5-메틸-3-옥소-2,3-디히드로피리다진-4-카르복스아미드;
a18) N-(3-플루오로-4-{[2-(5-{[(2-메톡시에틸)아미노]메틸}피리딘-2-일)티에노[3,2-b]피리딘-7-일]옥시}페닐)-5-메틸-3-옥소-2-페닐-2,3-디히드로피리다진-4-카르복스아미드;
a19) N-(3-플루오로-4-{[2-(5-{[(2-메톡시에틸)아미노]메틸}피리딘-2-일)티에노[3,2-b]피리딘-7-일]옥시}페닐)-3-옥소-2-페닐-2,3-디히드로피리다진-4-카르복스아미드;
a20) N-(3-플루오로-4-[{2-(5-[{(2-메톡시에틸)아미노}메틸]피리딘-2-일)티에노[3,2-b]피리딘-7-일}옥시]페닐)-2-(4-플루오로페닐)-3-옥소-2,3-디히드로피리다진-4-카르복스아미드;
a21) N-(3-플루오로-4-{[2-(5-{[(2-메톡시에틸)아미노]메틸}피리딘-2-일)티에노[3,2-b]피리딘-7-일]옥시}페닐)-6-메틸-2-옥소-1-페닐-1,2-디히드로피리딘-3-카르복스아미드;
a22) N-(3-플루오로-4-{[2-(5-{[(2-메톡시에틸)아미노]메틸}피리딘-2-일)티에노[3,2-b]피리딘-7-일]옥시}페닐)-1-(4-플루오로페닐)-6-메틸-2-옥소-1,2-디히드로피리딘-3-카르복스아미드;
a23) 5-브로모-N-(3-플루오로-4-{[2-(5-{[(2-메톡시에틸)아미노]메틸}피리딘-2-일)티에노[3,2-b]피리딘-7-일]옥시}페닐)-1-(4-플루오로페닐)-2-옥소-1,2-디히드로피리딘-3-카르복스아미드;
a24) 5-클로로-N-(3-플루오로-4-{[2-(5-{[(2-메톡시에틸)아미노]메틸}피리딘-2-일)티에노[3,2-b]피리딘-7-일]옥시}페닐)-1-(4-플루오로페닐)-2-옥소-1,2-디히드로피리딘-3-카르복스아미드;
a25) N-(3-플루오로-4-{[2-(5-{[(2-메톡시에틸)아미노]메틸}피리딘-2-일)티에노[3,2-b]피리딘-7-일]옥시}페닐)-1-(4-플루오로페닐)-4-메틸-2-옥소-1,2-디히드로피리딘-3-카르복스아미드;
a26) N-(2-클로로-4-{[2-(5-{[(2-메톡시에틸)아미노]메틸}피리딘-2-일)티에노[3,2-b]피리딘-7-일]옥시}페닐)-4-에톡시-1-(4-플루오로페닐)-2-옥소-1,2-디히드로피리딘-3-카르복스아미드;
a27) N-(3-플루오로-4-([2-(5-{[(2-메톡시에틸)아미노)메틸]피리딘-2-일}티에노[3,2-b]피리딘-7-일)옥시]페닐}-1-(4-플루오로페닐)-5,6-디메틸-2-옥소-1,2-디히드로피리딘-3-카르복스아미드;
a28) N-(3-플루오로-4-{[-2-(5-{[(2-메톡시에틸)아미노]메틸}피리딘-2-일)티에노[3,2-b]피리딘-7-일]옥시}페닐)-4-메틸-2-옥소-1-페닐-1,2-디히드로피리딘-3-카르복스아미드;
a29) N-(3-플루오로-4-{[-2-(5-{[(2-메톡시에틸)아미노]메틸}피리딘-2-일)티에노[3,2-b]피리딘-7-일]옥시}페닐)-1-(4-플루오로페닐)-5-메틸-2-옥소-1,2-디히드로피리딘-3-카르복스아미드;
a30) 4-에톡시-N-(3-플루오로-4-{[2-(5-{[(2-메톡시에틸)(메틸)아미노]메틸}피리딘-2-일)티에노[3,2-b]피리딘-7-일]옥시}페닐)-1-(4-플루오로페닐)-2-옥소-1,2-디히드로피리딘-3-카르복스아미드;
a31) 4-에톡시-N-[3-플루오로-4-({2-[5-(모르폴리노메틸)피리딘-2-일]티에노[3,2-b]피리딘-7-일}옥시)페닐]-1-(4-플루오로페닐)-2-옥소-1,2-디히드로피리딘-3-카르복스아미드;
a32) 4-에톡시-N-[3-플루오로-4-({2-[5-(모르폴리노메틸)피리딘-2-일]티에노[3,2-b]피리딘-7-일}옥시)페닐]-2-옥소-1-페닐-1,2-디히드로피리딘-3-카르복스아미드;
a33) 4-에톡시-N-{3-플루오로-4-[(2-{5-[(4-메틸피페라진-1-일)메틸]피리딘-2-일}티에노[3,2-b]피리딘-7-일)옥시]페닐}-1-(4-플루오로페닐)-2-옥소-1,2-디히드로피리딘-3-카르복스아미드;
a34) 4-에톡시-N-{3-플루오로-4-[(2-{5-[(4-메틸피페라진-1-일)메틸]피리딘-2-일}티에노[3,2-b]피리딘-7-일)옥시]페닐}-2-옥소-1-페닐-1,2-디히드로피리딘-3-카르복스아미드;
a35) 1-(4-클로로페닐)-4-에톡시-N-[3-플로오로-4-({2-[5-(모르폴리노메틸)피리딘-2-일]티에노[3,2-b]피리딘-7-일}옥시)페닐]-2-옥소-1,2-디히드로피리딘-3-카르복스아미드;
a36) N-[3-클로로-4-({2-[5-(모르폴리노메틸)피리딘-2-일]티에노[3,2-b]피리딘-7-일}옥시)페닐]-4-에톡시-1-(4-플루오로페닐)-2-옥소-1,2-디히드로피리딘-3-카르복스아미드; 및
a37) N-[2-클로로-4-({2-[5-(모르폴리노메틸)피리딘-2-일]티에노[3,2-b]피리딘-7-일}옥시)페닐]-4-에톡시-1-(4-플루오로페닐)-2-옥소-1,2-디히드로피리딘-3-카르복스아미드.
바람직하게는, 상기 화학식 1로 표시되는 화합물은
4-에톡시-N-[3-플루오로-4-({2-[5-(모르폴리노메틸)피리딘-2-일]티에노[3,2-b]피리딘-7-일}옥시)페닐]-1-(4-플루오로페닐)-2-옥소-1,2-디히드로피리딘-3-카르복스아미드;
4-에톡시-N-(3-플루오로-4-{[2-(5-{[(2-메톡시에틸)아미노]메틸}피리딘-2-일)티에노[3,2-b]피리딘-7-일]옥시}페닐)-2-옥소-1-페닐-1,2-디히드로피리딘-3-카르복스아미드; 및
4-에톡시-N-{3-플루오로-4-[(2-{5-[(4-메틸피페라진-1-일)메틸]피리딘-2-일}티에노[3,2-b]피리딘-7-일)옥시]페닐}-2-옥소-1-페닐-1,2-디히드로피리딘-3-카르복스아미드로 이루어진 군에서 선택되는 화합물일 수 있다.
본 발명에 따른 조성물에 사용되는 상기 화학식 1의 화합물은 대한민국 공개특허공보 제2019-0106802호에 개시된 방법으로 제조할 수 있으며, 기타 공지된 방법 및/또는 유기합성 분야의 기술에 근간한 다양한 방법들에 의해 제조될 수 있다. 상기 방법들을 기초로 치환기의 종류에 따라 적절한 합성방법을 사용하여 다양한 유도체들을 합성할 수 있다.
본 발명에서 사용되는 화학식 2의 화합물은 아래와 같이 표시된다.
[화학식 2]
상기 식에서,
L은 -NH- 또는 -CH2-이고,
R1 내지 R4는 각각 독립적으로 수소, 할로겐, 히드록시, 시아노, C1-4 알킬, C1-4 알콕시, C1-4 할로알킬, C2-4 알케닐, C2-4 알키닐, C3-7 사이클로알킬, C6-10 아릴, 5원 내지 9원의 헤테로아릴 또는 3원 내지 9원의 헤테로사이클로알킬이고,
X는 O, S, -CH(-Rx)- 또는 -N(-Rx)-이고,
Rx는 수소, C1-4 알킬, C1-4 알콕시, C1-4 할로알킬, C2-4 알케닐, C2-4 알키닐, C6-10 아릴, C6-10 아릴-C1-4 알킬, 또는 3원 내지 9원의 헤테로사이클로알킬이고,
A는 3원 내지 12원의 헤테로사이클이고,
R5 및 R6는 각각 독립적으로 수소, 니트로, 아미노, 할로겐, 히드록시, 시아노, C1-6 알킬, C1-6 할로알킬, C2-6 알케닐, C2-6 알키닐, C1-6 알콕시, 아미노-C1-6 알콕시, 아미노카르보닐, C1-6 알킬아미노카르보닐, 디C1-6 알킬아미노카르보닐, C1-6 알킬카르보닐아미노, C1-6 알킬아미노, C1-6 알킬-아미노-C1-6 알콕시, C6-10 아릴, C6-10 아릴-C1-4 알킬, 또는 5원 내지 9원의 헤테로아릴이고,
이때 R5 및 R6는 각각 독립적으로 C1-6 알킬; C1-6 알콕시-C1-6 알킬아미노, 3원 내지 9원의 사이클로알킬 및 3원 내지 9원의 헤테로사이클로알킬 중 어느 하나로 치환된 C1-6 알킬 또는 C1-6 알킬아미노-C1-6 알킬; 3원 내지 9원의 사이클로알킬; 또는 3원 내지 9원의 헤테로사이클로알킬로 치환되거나 치환되지 않고,
상기 사이클로알킬 또는 헤테로사이클로알킬은 할로겐, 옥소, 시아노, 히드록시, 히드록시-C1-6 알킬, 아미노, 디C1-6 알킬아미노, C1-6 알킬, C1-6 알콕시, 및 C1-6 알콕시-C1-6 알킬로 이루어진 군으로부터 선택되는 하나 이상의 치환기를 갖거나 갖지 않고,
상기 헤테로사이클, 헤테로아릴 및 헤테로사이클로알킬은 각각 독립적으로 N, O 및 S로 이루어진 군으로부터 선택되는 하나 이상의 헤테로원자를 포함한다.
또한, 상기 C1-6 알킬은 C1-3 알킬, C3-6 알킬 등을 포함할 수 있다. 또한, 상기 C1-6 알콕시는 C1-3 알콕시, C3-6 알콕시 등을 포함할 수 있다.
또한, 상기 3원 내지 12원의 헤테로사이클은 4원 내지 12원의 헤테로사이클, 4원 내지 10원의 헤테로사이클, 4원 또는 7원의 헤테로사이클, 7원 내지 12원의 헤테로사이클 등을 포함할 수 있다. 또한 상기 헤테로사이클은 방향족 고리 또는 비방향족 고리를 포함할 수 있으며, 일례로서, 상기 3원 내지 12원의 헤테로사이클은 하나 이상의 방향족 고리를 포함할 수 있다. 예를 들어, 상기 헤테로사이클은 퀴놀린, 퀴나졸린, 피리딘, 피리미딘, 티에노피리딘, 피롤로피리딘, 피라졸로피리딘, 이미다조피리딘, 피롤로피리미딘, 디히드로피롤로피리미딘, 퓨로피리딘, 피라졸로피리미딘, 퓨린, 인다졸, 아제티딘, 디아제티딘, 피롤리딘, 피롤, 이미다졸리딘, 이미다졸, 피라졸리딘, 피라졸, 옥사졸리딘, 옥사졸, 이속사졸리딘, 이속사졸, 티아졸리딘, 티아졸, 이소티아졸리딘, 이소티아졸, 피페리딘, 피리딘, 피페라진, 디아진, 모폴린, 티오모폴린, 아제판, 디아제판 등일 수 있다.
일 구현예에 따르면, 상기 화학식 2에서, R1 내지 R4는 각각 독립적으로 수소, C1-4 할로알킬, 또는 할로겐일 수 있다. 여기서 할로겐은 F, Cl, Br 또는 I일 수 있다. 구체적으로, R1은 수소, 트리플루오로메틸, 또는 플루오로이고, R2는 수소이고, R3는 플루오로이고, R4는 수소일 수 있다.
다른 구현예에 따르면, 상기 화학식 2에서, X는 O 또는 -CH(-Rx)-이고, Rx는 수소 또는 C1-6 알킬일 수 있다.
또 다른 구현예에 따르면, 상기 화학식 2에서, A는 퀴놀린, 티에노피리딘일 수 있다.
또 다른 구현예에 따르면, 상기 화학식 2에서, R5 및 R6는 각각 독립적으로 수소, 아미노, 할로겐, 시아노, C1-6 알킬, C1-6 할로알킬, C1-6 알콕시, 아미노-C1-6 알콕시, 아미노카르보닐, C1-6 알킬아미노카르보닐, 디C1-6 알킬카르보닐아미노, C1-6 알킬카르보닐아미노, C1-6 알킬아미노, C1-6 알킬-아미노-C1-6 알콕시, 또는 5원 내지 9원의 헤테로아릴이고, 이때 R5 및 R6는 각각 독립적으로 C1-6 알킬; C1-6 알콕시-C1-6 알킬-아미노, 3원 내지 9원의 사이클로알킬 및 3원 내지 9원의 헤테로사이클로알킬 중 어느 하나로 치환된 C1-6 알킬 또는 C1-6 알킬-아미노-C1-6 알킬; 3원 내지 9원의 사이클로알킬; 또는 3원 내지 9원의 헤테로사이클로알킬로 치환되거나 치환되지 않고, 상기 사이클로알킬 또는 헤테로사이클로알킬은 할로겐, 옥소, 시아노, 히드록시, 히드록시-C1-6 알킬, 아미노, 디C1-6 알킬아미노, C1-6 알킬, C1-6 알콕시, 및 C1-6 알콕시-C1-6 알킬로 이루어진 군으로부터 선택되는 하나 이상의 치환기를 갖거나 갖지 않고, 상기 헤테로아릴 및 상기 헤테로사이클로알킬은 각각 독립적으로 N, O 및 S로 이루어진 군으로부터 선택되는 하나 이상의 헤테로원자를 포함할 수 있다.
구체적으로, 상기 헤테로아릴은 피리디닐, 이미다졸릴, 또는 피라졸릴이고, 상기 헤테로사이클로알킬은 아제티디닐, 피롤리디닐, 테트라히드로피란일, 모폴리노, 모폴리닐, 디옥시도티오모폴리노, 피페라지닐, 피페리디닐, 또는 옥세탄일이고, 상기 사이클로알킬은 사이클로부틸, 사이클로펜틸, 또는 사이클로헥실일 수 있다.
또한 상기 헤테로아릴 또는 상기 헤테로사이클로알킬이 하나 이상의 N 원자를 포함하는 경우, 이들 중 어느 하나의 N 원자 위치에서 치환될 수 있으나, 특별히 한정되지는 않는다.
또 다른 구현예에 따르면, 상기 화학식 2에서, R1 및 R2는 수소, C1-4 할로알킬, 또는 할로겐이고, R3 및 R4는 수소 또는 할로겐이며, X는 O 또는 -CH(-Rx)-이고, Rx는 수소 또는 C1-4 알킬이고, A는 퀴놀린, 티에노피리딘이며, R5 및 R6는 각각 독립적으로 수소, 아미노, 할로겐, 시아노, C1-6 알킬, C1-6 할로알킬, C1-6 알콕시, 아미노-C1-6 알콕시, 아미노카르보닐, C1-6 알킬아미노카르보닐, 디C1-6 알킬카르보닐아미노, C1-6 알킬카르보닐아미노, C1-6 알킬아미노, C1-6 알킬-아미노-C1-6 알콕시, 또는 5원 내지 9원의 헤테로아릴이고, 이때 R5 및 R6는 각각 독립적으로 C1-6 알킬; C1-6 알콕시-C1-6 알킬-아미노, 3원 내지 9원의 사이클로알킬 및 3원 내지 9원의 헤테로사이클로알킬 중 어느 하나로 치환된 C1-6 알킬 또는 C1-6 알킬-아미노-C1-6 알킬; 3원 내지 9원의 사이클로알킬; 또는 3원 내지 9원의 헤테로사이클로알킬로 치환되거나 치환되지 않고, 상기 사이클로알킬 또는 헤테로사이클로알킬은 할로겐, 옥소, 시아노, 히드록시, 히드록시-C1-6 알킬, 아미노, 디C1-6 알킬아미노, C1-6 알킬, C1-6 알콕시, 및 C1-6 알콕시-C1-6 알킬로 이루어진 군으로부터 선택되는 하나 이상의 치환기를 갖거나 갖지 않고, 상기 헤테로아릴 및 상기 헤테로사이클로알킬은 각각 독립적으로 N, O 및 S로 이루어진 군으로부터 선택되는 하나 이상의 헤테로원자를 포함할 수 있다.
또 다른 구현예에 따르면, 상기 화학식 2에서, R5 및 R6는 각각 독립적으로 수소, 니트로, 아미노, 할로겐, 히드록시, 시아노, C1-6 알킬, C1-6 할로알킬, C1-6 알콕시, 아미노-C1-6 알콕시, 아미노카르보닐, C1-6 알킬아미노카르보닐, 디C1-6 알킬아미노카르보닐, C1-6 알킬카르보닐아미노, C1-6 알킬아미노, C1-6 알킬-아미노-C1-6 알콕시, C6-10 아릴, C6-10 아릴-C1-4 알킬, 또는 5원 내지 9원의 헤테로아릴이고, 상기 아미노, 상기 알킬, 상기 알콕시, 상기 아릴 및 상기 헤테로아릴은 각각 독립적으로 C1-6 알킬; C1-6 알콕시-C1-6 알킬아미노, 3원 내지 9원의 사이클로알킬 및 3원 내지 9원의 헤테로사이클로알킬 중 어느 하나로 치환된 C1-6 알킬 또는 C1-6 알킬아미노-C1-6 알킬; 3원 내지 9원의 사이클로알킬; 또는 3원 내지 9원의 헤테로사이클로알킬로 치환되거나 치환되지 않고, 상기 사이클로알킬 또는 헤테로사이클로알킬은 할로겐, 옥소, 시아노, 히드록시, 히드록시-C1-6 알킬, 아미노, 디C1-6 알킬아미노, C1-6 알킬, C1-6 알콕시, 및 C1-6 알콕시-C1-6 알킬로 이루어진 군으로부터 선택되는 하나 이상의 치환기를 갖거나 갖지 않고, 상기 헤테로사이클, 헤테로아릴 및 헤테로사이클로알킬은 각각 독립적으로 N, O 및 S로 이루어진 군으로부터 선택되는 하나 이상의 헤테로원자를 포함할 수 있다.
또 다른 구현예에 따르면, 상기 화학식 2에서, R5 및 R6는 동시에 C6-10 아릴, C6-10 아릴-C1-4 알킬, 또는 5원 내지 9원의 헤테로아릴이 아닐 수 있다. 또 다른 구현예에 따르면, 상기 화학식 2에서, R5 및 R6는 동시에 3원 내지 9원의 사이클로알킬 및 3원 내지 9원의 헤테로사이클로알킬 중 어느 하나로 치환된 C1-6 알킬 또는 C1-6 알킬아미노-C1-6 알킬; 3원 내지 9원의 사이클로알킬; 또는 3원 내지 9원의 헤테로사이클로알킬로 치환되지는 것은 아닐 수 있다. 구체적인 일례로서, R5가 아릴, 헤테로아릴 등의 고리를 포함할 경우, R6는 이들 고리를 동시에 포함하지는 않을 수 있다. 또한 R5가 사이클로알킬, 헤테로사이클로알킬 등의 고리를 포함하는 그룹으로 치환될 경우, R6는 이들 고리를 포함하는 그룹으로 동시에 치환되지는 않을 수 있다.
보다 구체적인 일례로서, R5는 C6-10 아릴, C6-10 아릴-C1-4 알킬, 또는 5원 내지 9원의 헤테로아릴이고, R6는 수소, 니트로, 아미노, 할로겐, 히드록시, 시아노, C1-6 알킬, C1-6 할로알킬, C1-6 알콕시, 아미노-C1-6 알콕시, 아미노카르보닐, C1-6 알킬아미노카르보닐, 디C1-6 알킬아미노카르보닐, C1-6 알킬카르보닐아미노, C1-6 알킬아미노, 또는 C1-6 알킬-아미노-C1-6 알콕시일 수 있다. 이때 R5는 C1-6 알킬; 또는 C1-6 알콕시-C1-6 알킬아미노, 3원 내지 9원의 사이클로알킬 및 3원 내지 9원의 헤테로사이클로알킬 중 어느 하나로 치환된 C1-6 알킬 또는 C1-6 알킬아미노-C1-6 알킬로 치환되거나 치환되지 않을 수 있다. 또한 R6는 3원 내지 9원의 사이클로알킬; 또는 3원 내지 9원의 헤테로사이클로알킬로 치환되거나 치환되지 않을 수 있다. 여기서 상기 사이클로알킬 또는 헤테로사이클로알킬은 할로겐, 옥소, 시아노, 히드록시, 히드록시-C1-6 알킬, 아미노, 디C1-6 알킬아미노, C1-6 알킬, C1-6 알콕시, 및 C1-6 알콕시-C1-6 알킬로 이루어진 군으로부터 선택되는 하나 이상의 치환기를 갖거나 갖지 않고, 상기 헤테로아릴 및 상기 헤테로사이클로알킬은 각각 독립적으로 N, O 및 S로 이루어진 군으로부터 선택되는 하나 이상의 헤테로원자를 포함할 수 있다.
또 다른 구현예에 따르면, 상기 화학식 2에서, R5 및 R6는 각각 독립적으로 수소, 아미노, 할로겐, 히드록시, C1-6 알콕시, 아미노카르보닐, C1-6 알킬아미노카르보닐, 디C1-6 알킬아미노카르보닐, C1-6 알킬카르보닐아미노, 시아노, C1-4 할로알킬, C1-6 알킬, 5원 내지 9원의 헤테로아릴, Ax-(CH2)a-L1-(CH2)b-L2-, 또는 Ax-(CH2)a-L1-(CH2)b-L2-피리디닐이고, Ax는 C3-6 사이클로알킬 또는 3원 내지 6원의 헤테로사이클로알킬이고, L1 및 L2는 각각 독립적으로 단일결합, -O-, -NH-, -C(=O)-NH-, 또는 -NH-C(=O)-이고, a 및 b는 각각 독립적으로 0 내지 3의 정수이되, b가 0인 경우에 L2는 단일결합이고, 상기 사이클로알킬, 헤테로아릴 및 헤테로사이클로알킬은 각각 독립적으로 할로겐, 옥소, 시아노, 히드록시, 히드록시메틸, C1-6 알킬, 메톡시, 메톡시메틸, 디메틸아미노, 및 메톡시에틸아미노메틸로 이루어진 군으로부터 선택되는 1개 또는 2개의 치환기를 갖거나 갖지 않고, 상기 헤테로아릴 및 상기 헤테로사이클로알킬은 각각 독립적으로 N, O 및 S로 이루어진 군으로부터 선택되는 하나 이상의 헤테로원자를 포함할 수 있고, 상기 헤테로아릴 및 상기 헤테로사이클로알킬은 각각 독립적으로 N, O 및 S로 이루어진 군으로부터 선택되는 하나 이상의 헤테로원자를 포함할 수 있다.
구체적인 일례에 따르면, 상기 화학식 2의 화합물은 하기 화학식 2a로 표시될 수 있다.
[화학식 2a]
상기 식에서
X, L, R1, R2, R3 및 R4는 상기 화학식 2에서 정의한 바와 같고,
B는 N 원자를 1개 또는 2개 함유하는 5원 또는 6원의 방향족 헤테로사이클이고,
R7은 C1-6 알킬; 또는 C1-6 알콕시-C1-6 알킬아미노, 3원 내지 9원의 사이클로알킬 및 3원 내지 9원의 헤테로사이클로알킬 중 어느 하나로 치환된 C1-6 알킬 또는 C1-6 알킬아미노-C1-6 알킬이고,
상기 사이클로알킬 또는 헤테로사이클로알킬은 할로겐, 옥소, 시아노, 히드록시, 히드록시-C1-6 알킬, 아미노, 디C1-6 알킬아미노, C1-6 알킬, C1-6 알콕시, 및 C1-6 알콕시-C1-6 알킬로 이루어진 군으로부터 선택되는 하나 이상의 치환기를 갖거나 갖지 않고,
상기 헤테로사이클로알킬은 N, O 및 S로 이루어진 군으로부터 선택되는 1 내지 4개의 헤테로원자를 포함한다.
상기 화학식 2a로 표시되는 화합물의 구체적인 예는 아래와 같다:
b1) N-(3-플루오로-4-((2-(5-메톡시에틸)아미노)메틸)피리딘-2-일)티에노[3,2-b]피리딘-7-일)옥시)페닐)-5-(4-플루오로페닐)-6-옥소-2,3,5,6-테트라히드로퓨로[3,2-c]피리딘-7-카르복스아미드;
b2) N-(3-플루오로-4-((2-(5-메톡시에틸)아미노)메틸)피리딘-2-일)티에노[3,2-b]피리딘-7-일)옥시)페닐)-6-옥소-5-페닐-2,3,5,6-테트라히드로퓨로[3,2-c]피리딘-7-카르복스아미드;
b3) N-(3-플루오로-4-((2-(피리딘-2-일)티에노[3,2-b]피리딘-7-일)옥시)페닐)-5-(4-플루오로페닐)-6-옥소-2,3,5,6-테트라히드로퓨로[3,2-c]피리딘-7-카르복스아미드;
b4) N-(3-플루오로-4-[(2-피리딘-2-일)티에노[3,2-b]피리딘-7-일)옥시)페닐)-6-옥소-5-페닐-2,3,5,6-테트라히드로퓨로[3,2-c]피리딘-7-카르복스아미드;
b5) N-(3-플루오로-4-((2-(5-모폴리노메틸)피리딘-2-일)티에노[3,2-b]피리딘-7-일)옥시)페닐)-5-(4-플루오로페닐)-6-옥소-2,3,5,6-테트라히드로퓨로[3,2-c]피리딘-7-카르복스아미드;
b6) N-(3-플루오로-4-((2-(5-모폴리노메틸)피리딘-2-일)티에노[3,2-b]피리딘-7-일)옥시)페닐)-6-옥소-5-페닐-2,3,5,6-테트라히드로퓨로[3,2-c]피리딘-7-카르복스아미드;
b7) N-(3-플루오로-4-((2-(5-모폴리노메틸)피리딘-2-일)티에노[3,2-b]피리딘-7-일)페닐)-2-(4-플루오로페닐)-3-옥소-3,5,6,7-테트라히드로-2H-사이클로펜타[c]피리딘-4-카르복스아미드;
b8) N-(3-플루오로-4-((2-(1-메틸-1H-이미다졸-4-일)티에노[3,2-b]피리딘-7-일)옥시)페닐)-5-(4-플루오로페닐)-6-옥소-2,3,5,6-테트라히드로퓨로[3,2-c]피리딘-7-카르복스아미드;
b9) N-(3-플루오로-4-((2-(1-메틸-1H-이미다졸-4-일)티에노[3,2-b]피리딘-7-일)옥시)페닐)-6-옥소-5-페닐-2,3,5,6-테트라히드로퓨로[3,2-c]피리딘-7-카르복스아미드;
b10) N-(3-플루오로-4-((2-(1-메틸-1H-피라졸-4-일)티에노[3,2-b]피리딘-7-일)옥시)페닐)-5-(4-플루오로페닐)-6-옥소-2,3,5,6-테트라히드로퓨로[3,2-c]피리딘-7-카르복스아미드;
b11) N-(3-플루오로-4-((2-(5-((3-히드록시아제티딘-1-일)메틸)피리딘-2-일)티에노[3,2-b]피리딘-7-일)옥시)페닐)-5-(4-플루오로페닐)-6-옥소-2,3,5,6-테트라히드로퓨로[3,2-c]피리딘-7-카르복스아미드;
b12) N-(3-플루오로-4-((2-(5-((3-(히드록시메틸)아제티딘-1-일)메틸)피리딘-2-일)티에노[3,2-b]피리딘-7-일)옥시)페닐)-5-(4-플루오로페닐)-6-옥소-2,3,5,6-테트라히드로퓨로[3,2-c]피리딘-7-카르복스아미드;
b13) N-(3-플루오로-4-((2-(5-((3-히드록시-3-메틸아제티딘-1-일)메틸)피리딘-2-일)티에노[3,2-b]피리딘-7-일)옥시)페닐)-5-(4-플루오로페닐)-6-옥소-2,3,5,6-테트라히드로퓨로[3,2-c]피리딘-7-카르복스아미드;
b14) N-(3-플루오로-4-((2-(5-((3-메톡시아제티딘-1-일)메틸)피리딘-2-일)티에노[3,2-b]피리딘-7-일)옥시)페닐)-5-(4-플루오로페닐)-6-옥소-2,3,5,6-테트라히드로퓨로[3,2-c]피리딘-7-카르복스아미드;
b15) N-(3-플루오로-4-((2-(5-((3-(메톡시메틸)아제티딘-1-일)메틸)피리딘-2-일)티에노[3,2-b]피리딘-7-일)옥시)페닐)-5-(4-플루오로페닐)-6-옥소-2,3,5,6-테트라히드로퓨로[3,2-c]피리딘-7-카르복스아미드;
b16) N-(3-플루오로-4-((2-(5-((3-메톡시-3-메틸아제티딘-1-일)메틸)피리딘-2-일)티에노[3,2-b]피리딘-7-일)옥시)페닐)-5-(4-플루오로페닐)-6-옥소-2,3,5,6-테트라히드로퓨로[3,2-c]피리딘-7-카르복스아미드;
b17) N-(3-플루오로-4-((2-(5-((3-플루오로아제티딘-1-일)메틸)피리딘-2-일)티에노[3,2-b]피리딘-7-일)옥시)페닐)-5-(4-플루오로페닐)-6-옥소-2,3,5,6-테트라히드로퓨로[3,2-c]피리딘-7-카르복스아미드;
b18) N-(4-((2-(5-((3,3-디플루오로아제티딘-1-일)메틸)피리딘-2-일)티에노[3,2-b]피리딘-7-일)옥시)-3-플루오로페닐)-5-(4-플루오로페닐)-6-옥소-2,3,5,6-테트라히드로퓨로[3,2-c]피리딘-7-카르복스아미드;
b19) N-(4-((2-(5-((3-시아노아제티딘-1-일)메틸)피리딘-2-일)티에노[3,2-b]피리딘-7-일)옥시)-3-플루오로페닐)-5-(4-플루오로페닐)-6-옥소-2,3,5,6-테트라히드로퓨로[3,2-c]피리딘-7-카르복스아미드;
b20) N-(4-((2-(5-((3-(디메틸아미노)아제티딘-1-일)메틸)피리딘-2-일)티에노[3,2-b]피리딘-7-일)옥시)-3-플루오로페닐)-5-(4-플루오로페닐)-6-옥소-2,3,5,6-테트라히드로퓨로[3,2-c]피리딘-7-카르복스아미드;
b21) N-(3-플루오로-4-((2-(5-((3-메틸아제티딘-1-일)메틸)피리딘-2-일)티에노[3,2-b]피리딘-7-일)옥시)페닐)-5-(4-플루오로페닐)-6-옥소-2,3,5,6-테트라히드로퓨로[3,2-c]피리딘-7-카르복스아미드;
b22) N-(4-((2-(5-((3,3-디메틸아제티딘-1-일)메틸)피리딘-2-일)티에노[3,2-b]피리딘-7-일)옥시)-3-플루오로페닐)-5-(4-플루오로페닐)-6-옥소-2,3,5,6-테트라히드로퓨로[3,2-c]피리딘-7-카르복스아미드;
b23) N-(3-플루오로-4-((2-(5-((3-히드록시피롤리딘-1-일)메틸)피리딘-2-일)티에노[3,2-b]피리딘-7-일)옥시)페닐)-5-(4-플루오로페닐)-6-옥소-2,3,5,6-테트라히드로퓨로[3,2-c]피리딘-7-카르복스아미드;
b24) N-(3-플루오로-4-((2-(5-((3-히드록시-3-메틸피롤리딘-1-일)메틸)피리딘-2-일)티에노[3,2-b]피리딘-7-일)옥시)페닐)-5-(4-플루오로페닐)-6-옥소-2,3,5,6-테트라히드로퓨로[3,2-c]피리딘-7-카르복스아미드;
b25) N-(3-플루오로-4-((2-(5-((3-메톡시피롤리딘-1-일)메틸)피리딘-2-일)티에노[3,2-b]피리딘-7-일)옥시)페닐)-5-(4-플루오로페닐)-6-옥소-2,3,5,6-테트라히드로퓨로[3,2-c]피리딘-7-카르복스아미드;
b26) N-(3-플루오로-4-((2-(5-(피롤리딘-1-일메틸)피리딘-2-일)티에노[3,2-b]피리딘-7-일)옥시)페닐)-5-(4-플루오로페닐)-6-옥소-2,3,5,6-테트라히드로퓨로[3,2-c]피리딘-7-카르복스아미드;
b27) N-(3-플루오로-4-((2-(5-((3-플루오로피롤리딘-1-일)메틸)피리딘-2-일)티에노[3,2-b]피리딘-7-일)옥시)페닐)-5-(4-플루오로페닐)-6-옥소-2,3,5,6-테트라히드로퓨로[3,2-c]피리딘-7-카르복스아미드;
b28) N-(4-((2-(5-((3,3-디플루오로피롤리딘-1-일)메틸)피리딘-2-일)티에노[3,2-b]피리딘-7-일)옥시)-3-플루오로페닐)-5-(4-플루오로페닐)-6-옥소-2,3,5,6-테트라히드로퓨로[3,2-c]피리딘-7-카르복스아미드;
b29) N-(3-플루오로-4-((2-(5-((4-히드록시피페리딘-1-일)메틸)피리딘-2-일)티에노[3,2-b]피리딘-7-일)옥시)페닐)-5-(4-플루오로페닐)-6-옥소-2,3,5,6-테트라히드로퓨로[3,2-c]피리딘-7-카르복스아미드;
b30) N-(3-플루오로-4-((2-(5-((3-히드록시피페리딘-1-일)메틸)피리딘-2-일)티에노[3,2-b]피리딘-7-일)옥시)페닐)-5-(4-플루오로페닐)-6-옥소-2,3,5,6-테트라히드로퓨로[3,2-c]피리딘-7-카르복스아미드;
b31) N-(3-플루오로-4-((2-(5-((4-메톡시피페리딘-1-일)메틸)피리딘-2-일)티에노[3,2-b]피리딘-7-일)옥시)페닐)-5-(4-플루오로페닐)-6-옥소-2,3,5,6-테트라히드로퓨로[3,2-c]피리딘-7-카르복스아미드;
b32) N-(3-플루오로-4-((2-(5-((3-메톡시피페리딘-1-일)메틸)피리딘-2-일)티에노[3,2-b]피리딘-7-일)옥시)페닐)-5-(4-플루오로페닐)-6-옥소-2,3,5,6-테트라히드로퓨로[3,2-c]피리딘-7-카르복스아미드;
b33) N-(3-플루오로-4-((2-(5-(피페리딘-1-일메틸)피리딘-2-일)티에노[3,2-b]피리딘-7-일)옥시)페닐)-5-(4-플루오로페닐)-6-옥소-2,3,5,6-테트라히드로퓨로[3,2-c]피리딘-7-카르복스아미드;
b34) N-(3-플루오로-4-((2-(5-((4-플루오로피페리딘-1-일)메틸)피리딘-2-일)티에노[3,2-b]피리딘-7-일)옥시)페닐)-5-(4-플루오로페닐)-6-옥소-2,3,5,6-테트라히드로퓨로[3,2-c]피리딘-7-카르복스아미드;
b35) N-(4-((2-(5-((4,4-디플루오로피페리딘-1-일)메틸)피리딘-2-일)티에노[3,2-b]피리딘-7-일)옥시)-3-플루오로페닐)-5-(4-플루오로페닐)-6-옥소-2,3,5,6-테트라히드로퓨로[3,2-c]피리딘-7-카르복스아미드;
b36) N-(3-플루오로-4-((2-(5-((4-메틸피페리딘-1-일)메틸)피리딘-2-일)티에노[3,2-b]피리딘-7-일)옥시)페닐)-5-(4-플루오로페닐)-6-옥소-2,3,5,6-테트라히드로퓨로[3,2-c]피리딘-7-카르복스아미드;
b37) N-(4-((2-(5-((4,4-디메틸피페리딘-1-일)메틸)피리딘-2-일)티에노[3,2-b]피리딘-7-일)옥시)-3-플루오로페닐)-5-(4-플루오로페닐)-6-옥소-2,3,5,6-테트라히드로퓨로[3,2-c]피리딘-7-카르복스아미드;
b38) N-(3-플루오로-4-((2-(5-((((3-히드록시사이클로헥실)메틸)아미노)메틸)피리딘-2-일)티에노[3,2-b]피리딘-7-일)옥시)페닐)-5-(4-플루오로페닐)-6-옥소-2,3,5,6-테트라히드로퓨로[3,2-c]피리딘-7-카르복스아미드; 및
b39) N-(3-플루오로-4-((2-(5-(((테트라히드로-2H-피란-4-일)아미노)메틸)피리딘-2-일)티에노[3,2-b]피리딘-7-일)옥시)페닐)-5-(4-플루오로페닐)-6-옥소-2,3,5,6-테트라히드로퓨로[3,2-c]피리딘-7-카르복스아미드.
구체적인 다른 예에 따르면, 상기 화학식 2의 화합물은 하기 화학식 2b로 표시될 수 있다.
[화학식 2b]
상기 식에서
X, L, R1, R2, R3 및 R4는 상기 화학식 2에서 정의한 바와 같고,
Y는 -N= 또는 -CH=이고,
R5 및 R6는 각각 독립적으로 수소, 아미노, 할로겐, 시아노, C1-6 알킬, C1-6 할로알킬, C1-6 알콕시, 아미노-C1-6 알콕시, 아미노카르보닐, C1-6 알킬아미노카르보닐, 디C1-6 알킬카르보닐아미노, C1-6 알킬카르보닐아미노, C1-6 알킬아미노, 또는 C1-6 알킬-아미노-C1-6 알콕시이고,
이때 R5 및 R6는 각각 독립적으로 3원 내지 9원의 사이클로알킬; 또는 3원 내지 9원의 헤테로사이클로알킬로 치환되거나 치환되지 않고,
상기 사이클로알킬 또는 헤테로사이클로알킬은 할로겐, 옥소, 시아노, 히드록시, 히드록시-C1-6 알킬, 아미노, 디C1-6 알킬아미노, C1-6 알킬, C1-6 알콕시, 및 C1-6 알콕시-C1-6 알킬로 이루어진 군으로부터 선택되는 하나 이상의 치환기를 갖거나 갖지 않고,
상기 헤테로사이클로알킬은 N, O 및 S로 이루어진 군으로부터 선택되는 1 내지 4개의 헤테로원자를 포함한다.
상기 화학식 2b로 표시되는 화합물의 구체적인 예는 아래와 같다:
b40) N-(4-((6,7-디메톡시퀴놀린-4-일)옥시)-3-플루오로페닐)-5-(4-플루오로페닐)-6-옥소-2,3,5,6-테트라히드로퓨로[3,2-c]피리딘-7-카르복스아미드;
b41) N-(4-((6,7-디메톡시퀴놀린-4-일)옥시)-3-플루오로페닐)-6-옥소-5-페닐-2,3,5,6-테트라히드로퓨로[3,2-c]피리딘-7-카르복스아미드;
b42) N-(4-((6,7-디메톡시퀴놀린-4-일)옥시)-3-플루오로페닐)-6-옥소-5-(4-(트리플루오로메틸)페닐)-2,3,5,6-테트라히드로퓨로[3,2-c]피리딘-7-카르복스아미드;
b43) N-(4-((6,7-디메톡시퀴놀린-4-일)옥시)-3-플루오로페닐)-6-옥소-5-(3-플루오로페닐)-2,3,5,6-테트라히드로퓨로[3,2-c]피리딘-7-카르복스아미드;
b44) N-(3-플루오로-4-((6-메톡시퀴놀린-4-일)옥시)페닐)-5-(4-플루오로페닐)-6-옥소-2,3,5,6-테트라히드로퓨로[3,2-c]피리딘-7-카르복스아미드;
b45) N-(3-플루오로-4-((7-메톡시퀴놀린-4-일)옥시)페닐)-5-(4-플루오로페닐)-6-옥소-2,3,5,6-테트라히드로퓨로[3,2-c]피리딘-7-카르복스아미드;
b46) N-(4-((6,7-디메톡시퀴나졸린-4-일)옥시)-3-플루오로페닐)-5-(4-플루오로페닐)-6-옥소-2,3,5,6-테트라히드로퓨로[3,2-c]피리딘-7-카르복스아미드;
b47) N-(4-((6-카르바모일-7-메톡시퀴놀린-4-일)옥시)-3-플루오로페닐)-5-(4-플루오로페닐)-6-옥소-2,3,5,6-테트라히드로퓨로[3,2-c]피리딘-7-카르복스아미드;
b48) N-(3-플루오로-4-((7-메톡시-6-(메틸카르바모일)퀴놀린-4-일)옥시)페닐)-5-(4-플루오로페닐)-6-옥소-2,3,5,6-테트라히드로퓨로[3,2-c]피리딘-7-카르복스아미드;
b49) N-(4-((6-(디메틸카르바모일)-7-메톡시퀴놀린-4-일)옥시)-3-플루오로페닐)-5-(4-플루오로페닐)-6-옥소-2,3,5,6-테트라히드로퓨로[3,2-c]피리딘-7-카르복스아미드;
b50) N-(3-플루오로-4-((7-메톡시-6-((2-모폴리노에틸)카르바모일)퀴놀린-4-일)옥시)페닐)-5-(4-플루오로페닐)-6-옥소-2,3,5,6-테트라히드로퓨로[3,2-c]피리딘-7-카르복스아미드;
b51) N-(4-((6-(에틸카르바모일)-7-메톡시퀴놀린-4-일)옥시)-3-플루오로페닐)-5-(4-플루오로페닐)-6-옥소-2,3,5,6-테트라히드로퓨로[3,2-c]피리딘-7-카르복스아미드;
b52) N-(4-((6-아세트아미도-7-메톡시퀴놀린-4-일)옥시)-3-플루오로페닐)-5-(4-플루오로페닐)-6-옥소-2,3,5,6-테트라히드로퓨로[3,2-c]피리딘-7-카르복스아미드;
b53) N-(3-플루오로-4-((7-메톡시-6-(2-모폴리노아세트아미도)퀴놀린-4-일)옥시)페닐)-5-(4-플루오로페닐)-6-옥소-2,3,5,6-테트라히드로퓨로[3,2-c]피리딘-7-카르복스아미드;
b76) N-(3-플루오로-4-((6-메톡시-7-(3-모폴리노프로폭시)퀴놀린-4-일)옥시)페닐)-5-(4-플루오로페닐)-6-옥소-2,3,5,6-테트라히드로퓨로[3,2-c]피리딘-7-카르복스아미드;
b77) N-(3-플루오로-4-((6-메톡시-7-(3-모폴리노프로폭시)퀴놀린-4-일)옥시)페닐)-2-(4-플루오로페닐)-3-옥소-3,5,6,7-테트라히드로-2H-사이클로펜타[c]피리딘-4-카르복스아미드;
b78) N-(3-플루오로-4-((6-메톡시-7-(2-모폴리노에톡시)퀴놀린-4-일)옥시)페닐)-5-(4-플루오로페닐)-6-옥소-2,3,5,6-테트라히드로퓨로[3,2-c]피리딘-7-카르복스아미드;
b79) N-(3-플루오로-4-((6-메톡시-7-(2-모폴리노에톡시)퀴놀린-4-일)옥시)페닐)-6-옥소-5-페닐-2,3,5,6-테트라히드로퓨로[3,2-c]피리딘-7-카르복스아미드;
b80) N-(3-플루오로-4-((6-메톡시-7-(3-(4-메틸피페라진-1-일)프로폭시)퀴놀린-4-일)옥시)페닐)-5-(4-플루오로페닐)-6-옥소-2,3,5,6-테트라히드로퓨로[3,2-c]피리딘-7-카르복스아미드;
b81) N-(3-플루오로-4-((7-(3-(3-히드록시아제티딘-1-일)프로폭시)-6-메톡시퀴놀린-4-일)옥시)페닐)-5-(4-플루오로페닐)-6-옥소-2,3,5,6-테트라히드로퓨로[3,2-c]피리딘-7-카르복스아미드;
b82) N-(3-플루오로-4-((7-(3-(3-히드록시-3-메틸아제티딘-1-일)프로폭시)-6-메톡시퀴놀린-4-일)옥시)페닐)-5-(4-플루오로페닐)-6-옥소-2,3,5,6-테트라히드로퓨로[3,2-c]피리딘-7-카르복스아미드;
b83) N-(3-플루오로-4-((7-(3-(3-(히드록시메틸)아제티딘-1-일)프로폭시)-6-메톡시퀴놀린-4-일)옥시)페닐)-5-(4-플루오로페닐)-6-옥소-2,3,5,6-테트라히드로퓨로[3,2-c]피리딘-7-카르복스아미드;
b84) N-(3-플루오로-4-((6-메톡시-7-(3-(3-메톡시아제티딘-1-일)프로폭시)퀴놀린-4-일)옥시)페닐)-5-(4-플루오로페닐)-6-옥소-2,3,5,6-테트라히드로퓨로[3,2-c]피리딘-7-카르복스아미드;
b85) N-(3-플루오로-4-((6-메톡시-7-(3-(3-메톡시-3-메틸아제티딘-1-일)프로폭시)퀴놀린-4-일)옥시)페닐)-5-(4-플루오로페닐)-6-옥소-2,3,5,6-테트라히드로퓨로[3,2-c]피리딘-7-카르복스아미드;
b86) N-(3-플루오로-4-((7-(3-(3-플루오로아제티딘-1-일)프로폭시)-6-메톡시퀴놀린-4-일)옥시)페닐)-5-(4-플루오로페닐)-6-옥소-2,3,5,6-테트라히드로퓨로[3,2-c]피리딘-7-카르복스아미드;
b87) N-(4-((7-(3-(3,3-디플루오로아제티딘-1-일)프로폭시)-6-메톡시퀴놀린-4-일)옥시)-3-플루오로페닐)-5-(4-플루오로페닐)-6-옥소-2,3,5,6-테트라히드로퓨로[3,2-c]피리딘-7-카르복스아미드;
b88) N-(4-((7-(3-(3-시아노아제티딘-1-일)프로폭시)-6-메톡시퀴놀린-4-일)옥시)-3-플루오로페닐)-5-(4-플루오로페닐)-6-옥소-2,3,5,6-테트라히드로퓨로[3,2-c]피리딘-7-카르복스아미드;
b89) N-(3-플루오로-4-((6-메톡시-7-(3-(3-메틸아제티딘-1-일)프로폭시)퀴놀린-4-일)옥시)페닐)-5-(4-플루오로페닐)-6-옥소-2,3,5,6-테트라히드로퓨로[3,2-c]피리딘-7-카르복스아미드;
b90) N-(3-플루오로-4-((7-(3-(3-히드록시피롤리딘-1-일)프로폭시)-6-메톡시퀴놀린-4-일)옥시)페닐)-5-(4-플루오로페닐)-6-옥소-2,3,5,6-테트라히드로퓨로[3,2-c]피리딘-7-카르복스아미드;
b91) N-(3-플루오로-4-((7-(3-(3-히드록시-3-메틸피롤리딘-1-일)프로폭시)-6-메톡시퀴놀린-4-일)옥시)페닐)-5-(4-플루오로페닐)-6-옥소-2,3,5,6-테트라히드로퓨로[3,2-c]피리딘-7-카르복스아미드;
b92) N-(3-플루오로-4-((6-메톡시-7-(3-(3-메톡시피롤리딘-1-일)프로폭시)퀴놀린-4-일)옥시)페닐)-5-(4-플루오로페닐)-6-옥소-2,3,5,6-테트라히드로퓨로[3,2-c]피리딘-7-카르복스아미드;
b93) N-(3-플루오로-4-((6-메톡시-7-(3-(피롤리딘-1-일)프로폭시)퀴놀린-4-일)옥시)페닐)-5-(4-플루오로페닐)-6-옥소-2,3,5,6-테트라히드로퓨로[3,2-c]피리딘-7-카르복스아미드;
b94) N-(3-플루오로-4-((7-(3-(3-플루오로피롤리딘-1-일)프로폭시)-6-메톡시퀴놀린-4-일)옥시)페닐)-5-(4-플루오로페닐)-6-옥소-2,3,5,6-테트라히드로퓨로[3,2-c]피리딘-7-카르복스아미드;
b95) N-(4-((7-(3-(3,3-디플루오로피롤리딘-1-일)프로폭시)-6-메톡시퀴놀린-4-일)옥시)-3-플루오로페닐)-5-(4-플루오로페닐)-6-옥소-2,3,5,6-테트라히드로퓨로[3,2-c]피리딘-7-카르복스아미드;
b96) N-(3-플루오로-4-((7-(3-(4-히드록시피페리딘-1-일)프로폭시)-6-메톡시퀴놀린-4-일)옥시)페닐)-5-(4-플루오로페닐)-6-옥소-2,3,5,6-테트라히드로퓨로[3,2-c]피리딘-7-카르복스아미드;
b97) N-(3-플루오로-4-((7-(3-(3-히드록시피페리딘-1-일)프로폭시)-6-메톡시퀴놀린-4-일)옥시)페닐)-5-(4-플루오로페닐)-6-옥소-2,3,5,6-테트라히드로퓨로[3,2-c]피리딘-7-카르복스아미드;
b98) N-(3-플루오로-4-((7-(3-(4-히드록시-4-메틸피페리딘-1-일)프로폭시)-6-메톡시퀴놀린-4-일)옥시)페닐)-5-(4-플루오로페닐)-6-옥소-2,3,5,6-테트라히드로퓨로[3,2-c]피리딘-7-카르복스아미드;
b99) N-(3-플루오로-4-(6-메톡시-7-(3-(4-메톡시피페리딘-1-일)프로폭시)퀴놀린-4-일)옥시)페닐)-5-(4-플루오로페닐)-6-옥소-2,3,5,6-테트라히드로퓨로[3,2-c]피리딘-7-카르복스아미드;
b100) N-(3-플루오로-4-((6-메톡시-7-(3-(3-메톡시피페리딘-1-일)프로폭시)퀴놀린-4-일)옥시)페닐)-5-(4-플루오로페닐)-6-옥소-2,3,5,6-테트라히드로퓨로[3,2-c]피리딘-7-카르복스아미드;
b101) N-(3-플루오로-4-((6-메톡시-7-(3-(4-옥소피페리딘-1-일)프로폭시)퀴놀린-4-일)옥시)페닐)-5-(4-플루오로페닐)-6-옥소-2,3,5,6-테트라히드로퓨로[3,2-c]피리딘-7-카르복스아미드;
b102) N-(4-((7-(3-(1,1-디옥시도티오모폴리노)프로폭시)-6-메톡시퀴놀린-4-일)옥시)-3-플루오로페닐)-5-(4-플루오로페닐)-6-옥소-2,3,5,6-테트라히드로퓨로[3,2-c]피리딘-7-카르복스아미드;
b103) N-(3-플루오로-4-(6-메톡시-7-(3-(피페리딘-1-일)프로폭시)퀴놀린-4-일)옥시)페닐)-5-(4-플루오로페닐)-6-옥소-2,3,5,6-테트라히드로퓨로[3,2-c]피리딘-7-카르복스아미드;
b104) N-(3-플루오로-4-((7-(3-(4-플루오로피페리딘-1-일)프로폭시)-6-메톡시퀴놀린-4-일)옥시)페닐)-5-(4-플루오로페닐)-6-옥소-2,3,5,6-테트라히드로퓨로[3,2-c]피리딘-7-카르복스아미드;
b105) N-(4-((7-(3-(4,4-디플루오로피페리딘-1-일)프로폭시)-6-메톡시퀴놀린-4-일)옥시)-3-플루오로페닐)-5-(4-플루오로페닐)-6-옥소-2,3,5,6-테트라히드로퓨로[3,2-c]피리딘-7-카르복스아미드;
b106) N-(3-플루오로-4-((6-메톡시-7-(3-(4-메틸피페리딘-1-일)프로폭시)퀴놀린-4-일)옥시)페닐)-5-(4-플루오로페닐)-6-옥소-2,3,5,6-테트라히드로퓨로[3,2-c]피리딘-7-카르복스아미드;
b107) N-(4-((7-(3-(4,4-디메틸피페리딘-1-일)프로폭시)-6-메톡시퀴놀린-4-일)옥시)-3-플루오로페닐)-5-(4-플루오로페닐)-6-옥소-2,3,5,6-테트라히드로퓨로[3,2-c]피리딘-7-카르복스아미드;
b108) N-(3-플루오로-4-((7-(3-((3-히드록시사이클로부틸)아미노)프로폭시)-6-메톡시퀴놀린-4-일)옥시)페닐)-5-(4-플루오로페닐)-6-옥소-2,3,5,6-테트라히드로퓨로[3,2-c]피리딘-7-카르복스아미드;
b109) N-(3-플루오로-4-((6-메톡시-7-(3-((3-메톡시사이클로부틸)아미노)프로폭시)퀴놀린-4-일)옥시)페닐)-5-(4-플루오로페닐)-6-옥소-2,3,5,6-테트라히드로퓨로[3,2-c]피리딘-7-카르복스아미드;
b110) N-(3-플루오로-4-((6-메톡시-7-(3-(옥세탄-3-일아미노)프로폭시)퀴놀린-4-일)옥시)페닐)-5-(4-플루오로페닐)-6-옥소-2,3,5,6-테트라히드로퓨로[3,2-c]피리딘-7-카르복스아미드;
b111) N-(3-플루오로-4-((6-메톡시-7-(3-((옥세탄-3-일메틸)아미노)프로폭시)퀴놀린-4-일)옥시)페닐)-5-(4-플루오로페닐)-6-옥소-2,3,5,6-테트라히드로퓨로[3,2-c]피리딘-7-카르복스아미드;
b112) N-(3-플루오로-4-((7-(3-((3-히드록시사이클로펜틸)아미노)프로폭시)-6-메톡시퀴놀린-4-일)옥시)페닐)-5-(4-플루오로페닐)-6-옥소-2,3,5,6-테트라히드로퓨로[3,2-c]피리딘-7-카르복스아미드;
b113) N-(3-플루오로-4-((7-(3-((3-히드록시사이클로헥실)아미노)프로폭시)-6-메톡시퀴놀린-4-일)옥시)페닐)-5-(4-플루오로페닐)-6-옥소-2,3,5,6-테트라히드로퓨로[3,2-c]피리딘-7-카르복스아미드;
b114) N-(3-플루오로-4-((7-(3-(((3-히드록시사이클로헥실)메틸)아미노)프로폭시)-6-메톡시퀴놀린-4-일)옥시)페닐)-5-(4-플루오로페닐)-6-옥소-2,3,5,6-테트라히드로퓨로[3,2-c]피리딘-7-카르복스아미드;
b115) N-(3-플루오로-4-((6-메톡시-7-(3-((테트라히드로-2H-파이란-4-일)아미노)프로폭시)퀴놀린-4-일)옥시)페닐)-5-(4-플루오로페닐)-6-옥소-2,3,5,6-테트라히드로퓨로[3,2-c]피리딘-7-카르복스아미드;
b116) N-(3-플루오로-4-((6-메톡시-7-(3-(((테트라히드로-2H-파이란-4-일)메틸)아미노)프로폭시)퀴놀린-4-일)옥시)페닐)-5-(4-플루오로페닐)-6-옥소-2,3,5,6-테트라히드로퓨로[3,2-c]피리딘-7-카르복스아미드;
b117) N-(3-플루오로-4-((7-(2-(3-히드록시아제티딘-1-일)에톡시)-6-메톡시퀴놀린-4-일)옥시)페닐)-5-(4-플루오로페닐)-6-옥소-2,3,5,6-테트라히드로퓨로[3,2-c]피리딘-7-카르복스아미드;
b118) N-(3-플루오로-4-((7-(2-(3-히드록시-3-메틸아제티딘-1-일)에톡시)-6-메톡시퀴놀린-4-일)옥시)페닐)-5-(4-플루오로페닐)-6-옥소-2,3,5,6-테트라히드로퓨로[3,2-c]피리딘-7-카르복스아미드;
b119) N-(3-플루오로-4-((7-(2-(3-(히드록시메틸)아제티딘-1-일)에톡시)-6-메톡시퀴놀린-4-일)옥시)페닐)-5-(4-플루오로페닐)-6-옥소-2,3,5,6-테트라히드로퓨로[3,2-c]피리딘-7-카르복스아미드;
b120) N-(3-플루오로-4-((6-메톡시-7-(2-(3-메톡시아제티딘-1-일)에톡시)퀴놀린-4-일)옥시)페닐)-5-(4-플루오로페닐)-6-옥소-2,3,5,6-테트라히드로퓨로[3,2-c]피리딘-7-카르복스아미드;
b121) N-(3-플루오로-4-((6-메톡시-7-(2-(3-메톡시-3-메틸아제티딘-1-일)에톡시)퀴놀린-4-일)옥시)페닐)-5-(4-플루오로페닐)-6-옥소-2,3,5,6-테트라히드로퓨로[3,2-c]피리딘-7-카르복스아미드;
b122) N-(3-플루오로-4-((6-메톡시-7-(2-(3-(메톡시메틸)아제티딘-1-일)에톡시)퀴놀린-4-일)옥시)페닐)-5-(4-플루오로페닐)-6-옥소-2,3,5,6-테트라히드로퓨로[3,2-c]피리딘-7-카르복스아미드;
b123) N-(3-플루오로-4-((7-(2-(3-플루오로아제티딘-1-일)에톡시)-6-메톡시퀴놀린-4-일)옥시)페닐)-5-(4-플루오로페닐)-6-옥소-2,3,5,6-테트라히드로퓨로[3,2-c]피리딘-7-카르복스아미드;
b124) N-(4-((7-(2-(3,3-디플루오로아제티딘-1-일)에톡시)-6-메톡시퀴놀린-4-일)옥시)-3-플루오로페닐)-5-(4-플루오로페닐)-6-옥소-2,3,5,6-테트라히드로퓨로[3,2-c]피리딘-7-카르복스아미드;
b125) N-(4-((7-(2-(3-에티닐아제티딘-1-일)에톡시)-6-메톡시퀴놀린-4-일)옥시)-3-플루오로페닐)-5-(4-플루오로페닐)-6-옥소-2,3,5,6-테트라히드로퓨로[3,2-c]피리딘-7-카르복스아미드;
b126) N-(3-플루오로-4-((6-메톡시-7-(2-(3-메틸아제티딘-1-일)에톡시)퀴놀린-4-일)옥시)페닐)-5-(4-플루오로페닐)-6-옥소-2,3,5,6-테트라히드로퓨로[3,2-c]피리딘-7-카르복스아미드;
b127) N-(4-((7-(2-(3,3-디메틸아제티딘-1-일)에톡시)-6-메톡시퀴놀린-4-일)옥시)-3-플루오로페닐)-5-(4-플루오로페닐)-6-옥소-2,3,5,6-테트라히드로퓨로[3,2-c]피리딘-7-카르복스아미드;
b128) N-(4-((7-(2-(3-(디메틸아미노)아제티딘-1-일)에톡시)-6-메톡시퀴놀린-4-일)옥시)-3-플루오로페닐)-5-(4-플루오로페닐)-6-옥소-2,3,5,6-테트라히드로퓨로[3,2-c]피리딘-7-카르복스아미드;
b129) N-(3-플루오로-4-((7-(2-(3-히드록시피롤리딘-1-일)에톡시)-6-메톡시퀴놀린-4-일)옥시)페닐)-5-(4-플루오로페닐)-6-옥소-2,3,5,6-테트라히드로퓨로[3,2-c]피리딘-7-카르복스아미드;
b130) N-(3-플루오로-4-((7-(2-(3-히드록시-3-메틸피롤리딘-1-일)에톡시)-6-메톡시퀴놀린-4-일)옥시)페닐)-5-(4-플루오로페닐)-6-옥소-2,3,5,6-테트라히드로퓨로[3,2-c]피리딘-7-카르복스아미드;
b131) N-(3-플루오로-4-((6-메톡시-7-(2-(3-메톡시피롤리딘-1-일)에톡시)퀴놀린-4-일)옥시)페닐)-5-(4-플루오로페닐)-6-옥소-2,3,5,6-테트라히드로퓨로[3,2-c]피리딘-7-카르복스아미드;
b132) N-(3-플루오로-4-((6-메톡시-7-(2-(피롤리딘-1-일)에톡시)퀴놀린-4-일)옥시)페닐)-5-(4-플루오로페닐)-6-옥소-2,3,5,6-테트라히드로퓨[3,2-c]피리딘-7-카르복스아미드;
b133) N-(3-플루오로-4-((7-(2-(3-플루오로피롤리딘-1-일)에톡시)-6-메톡시퀴놀린-4-일)옥시)페닐)-5-(4-플루오로페닐)-6-옥소-2,3,5,6-테트라히드로퓨로[3,2-c]피리딘-7-카르복스아미드;
b134) N-(4-((7-(2-(3,3-디플루오로피롤리딘-1-일)에톡시)-6-메톡시퀴놀린-4-일)옥시)-3-플루오로페닐)-5-(4-플루오로페닐)-6-옥소-2,3,5,6-테트라히드로퓨로[3,2-c]피리딘-7-카르복스아미드;
b135) N-(3-플루오로-4-((7-(2-(4-히드록시피페리딘-1-일)에톡시)-6-메톡시퀴놀린-4-일)옥시)페닐)-5-(4-플루오로페닐)-6-옥소-2,3,5,6-테트라히드로퓨로[3,2-c]피리딘-7-카르복스아미드;
b136) N-(3-플루오로-4-((7-(2-(3-히드록시피페리딘-1-일)에톡시)-6-메톡시퀴놀린-4-일)옥시)페닐)-5-(4-플루오로페닐)-6-옥소-2,3,5,6-테트라히드로퓨로[3,2-c]피리딘-7-카르복스아미드;
b137) N-(3-플루오로-4-((7-(2-(4-히드록시-4-메틸피페리딘-1-일)에톡시)-6-메톡시퀴놀린-4-일)옥시)페닐)-5-(4-플루오로페닐)-6-옥소-2,3,5,6-테트라히드로퓨로[3,2-c]피리딘-7-카르복스아미드;
b138) N-(3-플루오로-4-((6-메톡시-7-(2-(4-메톡시피페리딘-1-일)에톡시)퀴놀린-4-일)옥시)페닐)-5-(4-플루오로페닐)-6-옥소-2,3,5,6-테트라히드로퓨로[3,2-c]피리딘-7-카르복스아미드;
b139) N-(3-플루오로-4-((6-메톡시-7-(2-(3-메톡시피페리딘-1-일)에톡시)퀴놀린-4-일)옥시)페닐)-5-(4-플루오로페닐)-6-옥소-2,3,5,6-테트라히드로퓨로[3,2-c]피리딘-7-카르복스아미드;
b140) N-(3-플루오로-4-((6-메톡시-7-(2-(4-옥소피페리딘-1-일)에톡시)퀴놀린-4-일)옥시)페닐)-5-(4-플루오로페닐)-6-옥소-2,3,5,6-테트라히드로퓨로[3,2-c]피리딘-7-카르복스아미드;
b141) N-(3-플루오로-4-((6-메톡시-7-(2-(3-옥소피페리딘-1-일)에톡시)퀴놀린-4-일)옥시)페닐)-5-(4-플루오로페닐)-6-옥소-2,3,5,6-테트라히드로퓨로[3,2-c]피리딘-7-카르복스아미드;
b142) N-(4-((7-(2-(1,1-디옥시도티오모폴리노)에톡시)-6-메톡시퀴놀린-4-일)옥시)-3-플루오로페닐)-5-(4-플루오로페닐)-6-옥소-2,3,5,6-테트라히드로퓨로[3,2-c]피리딘-7-카르복스아미드;
b143) N-(3-플루오로-4-((6-메톡시-7-(2-(피페리딘-1-일)에톡시)퀴놀린-4-일)옥시)페닐)-5-(4-플루오로페닐)-6-옥소-2,3,5,6-테트라히드로퓨[3,2-c]피리딘-7-카르복스아미드;
b144) N-(3-플루오로-4-((7-(2-(4-플루오로피페리딘-1-일)에톡시)-6-메톡시퀴놀린-4-일)옥시)페닐)-5-(4-플루오로페닐)-6-옥소-2,3,5,6-테트라히드로퓨로[3,2-c]피리딘-7-카르복스아미드;
b145) N-(4-((7-(2-(4,4-디플루오로피페리딘-1-일)에톡시)-6-메톡시퀴놀린-4-일)옥시)-3-플루오로페닐)-5-(4-플루오로페닐)-6-옥소-2,3,5,6-테트라히드로퓨로[3,2-c]피리딘-7-카르복스아미드;
b146) N-(3-플루오로-4-((6메톡시-7-(2-(4-메틸피페리딘-1-일)에톡시)퀴놀린-4-일)옥시)페닐)-5-(4-플루오로페닐)-6-옥소-2,3,5,6-테트라히드로퓨로[3,2-c]피리딘-7-카르복스아미드;
b147) N-(4-((7-(2-(4,4-디메틸피페리딘-1-일)에톡시)-6-메톡시퀴놀린-4-일)옥시)-3-플루오로페닐)-5-(4-플루오로페닐)-6-옥소-2,3,5,6-테트라히드로퓨로[3,2-c]피리딘-7-카르복스아미드;
b148) N-(3-플루오로-4-((7-(2-((3-히드록시사이클로부틸)아미노)에톡시)-6-메톡시퀴놀린-4-일)옥시)페닐)-5-(4-플루오로페닐)-6-옥소-2,3,5,6-테트라히드로퓨로[3,2-c]피리딘-7-카르복스아미드;
b149) N-(3-플루오로-4-((6-메톡시-7-(2-((3-메톡시사이클로부틸)아미노)에톡시)퀴놀린-4-일)옥시)페닐)-5-(4-플루오로페닐)-6-옥소-2,3,5,6-테트라히드로퓨로[3,2-c]피리딘-7-카르복스아미드;
b150) N-(3-플루오로-4-((6-메톡시-7-(2-(옥세탄-3-일아미노)에톡시)퀴놀린-4-일)옥시)페닐)-5-(4-플루오로페닐)-6-옥소-2,3,5,6-테트라히드로퓨로[3,2-c]피리딘-7-카르복스아미드;
b151) N-(3-플루오로-4-((6-메톡시-7-(2-((옥세탄-3-일메틸)아미노)에톡시)퀴놀린-4-일)옥시)페닐)-5-(4-플루오로페닐)-6-옥소-2,3,5,6-테트라히드로퓨로[3,2-c]피리딘-7-카르복스아미드;
b152) N-(3-플루오로-4-((7-(2-((4-히드록시사이클로헥실)아미노)에톡시)-6-메톡시퀴놀린-4-일)옥시)페닐)-5-(4-플루오로페닐)-6-옥소-2,3,5,6-[3,2-c]피리딘-7-카르복스아미드;
b153) N-(3-플루오로-4-((7-(2-((3-히드록시사이클로헥실)아미노)에톡시)-6-메톡시퀴놀린-4-일)옥시)페닐)-5-(4-플루오로페닐)-6-옥소-2,3,5,6-테트라히드로퓨로[3,2-c]피리딘-7-카르복스아미드;
b154) N-(3-플루오로-4-((7-(2-(((3-히드록시사이클로헥실)메틸)아미노)에톡시)-6-메톡시퀴놀린-4-일)옥시)페닐)-5-(4-플루오로페닐)-6-옥소-2,3,5,6-테트라히드로퓨로[3,2-c]피리딘-7-카르복스아미드;
b155) N-(3-플루오로-4-((6-메톡시-7-(2-((테트라히드로-2H-피란-4-일)아미노)에톡시)퀴놀린-4-일)옥시)페닐)-5-(4-플루오로페닐)-6-옥소-2,3,5,6-테트라히드로퓨로[3,2-c]피리딘-7-카르복스아미드;
b156) N-(3-플루오로-4-((6-메톡시-7-(2-((4-메톡시사이클로헥실)아미노)에톡시)퀴놀린-4-일)옥시)페닐)-5-(4-플루오로페닐)-6-옥소-2,3,5,6-테트라히드로퓨로[3,2-c]피리딘-7-카르복스아미드;
b157) N-(3-플루오로-4-((7(2-모폴리닐에톡시)퀴놀린-4-일)옥시)페닐)-5-(4-플루오로페닐)-6-옥소-2,3,5,6-테트라히드로퓨로[3,2-c]피리딘-7-카르복스아미드;
b158) N-(3-플루오로-4-((7-(3-모폴리노프로폭시)퀴놀린-4-일)옥시)페닐)-5-(4-플루오로페닐)-6-옥소-2,3,5,6-테트라히드로퓨로[3,2-c]피리딘-7-카르복스아미드;
b159) N-(3-플루오로-4-((7-(3-모폴리노프로폭시)퀴놀린-4-일)옥시)페닐)-2-(4-플루오로페닐)-3-옥소-3,5,6,7-테트라히드로-2H-사이클로펜타[c]피리딘-4-카르복스아미드;
b160) N-(3-플루오로-4-((7-(3-(4-메틸피페라진-1-일)프로폭시)퀴놀린-4-일)옥시)페닐)-5-(4-플루오로페닐)-6-옥소-2,3,5,6-테트라히드로퓨로[3,2-c]피리딘-7-카르복스아미드;
b161) 7-(2-(3-플루오로-4-((7-(3-(피페리딘-1-일)프로폭시)퀴놀린-4-일)옥시)페닐)아세틸)-5-(4-플루오로페닐)-3,5-디히드로퓨로[3,2-c]피리딘-6(2H)-온;
b162) 7-(2-(3-플루오로-4-((7-(3-(4-메틸피페리딘-1-일)프로폭시)퀴놀린-4-일)옥시)페닐)아세틸)-5-(4-플루오로페닐)-3,5-디히드로퓨로[3,2-c]피리딘-6(2H)-온;
b163) N-(3-플루오로-4-((6-(메틸카르바모일)-7-(2-모폴리노에톡시)퀴놀린-4-일)옥시)페닐)-5-(4-플루오로페닐)-6-옥소-2,3,5,6-테트라히드로퓨로[3,2-c]피리딘-7-카르복스아미드;
b164) N-(3-플루오로-4-((6-(메틸카르바모일)-7-(3-모폴리노프로폭시)퀴놀린-4-일)옥시)페닐)-5-(4-플루오로페닐)-6-옥소-2,3,5,6-테트라히드로퓨로[3,2-c]피리딘-7-카르복스아미드;
b165) N-(3-플루오로-4-((6-메톡시-7-(메틸카르바모일)퀴놀린-4-일)옥시)페닐)-5-(4-플루오로페닐)-6-옥소-2,3,5,6-테트라히드로퓨로[3,2-c]피리딘-7-카르복스아미드;
b166) N-(3-플루오로-4-((7-(메틸카르바모일)-6-(2-모폴리노에톡시)퀴놀린-4-일)옥시)페닐)-5-(4-플루오로페닐)-6-옥소-2,3,5,6-테트라히드로퓨로[3,2-c]피리딘-7-카르복스아미드;
b167) N-(3-플루오로-4-((6-플루오로-7-(2-모폴리노에톡시)퀴놀린-4-일)옥시)페닐)-5-(4-플루오로페닐)-6-옥소-2,3,5,6-테트라히드로퓨로[3,2-c]피리딘-7-카르복스아미드;
b168) N-(3-플루오로-4-((6-플루오로-7-(3-모폴리노프로폭시)퀴놀린-4-일)옥시)페닐)-5-(4-플루오로페닐)-6-옥소-2,3,5,6-테트라히드로퓨로[3,2-c]피리딘-7-카르복스아미드;
b169) N-(3-플루오로-4-((7-(2-모폴리노에톡시)-6-(트리플루오로메틸)퀴놀린-4-일)옥시)페닐)-5-(4-플루오로페닐)-6-옥소-2,3,5,6-테트라히드로퓨로[3,2-c]피리딘-7-카르복스아미드;
b170) N-(3-플루오로-4-((7-(3-모폴리노프로폭시)-6-(트리플루오로메틸)퀴놀린-4-일)옥시)페닐)-5-(4-플루오로페닐)-6-옥소-2,3,5,6-테트라히드로퓨로[3,2-c]피리딘-7-카르복스아미드;
b171) N-4-((6-클로로-7-(2-모폴리노에톡시)퀴놀린-4-일)옥시)-3-플루오로페닐)-5-(4-플루오로페닐)-6-옥소-2,3,5,6-테트라히드로퓨로[3,2-c]피리딘-7-카르복스아미드;
b172) N-4-((6-클로로-7-(3-모폴리노프로폭시)퀴놀린-4-일)옥시)-3-플루오로페닐)-5-(4-플루오로페닐)-6-옥소-2,3,5,6-테트라히드로퓨로[3,2-c]피리딘-7-카르복스아미드;
b173) N-(4-((6-시아노-7-(2-모폴리노에톡시)퀴놀린-4-일)옥시)-3-플루오로페닐)-5-(4-플루오로페닐)-6-옥소-2,3,5,6-테트라히드로퓨로[3,2-c]피리딘-7-카르복스아미드;
b174) N-(4-((6-시아노-7-(3-모폴리노프로폭시)퀴놀린-4-일)옥시)-3-플루오로페닐)-5-(4-플루오로페닐)-6-옥소-2,3,5,6-테트라히드로퓨로[3,2-c]피리딘-7-카르복스아미드;
b175) N-(3-플루오로-4-((7-메톡시-6-(2-모폴리노에톡시)퀴놀린-4-일)옥시)페닐)-5-(4-플루오로페닐)-6-옥소-2,3,5,6-테트라히드로퓨로[3,2-c]피리딘-7-카르복스아미드;
b176) N-(3-플루오로-4-((7-메톡시-6-(3-모폴리노프로폭시)퀴놀린-4-일)옥시)페닐)-5-(4-플루오로페닐)-6-옥소-2,3,5,6-테트라히드로퓨로[3,2-c]피리딘-7-카르복스아미드;
b177) N-(3-플루오로-4-((6-(2-모폴리노에톡시)퀴놀린-4-일)옥시)페닐)-5-(4-플루오로페닐)-6-옥소-2,3,5,6-테트라히드로퓨로[3,2-c]피리딘-7-카르복스아미드;
b178) N-(3-플루오로-4-((6-(3-모폴리노프로폭시)퀴놀린-4-일)옥시)페닐)-5-(4-플루오로페닐)-6-옥소-2,3,5,6-테트라히드로퓨로[3,2-c]피리딘-7-카르복스아미드;
b179) N-(4-((6-아미노-7-메톡시퀴놀린-4-일)옥시)-3-플루오로페닐)-5-(4-플루오로페닐)-6-옥소-2,3,5,6-테트라히드로퓨로[3,2-c]피리딘-7-카르복스아미드;
b180) N-(3-플루오로-4-((7-메톡시-6-(3-모폴리노프로판아미도)퀴놀린-4-일)옥시)페닐)-5-(4-플루오로페닐)-6-옥소-2,3,5,6-테트라히드로퓨로[3,2-c]피리딘-7-카르복스아미드;
b181) N-(4-((7-아미노-6-메톡시퀴놀린-4-일)옥시)-3-플루오로페닐)-5-(4-플루오로페닐)-6-옥소-2,3,5,6-테트라히드로퓨로[3,2-c]피리딘-7-카르복스아미드;
b182) N-(3-플루오로-4-((6-메톡시-7-(2-모폴리노아세트아미도)퀴놀린-4-일)옥시)페닐)-5-(4-플루오로페닐)-6-옥소-2,3,5,6-테트라히드로퓨로[3,2-c]피리딘-7-카르복스아미드;
b183) N-(3-플루오로-4-((6-메톡시-7-(3-모폴리노프로파나미도)퀴놀린-4-일)옥시)페닐)-5-(4-플루오로페닐)-6-옥소-2,3,5,6-테트라히드로퓨로[3,2-c]피리딘-7-카르복스아미드;
b184) N-(4-((7-아세트아미도-6-메톡시퀴놀린-4-일)옥시)-3-플루오로페닐)-5-(4-플루오로페닐)-6-옥소-2,3,5,6-테트라히드로퓨로[3,2-c]피리딘-7-카르복스아미드;
b185) N-(3-플루오로-4-((7-메톡시-6-((2-모폴리노에틸)아미노)퀴놀린-4-일)옥시)페닐)-5-(4-플루오로페닐)-6-옥소-2,3,5,6-테트라히드로퓨로[3,2-c]피리딘-7-카르복스아미드;
b186) N-(3-플루오로-4-((7-메톡시-6-((3-모폴리노프로필)아미노)퀴놀린-4-일)옥시)페닐)-5-(4-플루오로페닐)-6-옥소-2,3,5,6-테트라히드로퓨로[3,2-c]피리딘-7-카르복스아미드;
b187) N-(3-플루오로-4-((6-메톡시-7-((2-모폴리노에틸)아미노)퀴놀린-4-일)옥시)페닐)-5-(4-플루오로페닐)-6-옥소-2,3,5,6-테트라히드로퓨로[3,2-c]피리딘-7-카르복스아미드; 및
b188) N-(3-플루오로-4-((6-메톡시-7-((3-모폴리노프로필)아미노)퀴놀린-4-일)옥시)페닐)-5-(4-플루오로페닐)-6-옥소-2,3,5,6-테트라히드로퓨로[3,2-c]피리딘-7-카르복스아미드.
바람직하게는, 상기 화학식 2로 표시되는 화합물은
N-(3-플루오로-4-((2-(1-메틸-1H-이미다졸-4-일)티에노[3,2-b]피리딘-7-일)옥시)페닐)-5-(4-플루오로페닐)-6-옥소-2,3,5,6-테트라히드로퓨로[3,2-c]피리딘-7-카르복스아미드;
N-(3-플루오로-4-((6-메톡시-7-(2-모폴리노에톡시)퀴놀린-4-일)옥시)페닐)-5-(4-플루오로페닐)-6-옥소-2,3,5,6-테트라히드로퓨로[3,2-c]피리딘-7-카르복스아미드; 및
N-(4-((7-(3-(3-시아노아제티딘-1-일)프로폭시)-6-메톡시퀴놀린-4-일)옥시)-3-플루오로페닐)-5-(4-플루오로페닐)-6-옥소-2,3,5,6-테트라히드로퓨로[3,2-c]피리딘-7-카르복스아미드로 이루어진 군에서 선택되는 화합물일 수 있다.
본 발명에 따른 조성물에 사용되는 상기 화학식 2의 화합물은 대한민국 공개특허공보 제2021-0015730호에 개시된 방법으로 제조할 수 있으며, 기타 공지된 방법 및/또는 유기합성 분야의 기술에 근간한 다양한 방법들에 의해 제조될 수 있다. 상기 방법들을 기초로 치환기의 종류에 따라 적절한 합성방법을 사용하여 다양한 유도체들을 합성할 수 있다.
구체적인 또 다른 예에 따르면, 본 발명의 약학 조성물에 유효성분으로 포함되는 화합물은 아래 화학식 3으로 표시될 수 있다. 즉 본 발명에 따른 약학 조성물은 하기 화학식 3으로 표시되는 화합물 또는 이의 약학적으로 허용가능한 염을 포함할 수 있다.
[화학식 3]
상기 식에서,
X는 수소 또는 할로겐이고;
Y는 수소 또는 할로겐이며;
R1 및 R2는 각각 독립적으로 수소 또는 C1-10 알콕시이거나, 또는 서로 연결되어 헤테로원자 O를 갖는 5원 내지 10원의 헤테로사이클로알킬을 형성하고;
R은 1개 또는 2개의 헤테로원자 N을 갖는 5원 내지 7원의 헤테로아릴이며;
R3는 수소 또는 -(CH2)n-R4이고;
여기서 n은 0 내지 10의 정수이며;
R4는 N, O 및 S로 이루어진 군으로부터 선택되는 1 또는 2개의 헤테로원자를 갖는 5원 내지 10원의 헤테로사이클이다.
일 구현예에 따르면, 상기 화학식 3에서, X 및 Y는 각각 수소 또는 플루오로일 수 있다.
다른 구현예에 따르면, 상기 화학식 3에서, R1 및 R2는 각각 독립적으로 수소, 메틸, 메톡시, 또는 에톡시이고 동시에 수소가 아닌, 또는 서로 연결되어 헤테로원자 O를 갖는 5원 내지 10원의 헤테로사이클로알킬일 수 있다.
또 다른 구현예에 따르면, 상기 화학식 3에서, R은 1개 또는 2개의 헤테로원자 N을 갖는 5원 내지 6원의 헤테로아릴일 수 있다.
또 다른 구현예에 따르면, 상기 화학식 3에서, R3는 수소 또는 -(CH2)n-R4이고, 여기서 n은 0 내지 4의 정수이며, R4는 N 및 O의 헤테로원자를 갖는 6원의 헤테로사이클일 수 있다.
또 다른 구현예에 따르면, 상기 화학식 3에서, X 및 Y는 플루오로이고; R1 및 R2는 각각 독립적으로 에톡시 또는 수소이고 동시에 수소가 아닌, 또는 서로 연결되어 헤테로원자 O를 갖는 5원의 헤테로사이클로알킬이며; R은 피리딘 또는 이미다졸이고; R3는 수소 또는 -(CH2)-R4이며; R4는 N 및 O의 헤테로원자를 갖는 6원의 헤테로사이클일 수 있다.
상기 화학식 3의 화합물은 대한민국 공개특허공보 제2019-0106802호 또는 제2021-0015730호에 개시된 방법으로 제조할 수 있으며, 기타 공지된 방법 및/또는 유기합성 분야의 기술에 근간한 다양한 방법들에 의해 제조될 수 있다. 상기 방법들을 기초로 치환기의 종류에 따라 적절한 합성방법을 사용하여 다양한 유도체들을 합성할 수 있다.
본 명세서에서, 용어 "할로겐"은 다른 언급이 없으면 F, Cl, Br 또는 I를 의미한다.
용어 "알킬"은, 달리 명시되지 않는 한, 선형 또는 분지형의 포화된 탄화수소 잔기를 의미한다. 예를 들어, "C1-10 알킬"은 1 내지 10개 탄소로 골격이 이루어진 알킬을 의미한다. 구체적으로 C1-10 알킬은 메틸, 에틸, n-프로필, i-프로필, n-부틸, i-부틸, t-부틸, n-펜틸, i-펜틸, t-펜틸, sec-펜틸, 네오펜틸, 헥실, 헵틸, 옥틸, 노닐, 데실 등을 포함할 수 있다.
용어 "할로알킬"은 하나 이상의 할로겐으로 치환된 알킬을 의미한다. 구체적으로, 할로알킬은 동종의 할로겐이 2개 이상 치환되거나 2종 이상의 할로겐이 치환된 알킬일 수 있다.
용어 "알콕시"는, 달리 명시되지 않는 한, 앞에 정의한 알킬기가 산소 원자를 통하여 모 화합물에 부착되어 있는, 화학식 -O-알킬을 갖는 기를 의미한다. 알콕시기의 알킬 부분은 1 내지 20개의 탄소원자(즉, C1-20 알콕시), 1 내지 12개의 탄소원자(즉, C1-12 알콕시), 또는 1 내지 6개의 탄소원자(즉, C1-6 알콕시)를 가질 수 있다. 적합한 알콕시기의 예로는 메톡시(-O-CH3 또는 -OMe), 에톡시(-OCH2CH3 또는 -OEt), t-부톡시(-O-C(CH3)3 또는 -O-tBu) 등이 있다.
용어 "아릴"은 모 방향족 고리 시스템을 구성하는 탄소원자로부터 1개의 수소 원자가 제거되어 유도되는 방향족 탄화수소 라디칼을 의미한다. 예를 들면, 아릴기는 6 내지 20개의 탄소원자, 6 내지 14개의 탄소원자, 또는 6 내지 10개의 탄소원자를 가질 수 있다.
용어 "사이클로알킬"은 고리 중에 탄소원자만을 포함하는 포화 모노사이클 또는 폴리사이클을 지칭한다. 사이클로알킬은, 모노사이클로서는 3 내지 7개의 탄소원자를, 바이사이클로서는 7 내지 12 탄소원자를, 폴리사이클로서는 최대 약 20개의 탄소원자를 가질 수 있다.
용어 "헤테로사이클"은 하나 이상의 헤테로원자를 갖는 방향족 또는 비방향족의 고리를 의미하며, 포화되거나 불포화될 수 있고, 단일고리 또는 다중고리일 수 있다. 예를 들어 "4 내지 10원의 헤테로사이클"은 헤테로원자 및 탄소원자를 포함하여 총 4 내지 10개의 원자로 골격이 이루어진 헤테로사이클을 의미한다. 구체적으로 4 내지 10원의 헤테로사이클은 아제티딘, 디아제티딘, 피롤리딘, 피롤, 이미다졸리딘, 이미다졸, 피라졸리딘, 피라졸, 옥사졸리딘, 옥사졸, 이속사졸리딘, 이속사졸, 티아졸리딘, 티아졸, 이소티아졸리딘, 이소티아졸, 피페리딘, 피리딘, 피페라진, 디아진, 모폴린, 티오모폴린, 아제판, 디아제판 등을 포함할 수 있다. 본 명세서에서 "헤테로사이클"이 치환기로서 기재될 경우 "헤테로아릴" 및 "헤테로사이클로알킬"을 포괄하는 용어로 사용될 수 있다.
용어 "헤테로아릴"은 고리 내에 하나 이상의 헤테로원자를 갖는 방향족 헤테로사이클릴을 지칭한다. 헤테로아릴의 비제한적인 예로는 피리디닐, 피롤릴, 옥사졸릴, 인돌릴, 이소인돌릴, 퓨리닐, 퓨라닐, 티에닐, 벤조퓨라닐, 벤조티오페닐, 카르바졸릴, 이미다졸릴, 티아졸릴, 이속사졸릴, 피라졸릴, 이소티아졸릴, 퀴놀릴, 이소퀴놀릴, 피리다질, 피리미딜, 피라질(이들은 고리에 하나 이상의 치환기를 가질 수 있음) 등이 있다.
용어 "헤테로사이클로알킬"은 고리 내에 하나 이상의 헤테로원자를 갖는 비방향족 헤테로사이클릴을 지칭한다. 헤테로사이클로알킬은 이중 결합의 존재로 인해 고리가 방향성(aromatic)을 갖지 않는 범위에서 고리 내에 하나 이상의 탄소-탄소 이중 결합 또는 탄소-헤테로원자 이중 결합을 가질 수 있다. 헤테로사이클로알킬의 비제한적인 예로는 아제티딘일, 아지리딘일, 피롤리딘일, 피페리딘일, 피페라진일, 호모피페라진일, 모폴리노, 티오모폴리노, 테트라히드로퓨란일, 테트라히드로티오퓨란일, 테트라히드로피란일, 피란일(이들은 고리에 하나 이상의 치환기를 가질 수 있음) 등이 있다.
용어 "헤테로원자"는 탄소(C) 이외의 원자를 의미하며, 구체적으로 질소(N), 산소(O) 또는 황(S) 원자일 수 있다. 위에서 언급한 헤테로아릴 및 헤테로사이클로알킬은 하나 이상의 헤테로원자를 포함하며, 예를 들어 1개, 1개 내지 2개, 1개 내지 3개, 또는 1개 내지 4개의 헤테로원자를 포함할 수 있다.
용어 "치환"은, 지정된 원자 상의 원자가(valence)를 초과하지 않으면서 이러한 치환으로부터 화학적으로 안정한 화합물이 되도록, 분자 구조체 내의 수소 원자를 치환기로 대체하는 것을 지칭한다. 예를 들어 "그룹 A가 치환기 B로 치환"된다거나 또는 "그룹 A가 치환기 B를 갖는다"는 것은, 그룹 A의 골격을 구성하는 탄소 등의 원자에 결합된 수소 원자가 치환기 B로 대체되어, 그룹 A와 치환기 B가 공유 결합을 형성함을 의미할 수 있다. 따라서 탈리가 가능한 수소 원자를 갖지 않는 그룹은 치환기를 갖는 것이 실질적으로 어렵거나 불가능하고, 이에 본 명세서에서 치환기를 가지기 어려운 그룹을 포함하는 다양한 그룹과 치환기의 조합의 범위를 예시하는 경우에는, 치환기 불가능한 것이 자명한 그룹과 치환기의 조합은 그 범위에서 제외하는 것으로 해석하여야 한다.
본 발명의 약학 조성물은 유효성분으로서 상기 화학식 1 또는 2로 표시되는 화합물 또는 이의 약학적으로 허용 가능한 염을, 조성물의 총 중량을 기준으로, 약 0.1 중량% 내지 약 90 중량%, 구체적으로 약 0.5 중량% 내지 약 75 중량%, 보다 구체적으로 약 1 중량% 내지 약 50 중량%로 함유할 수 있다.
본 발명의 약학 조성물은, 통상적인 방법에 따라 제제로 배합되는 통상적이고 무독성인 약학적으로 허용 가능한 첨가제를 포함할 수 있다. 예를 들어, 상기 약학 조성물은 약학적으로 허용되는 담체, 희석제 또는 부형제를 추가로 포함할 수 있다.
본 발명의 조성물에 사용되는 첨가제의 예는 감미제, 결합제, 용매, 용해 보조제, 습윤제, 유화제, 등장화제, 흡수제, 붕해제, 산화방지제, 보존제, 윤활제, 활택제, 충전제, 향미제 등을 포함할 수 있다. 예를 들어, 상기 첨가제는 락토오스, 덱스트로스, 수크로스, 만니톨, 소르비톨, 셀룰로스, 글리신, 실리카, 활석, 스테아르산, 스테아린, 마그네슘 스테아레이트, 마그네슘 알루미노실리케이트, 전분, 젤라틴, 트라가칸트 검, 알긴산, 나트륨 알기네이트, 메틸셀룰로스, 나트륨 카복시메틸셀룰로스, 한천, 물, 에탄올, 폴리에틸렌 글리콜, 폴리비닐피롤리돈, 염화나트륨, 염화칼슘, 오렌지 에센스, 딸기 에센스, 바닐라 향 등을 포함할 수 있다.
본 발명의 조성물은 경구 투여(예컨대, 정제, 환제, 산제, 캡슐제, 시럽 또는 에멀젼) 또는 비경구 투여(예컨대, 근육내, 정맥내 또는 피하 주사)를 위한 다양한 제제 형태로 배합될 수 있다.
바람직하게는 본 발명의 조성물은 경구 투여용 제제로 배합될 수 있다. 이때 사용되는 첨가제로는 셀룰로스, 칼슘 실리케이트, 옥수수 전분, 락토오스, 수크로스, 덱스트로스, 칼슘 포스페이트, 스테아르산, 마그네슘 스테아레이트, 칼슘 스테아레이트, 젤라틴, 활석, 계면활성제, 현탁제, 유화제, 희석제 등이 포함될 수 있다.
구체적으로, 경구 투여를 위한 고형 제제에는 정제, 환제, 산제, 과립제, 캡슐제 등이 포함되며, 이러한 고형 제제는 상기 조성물에 적어도 하나 이상의 부형제, 예를 들면 전분, 탄산칼슘, 수크로스, 락토즈, 젤라틴 등을 혼합하여 제형화될 수 있다. 또한, 단순한 부형제 이외에 마그네슘 스테아레이트, 탈크와 같은 윤활제가 사용될 수 있다.
또한, 경구 투여를 위한 액상 제제로는 현탁제, 유제, 시럽제 등이 예시될 수 있으며, 흔히 사용되는 단순 희석제인 물, 액체 파라핀 이외에 여러 가지 부형제, 예를 들면 습윤제, 감미제, 방향제, 보존제 등이 포함될 수 있다.
또한, 비경구 투여를 위한 제제에는 멸균된 수용액제, 비수성용제, 현탁제, 유제, 동결건조 제제 및 좌제가 포함된다. 비수성용제, 현탁제로는 프로필렌글리콜, 폴리에틸렌글리콜, 올리브 오일과 같은 식물성 기름, 에틸올레이트와 같은 주사 가능한 에스테르 등이 사용될 수 있다. 좌제의 기제로는 위텝솔, 마크로골, 트윈61. 카카오지, 라우린지, 글리세로제라틴 등이 사용될 수 있다. 한편, 주사제에는 용해제, 등장화제, 현탁화제, 유화제, 안정화제, 방부제 등과 같은 종래의 첨가제가 포함될 수 있다.
본 발명의 화합물 또는 조성물은 치료학적으로 유효한 양 또는 약학적으로 유효한 양으로 환자에 투여될 수 있다.
여기서 "치료학적으로 유효한 양" 또는 "약학적으로 유효한 양"이란 대상 질환을 예방 또는 치료하는데 유효한 화합물 또는 조성물의 양으로서, 의학적 치료에 적용 가능한 합리적인 수혜/위험 비율로 질환을 치료하기에 충분하며 부작용을 일으키지 않을 정도의 양을 의미한다. 상기 유효량의 수준은 환자의 건강상태, 질환의 종류, 중증도, 약물의 활성, 약물에 대한 민감도, 투여 방법, 투여 시간, 투여 경로 및 배출 비율, 치료 기간, 배합 또는 동시 사용되는 약물을 포함한 요소 및 기타 의학 분야에 잘 알려진 요소에 따라 결정될 수 있다.
본 발명의 화합물 또는 조성물은 개별 치료제로 투여하거나 다른 치료제와 병용하여 투여될 수 있고, 종래의 치료제와 순차적으로 또는 동시에 투여될 수 있으며, 단일 또는 다중 투여될 수 있다. 상기한 요소들을 모두 고려하여 최소한의 부작용 또는 부작용 없이 최소한의 양으로 최대 효과를 얻을 수 있는 양을 투여하는 것이 중요하며, 이는 당업자에 의해 용이하게 결정될 수 있다.
구체적으로, 본 발명의 조성물에서 화합물의 유효량은 환자의 나이, 성별, 체중에 따라 달라질 수 있으며, 일반적으로는 체중 kg 당 약 0.1 mg 내지 약 1,000 mg, 또는 약 5 mg 내지 약 200 mg을 매일 또는 격일 투여하거나 1일 1회 내지 3회로 나누어 투여할 수 있다. 그러나, 투여 경로, 질병의 중증도, 성별, 체중, 연령 등에 따라서 증감될 수 있으므로, 본 발명의 범위는 이에 한정되지 않는다.
바람직하게는, 본 발명의 화합물 또는 조성물은 화학요법, 방사선 요법, 면역요법, 호르몬 치료, 골수 이식, 줄기세포 대체치료, 다른 생물학적 치료, 수술적 개입 또는 이들의 조합과 병용하여 종양 요법을 위해 투여될 수 있다. 예컨대, 본 발명의 화합물 또는 조성물은 장기적으로 진행되는 다른 치료 전략과 함께 보조 요법으로 사용되거나, 중증 환자에서 종양 퇴행 또는 화학 예방 요법 후 환자의 상태를 유지하기 위해 사용될 수 있다.
본 발명의 약학 조성물은 1종 이상의 유효성분을 추가로 포함할 수 있으며, 상기 추가의 유효성분은 항-증식 화합물 예컨대, 아로마타제 저해제, 항-에스트로겐, 토포이소머라제 I 저해제, 토포이소머라제 II 저해제, 미세소관 활성 화합물, 알킬화 화합물, 히스톤 데아세틸라제 저해제, 세포 분화 과정을 유도하는 화합물, 사이클로옥시게나제 저해제, MMP 저해제, mTOR 저해제, 항-신생물, 항-대사물질, 백금계 화합물, 단백질 또는 지질 키나제 활성을 표적화/감소시키는 화합물, 항-혈관신생 화합물, 단백질 또는 지질 포스파타제의 활성을 표적화하거나 감소시키거나 저해하는 화합물, 고나도렐린 효능제, 항-안드로겐, 메티오닌 아미노펩티다제 저해제, 비스포스포네이트, 생물학적 반응 개질제, 항-증식성 항체, 헤파라나제 저해제, Ras 종양원성 이소형의 저해제, 텔로머라제 저해제, 프로테아솜 저해제, 혈액계 악성종양의 치료에 사용되는 화합물, Flt-3의 활성을 표적화하거나 감소시키거나 저해하는 화합물, Hsp90 저해제, 키네신 스핀들 단백질 저해제, MEK 저해제, 류코보린, EDG 결합제, 항-백혈병 화합물, 리보뉴클레오티드 리덕타제 저해제, S-아데노실메티오닌 데카르복실라제 저해제, 지혈성 스테로이드, 코르티코스테로이드, 다른 화학요법 화합물, 광감작 화합물일 수 있으나, 이에 제한되지 않는다.
상기 추가의 유효성분은 공지의 항암제일 수 있다. 상기 항암제의 비제한적인 예는 DNA 알킬화제(DNA alkylating agents)로 메클로에타민(mechloethamine), 클로람부칠(chlorambucil), 페닐알라닌(phenylalanine), 무스타드(mustard), 사이클로포스파미드(cyclophosphamide), 이포스파미드(ifosfamide), 카르무스틴(carmustine: BCNU), 로무스틴(lomustine: CCNU), 스트렙토조토신(streptozotocin), 부술판(busulfan), 티오테파(thiotepa), 시스플라틴(cisplatin) 및 카보플라틴(carboplatin); 항암 항생제(anti-cancer antibiotics)로 닥티노마이신(dactinomycin: actinomycin D), 독소루비신(doxorubicin: adriamycin), 다우노루비신(daunorubicin), 이다루비신(idarubicin), 미토크산트론(mitoxantrone), 플리카마이신(plicamycin), 마이토마이신 C(mitomycin C) 및 블레오마이신(bleomycin); 및 식물 알카로이드(plant alkaloids)로 빈크리스틴(vincristine), 빈블라스틴(vinblastine), 파클리탁셀(paclitaxel), 도세탁셀(docetaxel), 에토포시드(etoposide), 테니포시드(teniposide), 토포테칸(topotecan) 및 이리노테칸(irinotecan) 등을 포함한다.
이하, 본 발명을 하기 실시예에 의하여 더욱 상세하게 설명한다. 단, 하기 실시예는 본 발명을 예시하기 위한 것일 뿐, 본 발명의 범위가 이들만으로 한정되는 것은 아니다.
실시예 1: 4-에톡시-N-[3-플루오로-4-({2-[5-(모르폴리노메틸)피리딘-2-일]티에노[3,2-b]피리딘-7-일}옥시)페닐]-1-(4-플루오로페닐)-2-옥소-1,2-디히드로피리딘-3-카르복스아미드 염산염
표제 화합물은 대한민국 공개특허공보 제2019-0106802호의 실시예 31에서 기재된 방법으로 합성하였다.
1H NMR (500MHz, DMSO-d6) δ 10.66 (s, 1H), 8.81 (s, 1H), 8.60 (d, J = 5.0 Hz, 1H), 8.48 (s, 1H), 8.43 (d, J = 5.0 Hz, 1H), 8.23 (d, J = 5.0 Hz, 1H), 7.96 (d, J = 15.0 Hz, 1H), 7.87 (d, J = 5.0 Hz, 1H), 7.52-7.45 (m, 4H), 7.39-7.36 (m, 2H), 6.83 (d, J = 5.0 Hz, 1H), 6.53 (d, J = 10.0 Hz, 1H), 4.44 (s, 2H), 4.26 (qt, J = 5.0 H, 2H), 3.96-3.94 (m, 2H), 3.77 (t, J = 10.0 Hz, 2H), 3.32-3.30 (m, 2H), 3.14 (qt, J = 10.0 2H), 1.31 (t, J = 5.0 Hz, 3H)
실시예 2: 4-에톡시-N-(3-플루오로-4-{[2-(5-{[(2-메톡시에틸)아미노]메틸}피리딘-2-일)티에노[3,2-b]피리딘-7-일]옥시}페닐)-2-옥소-1-페닐-1,2-디히드로피리딘-3-카르복스아미드 염산염
표제 화합물은 대한민국 공개특허공보 제2019-0106802호의 실시예 1에서 기재된 방법으로 합성하였다.
1H NMR (500 MHz, DMSO-d6) δ 10.70 (brs, 1H), 9.50 (brs, 2H), 8.80 (s, 1H), 8.69 (d, J = 5.0 Hz, 1H), 8.47 (s, 1H), 8.44 (d, J = 5.0 Hz, 1H), 8.22 (dd, J = 10.0 and 5.0 Hz, 1H), 7.99 (d, J = 10.0 Hz, 1H), 7.88 (d, J = 5.0 Hz, 1H), 7.57-7.40 (m, 7H), 6.97 (d, J = 5.0 Hz, 1H), 6.53 (d, J = 5.0 Hz, 1H), 4.29-4.25 (m, 4H), 3.65 (t, J = 5.0 Hz, 2H), 3.31 (s, 3H), 3.16-3.12 (m, 2H), 1.31 (t, J = 5.0 Hz, 3H)
실시예 3: 4-에톡시-N-{3-플루오로-4-[(2-{5-[(4-메틸피페라진-1-일)메틸]피리딘-2-일}티에노[3,2-b]피리딘-7-일)옥시]페닐}-2-옥소-1-페닐-1,2-디히드로피리딘-3-카르복스아미드 염산염
표제 화합물은 대한민국 공개특허공보 제2019-0106802호의 실시예 34에서 기재된 방법으로 합성하였다.
1H NMR (500MHz, DMSO-d6) δ 10.68 (s, 1H), 8.82 (brs, 1H), 8.61 (d, J = 5.0 Hz, 1H), 8.47 (s, 1H), 8.41 (d, J = 5.0 Hz, 1H), 8.23 (s, 1H), 7.97 (d, J = 15.0 Hz, 1H), 7.87 (d, J = 5.0 Hz, 1H), 7.56-7.46 (m, 5H), 7.42-7.40 (m, 2H), 6.86 (d, J = 5.0 Hz, 1H), 6.52 (d, J = 5.0 Hz, 1H), 4.26 (qt, J = 5.0 H, 2H), 3.93 (brs, 8H), 3.58 (brs, 2H), 2.81 (s, 3H), 1.31 (t, J = 5.0 Hz, 3H)
실시예 4: N-(3-플루오로-4-((2-(1-메틸-1H-이미다졸-4-일)티에노[3,2-b]피리딘-7-일)옥시)페닐)-5-(4-플루오로페닐)-6-옥소-2,3,5,6-테트라히드로퓨로[3,2-c]피리딘-7-카르복스아미드
표제 화합물은 대한민국 공개특허공보 제2021-0015730호의 실시예 8에서 기재된 방법으로 합성하였다.
1H NMR (500 MHz, DMSO-d6) δ 11.92 (s, 1H), 8.43 (d, J = 5.0 Hz, 1H), 7.99 (d, J = 10.0 Hz, 1H), 7.87 (d, J = 5.0 Hz, 2H), 7.72 (s, 1H), 7.68 (s, 1H), 7.52-7.50 (m, 2H), 7.44-7.36 (m, 4H), 6.59 (d, J = 5.0 Hz, 1H), 4.85 (t, J = 10.0 Hz, 2H), 3.72 (s, 3H), 3.10 (t, J = 10.0 Hz, 2H)
실시예 5: N-(3-플루오로-4-((6-메톡시-7-(2-모폴리노에톡시)퀴놀린-4-일)옥시)페닐)-5-(4-플루오로페닐)-6-옥소-2,3,5,6-테트라히드로퓨로[3,2-c]피리딘-7-카르복스아미드
표제 화합물은 대한민국 공개특허공보 제2021-0015730호의 실시예 78에서 기재된 방법으로 합성하였다.
1H NMR (500 MHz, DMSO-d6) δ 11.89 (s, 1H), 8.48 (d, J = 5.0 Hz, 1H), 8.00 (d, J = 10.0 Hz, 1H), 7.88 (s, 1H), 7.54-7.49 (m, 3H), 7.45-7.37 (m, 5H), 6.48 (d, J = 5.0 Hz, 1H), 4.85 (t, J = 10.0 Hz, 2H), 4.32 (brs, 2H), 3.95 (s, 3H), 3.63 (brs, 4H), 3.11 (t, J = 10.0 Hz, 2H), 2.52 (m, 2H, partially overlapped with DMSO), 2.50 (m, 4H, overlapped with DMSO)
실시예 6: N-(4-((7-(3-(3-시아노아제티딘-1-일)프로폭시)-6-메톡시퀴놀린-4-일)옥시)-3-플루오로페닐)-5-(4-플루오로페닐)-6-옥소-2,3,5,6-테트라히드로퓨로[3,2-c]피리딘-7-카르복스아미드
표제 화합물은 대한민국 공개특허공보 제2021-0015730호의 실시예 88에서 기재된 방법으로 합성하였다.
1H NMR (400 MHz, CDCl3) δ 12.04 (S, 1H), 8.48 (d, J = 5.2 Hz, 1H), 8.03 (dd, J = 12.4, 2.4 Hz, 1H), 7.57 (s, 1H), 7.40-7.37 (m, 5H), 7.26-7.22 (m, 2H), 7.17 (t, J = 8.8 Hz, 1H), 6.44 (d, J = 5.6 Hz, 1H), 5.01 (t, J = 8.4 Hz, 2H), 4.26 (t, J = 6.4 Hz, 2H), 4.03 (s, 3H), 3.64 (t, J = 11.6 Hz, 4H), 3.20 (t, J = 8.0 Hz, 2H), 2.81 (t, J = 6.8 Hz, 2H), 2.05 (q, J = 6.8 Hz, 3H)
양성 대조군 1
양성 대조군 1의 화합물로서, 미국 등록특허 제8,536,200 B2호에 개시되어 있는 화합물 1인 N-{4-[(2-아미노-3-클로로-4-피리디닐)옥시]-3-플루오로페닐}-4-에톡시-1-(4-플루오로페닐)-2-옥소-1,2-디히드로-3-피리딘카르복스아미드를 사용하였으며, 이는 BMS-777607로 잘 알려진 RON 저해제이다.
양성 대조군 2
양성 대조군 2의 화합물로서, PCT 국제공개 WO 2013/017989 A1에 개시되어 있는 화합물 1인 3-[(R)-1-(2,6-디클로로-3-플루오로페닐)-에톡시]-5-[1-(피페리딘-4-일-1H-피라졸-4-일]-피리딘-2-아민을 사용하였으며, 이는 잘 알려진 항암제인 크리조티닙(crizotinib)이다.
양성 대조군 3
양성 대조군 3의 화합물로서, PCT 국제공개 WO 2014/165786 A1에 개시되어 있는 화합물 1인 N-(4-{[6,7-비스(메틸옥시)퀴놀린-4-일]옥시}페닐)-N'-(4-플루오로페닐)사이클로프로판-1,1-디카르복스아미드를 사용하였으며, 이는 잘 알려진 항암제인 카보잔티닙(cabozantinib)이다.
음성 대조군
음성 대조군의 화합물로서 디메틸설폭사이드(DMSO)를 사용하였다.
실험예 1. KRAS 돌연변이인 대장암 세포주의 RON 돌연변이 여부에 따른 화합물의 효능 분석
실시예 1, 실시예 2, 실시예 3, 실시예 4, 실시예 5, 실시예 6 및 양성 대조군 1의 화합물의 대장암 세포주에 대한 세포 독성을 비교하기 위하여, MTS 분석(assay)을 수행하고, 항암 활성을 비교하기 위하여 대장암 세포주에 대한 세포 사멸율을 분석하였다.
MTS 분석은 96 웰 플레이트에 웰 당 각각의 대장암 세포주를 1,000개씩 접종(seeding)하고 24시간 후에 각 웰 당 100 ㎕의 10% FBS-RPMI 배지(Welgene)에서 다양한 농도(0.000001 μM 내지 10 μM)의 실시예 1 내지 6 및 양성 대조군 1의 화합물을 처리하였다. 그리고 72시간 동안 세포를 배양한 다음 MTS 용액(Promega)을 20 ㎕씩 첨가하고 2시간 동안 배양한 다음 490 nm에서 흡광도를 측정하였으며 GraphPad PrismTM 5을 이용하여 실시예 1 내지 6 및 및 양성 대조군 1의 화합물에 대한 IC50를 도출하여 세포 독성을 분석하였다. 실시예 1 내지 6의 화합물의 경우에는 RON 비활성인 SNUC2A를 제외하고는 대부분의 세포주들에서 높은 효능을 나타냈다. 그 중 실시예 4의 화합물은 SW620을 제외하고 대부분의 mRON을 발현하거나 활성화된 RON(pTyr-wtRON)을 발현하는 세포주(HCT8 및 DLD-1)에서 높은 효능을 나타내는 것을 확인했다. 반면에 양성 대조군 1의 화합물의 경우 대부분의 세포주에서 높은 IC50 값을 보여 약물에 대한 반응성이 낮은 것을 확인할 수 있었다.
MTS 분석을 진행한 결과는 하기의 표 1에 기재된 바와 같다.
위 결과를 바탕으로 대표적인 물질인 실시예 1 및 양성 대조군 1의 화합물의 세포 사멸 유도능을 확인하기 위해 대장암 세포주인 SNU-C2A, HCT8, T84, SW620 각각을 60 mm 플레이트에 3x105개씩 접종하여 준비한 후, 24시간 동안 배양하였다. 24시간 후에, 실시예 1 및 양성 대조군 1을 1 μM씩 처리하고 48시간 동안 배양하였다.
또한, SW620 세포주를 60 mm 플레이트에 3x105개씩 접종하여 준비한 후, 24시간 동안 배양하였다. 24시간 후에, 실시예 1, 양성 대조군 1, 양성 대조군 2, 양성 대조군 3을 각각 1 μM씩 처리하였다.
48시간 후에, 트립신으로 처리하여 세포와 세포액을 수거하고 1X PBS로 재현탁하여 트리판 블루 용액(Sigma, cat# T8154))을 사용하여 염색하였다. 염색된 세포를 혈구계산판(hemocytometer)을 사용하여 계수하였다. 세포 계수를 반복 수행하여 평균과 표준편차를 계산하였다.
KRAS 돌연변이 대장암 세포주 중 RON 돌연변이 여부에 따른 실시예 화합물, 양성 대조군 1의 화합물의 세포 사멸 유도 효능을 확인한 결과, 도 1에서 보듯이, RON 야생형(wild type)이지만 티로신이 인산화된 RON(pTyr-wtRON)을 발현하는 세포주인 HCT8의 경우에는 실시예 1의 화합물 처리에 따른 세포 사멸 효능을 확인할 수 있었다. 또한, RON 돌연변이인 세포주의 경우 실시예 1의 화합물을 처리했을 때 돌연변이 유형에 상관없이 세포 사멸 유도 효능을 확인할 수 있었다. 한편, RON 비활성인 SNUC2A 세포주의 경우 실시예 1의 화합물에 대한 반응성을 나타내지 않았으며, 양성 대조군 1의 화합물은 RON 돌연변이를 보유하는 T84, SW620 세포주에서도 반응성이 거의 없는 것을 확인하였다. 또한, SW620 세포주에 실시예 1의 화합물을 처리한 결과 높은 세포 사멸율을 나타낸 것을 확인하였다. 반면 도 2에서 보듯이, 양성 대조군 1, 양성 대조군 2 또는 양성 대조군 3의 화합물을 처리한 SW620 세포주에서는 세포 사멸을 유도하지 않는 것을 확인하였다.
실험예 2. 대장암 환자 유래 세포주에서 화합물의 효능 분석
대장암 환자 유래 세포주에서 RON, KRAS, BRAF의 돌연변이 여부를 분석하였다. 각 환자의 정보는 하기의 표 2에, 유전자형을 분석한 결과는 하기의 표 3에 정리하였다.
대장암 환자 유래 세포주에서 트리졸 시약(Trizol reagent)을 이용하여 RNA를 추출한 후 이를 역전사효소를 통해 역전사 과정을 진행하였다. 역전사된 샘플의 RON 돌연변이를 확인할 수 있는 프라이머를 이용하여 PCR을 진행하고 각 밴드(band)를 염기서열 분석을 하여 돌연변이 여부를 확인하였다. 사용한 프라이머의 염기 서열은 다음과 같다.
KRAS의 경우에도 동일한 방법을 통해 분석하여 야생형 또는 돌연변이인지 확인하였다. 또한, 각 세포를 4% p-포름알데하이드로 고정한 후 면역염료 프로토콜에 따라 pTyr-RON을 염색하여 양성인지 또는 음성인지를 확인하였다. 그 후, 각 세포주에 1 μM 농도의 실시예 1의 화합물을 처리하고, 세포 사멸 유도 효능을 보이는지를 cleaved caspase 3의 염색을 통해 확인하고, 세포 사멸율을 계산하였다.
대장암 환자 유래 세포주에 대해 KRAS와 RON 돌연변이 여부를 분석한 후, RON이 야생형인 경우에는 pTyr-wtRON의 발현을 면역형광 염색을 통해 분석하였다(도 3 참조). 도 4에서 보듯이, RON 돌연변이 또는 pTyr-wtRON을 발현하는 세포주에서는 실시예 1의 화합물이 세포 사멸 효능을 나타내는 것을 확인하였고, RON 비활성인 세포주에서는 실시예 1의 화합물이 세포 사멸 유도 효능을 나타내지 않는 것을 확인하였다.
실험예 3. SW620 세포주 이식 마우스 모델에서 화합물의 효능 분석
5주령 암컷 BALB/c nude 마우스를 구입하여 일주일 동안 순화시킨 후, 인간 대장암 환자 유래 세포주 SW620(KRAS G12V/mRON △155) 5Х106 cells/mice를 마우스의 오른쪽 배 측면에 피하(100 ㎕)로 주사하였다. 종양의 크기가 약 100 mm3이 되었을 때 실시예 1의 화합물을 각각 경구로 투여하였다. 1일에 1회씩, 4주 동안 약물을 투여하였으며, 일주일에 2회씩 종양 크기와 마우스의 체중을 측정하였다. 약물 투여가 종료된 후, 실험 동물은 안락사시킨 후에 종양을 적출하여 무게를 측정하여 비교 분석하였다.
적출한 종양 조직 중 일부를 10% 포르말린에 고정하고 파라핀 블록을 제작한 후 박편을 만들었다. 슬라이드에 대한 염색은 면역화학 염색을 통해 진행하였으며, 적출한 종양 조직 일부는 분해(lysis)한 후 웨스턴 블럿 분석 방법을 통해 각 단백질들의 발현 변화를 확인하였다.
SW620 세포주(KRAS G12V/mRON △155) 이식 동물 모델에서 실시예 1의 화합물을 투여한 이후의 종양 성장 억제율을 하기 표 5에 기재하였다.
상기 표 5, 도 5 및 도 6에서 보듯이, 실시예 1의 화합물을 투여한 경우에 높은 종양 성장 억제 효능을 나타내는 것을 확인하였다. 또한, 적출한 종양 조직에 대하여 면역화학 염색을 수행한 결과, 도 7에서 보듯이, 실시예 1의 화합물을 투여한 마우스 모델에서 pTyr-mRON의 발현이 감소하고, cleaved caspase 3의 발현이 유도되는 것을 확인할 수 있었다 또한 PD(pharmacodynamic) 마커인 Cyclin D1의 발현이 감소하는 것을 확인하였다.
실험예 4. HCT8 세포주 이식 마우스 모델에서 화합물의 효능 분석
상기 실험예 3의 절차를 반복하되, 인간 대장암 환자 유래 세포주 SW620(KRAS G12V/mRON △155)을 대신하여 인간 대장암 환자 유래 세포주 HCT8(KRAS G13D/pTyr-wtRON(+))을 사용하고, 실시예 1, 양성 대조군 1 및 양성 대조군 2의 화합물을 투여하였다. HCT8(KRAS G13D/pTyr-wtRON(+)) 이식 동물 모델에서 실시예 1, 양성 대조군 1 및 양성 대조군 2의 화합물을 투여한 이후의 종양 성장 억제율을 하기 표 6에 기재하였다.
상기 표 6 및 도 8에서 보듯이 양성 대조군 1 또는 양성 대조군 2의 화합물을 투여한 동물 모델과 비교하여, 실시예 1의 화합물을 투여한 동물 모델에서 높은 종양 성장 억제 효능을 나타내는 것을 확인하였다. 또한 약물 투여 종료 후 종양 조직을 면역화학염색법을 통해 분석한 결과, 도 9에서 보듯이 pTyr-mRON, Cyclin D1의 발현이 감소하고 cleaved caspase 3의 발현이 유도되는 것을 확인할 수 있었다.
실험예 5. SW620 세포주에서 화합물의 작용 기전 분석
인간 대장암 환자 유래 세포주 SW620(KRAS G12V/mRON △155)에 공벡터(empty vector)와 β-카테닌 DNA(X87838.1, GENE ID: 1499)가 도입된 벡터인 human beta-카테닌 pcDNA3.1(Plasmid #16828, Addgene)를 각각 형질감염(transfection)한 후에 실시예 1의 화합물을 처리한 후, 48시간이 경과하였을 때 세포를 모두 수거하여 트리판 블루 배제 분석(trypan blue exclusion assay) 방법을 이용하여 세포 사멸 유도 효능을 비교 분석하였다. 이와 같이 SW620 세포주에 β-카테닌을 과발현한 후 실시예 1의 화합물을 처리하여 세포 사멸 유도 효능을 관찰한 결과, 도 10에서 보듯이, 세포 사멸 유도 효능이 감소되는 것을 확인하였다.
또한 이와 같이 SW620 세포주에 β-카테닌을 과발현한 후 실시예 1의 화합물을 처리한 샘플을 이용하여, 웨스턴 블럿 방법을 통해 β-카테닌, p-ERK, ERK, c-myc, Cyclin D1, pTyr-mRON, mRON, cleaved caspase 3의 발현을 확인하였다. 그 결과, 도 11에서 보듯이, pTyr-mRON의 발현은 β-카테닌과 관계 없이 실시예 1의 화합물에 의해 감소되었고, p-ERK, c-myc, Cyclin D1은 공벡터로 형질감염된(transfected) 세포주에서는 감소되었으나, β-카테닌 과발현시에는 다시 증가하는 것을 확인하였다.
실험예 6. HCT15 세포주 이식 마우스 모델에서 화합물의 효능 분석
5주령 암컷 BALB/c nude 마우스를 구입하여 일주일 동안 순화시킨 후, 인간 대장암 환주 유래 세포주 HCT15(KRAS G13D/mRON △160) 5Х106 cells/mice를 마우스의 오른쪽 배 측면에 피하(100 ㎕)로 주사하였다. 종양의 크기가 약 100 mm3이 되었을 때 실시예 1의 화합물을 경구로 투여하였다. 1일에 1회씩, 4주 동안 약물을 투여하였으며, 일주일에 2회씩 종양 크기와 마우스의 체중을 측정하였다. 그 결과 도 12에서 보듯이, 실시예 1의 화합물의 투여 그룹에서 높은 종양 성장 억제 효능이 나타나는 것을 확인할 수 있었다.
약물 투여가 종료된 후 종양 조직을 분석한 결과, 도 13에서 보듯이, pTyr-mRON의 발현이 실시예 1의 화합물의 투여 그룹에서 감소하는 것을 확인할 수 있었고, cleaved caspase 3 발현이 유도되는 것을 확인할 수 있었다. 추가로 실시예 1의 PD 마커인 Cyclin D1의 발현이 실시예 1의 화합물을 투여한 그룹에서 감소하는 것을 확인할 수 있었다.
Claims (12)
- 하기 화학식 1 또는 2로 표시되는 화합물 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 포함하는 KRAS(V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog) 돌연변이 및 활성화된 RON(recepteur d'origine nantais)이 존재하는 암의 예방 또는 치료용 약학 조성물로서,상기 KRAS 돌연변이는 서열번호 1의 아미노산 서열에서 13번째 위치의 아미노산 잔기 글리신이 다른 아미노산으로 치환되거나 12번째 위치의 아미노산 잔기 글리신이 다른 아미노산으로 치환된 것인, 약학 조성물:[화학식 1]상기 화학식 1에서,R1 및 R2는 각각 독립적으로 H, 할로겐, C1-10알콕시 또는 C1-10할로알킬이고;X는 -C(-R3)= 또는 -N=이고;R3 및 R4는 각각 독립적으로 H, 할로겐, C1-10알킬, 또는 C1-10알콕시이고;R5는 H, 할로겐, 또는 C1-10알킬이고;R6 및 R7은 이들이 결합된 N 원자와 함께 4 내지 10원의 헤테로사이클을 형성하거나, 또는 R6는 -C2H4-O-CH3이고, R7은 H, 메틸 또는 t-부톡시카보닐이고;상기 화학식 1의 치환기 정의 중에 언급된 헤테로사이클은 R6과 R7이 결합된 N 원자 이외에도 N, O 및 S로 이루어진 군으로부터 선택되는 1 또는 2개의 헤테로원자를 더 갖거나 갖지 않으며, 또한 상기 헤테로사이클은 할로겐 및 C1-6알킬 중에서 선택되는 하나 이상으로 치환되거나 비치환되고,[화학식 2]상기 화학식 2에서,L은 -NH- 또는 -CH2-이고,R1 내지 R4는 각각 독립적으로 수소, 할로겐, 히드록시, 시아노, C1-4 알킬, C1-4 알콕시, C1-4 할로알킬, C2-4 알케닐, C2-4 알키닐, C3-7 사이클로알킬, C6-10 아릴, 5원 내지 9원의 헤테로아릴 또는 3원 내지 9원의 헤테로사이클로알킬이고,X는 O, S, -CH(-Rx)- 또는 -N(-Rx)-이고,Rx는 수소, C1-4 알킬, C1-4 알콕시, C1-4 할로알킬, C2-4 알케닐, C2-4 알키닐, C6-10 아릴, C6-10 아릴-C1-4 알킬, 또는 3원 내지 9원의 헤테로사이클로알킬이고,A는 3원 내지 12원의 헤테로사이클이고,R5 및 R6는 각각 독립적으로 수소, 니트로, 아미노, 할로겐, 히드록시, 시아노, C1-6 알킬, C1-6 할로알킬, C2-6 알케닐, C2-6 알키닐, C1-6 알콕시, 아미노-C1-6 알콕시, 아미노카르보닐, C1-6 알킬아미노카르보닐, 디C1-6 알킬아미노카르보닐, C1-6 알킬카르보닐아미노, C1-6 알킬아미노, C1-6 알킬-아미노-C1-6 알콕시, C6-10 아릴, C6-10 아릴-C1-4 알킬, 또는 5원 내지 9원의 헤테로아릴이고,이때 R5 및 R6는 각각 독립적으로 C1-6 알킬; C1-6 알콕시-C1-6 알킬아미노, 3원 내지 9원의 사이클로알킬 및 3원 내지 9원의 헤테로사이클로알킬 중 어느 하나로 치환된 C1-6 알킬 또는 C1-6 알킬아미노-C1-6 알킬; 3원 내지 9원의 사이클로알킬; 또는 3원 내지 9원의 헤테로사이클로알킬로 치환되거나 치환되지 않고,상기 사이클로알킬 또는 헤테로사이클로알킬은 할로겐, 옥소, 시아노, 히드록시, 히드록시-C1-6 알킬, 아미노, 디C1-6 알킬아미노, C1-6 알킬, C1-6 알콕시, 및 C1-6 알콕시-C1-6 알킬로 이루어진 군으로부터 선택되는 하나 이상의 치환기를 갖거나 갖지 않고,상기 화학식 2의 치환기 정의 중에 언급된 헤테로사이클, 헤테로아릴 및 헤테로사이클로알킬은 각각 독립적으로 N, O 및 S로 이루어진 군으로부터 선택되는 하나 이상의 헤테로원자를 포함한다.
- 제 1 항에 있어서,상기 화학식 1로 표시되는 화합물이4-에톡시-N-[3-플루오로-4-({2-[5-(모르폴리노메틸)피리딘-2-일]티에노[3,2-b]피리딘-7-일}옥시)페닐]-1-(4-플루오로페닐)-2-옥소-1,2-디히드로피리딘-3-카르복스아미드;4-에톡시-N-(3-플루오로-4-{[2-(5-{[(2-메톡시에틸)아미노]메틸}피리딘-2-일)티에노[3,2-b]피리딘-7-일]옥시}페닐)-2-옥소-1-페닐-1,2-디히드로피리딘-3-카르복스아미드; 및4-에톡시-N-{3-플루오로-4-[(2-{5-[(4-메틸피페라진-1-일)메틸]피리딘-2-일}티에노[3,2-b]피리딘-7-일)옥시]페닐}-2-옥소-1-페닐-1,2-디히드로피리딘-3-카르복스아미드로 이루어진 군에서 선택되는 화합물인, 약학 조성물.
- 제 1 항에 있어서,상기 화학식 2로 표시되는 화합물이N-(3-플루오로-4-((2-(1-메틸-1H-이미다졸-4-일)티에노[3,2-b]피리딘-7-일)옥시)페닐)-5-(4-플루오로페닐)-6-옥소-2,3,5,6-테트라히드로퓨로[3,2-c]피리딘-7-카르복스아미드;N-(3-플루오로-4-((6-메톡시-7-(2-모폴리노에톡시)퀴놀린-4-일)옥시)페닐)-5-(4-플루오로페닐)-6-옥소-2,3,5,6-테트라히드로퓨로[3,2-c]피리딘-7-카르복스아미드; 및N-(4-((7-(3-(3-시아노아제티딘-1-일)프로폭시)-6-메톡시퀴놀린-4-일)옥시)-3-플루오로페닐)-5-(4-플루오로페닐)-6-옥소-2,3,5,6-테트라히드로퓨로[3,2-c]피리딘-7-카르복스아미드로 이루어진 군에서 선택되는 화합물인, 약학 조성물.
- 제 1 항에 있어서,상기 활성화된 RON은 RON 유전자의 스플라이싱 변이체(splicing variant)이거나 티로신이 인산화된 RON 단백질인, 약학 조성물.
- 제 4 항에 있어서,상기 RON 유전자의 스플라이싱 변이체는 엑손 5, 6 및 11이 결손된 mRONΔ155, 엑손 5 및 6이 결손된 mRONΔ160 또는 엑손 11이 결손된 RONΔ165인 것인, 약학 조성물.
- 제 1 항에 있어서,상기 KRAS 돌연변이는 12번째 위치의 글리신이 아스파르트산, 발린, 시스테인 및 히스티딘으로 이루어진 군에서 선택되는 어느 하나로 치환되는 것인, 약학 조성물.
- 제 1 항에 있어서,상기 KRAS 돌연변이는 13번째 위치의 글리신이 아스파르트산, 발린 및 아르기닌으로 이루어진 군에서 선택되는 어느 하나로 치환되는 것인, 약학 조성물.
- 제 1 항에 있어서,상기 암은 유방암, 폐암, 위암, 전립선암, 자궁암, 난소암, 신장암, 췌장암, 간암, 대장암, 피부암, 두경부암 및 갑상선암으로 이루어진 군에서 선택되는 것을 특징으로 하는, 약학 조성물.
- 제 1 항에서 정의된 화학식 1 또는 2로 표시되는 화합물 또는 이의 약학적으로 허용 가능한 염의, KRAS 돌연변이 및 활성화된 RON이 존재하는 암의 예방 또는 치료를 위한 용도로서,상기 KRAS 돌연변이는 서열번호 1의 아미노산 서열에서 13번째 위치의 아미노산 잔기 글리신이 다른 아미노산으로 치환되거나 12번째 위치의 아미노산 잔기 글리신이 다른 아미노산으로 치환된 것인, 용도.
- 제 1 항에서 정의된 화학식 1 또는 2로 표시되는 화합물 또는 이의 약학적으로 허용 가능한 염의, KRAS 돌연변이 및 활성화된 RON이 존재하는 암의 예방 또는 치료용 약제의 제조를 위한 용도로서,상기 KRAS 돌연변이는 서열번호 1의 아미노산 서열에서 13번째 위치의 아미노산 잔기 글리신이 다른 아미노산으로 치환되거나 12번째 위치의 아미노산 잔기 글리신이 다른 아미노산으로 치환된 것인, 용도.
- 제 1 항에서 정의된 화학식 1 또는 2로 표시되는 화합물 또는 이의 약학적으로 허용 가능한 염을 필요로 하는 대상에 투여하는 것을 포함하는, KRAS 돌연변이 및 활성화된 RON이 존재하는 암을 예방 또는 치료하는 방법으로서,상기 KRAS 돌연변이는 서열번호 1의 아미노산 서열에서 13번째 위치의 아미노산 잔기 글리신이 다른 아미노산으로 치환되거나 12번째 위치의 아미노산 잔기 글리신이 다른 아미노산으로 치환된 것인, 방법.
- 개체에서 KRAS의 돌연변이 및 활성화된 RON을 확인하는 단계; 및서열번호 1의 아미노산 서열에서 13번째 위치의 아미노산 잔기 글리신이 다른 아미노산으로 치환되거나 12번째 위치의 아미노산 잔기 글리신이 다른 아미노산으로 치환된 KRAS 돌연변이 및 활성화된 RON이 발견되면 제 1 항에서 정의된 화학식 1 또는 2로 표시되는 화합물 또는 이의 약학적으로 허용 가능한 염이 상기 개체의 항암 치료에 적합하다는 정보를 제공하는 단계를 포함하는, 항암 치료제에 대한 정보를 제공하는 방법.
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US17/800,141 US20230099204A1 (en) | 2020-03-03 | 2021-03-03 | Pharmaceutical composition for prevention or treatment of cancer in which kras mutation and activated ron are present |
CN202180017888.8A CN115209900A (zh) | 2020-03-03 | 2021-03-03 | 用于预防或治疗其中存在kras突变和活化ron的癌症的药物组合物 |
JP2022552782A JP2023516381A (ja) | 2020-03-03 | 2021-03-03 | Kras変異および活性化ronが存在する癌の予防または治療のための医薬組成物 |
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JP2023516381A (ja) | 2023-04-19 |
KR20210111711A (ko) | 2021-09-13 |
US20230099204A1 (en) | 2023-03-30 |
CN115209900A (zh) | 2022-10-18 |
EP4115887A1 (en) | 2023-01-11 |
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