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KR-20260065812-A - Substituted bicyclic heterocyclic YAP-TEAD and/or TAZ-TEAD inhibitors

KR20260065812AKR 20260065812 AKR20260065812 AKR 20260065812AKR-20260065812-A

Abstract

The present invention relates to heterocyclic compounds. These heterocyclic compounds are useful as TEAD binders and/or inhibitors of YAP-TEAD and TAZ-TEAD protein-protein interactions or binding, and for the prevention and/or treatment of cancer and other severe disorders and diseases.

Inventors

  • 하인리히 티모
  • 운수에 로페스 안드레아
  • 구네라 야쿱
  • 부르그도르프 라르스
  • 알베르스 리자
  • 감바르델라 알렉시아
  • 페테르손 칼

Assignees

  • 메르크 파텐트 게엠베하

Dates

Publication Date
20260511
Application Date
20240730
Priority Date
20230802

Claims (20)

  1. Compound of Formula I In the equation X 1 represents N or CR X1 ; R X1 represents H, a halogen, a straight-chain or branched C 1-4 -alkyl (which is unsubstituted or independently substituted with 1, 2, or 3 halogens, and/or OH); R1 represents a halogen, -NH2 , -CN, straight-chain or branched C1-4 -alkyl (which is unsubstituted or independently substituted with 1, 2, or 3 halogens); R₂ represents H, Alk₂ , Ar₂, Hetar₂ , Cyc₂ , Hetcyc₂ , -L₂ , -Ar₂a , -S(=O) ₂Rf ; R₃ represents H, -CN, -C(=O) -NH₂ , or a halogen; A represents 1,3-phenylene or a monocyclic divalent heteroaryl having 5 or 6 ring atoms (1, 2, or 3 of the ring atoms are heteroatom(s) selected from N, O, and/or S, and the remainder are carbon atoms), where 1,3-phenylene or monocyclic heteroaryl is Formula I A compound having a bicyclic ring system at the 1-position and an L1 -B radical of the compound of Formula I at the 3-position relative to the bicyclic ring system, wherein each of the 1,3-phenylene or monocyclic heteroaryl may be unsubstituted or independently monosubstituted or dissubstituted with a halogen, a straight-chain or branched C1-4 -alkyl, OC1-4 -alkyl, SC1-4 -alkyl, C3-7 -cycloalkyl, OC3-7 -cycloalkyl, or SC3-7 -cycloalkyl, wherein the C1-4 -alkyl, OC1-4 -alkyl, SC1-4 -alkyl, C3-7 -cycloalkyl, OC3-7 -cycloalkyl, or SC3-7 -cycloalkyl is unsubstituted or substituted with one, two, or three halogens; B represents Ar 1 , Hetar 1 , Cyc 1 , and Hetcyc 1 ; L1 represents -O-, -S-, -N( R4 )-, -O- CH2- , -O-CH( R5 )-, -O- SO2- , -N( R6 ) -CH2- , -N( R6 )-C(=O)-, -CH2- , -CH( R7 )-, -CH2CH2- , -CH2 - O- ; R 4 represents H, a straight-chain or branched C 1-6 -alkyl group; R5 , R6 , and R7 independently represent straight-chain or branched C1-6 -alkyl groups; L 2 represents -S(=O) 2 - gi; Alk 2 represents a straight-chain or branched C 1-6 -alkyl, C 2-6 -alkenyl, or C 2-6 -alkynyl (each of which is unsubstituted or independently substituted with R 2a1 , R 2a2 , and/or R 2a3 ); Ar 1 represents a mono- or bicyclic aryl having 5, 6, 7, 8, 9, or 10 cyclic carbon atoms, wherein the aryls are independently substituted with RC1 , RC2 , and/or RC3 ; Ar a , Ar 2 , and Ar 2a independently represent mono- or bicyclic aryls having 5, 6, 7, 8, 9, or 10 cyclic carbon atoms, wherein the aryls may be unsubstituted or independently substituted with R B1 , R B2 , R B3 , R B4 , and/or R B5 ; Hetar 1 represents a mono- or bicyclic heteroaryl having 5, 6, 7, 8, 9, 10, 11, or 12 ring atoms (1, 2, 3, 4, or 5 of the ring atoms are heteroatom(s) selected from N, O, and/or S, and the remainder are carbon atoms), wherein the heteroaryls are independently substituted with RC1 , RC2 , and/or RC3 ; Hetar a , Hetar 2 , and Hetar 2a independently represent mono- or bicyclic heteroaryls having 5, 6, 7, 8, 9, 10, 11, and 12 ring atoms (of which 1, 2, 3, 4, and 5 are heteroatom(s) selected from N, O, and/or S, and the remainder are carbon atoms), wherein the heteroaryls are unsubstituted or independently substituted with RB1 , RB2 , RB3 , RB4 , and/or RB5 ; Cyc 1 represents a saturated or partially unsaturated, mono-, bi-, or tricyclic carbocycle having 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 cyclic carbon atoms, wherein the carbocycle may be unsubstituted or independently substituted with RC6 , RC7 , RC8 , RC9 , RC10 , and/or RC11 ; Cyc a , Cyc 2 , and Cyc 2a independently represent saturated or partially unsaturated, mono-, bi-, or tricyclic carbocycles having 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 cyclic carbon atoms, wherein the carbocycles are unsubstituted or independently substituted with R B6 , R B7 , R B8 , R B9 , R B10 , and/or R B11 ; Hetcyc 1 represents a saturated or partially unsaturated, mono- or bicyclic heterocycle having 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 ring atoms (1, 2, 3, 4, or 5 of the ring atoms are heteroatom(s) selected from N, O, and/or S, and the remainder are carbon atoms), wherein the heterocycles are independently substituted with RC6 , RC7 , RC8 , RC9 , RC10 , and/or RC11 ; Hetcyc a , Hetcyc 2 , and Hetcyc 2a independently represent saturated or partially unsaturated, mono- or bicyclic heterocycles having 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12 ring atoms (of which 1, 2, 3, 4, and 5 are heteroatom(s) selected from N, O, and/or S, and the remainder are carbon atoms), wherein the heterocycles are unsubstituted or independently substituted with R B6 , R B7 , R B8 , R B9 , R B10 , and/or R B11 ; R 2a1 , R 2a2 , and R 2a3 independently represent halogen, -CF 3 , -CN, -NH 2 , -NHR a , -NR a R b , -OH, -OR c , -P(=O)R d R e , -SH, -SR f , -S(=O)R f , -S(=O) 2 R f , -S(=O)(=NR g )R f , -N=S(=O)R f R h , -C(=O)NH 2 , -C(=O)NHR a , -C(=O)NR a R b , -C(=O)OH, -C(=O)OR c , -NH-C(=O)-R i , Cyc 2a , Hetar 2a , and Hetcyc 2a ; and/or Among R2a1 , R2a2 , and R2a3 attached to the same carbon atom, two together form a dioxo (=O) group; R a , R b ...independently represent straight-chain or branched C 1-6 -alkyl (which are unsubstituted or substituted with 1, 2, or 3 halogens); Ar a , Cyc a , Hetar a , Hetcyc a ; or R a and R b form a saturated, partially unsaturated, or aromatic heterocycle having 3, 4, 5, 6, or 7 ring atoms together with the nitrogen atom to which they are attached (one of the ring atoms is the nitrogen atom, zero or one more ring atom is a heteroatom selected from N, O, or S, and the remainder is a carbon atom), wherein the heterocycle is unsubstituted or independently substituted with R B6 , R B7 , R B8 , R B9 , R B10 , and/or R B11 ; R c represents a straight-chain or branched C1-4 -alkyl, C2-4 -alkenyl, or C2-4 -alkynyl (each of which is unsubstituted or substituted with -OH); C3-7 -cycloalkyl (which is unsubstituted or substituted with -OH and/or halogens); R d and R e independently represent straight-chain or branched C 1-6 -alkyl groups; R f and R h independently represent straight-chain or branched C 1-6 -alkyl groups; R g represents H, a straight-chain or branched C 1-6 -alkyl group; Ri represents H, a straight-chain or branched C 1-6 -alkyl group; RB1 , RB2 , RB3 , RB4 , and RB5 independently represent halogens; -OH; -OC 1-4 -alkyl; C 1-4 -alkyl (which are unsubstituted or substituted with 1, 2, or 3 halogens); R B6 , R B7 , R B8 , R B9 , R B10 , R B11 independently represent halogens; OH; -OC 1-4 -alkyl; C 1-4 -alkyl (which are unsubstituted or substituted with 1 or 2 OH and/or 1, 2, or 3 halogens); and/or Two of R B6 , R B7 , R B8 , R B9 , R B10 , and R B11 attached to the same carbon atom of the above carbocycle or the above heterocycle form a dioxo (=O) group; and/or Two of R B6 , R B7 , R B8 , R B9 , R B10 , and R B11 attached to the same sulfur (S) atom of the above heterocycle form a divalent oxo (=O) group, and simultaneously, two more of R B6 , R B7 , R B8 , R B9 , R B10 , and R B11 attached to the same sulfur atom form a divalent oxo group or a divalent =NH or =NC 1-4 -alkyl group, thereby forming an -S(=O) 2 , -S(=O)(=NH), or -S(=O)(=NC 1-4 -alkyl) moiety; RC1 , RC2 , and RC3 independently represent halogens; C1-4 -alkyl, -SC1-4 -alkyl, or -OC1-4 -alkyl (each of which is unsubstituted or substituted with 1, 2, or 3 halogens); R C6 , R C7 , R C8 , R C9 , R C10 , and/or R C11 represent halogens independently; C 1-4 -alkyl (which is unsubstituted or independently substituted with 1, 2, or 3 substituents selected from halogens); -OC 1-4 -alkyl (which is unsubstituted or independently substituted with 1, 2, or 3 substituents selected from halogens); Halogens represent F, Cl, Br, and I; or any N-oxide, solvate, tautomeric or stereoisomer thereof and/or any pharmaceutically acceptable salt of each of the above (including mixtures of all ratios thereof).
  2. Compound of Formula I In the equation X 1 represents N or CR X1 ; R X1 represents H, a halogen, a straight-chain or branched C 1-4 -alkyl (which is unsubstituted or independently substituted with 1, 2, or 3 halogens, and/or OH); R1 represents a halogen, -NH2 , -CN, straight-chain or branched C1-4 -alkyl (which is unsubstituted or independently substituted with 1, 2, or 3 halogens); R₂ represents H, Alk₂ , Ar₂ , Hetar₂ , Cyc₂ , Hetcyc₂ , -L₂ - Ar₂a ; R3 represents H, -CN, or a halogen; A represents 1,3-phenylene or a monocyclic divalent heteroaryl having 5 or 6 ring atoms (1, 2, or 3 of the ring atoms are heteroatom(s) selected from N, O, and/or S, and the remainder are carbon atoms), where 1,3-phenylene or monocyclic heteroaryl is Formula I The compound of retains the bicyclic ring system at the 1-position and the L1 -B radical of the compound of Formula I at the 3-position relative to the bicyclic ring system, wherein each of the 1,3-phenylene or monocyclic heteroaryl may be unsubstituted or independently monosubstituted or dissubstituted with a halogen, a straight-chain or branched C1-4 -alkyl (which may be unsubstituted or substituted with 1, 2, or 3 halogens); B represents Ar 1 , Hetar 1 , Cyc 1 , and Hetcyc 1 ; L1 represents -O-, -N( R4 )-, -O- CH2- , -O-CH( R5 )-, -O- SO2- , -N( R6 ) -CH2- , -N( R6 )-C(=O)-, -CH2- , -CH( R7 )-, -CH2CH2- , -CH2 - O-; R 4 represents H, a straight-chain or branched C 1-6 -alkyl group; R5 , R6 , and R7 independently represent straight-chain or branched C1-6 -alkyl groups; L 2 represents -S(=O) 2 - gi; Alk 2 represents a straight-chain or branched C 1-6 -alkyl, C 2-6 -alkenyl, or C 2-6 -alkynyl (each of which is unsubstituted or independently substituted with R 2a1 , R 2a2 , and/or R 2a3 ); Ar 1 represents a mono- or bicyclic aryl having 5, 6, 7, 8, 9, or 10 cyclic carbon atoms, wherein the aryls are independently substituted with RC1 , RC2 , and/or RC3 ; Ar a , Ar 2 , and Ar 2a independently represent mono- or bicyclic aryls having 5, 6, 7, 8, 9, or 10 cyclic carbon atoms, wherein the aryls may be unsubstituted or independently substituted with R B1 , R B2 , R B3 , R B4 , and/or R B5 ; Hetar 1 represents a mono- or bicyclic heteroaryl having 5, 6, 7, 8, 9, 10, 11, or 12 ring atoms (1, 2, 3, 4, or 5 of the ring atoms are heteroatom(s) selected from N, O, and/or S, and the remainder are carbon atoms), wherein the heteroaryls are independently substituted with RC1 , RC2 , and/or RC3 ; Hetar a , Hetar 2 , and Hetar 2a independently represent mono- or bicyclic heteroaryls having 5, 6, 7, 8, 9, 10, 11, and 12 ring atoms (of which 1, 2, 3, 4, and 5 are heteroatom(s) selected from N, O, and/or S, and the remainder are carbon atoms), wherein the heteroaryls are unsubstituted or independently substituted with RB1 , RB2 , RB3 , RB4 , and/or RB5 ; Cyc 1 represents a saturated or partially unsaturated, mono-, bi-, or tricyclic carbocycle having 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 cyclic carbon atoms, wherein the carbocycle may be unsubstituted or independently substituted with RC6 , RC7 , RC8 , RC9 , RC10 , and/or RC11 ; Cyc 2 represents a saturated or partially unsaturated, mono-, bi-, or tricyclic carbocycle having 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 cyclic carbon atoms, wherein the carbocycle is unsubstituted or independently substituted with R B6 , R B7 , R B8 , R B9 , R B10 , and/or R B11 ; Hetcyc 1 represents a saturated or partially unsaturated, mono- or bicyclic heterocycle having 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 ring atoms (1, 2, 3, 4, or 5 of the ring atoms are heteroatom(s) selected from N, O, and/or S, and the remainder are carbon atoms), wherein the heterocycles are independently substituted with RC6 , RC7 , RC8 , RC9 , RC10 , and/or RC11 ; Hetcyc a , Hetcyc 2 , and Hetcyc 2a independently represent saturated or partially unsaturated, mono- or bicyclic heterocycles having 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12 ring atoms (of which 1, 2, 3, 4, and 5 are heteroatom(s) selected from N, O, and/or S, and the remainder are carbon atoms), wherein the heterocycles are unsubstituted or independently substituted with R B6 , R B7 , R B8 , R B9 , R B10 , and/or R B11 ; R 2a1 , R 2a2 , and R 2a3 independently represent halogen, -CN, -NH 2 , -NHR a , -NR a R b , -OH, -OR c , -P(=O)R d R e , -SH, -SR f , -S(=O)R f , -S(=O) 2 R f , -S(=O)(=NR g )R f , -N=S(=O)R f R h , -C(=O)NH 2 , -C(=O)NHR a , -C(=O)NR a R b , -C(=O)OH, -C(=O)OR c , -NH-C(=O)-R i , Hetar 2a , and Hetcyc 2a ; R a , R b ... independently represent straight-chain or branched C 1-6 -alkyl, Ar a , Hetar a , Hetcyc a ; or R a and R b form a saturated, partially unsaturated, or aromatic heterocycle having 3, 4, 5, 6, or 7 ring atoms together with the nitrogen atom to which they are attached (one of the ring atoms is the nitrogen atom, and zero or one more ring atom is a heteroatom selected from N, O, or S, and the remainder is a carbon atom), wherein the heterocycle is unsubstituted or independently substituted with R B6 , R B7 , R B8 , R B9 , R B10 , and/or R B11 ; R c represents a straight-chain or branched C1-4 -alkyl, C2-4 -alkenyl, or C2-4 -alkynyl (each of which is unsubstituted or substituted with -OH); C3-7 -cycloalkyl (which is unsubstituted or substituted with -OH and/or halogens); R d and R e independently represent straight-chain or branched C 1-6 -alkyl groups; R f and R h independently represent straight-chain or branched C 1-6 -alkyl groups; R g represents H, a straight-chain or branched C 1-6 -alkyl group; Ri represents H, a straight-chain or branched C 1-6 -alkyl group; RB1 , RB2 , RB3 , RB4 , and RB5 independently represent halogens; -OH; -OC 1-4 -alkyl; C 1-4 -alkyl (which are unsubstituted or substituted with 1, 2, or 3 halogens); R B6 , R B7 , R B8 , R B9 , R B10 , R B11 independently represent halogens; OH; -OC 1-4 -alkyl; C 1-4 -alkyl (which are unsubstituted or substituted with 1 or 2 OH and/or 1, 2, or 3 halogens); and/or Two of R B6 , R B7 , R B8 , R B9 , R B10 , and R B11 attached to the same carbon atom of the above carbocycle or the above heterocycle form a dioxo (=O) group; and/or Two of R B6 , R B7 , R B8 , R B9 , R B10 , and R B11 attached to the same sulfur (S) atom of the above heterocycle form a divalent oxo (=O) group, and simultaneously, two more of R B6 , R B7 , R B8 , R B9 , R B10 , and R B11 attached to the same sulfur atom form a divalent oxo group or a divalent =NH or =NC 1-4 -alkyl group, thereby forming an -S(=O) 2 , -S(=O)(=NH), or -S(=O)(=NC 1-4 -alkyl) moiety; RC1 , RC2 , and RC3 independently represent halogens; C1-4 -alkyl or -OC1-4 -alkyl (each of which is unsubstituted or substituted with 1, 2, or 3 halogens); R C6 , R C7 , R C8 , R C9 , R C10 , and/or R C11 represent halogens independently; C 1-4 -alkyl (which is unsubstituted or independently substituted with 1, 2, or 3 substituents selected from halogens); -OC 1-4 -alkyl (which is unsubstituted or independently substituted with 1, 2, or 3 substituents selected from halogens); Halogens represent F, Cl, Br, and I; or any N-oxide, solvate, tautomeric or stereoisomer thereof and/or any pharmaceutically acceptable salt of each of the above (including mixtures of all ratios thereof).
  3. In Article 1 or Article 2, X 1 represents N or CR X1 ; R X1 represents H A compound, or any N-oxide, solvate, tautomeric or stereoisomer thereof and/or any pharmaceutically acceptable salt of each of the above (including mixtures of all ratios thereof).
  4. In any one of paragraphs 1 to 3, X 1 represents CH A compound, or any N-oxide, solvate, tautomeric or stereoisomer thereof and/or any pharmaceutically acceptable salt of each of the above (including mixtures of all ratios thereof).
  5. In any one of paragraphs 1 to 4, R1 represents Cl, -CN, or -CF3 ; R3 represents H A compound, or any N-oxide, solvate, tautomeric or stereoisomer thereof and/or any pharmaceutically acceptable salt of each of the above (including mixtures of all ratios thereof).
  6. In any one of paragraphs 1 to 5, R1 represents Cl or -CF3 ; R3 represents H A compound, or any N-oxide, solvate, tautomeric or stereoisomer thereof and/or any pharmaceutically acceptable salt of each of the above (including mixtures of all ratios thereof).
  7. In any one of paragraphs 1 to 4, R1 represents -CH3 ; R3 represents F or -CN A compound, or any N-oxide, solvate, tautomeric or stereoisomer thereof and/or any pharmaceutically acceptable salt of each of the above (including mixtures of all ratios thereof).
  8. In any one of paragraphs 1 to 7, R₂ represents H, Alk₂ , Cyc₂, Hetar₂ , Hetcyc₂ , -L₂ -Ar₂a , -S ( =O) ₂Rf A compound, or any N-oxide, solvate, tautomeric or stereoisomer thereof and/or any pharmaceutically acceptable salt of each of the above (including mixtures of all ratios thereof).
  9. In any one of paragraphs 1 through 8, R₂ represents H, Alk₂ , Cyc₂, Hetar₂ , Hetcyc₂ , -L₂ -Ar₂a , -S ( =O) ₂Rf ; Alk 2 represents a straight-chain or branched C 1-6 -alkyl, C 1-6 -alkenyl, or C 2-6 -alkynyl (each of which is unsubstituted or independently substituted with R 2a1 , R 2a2 , and/or R 2a3 ); Cyc a , Cyc 2 , and Cyc 2a independently represent saturated monocyclic carbocycles having 3, 4, 5, 6, or 7 ring carbon atoms, wherein the carbocycles are unsubstituted or independently substituted with R B6 and/or R B7 ; Hetcyc a , Hetcyc 2 , and Hetcyc 2a independently represent saturated or partially unsaturated monocyclic heterocycles having 3, 4, 5, or 6 ring atoms (1 or 2 of the ring atoms are heteroatom(s) selected from N, O, and/or S, and the remainder are carbon atoms), wherein the heterocycles are unsubstituted or independently substituted with R B6 and/or R B7 and/or R B8 and R B9 together or R B6 and/or R B7 and/or R B8 and R B9 and R B10 and R B11 together; L 2 represents -S(=O) 2 - gi; Ar a and Ar 2a independently represent phenyl (which is unsubstituted or independently substituted with RB1 and/or RB2 ); Hetar a , Hetar 2 , and Hetar 2a represent a monocyclic heteroaryl having 5 or 6 ring atoms (1, 2, or 3 of the ring atoms are heteroatom(s) selected from N, O, and/or S, and the remainder are carbon atoms), wherein the heteroaryls are unsubstituted or independently substituted with R B1 and/or R B2 ; R 2a1 , R 2a2 , and R 2a3 independently represent halogen, -CF 3 , -CN, -NH 2 , -NHR a , -NR a R b , -OH, -OR c , -P(=O)R d R e , -SR f , -S(=O) 2 R f , -S(=O)(=NR g )R f , -N=S(=O)R f R h , -C(=O)NH 2 , -C(=O)NHR a , -C(=O)NR a R b , -C(=O)OH, -C(=O)OR c , -NH-C(=O)-R i , Cyc 2a , Hetar 2a , and Hetcyc 2a ; and/or Among R2a1 , R2a2 , and R2a3 attached to the same carbon atom, two together form a dioxo (=O) group; R a , R b ...independently represent straight-chain or branched C 1-6 -alkyl (which are unsubstituted or substituted with 1, 2, or 3 halogens); Ar a , Cyc a , Hetar a , Hetcyc a ; or R a and R b form a saturated or partially unsaturated heterocycle having 3, 4, 5, 6, or 7 ring atoms together with the nitrogen atom to which they are attached (one of the ring atoms is the nitrogen atom, and zero or one more ring atom is a heteroatom selected from N, O, or S, and the remainder are carbon atoms), wherein the heterocycle is unsubstituted or independently substituted with R B6 and/or R B7 and/or R B8 and R B9 together; R c represents a straight-chain or branched C1-4 -alkyl (which is unsubstituted or substituted with -OH); a straight-chain and unsubstituted C2-4 -alkynyl; and a C3-5 -cycloalkyl; R d , R e They independently represent straight-chain or branched C 1-6 -alkyl groups; R f , R h They independently represent straight-chain or branched C 1-6 -alkyl groups; R g represents H, a straight-chain or branched C 1-6 -alkyl group; Ri represents H, a straight-chain or branched C 1-6 -alkyl group; RB1 and RB2 independently represent halogens; C1-4 -alkyl (which is unsubstituted or substituted with 1, 2, or 3 halogens); and OH; R B6 and R B7 independently represent halogens; OH; -OC 1-4 -alkyl; C 1-4 -alkyl (which are unsubstituted or substituted with 1 OH or 1, 2, or 3 halogens); R B8 and R B9 attached to the same carbon atom of the above heterocycle form a divalent oxo (=O) group; or RB8 , RB9 , RB10 , and RB11 attached to the same sulfur (S) atom of the above heterocycle form a divalent oxo (=O) group, thereby forming an -S(=O) 2 moiety. A compound, or any N-oxide, solvate, tautomeric or stereoisomer thereof and/or any pharmaceutically acceptable salt of each of the above (including mixtures of all ratios thereof).
  10. In any one of paragraphs 1 through 9, R₂ represents H, Alk₂ , Cyc₂, Hetar₂ , Hetcyc₂ , -L₂ -Ar₂a , -S ( =O) ₂Rf ; Alk 2 represents a straight-chain or branched C 1-4 -alkyl, C 1-4 -alkenyl, or C 2-4 -alkynyl (each of which is unsubstituted or independently substituted with R 2a1 and/or R 2a2 ); Cyc 2 and Cyc 2a independently represent saturated monocyclic carbocycles having 3, 4, or 5 cyclic carbon atoms, wherein the carbocycles are monosubstituted with OH, -CH 2 OH; Hetcyc 2 represents a saturated monocyclic heterocycle having 5 ring atoms (one of the ring atoms is a heteroatom(s) selected from N and O and the remainder is a carbon atom, wherein the heterocycle is monosubstituted with OH), or represents a saturated monocyclic heterocycle having 4 ring atoms (one of the ring atoms is a heteroatom(s) selected from S and the remainder is a carbon atom, wherein the heterocycle is substituted with two oxo (=O) groups at the S atom); Hetcyc 2a represents a saturated monocyclic heterocycle having four ring atoms (one of the ring atoms is a heteroatom(s) selected from N or O and the remainder are carbon atoms, wherein the heterocycle is unsubstituted or monosubstituted with a halogen, -OH, -OC 1-4 -alkyl or C 1-4 -alkyl, or disubstituted with a halogen and a C 1-4 -alkyl, wherein the C 1-4 -alkyl may be unsubstituted or monosubstituted with -OH or -OC 1-4 -alkyl in each case); or represents a saturated monocyclic heterocycle having 5 ring atoms (wherein one of the ring atoms is a heteroatom selected from N or O, or two of the ring atoms are heteroatoms selected from N and/or O and the remainder is a carbon atom, wherein the heterocycle is unsubstituted, monosubstituted with -OH, C1-4 -alkyl or oxo (=O) groups, or disubstituted with C1-4 -alkyl and oxo (=O) groups); or represents a saturated monocyclic heterocycle having 6 ring atoms (wherein one of the ring atoms is a heteroatom selected from N or O, or two of the ring atoms are heteroatoms selected from N and/or O and the remainder is a carbon atom, wherein the heterocycle is unsubstituted, monosubstituted with OH, C1-4 -alkyl or oxo (=O) groups, or disubstituted with a halogen); or represents a partially unsaturated monocyclic heterocycle having six ring atoms (one of the ring atoms is a heteroatom selected from N and the rest are carbon atoms, wherein the heterocycle is monosubstituted with oxo (=O) groups); L 2 represents -S(=O) 2 - gi; Ar 2a represents a phenyl group monosubstituted with -CH 3 ; Hetar 2 and Hetar 2a independently represent a monocyclic heteroaryl having 5 or 6 ring atoms (1, 2, or 3 of the ring atoms are heteroatom(s) selected from N, O, and/or S, and the remainder are carbon atoms), wherein the heteroaryl is unsubstituted or monosubstituted with C 1-4 -alkyl; R 2a1 and R 2a2 independently represent -CF 3 , -CN, -NH 2 , -NHR a , -NR a R b , -OH, -OR c , -P(=O)R d R e , -SR f , -S(=O) 2 R f , -S(=O)(=NR g )R f , -C(=O)NH 2 , -C(=O)NHR a , -C(=O)NR a R b , -C(=O)OR c , -NH-C(=O)-R i , Cyc 2a , Hetar 2a , and Hetcyc 2a ; and/or R2a1 and R2a2 attached to the same carbon atom form a divalent oxo (=O) group together; R a , R b ...independently represent straight-chain or branched C1-4 -alkyl (which are unsubstituted or substituted with 1, 2, or 3 F groups); Ar a , Hetar a or R a and R b form a saturated heterocycle having 4, 5, or 6 ring atoms together with the nitrogen atom to which they are attached (one of the ring atoms is the nitrogen atom, 0 or 1 more ring atoms are heteroatoms selected from N or O, and the remainder are carbon atoms), wherein the heterocycle is unsubstituted, monosubstituted with C 1-4 -alkyl, or disubstituted with F; R c represents a straight-chain or branched C1-4 -alkyl (which is unsubstituted or substituted with -OH); an unsubstituted C2-4 -alkynyl; an unsubstituted C3-5 -cycloalkyl; R d , R e They independently represent straight-chain or branched C 1-4 -alkyl groups; R f represents a straight-chain or branched C 1-4 -alkyl group; R g represents H; Ri represents H, a straight-chain or branched C 1-4 -alkyl group; Ar a represents a phenyl group; Hetar a represents pyridyl A compound, or any N-oxide, solvate, tautomeric or stereoisomer thereof and/or any pharmaceutically acceptable salt of each of the above (including mixtures of all ratios thereof).
  11. In any one of Articles 1 to 10, R 2 is H; -CH 3 , -CH=CH-CF 3 , -C≡C-CH 2 -OH, -CH 2 -CN, -(CH 2 ) 2 -CN, -(CH 2 ) 3 -CN, -CH 2 -CH(OH)-CH 2 -CN, -(CH 2 ) 2 -NH 2 , -(CH 2 ) 2 -NHCH 3 , -(CH 2 ) 2 -NHCH 2 CF 3 , -(CH 2 ) 2 -NH-pyridin-2-yl, -(CH 2 ) 2 -N(CH 3 ) 2 , -(CH 2 ) 2 -N(CF 3 ) 2 , -CH 2 -CF 2 -CH 2 -NH 2 , -CH(CF 3 )-CH 2 -N(CH 3 ) 2 , 2-(azetidine-1-yl)ethyl, 2-(pyrrolidin-1-yl)ethyl, 2-(piperidin-1-yl)ethyl, 2-(4,4-difluoropiperidin-1-yl)ethyl, (N-methylmorpholine-3-yl)methyl, 2-(morpholine-1-yl)ethyl, 2-(4-methylpiperazine- 1- yl)ethyl, -( CH₂ ) ₃ - NH₂ , -( CH₂ ) ₃ - NHCH₃ , -( CH₂ ) ₃ - N(CH₃)₂ , - ( CH₂ ) ₄ - NHCH₃ , -( CH₂ ) ₄ -N( CH₃ ) ₂ , -( CH₂ ) ₂ -OH, -( CH₂ ) ₂ -O-(CH 2 ) 2 -OH, -(CH 2 ) 3 -OH, -CH 2 CH(OH)-CH 3 , -CH(CH 3 )CH 2 -OH, , -CH 2 -C(CH 3 ) 2 -OH, -CH(CH 2 OH) 2 , -CH 2 CH(CH 2 OH) 2 , -CH 2 -CH(OH)-CH 2 OH, -CH 2 -CH(OH)-CH 2 -OCH 3 , , -CH( CH2OCH3 ) 2 , -( CH2 ) 2 -O- CH2 -C≡CH, 2-hydroxy-1-(pyrazine-2-yl ) ethyl, -( CH2 ) 2 -S- CH3 , -( CH2 ) 2 -S - CH2CH3 , -( CH2 ) 2 -S(=O) 2 - CH3 , -( CH2 ) 2 -S(=O)(=NH) CH3 , -( CH2 ) 2 -S(=O)(=NH) CH2CH3 , -CH2 -P(=O)( CH3 ) 2 , -CH2 - C(=O) -NH2 , -CH2 -C(=O) -NHCH3 , -CH2 -C( = O) -NHCH2CH 3 , -CH2 -C(=O)-N( CH3 ) 2 , -CH2 -C(=O)-NH-phenyl, -( CH2 ) 2 -C(=O) -NH2 , -( CH2 ) 2 - C (=O)-NHCH3, -( CH2 ) 2 -C(=O)-N( CH3 ) 2 , -CH ( C(=O)OCH2CH3) 2 , -( CH2 ) 2 -NH- C (=O)-CH3, -C(=O) -CH3 , -C(=O)-( CH2 ) 2 - CH3 ; (1-hydroxycyclobutyl)methyl ( ), (1H-imidazole-2-yl)methyl, (1H-imidazole-4-yl)methyl, (1-methyl-1H-imidazole-4-yl)methyl, (1-methyl-1H-imidazole-5-yl)methyl, (1H-2-methylimidazole-4-yl)methyl, (1H-pyrazol-4-yl)methyl, (1H-pyrazol-5-yl)methyl, (1-methyl-1H-pyrazol-4-yl)methyl, 1,2-thiazole-3-yl, 1,3-thiazole-2-yl, (1H-1,2,3-triazole-4-yl)methyl, pyrazine-2-yl, (1,2,4-oxadiazole-3-yl)methyl, 2-(2-oxopyridine-1-yl)ethyl, (3-fluoroazetidine-3-yl)methyl, (1-methylazetidine-3-yl)methyl, (oxetane-3-yl)methyl, (3-fluorooxetane-3-yl)methyl ( ), (3-hydroxyoxetane-3-yl)methyl ( ), (3-methoxyoxetane-3-yl)methyl ( ), methyl(oxetane-3-yl)methanol ( ), (1-methylazetidin-3-yl)ethyl, 2-(oxetane-3-yl)ethyl, 1,1-dioxo-1-lambda-6-tiethane-3-yl ( ), (5-oxo-pyrrolidine-2-yl)methyl ( ), (5-oxo-pyrrolidine-3-yl)methyl ( ), oxolan-3-ylmethyl ( ), (3-hydroxyoxolan-3-yl)methyl ( ), (2-oxo-1,3-oxazolidin-4-yl)methyl ( ), (2-oxo-1,3-oxazolidin-5-yl)methyl ( ), (4-methyl-2-oxo-1,3-oxazolidin-4-yl)methyl ( ), (4-hydroxyoxane-4-yl)methyl ( ), 2-(4-hydroxyoxane-4-yl)ethyl ( ); 1-hydroxymethylcyclopropyl, 3-hydroxycyclobutyl, 2-hydroxycyclopentyl; ; Representing sulfonyl-4-methylphenyl A compound, or any N-oxide, solvate, tautomeric or stereoisomer thereof and/or any pharmaceutically acceptable salt of each of the above (including mixtures of all ratios thereof).
  12. In any one of paragraphs 1 to 11, R₂ is H; -CH₃ , -CH=CH- CF₃ , -CH₂ -CN, -( CH₂ ) ₂ -CN, -( CH₂ ) ₃ -CN, -CH₂ -CH(OH)-CH₂ - CN, -( CH₂ ) ₂ -N( CH₃ ) ₂ , -CH₂ -CF₃ - CH₂ - NH₂ , -CH ( CF₃ )-CH₂- N ( CH₃ ) ₂ , (N-methylmorpholine-3-yl)methyl, 2-(morpholine-1-yl)ethyl, 2-(4-methylpiperazine-1-yl)ethyl, -( CH₂ ) ₂ -OH, -( CH₂ ) ₂ -O-( CH₂ ) ₂ -OH, -( CH₂ ) ₃ -OH, -CH( CH₃ ) CH₂- OH, , -CH 2 -C(CH 3 ) 2 -OH, -CH(CH 2 OH) 2 , -CH 2 CH(CH 2 OH) 2 , -CH 2 -CH(OH)-CH 2 -OCH 3 , , -(CH 2 ) 2 -O-CH 2 -C≡CH, 2-hydroxy-1-(pyrazine-2-yl)ethyl, -(CH 2 ) 2 -S-CH 3 , -(CH 2 ) 2 -S-CH 2 CH 3 , -(CH 2 ) 2 -S(=O) 2 -CH 3 , -(CH 2 ) 2 -S (=O)(=NH)CH 3 , -CH 2 -C(=O)-NHCH 2 CH 3 , -(CH 2 ) 2 -C(=O)-NH 2 , -(CH 2 ) 2 -C(=O)-NHCH 3 , -CH(C(=O)OCH 2 CH 3 ) 2 , (1-hydroxycyclobutyl)methyl ( ), -(CH 2 ) 2 -NH-C(=O)-CH 3 ; (1H-imidazole-2-yl)methyl, (1H-imidazole-4-yl)methyl, (1-methyl-1H-imidazole-4-yl)methyl, (1-methyl-1H-imidazole-5-yl)methyl, (1H-2-methylimidazole-4-yl)methyl, (1H-pyrazol-4-yl)methyl, (1H-pyrazol-5-yl)methyl, (1-methyl-1H-pyrazol-4-yl)methyl, 1,2-thiazole-3-yl, 1,3-thiazole-2-yl, (1H-1,2,3-triazole-4-yl)methyl, pyrazine-2-yl, 2-(2-oxopyridine-1-yl)ethyl, (1,2,4-oxadiazole-3-yl)methyl, (oxetane-3-yl)methyl, (3-fluorooxetane-3-yl)methyl ( ), (3-hydroxyoxetane-3-yl)methyl ( ), (3-methoxyoxetane-3-yl)methyl ( ), methyl(oxetane-3-yl)methanol ( ), 2-(oxetane-3-yl)ethyl, 1,1-dioxo-1-lambda-6-tiethane-3-yl ( ), (5-oxo-pyrrolidin-2-yl)methyl, (5-oxo-pyrrolidin-3-yl)methyl, oxolan-3-ylmethyl, (3-hydroxyoxolan-3-yl)methyl, (2-oxo-1,3-oxazolidin-4-yl)methyl, (2-oxo-1,3-oxazolidin-5-yl)methyl, (4-methyl-2-oxo-1,3-oxazolidin-4-yl)methyl, (4-hydroxyoxane-4-yl)methyl, 2-(4-hydroxyoxane-4-yl)ethyl; 3-hydroxycyclobutyl; representing A compound, or any N-oxide, solvate, tautomeric or stereoisomer thereof and/or any pharmaceutically acceptable salt of each of the above (including mixtures of all ratios thereof).
  13. In any one of paragraphs 1 to 12, A is Represents, Here Eun Sik I Indicates the attachment site of ring A to the bicyclic ring system of the compound, represents the attachment site for the L1 -B radical of the compound of Formula I A compound, or any N-oxide, solvate, tautomeric or stereoisomer thereof and/or any pharmaceutically acceptable salt of each of the above (including mixtures of all ratios thereof).
  14. In any one of paragraphs 1 to 13, A is representing A compound, or any N-oxide, solvate, tautomeric or stereoisomer thereof and/or any pharmaceutically acceptable salt of each of the above (including mixtures of all ratios thereof).
  15. In any one of paragraphs 1 to 14, A is representing A compound, or any N-oxide, solvate, tautomeric or stereoisomer thereof and/or any pharmaceutically acceptable salt of each of the above (including mixtures of all ratios thereof).
  16. In any one of paragraphs 1 to 15, B represents Ar 1 , Hetar 1 , Cyc 1 , and Hetcyc 1 ; L 1 represents -O-, -S-, -N(R 4 )-, -O-CH 2 -, -O-CH(R 5 )-, -N(R 6 )-CH 2 -, -N(R 6 )-C(=O)-, -CH 2 -, -CH 2 CH 2 - and; R 4 represents H or CH 3 ; R 5 , R 6 It represents CH3 ; Ar 1 represents a phenyl group, where the phenyl is monosubstituted with R C1 ; Hetar 1 represents a mono-cyclic heteroaryl having 5 or 6 ring atoms (1 or 2 of the ring atoms are heteroatom(s) selected from N, O and/or S, and the remainder are carbon atoms), wherein the heteroaryl is monosubstituted with RC1 or disubstituted with RC1 and RC2 ; Cyc 1 represents a saturated, mono- or bi-cyclic carbocycle having 4, 5, 6, or 7 cyclic carbon atoms, wherein the carbocycle may be unsubstituted, monosubstituted with R C6 , or disubstituted with R C6 and R C7 ; Hetcyc 1 represents a saturated, mono- or bicyclic heterocycle having 5, 6, or 7 ring atoms (1 or 2 of the ring atoms are heteroatom(s) selected from N, O, and/or S, and the remainder are carbon atoms), wherein the heterocycle is monosubstituted with R C6 or disubstituted with R C6 and R C7 ; RG1 represents F , Cl, CHF2 , CF3 , CH2CF3 , OCF3 , or SCF3 ; RC2 represents CH3 or C2H5 ; R C6 represents F, Cl; CH₃ , CHF₂ , CF₃ , -OCH₃ , -OCHF₂ , -OCF₃ ; R C7 represents F A compound, or any N-oxide, solvate, tautomeric or stereoisomer thereof and/or any pharmaceutically acceptable salt of each of the above (including mixtures of all ratios thereof).
  17. In any one of paragraphs 1 to 16, L1 represents -O-, -NH-, or -O- CH2- A compound, or any N-oxide, solvate, tautomeric or stereoisomer thereof and/or any pharmaceutically acceptable salt of each of the above (including mixtures of all ratios thereof).
  18. In any one of paragraphs 1 through 17, B is representing A compound, or any N-oxide, solvate, tautomeric or stereoisomer thereof and/or any pharmaceutically acceptable salt of each of the above (including mixtures of all ratios thereof).
  19. In any one of paragraphs 1 through 18, L 1 represents -O- and; B is representing A compound, or any N-oxide, solvate, tautomeric or stereoisomer thereof and/or any pharmaceutically acceptable salt of each of the above (including mixtures of all ratios thereof).
  20. In any one of paragraphs 1 through 19, L 1 represents -O- and; B is representing A compound, or any N-oxide, solvate, tautomeric or stereoisomer thereof and/or any pharmaceutically acceptable salt of each of the above (including mixtures of all ratios thereof).

Description

Substituted bicyclic heterocyclic YAP-TEAD and/or TAZ-TEAD inhibitors The present invention relates to a biocyclic compound. This biocyclic compound is useful as a TEAD binder and/or as an inhibitor of YAP-TEAD and TAZ-TEAD protein-protein interactions or binding, and for the prevention and/or treatment of cancer and other severe disorders and diseases. Recently, the Hippo pathway has become a subject of interest for the treatment of hyperproliferative disorders and diseases, particularly cancer (S. A. Smith et al., J. Med. Chem. 2019, 62, 1291-1305; K. C. Lin et al., Annu. Rev. Cancer Biol. 2018, 2: 59-79; C.-L. Kim et al., Cells (2019), 8, 468; K. F. Harvey et al., Nature Reviews Cancer, Vol. 13, 246-257 (2013)). The Hippo pathway regulates cell growth, proliferation, and migration. In mammals, the Hippo pathway acts as a tumor suppressor, and dysfunction of Hippo signaling is presumed to be frequently observed in human cancers. Furthermore, since the Hippo pathway plays a role in various biological processes, such as the self-renewal and differentiation of stem and progenitor cells, wound healing and tissue regeneration, and interactions with other signaling pathways like Wnt, its dysfunction can also play a role in human diseases other than cancer (C.-L. Kim et al., Cells (2019), 8, 468; Y. Xiao et al., Genes & Development (2019) 33: 1491-1505; K. F. Harvey et al., Nature Reviews Cancer, Vol. 13, 246-257 (2013)). While various aspects of pathway activation and regulation remain subjects of further research, it is already established that in its "switch-on" state, the Hippo pathway involves a series of kinases (including Mst 1/2 and Lats 1/2) that result in the phosphorylation of two transcriptional co-activators in the cytoplasm: YAP (Yes-associated protein) and TAZ (a transcriptional co-activator with a PDZ binding motif). Phosphorylation of YAP/TAZ leads to their sequestration from the cytoplasm and ultimately their degradation. Conversely, when the Hippo pathway is "switch-off" or dysfunctional, non-phosphorylated, activated YAP/TAZ co-activators are translocated into the cell nucleus. Their primary target transcription factors are four proteins of the Transcription Enhancement-Associated Domain (TEAD) transcription factor family (TEAD1-4). The binding and activation of YAP or TAZ to TEAD (or other transcription factors) has been shown to induce the expression of numerous genes mediating cell survival and proliferation. Therefore, while activated, non-phosphorylated YAP and TAZ can act as oncogenes, the activated, switch-on Hippo pathway can act as a tumor suppressor by inactivating, i.e., phosphorylating, YAP and TAZ. In addition, the Hippo pathway may also play a role in the resistance mechanisms of cancer cells to oncological and immuno-oncological therapies (R. Reggiani et al., BBA - Reviews on Cancer 1873 (2020) 188341, 1-11). Recently, small molecule inhibitors have been described as pan-TEAD inhibitors, that is, compounds that block YAP/TAZ binding by binding not only to one member of the TEAD family but also to one or more, specifically all four human TEAD paralogs (T.J. Hagenbeek, et al., Nature Cancer, 4, 812-828 (2023); WO 2021/108483 A1). Consequently, dysfunction or abnormal regulation of the Hippo pathway as a tumor suppressor is considered to be a significant event in the development of a wide variety of cancer types and diseases. Examples and experimental sections The compounds of the present invention can be prepared using suitable materials according to the procedures of the schematic diagram and examples below, and are further illustrated by the specific examples below. The compounds are presented in Table 1 and Table 1A. Analytical data of the compounds prepared according to the examples below are also shown in Table 1 and Table 1A. The present invention will be described with reference to specific embodiments described in the following examples, but is not limited thereto. Unless otherwise indicated in the schematic diagrams, variables have the same meaning as those described above and in the claims. Unless otherwise specified, all starting materials are obtained from commercial sources and used without further purification, or are available by synthesis methods similar to those specifically described herein. Unless otherwise specified, all temperatures are expressed in °C, and all reactions are carried out at room temperature (RT). Compounds are purified by silica chromatography or preparative HPLC. The purity of reaction products (intermediates) used in subsequent reaction steps was generally confirmed by GC-MS (without further characterization of intermediates). 1H NMR: 1H -NMR data are provided in Table 1 and Table 1A below. Unless otherwise reported, 1H NMR spectra were acquired under standard conditions on 300 MHz, 400 MHz, 500 MHz, or 700 MHz NMR spectrometers, e.g., Bruker Avance DRX 500, Bruker Avance 400, Bruker DPX 300, or Bruker Avance III 700 MHz NMR spectrometers, u