WO2024120519A1 - Tead抑制剂、其制备方法和在医学上的应用 - Google Patents

Tead抑制剂、其制备方法和在医学上的应用 Download PDF

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WO2024120519A1
WO2024120519A1 PCT/CN2023/137418 CN2023137418W WO2024120519A1 WO 2024120519 A1 WO2024120519 A1 WO 2024120519A1 CN 2023137418 W CN2023137418 W CN 2023137418W WO 2024120519 A1 WO2024120519 A1 WO 2024120519A1
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ring
membered
alkyl
compound
pharmaceutically acceptable
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PCT/CN2023/137418
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French (fr)
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杨洵
张蕾
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捷思英达控股有限公司
杨洵
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • the present disclosure relates to the field of medical technology, and in particular to a YAP/TAZ-TEAD interaction inhibitor and uses thereof.
  • the Hippo signaling pathway is a cell growth-inhibiting pathway that was first discovered in Drosophila during a genetic screen for tumor suppressor genes involved in regulating organ size. Studies have shown that the Hippo pathway consists of a series of kinase cascade reactions that are mainly used to control organ size by regulating cell proliferation and apoptosis.
  • the upstream membrane protein receptor of the Hippo signaling pathway is the sensor of extracellular growth inhibitory signals. Once the upstream membrane protein receptor senses the extracellular growth inhibitory signal, the Hippo signaling pathway is turned on and a series of kinase cascade phosphorylation reactions are activated, namely, MST1 and MST2 kinases that form a complex with SAV1 phosphorylate and activate LATS1 and LATS2 kinases (LATS1/2-MOB1) that form a complex with MOB1; then the activated LATS1/2-MOB1 phosphorylates YAP (Yes Associated Protein)/TAZ (Transcriptional coactivator with PDZ-binding motif); then the phosphorylated YAP/TAZ is retained in the cytoplasm by 14-3-3 proteins or ubiquitinated and degraded by SCF ⁇ -Trcp E3 ligase, preventing YAP/TAZ from entering the nucleus.
  • MST1 and MST2 kinases that form
  • YAP/TAZ in the cytoplasm cannot be phosphorylated, and unphosphorylated YAP/TAZ will enter the nucleus.
  • TEAD Transcriptional enhanced associated domain
  • YAP/TAZ forms a complex with the nuclear transcription factor TEAD (Transcriptional enhanced associated domain) and binds to DNA, initiating the expression of downstream genes (CTGF, Cyr61, Axl, etc.), promoting cell proliferation and growth, and thus leading to the occurrence of tumors or other hyperproliferative diseases.
  • Patents WO2018204532, WO2017064277, WO2021133896, WO2019232216, WO2020243423, and WO2021186324 also reported compounds with different structures that can block the interaction between TEAD/YAP proteins and have the potential to treat related diseases.
  • the first aspect of the present application provides a novel benzene ring derivative represented by general formula (I), or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof.
  • the compound of general formula (I) can be used as an inhibitor to inhibit the interaction between TEAD and YAP/TAZ. The interaction between them.
  • the first aspect of the present disclosure relates to a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof:
  • X 1 is N or CR 1 ;
  • Each of X 2 and X 3 is independently selected from N or CR 2 ;
  • R 1 is selected from -CN, R 1A or -LR 1B ;
  • L is a bond, -O-, -NH-, -CO- or -CONH-;
  • R 1B is a spiro bicyclic ring, the spiro bicyclic ring is formed by two 3-8 membered saturated carbocyclic rings or saturated heterocyclic rings, wherein the 3-8 membered saturated heterocyclic ring has 1-2 heteroatoms selected from N, O and S, and the spiro bicyclic ring is optionally substituted by a substituent selected from H, halogen, -NH 2 , -CN, -OH, C 1-6 alkyl, C 1-6 alkoxy or C 1-6 haloalkyl, trifluorovinyl;
  • Ra and Rz are independently selected from H, halogen, -NH2 , -CN, -OH, C1-6 alkyl, C1-6 alkoxy or C1-6 haloalkyl, trifluorovinyl;
  • Rx and Ry are selected from H, C1-6 alkyl, C1-6 haloalkyl or trifluorovinyl; or Rx and Ry are attached together
  • the nitrogen atom of the alkylene group together forms a saturated or partially saturated 3-6-membered heterocycloalkyl group, or a 6-10-membered lactam ring, wherein the saturated or partially saturated 3-6-membered heterocycloalkyl group or the 6-10-membered lactam ring is optionally substituted by a group selected from H, -OH, -NH 2 , -CN, halogen, C 1-6 alkyl, C 1-6 haloalkyl or trifluorovinyl;
  • R 2 is independently selected at each occurrence from H, -OH, -NH 2 , halogen, -CN, C 1-6 alkyl, -O-C 1-6 alkyl or C 1-4 haloalkyl, trifluorovinyl; or, adjacent R 2 are combined to form an optionally substituted C 2-4 alkylene, -C(O)N(R a )R a - or -C(O)OR a -, wherein the optionally substituted C 2-4 alkylene is optionally substituted with 0, 1, 2 or 3 substituents selected from C 1-6 alkyl;
  • Each of X 4 and X 5 is independently selected from CH 2 , NH, C(R 3 R 4 ) or NR 5 ;
  • R 3 and R 4 are independently selected from H, -CN, C 1-4 alkyl optionally substituted by C 1-3 alkoxy or hydroxy, COO(C 1-4 alkyl), or amide; or R 3 , R 4 and the carbon atom to which they are attached form a ring R x , said ring R x being:
  • the spiral-fused bicyclic ring is The ring B' is a 5-8 membered lactam ring, a 5-8 membered lactone ring, a 4-6 membered aromatic heterocycle or an aliphatic heterocycle which may contain at least one heteroatom selected from N, O, and S; the ring B" is a 4-6 membered aromatic heterocycle or an aliphatic heterocycle which may contain at least one heteroatom selected from N, O, and S; n is 1-5, and m is 1-5; or
  • a spiro-fused tricyclic ring is wherein the ring B' may contain at least one aromatic heterocycle or aliphatic heterocycle with a heteroatom selected from N, O, and S, a 5-8-membered lactam ring, or a 5-8-membered lactone ring; the ring B" may contain at least one 5-6-membered aromatic heterocycle or aliphatic heterocycle with a heteroatom selected from N, O, and S; the ring B"' may contain at least one aromatic heterocycle or aliphatic heterocycle with a heteroatom selected from N, O, and S; wherein at least one of the rings B', B" and B"' contains at least one heteroatom; n is 1-4; m is 1-5;
  • R 5 is -MR 5a , M is a bond or a C 1-4 alkylene group;
  • R 5a is C 1-6 alkyl, C 1-6 alkoxy, 3-6 membered cycloalkyl, 3-8 membered heterocycloalkyl containing 1-2 heteroatoms selected from N, O and S as ring members, 5-12 membered aryl, 5-12 membered heteroaryl containing 1-4 heteroatoms selected from N, O and S as ring members; said R 5a optionally has 1-3 substituents selected from halogen, -CN, -OH, C 1-6 alkyl, C 1 -C 4 alkoxy, C 1-6 haloalkyl, or C 3-6 cycloalkyl or trifluorovinyl which is optionally substituted by C 1-6 alkyl or C 1-6 haloalkyl.
  • R w is selected from the group consisting of the following formulae W-1 to W-7:
  • each of R b , R c and R d is independently selected from H, , halogen or C 1-4 alkyl, said C 1-4 alkyl being optionally substituted with dimethylamino.
  • a second aspect of the present disclosure relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound according to formula (I) or any embodiment and sub-embodiment of formula (I) described in the present disclosure, or a pharmaceutically acceptable salt, tautomer, stereoisomer or deuterated analog of any of these compounds, and a pharmaceutically acceptable carrier or excipient.
  • a third aspect of the present disclosure relates to a method for treating a subject suffering from a disease or condition associated at least in part with increased expression or activity of TEAD, the method comprising administering to the subject an effective amount of a compound according to formula (I), or any embodiment of formula (I) described in the present disclosure, or a pharmaceutically acceptable salt, tautomer, stereoisomer or deuterated analog of any of these compounds, or a pharmaceutical composition of any compound described in the present disclosure.
  • the fourth aspect of the present disclosure relates to the use of a compound according to formula (I) or a composition comprising a compound of formula (I) in the preparation of a medicament for treating a disease or condition associated with increased expression or activity of TEAD.
  • a dash (“-") that is not between two letters or symbols is used to indicate the point of attachment of a substituent.
  • -CONR a R b is attached through a carbon atom.
  • the carbon, hydrogen, oxygen, sulfur, nitrogen or F, Cl, Br, I involved in the groups and compounds of the present invention include their isotopes, and the carbon, hydrogen, oxygen, sulfur or nitrogen involved in the groups and compounds of the present invention are optionally further One or more of their corresponding isotopes are replaced by carbon isotopes, wherein carbon isotopes include 12 C, 13 C and 14 C, hydrogen isotopes include protium (H), deuterium (D, also called heavy hydrogen), tritium (T, also called super tritium), oxygen isotopes include 16 O, 17 O and 18 O, sulfur isotopes include 32 S, 33 S, 34 S and 36 S, nitrogen isotopes include 14 N and 15 N, fluorine isotopes include 17 F and 19 F, chlorine isotopes include 35 Cl and 37 Cl, and bromine isotopes include 79 Br and 81 Br.
  • carbon isotopes include 12 C, 13 C and 14 C
  • alkyl herein refers to a hydrocarbon group selected from straight and branched saturated hydrocarbon groups having up to 18 carbon atoms, such as from 1 to 12 carbon atoms, further such as from 1 to 8 carbon atoms, and even further such as from 1 to 6 carbon atoms.
  • alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl, n-decyl, and the like.
  • an alkyl group may be optionally substituted by replacing the hydrogen atoms of the unsubstituted alkyl group with one or more substituents (such as one, two or three substituents, or 1-4 substituents, or up to the number of hydrogens present on the unsubstituted alkyl group).
  • suitable substituents for the alkyl group may be selected from the group consisting of halogen elements, D, CN, oxo, hydroxy, substituted or unsubstituted C 1 -C 4 alkoxy, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted 3-7 membered heterocycloalkyl containing 1 or 2 heteroatoms selected from N, O and S as ring members, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl containing 1 to 4 heteroatoms selected from N, O and S as ring members, amino, -NH(C 1 -C 4 alkyl), -N(C 1 -C 4 alkyl) 2 , -S( ⁇ O) 0-2(C 1 -C 4 alkyl), -S( ⁇ NR)( ⁇ O)(C 1 -C 4 alkyl), -C( ⁇ O)(C 1 -C 4 al
  • the substituents of the alkyl group are selected from, for example, halogen elements, CN, oxo, hydroxy, C 1 -C 4 alkoxy, C 3 -C 6 cycloalkyl, phenyl, amino, -NH(C 1 -C 4 alkyl), -N(C 1 -C 4 alkyl) 2 , C 1 -C 4 alkylthio, C 1 -C 4 alkylsulfonyl, -C( ⁇ O)(C 1 -C 4 alkyl), -CO 2 H, -CO 2 (C 1 -C 4 alkyl), -OC( ⁇ O)(C 1 -C 4 alkyl), -NHC( ⁇ O)(C 1 -C 4 alkyl), and -NHC( ⁇ O)O(C 1 -C 4 alkyl).
  • alkoxy herein refers to a straight or branched chain alkyl group comprising 1 to 18 carbon atoms connected by an oxygen bridge (e.g., methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, pentoxy, 2-pentoxy, isopentoxy, neopentoxy, hexoxy, 2-hexoxy, 3-hexoxy, 3-methylpentoxy, etc.).
  • the alkoxy group comprises 1 to 6 carbon atoms (e.g., 1 to 4 carbon atoms) connected by an oxygen bridge.
  • alkoxy groups may be optionally substituted by replacing the hydrogen atoms of the unsubstituted alkyl portion of the alkoxy group with one or more substituents (such as one, two or three substituents, or 1-4 substituents, or up to the number of hydrogens present on the unsubstituted alkoxy group).
  • substituents such as one, two or three substituents, or 1-4 substituents, or up to the number of hydrogens present on the unsubstituted alkoxy group.
  • suitable substituents are selected from, for example, the substituents listed above for alkyl groups, except that hydroxyl and amino groups are usually not present on the carbon directly connected to the oxygen of the substituted alkyl-O group.
  • alkenyl groups may be selected from ethenyl or vinyl (-CH ⁇ CH 2 ), prop-1-enyl (-CH ⁇ CHCH 3 ), prop-2-enyl (-CH 2 CH ⁇ CH 2 ), 2-methylprop-1-enyl, but-1-enyl, but-2-enyl, but-3-enyl, but-1,3-dienyl, 2-methylbut-1,3-diene, hex-1-enyl, hex-2-enyl, hex-3-enyl, hex-4-enyl, and hex-1,3-dienyl groups.
  • the point of attachment may be on an unsaturated carbon or a saturated carbon.
  • alkenyl groups may be substituted with one or more substituents (such as one, two or three substituents, or 1-4 substituents, or up to the number of hydrogens present on the unsubstituted alkenyl groups) to replace the unsubstituted hydrogen atoms of alkenyl groups.
  • substituents such as one, two or three substituents, or 1-4 substituents, or up to the number of hydrogens present on the unsubstituted alkenyl groups
  • suitable substituents are selected from, for example, the substituents for alkyl groups listed above.
  • alkynyl herein refers to a hydrocarbon group selected from straight and branched hydrocarbon groups, the hydrocarbon group comprising at least one -C ⁇ C- triple bond and 2 to 18 (e.g., 2 to 6) carbon atoms.
  • alkynyl groups include ethynyl (-C ⁇ CH), 1-propynyl (-C ⁇ CCH 3 ), 2-propynyl (propargyl, -CH 2 C ⁇ CH), 1-butynyl, 2-butynyl and 3-butynyl groups.
  • the point of attachment can be on an unsaturated carbon or a saturated carbon.
  • an alkynyl group may be optionally substituted by replacing the unsubstituted hydrogen atoms of the alkynyl group with one or more substituents (such as one, two or three substituents, or 1-4 substituents, or up to the number of hydrogens present on the unsubstituted alkynyl group).
  • substituents such as one, two or three substituents, or 1-4 substituents, or up to the number of hydrogens present on the unsubstituted alkynyl group.
  • suitable substituents are selected from, for example, the substituents listed above for alkyl groups.
  • alkylene refers to a divalent alkyl group including 1 to 10 carbon atoms and two expanded valence bonds connected to other molecular parts.
  • the two molecular parts connected to the alkylene can be on the same carbon atom or on different carbon atoms. Therefore, for example, propylene is a 3-carbon alkylene that can be 1,1-disubstituted, 1,2-disubstituted or 1,3-disubstituted.
  • alkylene refers to a part including 1 to 6 carbon atoms (such as 1 to 4 carbon atoms).
  • alkylene examples include, but are not limited to, methylene, ethylene, n-propylene, isopropylene, n-butylene, secondary butylene, isobutylene, tert-butylene, n-pentylene, isopentylene, neopentylene, n-hexylene, 3-methylhexylene, 2,2-dimethylpentylene, 2,3-dimethylpentylene, n-heptylene, n-octylene, n-nonylene, n-decylene, etc.
  • Substituted alkylene is an alkylene group containing one or more (such as one, two or three) substituents; unless otherwise specified, suitable substituents are selected, for example, from the substituents listed above for alkyl groups.
  • haloalkyl refers to a hydrocarbyl group as defined herein substituted with one or more halogen groups as defined herein. Unless otherwise specified, the hydrocarbyl portion of a haloalkyl group comprises 1 to 4 carbon atoms.
  • a haloalkyl group may be a monohaloalkyl, a dihaloalkyl, a trihaloalkyl, or a polyhaloalkyl (including a perhaloalkyl).
  • a monohaloalkyl group may have a halogen group or a halogen group. There is an iodine, bromine, chlorine or fluorine.
  • Dihaloalkyl groups and polyhaloalkyl groups can have two or more identical halogen atoms or a combination of different halogen groups in the hydrocarbon group.
  • Polyhaloalkyl includes, for example, up to 6, or 4, or 3, or 2 halogen groups.
  • haloalkyl include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl and dichloropropyl.
  • Perhaloalkyl refers to a hydrocarbon group (for example, trifluoromethyl) in which all hydrogen atoms are replaced by halogen atoms.
  • haloalkyl groups include methyl and ethyl groups (for example, -CF 3 , -CF 2 H, -CFH 2 and -CH 2 CF 3 ) substituted with monofluoro-, difluoro- and trifluoro-.
  • haloalkyl groups may be optionally substituted by one or more substituents (such as one, two or three substituents, or 1-4 substituents, or up to the number of hydrogens present in the unsubstituted haloalkyl groups) replacing the unsubstituted hydrogen atoms of haloalkyl.
  • substituents such as one, two or three substituents, or 1-4 substituents, or up to the number of hydrogens present in the unsubstituted haloalkyl groups
  • suitable substituents are selected from, for example, the substituents for alkyl groups as listed above.
  • haloalkoxy refers to haloalkyl-O-, wherein haloalkyl is as defined above.
  • haloalkoxy include, but are not limited to, fluoromethoxy, difluoromethoxy, trifluoromethoxy, trichloromethoxy, 2-chloroethoxy, 2,2,2-trifluoroethoxy, 1,1,1,3,3,3-hexafluoro-2-propoxy, and the like.
  • the haloalkoxy group includes 1-4 carbon atoms and up to three halogen elements, for example, monofluoro, difluoro and trifluoro substituted methoxy and ethoxy groups.
  • haloalkoxy groups may be optionally substituted by one or more substituents (such as one, two or three substituents, or 1-4 substituents, or as many as the number of hydrogens present in the unsubstituted haloalkoxy groups) replacing the hydrogen atom of the unsubstituted alkyl part of haloalkoxy.
  • substituents such as one, two or three substituents, or 1-4 substituents, or as many as the number of hydrogens present in the unsubstituted haloalkoxy groups
  • suitable substituents are selected from, for example, the substituents for alkyl groups listed above, except that hydroxyl and amino groups are usually not present on the carbon directly connected to the oxygen of substituted haloalkyl-O groups.
  • an alkylene group may be optionally substituted by replacing the unsubstituted hydrogen atoms of an alkylene group with one or more substituents (such as one, two or three substituents, or 1-4 substituents, or up to the number of hydrogens present on the unsubstituted alkylene group).
  • substituents such as one, two or three substituents, or 1-4 substituents, or up to the number of hydrogens present on the unsubstituted alkylene group.
  • suitable substituents are selected from, for example, the substituents for an alkyl group as listed above.
  • aryl refers to an aromatic hydrocarbon group including 5-15 carbon atoms in the ring portion.
  • aryl refers to a group selected from 5- and 6-membered carbocyclic aromatic rings, for example, phenyl; a bicyclic ring system (such as a 7- to 12-membered bicyclic ring system, wherein at least one ring is carbocyclic and aromatic) selected from, for example, naphthalene, indane, and 1,2,3,4-tetrahydroquinoline; and a tricyclic ring system (such as a 10- to 15-membered tricyclic ring system, wherein at least one ring is carbocyclic and aromatic), for example, fluorene.
  • the aryl group is selected from 5- and 6-membered carbocyclic aromatic rings fused to a 5- to 7-membered cycloalkyl or a heterocycle (as defined below in “heterocyclyl” or “heterocycle”) optionally including at least one heteroatom selected from, for example, N, O, and S, with the proviso that when the carbocyclic aromatic ring is fused to the heterocycle, the point of attachment is at the carbocyclic aromatic ring, and when the carbocyclic aromatic ring is fused to a cycloalkyl group, the point of attachment can be at the carbocyclic aromatic ring or at the cycloalkyl group.
  • Divalent radicals formed from substituted benzene derivatives and having free valences at ring atoms are named substituted phenylene groups.
  • spiro-fused bicyclic ring refers to a fused bicyclic ring that is spiro-fused to a parent ring.
  • spiro-fused tricyclic ring refers to a tricyclic ring structure comprising a fused bicyclic ring connected to a parent ring by a spiro connection.
  • aryl groups may be substituted by one or more substituents (such as one, two or three substituents, or 1-4 substituents, or up to the number of hydrogens present in the unsubstituted aryl groups) replacing the hydrogen atoms of unsubstituted aryl.
  • the substituted aryl comprises 1-5 substituents.
  • otherwise suitable substituents are selected from, for example, the substituents for alkyl groups as listed above.
  • heteroaryl refers to a group selected from a 5- to 7-membered aromatic monocyclic ring including at least one (e.g., 1 to 4 heteroatoms, or in some embodiments, 1 to 3 heteroatoms) heteroatom selected from, for example, N, O, and S, wherein the remaining ring atoms are carbon; an 8- to 12-membered bicyclic ring including at least one (e.g., 1 to 4 heteroatoms, or in some embodiments, 1 to 3 heteroatoms, or in other embodiments, 1 or 2 heteroatoms) heteroatom selected from, for example, N, O, and S, wherein the remaining ring atoms are carbon; carbon, and wherein at least one ring is aromatic and at least one heteroatom is present in the aromatic ring, and wherein the point of attachment is on any ring and on a carbon or heteroatom; and 11- to 14-membered tricyclic rings comprising at least one (e.g., 1 to 4 heteroatoms, or
  • the heteroaryl group comprises a 5- to 7-membered heterocyclic aromatic ring fused to a 5- to 7-membered cycloalkyl ring.
  • the point of attachment can be at the heteroaryl ring or at the cycloalkyl ring.
  • the heteroaryl group comprises a 5- to 7-membered heterocyclic aromatic ring fused to a 5- to 7-membered aryl ring.
  • the point of attachment may be at the heteroaryl ring or at the aryl ring.
  • Non-limiting examples include quinolyl and quinazolinyl.
  • the heteroaryl group comprises a 5- to 7-membered heterocyclic aromatic ring fused to an additional 5- to 7-membered heterocyclic aromatic ring.
  • Non-limiting examples include 1H-pyrazolo[3,4-b]pyridinyl and 1H-pyrrolo[2,3-b]pyridinyl.
  • the total number of S atoms and O atoms in the heteroaryl group exceeds 1, those heteroatoms are not adjacent to each other. In some embodiments, the total number of S atoms and O atoms in the heteroaryl group does not exceed 2. In some embodiments, the total number of S atoms and O atoms in the heteroaromatic ring does not exceed 1.
  • heteroaryl groups include, but are not limited to, pyridyl, pyridinyl, pyrazinyl, pyrimidinyl, imidazolyl, imidazolyl, pyridyl, isoxazolyl, oxazolyl, thiazolyl, isothiazolyl, thiadiazolyl, tetrazolyl, thienyl, triazinyl, benzothienyl, furanyl, benzofuranyl, benzimidazolyl, indolyl, isoindolyl, indolinyl, phthalazinyl, pyrazinyl, pyridazinyl, pyrimidinyl, pyrrolyl, triazolyl, quinolyl, isoquinolyl, isoquinolyl, pyrazolyl, pyrrolopyridinyl (e.g., 1H-pyrrolo[2,3-b]pyridin-3-
  • heteroaryl groups may be optionally substituted by one or more substituents (such as one, two or three substituents, or 1-4 substituents, or up to the number of hydrogens present in the unsubstituted heteroaryl groups) replacing the hydrogen atoms of the unsubstituted heteroaryl groups.
  • the substituted heteroaryl groups include 1, 2 or 3 substituents.
  • suitable substituents are selected from, for example, the substituents for alkyl groups as listed above.
  • Bicyclic refers to a group with two connected rings.
  • Bicyclic can be a carbocyclic ring (all ring atoms are carbon atoms) or a heterocyclic ring (in addition to carbon atoms, the ring atoms include, for example, 1, 2 or 3 heteroatoms, such as N, O or S). Both rings can be aliphatic (e.g., decalin and norbornane), or can be aromatic (e.g., naphthalene), or a combination of aliphatic and aromatic (e.g., tetralin).
  • Bicyclic includes (a) spirocyclic compounds, in which the two rings share only one single atom (spiro atom, which is usually a quaternary carbon). Examples of spirocyclic compounds include, but are not limited to:
  • bridged bicyclic compounds wherein the two rings share three or more atoms and the two bridgehead atoms are separated by a bridge comprising at least one atom.
  • norbornane also known as bicyclo[2.2.1]heptane
  • bridged bicyclic rings include, but are not limited to:
  • “Monocyclic” refers to a single carbon ring contained by itself or in combination with other terms.
  • “Carbocyclic” refers to a saturated or unsaturated aromatic or non-aromatic ring. When it is an aromatic ring, its definition is the same as the definition of "aryl” above; when it is a non-aromatic ring, it can be a 3-10-membered (e.g., 3, 4, 5, 6, 7, 8, 9, 10-membered) monocyclic ring, a 4-12-membered (e.g., 4, 5, 6, 7, 8, 9, 10, 11, 12-membered) bicyclic ring, or a 10-15-membered (e.g., 10, 11, 12, 13, 14, 15-membered) tricyclic ring system, which can be a bridged ring or a spirocyclic ring, without limitation.
  • Examples include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopentyl-1-enyl, 1-cyclopentyl-2-enyl, 1-cyclopentyl-3-enyl, cyclohexyl, 1-cyclohexyl-2-enyl, 1-cyclohexyl-3-enyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, and the "carbocyclyl" or "carbocycle” is optionally further substituted by one or more substituents.
  • cycloalkyl herein refers to a hydrocarbon group selected from saturated and partially unsaturated cyclic hydrocarbon groups (such as monocyclic and polycyclic (e.g., bicyclic and tricyclic, adamantyl and spirocycloalkyl) groups) comprising from 3 to 20 carbon atoms.
  • the group is a cycloalkyl group including 3 to 20 carbon atoms (e.g., 3 to 8 carbon atoms).
  • Examples of monocyclic cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl, cyclododecyl, and cyclohexenyl.
  • Bicycloalkyl groups include bridged bicycloalkyls, fused bicycloalkyls, and spirocycloalkyls.
  • Bridged bicycloalkyls contain a monocyclic cycloalkyl ring in which two non-adjacent carbon atoms of the monocyclic ring are connected by an alkylene bridge of one to three additional carbon atoms (i.e., a bridging group of the form -(CH 2 ) n-, where n is 1, 2, or 3).
  • bridged bicycloalkyls include, but are not limited to, bicyclo[2.2.1]heptene, bicyclo[3.1.1]heptane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, bicyclo[3.3.1]nonane, and bicyclo[4.2.1]nonane, among others.
  • Fused bicycloalkyls contain a monocyclic cycloalkyl ring fused to one of a phenyl, a monocyclic cycloalkyl, and a monocyclic heteroaryl.
  • fused bicycloalkyls include, but are not limited to, bicyclo[4.2.0]octa-1,3,5-triene, 2,3-dihydro-1H-indene, 6,7-dihydro-5H-cyclopenta[b]pyridine, 5,6-dihydro-4H-cyclopenta[b]thiophene, and decalin, among others.
  • Spirocycloalkyls contain two monocyclic ring systems that share a carbon atom forming a bicyclic ring system.
  • Examples of spirocycloalkyls include, but are not limited to Bicyclic cycloalkyl groups include, for example, 7 to 12 carbon atoms.
  • Tricyclic alkyl groups include bridged tricyclic alkyl groups as used herein, and the bridged tricyclic alkyl groups refer to: 1) a bridged bicyclic alkyl ring, wherein two non-adjacent carbon atoms of the bridged bicyclic alkyl ring are connected via an alkylene bridge of one to three additional carbon atoms (i.e., a bridging group of the form of -(CH 2 ) n-, wherein n is 1, 2 or 3); or 2) a fused bicyclic alkyl ring, wherein two non-shared ring atoms on each ring are connected via an alkylene bridge of one to three additional carbon atoms (i.e., a bridging group of the form of -(CH 2 ) n-, wherein n is 1, 2 or 3), wherein "
  • bridged tricyclic alkyl groups include, but are not limited to, adamantyl
  • bridged tricycloalkyl is attached to the parent molecular moiety through any ring atom.
  • Ring atoms disclosed herein refer to carbon atoms on the ring skeleton.
  • Cycloalkyl can be saturated or include at least one double bond (i.e., partially unsaturated), but is not completely conjugated and is not aromatic (as defined herein) cycloalkyl.
  • Cycloalkyl can be substituted with at least one heteroatom selected from, for example, O, S and N.
  • cycloalkyl groups may be substituted with one or more substituents (such as one, two or three substituents, or 1-4 substituents, or up to the number of hydrogens present in the unsubstituted cycloalkyl groups) to replace the hydrogen atoms of the unsubstituted cycloalkyl groups.
  • the substituted cycloalkyl groups include 1-4, such as 1-2 substituents.
  • suitable substituents are selected from, for example, the substituents for alkyl groups as listed above.
  • Heterocycloalkyl refers to a "cycloalkyl” as defined above in which at least one of the ring carbon atoms is replaced by a heteroatom independently selected from O, N, S.
  • the heterocyclyl includes, for example, 1, 2, 3 or 4 heteroatoms, and each of N, C and S can be independently oxidized in the cyclic ring system.
  • the N atom can also be substituted to form a tertiary amine or an ammonium salt.
  • the point of attachment of the heterocyclyl can be on a heteroatom or carbon.
  • Heterocyclyl herein also refers to a 5- to 7-membered saturated or partially unsaturated carbocyclic ring (heterocycle) comprising at least one heteroatom selected from, for example, N, O and S, which carbocyclic ring is fused to a 5-, 6- and/or 6-membered alkyl group.
  • heterocycle or carbocyclic aromatic ring fused, condition is when heterocycle and carbocyclic aromatic ring fused, connection point is at heterocycle, and when heterocycle and cycloalkyl fused, connection point can be at cycloalkyl or heterocycle.
  • Heterocyclic radical herein also refers to an aliphatic spirocycle including at least one heteroatom selected from, for example, N, O and S. Ring can be saturated or have at least one double bond (that is, partially unsaturated). Heterocyclic radical can be substituted by, for example, oxo group. Connection point can be carbon or heteroatom. Heterocyclic radical is not heteroaryl as defined herein.
  • heterocycles include, but are not limited to, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, pyranyl, morpholinyl, oxiranyl, aziridinyl, thiirane, azetidinyl, oxetanyl, thietanyl, dithietanyl, dihydropyridinyl, tetrahydropyridinyl, thiomorpholinyl, thioxanyl, homopiperazinyl, homopiperidinyl, azepanyl, oxetanyl, thietanyl, oxathianyl, dioxetanyl, oxathian ...
  • Substituted heterocycles also include ring systems substituted with one or more oxo moieties, such as piperidinyl N-oxide, morpholinyl-N-oxide, 1-oxo-1-thiomorpholinyl, 1,1-dioxo-1-thiomorpholinyl, 3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[4.1.0]heptanyl and azabicyclo[2.2.2]hexanyl.
  • oxo moieties such as piperidinyl N-oxide, morpholinyl-N-oxide, 1-oxo-1-thiomorpholinyl, 1,1-dioxo-1-thiomorpholinyl, 3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[4.1.0]heptanyl and azabicyclo[2.2.2]hexanyl.
  • Substituted heterocycles also include ring systems substituted with one or more oxo moieties, such as piperidinyl N-oxide, morpholinyl-N-oxide, 1-oxo-1-thiomorpholinyl, 1,1-dioxo-1-thiomorpholinyl,
  • the heterocyclic radical group may be optionally substituted by one or more substituents (such as one, two or three substituents, or 1-4 substituents, or up to the number of hydrogens present in the unsubstituted heterocyclic radical group) replacing the hydrogen atom of the unsubstituted heterocyclic radical.
  • the substituted heterocyclic radical comprises 1-4, such as 1-2 or 1-3 substituents.
  • otherwise suitable substituents are selected from, for example, the substituents for alkyl groups as listed above.
  • Lactam ring refers to a saturated or partially unsaturated (i.e., having one or more double bonds and/or triple bonds in the ring) cyclic group containing an amide bond.
  • a 4-10-membered lactam ring group, a 4-membered, a 5-membered, or a 6-membered lactam ring group, and non-limiting examples of lactam ring groups include, but are not limited to, pyrrolidone group, 1H-pyrrole-2(5H)-one group, 2,5-diketopyrrolidinyl group, 2,4-diketopyrrolidinyl group, 1H-imidazole-2(5H)-one group, and the like.
  • Lactone cyclic group refers to a saturated or partially unsaturated (i.e., having one or more double bonds and/or triple bonds in the ring) cyclic group containing an ester group.
  • a 4-10-membered lactone cyclic group, a 4-membered, a 5-membered, or a 6-membered lactone cyclic group and non-limiting examples of lactone cyclic groups include, but are not limited to, 1,3-oxazolidin-5-one group, a butyrolactone group, a valerolactone group, and the like.
  • alkoxy refers to that at least 1 carbon atom in alkyl is replaced by the group formed by oxygen atom.Non-limiting examples include methoxyl group, ethoxyl group, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentyloxy, n-hexyloxy, cyclopropyloxy and cyclobutyloxy.Described alkyl definition is identical with " alkyl " definition as described above.
  • otherwise alkoxy group can be substituted by the hydrogen atom of the unsubstituted alkyl part of alkoxy alternatively by one or more substituents (such as one, two or three substituents, or 1-4 substituents, or up to the number of hydrogen present in unsubstituted alkoxy groups).
  • substituent is selected from, for example, as listed above, for the substituent for alkyl group, except that hydroxyl and amino are usually not present on the
  • Haloalkyl refers to that the alkyl defined herein is replaced by one or more halogen groups defined herein. Unless otherwise specified, the alkyl portion of the haloalkyl includes 1-4 carbon atoms.
  • Haloalkyl can be monohaloalkyl, dihaloalkyl, trihaloalkyl or polyhaloalkyl (including perhaloalkyl).
  • Monohaloalkyl can have one iodine, bromine, chlorine or fluorine in the alkyl group.
  • Dihaloalkyl groups and polyhaloalkyl groups can have two or more identical halogen atoms or a combination of different halogen groups in the alkyl.
  • Polyhaloalkyl includes, for example, up to 6, or 4, or 3, or 2 halogen groups.
  • haloalkyl include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl and dichloropropyl.
  • Perhaloalkyl refers to a alkyl (for example, trifluoromethyl) in which all hydrogen atoms are replaced by halogen atoms.
  • haloalkyl groups include monofluoro-, difluoro- and trifluoro-substituted methyl and ethyl groups (e.g., -CF3 , -CF2H , -CFH2 and -CH2CF3 ) .
  • haloalkyl groups may be optionally substituted by replacing the unsubstituted hydrogen atoms of the haloalkyl with one or more substituents (e.g., one, two or three substituents, or 1-4 substituents, or up to the number of hydrogens present on the unsubstituted haloalkyl group).
  • substituents are selected, for example, from the substituents listed above for alkyl groups.
  • Haloalkoxy refers to haloalkyl-O-, wherein haloalkyl is as defined above.
  • haloalkoxy include, but are not limited to, fluoromethoxy, difluoromethoxy, trifluoromethoxy, trichloromethoxy, 2-chloroethoxy, 2,2,2-trifluoroethoxy, 1,1,1,3,3,3-hexafluoro-2-propoxy, etc.
  • the haloalkoxy group includes 1-4 carbon atoms and up to three halogen elements, for example, methoxy and ethoxy groups substituted with mono-, di- and trifluoro-fluorine.
  • the haloalkoxy group may be optionally substituted by one or more substituents (such as one, two or three substituents, or 1-4 substituents, or up to the number of hydrogens present in the unsubstituted haloalkoxy group) replacing the hydrogen atoms of the unsubstituted alkyl portion of the haloalkoxy group.
  • substituents such as one, two or three substituents, or 1-4 substituents, or up to the number of hydrogens present in the unsubstituted haloalkoxy group
  • suitable substituents are selected, for example, as listed above for alkyl groups, except that hydroxy and amino groups are generally not present on the carbon directly attached to the oxygen of a substituted haloalkyl-O group.
  • Hydrophilicity refers to an -OH group.
  • Halo refers to fluorine, chlorine, bromine and iodine.
  • Groups and moieties substituted with halogen elements such as alkyl substituted with halogen elements (haloalkyl) can be monohalogenated, polyhalogenated or perhalogenated.
  • chlorine and fluorine are examples of halogen substituents on an alkyl group or a cycloalkyl group; unless otherwise specified, fluorine, chlorine and bromine are used, for example, on an aryl group or a heteroaryl group.
  • Substituted means that one or more hydrogen atoms, preferably up to 5, more preferably 1 to 3 hydrogen atoms in the group are replaced independently of each other by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and the skilled person can determine (by experiment or theory) possible or impossible substitutions without undue effort. For example, amino or hydroxy groups with free hydrogens may be unstable when combined with carbon atoms with unsaturated (e.g. olefinic) bonds.
  • Compounds disclosed herein may contain asymmetric centers, and therefore may exist as enantiomers. In the case where compounds disclosed herein have two or more asymmetric centers, they may additionally exist as diastereomers. Enantiomers and diastereomers belong to the broader category of stereoisomers. It is well known in the art how to prepare optically active forms such as by resolving materials or by asymmetric synthesis. All such possible stereoisomers (such as substantially pure resolved enantiomers, their racemic mixtures, and mixtures of diastereomers) are intended to be included. All stereoisomers of compounds disclosed herein and/or their pharmaceutically acceptable salts are intended to be included. Unless otherwise explicitly mentioned, reference to an isomer is applicable to any one of the possible isomers. When the isomeric composition is not specified, all possible isomers are included.
  • salts include, but are not limited to, salts formed with inorganic acids selected from, for example, hydrochlorides, phosphates, hydrogen phosphates, hydrobromides, sulfates, sulfinates, and nitrates; and salts formed with organic acids selected from, for example, malate, maleate, fumarate, tartrate, succinate, citrate, lactate, methanesulfonate, p-toluenesulfonate, 2-hydroxyethanesulfonate, benzoate, salicylate, stearate, alkanoate (e.g., acetate), and salts formed with HOOC-(CH2) n -COOH, wherein n is selected from 0 to 4.
  • examples of pharmaceutically acceptable cations include, but are not limited to, sodium, potassium, calcium, aluminum, lithium, and ammonium.
  • “Pharmaceutical composition” means a mixture containing one or more compounds described herein or their physiologically pharmaceutically acceptable salts or prodrugs and other chemical components, as well as other components such as physiologically pharmaceutically acceptable carriers and excipients.
  • the purpose of a pharmaceutical composition is to facilitate administration to an organism, facilitate the absorption of the active ingredient, and thus exert biological activity.
  • Carrier refers to a material that does not cause significant irritation to an organism and does not abrogate the biological activity and properties of the administered compound.
  • Excipient refers to an inert substance added to a pharmaceutical composition to facilitate administration of a compound.
  • Non-limiting examples include calcium carbonate, calcium phosphate, sugars, starches, cellulose derivatives (including microcrystalline cellulose), gelatin, vegetable oils, polyethylene glycols, diluents, granulating agents, lubricants, binders, and disintegrants.
  • Prodrug refers to a compound of the present invention that can be converted into a biologically active compound through in vivo metabolism.
  • the prodrug of the present invention is prepared by modifying the amino or carboxyl group in the compound of the present invention, and the modification can be removed by conventional operations or in vivo to obtain the parent compound.
  • the prodrug of the present invention is administered to a mammalian subject, the prodrug is cleaved to form a free amino or carboxyl group.
  • Steps refer to isomers resulting from different spatial arrangements of atoms in a molecule, including cis-trans isomers, enantiomers and conformational isomers.
  • heterocyclyl optionally substituted with alkyl means that the alkyl group may but need not be present, and the description includes instances where the heterocyclyl group is substituted with alkyl group and instances where the heterocyclyl group is not substituted with alkyl group.
  • Treating refers to administering at least one compound disclosed herein, and/or at least one stereoisomer thereof (if any), at least one stable isotope thereof, or at least one pharmaceutically acceptable salt thereof, to a subject suffering from, for example, cancer, identified in need thereof.
  • an effective amount refers to an amount of an agent disclosed herein that is effective for “treating” (as defined above) a disease or disorder in a subject.
  • Scheme 1 illustrates a general method for preparing compounds of the present disclosure and intermediates. Detailed descriptions and syntheses are disclosed in the following examples. Those skilled in the art will be able to find other synthetic methods or modify the following methods using conventional chemistry to prepare suitable compounds encompassed by Formula I. Therefore, these methods are equally applicable to the preparation of compounds of other embodiments. Although specific starting materials and reagents are depicted in the scheme and discussed below, other starting materials and reagents can be easily replaced to provide various compounds and/or reaction conditions.
  • the mass spectrum is obtained by LC/MS, and the ionization method can be ESI or APCI.
  • the thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate.
  • the silica gel plate used in thin layer chromatography (TLC) adopts a specification of 0.15mm-0.2mm, and the specification used for thin layer chromatography separation and purification products is 0.4mm-0.5mm.
  • CD 3 OD deuterated methanol.
  • Argon atmosphere means that the reaction bottle is connected to an argon balloon with a capacity of about 1L.
  • the solution in the reaction refers to an aqueous solution.
  • the compound is purified using a silica gel column chromatography eluent system and thin layer chromatography, wherein the eluent system is selected from: A: petroleum ether and ethyl acetate system; B: dichloromethane and methanol system; C: dichloromethane: ethyl acetate; wherein the volume ratio of the solvent varies according to the polarity of the compound, and a small amount of acidic or alkaline reagents, such as acetic acid or triethylamine, may also be added for adjustment.
  • A petroleum ether and ethyl acetate system
  • B dichloromethane and methanol system
  • C dichloromethane: ethyl acetate
  • the volume ratio of the solvent varies according to the polarity of the compound, and a small amount of acidic or alkaline reagents, such as acetic acid or triethylamine, may also be added for adjustment.
  • TEAD inhibitors including TEAD1, TEAD2, TEAD3, TEAD4.
  • PE Petroleum ether
  • Step 1 Preparation of 5-nitro-1-(5-(trifluoromethyl)pyridin-2-yl)indol-2-one
  • Step 2 Preparation of 5-amino-1-(5-(trifluoromethyl)pyridin-2-yl)indol-2-one
  • Step 2 Preparation of 5'-nitro-1'-(5-(trifluoromethyl)pyridin-2-yl)spiro[cyclohexane-1,3'-dihydroindole]-2'-one
  • compound 2-2 80 mg, 0.32 mmol
  • 2-iodo-5-trifluoromethylpyridine 96 mg, 0.35 mmol
  • (1R, 2R)-(-)-N, N'-dimethyl-1,2-cyclohexanediamine 27.31 mg, 0.19 mmol
  • cuprous iodide 18.28 mg, 0.096 mmol
  • anhydrous potassium phosphate 203.78 mg, 0.96 mmol
  • Step 3 Preparation of 5'-amino-1'-(5-(trifluoromethyl)pyridin-2-yl)spiro[cyclohexane-1,3'-dihydroindole]-2'-one
  • Compound 2-3 34 mg, 0.087 mmol
  • Pd/C 10 mg
  • the mixture was replaced with hydrogen and stirred at room temperature for 2 h.
  • the mixture was filtered, concentrated and dried to give the title compound 2-4 (25 mg, yield: 79%).
  • Step 4 N-(2'-oxo-1'-(5-(trifluoromethyl)pyridin-2-yl)spiro[cyclohexane-1,3'-dihydroindole]-5'-yl)propane Preparation of enamide
  • Step 1 Preparation of 3,3-dimethyl-5-nitro-1-(5-(trifluoromethyl)pyridin-2-yl)indol-2-one
  • reaction solution was extracted with EA (3 ⁇ 10 mL), the organic phases were combined, washed with saturated brine (20 mL) and water (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a crude product.
  • Step 2 Preparation of 5-amino-3,3-dimethyl-1-(5-(trifluoromethyl)pyridin-2-yl)-indolin-2-one
  • Step 1 N-(4-methoxybenzyl)-N-methyl-2-oxo-1-(4-(trifluoromethyl)phenyl)indoline-5-sulfonamide
  • Step 1 N-(4-methoxybenzyl)-N-methyl-2-oxo-1-(4-(trifluoromethyl)phenyl)indoline-5-sulfonamide
  • Step 1 N-(4-methoxybenzyl)-N-methyl-2'-oxo-1'-(4-(trifluoromethyl)phenyl)spiro[cyclohexane-1,3'-dihydro Preparation of [indole]-5'-sulfonamide
  • compound 6-1 N-(4-methoxybenzyl)-N-methyl-2-oxo-1-(4-(trifluoromethyl)phenyl)indoline-5-sulfonamide, 60 mg, 0.12 mmol
  • 1,5-dibromopentane 55.19 mg, 0.24 mmol
  • cesium carbonate 117.30 mg, 0.36 mmol
  • Step 2 Preparation of N-methyl-2'-oxo-1'-(4-(trifluoromethyl)phenyl)spiro[cyclohexane-1,3'-dihydroindole]-5'-sulfonamide preparation
  • Step 1 Preparation of ethyl 2-fluoro-5-(N-(4-methoxybenzyl)-N-methylsulfamoyl)benzoate
  • Step 3 5-(N-(4-methoxybenzyl)-N-methylsulfamoyl)-2-((4-(trifluoromethyl)benzyl)amino ⁇ Preparation of Benzoic Acid
  • Step 5 N-(4-methoxybenzyl)-N-methyl-3-(1-methyl-1H-imidazol-4-yl)-2-oxo-1-(4-(trifluoromethyl) Preparation of (Benzyl)-2,3-dihydro-1H-benzo[d]imidazole-5-sulfonamide
  • Step 6 N-methyl-3-(1-methyl-1H-imidazol-4-yl)-2-oxo-1-(4-(trifluoromethyl)benzyl)-2,3-dihydro-1H- Preparation of benzo[d]imidazole-5-sulfonamide
  • Iron powder (201.06 mg, 3.60 mmol) and ammonium chloride (192.56 mg, 3.60 mmol) were added to a mixed solvent of ethanol (6 mL) and water (2 mL), stirred at room temperature for 30 minutes, and compound 8-3 (180 mg, 0.36 mmol) was added, and refluxed at 80°C for 2 hours.
  • MS showed that the reaction was complete.
  • the reaction solution was filtered (diatomaceous earth), dried by spin-drying, and purified by prep-HPLC. The mobile phase methanol concentration was 85% to obtain the product and collect the target product.
  • the target product was dried by spin-drying to obtain compound 8-4 (106 mg, yield: 62.68%) as a yellow solid.
  • Step 5 N-(4-methoxybenzyl)-N-methyl-3-(1-methyl-1H-imidazol-4-yl)-2-oxo-1-(4-(trifluoromethyl) Preparation of 2,3-dihydro-1H-benzo[d]imidazole-5-sulfonamide.
  • Step 6 N-methyl-3-(1-methyl-1H-imidazol-4-yl)-2-oxo-1-(4-(trifluoromethyl)phenyl)-2,3-dihydro-1H- Preparation of benzo[d]imidazole-5-sulfonamide
  • Step 1 N-(4-methoxybenzyl)-N,3,3-trimethyl-2-oxo-1-(4-(trifluoromethyl)phenyl)indoline-5-sulfonate Preparation of amide
  • Step 2 Preparation of N,3,3-trimethyl-2-oxo-1-(4-(trifluoromethyl)phenyl)indoline-5-sulfonamide
  • Test Example 1 TEAD-luciferase reporter gene test
  • TEAD was detected using Bright Glo luciferase assay (Promega).
  • the experimental method is briefly described as follows: 100 ⁇ L of 293T (20,000 cells per well) cell suspension was inoculated into a 96-well plate with a transparent white bottom, and cultured in a carbon dioxide incubator overnight to allow the cells to fully adhere to the wall. The next day, 100 ng of TEAD-luciferase reporter plasmid was transfected into each well using lipofectamine 3000. 24 hours after transfection, the supernatant of each well was aspirated, 90 ⁇ L of culture medium was added, and the compound was dissolved in DMSO to prepare a 10 mM stock solution.
  • the compound was continuously diluted 4-fold with DMSO to 10 different concentrations; 2 ⁇ L of the above gradient diluted compound solution was transferred to a 96-well plate containing 198 ⁇ L of culture medium and fully incubated. Mix well to obtain a 100 ⁇ compound stock solution; then transfer 10 ⁇ L of the above 100 ⁇ compound to a 96-well plate inoculated with 90 ⁇ L of cells to obtain a final 1 ⁇ concentration, and the final concentration of DMSO is 0.1%. Gently shake the plate to mix the drug thoroughly, and place the cell culture plate in a CO2 incubator for further culturing for 24 hours.
  • Inhibition rate (%) 100-(sample TEAD luciferase reporter signal/sample CTG signal)/(control group TEAD luciferase reporter signal/control group CTG signal) ⁇ 100.
  • Control group (cells) contained an equal amount of DMSO.
  • Curve fits and IC50 values were determined using GraphPad Prism 7 with a 3-parameter nonlinear regression equation (variable slope).
  • Test Example 2 Determination of the activity of the compounds of the present invention on H226 cells
  • the experimental method is briefly described as follows: 90 ⁇ L of tumor cell H226 (700 cells per well) cell suspension was inoculated into a 96-well plate. The culture plate was then placed in a CO2 incubator and cultured overnight to allow the cells to fully adhere. On the second day, the compound was dissolved in DMSO and then prepared into a 10 mM stock solution.
  • the compound was continuously diluted 4-fold with DMSO to 10 different concentrations; 2 ⁇ L of the above gradient diluted compound solution was transferred to a 96-well plate containing 198 ⁇ L of culture medium and mixed thoroughly to obtain a 100 ⁇ compound stock solution; then 10 ⁇ L of the above 100 ⁇ compound was transferred to a 96-well plate inoculated with 90 ⁇ L of cells to obtain a final 1 ⁇ concentration, and the final concentration of DMSO was 0.1%. The plate was gently shaken to fully mix the drug, and the cell culture plate was placed in a CO2 incubator for further culture for 7 days.
  • A represents less than 0.1 ⁇ M
  • B represents 0.1 to 0.5 ⁇ M
  • C represents 0.1 to 1 ⁇ M
  • D represents >1 ⁇ M

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Abstract

本发明提供了如下式(I)所示的化合物和/或式(I)的化合物的立体异构体、互变异构体或其可药用的盐或溶剂合物、其制备方法、包括式(I)的化合物的药物组合物和其作为治疗剂在疾病的治疗上的应用，所述疾病是与增加的TEAD表达或增加的TEAD活性相关的疾病，例如癌症。

Description

TEAD抑制剂、其制备方法和在医学上的应用 技术领域
本公开涉及医药技术领域，尤其涉及一种YAP/TAZ-TEAD相互作用抑制剂及其用途。
背景技术
Hippo信号通路(Hippo pathway)是一条抑制细胞生长的通路，其首次发现于在果蝇中对参与调节器官大小的肿瘤抑制基因进行遗传筛选的过程中。已有研究表明，Hippo通路由一系列的激酶级联反应组成，其主要用于通过调控细胞增殖和凋亡来控制器官大小。
Hippo信号通路上游膜蛋白受体是胞外生长抑制信号的感受器。一旦上游膜蛋白受体感受到胞外生长抑制信号，Hippo信号通路打开，激活一系列激酶级联磷酸化反应，即与SAV1形成复合体的MST1和MST2激酶磷酸化并激活与MOB1形成复合体的LATS1和LATS2激酶(LATS1/2-MOB1)；然后活化后的LATS1/2-MOB1磷酸化YAP(Yes Associated Protein)/TAZ(Transcriptional coactivator with PDZ-binding motif)；然后磷酸化的YAP/TAZ被14-3-3蛋白保留在细胞质中或被SCFβ-Trcp E3连接酶泛素化后降解而不能YAP/TAZ进入细胞核中。然而，当Hippo信号通路上的一个或多个成员的发生基因突变，细胞质内的YAP/TAZ不能被磷酸化时，未被磷酸化的YAP/TAZ会进入细胞核。进入细胞核内的YAP/TAZ与核内转录因子TEAD(Transcriptional enhanced associated domain)形成复合物后与DNA结合，启动下游基因(CTGF、Cyr61、Axl等)的表达，促进细胞的增殖生长，从而导致肿瘤或其他过度增殖性疾病的发生。
因此，通过药物干预来抑制YAP、TAZ、TEAD和YAP-TEAD或TAZ-TEAD蛋白间的相互作用似乎是预防和/或治疗癌症和其他过度增殖性疾病的合理且有价值的策略。
文献中报道化合物TEAD-347(Bum-Erdene et al.,2019,Cell Chem Biol26,378-389),Verteporfin(Liu-Chittenden et al.,2012,Gene Dev 26,1300-1305)，K-975(Ayumi Kaneda et al,Am J Cancer Res 2020；10(12):4399-4415),LM98(Léa Mélin et al,ChemMedChem 2021,16,1–22)能够抑制细胞中的TEAD/YAP蛋白间相互作用，表现出一定的抗肿瘤活性。专利中WO2018204532,WO2017064277,WO2021133896,WO2019232216,WO2020243423,WO2021186324,也报道了不同结构化合物，能够阻断TEAD/YAP蛋白间相互作用，具有潜在治疗相关疾病的潜力。
然而，在TEAD结合剂、YAP-TEAD或TAZ-TEAD蛋白间相互作用抑制剂方面，目前尚无相应药物获批上市。因此，仍然需要开发安全有效的抑制剂，用于抑制YAP-TEAD或TAZ-TEAD蛋白间的相互作用。
发明内容
本申请的第一方面提供了一种通式(I)所示的新型苯环类衍生物，或其立体异构体、互变异构体或其可药用的盐。所述通式(I)的化合物可用作抑制剂以抑制TEAD与YAP/TAZ之 间的相互作用。
本公开的第一方面涉及一种通式(I)所示的化合物或其可药用的盐：
其中：
X1为N或CR1；
X2和X3中的每一者独立地选自N或CR2；
R1选自-CN、R1A或-L-R1B；
R1A选自H、卤素、-OH、-ORa、NH2、＝O、-CN、C1-6烷基、C2-4烯基、C2-4炔基、C1-4烷氧基、C1-4卤代烷基、C1-4卤代烷氧基、-OC(O)Ra、-C(O)Ra、-CO2Ra、-C(O)N(RxRy)、-N(RxRy)、-N(Rx)C(O)Ra、-N(Rx)CO2Ra、-N(Ra)C(＝NRx)Rz、-N(Rx)S(O)1-2Ra、-N(Rz)C(O)N(RxRy)、-N(Rz)C(＝NRa)N(RxRy)、-N(Rz)S(O)1-2N(RxRy)、C3-6亚环烷基、3-6元环烷基、含有1-2个选自N、O和S的杂原子作为环成员的3-6元杂环烷基、5-6元芳基、含有1-4个选自N、O和S的杂原子作为环成员的5-6元杂芳基、或者8-10元稠合双环，所述8-10元稠合双环为其中，所述环A’可包含至少一个选自N、O、S的杂原子且为芳香环或脂肪环，所述环A”可包含至少一个选自N、O、S的杂原子且为芳香环或脂肪环，所述环A’和A”中的至少一个包含至少一个杂原子；其中，所述3-6元环烷基、含有1-2个选自N、O和S的杂原子作为环成员的3-6元杂环烷基、5-6元芳基、含有1-4个选自N、O和S的杂原子作为环成员的5-6元杂芳基以及8-10元稠合双环中的每一者可选地被选自H、卤素、-NH2、-CN、-OH、C1-6烷基、C1-6烷氧基、C1-6卤代烷基和三氟乙烯基的取代基团取代；
L为键、-O-、-NH-、-CO-或-CONH-；
R1B为螺合双环，所述螺合双环由两个3-8元饱和碳环或饱和杂环螺合形成，其中，所述3-8元饱和杂环具有1-2个选自N、O和S的杂原子，所述螺合双环可选地被选自H、卤素、-NH2、-CN、-OH、C1-6烷基、C1-6烷氧基或C1-6卤代烷基、三氟乙烯基的取代基取代；
Ra和Rz独立地选自H、卤素、-NH2、-CN、-OH、C1-6烷基、C1-6烷氧基或C1-6卤代烷基、三氟乙烯基；
Rx和Ry选自H、C1-6烷基、C1-6卤代烷基或三氟乙烯基；或者Rx和Ry与其共同附接 的氮原子一起形成饱和的或部分饱和的3-6元杂环烷基、或6-10元内酰胺环，所述饱和的或部分饱和的3-6元杂环烷基或6-10元内酰胺环可选地被选自H、-OH、-NH2、-CN、卤素、C1-6烷基、C1-6卤代烷基或三氟乙烯基的基团取代；
R2在每次出现时均独立地选自H、-OH、-NH2、卤素、-CN、C1-6烷基、‐O‐C1‐6烷基或C1-4卤代烷基、三氟乙烯基；或者，相邻的R2结合形成可选被取代的C2-4亚烷基、-C(O)N(Ra)Ra-或-C(O)ORa-，其中，所述可选被取代的C2-4亚烷基可选地被0、1、2或3个选自C1-6烷基的取代基取代；
X4和X5中的每一者均独立地选自CH2、NH、C(R3R4)或NR5；
R3和R4独立地选自H、-CN、可选地被C1-3烷氧基或羟基取代的C1-4烷基、COO(C1-4烷基)或酰胺基；或者R3、R4与其附接的碳原子形成环Rx，所述环Rx为：
1)3-8元饱和环、含有1-2个选自N、O和S的杂原子作为环成员的3-8元饱和杂环；
2)6-10元内酰胺环；
3)螺接-稠合双环；所述螺接-稠合双环为所述环B’为5-8元内酰胺环、5-8元内酯环、可包含至少一个选自N、O、S的杂原子的4-6元芳香杂环或脂肪杂环；所述环B”为可包含至少一个选自N、O、S的杂原子的4-6元芳香杂环或脂肪杂环；n为1-5,m为1-5；或
4)螺接-稠合三环；所述螺-稠合三环为其中，所述环B’可包含至少一个选自N、O、S的杂原子的芳香杂环或脂肪杂环、5-8元内酰胺环、5-8元内酯环；所述环B”可包含至少一个选自N、O、S的杂原子的5-6元芳香杂环或脂肪杂环；所述环B”’可包含至少一个选自N、O、S的杂原子的芳香杂环或脂肪杂环；其中，所述环B’、B”和B”’中的至少一个包含至少一个杂原子；n为1-4；m为1-5；
所述环Rx可选地具有1-4个选自H、＝O、磺酰基、酰胺基、3-8元环烷基、3-8元杂环烷基、卤素、-CN、-OH、C1-6烷基、C1-C6烷氧基、C1-6卤代烷基、三氟乙烯基或C3-6环烷基的取代基；
R5为-M-R5a，M为键或C1-4亚烷基；
R5a为C1-6烷基、C1-6烷氧基、3-6元环烷基、含有1-2个选自N、O和S的杂原子作为环成员的3-8元杂环烷基、5-12元芳基、含有1-4个选自N、O和S的杂原子作为环成员的5-12元杂芳基；所述R5a可选地具有1-3个选自卤素、-CN、-OH、C1-6烷基、C1-C4烷氧基、C1-6卤代烷基或可选地被C1-6烷基或C1-6卤代烷基取代的C3-6环烷基或三氟乙烯基的取代基。
Rw选自如下式W-1至W-7组成的组：
其中，Rb、Rc和Rd中的每一者均独立地选自H、、卤素或C1-4烷基，所述C1-4烷基可选地被二甲基氨基取代。
本文还提供根据式(I)的化合物或本公开中描述的式(I)的任何实施方案或任何这些化合物的药学上可接受的盐、互变异构体、立体异构体或氘代类似物的用途,或本公开中描述的任何化合物的药物组合物,用于治疗由TEAD的表达量增加引起的疾病或病症。
本公开的第二方面涉及药物组合物,其包含根据式(I)的化合物或本公开中描述的式(I)的任何实施例和子实施例,或其药学上可接受的盐、互变异构体、立体异构体或任何这些化合物的氘代类似物,以及药学上可接受的载体或赋形剂。
本公开的第三方面涉及治疗患有至少部分与TEAD的表达量或活性增加有关的疾病或病症的受试者的方法,所述方法包括向受试者施用有效量的根据式(I)的化合物,或本公开中描述的式(I)的任何实施方案,或任何这些化合物的药学上可接受的盐、互变异构体、立体异构体或氘代类似物,或本公开中描述的任何化合物的药物组合物。
本公开的第四方面涉及根据式(I)的化合物或者包括式(I)的化合物的组合物在制备用于治疗与TEAD的表达量或活性增加有关的疾病或病症的药物中的用途。
具体实施方式
定义
除非有相反陈述，否则本发明在说明书和权利要求书中所使用的部分术语定义如下：
不在两个字母或符号之间的破折号(“-”)用于表示取代基的连接点。例如，-CONRaRb通过碳原子连接。
本发明所述基团和化合物中所涉及的碳、氢、氧、硫、氮或F、Cl、Br、I均包括它们的同位素情况，及本发明所述基团和化合物中所涉及的碳、氢、氧、硫或氮任选进一步被 一个或多个它们对应的同位素所替代，其中碳的同位素包括12C、13C和14C，氢的同位素包括氕(H)、氘(D，又叫重氢)、氚(T，又叫超重氢)，氧的同位素包括16O、17O和18O，硫的同位素包括32S、33S、34S和36S,氮的同位素包括14N和15N，氟的同位素包括17F和19F，氯的同位素包括35Cl和37Cl，溴的同位素包括79Br和81Br。
本文中的术语“烷基”指选自具有多达18个碳原子(如从1个至12个碳原子，进一步地如从1个至8个碳原子，甚至更进一步地如从1个至6个碳原子)的直链和支链的饱和烃基的烃基。烷基的代表性实例包含，但不限于甲基、乙基、正丙基、异丙基、正丁基、仲丁基、异丁基、叔丁基、正戊基、异戊基、新戊基、正己基、3-甲基己基、2,2-二甲基戊基、2,3-二甲基戊基、正庚基、正辛基、正壬基、正癸基等。
除非明确说明，否则烷基基团可以可选地通过一个或更多个取代基(如一个、两个或三个取代基，或1-4个取代基，或多达存在于未被取代的烷基基团上的氢的数量)替代未被取代烷基的氢原子而被取代。如果没有另外规定，则烷基适合的取代基可以选自卤族元素、D、CN、桥氧基、羟基、被取代的或未被取代的C1-C4烷氧基、被取代的或未被取代的C3-C6环烷基、被取代的或未被取代的含有1个或2个选自N、O和S的杂原子作为环成员的3-7元杂环烷基、被取代的或未被取代的芳基、被取代的或未被取代的含有1个至4个选自N、O和S的杂原子作为环成员的杂芳基、氨基、-NH(C1-C4烷基)、-N(C1-C4烷基)2、-S(＝O)0-2(C1-C4烷基)、-S(＝NR)(＝O)(C1-C4烷基)、-C(＝O)(C1-C4烷基)、-C(＝NOH)(C1-C4烷基)、-CO2H、-CO2(C1-C4烷基)、-S(＝O)1-2NH2、-S(＝O)1-2NH(C1-C4烷基)、-S(＝O)1-2N(C1-C4烷基)2、-CONH2、-C(＝O)NH(C1-C4)、-C(＝O)N(C1-C4烷基)2、-C(＝NOH)NH(C1-C4烷基)、-OC(＝O)(C1-C4烷基)、-NHC(＝O)(C1-C4烷基)、-NHC(＝NOH)(C1-C4烷基)、-NH(C＝O)NH2、-NHC(＝O)O(C1-C4烷基)、-NHC(＝O)NH(C1-C4烷基)、NHC(＝NOH)NH(C1-C4烷基)、-NHS(＝O)1-2(C1-C4烷基)、-NHS(＝O)1-2NH2、以及-NHS(＝O)1-2NH(C1-C4烷基)；其中，用于被取代的C1-C4烷氧基、被取代的C3-C6环烷基、被取代的3-7元杂环烷基、被取代的芳基和被取代的杂芳基的取代基是多达三个独立地选自卤族元素、D、-CN、C1-C4烷基、C1-C4卤代烷基、桥氧基、羟基、C1-C4烷氧基、氨基、-NH(C1-C4烷基)、-N(C1-C4烷基)2的基团。在一些实施方案中，除非另有规定，否则烷基基团的取代基选自例如卤族元素、CN、桥氧基、羟基、C1-C4烷氧基、C3-C6环烷基、苯基、氨基、-NH(C1-C4烷基)、-N(C1-C4烷基)2、C1-C4烷硫基、C1-C4烷基磺酰基、-C(＝O)(C1-C4烷基)、-CO2H、-CO2(C1-C4烷基)、-OC(＝O)(C1-C4烷基)、-NHC(＝O)(C1-C4烷基)和-NHC(＝O)O(C1-C4烷基)。
本文中的术语“烷氧基”指通过氧桥连接的包括1至18个碳原子的直链或支链烷基基团(如甲氧基、乙氧基、丙氧基、异丙氧基、正丁氧基、仲丁氧基、叔丁氧基、戊氧基、2-戊氧基、异戊氧基、新戊氧基、己氧基、2-己氧基、3-己氧基、3-甲基戊氧基等)。通常，烷氧基基团包括通过氧桥连接的1至6个碳原子(如1至4个碳原子)。
除非明确说明，否则烷氧基基团可以可选地通过一个或更多个取代基(如一个、两个或三个取代基，或1-4个取代基，或多达存在于未被取代的烷氧基基团上的氢的数量)替代烷氧基的未被取代的烷基部分的氢原子而被取代。除非另有规定，否则适合的取代基选自例如如上文所列的用于烷基基团的取代基，除了羟基和氨基通常不存在于与被取代的烷基-O基团的氧直接连接的碳上。
本文中的术语“烯基”指选自直链和支链烃基的烃基，所述烃基包括至少一个C＝C双键和2至18个(如2至6个)碳原子。烯基基团的实例可以选自乙烯基(ethenyl)或乙烯基(vinyl)(-CH═CH2)、丙-1-烯基(-CH═CHCH3)、丙-2-烯基(-CH2CH═CH2)、2-甲基丙-1-烯基、丁-1-烯基、丁-2-烯基、丁-3-烯基、丁-1,3-二烯基、2-甲基丁-1,3-二烯、己-1-烯基、己-2-烯基、己-3-烯基、己-4-烯基和己-1,3-二烯基基团。连接点可以在不饱和碳或饱和碳上。
除非明确说明，否则烯基基团可以可选地通过一个或更多个取代基(如一个、两个或三个取代基，或1-4个取代基，或多达存在于未被取代的烯基基团上的氢的数量)替代烯基的未被取代的氢原子而被取代。除非另有规定，否则适合的取代基选自例如如上文所列的用于烷基基团的取代基。
本文中的术语“炔基”指选自直链和支链烃基的烃基，所述烃基包括至少一个-C≡C-三键和2至18个(如2个至6个)碳原子。炔基基团的实例包含乙炔基(-C≡CH)、1-丙炔基(-C≡CCH3)、2-丙炔基(炔丙基，-CH2C≡CH)、1-丁炔基、2-丁炔基和3-丁炔基基团。连接点可以在不饱和碳或饱和碳上。
除非明确说明，否则炔基基团可以可选地通过一个或更多个取代基(如一个、两个或三个取代基，或1-4个取代基，或多达存在于未被取代的炔基基团上的氢的数量)替代炔基的未被取代的氢原子而被取代。除非另有规定，否则适合的取代基选自例如如上文所列的用于烷基基团的取代基。
术语“亚烷基”指包括1至10个碳原子和连接至其他分子部分的两个展开价键的二价烷基基团。连接至亚烷基的两个分子部分可以在相同碳原子上或者在不同碳原子上。因此，例如，亚丙基为可以是1,1-二取代的、1,2-二取代的或1,3-二取代的3-碳亚烷基。除非另有规定，否则亚烷基指包括1至6个碳原子(如1至4个碳原子)的部分。亚烷基的代表性实例包含(但不限于)亚甲基、亚乙基、正亚丙基、异亚丙基、正亚丁基、仲亚丁基、异亚丁基、叔亚丁基、正亚戊基、异亚戊基、新亚戊基、正亚己基、3-甲基亚己基、2,2-二甲基亚戊基、2,3-二甲基亚戊基、正亚庚基、正亚辛基、正亚壬基、正亚癸基等。被取代的亚烷基是含有一个或更多个(如一个、两个或三个)取代基的亚烷基基团；除非另有规定，否则适合的取代基选自例如如上文所列的用于烷基基团的取代基。
术语“卤代烷基”指本文所定义的烃基被一个或多个本文所定义的卤素基团取代。除非另有规定，否则卤代烷基的烃基部分包括1-4个碳原子。卤代烷基可以是单卤代烷基、二卤代烷基、三卤代烷基或多卤代烷基(包含全卤代烷基)。单卤代烷基可以在烃基基团内具 有一个碘、溴、氯或氟。二卤代烷基基团和多卤代烷基基团可以在烃基内具有两个或更多个相同卤素原子或者不同卤素基团的组合。多卤代烷基包括例如多达6个、或4个、或3个、或2个卤素基团。卤代烷基的实例包含(但不限于)氟代甲基、二氟甲基、三氟甲基、氯代甲基、二氯甲基、三氯甲基、五氟乙基、七氟丙基、二氟氯甲基、二氯氟甲基、二氟乙基、二氟丙基、二氯乙基和二氯丙基。全卤代烷基指全部氢原子被卤素原子替换的烃基(例如，三氟甲基)。在一些实施方案中，除非另有规定，否则卤代烷基基团包含单氟-、二氟-和三氟-取代的甲基和乙基基团(例如，-CF3、-CF2H、-CFH2和-CH2CF3)。
除非明确说明，否则卤代烷基基团可以可选地通过一个或更多个取代基(如一个、两个或三个取代基，或1-4个取代基，或多达存在于未被取代的卤代烷基基团上的氢的数量)替代卤代烷基的未被取代的氢原子而被取代。除非另有规定，否则适合的取代基选自例如如上文所列的用于烷基基团的取代基。
如本文所使用的，术语“卤代烷氧基”指卤代烷基-O-，其中卤代烷基如上文所定义。卤代烷氧基的实例包含(但不限于)氟代甲氧基、二氟甲氧基、三氟甲氧基、三氯甲氧基、2-氯乙氧基、2,2,2-三氟乙氧基、1,1,1,3,3,3-六氟-2-丙氧基等。在一些实施方案中，卤代烷氧基基团包括1-4个碳原子和多达三个卤族元素，例如，单氟、二氟和三氟取代的甲氧基基团和乙氧基基团。
除非明确说明，否则卤代烷氧基基团可以可选地通过一个或更多个取代基(如一个、两个或三个取代基，或1-4个取代基，或多达存在于未被取代的卤代烷氧基团上的氢的数量)替代卤代烷氧基的未被取代的烷基部分的氢原子而被取代。除非另有规定，否则适合的取代基选自例如如上文所列的用于烷基基团的取代基，除了羟基和氨基通常不存在于与被取代的卤代烷基-O基团的氧直接连接的碳上。
除非明确说明，否则亚烷基基团可以可选地通过一个或更多个取代基(如一个、两个或三个取代基，或1-4个取代基，或多达存在于未被取代的亚烷基基团上的氢的数量)替代亚烷基的未被取代的氢原子而被取代。除非另有规定，否则适合的取代基选自例如如上文所列的用于烷基基团的取代基。
术语“芳基”指在环部分中包括5-15个碳原子的芳族烃基。在一些实施方案中，芳基指选自5元和6元碳环芳环的基团，例如，苯基；选自例如萘、二氢化茚和1,2,3,4-四氢喹啉的双环环系(如7元至12元双环环系，其中至少一个环是碳环且芳族的)；以及三环环系(如10元至15元三环环系，其中至少一个环是碳环且芳族的)，例如，芴。
在一些实施方案中，芳基基团选自稠合至5元至7元环烷基或可选地包括至少一个选自例如N、O和S的杂原子的杂环(如下文“杂环基”或“杂环”中所定义的)的5元和6元碳环芳环，条件是当碳环芳环与杂环稠合时，连接点在碳环芳环处，并且当碳环芳环与环烷基基团稠合时，连接点可以在碳环芳环处或者在环烷基基团处。由被取代的苯衍生物形成的并且在环原子处具有自由价的二价基团被命名为被取代的亚苯基基团。通过从名称以“-基” 结尾的一价多环烃基的具有自由价的碳原子上除去一个氢原子而获得的二价基团的命名是通过在其相应的一价基团中添加“亚基”来进行的，例如，具有两个连接点的萘基基团被称为亚萘基。然而，芳基不包括杂芳基或者不以任何方式与杂芳基重叠，其在下文中进行了单独定义。因此，如果一个或更多个碳环芳环与杂环芳环(例如，如下文定义的杂芳基)稠合，则所得的环系是如本文所定义的杂芳基，而非芳基。
在本文中，“螺接-稠合双环”是指螺接在母体上的稠合双环。
在本文中，“螺接-稠合三环”是指通过螺接的方式连接在母体上的包括稠合双环的三环结构。
除非明确说明，否则芳基基团可以可选地通过一个或更多个取代基(如一个、两个或三个取代基，或1-4个取代基，或多达存在于未被取代的芳基基团上的氢的数量)替代未被取代的芳基的氢原子而被取代。在一些实施方案中，取代的芳基包含1-5个，取代基。除非另有规定，否则适合的取代基选自例如如上文所列的用于烷基基团的取代基。
本文中的术语“杂芳基”指选自5元至7元芳族单环的基团，所述5元至7元芳族单环包括至少一个(例如，1至4个杂原子，或者在一些实施方案中，1至3个杂原子)选自例如N、O和S的杂原子，其中剩余的环原子是碳；8元至12元双环，所述8元至12元双环包括至少一个(例如，1至4个杂原子，或者在一些实施方案中，1至3个杂原子，或者在其他实施方案中，1个或2个杂原子)选自例如N、O和S的杂原子，其中剩余的环原子是碳，并且其中至少一个环是芳族的以及至少一个杂原子存在于芳环中，并且其中连接点在任何环上且在碳或杂原子上；以及11元至14元三环，所述11元至14元三环包括至少一个(例如，1至4个杂原子，或者在一些实施方案中，1至3个杂原子，或者在其他实施方案中，1个或2个杂原子)选自例如N、O和S的杂原子，其中剩余的环原子是碳，并且其中至少一个环是芳族的，并且至少一个杂原子存在于芳环中，并且其中连接点在任何环上。
在一些实施方案中，杂芳基基团包含稠合至5元至7元环烷基环的5元至7元杂环芳环。对于仅其中一个环包括至少一个杂原子的此类稠合双环杂芳基环系，连接点可以在杂芳环处或者在环烷基环处。
在一些实施方案中，杂芳基基团包含稠合至5元至7元芳基环的5元至7元杂环芳环。对于仅其中一个环包括至少一个杂原子的此类稠合双环杂芳基环系，连接点可以在杂芳环处或者在芳基环处。非限制性实例包含喹啉基和喹唑啉基。
在一些实施方案中，杂芳基基团包含稠合至另外的5元至7元杂环芳环的5元至7元杂环芳环。非限制性实例包含1H-吡唑并[3,4-b]吡啶基和1H-吡咯并[2,3-b]吡啶基。
当杂芳基基团中的S原子和O原子的总数量超过1时，那些杂原子不是彼此相邻的。在一些实施方案中，杂芳基基团中的S原子和O原子的总数量不超过2。在一些实施方案中，芳杂环中的S原子和O原子的总数量不超过1。
杂芳基基团的实例包含但不限于吡啶基、增啉基、吡嗪基、嘧啶基、咪唑基、咪唑并 吡啶基、异噁唑基、噁唑基、噻唑基、异噻唑基、噻二唑基、四唑基、噻吩基、三嗪基、苯并噻吩基、呋喃基、苯并呋喃基、苯并咪唑基、吲哚基、异吲哚基、二氢吲哚基、酞嗪基、吡嗪基、哒嗪基、嘧啶基、吡咯基、***基、喹啉基、异喹啉基、吡唑基、吡咯并吡啶基(如1H-吡咯并[2,3-b]吡啶-3-基)、吡唑并吡啶基(如1H-吡唑并[3,4-b]吡啶-3-基)、苯并噁唑基(如苯并[d]噁唑-6-基)、蝶啶基、嘌呤基、1-氧杂-2,3-二唑基、1-氧杂-2,4-二唑基、1-氧杂-2,5-二唑基、1-氧杂-3,4-二唑基、1-硫杂-2,3-二唑基、1-硫杂-2,4-二唑基、1-硫杂-2,5-二唑基、1-硫杂-3,4-二唑基、呋咱基、苯并呋咱基、苯并噻吩基、苯并噻唑基、苯并噁唑基、喹唑啉基、喹喔啉基、萘啶基、呋喃并吡啶基、苯并噻唑基(如苯并[d]噻唑-6-基)、吲唑基(如1H-吲唑-5-基)和5,6,7,8-四氢异喹啉。
除非明确说明，否则杂芳基基团可以可选地通过一个或更多个取代基(如一个、两个或三个取代基，或1-4个取代基，或多达存在于未被取代的杂芳基基团上的氢的数量)替代未被取代的杂芳基的氢原子而被取代。在一些实施方案中，取代的杂芳基包含1个、2个或3个取代基。除非另有规定，否则适合的取代基选自例如如上文所列的用于烷基基团的取代基。
“双环”指具有两个连接环的基团。双环可以为碳环(所有环原子为碳原子)或杂环(除了碳原子之外，环原子包括例如1、2或3个杂原子，例如N、O或S)。这两个环都可以是脂肪族的(例如萘烷和降冰片烷)，或可以是芳香族(例如萘)，或脂肪族和芳香族的组合(例如四氢化萘)。双环包括(a)螺环化合物，其中两个环只共享一个单原子(螺原子，其通常为季碳)。螺环化合物的实例包括但不限于：
(b)稠合的双环化合物，其中两个环共享两个相邻原子。换句话说，环共享一个共价键，即桥头原子直接连接(例如α‐崖柏烯和萘烷)。稠合的双环的实例包括但不限于：
和(c)桥联的双环化合物，其中两个环共享三个或更多个原子，并通过包含至少一个原子的桥将两个桥头原子隔开。例如，降冰片烷，也称为双环[2.2.1]庚烷，可以被认为是一对环戊烷环，每个环共享它们的五个碳原子中的三个。桥联的双环的实例包括但不限于：
“单环”指本身或与其他术语组合包含的单碳环。“碳环”是指饱和或者不饱和的芳香环或者非芳香环。当为芳香环时，其定义与上文“芳基”的定义相同；当为非芳香环时，其可以是3至10元(例如3、4、5、6、7、8、9、10元)的单环、4至12元(例如4、5、6、7、8、9、10、11、12元)双环或者10至15元(例如10、11、12、13、14、15元)三环体系，可以是桥环或者螺环，非限制性实施例包括环丙基、环丁基、环戊基、1-环戊基-1-烯基、1-环戊基-2-烯基、1-环戊基-3-烯基、环己基、1-环己基-2-烯基、1-环己基-3-烯基、环己烯基、环己二烯基、环庚基、环辛基、环壬基、环癸基、环十一烷基、环十二烷基、所述的“碳环基”或“碳环”任选进一步被1个或者多个取代基所取代。
本文中的术语“环烷基”指选自包括从3个至20个碳原子的饱和的和部分不饱和的环烃基(如单环和多环(例如，双环和三环、金刚烷基和螺环烷基)基团)的烃基。单环烷基 基团是包括3至20个碳原子(如3至8个碳原子)的环烃基。单环环烷基的实例包含，但不限于环丙基、环丁基、环戊基、环己基、环庚基、环辛基、环癸基、环十二烷基和环己烯基。双环烷基基团包含桥连的双环烷基、稠合的双环烷基和螺环烷基。桥连的双环烷基含有单环环烷基环，其中单环的两个不相邻的碳原子通过一个至三个附加碳原子的亚烷基桥(即，-(CH2)n-形式的桥连基团，其中n是1、2或3)连接。桥连双环烷基的实例包含但不限于双环[2.2.1]庚烯、双环[3.1.1]庚烷、双环[2.2.1]庚烷、双环[2.2.2]辛烷、双环[3.2.2]壬烷、双环[3.3.1]壬烷和双环[4.2.1]壬烷等。稠合的双环烷基含有稠合至苯基、单环环烷基和单环杂芳基中的一者的单环环烷基环。稠合的双环烷基的实例包含但不限于双环[4.2.0]辛-1,3,5-三烯、2,3-二氢-1H-茚、6,7-二氢-5H-环戊二烯并[b]吡啶、5,6-二氢-4H-环戊二烯并[b]噻吩和萘烷等。螺环烷基含有共享形成双环环系的碳原子的两个单环环系。螺环烷基的实例包含但不限于双环环烷基基团包括例如7至12个碳原子。单环烷基或双环烷基通过环烷基环内含有的任何碳原子附接到母体分子部分。三环烷基基团包含如本文所使用的桥连的三环烷基，所述桥连的三环烷基是指：1)桥连的双环烷基环，其中桥连的双环烷基环的两个不相邻的碳原子通过一个至三个附加碳原子的亚烷基桥(即，-(CH2)n-形式的桥连基团，其中n是1、2或3)连接；或者2)稠合的双环烷基环，其中每个环上的两个非共享的环原子通过一个至三个附加碳原子的亚烷基桥(即，-(CH2)n-形式的桥连基团，其中n是1、2或3)连接，其中“稠合的双环烷基环”指与单环烷基环稠合的单环烷基环。桥连的三环烷基基团的实例包含但不限于金刚烷基如本文所使用的，桥连的三环烷基通过任何环原子附加到母体分子部分。本文公开的环原子指环骨架上的碳原子。环烷基可以是饱和的或者包括至少一个双键(即，部分不饱和的)，但并非完全共轭，并且不是芳族的(如本文中所定义的芳族)环烷基。环烷基可以被至少一个选自例如O、S和N的杂原子取代。
除非明确说明，否则环烷基基团可以可选地通过一个或更多个取代基(如一个、两个或三个取代基，或1-4个取代基，或多达存在于未被取代的环烷基基团上的氢的数量)替代未被取代的环烷基的氢原子而被取代。在一些实施方案中，取代的环烷基包含1-4个，例如1-2个取代基。除非另有规定，否则适合的取代基选自例如如上文所列的用于烷基基团的取代基。
“杂环烷基”、“杂环基”或“杂环”指其至少一个环碳原子被独立地选自O、N、S的杂原子替换的如上所定义的“环烷基”。杂环基包括例如1、2、3或4个杂原子，并且N、C和S中的每一者可以在环状环系中独立地被氧化。N原子还可以被取代以形成叔胺或铵盐。杂环基的连接点可以在杂原子或碳上。本文中的“杂环基”也指包括至少一个选自例如N、O和S的杂原子的5元至7元饱和的或部分不饱和的碳环(杂环)，该碳环与5元、6元和/ 或7元的环烷基、杂环或碳环芳环稠合，条件是当杂环与碳环芳环稠合时，连接点在杂环处，并且当杂环与环烷基稠合时，连接点可以在环烷基或杂环处。本文中的“杂环基”也指包括至少一个选自例如N、O和S的杂原子的脂族螺环。环可以是饱和的或者至少具有一个双键(即，部分不饱和的)。杂环基可以被例如桥氧基取代。连接点可以是碳或杂原子。杂环基不是本文中所定义的杂芳基。
杂环的实例包含但不限于吡咯烷基、咪唑烷基、吡唑烷基、哌啶基、哌嗪基、吡喃基、吗啉基、环氧乙烷基、吖丙啶基、硫杂环丙烷基、氮杂环丁烷基、氧杂环丁烷基、硫杂环丁烷基、二硫杂环丁烷基、二氢吡啶基、四氢吡啶基、硫代吗啉基、噻噁烷基、高哌嗪基、高哌啶基、氮杂环庚烷基、氧杂环庚烷基、硫杂环庚烷基、氧硫杂环己烷基、二氧杂环庚烷基、氧杂硫杂环庚烷基、氧杂氮杂环庚烷基、二硫杂环庚烷基、硫杂氮杂环庚烷基和二氮杂环庚烷、二硫杂环己烷基、氮杂硫杂环己烷基、氧氮杂基、二氮杂基、硫杂氮杂基、二氢噻吩基、二氢吡喃基、二氢呋喃基、四氢呋喃基、四氢噻吩基、四氢吡喃基、四氢噻喃基、二氢吲哚基、二噁烷基、吡唑啉基、二硫杂环己烷基、二硫环戊烷基、吡唑烷基、咪唑啉基、嘧啶酮基(pyrimidinonyl)、1,1-二氧代-硫代吗啉基、3-氮杂双环[3.1.0]己烷基、3-氮杂双环[4.1.0]庚烷基和氮杂双环[2.2.2]己烷基。被取代的杂环还包含被一个或更多个氧代部分取代的环系，如哌啶基N-氧化物、吗啉基-N-氧化物、1-氧代-1-硫代吗啉基、1,1-二氧代-1-硫代吗啉基、
除非明确说明，否则杂环基基团可以可选地通过一个或更多个取代基(如一个、两个或三个取代基，或1-4个取代基，或多达存在于未被取代的杂环基基团上的氢的数量)替代未被取代的杂环基的氢原子而被取代。在一些实施方案中，取代的杂环基包含1-4个，例如1-2个或1-3个取代基。除非另有规定，否则适合的取代基选自例如如上文所列的用于烷基基团的取代基。
“内酰胺环”是指含有酰胺键的饱和或部分不饱和的(即在环内具有一个或多个双键和/或三键)环状基团。例如，4-10元内酰胺环基、4元、5元或6元内酰胺环基，内酰胺环基的非限制性实施例包括但不限于吡咯烷酮基、1H-吡咯-2(5H)-酮基、2,5-二酮吡咯烷基、2,4-二酮吡咯烷基、1H-咪唑-2(5H)-酮基等。
“内酯环基”是指含有酯基的饱和或部分不饱和的(即在环内具有一个或多个双键和/或三键)环状基团。例如，4-10元内酯环基、4元、5元或6元内酯环基，内酯环基的非限制性实施例包括但不限于1,3-恶唑烷-5-酮基、丁内酯基、戊内酯基等。
“烷氧基”是指烷基中至少1个碳原子被氧原子取代所形成的基团。非限制性实施例包括甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、仲丁氧基、叔丁氧基、正戊氧基、正己氧基、环丙氧基和环丁氧基。所述的烷基定义与上文所述的“烷基”定义相同。除非明确说明，否则烷氧基基团可以可选地通过一个或更多个取代基(如一个、两个或三个取代基，或1-4个取代基，或多达存在于未被取代的烷氧基基团上的氢的数量)替代烷氧基的未被取代的烷基部分的氢原子而被取代。除非另有规定，否则适合的取代基选自例如如上文所列的用于烷基基团的取代基，除了羟基和氨基通常不存在于与被取代的烷基-O基团的氧直接连接的碳上。
“卤代烷基”指本文所定义的烃基被一个或多个本文所定义的卤素基团取代。除非另有规定，否则卤代烷基的烃基部分包括1-4个碳原子。卤代烷基可以是单卤代烷基、二卤代烷基、三卤代烷基或多卤代烷基(包含全卤代烷基)。单卤代烷基可以在烃基基团内具有一个碘、溴、氯或氟。二卤代烷基基团和多卤代烷基基团可以在烃基内具有两个或更多个相同卤素原子或者不同卤素基团的组合。多卤代烷基包括例如多达6个、或4个、或3个、或2个卤素基团。卤代烷基的实例包含(但不限于)氟代甲基、二氟甲基、三氟甲基、氯代甲基、二氯甲基、三氯甲基、五氟乙基、七氟丙基、二氟氯甲基、二氯氟甲基、二氟乙基、二氟丙基、二氯乙基和二氯丙基。全卤代烷基指全部氢原子被卤素原子替换的烃基(例如，三氟甲基)。在一些实施方案中，除非另有规定，否则卤代烷基基团包含单氟-、二氟-和三氟-取代的甲基和乙基基团(例如，-CF3、-CF2H、-CFH2和-CH2CF3)。除非明确说明，否则卤代烷基基团可以可选地通过一个或更多个取代基(如一个、两个或三个取代基，或1-4个取代基，或多达存在于未被取代的卤代烷基基团上的氢的数量)替代卤代烷基的未被取代的氢原子而被取代。除非另有规定，否则适合的取代基选自例如如上文所列的用于烷基基团的取代基。
“卤代烷氧基”是指卤代烷基-O-，其中卤代烷基如上文所定义。卤代烷氧基的实例包含(但不限于)氟代甲氧基、二氟甲氧基、三氟甲氧基、三氯甲氧基、2-氯乙氧基、2,2,2-三氟乙氧基、1,1,1,3,3,3-六氟-2-丙氧基等。在一些实施方案中，卤代烷氧基基团包括1-4个碳原子和多达三个卤族元素，例如，单氟、二氟和三氟取代的甲氧基基团和乙氧基基团。除非明确说明，否则卤代烷氧基基团可以可选地通过一个或更多个取代基(如一个、两个或三个取代基，或1-4个取代基，或多达存在于未被取代的卤代烷氧基团上的氢的数量)替代卤代烷氧基的未被取代的烷基部分的氢原子而被取代。除非另有规定，否则适合的取代基选自例如如上文所列的用于烷基基团的取代基，除了羟基和氨基通常不存在于与被取代的卤代烷基-O基团的氧直接连接的碳上。
“羟基”指-OH基团。
“卤基”是指氟、氯、溴和碘。经卤族元素取代的基团和部分(如被卤族元素取代的烷基(卤代烷基))可以是单卤代的、多卤代的或全卤代的。在一些实施方案中，除非另有规定， 否则氯和氟是烷基基团或环烷基基团上的卤素取代基的实例；除非另有规定，否则氟、氯和溴例如在芳基基团或杂芳基基团上使用。
“取代的”指基团中的一个或多个氢原子，优选为最多5个，更优选为1～3个氢原子彼此独立地被相应数目的取代基取代。不言而喻，取代基仅处在它们的可能的化学位置，本领域技术人员能够在不付出过多努力的情况下确定(通过实验或理论)可能或不可能的取代。例如，具有游离氢的氨基或羟基与具有不饱和(如烯属)键的碳原子结合时可能是不稳定的。
当上文所述的“烷基”、“卤代烷基”、“烷氧基”、“双环”、“单环”、“芳基”、“杂芳基”、“杂环基”、“杂环”、“环烷基”、“杂环烷基”或者“杂环基”被取代时，可以选进一步被0、1、2、3、4、5、6、7、8、9或者10个选自F、Cl、Br、I、羟基、巯基、硝基、氰基、氨基、C1-6烷基氨基、＝O、C1-6烷基、C1-6烷氧基、C2-6烯基、C2-6炔基、-NRq4Rq5、＝NRq6、-C(＝O)OC1-6烷基、-OC(＝O)C1-6烷基、-C(＝O)NRq4Rq5、C3-8环烷基、C3-8杂环烷基、C6-10芳基、C5-10杂芳基、-C(＝O)OC6-10芳基、-OC(＝O)C6-10芳基、-OC(＝O)C5-10杂芳基、-C(＝O)OC5-10杂芳基、-OC(＝O)C3-8杂环烷基、-C(＝O)OC3-8杂环烷基、-OC(＝O)C3-8环烷基、-C(＝O)OC3-8环烷基、-NHC(＝O)C3-8杂环烷基、-NHC(＝O)C6-10芳基、-NHC(＝O)C5-10杂芳基、-NHC(＝O)C3-8环烷基、-NHC(＝O)C3-8杂环烷基、-NHC(＝O)C2-6烯基或者-NHC(＝O)C2-6炔基的取代基所取代，且其中所述的取代基C1-6烷基、C1-6烷氧基、C2-6烯基、C2-6炔基、C3-8环烷基、C3-8杂环烷基、C6-10芳基、C5-10杂芳基、-NHC(＝O)C6-10芳基、-NHC(＝O)C5-10杂芳基、-NHC(＝O)C3-8杂环烷基或者-NHC(＝O)C3-8环烷基任选进一步被1至3个选自OH、F、Cl、Br、I、C1-6烷基、C1-6烷氧基、-NRq4Rq5或者＝O的取代基所取代；Rq1选自C1-6烷基、C1-6烷氧基或者C6-10芳基；Rq2、Rq3选自H或者C1-6烷基；其中，Rq4、Rq5选自H、C1-6烷基、-NH(C＝NRq1)NRq2Rq3、-S(＝O)2NRq2Rq3、-C(＝O)Rq1或者-C(＝O)NRq2Rq3，其中所述的C1-6烷基任选进一步被1个或者多个选自OH、F、Cl、Br、I、C1-6烷基、C1-6烷氧基、C6-10芳基、C5-10杂芳基、C3-8环烷基或者C3-8杂环烷基的取代基所取代；或者Rq4与Rq5及N原子形成一个3至8元杂环，所述杂环可以含有1个或者多个选自N、O或者S的杂原子。
本文公开的化合物可以含有不对称中心，并且因此可以作为对映异构体存在。在本文公开的化合物具有两个或更多个不对称中心的情况下，它们可以附加地作为非对映异构体存在。对映异构体和非对映异构体属于立体异构体的更广泛类别。本领域公知如何如通过拆分材料或通过不对称合成来制备旋光体。全部这样的可能的立体异构体(如基本上纯的拆分的对映异构体、其外消旋混合物、以及非对映异构体的混合物)都旨在被包含在内。本文公开的化合物的全部立体异构体和/或其药学上可接受的盐都旨在被包含在内。除非另外明确提及，否则对一种异构体的提及适用于可能的异构体中的任何一种。当未指明异构组成时，全部可能的异构体都被包含在内。
当本文公开的化合物含有烯族双键时，除非另有规定，否则这样的双键意在包含E几 何异构体和Z几何异构体两者。
本文使用的“可药用的盐”包含但不限于与无机酸形成的盐，所述与无机酸形成的盐选自例如盐酸盐、磷酸盐、磷酸氢盐、氢溴酸盐、硫酸盐、亚磺酸盐和硝酸盐；以及与有机酸形成的盐，所述与有机酸形成的盐选自例如苹果酸盐、马来酸盐、延胡索酸盐、酒石酸盐、琥珀酸盐、柠檬酸盐、乳酸盐、甲磺酸盐、对甲苯磺酸盐、2-羟基乙磺酸盐、苯酸盐、水杨酸盐、硬脂酸盐、链烷酸盐(如乙酸盐)、以及与HOOC-(CH2)n-COOH形成的盐，其中n选自0至4。类似地，药学上可接受的阳离子的实例包含但不限于钠、钾、钙、铝、锂和铵。
此外，如果本文公开的化合物以酸加成盐的形式被获得，则可以通过碱化酸式盐的溶液来获得游离碱。相反地，如果产物是游离碱，则根据用于由碱化合物制备酸加成盐的常规程序，可以通过将游离碱溶解在适合的有机溶剂中并且用酸处理该溶液来生产加成盐(如药学上可接受的加成盐)。本领域技术人员将认识到可以用于制备无毒性的药学上可接受的加成盐而无需过度实验的各种合成方法。
“药物组合物”表示含有一种或多种本文所述化合物或其生理学上可药用的盐或前体药物与其他化学组分的混合物，以及其他组分例如生理学可药用的载体和赋形剂。药物组合物的目的是促进对生物体的给药，利于活性成分的吸收进而发挥生物活性。
“载体”是指不会对生物体产生明显刺激且不会消除所给予化合物的生物活性和特性的材料。
“赋形剂”是指加入到药物组合物中以促进化合物给药的惰性物质。非限制性实施例包括碳酸钙、磷酸钙、糖、淀粉、纤维素衍生物(包括微晶纤维素)、明胶、植物油、聚乙二醇类、稀释剂、成粒剂、润滑剂、粘合剂和崩解剂。
“前药”是指可经体内代谢转化为具有生物活性的本发明化合物。本发明的前药通过修饰本发明化合物中的氨基或者羧基来制备，该修饰可以通过常规的操作或者在体内被除去，而得到母体化合物。当本发明的前药被施予哺乳动物个体时，前药被割裂形成游离的氨基或者羧基。
“立体异构体”是指由分子中原子在空间上排列方式不同所产生的异构体，包括顺反异构体、对映异构体和构象异构体。
“可选”或“可选地”或“选择性的”或“选择性地”是指随后所述的事件或状况可以但未必发生，该描述包括其中发生该事件或状况的情况及其中未发生的情况。例如，“可选地被烷基取代的杂环基”是指该烷基可以但未必存在，该描述包括其中杂环基被烷基取代的情况，及其中杂环基未被烷基取代的情况。
“治疗(treating)”、“治疗(treat)”、“治疗(treatment)”或“缓解”指向确认有需要的患有例如癌症的受试者施用本文公开的至少一种化合物、和/或至少一种其立体异构体(如果有的话)、至少一种其稳定同位素、或至少一种其药学上可接受的盐。
术语“有效量”指对于“治疗”(如上文所定义的)受试者的疾病或紊乱有效的本文公开的 至少一种化合物、和/或至少一种其立体异构体(如果有的话)、至少一种其稳定同位素、或至少一种其药学上可接受的盐的量。
本文公开了各种实施方案。将认识到的是，每个实施方案中规定的特征可以与其他规定的特征组合以提供本公开的另外的实施方案。以下非限制性列举的实施方案是本公开的代表。
方案1示出用于制备本公开的化合物以及中间产物的一般方法。以下实施例中公开了详细说明和合成法。本领域技术人员将能够找到其他合成方法或者使用常规化学修改下述方法以制备式I所涵盖的适合的化合物。因此，这些方法同样适用于制备其他实施方案的化合物。尽管在方案中描绘了且在下文讨论了特定的起始材料和试剂，但可以容易地替换其他起始材料和试剂以提供各种化合物和/或反应条件。
以下实施例给出了式(I)所表示的代表性化合物的制备及相关结构鉴定数据。必须说明，下述实施例是用于说明本发明而不是对本发明的限制。1H NMR图谱是用Bruker仪器(400MHz)测定而得，化学位移用ppm表示。使用四甲基硅烷内标准(0.00ppm)。1H NMR的表示方法：s＝单峰，d＝双重峰，t＝三重峰，m＝多重峰，br＝变宽的，dd＝双重峰的双重峰，dt＝三重峰的双重峰。若提供偶合常数时，其单位为Hz。
质谱是用LC/MS仪测定得到，离子化方式可为ESI或APCI。
薄层层析硅胶板使用烟台黄海HSGF254或青岛GF254硅胶板，薄层色谱法(TLC)使用的硅胶板采用的规格是0.15mm～0.2mm，薄层层析分离纯化产品采用的规格是0.4mm～0.5mm。
柱层析一般使用烟台黄海硅胶200～300目硅胶为载体。
在下列实施例中，除非另有指明，所有温度为摄氏温度，除非另有指明，各种起始原料和试剂来自市售或者是根据已知的方法合成，市售原料和试剂均不经进一步纯化直接使用，除非另有指明，市售厂家包括但不限于Aldrich Chemical Company，ABCR GmbH&Co.KG，Acros Organics，广赞化工科技有限公司和景颜化工科技有限公司等处购买。
CD3OD：氘代甲醇。
CDCl3：氘代氯仿。
DMSO-d6：氘代二甲基亚砜。
氩气氛是指反应瓶连接一个约1L容积的氩气气球。
实施例中无特殊说明，反应中的溶液是指水溶液。
对化合物进行纯化，采用硅胶柱层析洗脱剂体系和薄层色谱法，其中洗脱剂体系选自：A：石油醚和乙酸乙酯体系；B：二氯甲烷和甲醇体系；C：二氯甲烷：乙酸乙酯；其中溶剂的体积比根据化合物的极性不同而不同，也可以加入少量的酸性或碱性试剂进行调节，如醋酸或三乙胺等。
下列实施例阐明了本公开的某些实施方案以及如何制造和使用它们。因此，下列实施 例并非旨在限制本发明的范围。本领域技术人员将容易地认识到可以改变或修改各种非关键性参数和条件以产生实质上相同的结果。根据本文所描述的测定中的一种或更多种，发现以下示例化合物可以是TEAD抑制剂，所述TEAD包括TEAD1、TEAD2、TEAD3、TEAD4。
以下结合实施例用于进一步描述本发明，但这些实施例并非限制着本发明的范围。
在下列实施例中，使用以下缩写：
PE：石油醚
EA:乙酸乙酯
NMP：N-甲基吡咯烷酮
DCM：二氯甲烷
TFA：三氟乙酸
DMSO：二甲基亚砜
DMA：N,N-二甲基乙酰胺
TLC：薄层色谱
中间体I-1的制备
中间体I-1:N-(4-甲氧基苄基)-N-甲基-2-氧代吲哚-5-磺酰胺的制备
氮气保护下于100ml三口瓶中将化合物I-1a(2-氧代-2,3-二氢-1H-吲哚-5-磺酰氯，5g,21.58mmol，根据J.Med.Chem.1999,42,5120-5130报道方法合成)，N-(4-甲氧基苄基)-N-甲胺(3.92g,25.90mmol)，无水碳酸钾(5.97g,43.16mmol)加入二氯甲烷(50mL)中，室温反应4小时。反应完毕，向反应液中加水，DCM:MeOH＝10:1萃取三次，饱和食盐水洗涤一次，无水硫酸钠干燥旋干得到标题化合物粗品(5.975g；收率：80％)。
实施例1
N-(2-氧代-1-(5-(三氟甲基)吡啶-2-基)吲哚-5-基)丙烯酰胺
第一步：5-硝基-1-(5-(三氟甲基)吡啶-2-基)吲哚-2-酮的制备
将化合物1-1(5-硝基氧化吲哚)(200mg,1.12mmol)，5-三氟甲基-2-碘吡啶(368mg,1.35mmol)，N,N'-二甲基乙二胺(20mg,0.225mmol)，碘化亚铜(21mg,0.112mmol)，碳酸钾(341mg,2.47mmol)加入乙腈(2mL)中，微波80℃反应30分钟。待反应液冷却，向反应液加入水(5mL)中，EA(10mL)萃取三次，有机相用饱和食盐水洗涤一次。有机相经无水硫酸钠干燥，真空下浓缩干，得到含有标题化合物1-2(5-硝基-1-(5-(三氟甲基)吡啶-2-基)吲哚-2-酮)的粗产品(108mg，收率：29.8％)。
第二步：5-氨基-1-(5-(三氟甲基)吡啶-2-基)吲哚-2-酮的制备
将化合物1-2(50mg,0.15mmol)与Pd/C(20mg)的混合物中加入甲醇(5mL)，经H2置换室温反应2小时，LCMS显示原料反应完全。将反应液过滤，浓缩干，得到标题化合物1-3的粗品(42mg，收率：92.59％)。
第三步：N-(2-氧代-1-(5-(三氟甲基)吡啶-2-基)吲哚-5-基)丙烯酰胺的制备
将化合物1-3的粗品42mg换算约(30mg,0.102mmol)和三乙胺(21mg,0.205mmol)加入二氯甲烷(2mL)中，降温到0℃，加入丙烯酰氯(11mg,0.123mmol)，室温反应2小时，LCMS显示反应完全。将反应液浓缩干，经prepHPLC(MeOH:H2O＝10:90→80：20)纯化浓缩得到白色固体状化合物1(N-(2-氧代-1-(5-(三氟甲基)吡啶-2-基)吲哚-5-基)丙烯酰胺)(21mg，收率：59.11％)。
MS(ESI)m/z:348.1[M+1]+
1H NMR(400MHz,DMSO-d6)δ10.18(s,1H),8.98(s,1H),8.39(dd,J＝8.7,2.8Hz,1H),8.10(d,J＝8.8Hz,1H),7.85–7.77(m,2H),7.49(d,J＝8.8Hz,1H),6.50–6.37(m,1H),6.26(dt,J＝17.1,2.1Hz,1H),5.75(dt,J＝10.0,2.0Hz,1H),3.90(s,2H).
19F NMR(376MHz,DMSO-d6)δ-60.55.
实施例2
N-(2'-氧代-1'-(5-(三氟甲基)吡啶-2-基)螺[环己烷-1,3'-二氢吲哚]-5'-基)丙烯酰胺
第一步:5'-亚硝基吡罗[环己烷-1,3'-二氢吲哚]-2'-酮的制备
氮气保护下于25ml三口瓶中加入化合物2-1(5’-硝基-2’-氧代螺[环己烷-1,3’-二氢吲哚]-1’-羧酸叔丁酯，根据专利CN112119077A合成)(300mg，0.866mmol)和二氯甲烷(5ml),冰水冷却至0℃,缓慢加入三氟乙酸(2ml),室温搅拌1h。反应完毕，浓缩旋干，加水(5ml),用2N NaOH水溶液调节pH＝9-10，乙酸乙酯萃取，水洗，饱和食盐水洗涤，有机相无水硫酸钠干燥，过滤，滤液旋干后通过硅胶柱层析(石油醚：乙酸乙酯＝5：1-1：1)得到标题化合物2-2(175mg,收率：82％)。
第二步：5'-硝基-1'-(5-(三氟甲基)吡啶-2-基)螺[环己烷-1,3'-二氢吲哚]-2'-酮的制备
氮气保护下将化合物2-2(80mg,0.32mmol),2-碘-5-三氟甲基吡啶(96mg,0.35mmol)、(1R,2R)-(-)-N,N'-二甲基-1,2-环己二胺(27.31mg,0.19mmol)、碘化亚铜(18.28mg,0.096mmol)和无水磷酸钾(203.78mg,0.96mmol)加入NMP(1mL)，微波加热160℃反应20min。反应完毕，加水，乙酸乙酯萃取，水洗，食盐水洗，有机相无水硫酸钠干燥，过滤，滤液旋干，经过prepHPLC纯化(A：H2O，0.1％NH4HCO3；B:MeOH)冻干后得到标题化合物2-3(34mg，收率：27％)。
第三步:5'-氨基-1'-(5-(三氟甲基)吡啶-2-基)螺[环己烷-1,3'-二氢吲哚]-2'-酮的制备将化合物2-3(34mg,0.087mmol)溶于甲醇(4mL)中，并加入Pd/C(10mg)加入反应液 中，氢气置换，氢气环境下室温搅拌2h。反应完毕，过滤，浓缩旋干得到标题化合物2-4(25mg，收率：79％)。
第四步:N-(2'-氧代-1'-(5-(三氟甲基)吡啶-2-基)螺[环己烷-1,3'-二氢吲哚]-5'-基)丙 烯酰胺的制备
氮气保护下将化合物2-4(25mg,0.069mmol)和三乙胺(13.96mg,0.14mmol)加入二氯甲烷(2mL)中，冰水冷却下加入丙酰氯(6.87mg,0.076mmol)，室温搅拌1h。反应完毕，浓缩旋干，经过prepHPLC纯化(A：H2O，0.1％CF3COOH；B:MeOH)冻干后得到目标产物2(9mg，收率：31％)。
MS(ESI)m/z:416.1[M+1]+
1H NMR(400MHz,DMSO-d6)δ10.22(s,1H),9.00(s,1H),8.41(d,J＝8.7Hz,1H),8.10–8.02(m,2H),7.81(d,J＝8.8Hz,1H),7.54(d,J＝8.3Hz,1H),6.43(dd,J＝17.1,10.0Hz,1H),6.27(d,J＝17.1Hz,1H),5.80–5.72(m,1H),1.99–1.82(m,4H),1.80–1.63(m,6H)
19F NMR(376MHz,DMSO-d6)δ-60.54
实施例3
N-(3,3-二甲基-2-氧代-1-(5-(三氟甲基)吡啶-2-基)-2,3-二氢-1H-吲哚-5-基)丙-2-烯酰 胺
第一步:3,3-二甲基-5-硝基-1-(5-(三氟甲基)吡啶-2-基)吲哚-2-酮的制备
向10mL微波管中加入化合物3-1(3,3-二甲基-5-硝基-2,3-二氢-1H-吲哚-2-酮，100mg,0.48mmol)、2-碘-5-(三氟甲基)吡啶(144.14mg,0.53mmol)，(1R,2R)-(-)-N,N'-二甲基-1,2-环己二胺(40.97mg,0.29mmol)、CuI(27.42mg,0.14mmol)、K3PO4(305.67mg,1.44mmol)和NMP(3mL)，在N2保护下160℃微波加热20min。反应完毕，反应液用EA(3X10mL)萃取，合并有机相，用饱和食盐水(20mL)和水(20mL)洗涤，无水硫酸钠干燥，过滤并减压浓缩得到粗品。将粗品加到1mm的TLC板上，用(PE/EA＝4:1)洗脱得到白色固体状化合物3-2(50mg,收率：29.35％)。
第二步：5-氨基-3,3-二甲基-1-(5-(三氟甲基)吡啶-2-基)-二氢吲哚-2-酮的制备
向100mL单口瓶中加入化合物3-2(3,3-二甲基-5-硝基-1-(5-(三氟甲基)吡啶-2-基)-2,3-二氢-1H-吲哚-2-酮，50mg,0.14mmol)，Pd/C(15mg,0.14mmol)和MeOH(6mL)。氢气置换，氢气环境下室温搅拌16h。反应完毕后，混合液过滤，用DCM/MeOH＝10/1冲洗，滤液浓缩得到粗品。将粗品经prepTLC(DCM/MeOH＝30/1)纯化得到暗紫色固体状化合物3-3(30mg,收率：65.62％)。
第三步:N-(3,3-二甲基-2-氧代-1-(5-(三氟甲基)吡啶-2-基)-二氢吲哚-5-基)丙烯酰胺 的制备
向50mL单口瓶中加入化合物3-3(5-氨基-3,3-二甲基-1-(5-(三氟甲基)吡啶-2-基)-2,3-二氢-1H-吲哚-2-酮，30mg,0.093mmol)，三乙胺(18.82mg,0.19mmol)和DCM(5mL)，在0℃下滴加丙烯酰氯(10.10mg,0.11mmol)，室温反应1.5h。反应结束，反应液减压浓缩，得到粗品。粗品通过prep-HPLC(A：0.1％CF3COOH,B:MeOH)纯化，冻干得到白色固体状化合物3-4(N-(3,3-二甲基-2-氧代-1-(5-(三氟甲基)吡啶-2-基)-2,3-二氢-1H-吲哚-5-基)丙-2-烯酰胺(5.65mg,收率：16.12％)。
MS(ESI)m/z:376.01[M+1]+
1H NMR(400MHz,DMSO-d6)δ10.23(s,1H),9.02–8.98(m,1H),8.41(dd,J＝8.9,2.5Hz,1H),8.13(d,J＝8.7Hz,1H),7.88–7.84(m,2H),7.49(dd,J＝8.8,2.2Hz,1H),6.44(dd,J＝17.0,10.0Hz,1H),6.26(dd,J＝17.0,2.1Hz,1H),5.76(dd,J＝10.0,2.0Hz,1H),1.43(s,6H)19F NMR(376MHz,DMSO-d6)δ-60.54
实施例4
N-甲基-2-氧代-1-(4-(三氟甲基)苯基)二氢吲哚-5-磺酰胺
第一步:N-(4-甲氧基苄基)-N-甲基-2-氧代-1-(4-(三氟甲基)苯基)二氢吲哚-5-磺酰胺 的制备
氮气保护下将中间体I-1(200mg,0.58mmol)，4-碘三氟甲苯(189.32mg,0.70mmol)，(1R,2R)-(-)-N,N'-二甲基-1,2-环己二胺(49.50mg,0.35mmol)，碘化亚铜(33.14mg,0.17mmol)和无水碳酸钾(240.12mg,1.74mmol)加入二氧六环(2mL)，微波加热160℃反应20min。反应完毕，加水稀释，用乙酸乙酯萃取，经水和饱和食盐水洗涤，有机相浓缩旋 干，经过prepHPLC纯化(A：H2O，0.1％NH4HCO3；B:MeOH)，冻干后得到标题化合物4-1(85mg,收率：30％)。
第二步:N-甲基-2-氧代-1-(4-(三氟甲基)苯基)二氢吲哚-5-磺酰胺的制备
将化合物4-1(85mg,0.17mmol)溶于二氯甲烷(5mL)，在0℃下滴加TFA(2mL)，随后室温搅拌反应1小时。反应完毕，将反应液减压浓缩，经prepHPLC纯化(A：H2O，0.1％CF3COOH；B:MeOH)冻干后得到目标产物(27mg，收率：42％)。
MS(ESI)m/z:370.7[M+1]+
1H NMR(400MHz,DMSO-d6)δ7.97(d,J＝8.1Hz,2H),7.77–7.70(m,3H),7.67(d,J＝8.4Hz,1H),7.40(d,J＝5.3Hz,1H),6.99(d,J＝8.4Hz,1H),3.90(s,2H),2.41(dd,J＝5.1,1.4Hz,3H)
19F NMR(376MHz,DMSO-d6)δ-61.02
实施例5
N-甲基-2-氧代-1-(5-(三氟甲基)吡啶-2-基)-2,3-二氢-1H-吲哚-5-磺酰胺
第一步:N-(4-甲氧基苄基)-N-甲基-2-氧代-1-(4-(三氟甲基)苯基)二氢吲哚-5-磺酰胺 的制备
氮气保护下将中间体I-1(100mg,0.29mmol)，2-碘-5-(三氟甲基)吡啶(95.00mg,0.35mmol)，(1R,2S)-N1,N2-二甲基环己烷-1,2-二胺(24.75mg,0.17mmol)，碘化亚铜(16.57mg,0.087mmol)和无水碳酸钾(120.06mg,0.87mmol)加入二氧六环(1.5mL)，微波加热160℃反应20min。反应完毕，加水稀释，用乙酸乙酯(2*10mL)萃取，经水(2*10mL)和饱和食盐水(20mL)洗涤，有机相浓缩旋干，经过prepHPLC纯化(A：H2O，0.1％NH4HCO3；B:MeOH)，冻干后得到标题化合物5-1(38mg,收率：26％)。
第二步:N-甲基-2-氧代-1-(5-(三氟甲基)吡啶-2-基)-二氢吲哚-5-磺酰胺的制备
将化合物5-1(N-[(4-甲氧基苯基)甲基]-N-甲基-2-氧代-1-(5-(三氟甲基)吡啶-2-基)-2,3-二氢-1H-吲哚-5-磺酰胺，38mg,0.077mmol)溶于DCM(2mL)，在0℃下滴加TFA(1mL)。室温搅拌反应1h。反应完毕，将反应液减压浓缩得到棕色固体粗品，经 过prep-HPLC(A：H2O，0.1％CF3COOH；B:MeOH)纯化冻干后得到白色固体状目标产物-化合物5(4.4mg,收率15.33％)。
MS(ESI)m/z:372.16[M+1]+
1H NMR(400MHz,DMSO-d6)δ9.04(s,1H),8.47(d,J＝8.7Hz,1H),8.04(d,J＝8.8Hz,1H),7.88–7.83(m,1H),7.78–7.70(m,2H),7.42(s,1H),3.99(s,2H),2.42(m,3H)
19F NMR(376MHz,DMSO-d6)δ-60.61
实施例6
N-甲基-2'-氧代-1'-(4-(三氟甲基)苯基)螺[环己烷-1,3'-吲哚啉]-5'-磺酰胺
第一步:N-(4-甲氧苄基)-N-甲基-2'-氧代-1'-(4-(三氟甲基)苯基)螺[环己烷-1,3'-二氢 吲哚]-5'-磺酰胺的制备
氮气保护下将化合物6-1(N-(4-甲氧苄基)-N-甲基-2-氧代-1-(4-(三氟甲基)苯基)二氢吲哚-5-磺酰胺，60mg,0.12mmol)，1,5-二溴戊烷(55.19mg,0.24mmol)和碳酸铯(117.30mg,0.36mmol)加入N,N-二甲基甲酰胺(1mL)，该到反应液室温搅拌2h。反应完毕，加水，乙酸乙酯萃取，水洗，食盐水洗，有机相无水硫酸钠干燥，过滤，滤液旋干，经过HPLC纯化(A：H2O，0.1％NH4HCO3；B:MeOH)冻干后得到标题化合物(25mg，收率：36％)。
第二步:N-甲基-2'-氧代-1'-(4-(三氟甲基)苯基)螺[环己烷-1,3'-二氢吲哚]-5'-磺酰胺的 制备
氮气保护下将化合物6-2(25mg,0.045mmol)加入到二氯甲烷(3mL)中，冰水冷却下，缓慢加入三氟乙酸(1.5mL,20.19mmol)，缓慢升至室温搅拌1小时。反应完毕，反应液浓缩旋干，经过prepHPLC纯化(A：H2O，0.1％CF3COOH；B:MeOH)，冻干后得到目标产物(8mg，收率：40％)。
MS(ESI)m/z:438.8[M+1]+
1H NMR(400MHz,DMSO-d6)δ8.01–7.92(m,3H),7.75(d,J＝8.1Hz,2H),7.69(d,J＝8.7Hz,1H),7.46–7.39(m,1H),7.01(dd,J＝8.2,2.1Hz,1H),2.42(dd,J＝5.2,2.1Hz,3H),1.98–1.61(m,10H).
19F NMR(376MHz,DMSO-d6)δ-61.02.
实施例7
N-甲基-3-(1-甲基-1H-咪唑-4-基)-2-氧代-1-(4-(三氟甲基)苄基)-2,3-二氢-1H- 苯并[d]咪唑-5-磺酰胺
第一步:2-氟-5-(N-(4-甲氧苄基)-N-甲基氨磺酰基)苯甲酸乙酯的制备
向高压釜中加入化合物7-1(3-溴-4-氟-N-(4-甲氧苄基)-N-甲基苯磺酰胺，500mg,1.29mmol，根据WO2020243415所述的方法合成)、Pd(dppf)Cl2·DCM(52.67mg,0.065mmol)、三乙胺(391.61mg,3.87mmol)和EtOH(20mL)。在CO，1Mpa条件下，油浴加热至100℃，搅拌反应5h，反应完毕。加水稀释，EA(3X20mL)萃取，合并有机相用水(2X20mL)洗涤,用饱和NaCl溶液(20mL)洗涤。无水Na2SO4干燥过滤，滤液浓缩得到粗品。粗品通过硅胶柱色谱(PE/EA＝10/1，5/1)纯化得到无色油状液体的化合物7-2(350mg,收率：71.25％)。
第二步:5-(N-(4-甲氧苄基)-N-甲基氨磺酰基)-2-((4-(三氟甲基)苄基)氨基} 苯甲酸乙酯的制备
向100mL单口瓶中加入化合物7-2(350mg,0.92mmol)，4-(三氟甲基)苄胺(193.37mg,1.10mmol)和DMSO(5mL)。反应加热至140℃搅拌反应2h。反应完成，反应液用EA(3X20mL)萃取，合并有机相水洗(2X20mL),饱和食盐水(20mL)洗。无水Na2SO4干燥过滤，滤液浓缩得到粗品。粗品通过硅胶柱色谱(PE/EA＝5/1)纯化得到白色固体化合物7-3(350mg,收率：71.09％)。
第三步:5-(N-(4-甲氧苄基)-N-甲基氨磺酰基)-2-((4-(三氟甲基)苄基)氨基} 苯甲酸的制备
将化合物7-3(300mg,0.56mmol)，LiOH·H2O(234.98mg,5.60mmol)，THF(12mL)和H2O(2mL)加入100mL单口瓶，60℃加热搅拌5h，反应结束。用AcOH调节pH至5-6，加入EA(3X10mL)萃取，用饱和食盐水(2X20mL)洗涤，无水硫酸钠干燥旋干得到粗品。粗品通过硅胶柱色谱(DCM/MeOH＝50/1)纯化得到白色固体状化合物7-4(280mg,收率：98.48％)。
第四步:N-[(4-甲氧苄基)-N-甲基-2-氧代-1-(4-(三氟甲基)苄基)-2,3-二氢-1H-苯并[d] 咪唑-5-磺酰胺的制备
向50mL单口瓶中加入化合物7-4(100mg,0.20mmol)、三乙胺(20.24mg,0.20mmol)、叠氮磷酸二苯酯(DPPA，55.04mg,0.20mmol)和DMA(5mL)。室温搅拌反应1h。再加热至120℃，搅拌反应2h。反应结束，反应液加水稀释，EA(3X10mL)萃取，合并有机相后用水(2 X 10mL)洗涤，用饱和食盐水(20mL)洗涤。无水硫酸钠干燥过滤，滤液浓缩得到粗品。粗品通过硅胶柱色谱(PE/EA＝5/1，1/2)纯化得到白色固体状化合物7-5(87mg，收率：87.52％)。
第五步:N-(4-甲氧苄基)-N-甲基-3-(1-甲基-1H-咪唑-4-基)-2-氧代-1-(4-(三氟甲基) 苄基)-2,3-二氢-1H-苯并[d]咪唑-5-磺酰胺的制备
向10mL微波管中加入化合物7-5(87mg,0.17mmol)、4-碘-1-甲基咪唑(38.90mg,0.19mmol)、碘化亚铜(9.71mg,0.051mmol)，(1R,2R)-(-)-N,N'-二甲基-1,2-环己二胺(14.51mg,0.10mmol)、磷酸钾(90.21mg,0.43mmol)和1,4-二氧六环(3mL)。N2条件下，120℃微波反应20min。反应完成后，向反应液中加水稀释，用EA(3X10mL)萃取，合并有机相后用水(2X15mL)和饱和食盐水(20mL)洗涤。无水硫酸钠干燥过滤，滤液浓缩得到白色固体状化合物7-6(90mg,收率：89.30％)。化合物7-6未进一步处理，直接进行下一步反应。
第六步：N-甲基-3-(1-甲基-1H-咪唑-4-基)-2-氧代-1-(4-(三氟甲基)苄基)-2,3-二氢-1H- 苯并[d]咪唑-5-磺酰胺的制备
向50mL单口瓶中加入化合物7-6(90mg，0.15mmol)和DCM(3mL)，冰浴下加入TFA(1mL)。随后加热至40℃搅拌反应1h。反应完成后，反应液减压浓缩得到粗品。粗品通过prep-HPLC(A：0.1％CF3COOH,B:MeOH)制备，冻干得到白色固体状化合物7(31.55mg,收率：44.10％)。
MS(ESI)m/z:465.69[M+1]+
1H NMR(400MHz,DMSO-d6)δ11.47(s,1H),7.72(d,J＝7.9Hz,2H),7.53(d,J＝8.1Hz,2H),7.44–7.40(m,1H),7.37(s,1H),7.31(q,J＝5.0Hz,1H),7.26(d,J＝8.3Hz,1H),5.17(s,2H),3.36(s,3H),2.36(d,J＝5.2Hz,3H).
19F NMR(376MHz,DMSO-d6)δ-60.99.
实施例8
N-甲基-3-(1-甲基-1H-咪唑-4-基)-2-氧代-1-(4-(三氟甲基)苯基)-2,3-二氢-1H-苯并[d] 咪唑-5-磺酰胺
第一步：4-氯-N-(4-甲氧苄基)-N-甲基-3-硝基苯磺酰胺的制备
将化合物8-1(4-氯-3-硝基苯磺酰氯，6g,23.43mmol)，N-(4-甲氧基苄基)-N-甲胺(4.25g,28.12mmol)加入DCM(50mL)中，室温反应2小时，MS显示原料反应完全。向反应液中加水，二氯甲烷:甲醇＝10：1萃取两次，合并有机相，用饱和食盐水洗涤一次，无水硫酸钠干燥，过滤。滤液浓缩干燥，加入乙酸乙酯打浆，过滤得到淡黄色固体状化合物8-2(5.53g,收率：63.64％)。
第二步：N-(4-甲氧苄基)-N-甲基-3-硝基-4-((4-(三氟甲基)苯基)氨基)苯磺酰胺 的制备
将化合物8-2(600mg,1.62mmol)、对三氟甲基苯胺(391.52mg,2.43mmol)、DIPEA(628.11mg,4.86mmol)加入DMSO(6mL)中，140℃反应五个小时，MS显示反应完全。向反应液加水，用乙酸乙酯萃取三次，合并有机相后用饱和食盐水洗涤一次，无水硫酸钠干燥，经过prep-HPLC纯化，收集目标产物，旋干得到黄色固体状化合物8-3(180mg,收率：22.45％)。
第三步：3-氨基-N-(4-甲氧苄基)-N-甲基-4-((4-(三氟甲基)苯基)氨基)苯磺酰胺 的制备
将铁粉(201.06mg,3.60mmol)和氯化铵(192.56mg,3.60mmol)加入乙醇(6mL)和水(2mL的混合溶剂中，室温搅拌反应30分钟，加入化合物8-3(180mg，0.36mmol)，80℃回流反应2小时，MS显示反应完全。将反应液过滤(硅藻土)，旋干，经过prep-HPLC纯化，流动相甲醇浓度为85％出产物，收集目标产物。将目标产物旋干得到黄色固体状化合物8-4(106mg,收率：62.68％)。
第四步：N-(4-甲氧苄基)-N-甲基-2-氧代-1-(4-(三氟甲基)苯基)-2,3-二氢-1H-苯并[d] 咪唑-5-磺酰胺的制备
将化合物8-4(106mg，0.23mmol)和三乙胺(116.37mg，0.35mmol)加入THF(2mL)中，降温到0℃，分批加入三光气(102.38mg,0.35mmol)，室温反应4小时，MS显示反应完全。向反应液中加水，加EA萃取两次，用饱和食盐水洗涤一次。无水硫酸钠干燥，旋干，用prep-HPLC纯化得到黄色固体状化合物8-5(26mg,收率：23.23％)。
第五步：N-(4-甲氧苄基)-N-甲基-3-(1-甲基-1H-咪唑-4-基)-2-氧代-1-(4-(三氟甲基) 苯基)-2,3-二氢-1H-苯并[d]咪唑-5-磺酰胺的制备.
将化合物8-5(26mg,0.053mmol)、4-碘-1-甲基咪唑(12.13mg,0.058mmol)、碘化亚铜(3.03mg,0.016mmol)、反-(1R,2R)-N,N'-二甲基1,2-环己烷二胺(4.52mg,0.032mmol)和磷酸钾(28.13mg,0.13mmol)加入1，4-二氧六环(1mL)中，微波140℃反应40分钟。M S显示反应完全。将反应液加入水中，用EA萃取三次，合并有机相后用饱和NaCl溶液洗涤一次。无水Na2SO4干燥过滤，旋干，用prep-HPLC纯化得到白色固体状化合物8-6(20mg,收率：66.14％)。
第六步：N-甲基-3-(1-甲基-1H-咪唑-4-基)-2-氧代-1-(4-(三氟甲基)苯基)-2,3-二氢-1H- 苯并[d]咪唑-5-磺酰胺的制备
将化合物8-6(20mg，0.002mmol)加入DCM中，降温到0℃，加入三氟乙酸，室温反应3小时，MS显示反应完全。将反应液旋干，反相柱制备得到白色固体状化合物8(14mg，收率：88.63％)
MS(ESI)m/z:451.7[M+1]+MS(ESI)
实施例9
N,3,3-三甲基-2-氧代-1-(4-(三氟甲基)苯基)吲哚-5-磺酰胺
第一步:N-(4-甲氧苄基)-N,3,3-三甲基-2-氧代-1-(4-(三氟甲基)苯基)二氢吲哚-5-磺 酰胺的制备
氮气保护下将化合物9-1(N-(4-甲氧苄基)-N-甲基-2-氧代-1-(4-(三氟甲基)苯基)二氢吲哚-5-磺酰胺，60mg,0.12mmol)和碘甲烷(51.10mg,0.36mmol)加入到四氢呋喃(1mL)，冰水冷却到0℃。氢化钠(10.56mg,0.26mmol)加入到反应液中，室温搅拌3h。反应完毕，加水，乙酸乙酯萃取，水洗，饱和食盐水洗涤，有机相用无水硫酸钠干燥，过滤，滤液旋干，经过prepHPLC纯化(A：H2O，0.1％NH4HCO3；B:MeOH)冻干后得到标题化合物9-2(28mg，收率：44％)。
第二步:N,3,3-三甲基-2-氧代-1-(4-(三氟甲基)苯基)二氢吲哚-5-磺酰胺的制备
氮气保护下将化合物9-2(28mg,0.054mmol)加入到二氯甲烷(3mL)中，冰水冷却下，缓慢加入三氟乙酸(1.5mL,20.19mmol)，室温搅拌1h。反应完毕，反应液浓缩旋干，经过prepHPLC纯化(A：H2O，0.1％CF3COOH；B:MeOH)冻干后得到目标化合物9(12mg，收率：55％)。
MS(ESI)m/z:398.78[M+1]+
19F NMR(376MHz,DMSO-d6)δ-61.01.
1H NMR(400MHz,DMSO-d6)δ7.98(d,J＝8.1Hz,2H),7.87(s,1H),7.77(d,J＝8.1Hz,2H),7.67(d,J＝8.4Hz,1H),7.36(d,J＝5.5Hz,1H),7.04(d,J＝8.4Hz,1H),2.46–2.40(m,3H),1.47(s,6H).
生物学评价
以下测定法用于测试本发明的示例性化合物。根据下述程序测试的那些实例的数据示于下表A中。
测试例1、TEAD-luciferase报告基因测试
使用Bright Glo luciferase assay(Promega)检测对TEAD的抑制作用。
实验方法简述如下：将100μL 293T(每孔20000个)细胞悬液接种到白板底透的96孔板中，放在二氧化碳培养箱中培养过夜让细胞充分贴壁。第二天通过lipofectamine 3000每孔转染100ng TEAD-luciferase reporter质粒，转染24h后吸去每孔上清，加入90μL培养基，将化合物用DMSO溶解，制备成10mM的储备溶液。用DMSO将化合物连续4倍梯度稀释至10个不同浓度；将2μL上述梯度稀释的化合物溶液转移到含有198μL培养基的96孔板中，充分 混匀得到100×化合物储备溶液；然后将10μL上述100×化合物转移到接种有90μL细胞的96孔板中，得到最终1×浓度，DMSO的最终浓度为0.1％。轻轻摇动平板将药物充分混匀，将细胞培养板放置再CO2培养箱中继续培养24h。24h后，每孔加入100μL Bright Glo luciferase试剂，常温放置5min后使用ID5多功能酶标仪测量发光强度。同时以相同实验条件、相同药物浓度和培养时间对293T细胞进行细胞活性(将CellTiter-Glo试剂(25μL)加入每个测试孔中，在摇床上混合2分钟，然后在室温下孵育25分钟。使用ID5多功能酶标仪测量发光强度)检测作为内部参照。抑制率(％)＝100-(样品TEAD luciferase reporter信号/样品CTG信号)/(对照组TEAD luciferase reporter信号/对照组CTG信号)×100。对照组(细胞)含有等量DMSO。使用带有3参数非线性回归方程(可变斜率)的GraphPad Prism 7确定曲线拟合和IC50值。
测试例2、本发明化合物对H226细胞活性测定
以下方法用于测定本发明优选化合物对肿瘤细胞增殖的影响。
实验方法简述如下：将90μL肿瘤细胞H226(每孔700个)细胞悬液接种到96孔板中。然后将培养板放在二氧化碳培养箱中培养过夜让细胞充分贴壁。第二天，将化合物用DMSO溶解，然后制备成10mM的储备溶液。用DMSO将化合物连续4倍梯度稀释至10个不同浓度；将2μL上述梯度稀释的化合物溶液转移到含有198μL培养基的96孔板中，充分混匀得到100×化合物储备溶液；然后将10μL上述100×化合物转移到接种有90μL细胞的96孔板中，得到最终1×浓度，DMSO的最终浓度为0.1％。轻轻摇动平板将药物充分混匀，将细胞培养板放置再CO2培养箱中继续培养7天。第7天，将CellTiter-Glo试剂(25μL)加入每个测试孔中，在摇床上混合2分钟，然后在室温下孵育25分钟。使用ID5多功能酶标仪测量发光强度。抑制率(％)＝100-100×(样品信号)÷(对照组信号)。对照组(细胞+CTG)具有相同浓度的DMSO。使用带有3参数非线性回归方程(可变斜率)的GraphPad Prism 7确定曲线拟合和IC50值，并示于下表中。
在下表中，A表示小于0.1μM；B表示0.1～0.5μM；C表示0.1～1μM；D表示＞1μM。
表1本发明优选化合物对TEAD蛋白活性抑制的IC50值

Claims (29)

  1. 一种通式(I)所示的化合物或其可药用的盐：
    其中：
    X1为N或CR1；
    X2和X3中的每一者独立地选自N或CR2；
    R1选自-CN、R1A或-L-R1B；
    R1A选自H、卤素、-OH、-ORa、NH2、＝O、-CN、C1-6烷基、C2-4烯基、C2-4炔基、C1-4烷氧基、C1-4卤代烷基、C1-4卤代烷氧基、-OC(O)Ra、-C(O)Ra、-CO2Ra、-C(O)N(RxRy)、-N(RxRy)、-N(Rx)C(O)Ra、-N(Rx)CO2Ra、-N(Ra)C(＝NRx)Rz、-N(Rx)S(O)1-2Ra、-N(Rz)C(O)N(RxRy)、-N(Rz)C(＝NRa)N(RxRy)、-N(Rz)S(O)1-2N(RxRy)、C3-6亚环烷基、3-6元环烷基、含有1-2个选自N、O和S的杂原子作为环成员的3-6元杂环烷基、5-6元芳基、含有1-4个选自N、O和S的杂原子作为环成员的5-6元杂芳基、或者8-10元稠合双环，所述8-10元稠合双环为其中，所述环A’可包含至少一个选自N、O、S的杂原子且为芳香环或脂肪环，所述环A”可包含至少一个选自N、O、S的杂原子且为芳香环或脂肪环，所述环A’和A”中的至少一个包含至少一个杂原子；其中，所述3-6元环烷基、含有1-2个选自N、O和S的杂原子作为环成员的3-6元杂环烷基、5-6元芳基、含有1-4个选自N、O和S的杂原子作为环成员的5-6元杂芳基以及8-10元稠合双环中的每一者可选地被选自H、卤素、-NH2、-CN、-OH、C1-6烷基、C1-6烷氧基、C1-6卤代烷基和三氟乙烯基的取代基团取代；
    L为键、-O-、-NH-、-CO-或-CONH-；
    R1B为螺合双环，所述螺合双环由两个3-8元饱和碳环或饱和杂环螺合形成，其中，所述3-8元饱和杂环具有1-2个选自N、O和S的杂原子，所述螺合双环可选地被选自H、卤素、-NH2、-CN、-OH、C1-6烷基、C1-6烷氧基或C1-6卤代烷基、三氟乙烯基的取代基取代；
    Ra和Rz独立地选自H、卤素、-NH2、-CN、-OH、C1-6烷基、C1-6烷氧基或C1-6卤代烷基、三氟乙烯基；
    Rx和Ry选自H、C1-6烷基、C1-6卤代烷基或三氟乙烯基；或者Rx和Ry与其共同附接的氮原子一起形成饱和的或部分饱和的3-6元杂环烷基、或6-10元内酰胺环，所述饱和的或部分饱和的3-6元杂环烷基或6-10元内酰胺环可选地被选自H、-OH、-NH2、-CN、卤素、C1-6烷基、C1-6卤代烷基或三氟乙烯基的基团取代；
    R2在每次出现时均独立地选自H、-OH、-NH2、卤素、-CN、C1-6烷基、‐O‐C1‐6烷基或C1-4卤代烷基、三氟乙烯基；或者，相邻的R2结合形成可选被取代的C2-4亚烷基、-C(O)N(Ra)Ra-或-C(O)ORa-，其中，所述可选被取代的C2-4亚烷基可选地被0、1、2或3个选自C1-6烷基的取代基取代；
    X4和X5中的每一者均独立地选自CH2、NH、C(R3R4)或NR5；
    R3和R4独立地选自H、-CN、可选地被C1-3烷氧基或羟基取代的C1-4烷基、COO(C1-4烷基)或酰胺基；或者R3、R4与其附接的碳原子形成环Rx，所述环Rx为：
    1)3-8元饱和环、含有1-2个选自N、O和S的杂原子作为环成员的3-8元饱和杂环；
    2)6-10元内酰胺环；
    3)螺接-稠合双环；所述螺接-稠合双环为所述环B’为5-8元内酰胺环、5-8元内酯环、可包含至少一个选自N、O、S的杂原子的4-6元芳香杂环或脂肪杂环；所述环B”为可包含至少一个选自N、O、S的杂原子的4-6元芳香杂环或脂肪杂环；n为1-5,m为1-5；或
    4)螺接-稠合三环；所述螺-稠合三环为其中，所述环B’可包含至少一个选自N、O、S的杂原子的芳香杂环或脂肪杂环、5-8元内酰胺环、5-8元内酯环；所述环B”可包含至少一个选自N、O、S的杂原子的5-6元芳香杂环或脂肪杂环；所述环B”’可包含至少一个选自N、O、S的杂原子的芳香杂环或脂肪杂环；其中，所述环B’、B”和B”’中的至少一个包含至少一个杂原子；n为1-4；m为1-5；
    所述环Rx可选地具有1-4个选自H、＝O、磺酰基、酰胺基、3-8元环烷基、3-8元杂环烷基、卤素、-CN、-OH、C1-6烷基、C1-C6烷氧基、C1-6卤代烷基、三氟乙烯基或C3-6环烷基的取代基；
    R5为-M-R5a，M为键或C1-4亚烷基；
    R5a为C1-6烷基、C1-6烷氧基、3-6元环烷基、含有1-2个选自N、O和S的杂原子作为环成员的3-8元杂环烷基、5-12元芳基、含有1-4个选自N、O和S的杂原子作为环成员的5-12元杂芳基；所述R5a可选地具有1-3个选自卤素、-CN、-OH、C1-6烷基、C1-C4烷氧基、C1-6卤代烷基或可选地被C1-6烷基或C1-6卤代烷基取代的C3-6环烷基或三氟乙烯基的取代基。
    Rw选自如下式W-1至W-7组成的组：
    其中，Rb、Rc和Rd中的每一者均独立地选自H、、卤素或C1-4烷基，所述C1-4烷基可选地被二甲基氨基取代。
  2. 如权利要求1所述的化合物或其可药用的盐，其中，所述化合物为通式(Ia)、(Ib)、(Ic)或(Id)所述的化合物：
  3. 如权利要求1或2所述的化合物或其可药用的盐，其中，所述X4或X5选自C(R3R4)或NR5。
  4. 如前述权利要求中的任一项所述的化合物或其可药用的盐，其中，所述R3、R4与其附接的碳原子形成环Rx。
  5. 如权利要求4所述的化合物或其可药用的盐，其中，所述环Rx为3-8元饱和环或含有1-2个选自N、O和S的杂原子作为环成员的3-8元饱和杂环。
  6. 如权利要求5所述的化合物或其可药用的盐，其中，所述环Rx为3-6元饱和环或含有1-2个选自N或O的杂原子作为环成员的3-6元饱和杂环。
  7. 如权利要求4所述的化合物或其可药用的盐，其中，所述环Rx为6-10元内酰胺环。
  8. 如权利要求4所述的化合物或其可药用的盐，其中，所述环Rx为6-8元内酰胺环。
  9. 如权利要求4所述的化合物或其可药用的盐，其中，所述环Rx为螺接-稠合双环，所述 螺接-稠合双环为所述环B’为5-8元内酰胺环、5-8元内酯环、或可包含至少一个选自N、O、S的杂原子的4-6元芳环或饱和脂肪环；所述环B”为可包含至少一个选自N、O、S的杂原子的4-6元芳环或脂肪环；n为1-2；以及m为1-2。
  10. 如权利要求9所述的化合物或其可药用的盐，其中，所述环B’为包含至少一个选自N、O、S的杂原子的4-6元芳环或饱和脂肪环，以及所述环B”为可包含至少一个选自N、O、S的杂原子的4-6元芳环或脂肪环，n为1且m为1。
  11. 如权利要求4所述的化合物或其可药用的盐，其中，所述环Rx为螺接-稠合三环，所述螺-稠合三环为其中，所述环B’为可包含至少一个选自N、O、S的杂原子的芳香杂环或脂肪杂环、5-8元内酰胺环、5-8元内酯环；所述环B”为可包含至少一个选自N、O、S的杂原子的5-6元芳香杂环或脂肪杂环；所述环B”’为可包含至少一个选自N、O、S的杂原子的芳香杂环或脂肪杂环；其中，所述环B’、B”和B”’中的至少一个包含至少一个杂原子；n为1-2；m为1-3。
  12. 如前述权利要求中的任一项所述的化合物或其可药用的盐，其中，所述环Rx具有1-4个选自H、＝O、磺酰基、酰胺基、3-8元环烷基、3-8元杂环烷基、卤素、-CN、-OH、C1-6烷基、C1-C6烷氧基、C1-6卤代烷基、三氟乙烯基或C3-6环烷基的取代基。
  13. 如权利要求1所述的化合物或其可药用的盐，其中，所述R5a选自3-6元环烷基、含有1-2个选自N、O和S的杂原子作为环成员的3-8元杂环烷基、5-12元芳基、含有1-4个选自N、O和S的杂原子作为环成员的5-12元杂芳基。
  14. 如权利要求13所述的化合物或其可药用的盐，其中，所述R5a选自含有1-2个选自N、O和S的杂原子作为环成员的3-8元杂环烷基。
  15. 如权利要求13所述的化合物或其可药用的盐，其中，所述R5a选自含有1-4个选自N、O和S的杂原子作为环成员的5-12元杂芳基。
  16. 如权利要求13所述的化合物或其可药用的盐，其中，所述R5a可选地具有1-3个选自卤素、C1-6烷基、C1-C4烷氧基、C1-6卤代烷基或三氟乙烯基的取代基。
  17. 如前述权利要求书中的任一项所述的化合物或其可药用的盐，其中，所述R1为R1A，所述R1A选自H、卤素、-OH、-ORa、NH2、＝O、-CN、C1-6烷基、C2-4烯基、C2-4炔基、 C1-4烷氧基、C1-4卤代烷基、C1-4卤代烷氧基、-OC(O)Ra、-C(O)Ra、-CO2Ra、-N(Rx)C(O)Ra、-N(Rx)CO2Ra、-N(Ra)C(＝NRx)Rz或-N(Rx)S(O)1-2Ra。
  18. 如前述权利要求书中的任一项所述的化合物或其可药用的盐，其中，所述R1为R1A，所述R1A选自-C(O)N(RxRy)、-N(RxRy)、-N(Rz)C(O)N(RxRy)、-N(Rz)C(＝NRa)N(RxRy)、-N(Rz)S(O)1-2N(RxRy)。
  19. 如权利要求18所述的化合物或其可药用的盐，其中，Rx和Ry与其共同附接的氮原子一起形成饱和的或部分饱和的3-6元杂环烷基、或6-10元内酰胺环，所述饱和的或部分饱和的3-6元杂环烷基或6-10元内酰胺环可选地被选自H、-OH、-NH2、-CN、卤素、C1-6烷基、C1-6卤代烷基或三氟乙烯基的基团取代。
  20. 如权利要求1-15中的任一项所述的化合物或其可药用的盐，其中，所述R1为R1A，所述R1A选自3-6元环烷基、含有1-2个选自N、O和S的杂原子作为环成员的3-6元杂环烷基、5-6元芳基、含有1-4个选自N、O和S的杂原子作为环成员的5-6元杂芳基。
  21. 如权利要求1所述的化合物或其可药用的盐，其中，所述R1为R1A，所述R1A选自8-10元稠合双环，所述8-10元稠合双环为其中，所述环A’可包含至少一个选自N、O、S的杂原子且为芳香环或脂肪环，所述环A”可包含至少一个选自N、O、S的杂原子且为芳香环或脂肪环，所述环A’和A”中的至少一个包含至少一个杂原子。
  22. 如权利要求1所述的化合物或其可药用的盐，其中，所述R1为-L-R1B，其中，L为键、-O-、-NH-、-CO-或-CONH-，所述R1B为螺合双环，所述螺合双环由3-6元饱和碳环或杂环与3-6元饱和碳环或杂环螺合形成，其中，所述3-6元杂环具有1-2个选自N和O的杂原子，所述螺合双环可选地被选自H、卤素、-NH2、-CN、-OH、C1-6烷基、C1-6烷氧基或C1-6卤代烷基、三氟乙烯基的取代基取代。
  23. 如前述权利要求中的任一项所述的化合物或其可要用的盐，其中，所述Rb、Rc和Rd中的每一者均独立地选自H、F、Cl、甲基、乙基或被二甲基氨基取代的甲基。
  24. 如前述权利要求中的任一项所述的化合物或其可要用的盐，所述Rw选自如下基团组成的组：
  25. 如前述权利要求中的任一项的化合物或其立体异构体、互变异构体或其可药用的盐，其中，所述的化合物包括：

  26. 一种药物组合物，所述药物组合物含有有效剂量的根据权利要求1～25中任何一项所述的化合物或其可药用的盐，及可药用的载体、赋形剂或它们的组合。
  27. 如权利要求1至26中任一项所述的化合物或其可药用的盐或如权利要求28所述的药物组合物在制备药物中的用途，所述药物用于治疗与TEAD表达增加有关的疾病或病症。
  28. 如权利要求27所述的用途，其中，所述TEAD表达增加有关的疾病或病症为癌症、神经退行性疾病、心脏相关病症或肾相关病症。
  29. 如权利要求28所述的用途，其中，所述疾病或病症为疾病或病症是多囊肾病、阿尔茨海默病、致心律失常性心肌病、Holt-Oram综合征、肝癌、上皮样血管内皮瘤、乳腺癌、肺癌、恶性间皮瘤、胰腺癌、卡波西肉瘤、葡萄膜黑色素瘤、肾细胞癌、结直肠癌、多发性骨髓瘤、2型神经纤维瘤、神经胶质瘤或胶质母细胞瘤。
PCT/CN2023/137418 2022-12-09 2023-12-08 Tead抑制剂、其制备方法和在医学上的应用 WO2024120519A1 (zh)

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