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JP-7855570-B2 - Triring heterocycle

JP7855570B2JP 7855570 B2JP7855570 B2JP 7855570B2JP-7855570-B2

Inventors

  • ヘインリッヒ，ティモ
  • シュレーシガー，サラー
  • グネラ，ヤークップ
  • ケッツナー，リサ
  • カルスウェル，エマ
  • ブルム，アンドレアス

Assignees

  • メルク パテント ゲゼルシャフト ミット ベシュレンクテル ハフツング
  • キャンサー リサーチ テクノロジー リミテッド

Dates

Publication Date
20260508
Application Date
20210720
Priority Date
20200723

Claims (14)

  1. Equation I During the ceremony W1 represents CR W1 ; W2 represents CR W2 ; W 3 represents CR W3 ; W 4 represents CR W4 ; R W1 represents H, C 1-6 - aliphatic, halogen; R W2 represents H, C 1-6 - aliphatic; halogen; R W3 represents H, C 1-6 -aliphatic, -OC 1-6 -aliphatic, halogen, -CN, -CH 2 -Ar W , or -CH 2 -CH 2 -Ar W ; R W4 represents H, C 1-6 - aliphatic, halogen; Z 1 is CH; The Z2 is the CR Z2 ; R 1 is, or Represents; R 2 represents -C (=O) - OR 2a ; Ar W represents a phenyl that is either unsubstituted or independently mono- or di-substituted with RW11 and/or RW12 ; R Z2 represents H; R 2a represents H, unsubstituted or substituted C 1-8 -aliphatic, aryl, heteroaryl, saturated or partially unsaturated heterocyclyl, or Cat; Cat represents a monovalent cation; R W11 and R W12 independently represent halogens, or unsubstituted or substituted C1-6 aliphatic elements; Halogens are F, Cl, Br, and I; Compounds represented by , or any N-oxide, solvate, tautomer, or stereoisomer thereof, and/or pharmaceutically acceptable salts thereof, as well as mixtures thereof in any proportion.
  2. In the formula, at least one of R W1 , R W2 , R W3 , and R W4 is not H at the same time. A compound according to claim 1, or an N-oxide, solvate, tautomer, or stereoisomer thereof, and/or a pharmaceutically acceptable salt thereof, as well as mixtures thereof in any proportion.
  3. In the formula (a) W1 represents CR W1 ; W2 represents CR W2 ; W 3 represents CR W3 ; W 4 represents CR W4 ; R W1 represents H; R W2 represents H; R W3 represents C 1-6 -aliphatic, -OC 1-6 -aliphatic, halogen, -CN, -CH 2 -Ar W , or -CH 2 -CH 2 -Ar W ; R W4 represents H; Ar W represents a phenyl compound that may be unsubstituted or monosubstituted with R W11 ; R W11 represents a halogen; or (b) W1 represents CR W1 ; W2 represents CR W2 ; W 3 represents CR W3 ; W 4 represents CR W4 ; R W1 represents H; R W2 represents C 1-6 - aliphatic; R W3 represents H; R W4 represents H; or (c) W1 represents CR W1 ; W2 represents CR W2 ; W 3 represents CR W3 ; W 4 represents CR W4 ; R W1 represents H; R W2 represents H; R W3 represents H; R W4 represents C 1-6 - aliphatic; or (i) W1 represents CR W1 ; W2 represents CR W2 ; W 3 represents CR W3 ; W 4 represents CR W4 ; R W1 represents H; R W2 represents C 1-6 - aliphatic; R W3 represents C 1-6 - aliphatic; R W4 represents H. A compound according to any one of claims 1 to 2, or an N-oxide, solvate, tautomer, or stereoisomer thereof, and/or a pharmaceutically acceptable salt thereof, as well as mixtures thereof in any proportion.
  4. In the formula (a) W1 represents CH; W 2 represents CH; W 3 represents CR W3 ; W 4 represents CH; A compound according to any one of claims 1 to 3, wherein R W3 represents methyl, ethyl, 2 -propyl, trifluoromethyl, methoxy, trifluoromethoxy, F, -CN, -CH2 -phenyl, -CH2-(2-fluorophenyl), -CH2- (3-fluorophenyl), -CH2- (4-fluorophenyl), or an N-oxide, solvate, tautomer, or stereoisomer thereof, and/or a pharmaceutically acceptable salt thereof, as well as mixtures thereof in any ratio.
  5. During the ceremony R 2 represents -C (=O) - OR 2a ; R 2a represents H, a linear or branched, unsubstituted or substituted C 1-4 alkyl group, or Cat; Cat represents a monovalent cation selected from the group consisting of lithium (Li), sodium (Na), and potassium (K); A compound according to any one of claims 1 to 4, or an N-oxide, solvate, tautomer, or stereoisomer thereof, and/or a pharmaceutically acceptable salt thereof, as well as mixtures thereof in any proportion.
  6. During the ceremony R 2a represents H, methyl, ethyl, or Cat; Cat represents a monovalent cation, which is sodium. The compounds described in claim 5, or any of them, including N-oxides, solvates, tautomers, or stereoisomers thereof, and/or pharmaceutically acceptable salts thereof, as well as mixtures thereof in any proportion.
  7. In the formula (a) W1 represents CH; W 2 represents CH; W 3 represents CR W3 ; W 4 represents CH; R W3 represents methyl, 2-propyl, trifluoromethyl, methoxy, trifluoromethoxy, F, -CN, -CH2 -phenyl, -CH2- (2-fluorophenyl), -CH2- (3-fluorophenyl), and -CH2- (4-fluorophenyl); Furthermore, here Z1 is CH; Z 2 is CH R 1 represents 4-trifluoromethylphenyl or 4-trifluoromethoxyphenyl; and R 2 represents -C(=O)-OH, -C(=O)-ONa, or -C(=O)-OCH 3 . A compound according to any one of claims 1 to 6, or an N-oxide, solvate, tautomer, or stereoisomer thereof, and/or a pharmaceutically acceptable salt thereof, as well as mixtures thereof in any proportion.
  8. Table 1 Compounds selected from the group consisting of the compounds , or N-oxides, solvates, tautomers, or stereoisomers thereof, and/or pharmaceutically acceptable salts of each thereof, as well as mixtures thereof in any proportion .
  9. A pharmaceutical composition comprising any one of the compounds described in claims 1 to 8, or an N-oxide, solvate, tautomer, or stereoisomer thereof, and/or a pharmaceutically acceptable salt thereof , or a mixture thereof in any ratio.
  10. A pharmaceutical composition comprising any of the compounds described in any one of claims 1 to 8, or an N-oxide, solvate, tautomer, or stereoisomer thereof, and/or a pharmaceutically acceptable salt thereof, or a mixture thereof in any ratio, for use in the prevention and/or treatment of a medical condition or disease selected from the group consisting of cancer, cardiovascular disease, and fibrosis.
  11. The pharmaceutical composition according to claim 10, wherein the medical condition or disease is selected from the group consisting of tumors (including solid tumors), breast cancer, lung cancer, liver cancer, ovarian cancer, squamous cell carcinoma, kidney cancer, stomach cancer, medulloblastoma, colon cancer, pancreatic cancer, tumors, cardiovascular disease, fibrosis, and hepatic fibrosis.
  12. A pharmaceutical composition comprising, together with a pharmaceutically acceptable carrier, an active ingredient, at least one compound described in any one of claims 1 to 8, or an N-oxide, solvate, tautomer, or stereoisomer thereof, and/or a pharmaceutically acceptable salt thereof , or a mixture thereof in any ratio.
  13. Further comprising a second active ingredient, or any N-oxide, solvate, tautomer, or stereoisomer thereof, and/or pharmaceutically acceptable salts thereof , or mixtures thereof in any ratio, The pharmaceutical composition according to claim 12, wherein the second active ingredient is a compound represented by formula I as defined in any one of claims 1 to 8.
  14. A process for producing any of the compounds described in claims 1 to 8, or an N-oxide, solvate, tautomer, or stereoisomer thereof, and/or each of the above pharmaceutically acceptable salts, and mixtures thereof in any ratio, wherein the process is (a) Equation II-a (In the formula, Z1 , Z2 , Z3 , W1 , W2 , W3 , W4 , and R2 are defined in any one of claims 1 to 8 for compounds represented by formula I (wherein R2 is neither -C(=O)-OH nor -C(=O)-OCat).) A compound represented by; (a)(1) is Equation III R 1 - Hal III (wherein R1 is as defined in any one of claims 1 to 8 for the compound represented by formula I, and Hal represents Cl, Br, or I) The compound represented by [the symbol] can be reacted with a CN cross-coupling reaction under suitable reaction conditions; or (a)(2) First, under suitable reaction conditions in the CN cross-coupling reaction, formula IV It is converted to a tricyclic compound represented by formula III; and then, formula III R 1 - Hal III The compound represented by [the symbol] can be reacted with another CN cross-coupling reaction under suitable reaction conditions; If either of the following occurs, (a)(3) A compound represented by formula I as defined in any one of claims 1 to 8 is provided; and optionally (a)(4) In the compound represented by formula I, if R 2 is -C(=O)-OR 2a (where R 2a is unsubstituted or substituted C1-8 -aliphatic), then the compound represented by formula I is provided under conditions suitable for saponification to yield the compounds represented by formula I (where R 2 is -C(=O)-OH or -C(=O)-OCat); or, (b) Equation II-b (In the formula, Z1 , Z2 , Z3 , W1 , W2 , W3 , W4 , and R2 are defined in any one of claims 1 to 8 for compounds represented by formula I ( wherein R2 is neither -C(=O)-OH nor -C(=O)-OCat).) A compound represented by; (b)(1) is equation V R 1 -NH 2 V (In the formula, R1 is defined as in any one of claims 1 to 8 for the compound represented by formula I.) A compound represented by formula I, as defined in any one of claims 1 to 8, is provided by reacting a compound represented by formula I with a compound represented by formula I under suitable reaction conditions in a CN cross-coupling reaction; and optionally (b)(2) The process characterized in that, in the compound represented by formula I, if R 2 is -C(=O)-OR 2a (where R 2a is unsubstituted or substituted C1-8 -aliphatic), then the compound represented by formula I is provided under conditions suitable for a saponification reaction to provide the compounds represented by formula I (where R 2 is -C(=O)-OH or -C(=O)-OCat).

Description

Field of the Invention: The present invention relates to tricyclic heterocyclic compounds. These heterocyclic compounds are useful as TEAD binders and/or inhibitors of YAP-TEAD protein-protein interactions or binding, as well as for the prevention and/or treatment of several medical conditions, including hyperproliferative disorders and diseases, particularly cancer. Background of the Invention : In recent years, the Hippo pathway has become an interesting target for the treatment of hyperproliferative disorders and diseases, particularly cancer (SASmith et al., J.Med.Chem. 2019, 62, 1291-1305; KCLin et al., Annu.Rev.Cancer Biol. 2018, 2:59-79; C.-L.Kim et al., Cells (2019), 8, 468; KFHarvey et al., Nature Reviews Cancer, Vol.13, 246-257 (2013)). The Hippo pathway regulates cell growth, proliferation, and migration. In mammals, the Hippo pathway is thought to act as a tumor suppressor, and dysfunction of Hippo signaling is frequently observed in human cancers. Furthermore, the Hippo pathway plays a role in several biological processes, including the self-renewal and differentiation of stem cells and progenitor cells, wound healing and tissue regeneration, and interactions with other signaling pathways such as Wnt. Dysfunction of this pathway 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 several aspects of the pathway's activity and regulation still require further investigation, it is already established that in its "switched-on" state, the Hippo pathway involves a cascade of kinases (including Mst 1/2 and Lats 1/2) in the cytoplasm, leading to the phosphorylation of two transcriptional coactivators, YAP (Yes-related protein) and TAZ (a transcriptional coactivator with a PDZ-binding motif). Phosphorylation of YAP/TAZ sequesters them in the cytoplasm, ultimately leading to their degradation. In contrast, when the Hippo pathway is "switched-off" or dysfunctional, the unphosphorylated activated YAP/TAZ coactivators are translocated into the cell nucleus. The primary target transcription factors are four proteins from the Transcriptional Enhanced Associate Domain (TEAD) transcription factor family (TEAD1-4). The binding of YAP or TAZ to TEAD (or other transcription factors) and the activation of TEAD (or other transcription factors) have been shown to induce the expression of several genes (many of which mediate cell survival and proliferation). Therefore, activated non-phosphorylated YAP and TAZ can act as oncogenes, while the activated, switch-on Hippo pathway can act as a tumor suppressor by inactivating (i.e., phosphorylating) YAP and TAZ. Furthermore, the Hippo pathway may also play a role in the resistance mechanisms of cancer cells to oncology and immuno-oncology therapy (R. Reggiani et al., BBA - Reviews on Cancer 1873(2020)188341,1-11). As a result, dysfunction or abnormal modulation 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. Therefore, pharmacological intervention to inhibit YAP, TAZ, TEAD, and the YAP-TEAD or TAZ-TEAD protein-protein interactions appears to be a reasonable and valuable strategy for preventing and/or treating cancers and other hyperproliferative disorders and diseases associated with Hippo pathway dysfunction. Description of the present invention : The present invention provides compounds useful for the prevention and/or treatment of medical conditions, disorders and/or diseases, particularly hyperproliferative disorders or diseases, wherein the compounds are TEAD binders and/or inhibitors of YAP-TEAD or TAZ-TEAD protein-protein interactions. In one embodiment, the present invention is based on the formula IA During the ceremony W1 represents CR W1 or N; W2 represents CR W2 or N; W 3 represents CR W3 or N; W 4 represents CR W4 or N; Here, either none of W1 , W2 , W3 , and W4 represent N, or only one of W1 , W2 , W3 , and W4 represents N at the same time; and R W1 represents H, C 1-6 - aliphatic, halogen; R W2 represents H, C 1-6 - aliphatic; halogen; R W3 represents H, C 1-6 -aliphatic, -OC 1-6 -aliphatic, halogen, -CN, -CH 2 -Ar W , or -CH 2 -CH 2 -Ar W ; R W4 represents H, C 1-6 - aliphatic, halogen; Z1 is either CH or N; Z 2 is CR Z2 or N; Z 3 is either CR Z3 or N; Here, at least two of Z1 , Z2 , and Z3 are not N; R1 represents Ar1 , Hetar1, Cyc1 , Hetcyc1 , L1 - Ar1 , L1 - Hetar1 , L2 - Cyc1 , L2 - Hetcyc1 , and C1-8 -aliphatic (which are substituted with one, two, or three halogens, which may be the same or different); R 2 is -C(=O)-OR 2a , -C(=O)-NR 2b R 2c , -(CH 2 ) w -C(=O)-NR 2b R 2c , -(CH 2 ) x -NR 2d -C(=O)-R 2e , -SR 2f , -S(=O)-R 2f , -S(=O) 2 -R 2g , -S(=O) 2 -NR 2h R 2i , -S(=O) 2 -OH, -S(=O)(=NR 2j )-OH, -S(=O)(=NR 2j )-R 2g , -S(=O)(=NR 2k )-NR 2l R 2m , -P(=O)(OR 2o )(OR 2p ), -