WO2024059317A1 - Inhibiteurs d'oncoprotéines yap/taz-tead - Google Patents

Inhibiteurs d'oncoprotéines yap/taz-tead Download PDF

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WO2024059317A1
WO2024059317A1 PCT/US2023/032957 US2023032957W WO2024059317A1 WO 2024059317 A1 WO2024059317 A1 WO 2024059317A1 US 2023032957 W US2023032957 W US 2023032957W WO 2024059317 A1 WO2024059317 A1 WO 2024059317A1
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compound
stereoisomer
pharmaceutically acceptable
solvate
acceptable salt
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Henry William Beecroft Johnson
Zhushou Luo
Chao Zhang
Michael J. Bishop
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Bridgene Biosciences, Inc.
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    • 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
    • C07D413/06—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 linked by a carbon chain containing only aliphatic carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/08—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
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    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
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    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/38—Halogen atoms or nitro radicals
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    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/40—Oxygen atoms
    • C07D211/44—Oxygen atoms attached in position 4
    • C07D211/48—Oxygen atoms attached in position 4 having an acyclic carbon atom attached in position 4
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    • 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
    • C07D401/06—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 linked by a carbon chain containing only aliphatic carbon atoms
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    • 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
    • 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
    • C07D413/08—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 linked by a carbon chain containing alicyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems

Definitions

  • the present invention relates generally to cancer therapy, and more specifically to the synthesis of covalent inhibitors of YAP/TAZ-TEAD oncoproteins and use thereof for the treatment of cancers.
  • BACKGROUND [0002]
  • TEA domain transcription factors (TEAD proteins) are effectors for oncogenic YAP/TAZ signaling in cancers with deregulated Hippo tumor suppressor pathway signaling.
  • activation of YAP/TAZ signaling has been described as a mechanism of resistance to other targeted cancer therapies, such as inhibitors of EGFR and MEK. [0003] Accordingly, inhibitors of TEAD1, 2, 3 and/or 4, can have great potential in the application of cancer therapy, both as monotherapy in cancers with deregulated Hippo pathway signaling and as combination therapy with other targeted agents.
  • R 6 is absent when bond a is a triple bond; or R 6 is selected from the group consisting of H, F, and C1-C3 alkyl when bond a is a double bond; - 2 - 1097257085 ⁇ 4 ⁇ AMERICAS Attorney Docket No.126662.00015 A is absent or selected from the group consisting of O, CH2, CH2CH2, CH(OH), CH(OCH3), C(CH3)2 and CH(CH3); and Ar is aryl or heteroaryl, each of which is optionally substituted with 1, 2, 3, or 4 R 9 groups; or ii) wherein bond a, X 1 , X 2 , R 4 , R 5 , R 6 , A, and Ar together form: X 2 is X 2a and X 2a is C; R 4 –(CH2)m-; m is 0, 1, or 2; X 1 is absent or is selected from the group consisting of CH2, CH2CH2, CH(CH3), O, CH2O, and OCH2; R
  • the present disclosure provides a pharmaceutical composition, comprising a pharmaceutically effective amount of the compound of the present application (including according to formula (I), (II), any embodiments herein, and any of Compounds 1-106) or a stereoisomer, and/or pharmaceutically acceptable salt, and/or solvate thereof, and a pharmaceutically acceptable carrier.
  • a method of treatment of a disease or disorder modulated by TEAD1, 2, 3, and/or 4 comprising administering to an individual in need thereof a therapeutically or prophylactically effective amount of a compound disclosed herein (including of Formula (I), (II), any embodiments, and any of compounds 1-106), or administering to an individual in need thereof a pharmaceutical composition comprising a therapeutically or prophylactically effective amount of a compound disclosed herein (including of Formula (I), (II), any embodiments, and any of compounds 1-106), and a pharmaceutically acceptable carrier.
  • the method is that wherein TEAD1 is inhibited selectively over TEAD2, 3, and 4.
  • the disease or disorder is selected from cancer, fibrotic diseases, neurofibromatosis type 2, and polycystic kidney disease.
  • the present disclosure provides a method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the compound disclosed herein (including according to formula (I), (II), any embodiments herein, and any of Compounds 1-106), or a stereoisomer, and/or a pharmaceutically acceptable salt, and/or solvate thereof; or a pharmaceutical composition a - 4 - 1097257085 ⁇ 4 ⁇ AMERICAS Attorney Docket No.126662.00015 therapeutically effective amount of the compound disclosed herein, or a stereoisomer, and/or a pharmaceutically acceptable salt, and/or solvate thereof and a pharmaceutically acceptable carrier.
  • a compound useful as an intermediate in the preparation of the compounds disclosed herein is a method of preparing a compound of Formula (I) according to any of the general schemes or synthetic examples.
  • the disclosure provides a method of inhibiting TEAD1, 2, 3, and/or 4 in a subject or in a sample comprising administering a compound of Formula (I) (including according to formula (I), (II), any embodiments herein, and any of Compounds 1-106) or a stereoisomer and/or a pharmaceutically acceptable salt thereof, and/or a solvate thereof.
  • the compound is at least one of the compounds as shown in Table 1 or a stereoisomer, and/or a pharmaceutically acceptable salt thereof, and/or a solvate thereof.
  • Fig.1 is a schematic illustration of how the disclosed compounds function as covalent TEAD1 inhibitors.
  • Fig.2 is a graph illustrating the percent of body weight changes in mice over time after treatment according to Example 5.
  • Fig.3 is a graph illustrating the percent of volume changes in mice tumors over time after treatment according to Example 5 DETAILED DESCRIPTION
  • the present disclosure is based on the discovery of a class of small-molecule compounds that inhibits TEAD1, 2, 3, and/or 4 activity, in some embodiments selectively inhibits the activity of TEAD1 over that of the other TEAD isoforms, which exhibits potential in the treatment of cancer, and in some embodiments, certain types of cancers.
  • TEAD1 belongs to TEADs family, which regulates cell growth and proliferation via TEAD1/YAP/TAZ complex.
  • TEAD1 regulates glioblastoma stemness and invasiveness by regulating EGFR and AQP4 expression, via the pathway of TEAD-EGFR/AQP4. Further via - 5 - 1097257085 ⁇ 4 ⁇ AMERICAS Attorney Docket No.126662.00015 the pathway of Hippo-YAP/TAZ-TEAD, YAP/TAZ-TEAD activation induces transcription of cell cycle-promoting genes; TEAD1 regulates expression of cytoskeleton remodeling gene; TEAD1 increases expression of other transcription factor like Myc and SP1; YAP/TAZ- TEAD1 axis regulates cell apoptosis; blocking TEAD1 aberrant activities will down regulates gene expression of MYC, KRAS, BRAF, NF2, LKB1 and PD-L1, etc.
  • inhibitor compounds that inhibit TEAD1, 2, 3, and/or 4 activity have potential in the treatment of cancers such as glioblastoma, gastric cancer, colorectal cancer, pancreatic ductal adenocarcinoma (PDAC), and malignant pleural mesothelioma (MPM).
  • cancers such as glioblastoma, gastric cancer, colorectal cancer, pancreatic ductal adenocarcinoma (PDAC), and malignant pleural mesothelioma (MPM).
  • references to “the method” includes one or more methods, and/or steps of the type described herein which will become apparent to those persons skilled in the art upon reading this disclosure.
  • references to “the method” includes one or more methods, and/or steps of the type described herein which will become apparent to those persons skilled in the art upon reading this disclosure.
  • Alkyl refers to a linear or branched, monovalent, saturated hydrocarbon, where the alkyl has 1 to 12 carbon atoms, and in some embodiments 1 to 10 carbons, in some embodiments 1 to 6 carbons, in some embodiments 1 to 3 carbons, or in some embodiments having 1, 2, 3 or 4 carbon atoms.
  • alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl n-pentyl, and n-hexyl groups.
  • “Lower alkyl” means an alkyl group having one to six carbon atoms.
  • “C0” alkyl (as in “C0-C6-alkyl”) is a covalent bond.
  • C6 alkyl refers to, for example, n-hexyl, iso-hexyl, and the like. In some embodiments, alkyl is C1-3alkyl or C1-4alkyl.
  • Alkylcarbonyl refers to a -C(O)R group where R is alkyl, as defined herein. In some embodiments, acyl is acetyl. Lower alkylcarbonyl is where the alkyl is C1-C6alkyl.
  • Alkylcarbonyloxy refers to a -OC(O)R group where R is alkyl, as defined herein.
  • Alkylsulfonyl refers to a –S(O)2R group where R is alkyl, as defined herein.
  • C1-C6Alkylthio refers to an —SR group, where R is alkyl, as defined herein.
  • Alkoxy refers to an —OR group, where R is alkyl, as defined herein. Exemplary alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, isopropoxy, sec-butoxy, tert-butoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, and cyclohexyloxy groups. In some embodiments, alkoxy is methoxy.
  • “Lower alkoxy” means an —OR, where R is alkyl having one to six carbon atoms.
  • C1-C6alkoxycarbonyl refers to a –C(O)R group where R is C1-C6alkoxy, as defined herein,
  • “Haloalkyl” refers to an alkyl group, as defined herein, substituted with one or more halogens, for example one, two, three, four, or five halo atoms. Representative examples includes 2,2-difluoroethyl, trifluoromethyl, and 2-chloro-1-fluoroethyl, and the like.
  • “Lower haloalkyl” means the alkyl has one to six carbon atoms. In some embodiments, the haloalkyl is trifluoromethyl. “Lower perhaloalkyl” means that every hydrogen in the alkyl is replaced with a halo.
  • “C1-C6haloalkylthio” refers to an –SR group where R is a C1-C6haloalkyl group as defined herein.
  • “Haloalkenyl” refers to an alkenyl group, as defined herein, substituted with one or more halogens, for example one, two, three, four, or five halo atoms.
  • “Lower haloalkenyl” means the alkenyl has two to six carbon atoms.
  • “Haloalkynyl” refers to an alkynyl group, as defined herein, substituted with one or more halogens, for example one, two, three, four, or five halo atoms.
  • “Lower haloalkynyl” means the alkynyl has two to six carbon atoms.
  • “Haloalkoxy” refers to an –OR group where R is haloalkyl, as defined herein. “Lower perhaloalkoxy” means that every hydrogen in the alkyl is replaced with a halo.
  • Cycloalkyl refers to a monocyclic or bicyclic, monovalent group hydrocarbon having three to fourteen carbon ring atoms. Cycloalkyl is saturated or partially saturated but cannot contain an aromatic ring. Cycloalkyl includes fused, bridged, and spiro ring systems, - 8 - 1097257085 ⁇ 4 ⁇ AMERICAS Attorney Docket No.126662.00015 In some embodiments, cycloalkyl has from 3 to 12, 3 to 10, 3 to 8, 4 to 6, or 3, 4, 5, 6 or 7 carbon atoms. Examples of monocyclic cycloalkyl includes, but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl groups.
  • bicyclic cycloalkyl examples include, but are not limited to, bicyclo[4.4.0]decanyl, bicyclo[2.2.1]heptanyl, spiro[2.2]pentanyl, and the like.
  • Cycloalkylene refers to a divalent cycloalkyl, a defined herein.
  • Examples of monocyclic cycloalkylene include, but are not limited to cycloprop-diyl, cyclobut-diyl, cyclopent-diyl, and cyclohex-diyl groups.
  • bicyclic cycloalkylene examples include, but are not limited to, bicyclo[4.4.0]decan-diyl, bicyclo[2.2.1]heptan-diyl, spiro[2.2]pentan-diyl, and the like.
  • cycloalkylene is C4-C6 cycloalkylene.
  • Alkenyl refers to a linear or branched, momvalent hydrocarbon radical comprising 2 to 12 carbon atoms and one or more double bonds between two carbon atoms.
  • alkenyl has from 2 to about 10 carbon atoms, in some embodiments 2 to 8 carbon atoms, in some embodiments from 2 to about 6 carbon atoms, or in some embodiments 22, 3 or 4 carbon atoms
  • “Lower alkenyl” means an alkenyl group having two to six carbon atoms.
  • Alkynyl refers to a straight or branched hydrocarbon radical, with one or more triple bonds between two carbon atoms, and 2 to 12 carbon atoms, in some embodiments from 2 to 10 carbon atoms, in some embodiments from 2 to 6 carbon atoms, or 2, 3 or in some embodiments 4 carbon atoms
  • Exemplary alkynyl groups include, but are not limited to, ethynyl, propargyl, and -C ⁇ C(CH3), among others.
  • “Lower alkynyl” means an alkynyl group having two to six carbon atoms.
  • Aryl means a monovalent six- to fourteen-membered, mono- or bi-carbocyclic ring, wherein the monocyclic ring is aromatic and at least one of the rings in the bicyclic ring is aromatic.
  • the aryl contains 6 to 10 carbon ring atoms. Representative examples include phenyl, naphthyl, and indanyl, and the like. In some embodiments, aryl is phenyl.
  • Heteroaryl refers to a monocyclic, fused bicyclic, or fused tricyclic, monovalent radical of 5 to 14 ring atoms containing one or more heteroatoms, for example one, two, three, - 9 - 1097257085 ⁇ 4 ⁇ AMERICAS Attorney Docket No.126662.00015 or four ring heteroatoms, independently selected from N, -N(R x )-, O, S, and S(O)n- (n is 0, 1, or 2) and the remaining ring atoms being carbon, wherein the ring comprising a monocyclic radical is aromatic and wherein at least one of the fused rings comprising a bicyclic or tricyclic radical is aromatic,.
  • R x is hydrogen, alkyl, hydroxy, alkoxy, acyl, or alkylsulfonyl.
  • Fused bicyclic radical includes bridged ring systems. Unless stated otherwise, the point of attachment may be located on any atom of any ring of the heteroaryl group, valency rules permitting. In particular, when the point of attachment is located on the nitrogen, R x is absent.
  • Heteroaryl includes, but is not limited to, isoxazolyl, oxazolyl, oxadiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, thiazolyl, pyrazolyl, 1,2,4-triazolyl, 1,3,5-triazolyl, tetrazoyl, pyrrolyl, imidazolyl, thienyl, furanyl, indolyl, 2,3-dihydro-1H-indolyl (including, for example, 2,3-dihydro-1H-indol-2-yl or 2,3-dihydro-1H-indol-5-yl, and the like), isoindolyl, indolinyl, isoindolinyl, phthalimidyl, pyrazolopyridyl, benzofuranyl, benzimidazolyl, benzodioxo
  • heteroaryl is a 5-membered or 6-membered heteroaryl.
  • heteroaryl is pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, pyrimidinyl, or pyridinyl.
  • heteroaryl is pyrazolyl, pyrimidinyl, or pyridinyl.
  • heteroaryl is pyrazolyl or pyrimidinyl.
  • heteroaryl is oxazolyl, isoxazolyl, thiazolyl, or pyridinyl.
  • fused arylene refers to a divalent, monocyclic aryl ring, as defined herein, which is fused to second ring, and is represented by Ar 1 portion in the following .
  • Ar 1 fused arylene (benzo).
  • - 10 - 1097257085 ⁇ 4 ⁇ AMERICAS Attorney Docket No.126662.00015
  • fused heteroarylene refers to a divalent, monocyclic heteroaryl ring, as defined herein, which is fused to second ring, and is represented by Ar 1 portion in the following ring: .
  • the Ar 1 fused heteroarylene refers to a divalent, monocyclic heteroaryl ring, as defined herein, which is fused to second ring, and is represented by Ar 1 portion in the following ring: .
  • the Ar 1 fused heteroarylene .
  • Fused bicyclic radical includes bridged ring systems. Unless otherwise stated, the point of attachment of the group may be located on any atom of any ring within the radical, valency rules permitting. In particular, when the point of attachment is located on a nitrogen atom, R y is absent.
  • heterocycloalkyl includes, but is not limited to, azetidinyl, pyrrolidinyl, 2-oxopyrrolidinyl, 2,5-dihydro-1H-pyrrolyl, piperidinyl, 4-piperidonyl, morpholinyl, piperazinyl, 2-oxopiperazinyl, tetrahydropyranyl, 2-oxopiperidinyl, thiomorpholinyl, thiamorpholinyl, perhydroazepinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, dihydropyridinyl, tetrahydropyridinyl, oxazolinyl, oxazolidinyl, isoxazolidinyl, thiazolinyl, thiazolidinyl, quinuclidinyl, isothiazolidinyl, octahydroindo
  • Halogen groups include F, Cl, Br, and I; nitro group refers to –NO2; and cyano group refers to –CN.
  • Amogen groups include F, Cl, Br, and I; nitro group refers to –NO2; and cyano group refers to –CN.
  • Amogen groups include F, Cl, Br, and I; nitro group refers to –NO2; and cyano group refers to –CN.
  • Amogen groups include F, Cl, Br, and I; nitro group refers to –NO2; and cyano group refers to –CN.
  • Amogen groups include F, Cl, Br, and I; nitro group refers to –NO2; and cyano group refers to –CN.
  • Amino refers to –NH2.
  • substituted heteroaryl refers to heteroaryl, as defined herein, substituted with one or more (1, 2, 3, or 4) substituents independently selected from the following groups: lower alkyl, lower alkenyl, lower alkynyl, C3-C6heterocycloalkyl, lower haloalkyl, lower haloalkenyl, lower haloalkynyl, lower perhaloalkyl, lower perhaloalkoxy, C3-C6cycloalkyl, phenyl, lower alkoxy, lower haloalkoxy, oxo, lower alkylcarbonyloxy, lower alkylcarbonyl, C1-C6alkoxycarbonyl, -C(O)NH2, -C(O)NH(C1-C6alkyl), -C(O)N(C1-C6alkyl)2, cyano, - 11 - 1097257085 ⁇ 4 ⁇ AMERICAS Attorney Docke
  • protecting group refers to a group that is added to an oxygen, nitrogen or phosphorus atom to prevent its further reaction or for other purposes.
  • oxygen and nitrogen protecting groups are known to those skilled in the art of organic synthesis.
  • a “nitrogen-protecting group” is 9-fluorenylmethyloxycarbonyl (Fmoc), tert-butoxycarbonyl (Boc), benzyloxycarbonyl (CBz), acetyl, trichloroacetyl, trifluoroacetyl, -C(O)OCH2CCl3 (Troc), p-methoxyphenyl, benzyl, p-methoxybenzyl, p-methoxybenzylcarbonyl, triphenylmethyl, benzylidenyl, 2,2,2-trichloroethoxysulfonyl (Tces), p-methoxybenzenesulfonyl (Mbs) or p-toluenesulfony
  • an oxygen-protecting group (e.g. for X 1 ) is methoxymethyl (MOM), ethoxyethyl, methoxyethoxymethyl, tetrahydrofuranyl, tetrahydropyranyl, methyl, tert-butyl, allyl, benzyl, trimethylsilyl, triethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, acetyl, pivalyl, benzoyl, dimethoxytrityl, trityl, methoxytrityl, p-methoxybenzyl, or methylthiomethyl.
  • MOM methoxymethyl
  • ethoxyethyl methoxyethoxymethyl
  • tetrahydrofuranyl tetrahydropyranyl
  • methyl tert-butyl
  • allyl
  • Stereoisomer refers to compounds which have the same molecular formula and sequence of bonded atoms (constitution), but differ in the three-dimensional orientations of their atoms in space.
  • Stereoisomer includes enantiomers, diastereomers, geometric isomers (e.g., regioisomers, cis and trans isomers, Z and E isomers), and atropisomers.
  • Enantiomers are a pair of molecules with the exact same connectivity that exist in two forms that are mirror images of one another but cannot be superimposed one upon the other.
  • Diastereoisomers are non-identical stereoisomers which have different configurations at one or more of the equivalent stereocenters and are not mirror images of each other.
  • Geometric isomers include cis-trans isomers or configurational isomers, and refer to pairs of molecules which have the same formula but whose functional groups are in different orientations in three-dimensional space.
  • cis–trans Stereoisomers contain double bonds that do not rotate, or they may contain ring structures, where the rotation of bonds is restricted or prevented. cis indicates that the functional groups (substituents) are on the same side of some plane, while trans conveys that they are on opposing (transverse) sides.
  • Atropisomers are stereoisomers resulting from - 12 - 1097257085 ⁇ 4 ⁇ AMERICAS Attorney Docket No.126662.00015 hindered rotation about single bonds where the steric strain barrier to rotation is high enough to allow for the isolation of the conformers.
  • the stereoisomer is a geometric isomer. In some or any embodiments, the stereoisomer is an enantiomer. In some or any embodiments, the stereoisomer is an enantiomer and geometric isomer. [00051]
  • the term “substantially free of” or “substantially in the absence of” stereoisomers (for example, geometric isomers) with respect to a composition refers to a composition that includes at least 85 or 90% by weight, in some or any embodiments 95%, 98 %, 99% or 100% by weight, of a designated stereoisomer (for example, geometric isomer) of a compound in the composition.
  • the compounds are substantially free of stereoisomers (for example, geometric isomers) of the designated compound.
  • isolated refers to a composition that includes at least 85, 90%, 95%, 98%, 99% to 100% by weight, of a specified compound, the remainder comprising other chemical species, or stereoisomers (for example, geometric isomers) thereof.
  • solvate refers to a compound provided herein or a salt thereof, that further includes a stoichiometric or non- stoichiometric amount of solvent bound by non-covalent intermolecular forces.
  • compositions described herein include conventional nontoxic salts or quaternary ammonium salts of a compound, e.g., from non- toxic organic or inorganic acids.
  • such conventional nontoxic salts include those derived from inorganic acids such as hydrochloride, hydrobromic, sulfuric, sulfamic, phosphoric, nitric, and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, palmitic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicyclic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isothionic, and the like.
  • inorganic acids such as hydrochloride, hydrobromic, sulfuric, sulfamic, phosphoric, nitric, and the like
  • organic acids such as acetic, propionic, succinic, glycolic, stearic,
  • described compounds may contain one or more acidic functional groups and, thus, are capable of forming pharmaceutically acceptable salts with pharmaceutically acceptable bases.
  • These salts can likewise be prepared in situ in the administration vehicle or - 13 - 1097257085 ⁇ 4 ⁇ AMERICAS Attorney Docket No.126662.00015 the dosage form manufacturing process, or by separately reacting the purified compound in its free acid form with a suitable base, such as the hydroxide, carbonate or bicarbonate of a pharmaceutically acceptable metal cation, with ammonia, or with a pharmaceutically acceptable organic primary, secondary or tertiary amine.
  • a suitable base such as the hydroxide, carbonate or bicarbonate of a pharmaceutically acceptable metal cation, with ammonia, or with a pharmaceutically acceptable organic primary, secondary or tertiary amine.
  • Representative alkali or alkaline earth salts include the lithium, sodium, potassium, calcium, magnesium, and aluminum salts and the like.
  • Representative organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine and the like.
  • Compounds [00055] The aspects and embodiments described herein include the recited compounds as well as a pharmaceutically acceptable salt, and/or hydrate, and/or solvate, and/or stereoisomer, and/or tautomer, and/or mixture, or any combination thereof. In some embodiments, the recited compounds are provided as a pharmaceutically acceptable salt, and/or stereoisomer, and/or tautomer, and/or mixture, or any combination thereof.
  • the recited compounds are provided as a pharmaceutically acceptable salt, and/or stereoisomer, and/or tautomer thereof. In some embodiments, the recited compounds are provided as a pharmaceutically acceptable salt thereof.
  • Certain multicyclic structures provided herein are drawn with one or more floating substituents. Unless provided otherwise or otherwise clear from the context, the substituent(s) may be present on any atom of the multicyclic ring, where chemically feasible and valency rules permitting. For example, in the , the R 9 substituents can be on the benzo portion of the bicyclic ring or the of the bicyclic ring.
  • Embodiment A the compound of Formula (I) is that wherein ; R 1 is H or C1-3alkyl (in some embodiments, methyl); - 14 - 1097257085 ⁇ 4 ⁇ AMERICAS Attorney Docket No.126662.00015 R 1a is absent when bond b is a triple bond; and R 1a is H when bond b is a double bond; R 2 is selected from the group consisting of H, C1-2alkyl, methoxy, -NH-heteroaryl (in some embodiments, -NH-pyrimidinyl), and 5-membered heteroaryl (in some embodiments, pyrazolyl); R 3 is H or methyl; and R 8 is absent when bond b is a triple bond; and R 8 is selected from the group consisting of H and F when bond b is a double bond; and i) wherein bond a, X 1 , X 2 , R 4 , R 5 , R 6 , A, and
  • R 6 is absent when bond a is a triple bond; or R 6 is H, when bond a is a double bond; A is absent or is selected from the group consisting of CH2, CH(OH), CH(OCH3), and C(CH3)2; and Ar is phenyl, oxazolyl, thiazolyl, or pyridinyl, each of which is optionally substituted with 1 or 2 R 9 groups; or ii) wherein bond a, X 1 , X 2 , R 4 , R 5 , R 6 , A, and Ar together form: X 2 is X 2a and X 2a is C; R 4 –(CH2)m-; m is 0, 1, or 2; X 1 is absent or is selected from the group consisting of CH2, O, CH2O and OCH2; R 5 is H; A is absent; and Ar is phenyl optionally substituted with 1 R 9 group; provided that m is 1 or 2 when X 1 is absent; or - 15 -
  • Embodiment B the compound of Formula (I) is that wherein ; R 1 is H; R 1a is absent when bond b is a triple bond; and R 1a is H when bond b is a double bond; R 2 is selected from the group consisting of H, C1-2alkyl, methoxy, and 5-membered heteroaryl (in some embodiments, pyrazolyl); R 3 is H or methyl; and - 16 - 1097257085 ⁇ 4 ⁇ AMERICAS Attorney Docket No.126662.00015 R 8 is absent when bond b is a triple bond; and R 8 is selected from the group consisting of H, and F when bond b is a double bond; and i) wherein bond a, X 1 , X 2 , R 4 , R 5 , R 6 , A, and Ar are as follows: bond a is a double bond or triple bond; X 1 is absent or is CH2, and R 4 is selected from the group consisting of H
  • Embodiment 1 Provided is a compound of formula (I), or a stereoisomer, and/or a pharmaceutically acceptable salt, and/or solvate thereof, as provided in the first aspect.
  • the compound of formula (I) is according to Embodiment A or B.
  • Embodiment 1A Provided is a compound of formula (I), or a stereoisomer, and/or a pharmaceutically acceptable salt, and/or solvate thereof, wherein: bond b is a double bond or triple bond; R 1 is selected from the group consisting of H, C1-3alkyl, morpholin-4-yl, and -CH2N(C1- 3alkyl)2; R 1a is absent when bond b is a triple bond; and R 1a is H when bond b is a double bond; R 2 is selected from the group consisting of H, F, -OH, C1-3alkyl, -OC1-3alkyl, -NH-heteroaryl, heteroaryl, -NH-(substituted heteroaryl), and substituted heteroaryl; R 3 is selected from the group consisting of H, and C1-3alkyl; and R 8 is absent when bond b is a triple bond; and R 8 is selected from the group consisting of H, F, CN
  • R 6 is absent when bond a is a triple bond; or R 6 is selected from the group consisting of H, F, and C1-C3 alkyl when bond a is a double bond; A is absent or selected from the group consisting of O, CH2, CH2CH2, and CH(CH3); and Ar is aryl or heteroaryl group, optionally substituted with 1, 2, 3, or 4 R 9 groups; or ii) wherein bond a, X 1 , X 2 , R 4 , R 5 , R 6 , A, and Ar together form: X 2 is X 2a and X 2a is C; R 4 –(CH2)m-; m is 1 or 2; X 1 is absent or is selected from the group consisting of CH2, CH2CH2, and CH(CH3); R 5 is selected from the group consisting of H, F, and C1-C3 alkyl; A is absent or selected from the group consisting of O, CH2, CH2CH2, and CH(CH3); and Ar is aryl or
  • Embodiment 2 In embodiment 2, provided is a compound of any one of embodiments 1, 1A, A, and B, wherein bond b is a double bond and R 1a is H; or a stereoisomer, and/or a pharmaceutically acceptable salt, and/or solvate thereof. [00062] Embodiment 3. In embodiment 3, provided is a compound of any one of embodiments 1, 1A, A, and B, wherein bond b is a triple bond and R 1a and R 8 are absent; or a stereoisomer, and/or a pharmaceutically acceptable salt, and/or solvate thereof. [00063] Embodiment 4.
  • Embodiment 4 provided is a compound of any one of embodiments A and 1-3, wherein R 1 is H; or a stereoisomer, and/or a pharmaceutically acceptable salt, and/or solvate thereof.
  • Embodiment 5 provided is a compound of any one of embodiments A and 1-3, wherein R 1 is Me; or a stereoisomer, and/or a pharmaceutically acceptable salt, and/or solvate thereof [00065] Embodiment 6.
  • Embodiment 7a provided is a compound of any one of embodiments A and 1-3, wherein R 1 is selected from the group consisting of H and C1-3alkyl; or a stereoisomer, and/or a pharmaceutically acceptable salt, and/or solvate thereof. [00067] Embodiment 7.
  • Embodiment 7 provided is a compound of any one of embodiments A, 1-3 and 7a, wherein R 1 is selected from the group consisting of H and Me; or a stereoisomer, and/or a pharmaceutically acceptable salt, and/or solvate thereof.
  • Embodiment 8 provided is a compound of any one of embodiments A, B, and 1-7, wherein R 2 is H; or a stereoisomer, and/or a pharmaceutically acceptable salt, and/or solvate thereof.
  • Embodiment 9. provided is a compound of any one of embodiments 1-7, wherein R 2 is F; or a stereoisomer, and/or a pharmaceutically acceptable salt, and/or solvate thereof.
  • Embodiment 10 In embodiment 10, provided is a compound of any one of embodiments 1-7, wherein R 2 is -OH; or a stereoisomer, and/or a pharmaceutically acceptable salt, and/or solvate thereof. [00071] Embodiment 11. In embodiment 11, provided is a compound of any one of embodiments 1-7, wherein R 2 is C1-3alkyl; or a stereoisomer, and/or a pharmaceutically acceptable salt, and/or solvate thereof. In embodiment 11, provided is a compound of any one of embodiments A, B, and 1-7, wherein R 2 is C1-2alkyl; or a stereoisomer, and/or a pharmaceutically acceptable salt, and/or solvate thereof. [00072] Embodiment 12.
  • Embodiment 12 provided is a compound of any one of embodiments A, B, and 1-7, wherein R 2 is H, methyl or ethyl; or a stereoisomer, and/or a pharmaceutically acceptable salt, and/or solvate thereof.
  • Embodiment 13a provided is a compound of any one of embodiments 1-7, wherein R 2 is -OC1-3alkyl; or a stereoisomer, and/or a pharmaceutically acceptable salt, and/or solvate thereof.
  • Embodiment 13 provided is a compound of any one of embodiments 1-7, wherein R 2 is -OC1-3alkyl; or a stereoisomer, and/or a pharmaceutically acceptable salt, and/or solvate thereof.
  • Embodiment 13 provided is a compound of any one of embodiments A, B, and 1-7, wherein R 2 is -OMe; or a stereoisomer, and/or a pharmaceutically acceptable salt, and/or solvate thereof.
  • R 2 is -OMe; or a stereoisomer, and/or a pharmaceutically acceptable salt, and/or solvate thereof.
  • - 21 - 1097257085 ⁇ 4 ⁇ AMERICAS Attorney Docket No.126662.00015
  • Embodiment 14 provided is a compound of any one of embodiments 1-7, wherein R 2 is -NH-heteroaryl or -NH-(substituted heteroaryl); or a stereoisomer, and/or a pharmaceutically acceptable salt, and/or solvate thereof.
  • embodiment 15 provided is a compound of any one of embodiments 1-7, wherein R 2 is unsubstituted heteroaryl (in some embodiments, pyrazolyl) or substituted heteroaryl (in some embodiments, pyrazolyl); or a stereoisomer, and/or a pharmaceutically acceptable salt, and/or solvate thereof.
  • R 2 is unsubstituted heteroaryl (in some embodiments, pyrazolyl) or substituted heteroaryl (in some embodiments, pyrazolyl); or a stereoisomer, and/or a pharmaceutically acceptable salt, and/or solvate thereof.
  • R 2 is H, methyl, ethyl, methoxy, -NH-heteroaryl (in some embodiments, -NH-pyrimidinyl), or unsubstituted heteroaryl (in some embodiments, pyrazolyl).
  • Embodiment 17 provided is a compound of any one of embodiments A, B, and 1-7, wherein R 2 is H, methyl, ethyl, or unsubstituted pyrazolyl; or a stereoisomer, and/or a pharmaceutically acceptable salt, and/or solvate thereof.
  • Embodiment 18 provided is a compound of any one of embodiments A, B, and 1-17, wherein R 3 is H; or a stereoisomer, and/or a pharmaceutically acceptable salt, and/or solvate thereof.
  • Embodiment 19 Embodiment 19.
  • Embodiment 19 provided is a compound of any one of embodiments 1-17, wherein R 3 is F; or a stereoisomer, and/or a pharmaceutically acceptable salt, and/or solvate thereof.
  • Embodiment 20 provided is a compound of any one of embodiments 1-17, wherein R 3 is methyl or ethyl; or a stereoisomer, and/or a pharmaceutically acceptable salt, and/or solvate thereof.
  • provided is a compound of any one of embodiments A, B, 1, and 2-17, wherein R 3 is methyl; or a stereoisomer, and/or a pharmaceutically acceptable salt, and/or solvate thereof.
  • Embodiment 21 In embodiment 21, provided is a compound of any one of embodiments A, B, and 1, 2, and 4-20, wherein bond b is a double bond and R 8 is H; or a stereoisomer, and/or a pharmaceutically acceptable salt, and/or solvate thereof.
  • Embodiment 22 In embodiment 22, provided is a compound of any one of embodiments A, B, and 1, 2, and 4-20, wherein bond b is a double bond and R 8 is F; or a stereoisomer, and/or a pharmaceutically acceptable salt, and/or solvate thereof.
  • Embodiment 23 Embodiment 23.
  • Embodiment 23 provided is a compound of any one of embodiments 1, 2, and 4-20, wherein bond b is a double bond and R 8 is CN; or a stereoisomer, and/or a pharmaceutically acceptable salt, and/or solvate thereof.
  • Embodiment 24 provided is a compound of any one of embodiments 1, 2, and 4-20, wherein bond b is a double bond and R 8 is Me; or a stereoisomer, and/or a pharmaceutically acceptable salt, and/or solvate thereof.
  • Embodiment 25 provided is a compound of any one of embodiments 1, 2, and 4-20, wherein bond b is a double bond and R 8 is Me; or a stereoisomer, and/or a pharmaceutically acceptable salt, and/or solvate thereof.
  • Embodiment 25 provided is a compound of any one of embodiments A, B, and 1-24, wherein bond a, X 1 , X 2 , R 4 , R 5 , R 6 , A, and Ar are according to i); and/ or a stereoisomer, and/or a pharmaceutically acceptable salt, and/or solvate thereof.
  • Embodiment 26a provided is a compound of embodiment 25 (as it depends from embodiments A, 1, and 2-24), or a stereoisomer, and/or a pharmaceutically acceptable salt, and/or solvate thereof, wherein X 1 is absent, CH2, CH(OH), or C(CH3)2.
  • Embodiment 26 provided is a compound of embodiment 25, wherein X 1 is absent; or a stereoisomer, and/or a pharmaceutically acceptable salt, and/or solvate thereof.
  • Embodiment 27 provided is a compound of embodiment 25, wherein X 1 is CH2; or a stereoisomer, and/or a pharmaceutically acceptable salt, and/or solvate thereof.
  • Embodiment 28 provided is a compound of embodiment 25, wherein X 1 is CH2; or a stereoisomer, and/or a pharmaceutically acceptable salt, and/or solvate thereof.
  • Embodiment 28 provided is a compound of any one of embodiments A, B, 1, and IA, according to the following formula: - 23 - 1097257085 ⁇ 4 ⁇ AMERICAS Attorney Docket No.126662.00015 (II); or a stereoisomer, and/or a acceptable salt, and/or solvate thereof.
  • Embodiment 29 In embodiment is a compound of any one of embodiments 25-28, wherein R 4 is H; or a stereoisomer, and/or a pharmaceutically acceptable salt, and/or solvate thereof.
  • Embodiment 30 Embodiment 30.
  • Embodiment 31 In embodiment 31, provided is a compound of any one of embodiments 25-28, wherein R 4 is C1-C4 alkyl (methyl); or a stereoisomer, and/or a pharmaceutically acceptable salt, and/or solvate thereof.
  • Embodiment 31 In embodiment 31, provided is a compound of any one of embodiments 25-28, wherein R 4 is cyclopropyl; or a stereoisomer, and/or a pharmaceutically acceptable salt, and/or solvate thereof.
  • Embodiment 32 In embodiment 32, provided is a compound of any one of embodiments 25-28, wherein R 4 is F; or a stereoisomer, and/or a pharmaceutically acceptable salt, and/or solvate thereof.
  • Embodiment 33 In embodiment 33, provided is a compound of any one of embodiments 25-28, wherein R 4 is Cl; or a stereoisomer, and/or a pharmaceutically acceptable salt, and/or solvate thereof.
  • Embodiment 34 In embodiment 34, provided is a compound of any one of embodiments 25-28, wherein R 4 is -OH; or a stereoisomer, and/or a pharmaceutically acceptable salt, and/or solvate thereof.
  • Embodiment 35 In embodiment 35, provided is a compound of any one of embodiments 25-28, wherein R 4 is -OMe; or a stereoisomer, and/or a pharmaceutically acceptable salt, and/or solvate thereof.
  • Embodiment 36 In embodiment 36, provided is a compound of any one of embodiments 25-28, wherein R 4 is CN; or a stereoisomer, and/or a pharmaceutically acceptable salt, and/or solvate thereof.
  • Embodiment 37 In embodiment 37, provided is a compound of any one of embodiments 25-28, wherein R 4 is NHR 7 , and R 7 is selected from the group consisting of H and C1-C3 alkyl; or a stereoisomer, and/or a pharmaceutically acceptable salt, and/or solvate thereof.
  • - 24 - 1097257085 ⁇ 4 ⁇ AMERICAS Attorney Docket No.126662.00015 [000100] Embodiment 38.
  • Embodiment 38 provided is a compound of embodiment 25, wherein X 1 and R 4 together with the carbon to which they are attached form a C4-C6 cycloalkylene; or a stereoisomer, and/or a pharmaceutically acceptable salt, and/or solvate thereof.
  • Embodiment 39 provided is a compound of embodiment 25 or 38, wherein X 1 and R 4 together with the carbon to which they are attached form a C4 cycloalkylene or C6 cycloalkylene; or a stereoisomer, and/or a pharmaceutically acceptable salt, and/or solvate thereof.
  • Embodiment 40 Embodiment 40.
  • Embodiment 40 provided is a compound of any one of embodiments 25-39, wherein bond a is a double bond; or a stereoisomer, and/or a pharmaceutically acceptable salt, and/or solvate thereof.
  • Embodiment 41 provided is a compound of any one of embodiments 25-40, wherein bond a is a double bond and R 5 and R 6 are each H; or a stereoisomer, and/or a pharmaceutically acceptable salt, and/or solvate thereof.
  • Embodiment 42 Embodiment 42.
  • Embodiment 42 provided is a compound of any one of embodiments 25-41, wherein bond a is a double bond and is cis; or a stereoisomer, and/or a pharmaceutically acceptable salt, and/or solvate thereof.
  • Embodiment 43 provided is a compound of any one of embodiments 25-41, wherein bond a is a double bond and is trans; or a stereoisomer, and/or a pharmaceutically acceptable salt, and/or solvate thereof.
  • Embodiment 44 Embodiment 44.
  • Embodiment 44 provided is a compound of any one of embodiments 25-39, wherein bond a is a triple bond and R 5 and R 6 are absent; or a stereoisomer, and/or a pharmaceutically acceptable salt, and/or solvate thereof.
  • Embodiment 45 provided is a compound of any one of embodiments A, B, and 1-24, wherein bond a, X 1 , X 2 , R 4 , R 5 , R 6 , A, and Ar are according to ii).
  • Embodiment 46 provided is a compound of embodiment 45, wherein m is 1; or a stereoisomer, and/or a pharmaceutically acceptable salt, and/or solvate thereof.
  • Embodiment 47 In embodiment 47, provided is a compound of embodiment 45, wherein m is 2; or a stereoisomer, and/or a pharmaceutically acceptable salt, and/or solvate thereof. [000110] Embodiment 48. In embodiment 48, provided is a compound of any one of embodiments 45-47, wherein X 1 is absent; or a stereoisomer, and/or a pharmaceutically acceptable salt, and/or solvate thereof. [000111] Embodiment 48a.
  • embodiment 48a provided is a compound of embodiment 45 (as it depends from any one of embodiments A, 1, and 2-24), or a stereoisomer, and/or a pharmaceutically acceptable salt, and/or solvate thereof, wherein m is 0 and X 1 is other than absent.
  • Embodiment 48b provided is a compound of any one of embodiments 45-47 (as each of these depends from any one of A, 1, and 2-24), wherein X 1 is absent or is selected from the group consisting of CH2, O, CH2O, and OCH2.
  • Embodiment 48c Embodiment 48c.
  • X 1 is CH2, CH2CH2, or CH(CH3), preferably CH2; or a stereoisomer, and/or a pharmaceutically acceptable salt, and/or solvate thereof.
  • X 1 is CH2.
  • R 5 is H; or a stereoisomer, and/or a pharmaceutically acceptable salt, and/or solvate thereof.
  • Embodiment 51a provided is a compound of any one of embodiments 25-49, wherein A is absent; or a stereoisomer, and/or a pharmaceutically acceptable salt, and/or solvate thereof.
  • Embodiment 51a provided is a compound of any one of embodiments 25-44 (as each of these depends from any one of embodiments A, 1, and 2-24), or a stereoisomer, and/or a pharmaceutically acceptable salt, and/or solvate thereof, wherein A is selected from the group consisting of CH2, CH(OH), CH(OCH3), and C(CH3)2.
  • embodiment 51 provided is a compound of any one of embodiments 25-50, wherein Ar is aryl optionally substituted with 1, 2, 3, or 4 R 9 groups; or a stereoisomer, and/or a pharmaceutically acceptable salt, and/or solvate thereof.
  • Ar is aryl optionally substituted with 1, 2, 3, or 4 R 9 groups; or a stereoisomer, and/or a pharmaceutically acceptable salt, and/or solvate thereof.
  • - 26 - 1097257085 ⁇ 4 ⁇ AMERICAS Attorney Docket No.126662.00015 [000118]
  • Embodiment 52a provided is a compound of any one of embodiments 20-46, or a stereoisomer, and/or a pharmaceutically acceptable salt, and/or solvate thereof, wherein Ar is phenyl optionally substituted with 1, 2, 3, or 4 R 9 groups (in some embodiments, the phenyl is optionally substituted with 1 R 9 ).
  • Embodiment 52 In embodiment 52, provided is a compound of any one of embodiments 25-51, wherein Ar is phenyl optionally substituted with 1, 2, 3, or 4 R 9 groups; or a stereoisomer, and/or a pharmaceutically acceptable salt, and/or solvate thereof. [000120] Embodiment 53a.
  • embodiment 53a provided is a compound of any one of embodiments 20-46, or a stereoisomer, and/or a pharmaceutically acceptable salt, and/or solvate thereof, wherein Ar is heteroaryl, (preferably oxazolyl, imidazolyl, or pyridinyl), optionally substituted with 1, 2, 3, or 4 R 9 groups (in some embodiments, the heteroaryl is optionally substituted with 1 R 9 ).
  • Ar is heteroaryl, (preferably oxazolyl, imidazolyl, or pyridinyl), optionally substituted with 1, 2, 3, or 4 R 9 groups (in some embodiments, the heteroaryl is optionally substituted with 1 R 9 ).
  • Embodiment 53 provided is a compound of any one of embodiments 25-50, wherein Ar is heteroaryl group, preferably oxazolyl, imidazolyl, or pyridinyl, optionally substituted with 1, 2, 3, or 4 R 9 groups; or a stereoisomer, and/or a pharmaceutically acceptable salt, and/or solvate thereof.
  • Ar is heteroaryl group, preferably oxazolyl, imidazolyl, or pyridinyl, optionally substituted with 1, 2, 3, or 4 R 9 groups; or a stereoisomer, and/or a pharmaceutically acceptable salt, and/or solvate thereof.
  • Embodiment 54 provided is a compound of any one of embodiments 1-24, wherein bond a, X 1 , X 2 , R 4 , R 5 , R 6 , A, and Ar are according to iii).
  • Embodiment 55 is provided in embodiment 54, provided is a compound of any one of embodiments 1-24, wherein bond
  • Embodiment 55 provided is a compound of embodiment 54, wherein X 1 is absent, and R 4 is H; or a stereoisomer, and/or a pharmaceutically acceptable salt, and/or solvate thereof.
  • Embodiment 56 provided is a compound of any one of embodiments 1-24, wherein bond a, X 1 , X 2 , R 4 , R 5 , R 6 , A, and Ar are according to iv).
  • Embodiment 57 provided is a compound of embodiment 56, wherein X 2 is CH; or a stereoisomer, and/or a pharmaceutically acceptable salt, and/or solvate thereof.
  • Embodiment 58 Embodiment 58.
  • Embodiment 58 provided is a compound of embodiment 56, wherein X 2 is N; or a stereoisomer, and/or a pharmaceutically acceptable salt, and/or solvate thereof.
  • X 2 is N; or a stereoisomer, and/or a pharmaceutically acceptable salt, and/or solvate thereof.
  • - 27 - 1097257085 ⁇ 4 ⁇ AMERICAS Attorney Docket No.126662.00015
  • Embodiment 59 provided is a compound of any one of embodiments 56-58, wherein X 1 is absent and R 4 is H; or a stereoisomer, and/or a pharmaceutically acceptable salt, and/or solvate thereof.
  • Embodiment 60 provided is a compound of any one of embodiments 56-58, wherein X 1 is absent and R 4 is H; or a stereoisomer, and/or a pharmaceutically acceptable salt, and/or solvate thereof.
  • Embodiment 60 provided is a compound of any one of embodiments 56-59, wherein X 3 is O, NH, N(Me); or a stereoisomer, and/or a pharmaceutically acceptable salt, and/or solvate thereof.
  • X 3 is O, NH, N(Me); or a stereoisomer, and/or a pharmaceutically acceptable salt, and/or solvate thereof.
  • Embodiment 61 provided is a compound of any one of embodiments 56-60, wherein Ar1 is benzo or pyrido, optionally substituted with 1, 2, 3, or 4 R 9 groups; or a stereoisomer, and/or a pharmaceutically acceptable salt, and/or solvate thereof.
  • Embodiment 62 Embodiment 62.
  • each R 9 is independently selected from the group consisting of C1-C6 alkyl, C2-C6 alkynyl, halo, C1-C6 haloalkyl, and C1-C6 alkoxy; or each R 9 is independently selected from the group consisting of methyl, ethynyl, F, CF3, and methoxy; or a stereoisomer, and/or a pharmaceutically acceptable salt, and/or solvate thereof.
  • Embodiment 63 is independently selected from the group consisting of C1-C6 alkyl, C2-C6 alkynyl, halo, C1-C6 haloalkyl, and C1-C6 alkoxy; or each R 9 is independently selected from the group consisting of methyl, ethynyl, F, CF3, and methoxy; or a stereoisomer, and/or a pharmaceutically acceptable salt, and/or solvate thereof.
  • Embodiment 64 provided is a compound of any one of embodiments 1-62, wherein 1 or 2 R 9 are present and are independently selected; or a stereoisomer, and/or a pharmaceutically acceptable salt, and/or solvate thereof.
  • Embodiment 64 provided is a compound of any one of embodiments 1-63, wherein one R 9 is CF3; or a stereoisomer, and/or a pharmaceutically acceptable salt, and/or solvate thereof.
  • Embodiment 65a provided is a compound of any one of embodiments 1-64, wherein ; or a stereoisomer, and/or a [000134] Embodiment 65.
  • Embodiment 65 provided is a compound of any one of embodiments 1-64, wherein - 28 - 1097257085 ⁇ 4 ⁇ AMERICAS Attorney Docket No.126662.00015 ; or a stereoisomer, and/or a is a compound of any one of embodiments 1-65, wherein ; or a stereoisomer, and/or a pharmaceutically acceptable salt, [000136]
  • Embodiment 67 provided is a compound of any one of embodiments 1-65, wherein ; or a stereoisomer, and/or a pharmaceutically acceptable salt, [000137] Embodiment 68.
  • Embodiment 69 provided is a compound of any one of embodiments 1-65, wherein ; or a stereoisomer, and/or a pharmaceutically acceptable salt, [000138]
  • Embodiment 69 provided is a compound of embodiment 1 being selected from the compounds in Table 1; or a stereoisomer, and/or a pharmaceutically acceptable salt, and/or solvate thereof.
  • Embodiment 70 provided is a compound of embodiment 1, selected from the group consisting of: - 29 - 1097257085 ⁇ 4 ⁇ AMERICAS Attorney Docket No.126662.00015 ; or a stereoisomer, and/or a pharmaceutically acceptable salt, [000140] Embodiment 71.
  • a pharmaceutical composition comprising a pharmaceutically effective amount of the compound according to any one of embodiments 1-106 or a stereoisomer, and/or a pharmaceutically acceptable salt, and/or solvate thereof; and a pharmaceutically acceptable carrier.
  • Embodiment 72 In embodiment 72, provided is a method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the compound of any one of embodiments 1-106, or a stereoisomer, and/or a pharmaceutically acceptable salt, and/or solvate thereof; or the pharmaceutical composition of embodiment 71.
  • Embodiment 73 Embodiment 73.
  • a method of embodiment 72 wherein the cancer is selected from the group consisting of bladder cancer, breast cancer, ovarian cancer, pancreatic ductal adenocarcinoma (PDAC), glioblastoma, gastric cancer, cervical cancer, colon cancer, endometrial cancer, head and neck cancer, lung cancer, melanoma, multiple myeloma, leukemia, non-Hodgkin’s lymphoma, prostate cancer, rectal cancer, malignant melanomas, alimentary/gastrointestinal tract cancer, liver cancer, skin cancer, lymphoma, malignant pleural mesothelioma (MPM), kidney cancer, muscle cancer, bone cancer, brain cancer, eye or ocular cancer, rectal cancer, colorectal cancer, cervical cancer, oral cancer, benign and malignant tumors, stomach cancer, corpus uteri, testicular cancer, renal cancer, throat cancer, acute lymphocytic leukemia, acute myelogenous leukemia, Ewing's Sarcom
  • PDAC pancreatic
  • Embodiment 74 In embodiment 74, provided is a method of embodiment 72, wherein the cancer is selected from the group consisting of glioblastoma, gastric cancer, colorectal cancer, pancreatic ductal adenocarcinoma (PDAC), and malignant pleural mesothelioma (MPM).
  • the cancer is selected from the group consisting of glioblastoma, gastric cancer, colorectal cancer, pancreatic ductal adenocarcinoma (PDAC), and malignant pleural mesothelioma (MPM).
  • PDAC pancreatic ductal adenocarcinoma
  • MPM malignant pleural mesothelioma
  • embodiment 75 provided is a method of any one of embodiments 72-74, wherein the method further comprises simultaneously or sequentially administering one or more KRAS G12C and/or G12D inhibitors; one or more CDK4/6 inhibitors; one or more EGFR inhibitors; one or more RAF inhibitors; one or more MEK inhibitors; one or more Wnt signaling inhibitors, such as anti- ⁇ -catenin inhibitors, GSK3 inhibitors, JNK inhibitors, and CK1 inhibitors; one or more TGF- ⁇ signaling inhibitors, such as atezolizumab, durvalumab, and avelumab; one or more PD-1/PD-L1 inhibitors; and/or radiotherapy.
  • KRAS G12C and/or G12D inhibitors one or more CDK4/6 inhibitors
  • one or more EGFR inhibitors one or more RAF inhibitors
  • MEK inhibitors one or more Wnt signaling inhibitors, such as anti- ⁇ -catenin inhibitors, GSK
  • embodiment 75 provided is a method of any one of embodiments 72-74, wherein the method further comprises simultaneously or sequentially administering one or more additional anti-cancer therapies, preferably wherein the one or more additional therapies comprises a KRAS G12C and/or G12D inhibitor, more preferably, wherein KRAS G12C and/or G12D inhibitor is sotorasib or adagrasib.
  • the one or more additional therapies comprises a KRAS G12C and/or G12D inhibitor, more preferably, wherein KRAS G12C and/or G12D inhibitor is sotorasib or adagrasib.
  • embodiment 76 provided is a method of inhibiting TEAD1, 2, 3, and/or 4 in a subject or in a sample, comprising administering to the subject a therapeutically effective amount of the compound of any one of embodiments 1-106, or a stereoisomer, and/or a pharmaceutically acceptable salt, and/or solvate thereof; or the pharmaceutical composition of embodiment 71.
  • Embodiment 77 provided is a method of embodiment 76, wherein TEAD1 is inhibited selectively over TEAD2, 3, and 4. - 31 - 1097257085 ⁇ 4 ⁇ AMERICAS Attorney Docket No.126662.00015 [000148] Table 1 shows the structures of compounds described in the Examples of this disclosure. Table 1.
  • any racemic, optically-active, diastereomeric, geometric isomeric, tautomeric, or other stereoisomeric forms, mixture, or combination thereof, of a compound provided herein, which possess the useful properties described herein is within the scope of the invention. It being well known in the art how to prepare optically active forms (in some or any embodiments, by resolution of the racemic form by recrystallization techniques, by synthesis from optically- active starting materials, by chiral synthesis, or by chromatographic separation using a chiral stationary phase).
  • optically active materials in some embodiments, compounds which are substantially pure or are “substantially free of” of an undesignated isomer or are “substantially in the absence of” of an undesignated isomer
  • methods to obtain optically active materials include at least the following. - 43 - 1097257085 ⁇ 4 ⁇ AMERICAS Attorney Docket No.126662.00015 i) physical separation of crystals - a technique whereby macroscopic crystals of the individual stereoisomers are manually separated.
  • This technique can be used if crystals of the separate stereoisomers exist, i.e., the material is a conglomerate, and the crystals are visually distinct; ii) simultaneous crystallization - a technique whereby the individual stereoisomers are separately crystallized from a solution of the racemate, possible only if the latter is a conglomerate in the solid state; iii) enzymatic resolutions - a technique whereby partial or complete separation of a racemate by virtue of differing rates of reaction for the stereoisomers with an enzyme; iv) enzymatic asymmetric synthesis - a synthetic technique whereby at least one step of the synthesis uses an enzymatic reaction to obtain a stereoisomerically pure or enriched synthetic precursor of the desired stereoisomer; v) chemical asymmetric synthesis - a synthetic technique whereby the desired stereoisomer is synthesized from an achiral precursor under conditions that produce asymmetry (i.e., chirality) in the product, which may be
  • the resulting diastereomers are then separated by chromatography or crystallization by virtue of their now more distinct structural differences and the chiral auxiliary later removed to obtain the desired enantiomer; vii) first- and second-order asymmetric transformations - a technique whereby diastereomers from the racemate equilibrate to yield a preponderance in solution of the diastereomer from the desired enantiomer or where preferential crystallization of the diastereomer from the desired enantiomer perturbs the equilibrium such that eventually in principle all the material is converted to the crystalline diastereomer from the desired enantiomer.
  • kinetic resolutions refers to the achievement of partial or complete resolution of a racemate (or of a further resolution of a partially resolved compound) - 44 - 1097257085 ⁇ 4 ⁇ AMERICAS Attorney Docket No.126662.00015 by virtue of unequal reaction rates of the stereoisomers with a chiral, non-racemic reagent or catalyst under kinetic conditions; ix) stereospecific synthesis from non-racemic precursors - a synthetic technique whereby the desired stereoisomer is obtained from non-chiral starting materials and where the stereochemical integrity is not or is only minimally compromised over the course of the synthesis; x) chiral liquid chromatography - a technique whereby the stereoisomers of a racemate are separated in a liquid mobile phase by virtue of their differing interactions with a stationary phase.
  • the stationary phase can be made of chiral material or the mobile phase can contain an additional chiral material to provoke the differing interactions; xi) chiral gas chromatography - a technique whereby the racemate is volatilized and stereoisomers are separated by virtue of their differing interactions in the gaseous mobile phase with a column containing a fixed non-racemic chiral adsorbent phase; xii) extraction with chiral solvents - a technique whereby the stereoisomers are separated by virtue of preferential dissolution of one stereoisomer into a particular chiral solvent; xiii) transport across chiral membranes - a technique whereby a racemate is placed in contact with a thin membrane barrier.
  • the barrier typically separates two miscible fluids, one containing the racemate, and a driving force such as concentration or pressure differential causes preferential transport across the membrane barrier. Separation occurs as a result of the non-racemic chiral nature of the membrane which allows only one stereoisomer of the racemate to pass through.
  • a composition of compound that comprises a substantially pure designated stereoisomer (e.g., enantiomer, diastereomer) or geometric isomer of the compound.
  • the compounds are substantially free of other stereoisomers (e.g., enantiomers, diastereomers) and/or geometric isomers thereof.
  • a composition includes a compound that is at least 85%, 90%, 95%, 98%, 99% or 100% by weight, of the specific compound, the remainder comprising other chemical species, geometric isomers, and/or stereoisomers (e.g., enantiomers, diastereomers) thereof.
  • isotopically Enriched Compounds [000153] Also provided herein are isotopically enriched compounds.
  • isotopic composition refers to the amount of each isotope present for a given atom
  • naturally occurring isotopic composition refers to the naturally occurring isotopic composition or abundance for a given atom
  • Atoms containing their natural isotopic composition may also be referred to herein as “non-enriched” atoms. Unless otherwise designated, the atoms of the compounds recited herein are meant to represent any stable isotope of that atom.
  • isotopic enrichment refers to the percentage of incorporation of an amount of a specific isotope at a given atom in a molecule in the place of that atom’s natural isotopic abundance.
  • deuterium enrichment of 1% at a given position means that 1% of the molecules in a given sample contain deuterium at the specified position.
  • isotopic enrichment of the compounds provided herein can be determined using conventional analytical methods known to one of ordinary skill in the art, including mass spectrometry and nuclear magnetic resonance spectroscopy.
  • the term “isotopically enriched,” as used herein, and unless otherwise specified, refers to an atom having an isotopic composition other than the natural isotopic composition of that atom. “Isotopically enriched” may also refer to a compound containing at least one atom having an isotopic composition other than the natural isotopic composition of that atom.
  • Isotopic enrichment of a drug can be used, in some or any embodiments, to (1) reduce or eliminate unwanted metabolites, (2) increase the half-life of the parent drug, (3) - 46 - 1097257085 ⁇ 4 ⁇ AMERICAS Attorney Docket No.126662.00015 decrease the number of doses needed to achieve a desired effect, (4) decrease the amount of a dose necessary to achieve a desired effect, (5) increase the formation of active metabolites, if any are formed, and/or (6) decrees the production of deleterious metabolites in specific tissues and/or create a more effective drug and/or a safer drug for combination therapy, whether the combination therapy is intentional or not.
  • KIE Kinetic Isotope Effect
  • DKIE Deuterium Kinetic Isotope Effect
  • the magnitude of the DKIE can be expressed as the ratio between the rates of a given reaction in which a C–H bond is broken, and the same reaction where deuterium is substituted for hydrogen.
  • the DKIE can range from about 1 (no isotope effect) to very large numbers, such as 50 or more, meaning that the reaction can be fifty, or more, times slower when deuterium is substituted for hydrogen.
  • High DKIE values may be due in part to a phenomenon known as tunneling, which is a consequence of the uncertainty principle. Tunneling is ascribed to the small mass of a hydrogen atom, and occurs because transition states involving a proton can sometimes form in the absence of the required activation energy.
  • the DKIE was used to decrease the hepatotoxicity of halothane by presumably limiting the production of reactive species such as trifluoroacetyl chloride.
  • this method may not be applicable to all drug classes.
  • deuterium incorporation can lead to metabolic switching.
  • the concept of metabolic switching asserts that xenogens, when sequestered by Phase I enzymes, may bind transiently and re-bind in a variety of conformations prior to the chemical reaction (e.g., oxidation). This hypothesis is supported by the relatively vast size of binding pockets in many Phase I enzymes and the promiscuous nature of many metabolic reactions. Metabolic switching can potentially lead to different proportions of known metabolites as well as altogether new metabolites.
  • the compounds described herein may be used as radiopharmaceuticals such as, for example, imaging agents.
  • radiopharmaceuticals are positron emission tomography (PET) imaging agents.
  • PET positron emission tomography
  • substitution of radionuclides (e.g., positron emitting isotopes) for atoms in the compounds allows for the syntheses of radiopharmaceuticals that can function as imaging agents.
  • radionuclides which can be substituted in the compounds described herein include, and are not limited to, 18 F, 11 C, 13 N, 15 O, 76 Br, and 124 I.
  • the compound is isotopically enriched at one or more atoms, one atom, two atoms, or three atoms. In some embodiments, the compound is administered as an isotopic composition.
  • the animal body expresses a variety of enzymes for the purpose of eliminating foreign substances, such as therapeutic agents, from its circulation system. In some or any embodiments, such enzymes include the cytochrome P450 enzymes (“CYPs”), esterases, proteases, reductases, dehydrogenases, and monoamine oxidases, to react with and convert these foreign substances to more polar intermediates or metabolites for renal excretion.
  • CYPs cytochrome P450 enzymes
  • Some of the most common metabolic reactions of pharmaceutical compounds involve the oxidation of a carbon-hydrogen (C–H) bond to either a carbon-oxygen (C–O) or carbon-carbon (C–C) - 48 - 1097257085 ⁇ 4 ⁇ AMERICAS Attorney Docket No.126662.00015 pi-bond.
  • the resultant metabolites may be stable or unstable under physiological conditions, and can have substantially different pharmacokinetic, pharmacodynamic, and acute and long- term toxicity profiles relative to the parent compounds. For many drugs, such oxidations are rapid. These drugs therefore often require the administration of multiple or high daily doses.
  • stereoisomers e.g., enantiomers, diastereomers
  • geometric isomers e.g., regioisomers, cis and trans isomers, Z and E isomers
  • individual stereoisomers e.g., enantiomers, diastereomers
  • geometric isomers e.g., regioisomers, cis and trans isomers, Z and E isomers
  • Scheme 2 illustrates a synthesis of compounds of Formula (I) according to some aspects and embodiments of the present disclosure.
  • stereoisomers e.g., enantiomers, diastereomers
  • geometric isomers e.g., regioisomers, cis and trans isomers, Z and E isomers
  • individual stereoisomers e.g., enantiomers, diastereomers
  • geometric isomers e.g., regioisomers, cis and trans isomers, Z and E isomers
  • stereoisomers e.g., enantiomers, diastereomers
  • geometric isomers e.g., regioisomers, cis and trans isomers, Z and E isomers
  • individual stereoisomers e.g., enantiomers, diastereomers
  • geometric isomers e.g., regioisomers, cis and trans isomers, Z and E isomers
  • Scheme 4 illustrates a synthesis of compounds of Formula (I) according to some aspects and embodiments of the present disclosure. Under different conditions for the reduction of the alkyne functionality in the second step, one specific Z or E olefin isomer can be obtained (only E isomer is shown in Scheme 4 for simplicity).
  • stereoisomers e.g., enantiomers, diastereomers
  • geometric isomers e.g., regioisomers, cis and trans isomers, Z and E isomers
  • individual stereoisomers e.g., enantiomers, diastereomers
  • geometric isomers e.g., regioisomers, cis and trans isomers, Z and E isomers
  • Z and E isomers can be separated using (chiral) chromatography to obtain single stereoisomers (e.g., enantiomers, diastereomers) and/or geometric isomers(e.g., regioisomers, cis and trans isomers, Z and E isomers) thereof.
  • stereoisomers e.g., enantiomers, diastereomers
  • geometric isomers e.g., regioisomers, cis and trans isomers, Z and E isomers
  • individual stereoisomers e.g., enantiomers, diastereomers
  • geometric isomers e.g., regioisomers, cis and trans isomers, Z and E isomers
  • treatment is used interchangeably herein with the term “therapeutic method” and refers to both 1) therapeutic treatments or measures that cure, slow down, lessen symptoms of, and/or halt progression of a diagnosed pathologic conditions, disease or disorder, and 2) and prophylactic/ preventative measures.
  • Those in need of treatment may include individuals already having a particular medical disease or disorder as well as those who may ultimately acquire the disorder (i.e., those needing preventive measures).
  • Treating” or “treatment” of any condition or disorder refers, in some or any embodiments, to ameliorating a condition or disorder that exists in a subject, including prophylactically.
  • “treating” or “treatment” includes ameliorating at least one physical parameter, which may be indiscernible by the subject.
  • “treating” or “treatment” includes modulating the condition or disorder, either physically (e.g., stabilization of a discernible symptom) or physiologically (e.g., stabilization of a physical parameter) or both.
  • “treating” or “treatment” includes delaying the onset of the condition or disorder.
  • “treating” or “treatment” includes the reduction or elimination of either the condition (e.g. cancer) or one or more parameters (e.g. tumor size or tumor growth rate) of the condition (e.g. cancer), or to retard the progression of the condition (e.g. cancer) or of one or more parameters (e.g. tumor size or tumor growth rate) of the condition (e.g. cancer), or to reduce the severity of the condition (e.g. cancer) or of one or more parameters (e.g. tumor size or tumor growth rate) of the condition (e.g. cancer).
  • “treating” or “treatment” includes administering a compound described herein prophylactically.
  • Treating” or “treatment” of a disease includes: (1) inhibiting the disease, i.e., arresting (i.e., stabilizing) or reducing the development of the disease or its clinical symptoms; or (2) relieving the disease, i.e., causing regression of the disease or its clinical symptoms.
  • the term “subject” as used herein refers to any individual or patient to which the subject methods are performed. Generally, the subject is human, although as will be appreciated by those in the art, the subject may be an animal.
  • terapéuticaally effective amount refers to the amount of a subject compound or composition that will elicit the biological or medical response in a tissue, system, animal, individual, or human that is being sought by administering said compound.
  • the biological or medical response includes one or more of the following: (1) Preventing the disease; for example, preventing a disease, condition or disorder in an individual that may be predisposed to the disease, condition or disorder but does not yet experience or display the pathology or symptomatology of the disease, (2) Inhibiting the disease; for example, inhibiting a disease, condition or disorder in an individual that is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., arresting further development of - 54 - 1097257085 ⁇ 4 ⁇ AMERICAS Attorney Docket No.126662.00015 the pathology and/or symptomatology), and (3) Ameliorating the disease; for example, ameliorating a disease, condition or disorder in an individual that is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., reversing the pathology and/or symptomatology).
  • compositions comprising compounds disclosed herein (including according to formula (I), (II), any embodiments herein, and any of Compounds 1-106).
  • pharmaceutically acceptable carrier refers to a non-toxic carrier that may be administered to a patient, together with a compound of this disclosure, and which does not destroy the pharmacological activity thereof.
  • compositions include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat.
  • ion exchangers alumina, aluminum stearate, lecithin
  • serum proteins such as human serum albumin
  • buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glycer
  • Pharmaceutically acceptable carriers that may be used in the pharmaceutical compositions of this disclosure include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene- polyoxypropylene-block polymers, wool fat and self-emulsifying drug delivery systems (SEDDS) such as ⁇ -tocopherol, polyethyleneglycol 1000 succinate, or other similar polymeric delivery matrices.
  • SEDDS self-emul
  • compositions comprising only the compounds described herein (including according to formula (I), (II), any embodiments herein, and any of Compounds 1- - 55 - 1097257085 ⁇ 4 ⁇ AMERICAS Attorney Docket No.126662.00015 106) as the active component, methods for administering these compositions may additionally comprise the step of administering to the subject an additional agent or therapy.
  • Such therapies include, but are not limited to, an anemia therapy, a diabetes therapy, a hypertension therapy, a cholesterol therapy, neuropharmacologic drugs, drugs modulating cardiovascular function, drugs modulating inflammation, immune function, production of blood cells; hormones and antagonists, drugs affecting gastrointestinal function, chemotherapeutics of microbial diseases, and/or chemotherapeutics of neoplastic disease.
  • the therapy is an anemia therapy, a diabetes therapy, a hypertension therapy, a cholesterol therapy, neuropharmacologic drugs, drugs modulating cardiovascular function, drugs modulating inflammation, immune function, production of blood cells; hormones and antagonists, drugs affecting gastrointestinal function, and/or chemotherapeutics of neoplastic disease.
  • Other pharmacological therapies can include any other drug or biologic found in any drug class.
  • other drug classes can comprise allergy/cold/ENT therapies, analgesics, anesthetics, anti-inflammatories, antimicrobials, antivirals, asthma/pulmonary therapies, cardiovascular therapies, dermatology therapies, endocrine/metabolic therapies, gastrointestinal therapies, cancer therapies, immunology therapies, neurologic therapies, ophthalmic therapies, psychiatric therapies or rheumatologic therapies.
  • the therapy is selected from anti-inflammatories, endocrine/metabolic therapies, gastrointestinal therapies, cancer therapies, immunology therapies, neurologic therapies, and rheumatologic therapies.
  • agents or therapies that can be administered with the compounds described herein include a matrix metalloprotease inhibitor, a lipoxygenase inhibitor, a cytokine antagonist, an immunosuppressant, a cytokine, a growth factor, an immunomodulator, a prostaglandin or an anti-vascular hyperproliferation compound.
  • a compound disclosed herein (including according to formula (I), (II), any embodiments herein, and any of Compounds 1-106) is used with another anti-cancer agent, such as, one or more selected from EGFR inhibitors, MEK inhibitors, KRAS G12C inhibitors, KRAS G12D inhibitors, immune checkpoint inhibitors, and chemotherapeutic agents for neoplastic disease.
  • another anti-cancer agent such as, one or more selected from EGFR inhibitors, MEK inhibitors, KRAS G12C inhibitors, KRAS G12D inhibitors, immune checkpoint inhibitors, and chemotherapeutic agents for neoplastic disease.
  • the compounds of this disclosure (including according to formula (I), (II), any embodiments herein, and any of Compounds 1-106) may be employed in a conventional manner for controlling the disease described herein, including, but not limited to, cancer.
  • Such - 56 - 1097257085 ⁇ 4 ⁇ AMERICAS Attorney Docket No.126662.00015 methods of treatment their dosage levels and requirements may be selected by those of ordinary skill in the art from available methods and techniques.
  • the compounds of this disclosure may be combined with a pharmaceutically acceptable adjuvant for administration to a patient suffering from cancer in a pharmaceutically acceptable manner and in an amount effective to treat cancer.
  • the compounds of this disclosure including according to formula (I), (II), any embodiments herein, and any of Compounds 1-106) may be used in compositions and methods for treating or protecting individuals against the diseases described herein, including but not limited to cancer, over extended periods of time.
  • the compounds may be employed in such compositions either alone or together with other compounds of this disclosure in a manner consistent with the conventional utilization of such compounds in pharmaceutical compositions.
  • a compound of this disclosure may be combined with pharmaceutically acceptable adjuvants conventionally employed in vaccines and administered in prophylactically effective amounts to protect individuals over an extended period of time against the diseases described herein, including, but not limited to, cancer.
  • the terms “combination,” “combined,” and related terms refer to the simultaneous or sequential administration of therapeutic agents in accordance with this disclosure.
  • a described compound including according to formula (I), (II), any embodiments herein, and any of Compounds 1-106
  • the present disclosure provides a single unit dosage form comprising a described compound, an additional therapeutic agent, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.
  • Two or more agents are typically considered to be administered “in combination” when a patient or individual is simultaneously exposed to both agents.
  • two or more agents are considered to be administered “in combination” when a patient or individual simultaneously shows therapeutically relevant levels of the agents in a particular target tissue or sample (e.g., in brain, in serum, etc.).
  • compositions according to this disclosure comprise a combination of a compound described herein (including according to formula (I), (II), any embodiments herein, and any of Compounds 1-106), and another therapeutic or prophylactic agent.
  • compositions of this disclosure are formulated for pharmaceutical administration to a subject or patient, e.g., a mammal, preferably a human being.
  • compositions are used to ameliorate, treat or prevent any of the diseases described herein including but not limited to cancer in a subject.
  • Agents of the disclosure are often administered as pharmaceutical compositions comprising an active therapeutic agent, i.e., and a variety of other pharmaceutically acceptable components. See Remington's Pharmaceutical Science (15th ed., Mack Publishing Company, Easton, Pa., 1980). The preferred form depends on the intended mode of administration and therapeutic application.
  • the compositions can also include, depending on the formulation desired, pharmaceutically acceptable, non-toxic carriers or diluents, which are defined as vehicles commonly used to formulate pharmaceutical compositions for animal or human administration. The diluent is selected so as not to affect the biological activity of the combination.
  • compositions or formulation may also include other carriers, adjuvants, or nontoxic, nontherapeutic, nonimmunogenic stabilizers and the like.
  • the present disclosure provides pharmaceutically acceptable compositions comprising a therapeutically effective amount of one or more of a described compound (including according to formula (I), (II), any embodiments herein, and any of - 58 - 1097257085 ⁇ 4 ⁇ AMERICAS Attorney Docket No.126662.00015 Compounds 1-106), formulated together with one or more pharmaceutically acceptable carriers (additives) and/or diluents for use in treating the diseases described herein, including, but not limited to cancer.
  • a described compound including according to formula (I), (II), any embodiments herein, and any of - 58 - 1097257085 ⁇ 4 ⁇ AMERICAS Attorney Docket No.126662.00015 Compounds 1-106
  • Described compounds may be formulated for administration in any convenient way for use in human or veterinary medicine, by analogy with other pharmaceuticals.
  • compositions of the present disclosure may be specially formulated for administration in solid or liquid form, including those adapted for the following: oral administration, for example, drenches (aqueous or non-aqueous solutions or suspensions), tablets, e.g., those targeted for buccal, sublingual, and systemic absorption, boluses, powders, granules, pastes for application to the tongue; parenteral administration, for example, by subcutaneous, intramuscular, intravenous or epidural injection as, for example, a sterile solution or suspension, or sustained-release formulation; topical application, for example, as a cream, ointment, or a controlled-release patch or spray applied to the skin, lungs, or oral cavity; intravaginally or intrarectally, for example, as a pessary, cream or foam; sublingually; ocularly; transdermally; or nasally, pulmonary and to other mucosal surfaces.
  • oral administration for example, drenches (aqueous or non-aqueous solutions
  • wetting agents such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the compositions.
  • antioxidants examples include: water soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol, and the like; and metal chelating agents, such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like.
  • water soluble antioxidants such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like
  • oil-soluble antioxidants such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin
  • Formulations for use in accordance with the present disclosure include those suitable for oral, nasal, topical (including buccal and sublingual), rectal, vaginal and/or - 59 - 1097257085 ⁇ 4 ⁇ AMERICAS Attorney Docket No.126662.00015 parenteral administration.
  • the formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy.
  • the amount of active ingredient, which can be combined with a carrier material, to produce a single dosage form will vary depending upon the host being treated, and the particular mode of administration.
  • the amount of active ingredient that can be combined with a carrier material to produce a single dosage form will generally be that amount of the compound, which produces a therapeutic effect.
  • a formulation as described herein comprises an excipient selected from the group consisting of cyclodextrins, liposomes, micelle forming agents, e.g., bile acids, and polymeric carriers, e.g., polyesters and polyanhydrides; and a compound of the present disclosure (including according to formula (I), (II), any embodiments herein, and any of Compounds 1-106).
  • an aforementioned formulation renders orally bioavailable a described compound of the present disclosure (including according to formula (I), (II), any embodiments herein, and any of Compounds 1-106).
  • Methods of preparing formulations or compositions comprising described compounds (including according to formula (I), (II), any embodiments herein, and any of Compounds 1-106) include a step of bringing into association a compound of the present disclosure (including according to formula (I), (II), any embodiments herein, and any of Compounds 1-106) with the carrier and, optionally, one or more accessory ingredients.
  • formulations may be prepared by uniformly and intimately bringing into association a compound of the present disclosure (including according to formula (I), (II), any embodiments herein, and any of Compounds 1-106) with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product.
  • the pharmaceutical compositions may be in the form of a sterile injectable preparation, for example, as a sterile injectable aqueous or oleaginous suspension.
  • This suspension may be formulated according to techniques known in the art using suitable dispersing or wetting agents (such as, for example, Tween 80) and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non- toxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. - 60 - 1097257085 ⁇ 4 ⁇ AMERICAS Attorney Docket No.126662.00015
  • acceptable vehicles and solvents that may be employed are mannitol, water, Ringer's solution and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono- or diglycerides.
  • Fatty acids such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions.
  • oils such as olive oil or castor oil, especially in their polyoxyethylated versions.
  • These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, such as those described in Pharmacopeia Helvetica, or a similar alcohol.
  • Other commonly used surfactants such as Tweens, Spans and other emulsifying agents or bioavailability enhancers which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used for the purposes of formulation.
  • the absorption of the drug in order to prolong the effect of a drug, it may be desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material having poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution, which in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle.
  • Injectable depot forms are made by forming microencapsule matrices of the described compounds (including according to formula (I), (II), any embodiments herein, and any of Compounds 1-106) in biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of drug to polymer, and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions, which are compatible with body tissue.
  • compositions of this disclosure may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, and aqueous suspensions and solutions.
  • carriers which are commonly used include lactose and corn starch.
  • Lubricating agents such as magnesium stearate, are also typically added.
  • useful diluents include lactose and - 61 - 1097257085 ⁇ 4 ⁇ AMERICAS Attorney Docket No.126662.00015 dried cornstarch.
  • Formulations described herein suitable for oral administration may be in the form of capsules, cachets, pills, tablets, lozenges (using a flavored basis, usually sucrose and acacia or tragacanth), powders, granules, or as a solution or a suspension in an aqueous or non- aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup, or as pastilles (using an inert base, such as gelatin and glycerin, or sucrose and acacia) and/or as mouth washes and the like, each containing a predetermined amount of a compound of the present disclosure (including according to formula (I), (II), any embodiments herein, and any of Compounds 1-106) as an active ingredient.
  • an active ingredient is mixed with one or more pharmaceutically-acceptable carriers, such as sodium citrate or dicalcium phosphate, and/or any of the following: fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and/or silicic acid; binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and/or acacia; humectants, such as glycerol; disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and
  • the pharmaceutical compositions may also comprise buffering agents.
  • Solid compositions of a similar type may also be employed as fillers in soft and hard-shelled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.
  • Tablets may be made by compression or molding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared using binder (for example, gelatin - 62 - 1097257085 ⁇ 4 ⁇ AMERICAS Attorney Docket No.126662.00015 or hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface- active or dispersing agent. Molded tablets may be made in a suitable machine in which a mixture of the powdered compound is moistened with an inert liquid diluent. If a solid carrier is used, the preparation can be in tablet form, placed in a hard gelatin capsule in powder or pellet form, or in the form of a troche or lozenge.
  • binder for example, gelatin - 62 - 1097257085 ⁇ 4 ⁇ AMERICAS Attorney Docket No.126662.00015 or hydroxypropylmethyl cellulose
  • lubricant for example, gelatin - 62 - 1097257085 ⁇ 4
  • the amount of solid carrier will vary, e.g., from about 25 to 800 mg, preferably about 25 mg to 400 mg.
  • the preparation can be, e.g., in the form of a syrup, emulsion, soft gelatin capsule, sterile injectable liquid such as an ampule or nonaqueous liquid suspension.
  • any routine encapsulation is suitable, for example, using the aforementioned carriers in a hard gelatin capsule shell.
  • Tablets and other solid dosage forms such as dragees, capsules, pills and granules, may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical-formulating art.
  • They may alternatively or additionally be formulated so as to provide slow or controlled release of the active ingredient therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile, other polymer matrices, liposomes and/or microspheres. They may be formulated for rapid release, e.g., freeze- dried. They may be sterilized by, for example, filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions that can be dissolved in sterile water, or some other sterile injectable medium immediately before use.
  • compositions may also optionally contain opacifying agents and may be of a composition that they release the active ingredient(s) only, or preferentially, in a certain portion of the gastrointestinal tract, optionally, in a delayed manner.
  • embedding compositions include polymeric substances and waxes.
  • the active ingredient can also be in micro-encapsulated form, if appropriate, with one or more of the above-described excipients.
  • Liquid dosage forms for oral administration of compounds of the disclosure include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
  • the liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, - 63 - 1097257085 ⁇ 4 ⁇ AMERICAS Attorney Docket No.126662.00015 solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3- butylene glycol, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
  • inert diluents commonly used in the art, such as, for example, water or other solvents, - 63 - 1097257085 ⁇ 4 ⁇ AMERICAS Attorney Docket No.126662.000
  • oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.
  • Suspensions in addition to active compounds (including according to formula (I), (II), any embodiments herein, and any of Compounds 1-106), may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.
  • compositions of this disclosure may also be administered in the form of suppositories for rectal administration.
  • These compositions can be prepared by mixing a compound of this disclosure (including according to formula (I), (II), any embodiments herein, and any of Compounds 1-106) with a suitable non-irritating excipient, which is solid at room temperature but liquid at the rectal temperature and therefore will melt in the rectum to release the active components.
  • suitable non-irritating excipient include, but are not limited to, cocoa butter, beeswax and polyethylene glycols.
  • Topical administration of the pharmaceutical compositions of this disclosure is especially useful when the desired treatment involves areas or organs readily accessible by topical application.
  • the pharmaceutical composition should be formulated with a suitable ointment containing the active components suspended or dissolved in a carrier.
  • Carriers for topical administration of the compounds of this disclosure include, but are not limited to, mineral oil, liquid petroleum, white petroleum, propylene glycol, polyoxyethylene polyoxypropylene compound, emulsifying wax and water.
  • the pharmaceutical composition can be formulated with a suitable lotion or cream containing the active compound suspended or dissolved in a carrier.
  • Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate-60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and - 64 - 1097257085 ⁇ 4 ⁇ AMERICAS Attorney Docket No.126662.00015 water.
  • the pharmaceutical compositions of this disclosure may also be topically applied to the lower intestinal tract by rectal suppository formulation or in a suitable enema formulation. Topically-administered transdermal patches are also included in this disclosure. [000209]
  • the pharmaceutical compositions of this disclosure may be administered by nasal aerosol or inhalation.
  • compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other solubilizing or dispersing agents known in the art.
  • the pharmaceutical compositions may be formulated as micronized suspensions in isotonic, pH adjusted sterile saline, or, preferably, as solutions in isotonic, pH adjusted sterile saline, either with or without a preservative such as benzylalkonium chloride.
  • Transdermal patches have the added advantage of providing controlled delivery of a compound of the present disclosure (including according to formula (I), (II), any embodiments herein, and any of Compounds 1-106) to the body. Dissolving or dispersing the compound in the proper medium can make such dosage forms. Absorption enhancers can also be used to increase the flux of the compound across the skin. Either providing a rate controlling membrane or dispersing the compound in a polymer matrix or gel can control the rate of such flux.
  • aqueous and nonaqueous carriers examples include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate.
  • polyols such as glycerol, propylene glycol, polyethylene glycol, and the like
  • vegetable oils such as olive oil
  • injectable organic esters such as ethyl oleate.
  • Proper fluidity can be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.
  • Such compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents.
  • antibacterial and/or antifungal agents for example, paraben, chlorobutanol, phenol sorbic acid, and the like, may be desirable in certain embodiments. It may alternatively or additionally be - 65 - 1097257085 ⁇ 4 ⁇ AMERICAS Attorney Docket No.126662.00015 desirable to include isotonic agents, such as sugars, sodium chloride, and the like into the compositions.
  • isotonic agents such as sugars, sodium chloride, and the like into the compositions.
  • prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents, which delay absorption such as aluminum monostearate and gelatin.
  • a described compound (including according to formula (I), (II), any embodiments herein, and any of Compounds 1-106) or pharmaceutical preparation is administered orally.
  • a described compound (including according to formula (I), (II), any embodiments herein, and any of Compounds 1-106) or pharmaceutical preparation is administered intravenously.
  • Alternative routes of administration include sublingual, intramuscular, and transdermal administrations.
  • compositions of the disclosure may be varied so as to obtain an amount of the active ingredient that is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient.
  • administration of and or “administering” should be understood to mean providing a pharmaceutical composition in a therapeutically effective amount to the subject in need of treatment.
  • Administration routes can be enteral, topical or parenteral.
  • administration routes include but are not limited to intracutaneous, subcutaneous, intravenous, intraperitoneal, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, transdermal, transtracheal, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal and intrasternal, oral, sublingual buccal, rectal, vaginal, nasal ocular administrations, as well infusion, inhalation, and nebulization.
  • cancer refers to a group of diseases characterized by abnormal and uncontrolled cell proliferation starting at one site (primary site) with the potential to invade and to spread to others sites (secondary sites, metastases) which differentiate cancer (malignant tumor) from benign tumor. Virtually all the organs can be affected, leading to more than 100 types of cancer that can affect humans. Cancers can result from many causes including genetic predisposition, viral infection, exposure to ionizing radiation, exposure environmental pollutant, tobacco and or alcohol use, obesity, poor diet, lack of physical activity or any combination thereof.
  • Exemplary cancers described by the national cancer institute include: Acute Lymphoblastic Leukemia, Adult; Acute Lymphoblastic Leukemia, Childhood; Acute Myeloid Leukemia, Adult; Adrenocortical Carcinoma; Adrenocortical Carcinoma, Childhood; AIDS- Related Lymphoma; AIDS-Related Malignancies; Anal Cancer; Astrocytoma, Childhood Cerebellar; Astrocytoma, Childhood Cerebral; Bile Duct Cancer, Extrahepatic; Bladder Cancer; Bladder Cancer, Childhood; Bone Cancer, Osteosarcoma/Malignant Fibrous Histiocytoma; Brain Stem Glioma, Childhood; Brain Tumor, Adult; Brain Tumor, Brain Stem Glioma, Childhood; Brain Tumor, Cerebellar Astrocytoma, Childhood; Brain Tumor, Cerebral Astrocytoma/Malignant Glioma, Childhood; Brain Tumor, Ependym
  • cancer include Lung cancer, Breast cancer, Colorectal cancer, Prostate cancer, Stomach cancer, Liver cancer, cervical cancer, Esophageal cancer, Bladder cancer, Non-Hodgkin lymphoma, Leukemia, Pancreatic cancer, Kidney cancer, endometrial cancer, Head and neck cancer, Lip cancer, oral cancer, Thyroid cancer, Brain cancer, Ovary cancer, Melanoma, Gallbladder cancer, Laryngeal cancer, Multiple myeloma, Nasopharyngeal cancer, Hodgkin lymphoma, Testis cancer and Kaposi sarcoma.
  • the compounds of the disclosure can be administered in combination with one or more additional therapeutic agents.
  • the phrases “combination therapy”, “combined with” and the like refer to the use of more than one medication or treatment simultaneously to increase the response.
  • the TEAD1, 2, 3, and/or 4 inhibitor of the present disclosure might for example be used in combination with other drugs or treatment in use to treat cancer.
  • the compound is administered prior to, simultaneously with or following the administration of the chemotherapeutic agent.
  • Anti-cancer therapies which could be used in combination with the compounds disclosed herein refer to any therapy or treatment that can be used for the treatment of a cancer.
  • Anti-cancer therapies include, but are not limited to, small molecule or large molecule therapies, surgery, radiotherapy, chemotherapy, immune therapy and targeted therapies.
  • the additional anti-cancer therapy is a KRAS G12C and/or G12D inhibitor; in some embodiments, the KRAS G12C and/or G12D inhibitor is sotorasib or adagrasib.
  • combination therapy can include, but is not limited to, compounds disclosed herein (including any of Compounds 1-106) administered in combination with one or more CDK4/6 inhibitors; one or more EGFR inhibitors; one or more RAF inhibitors; one or more MEK inhibitors; one or more Wnt signaling inhibitors, such as anti- ⁇ -catenin inhibitors, GSK3 inhibitors, JNK inhibitors, and CK1 inhibitors; one or more TGF- ⁇ signaling inhibitors, such as atezolizumab, durvalumab, and avelumab; one or more PD-1/PD-L1 inhibitors; and/or radiotherapy.
  • chemotherapeutic agents or anti-cancer agents include, but are not limited to, Actinomycin, Azacitidine, Azathioprine, Bleomycin, Bortezomib, Carboplatin, Capecitabine, Cisplatin, Chlorambucil, Cyclophosphamide, Cytarabine, Daunorubicin, Docetaxel, Doxifluridine, Doxorubicin, Epirubicin, Epothilone, Etoposide, Fiuorouracil, Gemcitabine, Hydroxyurea, Idarubicin, Imatinib, lrinotecan, Mechlorethamine, Mercaptopurine, Methotrexate, Mitoxantrone, Oxaliplatin, Paclitaxel, Pemetrexed, Teniposide, Tioguanine, Topotecan, Valrubicin
  • immunotherapeutic agent examples include, but are not limited to, interleukins (Il-2, Il-7, Il-12), cytokines (Interferons, G-CSF, imiquimod), chemokines (CCL3, CCl26, CXCL7), immunomodulatory imide drugs (thalidomide and its analogues).
  • the present disclosure is directed to the use of compounds of Formula (I) or a stereoisomer, and/or a pharmaceutically acceptable salt thereof, and/or a solvate thereof in the treatment of any cancer indication where YAP is localized in the nucleus of the tumor cells, including, but is not limited to, lung, thyroid, ovarian, colorectal, prostate, pancreas, esophagus, liver, breast, and skin cancer.
  • the disclosed compounds (including according to formula (I), (II), any embodiments herein, and any of Compounds 1-106) or pharmaceutical composition thereof can disrupt YAP interactions with TEAD1, 2, 3, and/or 4.
  • the disclosed compounds (including according to formula (I), (II), any embodiments herein, and any of Compounds 1-106) or pharmaceutical composition thereof can prevent YAP from binding to TEAD1, 2, 3, and/or 4.
  • the disclosed compounds (including according to formula (I), (II), any embodiments herein, and any of Compounds 1-106) or pharmaceutical composition thereof can compete with YAP for binding to TEAD1, 2, 3, and/or 4. In some embodiments, the disclosed compounds (including according to formula (I), (II), any embodiments herein, and any of Compounds 1-106) or pharmaceutical composition thereof can bind to TEAD1, 2, 3, and/or 4. In some embodiments, the disclosed compounds or pharmaceutical composition thereof can bind to TEAD1. In some embodiments, the disclosed compounds or pharmaceutical composition thereof can selectively bind to TEAD1 over that of the other TEAD isoforms.
  • the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
  • the carrier, diluent, or excipient or composition thereof may be administered to a subject along with a TEAD1, 2, 3, and/or 4 inhibitor of the disclosure (including according to formula (I), (II), any embodiments herein, and any of Compounds 1-106) without causing any undesirable biological effects or interacting in an undesirable manner with the TEAD1, 2, 3, and/or 4 inhibitor of the pharmaceutical composition in which it is contained.
  • the dose of agent optionally ranges from about 0.0001 mg/kg to 100 mg/kg, about 0.01 mg/kg to 5 mg/kg, about 0.15 mg/kg to 3 mg/kg, 0.5 mg/kg to 2 mg/kg and about 1 mg/kg to 2 mg/kg of the subject's body weight. In other embodiments the dose ranges from about 100 mg/kg to 5 g/kg, about 500 mg/kg to 2 mg/kg and about 750 mg/kg to 1.5 g/kg of the subject's body weight.
  • ⁇ g/kg to 15 mg/kg (e.g., 0.1-20 mg/kg) of agent is a candidate dosage for administration to the patient, whether, for example, by one or more separate administrations, or by continuous infusion.
  • a typical daily dosage is in the range from about 1 ⁇ g/kg to 100 mg/kg or more, depending on the factors mentioned above.
  • the treatment is sustained until a desired suppression of disease symptoms occurs.
  • other dosage regimens may be useful.
  • Unit doses can be in the range, for instance of about 5 mg to 500 mg, such as 50 mg, 100 mg, 150 mg, 200 mg, 250 mg and 300 mg. The progress of therapy is monitored by conventional techniques and assays. [000231]
  • an agent is administered to a human patient at an effective amount (or dose) of less than about 1 ⁇ g/kg, for instance, about 0.35 to 0.75 ⁇ g/kg or about 0.40 to 0.60 ⁇ g/kg.
  • the dose of an agent is about 0.35 ⁇ g/kg, or about 0.40 ⁇ g/kg, or about 0.45 ⁇ g/kg, or about 0.50 ⁇ g/kg, or about 0.55 ⁇ g/kg, or about 0.60 ⁇ g/kg, or about 0.65 ⁇ g/kg, or about 0.70 ⁇ g/kg, or about 0.75 ⁇ g/kg, or about 0.80 ⁇ g/kg, or about 0.85 ⁇ g/kg, or about 0.90 ⁇ g/kg, or about 0.95 ⁇ g/kg or about 1 ⁇ g/kg.
  • the absolute dose of an agent is about 2 ⁇ g/subject to 45 ⁇ g/subject, or about 5 to 40, or about 10 to 30, or about 15 to 25 ⁇ g/subject. In some embodiments, the absolute dose of an agent is about 20 ⁇ g, or about 30 ⁇ g, or about 40 ⁇ g. [000232] In various embodiments, the dose of an agent may be determined by the human patient’s body weight. For example, an absolute dose of an agent of about 2 ⁇ g for a pediatric human patient of about 0 to 5 kg (e.g. about 0, or about 1, or about 2, or about 3, or about 4, or about 5 kg); or about 3 ⁇ g for a pediatric human patient of about 6 to 8 kg (e.g.
  • a pediatric human patient of about 9 to 13 kg e.g.9, or about 10, or about 11, or about 12, or about 13 kg
  • about 8 ⁇ g for a pediatric human patient of about 14 to about 20 kg e.g. about 14, or about 16, or about 18, or about 20 kg
  • about 12 ⁇ g for a pediatric human patient of about 21 to about 30 kg e.g. about 21, or about 23, or about 25, or about 27, or about 30 kg
  • about 13 ⁇ g for a pediatric human patient of about 31 to about 33 kg e.g. about 31, or about 32, or about 33 kg
  • 20 ⁇ g for an adult human patient of about 34 to about 50 kg e.g.
  • an agent in accordance with the methods provided herein is administered subcutaneously (s.c.), intraveneously (i.v.), intramuscularly (i.m.), intranasally - 73 - 1097257085 ⁇ 4 ⁇ AMERICAS Attorney Docket No.126662.00015 or topically.
  • Administration of an agent described herein can, independently, be one to four times daily or one to four times per month or one to six times per year or once every two, three, four or five years.
  • Administration can be for the duration of one day or one month, two months, three months, six months, one year, two years, three years, and may even be for the life of the human patient.
  • the dosage may be administered as a single dose or divided into multiple doses.
  • an agent is administered about 1 to 3 times (e.g.1, or 2 or 3 times).
  • SYNTHETIC EXAMPLES [000234] Presented below are examples discussing synthesis and characterization of TEAD1, 2, 3, and/or 4 inhibitors contemplated for the discussed applications. The following examples are provided to further illustrate the embodiments of the present invention, but are not intended to limit the scope of the invention. While they are typical of those that might be used, other procedures, methodologies, or techniques known to those skilled in the art may alternatively be used.
  • Example 1 Synthesis of 1- ⁇ 3-[(2Z)-3-[5-(trifluoromethyl)-1,2-oxazol-3-yl]prop-2- en-1-yl]azetidin-1-yl ⁇ prop-2-en-1-one - 75 - 1097257085 ⁇ 4 ⁇ AMERICAS Attorney Docket No.126662.00015 [000239] Synthesis of tert-butyl 3- ⁇ 3-[5-(trifluoromethyl)-1,2-oxazol-3-yl]prop-2-en-1- yl ⁇ azetidine-1-carboxylate [000240] Diethyl [5-(trifluoromethyl)-1,2-oxazol-3-yl]methylphosphonate (300 mg, 1.045 mmol), tert-butyl 3-(2-oxoethyl)azetidine-1-carboxylate (250 mg, 1.255 mmol), a stir bar, and THF (10 mL) were
  • Example 2 Synthesis of 1- ⁇ 3-[(2E)-3-[5-(trifluoromethyl)-1,2-oxazol-3-yl]prop-2- en-1-yl]azetidin-1-yl ⁇ prop-2-en-1-one 2-en-1- yl]azetidin-1-yl ⁇ prop-2-en-1-one [000248] 3-[3-(azetidin-3-yl)prop-1-en-1-yl]-5-(trifluoromethyl)-1,2-oxazole 2,2,2- trifluoroacetate (300 mg, 0.866 mmol), a stir bar, Et3N (438 mg, 4.328 mmol), DCM (8 mL) were added to a 50 mL round-bottom flask and stirred until homogeneous, then treated with a solution of acryloyl chloride (118 mg, 1.304 mmol) in DCM (2 mL) dropwise.
  • acryloyl chloride 118 mg, 1.304
  • reaction mixture was stirred d for 1 h at r.t, then diluted with water (5 mL) and extracted with DCM (5 mL x 3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum.
  • Example 8 Synthesis of (Z)-1-(3-fluoro-3-(2-(5-(trifluoromethyl)isoxazol-3- yl)vinyl)azetidin-1-yl)prop-2-en-1-one - 89 - 1097257085 ⁇ 4 ⁇ AMERICAS Attorney Docket No.126662.00015 [000302] Synthetic Route: 3-yl)vinyl)azetidin- 1-yl)prop-2-en-1-one [000304] 3-(2-(3-fluoroazetidin-3-yl)vinyl)-5-(trifluoromethyl)isoxazole 2,2,2- trifluoroacetate (378 mg, 1.386 mmol), TEA (808 mg, 7.985 mmol), a stir bar and DCM (4 mL) were added to a 100 mL round-bottom flask and stirred until homogenous, then treated with acryloyl chloride (216 mg, 2.386
  • Example 10 Synthesis of 1-[(3R)-3- ⁇ 2-[4- (trifluoromethyl)phenyl]ethenyl ⁇ pyrrolidin-1-yl]prop-2-en-1-one - 92 - 1097257085 ⁇ 4 ⁇ AMERICAS Attorney Docket No.126662.00015 [000318] Synthesis of 1-[(3R)-3- ⁇ 2-[4-(trifluoromethyl)phenyl]ethenyl ⁇ pyrrolidin-1-yl]prop- 2-en-1-one [000319] The racemic product was separated by SFC (Column: CHIRAL ART Cellulose-SB, 2*25 cm, 5 ⁇ m; Mobile Phase A: Hex(0.5% 2M NH3-MeOH)--HPLC, Mobile Phase B: IPA-- HPLC; Flow rate: 20 mL/min; Gradient: 15% B to 15% B in 21 min; Wave Length: 220/254 nm; RT2(min
  • Example 11 Synthesis of 1-(3-(2-(5-(trifluoromethyl)pyridin-2-yl)vinyl)azetidin-1- yl)prop-2-en-1-one O O O H OMs P O N K Ot- O [000323] (5-(trifluoromethyl)pyridin-2-yl)methanol (1.0 g, 5.646 mmol), a stir bar, Et3N (1.14 g, 11.292 mmol), DCM (20 mL) were added to a 100 mL round-bottom flask and stirred until homogeneous, then treated with MsCl (0.78 g, 6.810 mmol) dropwise.
  • Example 13 Synthesis of 1- ⁇ 3-[(E)-2-[2-(trifluoromethyl)-1,3-thiazol-5- yl]ethenyl]azetidin-1-yl ⁇ prop-2-en-1-one F 3 C -1,3-thiazol-5-yl]ethenyl]azetidin-1- yl ⁇ prop-2-en-1-one [000347] 5-[2-(azetidin-3-yl)ethenyl]-2-(trifluoromethyl)-1,3-thiazole 2,2,2-trifluoroacetate (400 mg, 1.149 mmol), a stir bar, Et 3 N (596 mg, 5.890 mmol), DCM (10 mL) were added to a 50 mL round-bottom flask and stirred until homogeneous, then treated with a solution of acryloyl chloride (156 mg, 1.724 mmol) in DCM (2 mL) dropwise.
  • Example 14 Synthesis of 1-(3-(3-(trifluoromethyl)styryl)azetidin-1-yl)prop-2-en-1- one [000351] The mixture of 1-(bromomethyl)-3-(trifluoromethyl)benzene (1.0 g, 4.183 mmol) and triethyl phosphite (10 mL) was heated to 110 °C and stirred overnight, then cooled to r.t. and concentrated under vacuum.
  • Example 17 Synthesis of 1-(3-methoxy-3-(4-(trifluoromethyl)styryl)azetidin-1- yl)prop-2-en-1-one To a solution of (COCl) 2 (1.1 g, 8.657 mmol) in DCM (5 mL) was added dropwise a solution of DMSO (1.3 g, 16.651 mmol) in DCM (4 mL) at -70 °C under nitrogen atmosphere.
  • Example 20 Synthesis of 1-(6-(4-(trifluoromethyl)styryl)-2-azaspiro[3.3]heptan-2- yl)prop-2-en-1-one - 111 - 1097257085 ⁇ 4 ⁇ AMERICAS Attorney Docket No.126662.00015 [000407] Synthetic Route: CF 3 NBoc O h 2- carboxylate [000409] Diethyl (4-(trifluoromethyl)benzyl)phosphonate (330 mg, 1.114 mmol), a stir bar, tert-butyl 6-formyl-2-azaspiro[3.3]heptane-2-carboxylate (301 mg, 1.336 mmol) and THF (12 mL) were added to a 50 mL round-bottom flask and stirred until homogeneous, and then treated with t-BuOK (188 mg, 1.675 mmol) at 0 °C.
  • the resulting mixture was stirred for 2 h at room temperature under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The resulting mixture was extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with water (2 x 5 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure.
  • Example 22 Synthesis of 1- ⁇ 6-[(E)-2-[5-(trifluoromethyl)-1,2-oxazol-3- yl]ethenyl]-2-azaspiro[3.3]heptan-2-yl ⁇ prop-2-en-1-one - 115 - 1097257085 ⁇ 4 ⁇ AMERICAS Attorney Docket No.126662.00015 [000425] Synthesis of tert-butyl 6-(2-(5-(trifluoromethyl)isoxazol-3-yl)vinyl)-2- azaspiro[3.3]heptane-2-carboxylate [000426] Diethyl [5-(trifluoromethyl)-1,2-oxazol-3-yl]methylphosphonate (300 mg, 1.045 mmol), tert-butyl 6-formyl-2-azaspiro[3.3]heptane-2-carboxylate (285 mg, 1.265 mmol), a stir bar,
  • Example 24 Synthesis of 1- ⁇ 7-[(E)-2-[5-(trifluoromethyl)-1,2-oxazol-3- yl]ethenyl]-2-azaspiro[3.5]nonan-2-yl ⁇ prop-2-en-1-one -2- azaspiro[3.5]nonane-2-carboxylate [000438] Diethyl [5-(trifluoromethyl)-1,2-oxazol-3-yl]methylphosphonate (300 mg, 1.045 mmol), tert-butyl 7-formyl-2-azaspiro[3.5]nonane-2-carboxylate (330 mg, 1.303 mmol), a stir bar, and THF (10 mL) were added to a 100 mL round-bottom flask and stirred until homogeneous, then treated with potassium t-butoxide (181 mg, 1.613 mmol) at 0 °C.
  • Example 26 Synthesis of 1- ⁇ 3-[(Z)-2-[5-(trifluoromethyl)-1,2-oxazol-3- yl]ethenyl]azetidin-1-yl ⁇ prop-2-en-1-one Route: trifluoroacetate [000450] Tert-butyl 3-(2-(5-(trifluoromethyl)isoxazol-3-yl)vinyl)azetidine-1-carboxylate (300 mg, 0.943 mmol), a stir bar, DCM (5 mL) were added to a 100 mL round-bottom flask and stirred until homogeneous, and then treated with TFA (1 mL).
  • Example 27 Synthesis of (S*,E)-1-(3-hydroxy-3-(4- (trifluoromethyl)styryl)pyrrolidin-1-yl)prop-2-en-1-one pyrrolidin-1-yl)prop- 2-en-1-one [000456] 3-[(E)-2-[4-(Trifluoromethyl)phenyl]ethenyl]pyrrolidin-3-ol hydrochloride (550 mg, 1.873 mmol), triethylamine (758 mg, 7.492 mmol), a stir bar and DCM (10 mL) were added to a 100 mL round-bottom flask and stirred until homogeneous, then treated with acryloyl chloride (203 mg, 2.248 mmol) in DCM (2 mL) at r.t.
  • acryloyl chloride 203 mg, 2.248 mmol
  • Example 28 Synthesis of (R*,E)-1-(3-hydroxy-3-(4- (trifluoromethyl)styryl)pyrrolidin-1-yl)prop-2-en-1-one [000458] Synthetic Route: (trifluoromethyl)phenyl)ethynyl)pyrrolidine-1-carboxylate [000460] To a solution of 1-ethynyl-4-(trifluoromethyl)benzene (3.03 g, 17.817 mmol) in THF (35 mL) was added butyllithium (7.77 mL, 19.436 mmol) at -78 °C under nitrogen.
  • the racemic product was further separated by SFC (Column: CHIRALPAK IH, 2*25 cm, 5 ⁇ m; Mobile Phase A: Hex(0.5% 2M NH3-MeOH)--HPLC, Mobile Phase B: EtOH--HPLC; Flow rate: 20 mL/min; Gradient: 7% B to 7% B in 18 min; Wave Length: 220/254 nm; RT1(min): 12.588; Sample Solvent: EtOH--HPLC; Injection Volume: 0.3 mL) to afford (single stereoisomer, absolute stereochemistry randomly assigned as S) 1-[(3S*)-3-methyl-3- ⁇ 2-[4- - 127 - 1097257085 ⁇ 4 ⁇ AMERICAS Attorney Docket No.126662.00015 (trifluoromethyl)phenyl]ethenyl ⁇ pyrrolidin-1-yl]prop-2-en-1-one as a colorless oil (119.4 mg).
  • the racemic product was - 128 - 1097257085 ⁇ 4 ⁇ AMERICAS Attorney Docket No.126662.00015 further separated by SFC (Column: CHIRALPAK IH, 2*25 cm, 5 ⁇ m; Mobile Phase A: Hex(0.5% 2M NH3-MeOH)--HPLC, Mobile Phase B: EtOH--HPLC; Flow rate: 20 mL/min; Gradient: 7% B to 7% B in 18 min; Wave Length: 220/254 nm; RT2(min): 15.997; Sample Solvent: EtOH--HPLC; Injection Volume: 0.3 mL) to afford (single stereoisomer, absolute stereochemistry randomly assigned as R) 1-[(3R*)-3-methyl-3- ⁇ 2-[4- (trifluoromethyl)phenyl]ethenyl ⁇ pyrrolidin-1-yl]prop-2-en-1-one) as colorless oil (128.6 mg).
  • Example 31 Synthesis of 1- ⁇ 3-ethyl-4-[(Z)-2-[4- (trifluoromethyl)phenyl]ethenyl]pyrrolidin-1-yl ⁇ prop-2-en-1-one [000482] Synthetic Route: - 129 - 1097257085 ⁇ 4 ⁇ AMERICAS Attorney Docket No.126662.00015 [000483] Synthesis of 1-tert-butyl 3-ethyl (3R,4R)-4-ethylpyrrolidine-1,3-dicarboxylate [000484] Ethyl (3R,4R)-1-benzyl-4-ethylpyrrolidine-3-carboxylate (2.5 g, 9.565 mmol), a stir bar, and MeOH (40 mL) were added to a 100 mL round-bottom flask and stirred until homogeneous, and then treated with ammonium formate (1.81 g, 28.705 mmol) and Pd/
  • Example 34 Synthesis of 1-acryloyl-3-(2-(5-(trifluoromethyl)isoxazol-3- yl)vinyl)azetidine-3-carbonitrile - 136 - 1097257085 ⁇ 4 ⁇ AMERICAS Attorney Docket No.126662.00015 [000512]
  • tert-butyl 3-cyanoazetidine-1-carboxylate (5.0 g, 27.439 mmol) in THF (40 mL) was added and stirring continued for 1 h.
  • 1,2,3-benzotriazol-1-ylmethanol (8.2 g, 54.977 mmol).
  • the resulting mixture was stirred for additional 2 h at -70 °C.
  • the reaction mixture was then quenched with water (100 mL), extracted with EA (3 x 200 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under vacuum.
  • Example 35 Synthesis of (E)-1-(3-methoxy-3-(4-(trifluoromethyl)styryl)pyrrolidin- 1-yl)prop-2-en-1-one 1- carboxylate [000526] To a solution of tert-butyl 3-hydroxy-3-[(E)-2-[4- (trifluoromethyl)phenyl]ethenyl]pyrrolidine-1-carboxylate (700 mg, 1.959 mmol) in DMF (10 - 139 - 1097257085 ⁇ 4 ⁇ AMERICAS Attorney Docket No.126662.00015 mL) was added NaH (94 mg, 2.351 mmol, 60%) under nitrogen at 0 °C.
  • Example 36 Synthesis of Example 371-(3-methoxy-4-(4- (trifluoromethyl)styryl)pyrrolidin-1-yl)prop-2-en-1-one [000532] Synthetic Route: 1-tert-butyl 3-ethyl 4-hydroxypyrrolidine-1,3-dicarboxylate (1 g, 3.857 mmol), MeI (2.7 g, 19.022 mmol), a stir bar, and DCM (20 mL) were added to a 40 mL vial and stirred until homogeneous, and then treated with Ag2O (2.7 g, 11.651 mmol).
  • Example 37 Synthesis of 1-acryloyl-3-(4-(trifluoromethyl)styryl)azetidine-3- carbonitrile [000545] Synthetic Route: [000547] Diethyl (4-(trifluoromethyl)benzyl)phosphonate (650 mg, 2.194 mmol), tert-butyl 3-cyano-3-formylazetidine-1-carboxylate (554 mg, 2.635 mmol), a stir bar, and THF (10 mL) were added to a 50 mL round-bottom flask and stirred until homogeneous, and then treated with t-BuOK (369 mg, 3.288 mmol) at 0 °C.
  • Example 38 Synthesis of 1-(3-((4-(trifluoromethyl)phenyl)ethynyl)pyrrolidin-1- yl)prop-2-en-1-one - 145 - 1097257085 ⁇ 4 ⁇ AMERICAS Attorney Docket No.126662.00015 [000553] Synthetic Route: carboxylate [000555] 1-iodo-4-(trifluoromethyl)benzene (650 mg, 2.390 mmol), a stir bar, TEA (10 mL) and tert-butyl 3-ethynylpyrrolidine-1-carboxylate (466 mg, 2.387 mmol) were added to an oven-dried and nitrogen-purged 25 mL round-bottom flask and stirred until homogenous, then treated with CuI (91 mg, 0.478 mmol) and Pd(PPh 3 ) 2 Cl 2 (335 mg, 0.477 mmol) in batches at rt.
  • Example 39 Synthesis of 1-((3S*,4S*)-3-methyl-4-((E)-4- (trifluoromethyl)styryl)pyrrolidin-1-yl)prop-2-en-1-one [000561] Synthetic Route: 1097257085 ⁇ 4 ⁇ AMERICAS Attorney Docket No.126662.00015 [000562] Synthesis of 1-((3S*,4S*)-3-methyl-4-((E)-4-(trifluoromethyl)styryl)pyrrolidin-1- yl)prop-2-en-1-one [000563] To a solution of 3-methyl-4-[(E)-2-[4-(trifluoromethyl)phenyl]ethenyl]pyrrolidine hydrochloride (400 mg, 1.371 mmol) in DCM (4 mL) was added triethylamine (694 mg, 6.855 mmol) and acryloyl chloride (149 mg, 1.645 mmol) in
  • Example 40 Synthesis of 1-[(3R*,4R*)-3-methyl-4- ⁇ 2-[4- (trifluoromethyl)phenyl]ethenyl ⁇ pyrrolidin-1-yl]prop-2-en-1-one - 148 - 1097257085 ⁇ 4 ⁇ AMERICAS Attorney Docket No.126662.00015 [000565] Synthetic Route: a g, was DMSO (1.29 g, 16.568 mmol) in DCM (3 mL) at -70 °C.
  • Example 41 Synthesis of (S*,Z)-1-(3-(3-(trifluoromethyl)styryl)pyrrolidin-1- yl)prop-2-en-1-one Synthetic Route: [000576] 1-(bromomethyl)-3-(trifluoromethyl)benzene (1 g, 4.183 mmol), a stir bar and triethyl phosphite (10 mL) were added to a 40 mL vial. The reaction mixture was stirred overnight at 100 °C, then cooled to r.t. and concentrated under vacuum.
  • Example 42 Synthesis of (R*,Z)-1-(3-(3-(trifluoromethyl)styryl)pyrrolidin-1- yl)prop-2-en-1-one [000584] Synthetic Route: [000585] prop-2-en-1-one [000586] 3-(3-(trifluoromethyl)styryl)pyrrolidine 2,2,2-trifluoroacetate (0.63 g, 1.773 mmol), DCM (10 mL), triethylamine (1 g, 9.882 mmol) and a stir bar were added to a 50 mL round- bottom flask and stirred until homogenous, then treated with acryloyl chloride (0.24 g, 2.652 mmol).
  • Example 45 Synthesis of (E)-1-(3-(3-ethynyl-4-(trifluoromethyl)styryl)azetidin-1- yl)prop-2-en-1-one [000598] 3-bromo-4-(trifluoromethyl)benzoic acid (4 g, 14.869 mmol), a stir bar and BH3 in the THF (40 mL) were added to a 100 mL round-bottom flask and stirred until homogenous at rt. The resulting mixture was stirred for 2 h at 25 °C, then quenched with water.
  • Example 46 Synthesis of 1-(7-(4-(trifluoromethyl)phenyl)-2-azaspiro[3.5]non-6- en-2-yl)prop-2-en-1-one carboxylate [000614] To a solution of tert-butyl 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2- azaspiro[3.5]non-6-ene-2-carboxylate (110 mg, 0.315 mmol) in dioxane (1.5 mL) and H 2 O (0.3 mL) was added 1-bromo-4-(trifluoromethyl)benzene (156 mg, 0.693 mmol), potassium carbonate (132 mg, 0.945 mmol) and Pd(dppf)Cl 2 (23 mg, 0.032 mmol).
  • Example 47 Synthesis of 1-(6-(4-(trifluoromethyl)phenyl)-2-azaspiro[3.4]oct-5-en- 2-yl)prop-2-en-1-one azaspiro[3.4]octane-2-carboxylate [000621] To a solution of tert-butyl 6-oxo-2-azaspiro[3.4]octane-2-carboxylate (1.5 g, 6.658 mmol) in THF (16 mL) was added bromo[4-(trifluoromethyl)phenyl]magnesium (11 mL, 6.658 mmol) at -10 °C under nitrogen atmosphere.
  • Example 48 Synthesis of 1-(6-(4-(trifluoromethyl)phenyl)-2-azaspiro[3.4]oct-6-en- 2-yl)prop-2-en-1-one - 162 - 1097257085 ⁇ 4 ⁇ AMERICAS Attorney Docket No.126662.00015 [000627] Synthetic Route: 2- en-1-one [000629] To a mixture of 6-[4-(trifluoromethyl)phenyl]-2-azaspiro[3.4]oct-5-ene trifluoroacetate and of 6-[4-(trifluoromethyl)phenyl]-2-azaspiro[3.4]oct-6-ene trifluoroacetate (160 mg, 0.455 mmol) in DCM (4 mL) was added triethylamine (276 mg, 2.730 mmol) and acryloyl chloride (49 mg, 0.546 mmol) in DCM (1 mL) at r.t.
  • Example 49 Synthesis of 1- ⁇ 3-[6-(trifluoromethyl)-1-benzofuran-2-yl]azetidin-1- yl ⁇ prop-2-en-1-one) - 163 - 1097257085 ⁇ 4 ⁇ AMERICAS Attorney Docket No.126662.00015 [000631] Synthetic Route: [000633] 2-hydroxy-4-(trifluoromethyl)benzaldehyde (2 g, 10.520 mmol), a stir bar, carbon tetrabromide (10.47 g, 31.572 mmol) and DCM (30 mL) were added to an oven-dried and nitrogen-purged 250 mL round-bottomed flask.
  • the reaction mixture was stirred for 20 min at 0 °C, then treated with a solution of triphenylphosphine (8.28 g, 31.560 mmol) in DCM (10 mL) over 5 min, and the resulting mixture stirred for 1 h, before increasing the temperature to room temperature and stirring continued for 2 h.
  • the resulting mixture was quenched with NH4Cl solution, and extracted with DCM (300 mL ⁇ 2). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under vacuum.
  • Example 50 Synthesis of 1-(3-(5-(trifluoromethyl)pyrazolo[1,5-a]pyridin-2- yl)azetidin-1-yl)prop-2-en-1-one - 166 - 1097257085 ⁇ 4 ⁇ AMERICAS Attorney Docket No.126662.00015 [000645]
  • Example 52 Synthesis of 1- ⁇ 3-[6-(trifluoromethyl)-1H-indol-2-yl]azetidin-1- yl ⁇ prop-2-en-1-one [000667] 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6-(trifluoromethyl)-1H-indole (980 mg, 3.150 mmol), tert-butyl 3-iodoazetidine-1-carboxylate (1340 mg, 4.733 mmol), Na2CO3 (1000 mg, 9.435 mmol), a stir bar, 1,4-dioxane (15 mL) and H2O (3 mL) were added to a 40 mL vial,
  • Example 53 Synthesis of 1- ⁇ 3-[1-methyl-6-(trifluoromethyl)indol-2-yl]azetidin-1- yl ⁇ prop-2-en-1-one yl ⁇ prop-2-en- 1-one [000675] 1- ⁇ 3-[6-(trifluoromethyl)-1H-indol-2-yl]azetidin-1-yl ⁇ prop-2-en-1-one (150 mg, 0.510 mmol), Cs2CO3 (249 mg, 0.764 mmol), a stir bar, DMF (10 mL) were added to a 40 mL vial and stirred until homogeneous, then treated with MeI (109 mg, 0.768 mmol).
  • Example 57 Synthesis of (S*)-1-(3-((3-(trifluoromethyl)phenyl)ethynyl)pyrrolidin- 1-yl)prop-2-en-1-one phenyl)ethynyl)pyrrolidin-1-yl)prop-2- en- one [000699] 3-((3-(trifluoromethyl)phenyl)ethynyl)pyrrolidine 2,2,2-trifluoroacetatee (0.83 g, 2.350 mmol), DCM (9 mL), TEA (1.43 g, 14.100 mmol) and a stir bar were added to a 50 mL round-bottom flask and stirred until homogeneous, then treated with prop-2-enoyl chloride (0.28 g, 3.055 mmol) in DCM (1 mL) at 0
  • the first eluting was lyophilized to afford (absolute stereochemistry unknown, randomly assigns as S) (S*)-1-(3- ((3-(trifluoromethyl)phenyl)ethynyl)pyrrolidin-1-yl)prop-2-en-1-one as a colorless oil.
  • Example 58 Synthesis of (S*)-1-(3-methoxy-3-((4- (trifluoromethyl)phenyl)ethynyl)pyrrolidin-1-yl)prop-2-en-1-one (trifluoromethyl)phenyl)ethynyl)pyrrolidine-1-carboxylate [000703] Tert-butyl 3-hydroxy-3- ⁇ 2-[4-(trifluoromethyl)phenyl]ethynyl ⁇ pyrrolidine-1- carboxylate (400 mg, 1.126 mmol, see Example 28), NaH (32.42 mg, 1.351 mmol), a stir bar and dimethylformamide (8 mL) were added to a 20 mL vial and stirred until homogeneous at 0 °C for 30 min, and then treated with CH3I (191.72 mg, 1.351 mmol) in
  • Example 59 Synthesis of (R*)-1-(3-methoxy-3-((4- (trifluoromethyl)phenyl)ethynyl)pyrrolidin-1-yl)prop-2-en-1-one pyrrolidin- 1-yl)prop-2-en-1-one [000711] 3-methoxy-3-((4-(trifluoromethyl)phenyl)ethynyl)pyrrolidine 2,2,2-trifluoroacetate (320 mg, 0.871 mmol), triethylamine (440.82 mg, 4.355 mmol), a stir bar, and DCM (8 mL) were added to a 40 mL vial and stirred until homogeneous, then traeted with acryloyl chloride (78.86 mg, 0.871 mmol) at 0 °C.
  • the first eluting was lyophilized to afford (randomly assigned absolute stereochemistry as R) (R*)-1-(3-methoxy-3-((4- (trifluoromethyl)phenyl)ethynyl)pyrrolidin-1-yl)prop-2-en-1-one as a light yellow oil (53.8 - 181 - 1097257085 ⁇ 4 ⁇ AMERICAS Attorney Docket No.126662.00015 mg, 19.10%).
  • MS (ESI) calcd. for C17H16F3NO2, 323.11 m/z, found, 324.15 [M+H] + .
  • Example 60 Synthesis of 1-[(3R*)-3-methyl-3- ⁇ 2-[4- (trifluoromethyl)phenyl]ethynyl ⁇ pyrrolidin-1-yl]prop-2-en-1-one (trifluoromethyl)phenyl]ethynyl ⁇ pyrrolidine-1-carboxylate [000715] Tert-butyl 3-ethynyl-3-methylpyrrolidine-1-carboxylate (250 mg, 1.195 mmol), 1- iodo-4-(trifluoromethyl)benzene (358 mg, 1.316 mmol), a stir bar, and Et3N (8 mL) were added to a 40 mL vial and stirred until homogeneous, and then treated with CuI (46 mg, 0.242 mmol) and Bis(triphenylphosphine)palladium(II) chloride (168 mg, 0.239 mmol).
  • Example 61 Synthesis of 1-[(3S*)-3-methyl-3- ⁇ 2-[4- (trifluoromethyl)phenyl]ethynyl ⁇ pyrrolidin-1-yl]prop-2-en-1-one phenyl]ethynyl ⁇ pyrrolidin- 1-yl]prop-2-en-1-one [000723] 3-methyl-3-((4-(trifluoromethyl)phenyl)ethynyl)pyrrolidine 2,2,2-trifluoroacetate (660 mg, 1.797 mmol), a stir bar, DCM (14.5 mL), and triethylamine (910 mg, 8.993 mmol) were added to a 50 mL round-bottom flask and stirred until homogeneous, then treated with a solution of acryloyl chloride (243 mg, 2.685 mmol) in DCM (
  • the first eluting was lyophilized to afford (absolute stereochemistry randomly assigned as S) 1-[(3S*)-3-methyl-3- ⁇ 2-[4-(trifluoromethyl)phenyl]ethynyl ⁇ pyrrolidin-1- yl]prop-2-en-1-one as a light yellow oil (MS (ESI) calcd.
  • Example 62 Synthesis of (S*)-1-(3-fluoro-3-((4- (trifluoromethyl)phenyl)ethynyl)pyrrolidin-1-yl)prop-2-en-1-one pyrrolidine- 1-carboxylate [000727] Tert-butyl 3-hydroxy-3- ⁇ 2-[4-(trifluoromethyl)phenyl]ethynyl ⁇ pyrrolidine-1- carboxylate (630 mg, 1.773 mmol), a stir bar, and DCM (15 mL) were added to a 100 mL round-bottom flask and stirred until homogeneous, which was subsequently cooled to -70 °C and slowly charged with DAST (450 mg, 0.174 mmol).
  • Example 63 Synthesis of Trifluoromethyl)phenyl)ethynyl)pyrrolidin-1-yl)prop-2- en-1-one phenyl)ethynyl)pyrrolidin-1- yl)prop-2-en-1-one [000735] 3-fluoro-3- ⁇ 2-[4-(trifluoromethyl)phenyl]ethynyl ⁇ pyrrolidine 2,2,2-trifluoroacetate (480 mg, 1.293 mmol), triethylamine (655 mg, 6.473 mmol), a stir bar, and DCM (10 mL) were added to a 100 mL round-bottom flask and stirred until homogeneous, then treated with acryloyl chloride (235 mg, 2.596 mmol) at 0 °C.
  • the first eluting was lyophilized to afford (absolute stereochemistry unknown, randomly assigns as R) (R*)-1-(3-fluoro-3-((4-(trifluoromethyl)phenyl)ethynyl)pyrrolidin-1-yl)prop-2-en-1-one as a white solid (MS (ESI) mass calcd. for C16H13F4NO, 311.09 m/z, found, 312.10 [M+H] + ).
  • Example 64 Synthesis of (S*)-1-(3-hydroxy-3-((4- (trifluoromethyl)phenyl)ethynyl)pyrrolidin-1-yl)prop-2-en-1-one ethynyl)pyrrolidin-1- yl)prop-2-en-1-one [000739] 3-((4-(trifluoromethyl)phenyl)ethynyl)pyrrolidin-3-ol 2,2,2-trifluoroacetate (441 mg, 1.194 mmol), TEA (604 mg, 5.969 mmol), a stir bar and DCM (8 mL) were added to a 50 mL round-bottom flask and stirred until homogeneous, and then treated with acryloyl chloride (108 mg, 1.193 mmol) at 0 °C.
  • Example 66 Synthesis of (R*)-1-(3-((4-(trifluoromethyl)phenyl)ethynyl)pyrrolidin- 1-yl)prop-2-en-1-one - 190 - 1097257085 ⁇ 4 ⁇ AMERICAS Attorney Docket No.126662.00015 carboxylate [000748] 1-iodo-4-(trifluoromethyl)benzene (650 mg, 2.390 mmol), a stir bar, TEA (10 mL) and tert-butyl 3-ethynylpyrrolidine-1-carboxylate (466 mg, 2.387 mmol) were added to an oven-dried and nitrogen-purged 25 mL round-bottom flask and stirred until homogenous, then treated with CuI (91 mg, 0.478 mmol) and Pd(PPh 3 ) 2 Cl 2 (335 mg, 0.477 mmol).
  • Example 68 Synthesis of (S, E)-2-fluoro-1-(3-(4-(trifluoromethyl)styryl)pyrrolidin- 1-yl) prop-2-en-1-one 1-yl)prop-2- en-1-one 2-Fluoroprop-2-enoic acid (421 mg, 4.68 mmol), EDCI (894 mg,4.66 mmol) and HOBt (632 mg, 4.677 mmol) were added to DMF (10 ml) in an oven-dried 40 ml vial, and stirred until homogeneous, then (E)-3-(4-(trifluoromethyl)styryl)pyrrolidine hydrochloride (500 mg, 1.800 mmol) was added followed by DIEA (1.16 g, 8.99 mmol).
  • Example 69 Synthesis of (R,E)-2-fluoro-1-(3-(4-(trifluoromethyl)styryl)pyrrolidin- 1-yl)prop-2-en-1-one 1-yl)prop-2- en-1-one [000763] 2-Fluoroprop-2-enoic acid (421 mg, 4.68 mmol), EDCI (894 mg,4.66 mmol) and HOBt (632 mg, 4.68 mmol) were added to DMF (10 ml) in an oven-dried 40 ml vial, and stirred until homogeneous, then (E)-3-(4-(trifluoromethyl)styryl)pyrrolidine hydrochloride (500 mg, 1.80 mmol) was added followed by DIEA (1.16 g, 8.99 mmol).
  • Example 70 Synthesis of (E)-1-(3-(1H-pyrazol-1-yl)-4-(4-(trifluoromethyl)styryl) pyrrolidine-1-yl)prop-2-en-1-one N N HO MsO O ) O, TEA HN N N (CH S N NaBH , CaCl N Dess-martin N dicarboxylate [000767] 1-tert-Butyl 3-ethyl 4-hydroxypyrrolidine-1,3-dicarboxylate (3 g, 11.6 mmol), TEA (2.40 g, 23.7 mmol), a stir bar, and DCM (60 mL) were added to a 250 mL round-bottom flask and stirred until homogeneous, and then treated with methanesulfonic anhydride (3.0 g, 17.2 mmol).
  • Example 71 Synthesis of 1-(4-methoxy-4-((4- (trifluoromethyl)phenyl)ethynyl)piperidin-1-yl)prop-2-en-1-one (trifluoromethyl)phenyl)ethynyl)piperidine-1-carboxylate [000783] tert-Butyl 4-hydroxy-4-((4-(trifluoromethyl)phenyl)ethynyl)piperidine-1- carboxylate (100 mg, 0.271 mmol), CH3I (369 mg, 2.60 mmol), a stir bar and DMF (8 mL) were added to 20 mL vial and stirred until homogenous, then treated 60% NaH (62 mg, 2.60 mmol) at room temperature.
  • Example 72 Synthesis of 1-(4-fluoro-4-((4- (trifluoromethyl)phenyl)ethynyl)piperidin-1-yl)prop-2-en-1-one 1- carboxylate [000790] tert-Butyl 4-hydroxy-4-((4-(trifluoromethyl)phenyl)ethynyl)piperidine-1- carboxylate (600 mg, 1.62 mmol), a stir bar and DCM (8 mL) were added to a 100 mL flask and stirred until homogenous, then treated with a solution of diethyl(trifluoro-lambda4- sulfanyl)amine (393 mg, 2.44 mmol) in DCM (2 mL) at -78 °C.
  • Example 73 Synthesis of 1-(4-hydroxy-4-((4- (trifluoromethyl)phenyl)ethynyl)piperidin-1-yl)prop-2-en-1-one - 202 - 1097257085 ⁇ 4 ⁇ AMERICAS Attorney Docket No.126662.00015 [000796] Synthetic Route: 1-carboxylate [000798] 1-Ethynyl-4-(trifluoromethyl)benzene (1.88 g, 11.0 mmol), a stir bar, and THF (30 mL) were added to a 3-necked round-bottom flask, and stirred until homogenous, then treated with butyllithium (5.2 mL, 13.0 mmol) dropwise at -78 °C under nitrogen.
  • Example 74 Synthesis of 1-(4-methyl-4-((4- (trifluoromethyl)phenyl)ethynyl)piperidin-1-yl)prop-2-en-1-one 1-carboxylate
  • 1-Iodo-4-(trifluoromethyl)benzene 300 mg, 1.10 mmol
  • CuI 42 mg, 0.221 mmol
  • Pd(PPh3)2Cl2 155 mg, 0.221 mmol
  • TEA 10 mL
  • Example 75 Synthesis of 1-(3-((3-(trifluoromethyl)phenyl)ethynyl)piperidin-1- yl)prop-2-en-1-one carboxylate [000815] 1-Bromo-3-(trifluoromethyl)benzene (500 mg, 2.22 mmol), a stir bar, TEA (5 mL) and tert-butyl 3-ethynylpiperidine-1-carboxylate (466 mg, 2.23 mmol) were added to an oven-dried and nitrogen-purged 25 mL round-bottom flask and stirred until homogenous, then treated with Pd(PPh 3 ) 2 Cl 2 (313 mg, 0.446 mmol) and CuI (85 mg, 0.446 mmol) in batches at room temperature.
  • Pd(PPh 3 ) 2 Cl 2 313 mg, 0.446 mmol
  • CuI 85 mg, 0.446 mmol
  • Example 76 Synthesis of 1-(3-((4-(trifluoromethyl)phenyl)ethynyl)piperidin-1- yl)prop-2-en-1-one - 207 - 1097257085 ⁇ 4 ⁇ AMERICAS Attorney Docket No.126662.00015 [000821] Synthetic Route: 1- carboxylate [000823] 1-Iodo-4-(trifluoromethyl)benzene (500 mg, 1.84 mmol), a stir bar, TEA (5 mL) and tert-butyl 3-ethynylpiperidine-1-carboxylate (384 mg, 1.84 mmol) were added to an oven-dried and nitrogen-purged 25 mL round-bottom flask and stirred until homogenous, then treated with Pd(PPh 3 ) 2 Cl 2 (258 mg, 0.368 mmol,) and CuI (70 mg, 0.368 mmol) in batches at rt.
  • Example 77 Synthesis of (E)-1-(3-(4-(trifluoromethyl)styryl)azetidin-1-yl)but-2- yn-1-one one [000831] (E)-3-(4-(Trifluoromethyl)styryl)azetidine 2,2,2-trifluoroacetate (280 mg, 0.821 mmol), DCM (4.5 mL), TEA (500 mg, 4.94 mmol) and a stir bar were added to a 20 mL vial - 209 - 1097257085 ⁇ 4 ⁇ AMERICAS Attorney Docket No.126662.00015 and stirred until homogenous, then treated with a solution of but-2-ynoyl chloride (101 mg, 0.985 mmol) in DCM (0.5 mL) at 0 °C.
  • Example 78 Synthesis of (E)-1-(3-(4-(trifluoromethyl)styryl)azetidin-1-yl)prop-2- yn-1-one [000835] tert-Butyl 3-((E)-2-(4-(trifluoromethyl)phenyl]ethenyl)azetidine-1-carboxylate (200 mg, 0.611 mmol), 2,2,2-trifluoroacetic acid (1 mL), a stir bar and DCM (4 mL) were added to 20 mL vial.
  • Example 79 Synthesis of 1-(4-((3-(trifluoromethyl)phenyl)ethynyl)piperidin-1- yl)prop-2-en-1-one - - 1097257085 ⁇ 4 ⁇ AMERICAS Attorney Docket No.126662.00015
  • 1-Bromo-3-(trifluoromethyl)benzene 500 mg, 2.22 mmol
  • Pd(PPh3)2Cl2 312 mg, 0.445 mmol
  • CuI 84 mg, 0.441 mmol
  • Et3N 10 mL
  • Example 80 Synthesis of 1-(4-((4-(trifluoromethyl)phenyl)ethynyl)piperidin-1- yl)prop-2-en-1-one carboxylate [000849] 1-Iodo-4-(trifluoromethyl)benzene (500 mg, 1.84 mmol), a stir bar, tert-butyl 4- ethynylpiperidine-1-carboxylate (461 mg, 2.20 mmol), Pd(PPh 3 ) 2 Cl 2 (257 mg, 0.366 mmol), CuI (70 mg, 0.368 mmol) and Et 3 N (8 mL) were added to a 40 mL sealed vial and stirred until homogeneous.
  • Example 82 Synthesis of (R, E)-1-(3-(4-(trifluoromethyl)styryl)pyrrolidin-1- yl)prop-2-yn-1-one 1-yl)prop-2-yn-1-one [000860] Propiolic acid (152 mg, 2.17 mmol), DIEA (559 mg, 4.33 mmol), (R, E)-3-(4- (Trifluoromethyl) styryl)pyrrolidine hydrochloride (400 mg,1.44 mmol), a stir bar, DCM (15 mL) were added to a nitrogen-purged 100 mL round-bottom flask and stirred until - 215 - 1097257085 ⁇ 4 ⁇ AMERICAS Attorney Docket No.126662.00015 homogeneous, then treated with HATU (823 mg, 0.271 mmol) in batches.
  • Example 83 Synthesis of 1-((3S,4R)-3-(pyrimidin-2-ylamino)-4-((E)-4- (trifluoromethyl) styryl)pyrrolidin-1-yl)prop-2-en-1-one dicarboxylate - 216 - 1097257085 ⁇ 4 ⁇ AMERICAS Attorney Docket No.126662.00015 [000864]
  • 1-(tert-Butyl) 3-ethyl 4-oxopyrrolidine-1,3-dicarboxylate (10 g, 38.9 mmol), sodium bicarbonate (4.9 g, 58.3 mmol), a stir bar, THF (50 mL) and EtOH (100 mL) were added to a 500 mL flask and stirred until homogenous, then treated with hydroxylamine hydrochloride (4.05 g, 58.3 mmol).
  • Example 84 Synthesis of 1-((3R,4S)-3-(pyrimidin-2-ylamino)-4-((E)-4- (trifluoromethyl) styryl)pyrrolidin-1-yl)prop-2-en-1-one -4- (trifluoromethyl)styryl)pyrrolidin -1-yl)prop-2-en-1-one [000888] (E)-N-(4-(4-(trifluoromethyl)styryl)pyrrolidin-3-yl)pyrimidin-2-amine trihydrochloride (250 mg, 0.563 mmol), triethylamine (342 mg, 3.38mmol), a stir bar and DCM (3 mL) were added to a 8 mL vial and stirred until homogenous, then treated with a solution of prop-2-enoyl prop-2-enoate (85 mg, 0.056 mmol) in DCM (1 mL) dropwise.
  • Example 85 Synthesis of (S, E)-1-(3-(3-(4- (trifluoromethyl)phenyl)allyl)pyrrolidin-1-yl)prop-2-en-1-one O N
  • (R)-2-(1-(tert-Butoxycarbonyl)pyrrolidin-3-yl)acetic acid (2 g, 8.72 mmol) a stir bar and BH3-THF (30 mL) were added to 100 mL round-bottom flask and stirred until homogenous. The resulting mixture was stirred for 2 hours at room temperature, then quenched with MeOH. The resulting mixture was extracted with EA (60 mL x 2).
  • tert-butyl (R)-3-(2-hydroxyethyl)pyrrolidine-1-carboxylate (1 g, 4.65 mmol) in DCM (5 mL) was added dropwise and stirring continued for 30 min.
  • Et3N 3.76 g, 37.2 mmol
  • the resulting mixture was stirred at -70°C for 30 min, then warmed to room temperature and stirred for 1 hour, then diluted with DCM.
  • the resulting mixture was extracted with DCM (10 mL x 2). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under the reduced pressure.
  • Example 86 Synthesis of (R, E)-1-(3-(2-methyl-4-(4-(trifluoromethyl)phenyl)but- 3-en-2-yl)pyrrolidin-1-yl)prop-2-en-1-one - 224 - 1097257085 ⁇ 4 ⁇ AMERICAS Attorney Docket No.126662.00015 [000904] (R)-2-(1-(tert-Butoxycarbonyl)pyrrolidin-3-yl)acetic acid (4.0 g, 17.4 mmol), a stir bar, methyl iodide (2.97 g, 20.9 mmol) and DMF (40 mL) were added to a 250 mL round- bottom flask and stirred until homogeneous, then treated with potassium carbonate (4.86 g, 34.9 mmol).
  • Example 87 Synthesis of (R, Z)-1-(3-(4-(trifluoromethyl)styryl)pyrrolidin-1- yl)prop-2-en-1-one - 228 - 1097257085 ⁇ 4 ⁇ AMERICAS Attorney Docket No.126662.00015 [000920] Synthetic route [000922] To the mixed solution of triphenylphosphine (6.52 g, 24.9 mmol) and imidazole (1.69 g, 24.9 mmol) in DCM (17.5 mL) at 0 o C was added I2 (5.04 g, 19.9 mmol). The suspension was stirred at this temperature for 1 hour.
  • Example 88 Synthesis of (E)-1-(3-(3-(4-(trifluoromethyl)phenyl)prop-1-en-1- yl)pyrrolidin-1-yl)prop-2-en-1-one [000934] 1-(2-Bromoethyl)-4-(trifluoromethyl)benzene (3 g, 11.9 mmol), a stir bar, triphenylphosphine (3.26 g, 12.4 mmol), ACN (30 mL) were added to a 250 mL round-bottom flask and stirred until homogeneous.
  • HMPA (12 mL, 68.6 mmol) was added dropwise and stirring continued for 30 min.
  • the mixture was quenched with NH4Cl solution (40 mL) and extracted with EA (300 mL x 3).
  • Example 89 Synthesis of (Z)-1-(3-(3-(4-(trifluoromethyl)phenyl)prop-1-en-1- yl)pyrrolidin-1-yl)prop-2-en-1-one O O O HN N F F 1-yl)pyrrolidin-1- yl)prop-2-en-1-one [000944] 3-(3-(4-(Trifluoromethyl)phenyl)prop-1-en-1-yl)pyrrolidine 2,2,2-trifluoroacetate (450 mg, 1.22 mmol), a stir bar, DCM (4 mL) were added to a 20 mL vial and stirred until homogeneous before the reaction vessel was cooled to 0 °C, then treated with Et 3 N (640 mg, 6.33 mmol) and a solution of prop-2-enoyl prop-2-enoate (240 mg, 1.90 mmol) in DCM (1 mL) dropwise.
  • Et 3 N 640 mg, 6.33 mmol
  • Example 90 Synthesis of (E)-1-(4-(3-(4-(trifluoromethyl)phenyl)allyl)piperidin-1- yl)prop-2-en-1-one carboxylate [000948] Diethyl (4-(trifluoromethyl)phenyl)methylphosphonate (500 mg, 1.69 mmol), a stir bar, tert-butyl 4-(2-oxoethyl)piperidine-1-carboxylate (422 mg, 1.86 mmol) and THF (13 mL) were added to a 40 mL vial and stirred until homogeneous, then treated with potassium tert- butoxide (227 mg, 2.03 mmol) at 0°C.
  • Example 91 Synthesis of (Z)-1-(3-(3-methyl-3-(4-(trifluoromethyl)phenyl)but-1- en-1-yl) pyrrolidin-1-yl)prop-2-en-1-one [000956] Ethyl 2-(4-(trifluoromethyl)phenyl)acetate (10 g, 43.1 mmol), MeI (15.9 g, 112 mmol), a stir bar, and THF (200 mL) were added to a 500 mL round-bottom flask and stirred until homogeneous, and then treated with NaH (4 g, 100 mmol, 60% in oil).
  • Example 92 Synthesis of (E)-1-(3-(3-methyl-3-(4-(trifluoromethyl)phenyl)but-1- en-1-yl) pyrrolidin-1-yl)prop-2-en-1-one pyrrolidin-1-yl)prop-2-en-1-one [000972] 3-(3-Methyl-3-(4-(trifluoromethyl)phenyl)but-1-en-1-yl)pyrrolidine 2,2,2- trifluoroacetate (170 mg, 0.428 mmol), triethylamine (216 mg, 2.14 mmol), a stir bar and DCM (5 mL) were added to a 20 mL vial and stirred until homogenous, then treated with a solution of prop-2-enoyl prop-2-enoate (64.74 mg, 0.514 mmol) in DCM (1 mL) dropwise at 0°C.
  • Example 93 Synthesis of (S, E)-1-(3-(3-(4-(trifluoromethyl)phenyl)prop-1-en-1-yl) pyrrolidin-1-yl)prop-2-en-1-one prop-1-en-1-yl) pyrrolidin-1- yl)prop-2-en-1-one [000976] (E)-1-(3-(3-(4-(Trifluoromethyl)phenyl)prop-1-en-1-yl)pyrrolidin-1-yl)prop-2-en- 1-one (30 mg, 0.10 mmol) was separated by Chiral HPLC (Column: CHIRALPAK AS 2*25 cm, 5 ⁇ m; Mobile Phase A: HEX(0.5% 2M NH 3 -MeOH), Mobile Phase B: ETOH; Flow rate: 20 mL/min; Gradient: isocratic 10; Wave Length: 220/254 nm; RT1(min): 17.549
  • Example 94 Synthesis of (R, E)-1-(3-(3-(4-(trifluoromethyl)phenyl)prop-1-en-1-yl) pyrrolidin-1-yl)prop-2-en-1-one - 240 - 1097257085 ⁇ 4 ⁇ AMERICAS Attorney Docket No.126662.00015 [000978] Synthetic Route: 1-yl)prop-2-en-1-one [000980] (E)-1-(3-(3-(4-(trifluoromethyl)phenyl)prop-1-en-1-yl)pyrrolidin-1-yl)prop-2-en-1- one (30 mg, 0.10 mmol) was separated by Chiral HPLC (Column: CHIRALPAK AS 2*25 cm, 5 ⁇ m; Mobile Phase A: HEX(0.5% 2M NH3-MeOH), Mobile Phase B: ETOH; Flow rate: 20 mL/min; Gradient: isocratic 10; Wave Length:
  • Example 95 Synthesis of 1-(7-(4-(trifluoromethyl)phenyl)-2-azaspiro[4.4]non-6- en-2-yl)prop-2-en-1-one - 241 - 1097257085 ⁇ 4 ⁇ AMERICAS Attorney Docket No.126662.00015 [000983] Synthesis of tert-butyl 7-hydroxy-7-(4-(trifluoromethyl)phenyl)-2- azaspiro[4.4]nonane-2-carboxylate [000984] tert-Butyl 7-oxo-2-azaspiro[4.4]nonane-2-carboxylate (1.63 g, 6.81 mmol), a stir bar and THF (20 mL) were added to a 250 mL three-necked flask and stirred until homogeneous, then treated with LaCl3 ⁇ 2LiCl (34 mL, 20.4 mmol, 0.6 M in THF)
  • the mixture was separated by Prep-HPLC (Column: XSelect CSH C18 Column, 19*250 mm, 5 ⁇ m; Mobile Phase A: Water(0.1% FA), Mobile Phase B: ACN; Flow rate: 25 mL/min mL/min; Gradient: 33% B to 58% B in15min; Wave Length: 254nm nm; RT1(min): 14.3, 14.59(min) ).
  • Example 96 Synthesis of 1-(7-(4-(trifluoromethyl)phenyl)-2-azaspiro[4.4]non-7- en-2-yl) prop-2-en-1-one F F F F en-1-one [000992] A mixture of 7-(4-(trifluoromethyl)phenyl)-2-azaspiro[4.4]non-7-ene 2,2,2- trifluoroacetate and 7-(4-(trifluoromethyl)phenyl)-2-azaspiro[4.4]non-6-ene 2,2,2- trifluoroacetate (700 mg, 1.74 mmol), a stir bar, DCM (6.5 mL) and Et3N (556 mg, 5.49 - 243 - 1097257085 ⁇ 4 ⁇ AMERICAS Attorney Docket No.126662.00015 mmol) were added to a 40 mL vial and stirred until homogeneous, then treated with a solution of prop-2-enoyl prop-2
  • Example 97 Synthesis of 1-(3-(4-(trifluoromethyl)phenyl)-1-oxa-7- azaspiro[4.4]non-3-en-7-yl)prop-2-en-1-one - 244 - 1097257085 ⁇ 4 ⁇ AMERICAS Attorney Docket No.126662.00015 [000995] Synthesis of tert-butyl 3-hydroxy-3-(4-(trifluoromethyl)phenyl)-1-oxa-7- azaspiro[4.4] nonane-7-carboxylate [000996] tert-Butyl 3-oxo-1-oxa-7-azaspiro[4.4]nonane-7-carboxylate (1.5 g, 6.22 mmol), a stir bar, THF (10 mL) and 0.6 M bromo[4-(trifluoromethyl)phenyl]magnesium in THF (15.56 mL, 9.336 mmol) were added to 40
  • Example 98 Synthesis of 1-(3-(4-(trifluoromethyl)phenyl)-1-oxa-7- azaspiro[4.4]non-2-en-7-yl)prop-2-en-1-one yl)prop-2-en-1-one [0001006]A mixture of 3-(4-(trifluoromethyl)phenyl)-1-oxa-7-azaspiro[4.4] non-3-ene 2,2,2- trifluoroacetate and 3-(4-(trifluoromethyl)phenyl)-1-oxa-7-azaspiro[4.4]non-2-ene 2,2,2- trifluoroacetate (600 mg, 1.57 mmol), a stir bar, DCM (9 mL) and TEA (230 mg, 2.27 mmol) were added to a 20 mL vial and stirred until homogenous, then treated
  • Example 99 Synthesis of (E)-1-(3-(3-hydroxy-3-(4-(trifluoromethyl)phenyl)prop- 1-en-1-yl)pyrrolidin-1-yl)prop-2-en-1-one OH O pyrrolidine-1-carboxylate [0001010]tert-Butyl 3-ethynylpyrrolidine-1-carboxylate (3 g, 15.4 mmol), a stir bar and THF (37 mL) were added to a 100 mL three-neck flask and stirred until homogeneous, then cooled to -78 °C, treated with butyllithium (7.5 mL, 18.8 mmol, 2.5M) dropwise at -78 °C.
  • Example 100 Synthesis of (Z)-1-(3-(3-hydroxy-3-(4-(trifluoromethyl)phenyl)prop- 1-en-1-yl)pyrrolidin-1-yl)prop-2-en-1-one yl)pyrrolidine-1-carboxylate [0001020]tert-Butyl 3-(3-hydroxy-3-(4-(trifluoromethyl)phenyl)prop-1-yn-1-yl)pyrrolidine-1- carboxylate (500 mg, 1.35 mmol), a stir bar and EA (10 mL) were added to a 50 mL round- bottom flask and stirred until homogeneous, then treated with Lindlar catalyst (50 mg, 0.242 mmol) at room temperature.
  • Lindlar catalyst 50 mg, 0.242 mmol

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Abstract

L'invention concerne des inhibiteurs d'oncoprotéines YAP/TAZ-TEAD de formule (I), ou un stéréoisomère, et/ou un sel pharmaceutiquement acceptable, et/ou un solvate de ceux-ci, des compositions pharmaceutiques de ceux-ci ainsi que des méthodes de traitement.
PCT/US2023/032957 2022-09-15 2023-09-15 Inhibiteurs d'oncoprotéines yap/taz-tead WO2024059317A1 (fr)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020081572A1 (fr) * 2018-10-15 2020-04-23 Dana-Farber Cancer Institute, Inc. Inhibiteurs du facteur de transcription à domaine associé transcriptionnel amélioré (tead) et leurs utilisations
WO2022006548A1 (fr) * 2020-07-02 2022-01-06 Bridgene Biosciences, Inc. Inhibiteurs d'oncoprotéines yap/taz-tead, leur synthèse et leur utilisation

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020081572A1 (fr) * 2018-10-15 2020-04-23 Dana-Farber Cancer Institute, Inc. Inhibiteurs du facteur de transcription à domaine associé transcriptionnel amélioré (tead) et leurs utilisations
WO2022006548A1 (fr) * 2020-07-02 2022-01-06 Bridgene Biosciences, Inc. Inhibiteurs d'oncoprotéines yap/taz-tead, leur synthèse et leur utilisation

Non-Patent Citations (13)

* Cited by examiner, † Cited by third party
Title
"Remington's Pharmaceutical Science", 1980, MACK PUBLISHING COMPANY
FOSTER ET AL., ADV. DRUG RES., vol. 14, 1985, pages 1 - 36
GATELY, J. NUCL. MED., vol. 27, 1986, pages 388
GORDON, DRUG METAB. DISPOS., vol. 15, 1987, pages 589
GREENE ET AL.: "Protective Groups in Organic Synthesis", 2006, JOHN WILEY AND SONS
JOURNAL OF BIOLOGICAL CHEMISTRY
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
KUSHNER ET AL., CAN. J. PHYSIOL. PHARMACOL., vol. 77, 1999, pages 79 - 88
LIJINSKY, FOOD COSMET. TOXICOL., vol. 20, 1982, pages 393
LIJINSKY, J. NAT. CANCER INST., vol. 69, 1982, pages 1127
MANGOLD, MUTATION RES, vol. 308, 1994, pages 33
WADE D, CHEM. BIOL. INTERACT., vol. 117, 1999, pages 191
ZELLO, METABOLISM, vol. 43, 1994, pages 487

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