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KR-20260064598-A - Novel heterobicyclic compound for inhibiting YAP-TEAD interaction and pharmaceutical composition comprising same

KR20260064598AKR 20260064598 AKR20260064598 AKR 20260064598AKR-20260064598-A

Abstract

The present invention relates to a compound selected from the compound of Formula 1, its optical isomers, diastereomers, solvates, hydrates, and pharmaceutically acceptable salts thereof, a method for preparing the same, and uses thereof.

Inventors

  • 김지숙
  • 김수호
  • 변주연
  • 신충훈
  • 안영길
  • 윤지수
  • 전영교
  • 정승현

Assignees

  • 한미약품 주식회사

Dates

Publication Date
20260507
Application Date
20251029
Priority Date
20241030

Claims (13)

  1. Compounds of Formula 1 below, or optical isomers, diastereomers, solvates, hydrates, or pharmaceutically acceptable salts thereof: [Chemical Formula 1] In the above chemical formula 1, X 1 and X 3 are each independently selected from O, S, C, N, C(R 4 ), C(R 4a )(R 4b ), and N(R 4a ); X 2 , X 5 , and X 6 are each independently selected from C, N, C(R 5 ), C(R 5a )(R 5b ), and N(R 5a ), and X 4 , X 7 , X 8 , and X 9 are each independently selected from C, N, and C(R 6 ); L1 is a bond, -O-, -S-, -NH-, C1-3 alkylene, or C2-6 alkenylene; L2 is a bond, a C1-3 alkylene, or a C1-3 alkylene substituted with 1 to 3 R7s ; R1 is selected from C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C3-10 cycloalkenyl, C2-9 heterocycloalkyl, C2-9 heterocycloalkenyl, C6-10 aryl, and C1-9 heteroaryl, and Here, R1 is substituted or unsubstituted with 1 to 3 substituents independently selected from R8 , respectively; R₂ is hydrogen, a halogen, or a C1-6 alkyl; R3 is selected from C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C3-10 cycloalkenyl, C2-9 heterocycloalkyl, C2-9 heterocycloalkenyl, C6-10 aryl, monocyclic C1-9 heteroaryl, and bicyclic C4-14 heteroaryl, and Here, R3 is substituted or unsubstituted with 1 to 3 substituents independently selected from R9 ; R 4 , R 4a , R 4b , R 5 , R 5a , R 5b , R 6 , and R7 are each independently selected from hydrogen, halogen, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C3-10 halocycloalkyl, C6-10 aryl, C1-9 heteroaryl, and C2-9 heterocycloalkyl; R8 and R9 are hydrogen, halogen, oxo, cyano, hydroxy, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C3-10 cycloalkyl, -( CH2 ) n -C3-6 cycloalkyl, -NH- C3-6 cycloalkyl, hydroxyC1-6 alkyl, C3-10 cycloalkenyl, C2-9 heterocycloalkyl, -( CH2 ) n -C2-9 heterocycloalkyl, C2-9 heterocycloalkenyl, C6-10 aryl, -( CH2 ) n -C6-10 aryl, monocyclic C1-9 heteroaryl, -( CH2 ) n -C 1-9 heteroaryl, bicyclic C 4-14 heteroaryl, Hydroxy( C2-9 heterocycloalkyl), hydroxyC1-6 alkyl( C2-9 heterocycloalkyl), C1-3 alkoxy( C2-9 heterocycloalkyl), -OR 10 , -SR 10 , -SF 5 , , -N(R 10 )(R 11 ), -C(O)OR 10 , -OC(O)N(R 10 )(R 11 ), -N(R 10 )C(O)N(R 10 )(R 11 ), -N(R 10 )C(O)OR 10 , -N(R 10 )SO 2 R 10 , -C(O)R 10 , -S(O)R 10 , -OC(O)R 10 , -C(O)N(R 10 )(R 11 ), -C(O)C(O)N(R 10 )(R 11 ), -N(R 10 )C(O)R 10 , -SO 2 R 10 , -SO 2 N(R 10 )(R 11 ), -N=S(=O)(R 10 )(R 11 ), -S(=O)(=NH)N(R 10 )(R 11 ), -S(=O)(=NH)C(R 10 )(R 11 ), -S(=O)(=NR 10 )(R 11 ), -CH 2 C(O)N(R 10 )(R 11 ), -CH 2 N(R 10 )C(O)R 11 , -CH 2 SO 2 R 10 , or -CH 2 SO 2 N(R 10 )(R 11 ) and; R 10 and R 11 are each selected from hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, (C 1-6 alkoxy)C 1-6 alkyl, hydroxyC 1-6 alkyl, C 3-10 cycloalkyl, -(CH 2 ) n -C 3-6 cycloalkyl, -NH-C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, -(CH 2 ) n -C 2-9 heterocycloalkyl, C 6-10 aryl, -(CH 2 ) n -C 6-10 aryl, C 1-9 heteroaryl, and -(CH 2 ) n -C 1-9 heteroaryl; Or optionally, R10 and R11 are connected to each other to form a C3-6 cycloalkyl C2-9 heterocycloalkyl or a C5-12 spiroheterocycloalkyl; Here, the C3-6 cycloalkyl, C2-9 heterocycloalkyl, or C5-12 spiroheterocycloalkyl formed by the linkage of R10 and R11 are, respectively Substituted or unsubstituted with 1 to 3 substituents independently selected from hydrogen, halogen, oxo, cyano, hydroxy, C1-6 alkyl , hydroxyC1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C3-10 cycloalkyl, C2-9 heterocycloalkyl, C6-10 aryl, and C1-9 heteroaryl; n is 1 to 3 and; All atoms represent a single or double bond that satisfies the valence required for bonding.
  2. In claim 1, X 1 is CH, N, O, S, N(C 1-6 alkyl), N(C 1-6 haloalkyl), or N(C 3-10 cycloalkyl); X 2 is CH and; X 3 is O, S, N, N(C 1-6 alkyl), or CH; X 4 is C and; X 5 is N or CH and; X 6 is N or CH and; X 7 is C and; X 8 is N or CH and; X 9 is a compound in which N or CH.
  3. In claim 1, The above compound is any one of the following chemical formulas 1a to 1g, or its optical isomer, diastereomer, solvate, hydrate, or pharmaceutically acceptable salt thereof: [Chemical Formula 1a] [Chemical Formula 1b] [Chemical Formula 1c] [Chemical Formula 1d] [Chemical Formula 1e] [Chemical Formula 1f] [Chemical formula 1g] In the above chemical formulas 1a to 1g, R 4c is hydrogen, halogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or C 1-6 haloalkyl; The definitions of L1 , L2 , R1 , and R3 are as in claim 1.
  4. In claim 1, L 1 is a bond or -O- and; R1 is a C3-10 cycloalkenyl, C6-10 aryl, or C1-9 heteroaryl, and Here, R1 is a compound substituted or unsubstituted with 1 to 3 substituents independently selected from hydrogen, halogen, cyano, hydroxy, C1-6 alkyl, C3-6 cycloalkyl, C1-6 haloalkyl, C1-6 alkoxy, and C1-6 haloalkoxy.
  5. In claim 1, -L 1 -R 1 is , , , , , and It is one of the selected from among them; Here, R 8a is a compound that is hydrogen, halogen, C 1-3 alkyl, C 1-3 haloalkyl, C 3-6 cycloalkyl, C 1-3 alkoxy, or C 1-3 haloalkoxy, respectively.
  6. In claim 1, L2 is a bond, a C1-3 alkylene, or a C1-3 alkylene substituted with a C1-3 alkyl; R3 is a straight-chain or branched C1-6 alkyl, C3-10 cycloalkyl, C2-9 heterocycloalkyl, C6-10 aryl, monocyclic C1-9 heteroaryl, or noncyclic C4-14 heteroaryl, and Here, R3 is substituted or unsubstituted with 1 to 3 substituents independently selected from -OR10c , -N( R10c )( R10d ), halogen, C1-6 alkyl, C2-9 heterocycloalkyl, hydroxy( C2-9 heterocycloalkyl), hydroxyC1-6 alkyl( C2-9 heterocycloalkyl), and C1-3 alkoxy( C2-9 heterocycloalkyl); R 10c and R 10d are each independently selected from hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, hydroxyC 1-6 alkyl, (C 1-3 alkoxy)C 1-3 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl; Or optionally, R10c and R10d are connected to each other to form a C3-6 cycloalkyl, C2-9 heterocycloalkyl, or C5-12 spiroheterocycloalkyl, and Here, the C3-6 cycloalkyl, C2-9 heterocycloalkyl, or C5-12 spiroheterocycloalkyl formed by the linkage of R10c and R10d are, respectively A compound substituted or unsubstituted with 1 to 3 substituents independently selected from halogen, cyano, hydroxy, hydroxy C1-6 alkyl, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, and C1-6 haloalkoxy.
  7. In claim 1, L2 is a bond, a C1-3 alkylene, or a C1-3 alkylene substituted with a C1-3 alkyl; R3 is a straight-chain C1-6 alkyl, a branched C3-6 alkyl, pyridine, pyrimidine, pyrazine, pyrazole, pyridazine, pyrrole, imidazole, triazine, thiazole, oxazole, isoxazole, or indazole, and Here, R3 is a halogen, C1-6 alkyl, amino group, -NH( C1-6 alkyl), -N( C1-6 alkyl)( C1-6 alkyl), -NH( hydroxyC1-6 alkyl), -NH( cycloC1-6 alkyl), -N( C1-6 alkyl)( hydroxyC1-6 alkyl), -NH( C1-6 alkoxy ), -NH( C1-6 alkoxyC1-6 alkyl), -N(C1-6 alkyl )( C1-6 alkoxyC1-6 alkyl), -O-( C1-6 alkyl), -O-( hydroxyC1-6 alkyl), -O-( C1-6 alkoxyC1-6 alkyl), C2-9 heterocycloalkyl, hydroxy( C2-9 heterocycloalkyl), A compound substituted or unsubstituted with 1 to 3 substituents independently selected from hydroxy C 1-6 alkyl (C 2-9 heterocycloalkyl), C 1-3 alkoxy (C 2-9 heterocycloalkyl), and C 5-12 spiroheterocycloalkyl.
  8. In claim 1, -L 2 -R 3 is , , , , , , , , , , , and It is one of the selected from among them; Here, R 12 is hydrogen, fluorine, chlorine, bromine, iodine, , , , , , , , , , , , , , , , , , , , and It is one of the selected from among them; R 13 is a compound in which hydrogen, a halogen, or a C 1-3 alkyl.
  9. In claim 1, X 1 is CH, N, N(methyl), N(ethyl), N(propyl), N(butyl), N(cyclopropyl), N(cyclobutyl), O, S, or N(C 1-4 haloalkyl); X 2 is CH and; X 3 is O, S, N, or CH; X 4 and X 7 are C; X 5 and X 6 are N or CH; X 8 is N or CH and; X 9 is N or CH and; L 1 is a bond or -O- and; L2 is a bond, methylene, or methylene substituted with a C1-3 alkyl group; R1 is cyclohexene, phenyl, or pyridine, and Here, R1 is substituted or unsubstituted with 1 to 3 substituents, each independently selected from halogen, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, C1-3 haloalkoxy, and C3-6 cycloalkyl; R₂ is hydrogen; R3 is a straight-chain C1-3 alkyl, a branched C3-6 alkyl, pyridine, pyrimidine, pyrazine, pyrazol, or pyridazine, and Here, R3 is a halogen, C1-3 alkyl, amino group, -NH( C1-3 alkyl), -N( C1-3 alkyl)( C1-3 alkyl), -N(C1-3 alkyl)( hydroxyC1-3 alkyl), -NH(hydroxyC1-3 alkyl ), -NH( cycloC1-6 alkyl), -NH( C1-3 alkoxy ), -NH( C1-3 alkoxyC1-3 alkyl), -N(C1-3 alkyl )( C1-3 alkoxyC1-3 alkyl), -O-( C1-3 alkyl), -O-( hydroxyC1-3 alkyl ), -O-( C1-3 alkoxyC1-3 alkyl), azetidinyl, pyrrolidinyl, morpholineyl, piperidinyl, piperazineyl, A compound substituted or unsubstituted with 1 to 3 substituents independently selected from hydroxyazetidine yl, C 1-3 alkoxyazetidine yl, hydroxypyrrolidin yl, C 1-3 alkoxypyrrolidin yl, hydroxypiperidin yl, hydroxymorpholine yl, hydroxypiperazine yl, indazole, and oxazaspiro[3.3]heptan yl.
  10. In claim 1, any one compound selected from the group consisting of 1) to 85) below, or an optical isomer, diastereomer, solvate, hydrate, or pharmaceutically acceptable salt thereof: 1) 4-(9-methyl-6-phenyl-9 H -purine-2-yl)-1-((2-(methylamino)pyrimidine-4-yl)methyl)pyridine-2(1 H )-one; 2) 4-(6-(4-(fluorophenyl)-9-methyl-9 H -purine-2-yl)-1-((2-(methylamino)pyrimidine-4-yl)methyl)pyridine-2(1 H )-one; 3) 4-(6-(4-(chlorophenyl)-9-methyl-9 H -purine-2-yl)-1-((2-(methylamino)pyrimidine-4-yl)methyl)pyridine-2(1 H )-one; 4) 4-(6-(4-(difluoromethyl)phenyl)-9-methyl-9 H -purine-2-yl)-1-((2-(methylamino)pyrimidine-4-yl)methyl)pyridine-2(1 H )-one; 5) 4-(6-(4-(cyclopropylphenyl)-9-methyl-9 H -purine-2-yl)-1-((2-(methylamino)pyrimidine-4-yl)methyl)pyridine-2(1 H )-one; 6) 4-(6-(4-( tert -butyl)phenyl)-9-methyl-9 H -purine-2-yl)-1-((2-(methylamino)pyrimidine-4-yl)methyl)pyridine-2(1 H )-one; 7) 4-(9-methyl-6-(4-(trifluoromethyl)cyclohex-1-en-1-yl)-9 H -purine-2-yl)-1-((2-(methylamino)pyrimidine-4-yl)methyl)pyridine-2(1 H )-one; 8) 4-(6-(4,4-dimethylcyclohex-1-en-1-yl)-9-methyl-9 H -purine-2-yl)-1-((2-(methylamino)pyrimidine-4-yl)methyl)pyridine-2(1 H )-one; 9) 5-(9-methyl-6-(4-(trifluoromethyl)phenyl)-9 H -purine-2-yl)-1-((2-(methylamino)pyrimidine-4-yl)methyl)pyridine-2(1 H )-one; 10) 4-(9-methyl-6-(4-(trifluoromethyl)phenyl)-9 H -purine-2-yl)-1-((2-(methylamino)pyrimidine-4-yl)methyl)pyridine-2(1 H )-one; 11) 4-(6-(4-(chlorodifluoromethoxy)phenyl)-9-methyl-9 H -purine-2-yl)-1-((2 (methylamino)pyrimidine-4-yl)methyl)pyridine-2(1 H )-one; 12) 4-(9-methyl-6-(4-(trifluoromethoxy)phenyl)-9 H -purine-2-yl)-1-((2-(methylamino)pyrimidine-4-yl)methyl)pyridine-2(1 H )-one; 13) 4-(9-methyl-6-(4-(trifluoromethoxy)phenyl)-9 H -purine-2-yl)-1-((2-(methylamino)pyridine-4-yl)methyl)pyridine-2(1 H )-one; 14) 4-(9-methyl-6-(4-(trifluoromethoxy)phenyl)-9 H -purine-2-yl)-1-((4-(methylamino)pyrimidine-2-yl)methyl)pyridine-2(1 H )-one; 15) 4-(6-(2-fluoro-4-(trifluoromethoxy)phenyl)-9-methyl-9 H -purine-2-yl)-1-((2-(methylamino)pyrimidine-4-yl)methyl)pyridine-2(1 H )-one; 16) 4-(6-(3-chloro-4-(trifluoromethoxy)phenyl)-9-methyl-9 H -purine-2-yl)-1-((2-(methylamino)pyrimidine-4-yl)methyl)pyridine-2(1 H )-one; 17) 4-(9-methyl-6-(2-methyl-4-(trifluoromethyl)phenyl)-9 H -purine-2-yl)-1-((2-(methylamino)pyrimidine-4-yl)methyl)pyridine-2(1 H )-one; 18) 1-((2-(dimethylamino)pyrimidine-4-yl)methyl)-4-(9-methyl-6-(4-(trifluoromethoxy)phenyl)-9 H -purine-2-yl)pyridine-2(1 H )-one; 19) 1-((2-aminopyrimidine-4-yl)methyl)-4-(9-methyl-6-(4-(trifluoromethoxy)phenyl)-9 H -purine-2-yl)pyridine-2(1 H )-one; 20) 1-((2-(isopropylamino)pyrimidine-4-yl)methyl)-4-(9-methyl-6-(4-(trifluoromethoxy)phenyl)-9 H -purine-2-yl)pyridine-2(1 H )-one; 21) 4-(6-(4-(chlorodifluoromethoxy)phenyl)-9-methyl-9 H -purine-2-yl)-1-((2-(isopropylamino)pyrimidine-4-yl)methyl)pyridine-2(1 H )-one; 22) 1-((2-(cyclopropylamino)pyrimidine-4-yl)methyl)-4-(9-methyl-6-(4-(trifluoromethoxy)phenyl)-9 H -purine-2-yl)pyridine-2(1 H )-one; 23) 1-((2-(cyclobutylamino)pyrimidine-4-yl)methyl)-4-(9-methyl-6-(4-(trifluoromethoxy)phenyl)-9 H -purine-2-yl)pyridine-2(1 H )-one; 24) 1-((2-(cyclopentylamino)pyrimidine-4-yl)methyl)-4-(9-methyl-6-(4-(trifluoromethoxy)phenyl)-9 H -purine-2-yl)pyridine-2(1 H )-one; 25) 1-((2-(cyclopropylamino)pyrimidine-4-yl)methyl)-4-(9-methyl-6-(4-(trifluoromethyl)cyclohex-1-en-1-yl)-9 H -purine-2-yl)pyridine-2(1 H )-one; 26) 1-((2-((2-hydroxyethyl)amino)pyrimidine-4-yl)methyl)-4-(9-methyl-6-(4-(trifluoromethoxy)phenyl)-9 H -purine-2-yl)pyridine-2(1 H )-one; 27) 1-((2-((2-hydroxyethyl)amino)pyrimidine-4-yl)methyl)-4-(9-methyl-6-(4-(trifluoromethyl)cyclohex-1-en-1-yl)-9 H -purine-2-yl)pyridine-2(1 H )-one; 28) 4-(6-(4,4-dimethylcyclohex-1-en-1-yl)-9-methyl-9 H -purine-2-yl)-1-((2-(isopropylamino)pyrimidine-4-yl)methyl)pyridine-2(1 H )-one; 29) 4-(6-(4,4-dimethylcyclohex-1-en-1-yl)-9-methyl-9 H -purine-2-yl)-1-((2-((2-methoxyethyl)amino)pyrimidine-4-yl)methyl)pyridine-2(1 H )-one; 30) 1-((2-((2-hydroxyethyl)(methyl)amino)pyrimidine-4-yl)methyl)-4-(9-methyl-6-(4-(trifluoromethoxy)phenyl)-9 H -purine-2-yl)pyridine-2(1 H )-one; 31) 1-((2-((2-methoxyethyl)(methyl)amino)pyrimidine-4-yl)methyl)-4-(9-methyl-6-(4-(trifluoromethoxy)phenyl)-9 H -purine-2-yl)pyridine-2(1 H )-one; 32) 4-(6-(4-(chlorodifluoromethoxy)phenyl)-9-methyl-9 H -purine-2-yl)-1-((2-((2-methoxyethyl)amino)pyrimidine-4-yl)methyl)pyridine-2(1 H )-one; 33) 1-((2-((2-methoxyethyl)amino)pyrimidine-4-yl)methyl)-4-(9-methyl-6-(4-(trifluoromethoxy)phenyl)-9 H -purine-2-yl)pyridine-2(1 H )-one; 34) 1-((2-(3-hydroxyazetidine-1-yl)pyrimidine-4-yl)methyl)-4-(9-methyl-6-(4-(trifluoromethoxy)phenyl)-9 H -purine-2-yl)pyridine-2(1 H )-one; 35) 1-((2-(3-methoxyazetidine-1-yl)pyrimidine-4-yl)methyl)-4-(9-methyl-6-(4-(trifluoromethoxy)phenyl)-9 H -purine-2-yl)pyridine-2(1 H )-one; 36) ( S )-1-((2-(3-hydroxypyrrolidin-1-yl)pyrimidine-4-yl)methyl)-4-(9-methyl-6-(4-(trifluoromethoxy)phenyl)-9 H -purine-2-yl)pyridine-2(1 H )-one; 37) 1-((2-(3-methoxypyrrolidin-1-yl)pyrimidine-4-yl)methyl)-4-(9-methyl-6-(4-(trifluoromethoxy)phenyl)-9 H -purine-2-yl)pyridine-2(1 H )-one; 38) 4-(9-methyl-6-(4-(trifluoromethoxy)phenyl)-9 H -purine-2-yl)-1-((2-morpholinopyrimidine-4-yl)methyl)pyrimidine-2(1 H )-one; 39) 1-((2-(2-oxa-6-azaspiro[3,3]heptane-6-yl)pyrimidine-4-yl)methyl)-4-(9-methyl-6-(4-(trifluoromethoxy)phenyl)-9 H -purine-2-yl)pyridine-2(1 H )-one; 40) 4-(9-methyl-6-(4-(trifluoromethoxy)phenyl)-9 H -purine-2-yl)-1-(pyridine-2-ylmethyl)pyridine-2(1 H )-one; 41) 4-(9-methyl-6-(4-(trifluoromethoxy)phenyl)-9 H -purine-2-yl)-1-(pyridazine-3-ylmethyl)pyridine-2(1 H )-one; 42) 4-(9-methyl-6-(4-(trifluoromethoxy)phenyl)-9 H -purine-2-yl)-1-(1-(pyridine-2-yl)ethyl)pyridine-2(1 H )-one; 43) 4-(9-methyl-6-(4-(trifluoromethyl)cyclohex-1-en-1-yl)-9 H -purine-2-yl)-1-(pyridine-2-ylmethyl)pyridine-2(1 H )-one; 44) 4-(9-methyl-6-(4-(trifluoromethoxy)phenyl)-9 H -purine-2-yl)-1-(pyridine-3-ylmethyl)pyridine-2(1 H )-one; 45) 4-(9-methyl-6-(4-(trifluoromethoxy)phenyl)-9 H -purine-2-yl)-1-(pyridine-4-ylmethyl)pyridine-2(1 H )-one; 46) 1-((1-methyl-1 H -pyrazole-3-yl)methyl)-4-(9-methyl-6-(4-(trifluoromethoxy)phenyl)-9 H -purine-2-yl)pyridine-2(1 H )-one; 47) 4-(9-methyl-6-(4-(trifluoromethoxy)phenyl)-9 H -purine-2-yl)-1-((6-(methylamino)pyridine-2-yl)methyl)pyridine-2(1 H )-one; 48) 4-(1-methyl-4-(4-(trifluoromethoxy)phenyl)-1 H -imidazo[4,5- c ]pyridine-6-yl)-1-((2-(methylamino)pyrimidine-4-yl)methyl)pyridine-2(1 H )-one; 49) 4-(4-(2-fluoro-4-(trifluoromethoxy)phenyl)-1-methyl-1 H -imidazo[4,5- c ]pyridin-6-yl)-1-((2-(methylamino)pyrimidin-4-yl)methyl)pyridin-2(1 H )-one; 50) 1-((2-(2-methoxyethyl)amino)-pyrimidine-4-yl)methyl)-4-(1-methyl-4-(4-(trifluoromethoxy)phenyl)-1 H -imidazo[4,5- c ]pyridine-6-yl)pyridine-2(1 H )-one; 51) 1-((2-(isopropylamino)-pyrimidine-4-yl)methyl)-4-(1-methyl-4-(4-(trifluoromethoxy)phenyl)-1 H -imidazo[4,5- c ]pyridine-6-yl)pyridine-2(1 H )-one; 52) 4-(3-methyl-7-(4-(trifluoromethoxy)phenyl)-3 H -imidazo[4,5- b ]pyridin-5-yl)-1-((2-(methylamino)pyrimidin-4-yl)methyl)pyridin-2(1 H )-one; 53) 4-(9-cyclopropyl-6-(4-(trifluoromethoxy)phenyl)-9 H -purine-2-yl)-1-((2-(methylamino)pyrimidine-4-yl)methyl)pyridine-2(1 H )-one; 54) 4-(9-cyclopropyl-6-(4-(trifluoromethoxy)phenyl)-9 H -purine-2-yl)-1-((1-methyl-1 H -pyrazole-3-yl)methyl)pyridine-2(1 H )-one; 55) 4-(7-methyl-4-(4-(trifluoromethoxy)phenyl)-7 H -pyrrolo[2,3- d ]pyrimidine-2-yl)-1-((2-(methylamino)pyrimidine-4-yl)methyl)pyridine-2(1 H )-one; 56) 1-((2-(2-methoxyethyl)amino)-pyrimidine-4-yl)methyl)-4-(7-methyl-4-(4-(trifluoromethoxy)phenyl)-7 H -pyrrolo[2,3- d ]pyrimidine-2-yl)pyridine-2(1 H )-one; 57) 1-((2-(isopropylamino)pyrimidine-4-yl)methyl)-4-(7-methyl-4-(4-(trifluoromethoxy)phenyl)-7 H -pyrrolo[2,3-d]pyrimidine-2-yl)pyridine-2(1 H )-one; 58) 1-((2-((2-hydroxyethyl)amino)pyrimidine-4-yl)methyl)-4-(7-methyl-4-(4-(trifluoromethoxy)phenyl)-7 H -pyrrolo[2,3- d ]pyrimidine-2-yl)pyridine-2(1 H )-one; 59) 4-(7-methyl-4-(4-(trifluoromethoxy)phenyl)-7 H -pyrrolo[2,3- d ]pyrimidine-2-yl)-1-(pyridine-2-ylmethyl)pyridine-2(1 H )-one; 60) 1-((2-(methylamino)pyrimidine-4-yl)methyl)-4-(4-(4-(trifluoromethoxy)phenyl)thieno[3,2- d ]pyrimidine-2-yl)pyridine-2( 1H )-one; 61) 1-((2-(methylamino)pyrimidine-4-yl)methyl)-4-(4-(4-(trifluoromethoxy)phenyl)furo[3,2- d ]pyrimidine-2-yl)pyridine-2( 1H )-one; 62) 1-((2-(methylamino)pyrimidine-4-yl)methyl)-4-(7-(4-(trifluoromethoxy)phenyl)thiazolo[5,4- d ]pyrimidine-5-yl)pyridine-2(1 H )-one; 63) 1-((2-methoxypyrimidine-4-yl)methyl)-4-(9-methyl-6-(4-(trifluoromethoxy)phenyl)-9 H -purine-2-yl)pyridine-2(1 H )-one; 64) 1-((2-(2-methoxyethoxy)pyrimidine-4-yl)methyl)-4-(9-methyl-6-(4-(trifluoromethoxy)phenyl)-9 H -purine-2-yl)pyridine-2(1 H )-one; 65) 1-((2-(2-hydroxyethoxy)pyrimidine-4-yl)methyl)-4-(9-methyl-6-(4-(trifluoromethoxy)phenyl)-9 H -purine-2-yl)pyridine-2(1 H )-one; 66) 1-((2-chloropyrimidine-4-yl)methyl)-4-(9-methyl-6-(4-(trifluoromethoxy)phenyl)-9 H -purine-2-yl)pyridine-2(1 H )-one; 67) 4-(9-methyl-6-(4-(trifluoromethyl)phenoxy)-9 H -purine-2-yl)-1-((2-(methylamino)pyrimidine-4-yl)methyl)pyridine-2(1 H )-one; 68) 4-(6-(4-chlorophenoxy)-9-methyl-9 H -purine-2-yl)-1-((2-(methylamino)pyrimidine-4-yl)methyl)pyridine-2(1 H )-one; 69) 4-(9-methyl-6-( p -tolyloxy)-9 H -purine-2-yl)-1-((2-(methylamino)pyrimidine-4-yl)methyl)pyridine-2(1 H )-one; 70) 1-((2-((2-hydroxyethyl)amino)pyrimidine-4-yl)methyl)-4-(9-methyl-6-(4-(trifluoromethyl)phenoxy)-9 H- purine-2-yl)pyridine-2(1 H )-one; 71) 4-(9-methyl-6-(4-(trifluoromethyl)phenoxy)-9 H -purine-2-yl)-1-(pyridine-2-ylmethyl)pyridine-2(1 H )-one; 72) 1-((2-((2-methoxyethyl)amino)pyrimidine-4-yl)methyl)-4-(9-methyl-6-(4-(trifluoromethyl)phenoxy)-9 H -purine-2-yl)pyridine-2(1 H )-one; 73) 4-(9-cyclopropyl-6-(4-(trifluoromethoxy)phenyl)-9H-purine-2-yl)-1-((2-((2-hydroxyethyl)amino)pyrimidine-4-yl)methyl)pyridine-2(1 H )-one; 74) 1-((2-(cyclopropylamino)pyrimidine-4-yl)methyl)-4-(9-methyl-6-(4-(trifluoromethyl)phenoxy)-9 H -purine-2-yl)pyridine-2(1 H )-one; 75) 4-(7-methyl-4-(4-(trifluoromethyl)phenoxy)-7 H -pyrrolo[2,3- d ]pyrimidine-2-yl)-1-((2-(methylamino)pyrimidine-4-yl)methyl)pyridine-2(1 H )-one; 76) 4-(9-methyl-6-(6-(trifluoromethoxy)pyridine-3-yl)-9 H- purine-2-yl)-1-((2-(methylamino)pyrimidine-4-yl)methyl)pyridine-2(1 H )-one; 77) 1-((1 H -indazole-7-yl)methyl)-4-(9-methyl-6-(4-(trifluoromethoxy)phenyl)-9 H -purine-2-yl)pyridine-2(1 H )-one hydrochloride; 78) 4-((4-(9-methyl-6-(4-(trifluoromethoxy)phenyl)-9 H -purine-2-yl)-2-oxopyridine-1(2 H )-yl)methyl)pyrimidine-2-carboxaamide; 79) 4-(9-methyl-6-(4-(trifluoromethoxy)phenyl)-9 H -purine-2-yl)-1-(oxazole-2-ylmethyl)pyridine-2(1 H )-one; 80) 4-(6-(cyclohex-1-en-1-yl)-9-methyl-9 H -purine-2-yl)-1-((2-(methylamino)pyrimidine-4-yl)methyl)pyridine-2(1 H )-one; 81) ( R )-4-(9-methyl-6-(4-(trifluoromethyl)cyclohex-1-en-1-yl)-9 H -purine-2-yl)-1-((2-(methylamino)pyrimidine-4-yl)methyl)pyridine-2(1 H )-one; 82) ( S )-4-(9-methyl-6-(4-(trifluoromethyl)cyclohex-1-en-1-yl)-9 H -purine-2-yl)-1-((2-(methylamino)pyrimidine-4-yl)methyl)pyridine-2(1 H )-one; 83) 4-(6-(cyclohex-1-en-1-yl)-9-methyl-9 H -purine-2-yl)-1-((2-((2-methoxyethyl)amino)pyrimidine-4-yl)methyl)pyridine-2(1 H )-one; 84) 4-(6-(4,4-difluorocyclohex-1-en-1-yl)-9-methyl-9 H -purine-2-yl)-1-((2-(methylamino)pyrimidine-4-yl)methyl)pyridine-2(1 H )-one; and 85) 4-(9-methyl-6-(4-(trifluoromethoxy)phenyl)-9 H -purine-2-yl)-1-((2-(methyleneamino)pyrimidine-4-yl)methyl)pyridine-2(1 H )-one.
  11. A pharmaceutical composition for treating or preventing a related disease caused by transcriptional enhancer associate domain (TEAD) activation, comprising as an active ingredient the compound of claim 1, or its optical isomer, diastereomer, solvate, hydrate, or pharmaceutically acceptable salt thereof.
  12. The pharmaceutical composition of claim 11, wherein the composition exhibits activity that inhibits Yes associated protein (YAP)-transcriptional enhancer associate domain (TEAD) binding.
  13. The pharmaceutical composition of claim 11 for treating cancer or tumors that can be treated by exhibiting inhibitory activity against YAP-TEAD binding.

Description

Novel heterobicyclic compound for inhibiting YAP-TEAD interaction and pharmaceutical composition comprising same The present invention relates to a pharmaceutical composition comprising a heterocyclic compound that inhibits the binding of a Yes associated protein (YAP) to a transcriptional enhancer associate domain (TEAD). The compound according to the present invention can directly inhibit the YAP-TEAD binding in the Hippo pathway, which plays a key role in the development of cancer. The Hippo signaling cascade is an important pathway for oncogenesis and tumor maintenance. YAP and tafazzin (TAZ) are transcriptional co-activators of the Hippo pathway network and regulate cell proliferation, migration, and apoptosis. Inactivation of the Hippo signaling pathway promotes the nuclear translocation of YAP/TAZ, where YAP/TAZ interacts with transcription enhancer-associated domain (TEAD) transcription factors to co-activate the expression of target genes and promote cell proliferation. Target genes closely correlated with oncogenesis, such as connective tissue growth factor (CTGF), Cyr61, AXL receptor tyrosine kinase, and MYC, are regulated by TEAD. Furthermore, TEAD has been shown to be overexpressed in breast cancer stem cells as well as in breast, ovarian, germ cell tumors, renal cell carcinoma, medulloblastoma, and gastric cancer. Overactivation of YAP and TAZ and/or mutations in one or more members of the Hippo pathway network are associated with numerous cancers. Additionally, recent studies have reported that YAP overexpression or amplification is associated with epithelial-mesenchymal transition (EMT) phenotypic changes for resistance to the EGFR tyrosine kinase inhibitors Tarceva (erlotinib), Iressa (gefitinib), or Tagrisso (osimertinib). The inventors completed the present invention by developing a novel heterocyclic compound for inhibiting YAP-TEAD protein interactions. The present invention will be described in more detail below. All technical terms used in this invention, unless otherwise defined, are used in the sense generally understood by those skilled in the art in the relevant field of this invention. Additionally, while preferred methods or samples are described herein, similar or equivalents are also included within the scope of this invention. definition In this specification, the term "halogen" may be F, Cl, Br, or I. In this specification, the term “alkyl” refers to a monovalent group derived from a saturated hydrocarbon by removing one hydrogen atom, unless otherwise noted. The alkyl comprises a straight-chain, branched, or cyclic hydrocarbon residue that may be substituted or unsubstituted, and may be, for example, methyl, ethyl, propyl, butyl, pentyl, isopropyl, isobutyl, or t- butyl (or tert- butyl), but is not limited thereto. Unless otherwise noted, the term “alkenyl” refers to a monovalent group derived from a hydrocarbon by removing one hydrogen atom and comprises one or more unsaturated regions and at least one carbon-carbon double bond. The alkenyl comprises an alkyl group containing one or more double bonds that may be substituted or unsubstituted, and may be, for example, prop-1-en, but-1-en, but-2-en, 3-methylbut-1-en, or pent-1-en, but is not limited thereto. In this specification, the term “alkynyl” refers to a monovalent group derived from a hydrocarbon by removing one hydrogen atom, unless otherwise noted, and comprises one or more unsaturated regions, namely at least one carbon-carbon triple bond. The alkynyl may be -C≡CH, -CH₂C≡CH , or -CH₂CH₂CH₂C≡C- , but is not limited thereto. As used herein, the term “alkylene” refers to a straight-chain, branched, or cyclic saturated divalent hydrocarbon group having two monovalent radical centers derived by removing two hydrogen atoms from the same or two different carbon atoms of a parent alkane. An alkylene may also be represented as ( -CH2- ) p (where p is any integer) and may be, for example, methylene ( -CH2- ), 1,1-ethyl (-CH( CH3 )-), 1,2- ethyl ( -CH2CH2- ), 1,1-propyl (-CH( CH2CH3 ) - ), 1,2-propyl ( -CH2CH ( CH3 ) -), 1,3 - propyl ( -CH2CH2CH2- ) , or 1,4-butyl ( -CH2CH2CH2CH2- ), but is not limited thereto . As used herein, the term "alkenylene" refers to a divalent group derived from an alkenyl by removing one hydrogen atom. In other words, alkenylene refers to a straight-chain, branched, or cyclic unsaturated divalent hydrocarbon group having two monovalent radical centers derived by removing two hydrogen atoms from the same or two different carbon atoms of a parent alkene. For example, alkenylene may be methylene (-CH=) or 1,2-ethylene (-CH=CH-), but is not limited thereto. As used herein, the term "alkynylene" refers to a divalent group derived from an alkyne by removing one hydrogen atom. In other words, alkynylene refers to a straight-chain, branched, or cyclic unsaturated divalent hydrocarbon group having two monovalent radical centers derived by removing two hydrogen atoms from the same or two different carbon ato