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US 2023/0286904 A1Published application
Inhibitors of yap/taz-tead oncoproteins, synthesis and use thereof
AssigneeBridGene Biosciences, Inc.
InventorsChao ZHANG, Michael J. BISHOP, Hang CHEN, Ping CAO
Life of this patent
Estimating the term…
Abstract
Disclosed herein are synthesis and use of covalent inhibitors selective for Transcriptional Enhancer Factor TEF-1 (TEAD1), which can be used for treatment of cancers such as glioblastoma, gastric cancer, colorectal cancer, pancreatic ductal adenocarcinoma (PDAC), and malignant pleural mesothelioma (MPM). Further disclosed herein are pharmaceutical compositions including the TEAD1 inhibitor and methods of treating cancers using the same.
Claims23
A compound according to Formula (I):
- or an optically pure stereoisomer, pharmaceutically acceptable salt, or solvate thereof, wherein
- Ring1 is selected from the group consisting of phenyl, naphthyl, anthracene,
- Ring2 is selected from the group consisting of naphthyl, anthracene,
- A is —O—(CH2)p—, —CO—(CH2)p—, —CO—O—(CH2)p—, —S—(CH2)p—, —SO—(CH2)p—, —SO2—(CH2)p—, —NR4—(CH2)p—, —CO—NR4—(CH2)p—, —NR4—CO—NR4—(CH2)p—, —OPO—(CH2)p—, —OPO2—(CH2)p—, or —(CR6R7)p—;
- each R1 is independently selected from the group consisting of
- each R2 is independently F, Br, Cl, CF3, CN, N3, NH2, NO2, OH, OCH3, CO(CH2)0-5CH3, O(CH2)0-5CH3, (CH2)0-9CH3, OCO(CH2)0-5CH3, NHCO(CH2)0-5CH3, NHCONH(CH2)0-5CH3, NH(CH2)0-5CH3, (CH2)0-5CH═CH2, (CH2)0-5CH═CHCH3, (CH2)0-5C≡CH, (CH2)0-5C≡CCH3, NHCO(CH2)0-5CH═CH2, NHCO(CH2)0-5CH═CHCH3, NHCONH(CH2)0-5CH═CH2, NHCONH(CH2)0-5CH═CHCH3, O(CH2)0-5CH═CH2, O(CH2)0-5CH═CHCH3, CO(CH2)0-5CH═CH2, CO(CH2)0-5CH═CHCH3, OCO(CH2)0-5CH═CH2, OCO(CH2)0-5CH═CHCH3, SO2(CH2)0-5CH═CH2, SO2(CH2)0-5CH═CHCH3, NHCO(CH2)0-5C≡CH, NHCO(CH2)0-5C≡CCH3, NHCONH(CH2)0-5C≡CH, NHCONH(CH2)0-5C≡CCH3, O(CH2)0-5C≡CH, O(CH2)0-5C≡CCH3, SO2(CH2)0-5C≡ CH, SO2(CH2)0-5C≡CCH3, CO(CH2)0-5C≡CH, CO(CH2)0-5C≡CCH3, OCO(CH2)0-5C ≡CH, or OCO(CH2)0-5C≡CCH3, each of these groups is optionally substituted by one, two, three, or four R5.;
- R3 is selected from the group consisting of H, F, Br, Cl, CF3, CN, N3, NH2, NOz, OH, and OCH3;
- n is an integer selected from 0 to 5;
- m is an integer selected from 0 to 5;
- each R4 is independently H or C1-3alkyl optionally substituted by one, two, three, or four R5;
- each R5 is independently selected from the group consisting of H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, F, Br, Cl, CF3, NOz, OH, OCH3, CN, and amino group unsubstituted or substituted with methyl, ethyl, or propyl;
- p is an integer selected from 0 to 3;
- and
- each R6 and R7 is independently H, methyl, ethyl, F, Br, Cl, CF3, NOz, OH, OCH3, or CN.
11 more elements
A compound according to Formula (III):
- or an optically pure stereoisomer, pharmaceutically acceptable salt, or solvate thereof, wherein
- Ar is selected from the group consisting of phenyl, naphthyl, anthracene, pyridyl,
- each R1 is independently CO(CH2)0-5CH3, O(CH2)0-5CH3, OCO(CH2)0-5CH3, NHCO(CH2)0-5CH3, NHCONH(CH2)0-5CH3, NH(CH2)0-5CH3, (CH2)0-5CH═CH2, (CH2)0-5CH═CHCH3, (CH2)0-5C ≡ CH, (CH2)0-5C ≡ CCH3, NHCO(CH2)0-5CH═CH2, NHCO(CH2)0-5CH═CHCH3, NHCONH(CH2)0-5CH═CH2, NHCONH(CH2)0-5CH═CHCH3, O(CH2)0-5CH═CH2, O(CH2)0-5CH═CHCH3, CO(CH2)0-5CH═CH2, CO(CH2)0-5CH═CHCH3, OCO(CH2)0-5CH═CH2, OCO(CH2)0-5CH═CHCH3, SO2(CH2)0-5CH═CH2, SO2(CH2)0-5CH═CHCH3, NHCO(CH2)0-5C ≡ CH, NHCO(CH2)0-5C ≡ CCH3, NHCONH(CH2)0-5C≡CH, NHCONH(CH2)0-5C≡CCH3, O(CH2)0-5C≡CH, O(CH2)0-5C ≡CCH3, SO2(CH2)0-5C≡CH, SO2(CHz)0-5C≡CCH3, CO(CH2)0-5C≡CH, CO(CH2)0-5C ≡CCH3, OCO(CH2)0-5C≡CH, or OCO(CH2)0-5C≡CCH3, each of which is optionally substituted by one, two, three, or four R5;
- m is an integer selected from 1 to 4;
- each R2 is independently F, Br, Cl, CF3, CN, N3, NH2, NOz, OH, OCH3, CO(CH2)0-5CH3, O(CH2)0-5CH3, OCO(CH2)0-5CH3, NHCO(CH2)0-5CH3, NHCONH(CH2)0-5CH3, NH(CH2)0-5CH3, (CH2)0-5CH═CH2, (CH2)0-5CH═CHCH3, (CH2)0-5C≡CH, (CH2)0-5C≡ CCH3, NHCO(CH2)0-5CH═CH2, NHCO(CH2)0-5CH═CHCH3, NHCONH(CH2)0-5CH═CH2, NHCONH(CH2)0-5CH═CHCH3, O(CH2)0-5CH═CH2, O(CH2)0-5CH═CHCH3, CO(CH2)0-5CH═CH2, CO(CH2)0-5CH═CHCH3, OCO(CH2)0-5CH═CH2, OCO(CH2)0-5CH═CHCH3, SO2(CH2)0-5CH═CH2, SO2(CH2)0-5CH═CHCH3, NHCO(CH2)0-5C≡CH, NHCO(CH2)0-5C ≡CCH3, NHCONH(CH2)0-5C≡CH, NHCONH(CH2)0-5C≡CCH3, O(CH2)0-5C≡CH, O(CH2)0-5C≡CCH3, SO2(CH2)0-5C≡CH, SO2(CH2)0-5C≡CCH3, CO(CH2)0-5C≡CH, CO(CH2)0-5C≡CCH3, OCO(CH2)0-5C≡CH, or OCO(CH2)0-5C≡CCH3, each of these groups can be optionally substituted by one, two, three, or four R5;
- R3 is H or C1-8alkyl optionally substituted by one, two, three, or four R5;
- or R2 and R3 together form a bicyclic structure with Ar, the cyclic moiety between R2 and R3 comprises—(CR7R8)n—, wherein n is an integer selected from 1 to 5;
- R4 is H, C1-8alkyl, CO(CH2)0-5CH3, CH2CH2(OCH2CH2)1-5, (CH2)0-5CH═CH2, (CH2)0-5C≡CH, CONH(CH2)0-5CH═CH2, CO(CH2)0-5CH═CH2, SO2(CH2)0-5CH═CH2, CONH(CH2)0-5C≡CH, CO(CH2)0-5C≡CH, or SO2(CH2)0-5C≡CH, each of which is optionally substituted by one, two, three, or four R5;
- each R5 is independently selected from the group consisting of H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, F, Br, Cl, CF3, NO2, OH, OCH3, CN, and amino group unsubstituted or substituted with methyl, ethyl, or propyl;
- each R6 is independently H or C1-3alkyl;
- and
- each R7 and R8 is independently H, methyl, ethyl, F, Br, Cl, CF3, or CN.
9 more elements
A compound according to Formula (IV):
- or an optically pure stereoisomer, pharmaceutically acceptable salt, or solvate thereof, wherein
- each R1 is independently CO(CH2)0-5CH3, O(CH2)0-5CH3, OCO(CH2)0-5CH3, NHCO(CH2)0-5CH3, NHCONH(CH2)0-5CH3, NH(CH2)0-5CH3, (CH2)0-5CH═CH2, (CH2)0-5CH═CHCH3, (CH2)0-5C ≡ CH, (CH2)0-5C ≡ CCH3, NHCO(CH2)0-5CH═CH2, NHCO(CH2)0-5CH═CHCH3, NHCONH(CH2)0-5CH═CH2, NHCONH(CH2)0-5CH═CHCH3, O(CH2)0-5CH═CH2, O(CH2)0-5CH═CHCH3, CO(CH2)0-5CH═CH2, CO(CH2)0-5CH═CHCH3, OCO(CH2)0-5CH═CH2, OCO(CH2)0-5CH═CHCH3, SO2(CH2)0-5CH═CH2, SO2(CH2)0-5CH═CHCH3, NHCO(CH2)0-5C ≡ CH, NHCO(CH2)0-5C ≡ CCH3, NHCONH(CH2)0-5C≡CH, NHCONH(CH2)0-5C≡CCH3, O(CH2)0-5C≡CH, O(CH2)0-5C ≡CCH3, SO2(CH2)0-5C≡CH, SO2(CH2)0-5C≡CCH3, CO(CH2)0-5C≡CH, CO(CH2)0-5C ≡CCH3, OCO(CH2)0-5C≡CH, or OCO(CH2)0-5C≡CCH3, each of which is optionally substituted by one, two, three, or four Rs;
- n is an integer selected from 1 to 5;
- m is an integer selected from 1 to 4;
- R2 is H, C1-8alkyl, CO(CH2)0-5CH3, CH2CH2(OCH2CH2)1-5, (CH2)0-5CH═CH2, (CH2)0-5C≡CH, CONH(CH2)0-5CH═CH2, CO(CH2)0-5CH═CH2, SO2(CH2)0-5CH═CH2, CONH(CH2)0-5C≡CH, CO(CH2)0-5C≡CH, or SO2(CH2)0-5C≡CH, each of which is optionally substituted by one, two, three, or four Rs;
- each R3 and R4 is independently H, methyl, ethyl, F, Br, Cl, CF3, or CN;
- and
- each R5 is independently selected from the group consisting of H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, F, Br, Cl, CF3, NOz, OH, OCH3, CN, and amino group unsubstituted or substituted with methyl, ethyl, or propyl.
5 more elements
A compound according to Formula (VI):
- or an optically pure stereoisomer, pharmaceutically acceptable salt, or solvate thereof, wherein
- each Ring1 and Ring2 is independently selected from the group consisting of phenyl, naphthyl, anthracene,
- each R1 is independently CO(CH2)0-5CH3, O(CH2)0-5CH3, OCO(CH2)0-5CH3, NHCO(CH2)0-5CH3, NHCONH(CH2)0-5CH3, NH(CH2)0-5CH3, (CH2)0-5CH═CH2, (CH2)0-5CH═CHCH3, (CH2)0-5C ≡ CH, (CH2)0-5C ≡ CCH3, NHCO(CH2)0-5CH═CH2, NHCO(CH2)0-5CH═CHCH3, NHCONH(CH2)0-5CH═CH2, NHCONH(CH2)0-5CH═CHCH3, O(CH2)0-5CH═CH2, O(CH2)0-5CH═CHCH3, CO(CH2)0-5CH═CH2, CO(CH2)0-5CH═CHCH3, OCO(CH2)0-5CH═CH2, OCO(CH2)0-5CH═CHCH3, SO2(CH2)0-5CH═CH2, SO2(CH2)0-5CH═CHCH3, NHCO(CH2)0-5C ≡ CH, NHCO(CH2)0-5C ≡ CCH3, NHCONH(CH2)0-5C≡CH, NHCONH(CH2)0-5C≡CCH3, O(CH2)0-5C≡CH, O(CH2)0-5C ≡CCH3, SO2(CH2)0-5C≡CH, SO2(CH2)0-5C≡CCH3, CO(CH2)0-5C≡CH, CO(CH2)0-5C ≡ CCH3, OCO(CH2)0-5C ≡CH, or OCO(CH2)0-5C ≡ CCH3, each of which can be optionally substituted by one, two, three, or four R3;
- each R2 is independently F, Br, Cl, CF3, CN, N3, NH2, NOz, OH, OCH3, CO(CH2)0. 5CH3, O(CH2)0-5CH3, (CH2)0-9CH3, OCO(CH2)0-5CH3, NHCO(CH2)0-5CH3, NHCONH(CH2)0-5CH3, NH(CH2)0-5CH3, (CH2)0-5CH═CH2, (CH2)0-5CH═CHCH3, (CH2)0-5C ≡ CH, (CH2)0-5C ≡ CCH3, NHCO(CH2)0-5CH═CH2, NHCO(CH2)0-5CH═CHCH3, NHCONH(CH2)0-5CH═CH2, NHCONH(CH2)0-5CH═CHCH3, O(CH2)0-5CH═CH2, O(CH2)0-5CH═CHCH3, CO(CH2)0-5CH═CH2, CO(CH2)0-5CH═CHCH3, OCO(CH2)0-5CH═CH2, OCO(CH2)0-5CH═CHCH3, SO2(CH2)0-5CH═CH2, SO2(CH2)0-5CH═CHCH3, NHCO(CH2)0-5C ≡ CH, NHCO(CH2)0-5C ≡ CCH3, NHCONH(CH2)0-5C ≡ CH, NHCONH(CH2)0-5C≡CCH3, O(CH2)0-5C≡CH, O(CH2)0-5C≡CCH3, SO2(CH2)0-5C≡ CH, SO2(CH2)0-5C≡CCH3, CO(CH2)0-5C≡CH, CO(CH2)0-5C≡CCH3, OCO(CH2)0-5C ≡CH, or OCO(CH2)0-5C≡CCH3, each of these groups can be optionally substituted by one, two, three, or four R3;
- each R3 is independently selected from the group consisting of H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, F, Br, Cl, CF3, NOz, OH, OCH3, CN, and amino group unsubstituted or substituted with methyl, ethyl, or propyl;
- n is an integer selected from 0 to 5;
- m is an integer selected from 0 to 5;
- and
- each R4 is independently H or C1-3alkyl optionally substituted by one, two, three, or four R3.
6 more elements
A compound according to Formula (VII):
- or an optically pure stereoisomer, pharmaceutically acceptable salt, or solvate thereof, wherein
- n is an integer selected from 0 to 5;
- A is —O—(CH2)m—, —CO—(CH2)m—, —CO—O—(CH2)m-, —S—(CH2)m—,—SO—(CH2)m—, —SO2—(CH2)m-, —NR4—(CH2)m—, —CO—NR4—(CH2)m—, —NR4—CO—NR4—(CH2)m—, —OPO—(CH2)m—, —OPO2—(CH2)m-, or —(CR5R6)m—;
- n is an integer selected from 0 to 5;
- each m is independently an integer selected from 0 to 5;
- Ring is selected from the group consisting of phenyl, naphthyl, anthracene,
- each R1 is independently CO(CH2)0-5CH3, O(CH2)0-5CH3, OCO(CH2)0-5CH3, NHCO(CH2)0-5CH3, NHCONH(CH2)0-5CH3, NH(CH2)0-5CH3, (CH2)0-5CH═CH2, (CH2)0-5CH═CHCH3, (CH2)0-5C ≡ CH, (CH2)0-5C ≡ CCH3, NHCO(CH2)0-5CH═CH2, NHCO(CH2)0-5CH═CHCH3, NHCONH(CH2)0-5CH═CH2, NHCONH(CH2)0-5CH═CHCH3, O(CH2)0-5CH═CH2, O(CH2)0-5CH═CHCH3, CO(CH2)0-5CH═CH2, CO(CH2)0-5CH═CHCH3, OCO(CH2)0-5CH═CH2, OCO(CH2)0-5CH═CHCH3, SO2(CH2)0-5CH═CH2, SO2(CH2)0-5CH═CHCH3, NHCO(CH2)0-5C ≡ CH, NHCO(CH2)0-5C ≡ CCH3, NHCONH(CH2)0-5C≡CH, NHCONH(CH2)0-5C≡CCH3, O(CH2)0-5C≡CH, O(CH2)0-5C ≡CCH3, SO2(CH2)0-5C≡CH, SO2(CH2)0-5C≡CCH3, CO(CH2)0-5C≡CH, CO(CH2)0-5C≡ CCH3, OCO(CH2)0-5C ≡ CH, or OCO(CH2)0-5C ≡CCH3, each of which can be optionally substituted by one, two, three, or four R3;
- B is carbon or nitrogen;
- when B is carbon, R2 is selected from the group consisting of
- when B is nitrogen, R2 is connected to B to form
- each R3 can be independently selected from the group consisting of H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, F, Br, Cl, CF3, NOz, OH, OCH3, CN, and amino group unsubstituted or substituted with methyl, ethyl, or propyl;
- each R4 can be independently H or C1-3alkyl optionally substituted by one, two, three, or four R3;
- and
- each R5 and R6 can be independently H, methyl, ethyl, F, Br, Cl, CF3, NOz, OH, OCH3, or CN.
11 more elements
Dependencies are inferred from the claim text.