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WO2025201397A1 - Inhibiteurs de tead et leurs procédés d'utilisation - Google Patents

Inhibiteurs de tead et leurs procédés d'utilisation

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Publication number
WO2025201397A1
WO2025201397A1 PCT/CN2025/085011 CN2025085011W WO2025201397A1 WO 2025201397 A1 WO2025201397 A1 WO 2025201397A1 CN 2025085011 W CN2025085011 W CN 2025085011W WO 2025201397 A1 WO2025201397 A1 WO 2025201397A1
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WIPO (PCT)
Prior art keywords
heterocycloalkyl
alkyl
cycloalkyl
heteroaryl
aryl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/CN2025/085011
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English (en)
Inventor
Xiao DING
Jinxin LIU
Jianfei WAN
Wei Zhu
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
InSilico Medicine IP Ltd
Original Assignee
InSilico Medicine IP Ltd
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Filing date
Publication date
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Publication of WO2025201397A1 publication Critical patent/WO2025201397A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A61K31/416—1,2-Diazoles condensed with carbocyclic ring systems, e.g. indazole
    • 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
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/541—Non-condensed thiazines containing further heterocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/36—Radicals substituted by singly-bound nitrogen atoms
    • C07D213/40—Acylated substituent nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
    • C07D231/56—Benzopyrazoles; Hydrogenated benzopyrazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • a method of treating a cancer in a subject in need thereof comprising administering an effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt, or stereoisomer thereof, to the subject in need thereof.
  • the cancer is mesothelioma. In some embodiments of a method of treating cancer, the cancer is NF2 deficient mesothelioma.
  • the cancer is epithelioid hemangioendothelioma.
  • the cancer is a solid tumor.
  • the solid tumor has a NF2 mutation, a LATS1 mutation, a LATS2 mutation, or any combination thereof. In some embodiments of a method of treating cancer, the solid tumor has a NF2 mutation. In some embodiments of a method of treating cancer, the solid tumor has a LATS1 mutation. In some embodiments of a method of treating cancer, the solid tumor has a LATS2 mutation. In some embodiments of a method of treating cancer, the solid tumor has a YAP1/TAZ gene fusion. INCORPORATION BY REFERENCE
  • Carboxyl refers to -COOH.
  • Cyano refers to -CN.
  • Alkyl refers to a straight-chain, or branched-chain saturated hydrocarbon monoradical having from one to about ten carbon atoms, more preferably one to six carbon atoms. Examples include, but are not limited to methyl, ethyl, n-propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2, 2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2, 2-dimethyl-1-butyl, 3, 3-dimethyl-1-butyl, 2-ethyl-1-butyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopent
  • a numerical range such as “C 1 -C 6 alkyl” or “C 1-6 alkyl” means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkyl” where no numerical range is designated.
  • the alkyl is a C 1-10 alkyl.
  • the alkyl is a C 1-6 alkyl.
  • the alkyl is a C 1-5 alkyl.
  • the alkyl is a C 1-4 alkyl.
  • the alkyl is a C 1-3 alkyl.
  • an alkyl group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • the alkyl is optionally substituted with oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH 2 , or -NO 2 .
  • the alkyl is optionally substituted with halogen, -CN, -OH, or -OMe.
  • the alkyl is optionally substituted with halogen.
  • Alkenyl refers to a straight-chain, or branched-chain hydrocarbon monoradical having one or more carbon-carbon double-bonds and having from two to about ten carbon atoms, more preferably two to about six carbon atoms.
  • an alkenyl group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • the alkenyl is optionally substituted with oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH 2 , or -NO 2 .
  • the alkenyl is optionally substituted with halogen, -CN, -OH, or -OMe.
  • the alkenyl is optionally substituted with halogen.
  • Alkynyl refers to a straight-chain or branched-chain hydrocarbon monoradical having one or more carbon-carbon triple-bonds and having from two to about ten carbon atoms, more preferably from two to about six carbon atoms. Examples include, but are not limited to ethynyl, 2-propynyl, 2-butynyl, 1, 3-butadiynyl and the like.
  • a numerical range such as “C 2 -C 6 alkynyl” or “C 2- 6 alkynyl” means that the alkynyl group may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkynyl” where no numerical range is designated.
  • an alkynyl group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • the alkynyl is optionally substituted with oxo, halogen, -CN, -COOH, COOMe, -OH, -OMe, -NH 2 , or -NO 2 .
  • the alkynyl is optionally substituted with halogen, -CN, -OH, or -OMe.
  • the alkynyl is optionally substituted with halogen.
  • Alkylidenyl is alkenyl as defined above that is attached via the terminal divalent carbon.
  • the alkylidenyl group is enclosed by the box which is indicated by the arrow.
  • Alkoxy refers to a radical of the formula -Oalkyl where alkyl is as defined above. Unless stated otherwise specifically in the specification, an alkoxy group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the alkoxy is optionally substituted with halogen, -CN, -COOH, COOMe, -OH, -OMe, -NH 2 , or -NO 2 . In some embodiments, the alkoxy is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, the alkoxy is optionally substituted with halogen.
  • L 2 is absent, -NR 2 -, or C (R 3 ) 2 -. In some embodiments, L 2 is absent, or -NR 2 -. In some embodiments, L 2 is absent. In some embodiments, L 2 is -NR 2 -. In some embodiments, L 2 is -NH-.
  • R 2 is hydrogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments, R 2 is hydrogen or C 1 -C 6 alkyl. In some embodiments, R 2 is hydrogen.
  • each R 3 is independently hydrogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments, each R 3 is independently hydrogen or C 1 -C 6 alkyl. In some embodiments, each R 3 is hydrogen.
  • Ring A is cycloalkyl or heterocycloalkyl. In some embodiments, Ring A is cycloalkyl. In some embodiments, Ring A is fully saturated cycloalkyl. In some embodiments, Ring A is fully saturated C 5 -C 6 mono-cycloalkyl, fully saturated C 7 -C 10 spiro-cycloalkyl, or fully saturated C 7- C 10 bridged-cycloalkyl. In some embodiments, Ring A is partially saturated cycloalkyl. In some embodiments, Ring A is partially saturated C 5 -C 6 cycloalkyl. In some embodiments, Ring A is heterocycloalkyl.
  • Ring A is mono-heterocycloalkyl, fused-heterocycloalkyl, spiro-heterocycloalkyl, or bridged-heterocycloalkyl. In some embodiments, Ring A is 5-or 6-membered mono-heterocycloalkyl, 7-to 10-membered spiro-heterocycloalkyl, or 7-to 10-membered bridged-heterocycloalkyl. In some embodiments, Ring A is aryl or heteroaryl. In some embodiments, Ring A is aryl. In some embodiments, Ring A is phenyl. In some embodiments, Ring A is heteroaryl. In some embodiments, Ring A is 5-or 6-membered heteroaryl. In some embodiments, Ring A is pyridyl or pyrimidyl.
  • each R 1 is independently halogen, -CN, -OH, -OR a , -NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments, each R 1 is independently halogen, -OR a , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments, each R 1 is independently halogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments, each R 1 is independently halogen or C 1 -C 6 haloalkyl.
  • each R 1 is independently C 1 -C 6 haloalkyl. In some embodiments, each R 1 is independently halogen. In some embodiments, each R 1 is independently -OCF 3 , -CF 3 , -CHF 2 , -F, -Cl, -SF 5 , methyl, ethyl, isopropyl, or n-propyl.
  • each R 1a is independently halogen, -CN, -OH, -OR a , -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, or C 1 -C 6 heteroalkyl.
  • each R 1a is independently halogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.
  • n is 0, 1, 2, or 3. In some embodiments, n is 0, 1, or 2. In some embodiments, n is 0 or 1. In some embodiments, n is 1 or 2. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3.
  • each R 1aa is independently hydrogen or R 1 .
  • a compound of Formula (I) or (Ia) - (Id) is In some embodiments is In some embodiments, is In some embodiments, is In some embodiments, is In some embodiments, is
  • Ring C is cycloalkyl, provided that when Ring C is cyclopropyl, then Ring B is absent. In some embodiments, Ring C is fully saturated cycloalkyl, provided Ring C is not cyclopropyl. n some embodiments, Ring C is fully saturated C 3 -C 6 mono-cycloalkyl, fully saturated C 7 -C 10 spiro-cycloalkyl, or fully saturated C 7- C 10 bridged-cycloalkyl, provided that when Ring C is cyclopropyl, then Ring B is absent.
  • Ring C is cycloalkyl, provided that Ring C is not cyclopropyl. In some embodiments, Ring C is fully saturated cycloalkyl, provided Ring C is not cyclopropyl. In some embodiments, Ring C is fully saturated C 3 -C 6 mono-cycloalkyl, fully saturated C 7 -C 10 spiro-cycloalkyl, or fully saturated C 7- C 10 bridged-cycloalkyl, provided Ring C is not cyclopropyl.
  • Ring C is cycloalkyl. In some embodiments, Ring C is fully saturated cycloalkyl. In some embodiments, Ring C is fully saturated C 3 -C 6 mono-cycloalkyl, fully saturated C 7 -C 10 spiro-cycloalkyl, or fully saturated C 7- C 10 bridged-cycloalkyl. In some embodiments, Ring C is cyclopropyl.
  • Ring C is heterocycloalkyl.
  • Ring C is mono-heterocycloalkyl, fused-heterocycloalkyl, spiro-heterocycloalkyl, or bridged-heterocycloalkyl.
  • Ring C is 3-or 6-membered mono-heterocycloalkyl, 7-to 10-membered spiro-heterocycloalkyl, or 7-to 10-membered bridged-heterocycloalkyl.
  • Ring C is 4-or 6-membered mono-heterocycloalkyl.
  • Ring C is
  • Ring C is aryl or heteroaryl. In some embodiments, Ring C is aryl. In some embodiments, Ring C is phenyl. In some embodiments, Ring C is heteroaryl. In some embodiments, Ring C is 5-or 6-membered heteroaryl.
  • a compound of Formula (Ic) is In some embodiments of a compound, is In some embodiments of a compound, is
  • R 4 is hydrogen or C 1 -C 6 alkyl. In some embodiments, R 4 is hydrogen.
  • R 5 is hydrogen or C 1 -C 6 alkyl. In some embodiments, R 5 is hydrogen.
  • R 6 is hydrogen or C 1 -C 6 alkyl. In some embodiments, R 6 is hydrogen.
  • R 7 is hydrogen, -OH or C 1 -C 6 alkyl. In some embodiments, R 7 is hydrogen. In some embodiments, R 7 is -OH.
  • p is 0, 1, 2, 3, or 4. In some embodiments, p is 0, 1, 2, or 3. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, p is 3. In some embodiments, p is 4.
  • R 8 is hydrogen.
  • R 9 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, cycloalkyl, or heterocycloalkyl, wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R 9a .
  • R 9 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, cycloalkyl, or heterocycloalkyl.
  • R 9 is hydrogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.
  • R 9 is hydrogen or C 1 -C 6 alkyl.
  • R 9 is hydrogen.
  • each R 12 is independently phenyl. In some embodiments, each R 12 is independently 5-or 6-membered heteroaryl. In some embodiments, each R 12 is independently C 3- C 6 cycloalkyl. In some embodiments, each R 12 is independently 5-or 6-membered heterocycloalkyl. In some embodiments, each R 12 is independently -CN, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments, each R 12 is independently C 1 -C 6 alkyl. In some embodiments, each R 12 is independently -CN, methyl, -CHF 2 , cyclopropyl, or pyridyl. In some embodiments, methyl is -CD 3 .
  • each R 12aa is independently hydrogen or R 12 . In some embodiments, is each R 12aa is independently hydrogen or R 12 . In some embodiments, is each R 12aa is independently hydrogen or R 12 . In some embodiments, is each R 12aa is independently hydrogen or R 12 .
  • each R a is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R.
  • each R a is independently C 1 -C 6 alkylene (cycloalkyl) , C 1 -C 6 alkylene (heterocycloalkyl) , C 1 -C 6 alkylene (aryl) , or C 1 -C 6 alkylene (heteroaryl) , wherein each alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R.
  • each R a is independently C 1 -C 6 alkyl or C 1 -C 6 haloalkyl. In some embodiments of a compound disclosed herein, each R a is independently C 1 -C 6 alkyl.
  • each R b is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkylene (cycloalkyl) , C 1 -C 6 alkylene (heterocycloalkyl) , C 1 -C 6 alkylene (aryl) , or C 1 -C 6 alkylene (heteroaryl) , wherein each alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R.
  • each R b is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R.
  • each R b is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, cycloalkyl, or heterocycloalkyl.
  • each R b is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, or C 1 -C 6 heteroalkyl.
  • each R b is independently hydrogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments of a compound disclosed herein, each R b is independently hydrogen or C 1 -C 6 alkyl. In some embodiments of a compound disclosed herein, each R b is hydrogen. In some embodiments of a compound disclosed herein, each R b is independently C 1 -C 6 alkyl.
  • R c and R d are each independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkylene (cycloalkyl) , C 1 -C 6 alkylene (heterocycloalkyl) , C 1 -C 6 alkylene (aryl) , or C 1 -C 6 alkylene (heteroaryl) , wherein each alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R.
  • R c and R d are each independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R.
  • each R b is independently hydrogen, C 1 -C 6 alkylene (cycloalkyl) , C 1 -C 6 alkylene (heterocycloalkyl) , C 1 -C 6 alkylene (aryl) , or C 1 -C 6 alkylene (heteroaryl) , wherein each alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R.
  • R c and R d are each independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, cycloalkyl, or heterocycloalkyl.
  • R c and R d are each independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, or C 1 -C 6 heteroalkyl.
  • R c and R d are each independently hydrogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments of a compound disclosed herein, R c and R d are each independently hydrogen or C 1 -C 6 alkyl. In some embodiments of a compound disclosed herein, R c and R d are each hydrogen. In some embodiments of a compound disclosed herein, R c and R d are each independently C 1 -C 6 alkyl.
  • R c and R d are taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more R.
  • each R is independently halogen, -CN, -OH, -NH 2 , C 1 -C 3 alkyl, or C 1 -C 3 haloalkyl; or two R on the same atom form an oxo. In some embodiments of a compound disclosed herein, each R is independently halogen, C 1 -C 3 alkyl, or C 1 -C 3 haloalkyl; or two R on the same atom form an oxo.
  • one or more of R, R 1 , R 1a , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 9a , R 10 , R 10a , R 10b , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R X , R Y , R a , R b , R c , and R d groups comprise deuterium at a percentage higher than the natural abundance of deuterium.
  • one or more 1 H are replaced with one or more deuteriums in one or more of the following groups R, R 1 , R 1a , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 9a , R 10 , R 10a , R 10b , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R X , R Y , R a , R b , R c , and R d .
  • the compound disclosed herein, or a pharmaceutically acceptable salt, or stereoisomer thereof is one of the compounds in Table 1. TABLE 1
  • the compound disclosed herein, or a pharmaceutically acceptable salt, or stereoisomer thereof is one of the compounds in Table 2.
  • the compounds described herein exist as geometric isomers. In some embodiments, the compounds described herein possess one or more double bonds. The compounds presented herein include all cis, trans, syn, anti,
  • Z) isomers as well as the corresponding mixtures thereof. In some situations, the compounds described herein possess one or more chiral centers and each center exists in the R configuration, or S configuration. The compounds described herein include all diastereomeric, enantiomeric, and epimeric forms as well as the corresponding mixtures thereof.
  • mixtures of enantiomers and/or diastereoisomers, resulting from a single preparative step, combination, or interconversion are useful for the applications described herein.
  • the compounds described herein are prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds, separating the diastereomers and recovering the optically pure enantiomers.
  • dissociable complexes are preferred.
  • the diastereomers have distinct physical properties (e.g., melting points, boiling points, solubilities, reactivity, etc.
  • bonds represented by solid wedge lines and dashed wedge lines are used to indicate absolute configuration of a chiral center
  • bonds represented by solid lines and dashed lines are used to indicate relative configuration of a chiral center
  • a bond represented by a wavy line is used to indicate (1) a solid wedge line or a dashed wedge line or (2) a solid line or a dashed line Isotopically enriched compounds
  • the compounds described herein may be artificially enriched in one or more particular isotopes.
  • the compounds described herein may be artificially enriched in one or more isotopes that are not predominantly found in nature.
  • the compounds described herein may be artificially enriched in one or more isotopes selected from deuterium ( 2 H) , tritium ( 3 H) , iodine-125 ( 125 I) , or carbon-14 ( 14 C) .
  • the compounds described herein are artificially enriched in one or more isotopes selected from 2 H, 11 C, 13 C, 14 C, 15 C, 12 N, 13 N, 15 N, 16 N, 16 O, 17 O, 14 F, 15 F, 16 F, 17 F, 18 F, 33 S, 34 S, 35 S, 36 S, 35 Cl, 37 Cl, 79 Br, 81 Br, 131 I, and 125 I.
  • the abundance of the enriched isotopes is independently at least 1%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or 100%by molar.
  • the compound is deuterated in at least one position.
  • the compounds disclosed herein have some or all of the 1 H atoms replaced with 2 H atoms.
  • Deuterated starting materials are readily available and are subjected to the synthetic methods described herein to provide for the synthesis of deuterium-containing compounds.
  • Large numbers of deuterium-containing reagents and building blocks are available commercially from chemical vendors, such as Aldrich Chemical Co.
  • Pharmaceutically acceptable salts are available commercially from chemical vendors, such as Aldrich Chemical Co.
  • Examples of pharmaceutically acceptable salts include those salts prepared by reaction of the compounds described herein with a mineral, organic acid or inorganic base, such salts including, acetate, acrylate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, bisulfite, bromide, butyrate, butyn-1, 4-dioate, camphorate, camphorsulfonate, caproate, caprylate, chlorobenzoate, chloride, citrate, cyclopentanepropionate, decanoate, digluconate, dihydrogenphosphate, dinitrobenzoate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptanoate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hexyne-1, 6-dioate, hydroxybenzoate,
  • Organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine and the like. It should be understood that the compounds described herein also include the quaternization of any basic nitrogen-containing groups they contain. In some embodiments, water or oil-soluble or dispersible products are obtained by such quaternization. Solvates
  • Tautomers are compounds that are interconvertible by migration of a hydrogen atom, accompanied by a switch of a single bond and adjacent double bond. In bonding arrangements where tautomerization is possible, a chemical equilibrium of the tautomers will exist. All tautomeric forms of the compounds disclosed herein are contemplated. The exact ratio of the tautomers depends on several factors, including temperature, solvent, and pH.
  • the cancer is a cancer in which YAP is localized in the nucleus of cells of the cancer.
  • Also disclosed herein is a method of treating a cancer in a subject in need thereof, the method comprising administering an effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt, or stereoisomer thereof, to the subject in need thereof, or a pharmaceutical composition disclosed herein.
  • the cancer is mesothelioma. In some embodiments of a method of treating cancer, the cancer is NF2 deficient mesothelioma.
  • the cancer is epithelioid hemangioendothelioma.
  • the fibrosis disease is a disorder associated with fibrosis, lung fibrosis, pulmonary fibrosis, idiopathic pulmonary fibrosis, renal fibrosis, cardiac fibrosis, skin fibrosis, systemic sclerosis, scleroderma, keloid or keloid scar, liver fibrosis, cirrhosis, diabetic retinopathy, intestinal fibrosis, cystic fibrosis, prostate fibrosis, muscle fibrosis, pancreatic fibrosis, hypertrophic scar, morphea, fibrosis as a result of graft-versus-host discase, subepithelial fibrosis, endomyocardial fibrosis, uterine fibrosis, myelofibrosis, retroperitoneal fibrosis, nephrogenic systemic fibrosis, scarring after surgery, asthma, fibrosis as a result of aberrant wound healing, glomerulonephritis
  • Also disclosed herein is a method of treating a disease in which Hippo pathway inhibition is beneficial in a subject in need thereof, the method comprising administering an effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt, or stereoisomer thereof, to the subject in need thereof, or a pharmaceutical composition disclosed herein.
  • a maintenance dose is administered if necessary. Subsequently, in specific embodiments, the dosage, or the frequency of administration, or both, is reduced, as a function of the symptoms.
  • doses employed for adult human treatment are typically in the range of 0.01 mg-5000 mg per day.
  • the daily dosages appropriate for the compound described herein, or a pharmaceutically acceptable salt thereof are from about 0.01 to about 50 mg/kg per body weight.
  • the daily and unit dosages are altered depending on a number of variables including, but not limited to, the activity of the compound used, the disease or condition to be treated, the mode of administration, the requirements of the individual subject, the severity of the disease or condition being treated, and the judgment of the practitioner. Routes of Administration
  • a compound as described herein is administered in a local rather than systemic manner, for example, via injection of the compound directly into an organ, often in a depot preparation or sustained release formulation.
  • long-acting formulations are administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection.
  • the drug is delivered in a targeted drug delivery system, for example, in a liposome coated with organ specific antibody.
  • the liposomes are targeted to and taken up selectively by the organ.
  • the compound as described herein is provided in the form of a rapid release formulation, in the form of an extended-release formulation, or in the form of an intermediate release formulation.
  • compositions comprising a compound described herein, or a pharmaceutically acceptable salt, or stereoisomer thereof, and at least one pharmaceutically acceptable excipient.
  • Pharmaceutical compositions are formulated in a conventional manner using one or more pharmaceutically acceptable excipients that facilitate processing of the active compounds into preparations that can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen.
  • a summary of pharmaceutical compositions described herein can be found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995) ; Hoover, John E., Remington’s Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H.A.
  • the pharmaceutically acceptable excipient is selected from carriers, binders, filling agents, suspending agents, flavoring agents, sweetening agents, disintegrating agents, dispersing agents, surfactants, lubricants, colorants, diluents, solubilizers, moistening agents, plasticizers, stabilizers, penetration enhancers, wetting agents, anti-foaming agents, antioxidants, preservatives, and any combinations thereof.
  • the pharmaceutical formulations described herein include, but are not limited to, aqueous liquid dispersions, liquids, gels, syrups, elixirs, slurries, suspensions, self-emulsifying dispersions, solid solutions, liposomal dispersions, aerosols, solid oral dosage forms, powders, immediate release formulations, controlled release formulations, fast melt formulations, tablets, capsules, pills, powders, dragees, effervescent formulations, lyophilized formulations, delayed release formulations, extended release formulations, pulsatile release formulations, multiparticulate formulations, and mixed immediate and controlled release formulations.
  • Combination aqueous liquid dispersions, liquids, gels, syrups, elixirs, slurries, suspensions, self-emulsifying dispersions, solid solutions, liposomal dispersions, aerosols, solid oral dosage forms, powders, immediate release formulations, controlled release formulations, fast melt formulations, tablets, capsules, pills,
  • the additional therapeutic agent is administered at the same time as the compound disclosed herein. In some embodiments, the additional therapeutic agent and the compound disclosed herein are administered sequentially. In some embodiments, the additional therapeutic agent is administered less frequently than the compound disclosed herein. In some embodiments, the additional therapeutic agent is administered more frequently than the compound disclosed herein. In some embodiments, the additional therapeutic agent is administered prior than the administration of the compound disclosed herein. In some embodiments, the additional therapeutic agent is administered after the administration of the compound disclosed herein.
  • the additional therapeutic agent is an anti-cancer agent.
  • Cells were plated into 384-well microplate (150 cells/well, 50 mL medium/well) . Also seeding an extra plate as Day 0 control measurement. The microplates were incubated at 37°C, 5%CO 2 overnight.
  • the final DMSO concentration was 0.1%

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Abstract

L'invention concerne des composés et des procédés de modulation ou d'inhibition de TEAD. L'invention concerne en outre des compositions pharmaceutiques comprenant les inhibiteurs de TEAD et des méthodes de traitement utilisant les inhibiteurs de TEAD ou les compositions pharmaceutiques.
PCT/CN2025/085011 2024-03-27 2025-03-26 Inhibiteurs de tead et leurs procédés d'utilisation Pending WO2025201397A1 (fr)

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CNPCT/CN2024/084120 2024-03-27
CN2024084120 2024-03-27

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