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WO2024215923A2 - Inhibiteurs de wrn à base de sulfone vinylique cyclique - Google Patents

Inhibiteurs de wrn à base de sulfone vinylique cyclique Download PDF

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Publication number
WO2024215923A2
WO2024215923A2 PCT/US2024/024124 US2024024124W WO2024215923A2 WO 2024215923 A2 WO2024215923 A2 WO 2024215923A2 US 2024024124 W US2024024124 W US 2024024124W WO 2024215923 A2 WO2024215923 A2 WO 2024215923A2
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independently selected
compound
nitrogen
sulfur
oxygen
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WO2024215923A3 (fr
Inventor
Florian Bartels
Jennifer BORTHWICK
Sebastien Campos
Justin Caravella
Leela DODDA
Robert Lee Dow
Scott D. Edmondson
Nathan E. GENUNG
Silvana Marcel LEIT DE MORADEI
Derun Li
Angela V. West
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Nimbus Wadjet Inc
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Nimbus Wadjet Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/46—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings substituted on the ring sulfur atom
    • C07D333/48—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings substituted on the ring sulfur atom by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • 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
    • C07D413/12—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 chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero 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
    • C07D417/12—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 chain containing hetero atoms as chain links
    • 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
    • C07D417/14—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 three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • 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
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C07D491/048—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being five-membered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems

Definitions

  • the invention provides bicyclic compounds and compositions, the use thereof and methods using the compounds, for inhibiting Werner Syndrome RecQ DNA helicase (WRN) and methods of treating disease using said compounds, in particular the use in treating cancer, and in particular the treatment of cancer characterized as microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR), including colorectal, gastric and endometrial cancer.
  • WRN Werner Syndrome RecQ DNA helicase
  • MSI-H microsatellite instability-high
  • dMMR mismatch repair deficient
  • the invention also provides the use of said compounds as research chemicals, intermediate compounds, combinations, processes and formulations.
  • Loss of DNA mismatch repair is a common initiating event in cancer development occurring in 10-30% of colorectal, endometrial, ovarian and gastric cancers (Aaltonen, L. A. et al. Clues to the pathogenesis of familial colorectal cancer, Science 260, 812-816 (1993), Bonneville R et al., Landscape of Microsatellite Instability Across 39 Cancer Types. JCO Precis Oncol. 1: PO.17.00073 (2017)).
  • MSI microsatellite instability
  • WRN is synthetically lethal with MSI cancers. Depletion of WRN leads to anti-proliferative effects and results in activation of multiple DNA damage signaling markers, induction of cell cycle arrest and apoptosis in MSI-H cancer models but not cancer cells with an intact MMR pathway (otherwise known as microsatellite stable or MSS). The anti-proliferative effects of WRN depletion could not be rescued with a helicase deficient WRN construct, demonstrating that helicase activity of WRN is required for MSI-H viability. These findings indicate that WRN helicase provides a DNA repair and maintenance function that is essential for cell survival in MSI cancers. Recently, the mechanism of WRN dependence has been elucidated.
  • dinucleotide TA repeats are selectively unstable in MSI cells and undergo large scale expansions. These expanded TA repeats form secondary DNA structures that require the WRN helicase for unwinding (van Wietmarschen, N. et al. Repeat expansions confer WRN dependence in microsatellite-unstable cancers. Nature 586, 292-298, 2020).
  • WRN or upon WRN helicase inhibition
  • expanded TA repeats in MSI cells are subject to nuclease cleavage and chromosome breakage.
  • inhibiting the WRN helicase is an attractive strategy for the treatment of MSI-H cancers.
  • the invention provides compounds, pharmaceutically acceptable salts thereof, pharmaceutical compositions thereof and combinations thereof, said compounds being inhibitors of Werner Syndrome RecQ DNA Helicase (WRN).
  • WRN Werner Syndrome RecQ DNA Helicase
  • the invention further provides methods of treating, preventing, or ameliorating a disease or condition, comprising administering to a subject in need thereof an effective amount of a WRN inhibitor.
  • the invention also provides compounds, pharmaceutically acceptable salts thereof, pharmaceutical compositions thereof and combinations thereof, said compounds being useful for the treatment of cancer, in particular cancers characterized as microsatellite instability-high (MSI- H) or mismatch repair deficient (dMMR). Also provided are compounds that bind to, and/or inhibit WRN, and are therefore useful as research chemicals, e.g. as a chemical probe, and as tool compounds. Various embodiments of the invention are described herein.
  • the disclosure provides a compound, or pharmaceutically acceptable salt thereof, according to the Formula I: or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , m, n, x, and Ring A are as described and defined herein.
  • the invention provides a pharmaceutical composition comprising a compound of Formula I of the present invention and one or more pharmaceutically acceptable carriers.
  • the invention provides a combination, in particular a pharmaceutical combination, comprising a compound of Formula I of the present invention and one or more therapeutically active agents.
  • the invention provides a compound of Formula I of the present invention for use as a medicament, in particular for the treatment of a disorder or disease which can be treated by WRN inhibition.
  • the invention provides a compound of Formula I of the present invention for use in the treatment of cancer, particularly wherein the cancer is characterized as microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR).
  • MSI-H microsatellite instability-high
  • dMMR mismatch repair deficient
  • the invention provides a method of treating a disorder or disease which can be treated by WRN inhibition in a subject, comprising administering to the subject a therapeutically effective amount of a compound of Formula I of the present invention.
  • the invention provides a method of treating cancer in a subject, more particularly wherein the cancer is characterized as microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR), comprising administering to the subject a therapeutically effective amount of a compound of Formula I of the present invention.
  • MSI-H microsatellite instability-high
  • dMMR mismatch repair deficient
  • the invention provides the use of a compound of Formula I of the present invention in the manufacture of a medicament for the treatment of a disorder or disease which can be treated by WRN inhibition.
  • the invention provides a compound of Formula I of the present invention for use as a research chemical, for example as a chemical probe or as a tool compound.
  • the invention provides a solid form, process or intermediate as described herein.
  • DETAILED DESCRIPTION 1 General Description of Certain Embodiments of the Invention: [0016]
  • the disclosure provides a compound, or pharmaceutically acceptable salt thereof, according to the Formula I: (I) wherein Ring A is a bivalent cyclic group selected from: a 3-8 membered saturated or partially unsaturated monocyclic carbocyclylene, phenylene, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroarylene having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an 8-10 membered bicyclic heteroarylene ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 7-12 membered saturated or partially unsaturated bicyclic heterocyclylene having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-12
  • the invention provides a method of treating a disorder or disease which can be treated by WRN inhibition in a subject, comprising administering to the subject a therapeutically effective amount of a compound of Formula I of the present invention.
  • Compounds and Definitions [0018] Compounds of the present invention include those described generally herein, and are further illustrated by the classes, subclasses, and species disclosed herein. As used herein, the following definitions shall apply unless otherwise indicated. For purposes of this invention, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75 th Ed.
  • aliphatic or “aliphatic group,” as used herein, means a straight-chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is completely saturated or that contains one or more units of unsaturation, or a monocyclic hydrocarbon or bicyclic hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic (also referred to herein as “carbocycle,” “cycloaliphatic” or “cycloalkyl”), that has a single point of attachment to the rest of the molecule.
  • aliphatic groups contain 1-6 aliphatic carbon atoms.
  • aliphatic groups contain 1-5 aliphatic carbon atoms. In other embodiments, aliphatic groups contain 1-4 aliphatic carbon atoms. In still other embodiments, aliphatic groups contain 1-3 aliphatic carbon atoms, and in yet other embodiments, aliphatic groups contain 1-2 aliphatic carbon atoms.
  • “cycloaliphatic” (or “carbocycle” or “cycloalkyl”) refers to a monocyclic C 3 -C 6 hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic, that has a single point of attachment to the rest of the molecule.
  • Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl groups and hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl.
  • bridged bicyclic refers to any bicyclic ring system, i.e., carbocyclic or heterocyclic, saturated or partially unsaturated, having at least one bridge.
  • a “bridge” is an unbranched chain of atoms or an atom or a valence bond connecting two bridgeheads, where a “bridgehead” is any skeletal atom of the ring system which is bonded to three or more skeletal atoms (excluding hydrogen).
  • a bridged bicyclic group has 5-12 ring members and 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur unless otherwise specified, a bridged bicyclic group is optionally substituted with one or more substituents as set forth for aliphatic groups. Additionally or alternatively, any substitutable nitrogen of a bridged bicyclic group is optionally substituted.
  • alkyl refers to a C 1-12 straight or branched saturated aliphatic group. In certain instances, alkyl refers to a C 1-8 straight or branched saturated aliphatic group or a C 1-6 straight or branched saturated aliphatic group.
  • lower alkyl refers to a C 1-4 straight or branched alkyl group.
  • Exemplary lower alkyl groups are methyl, ethyl, propyl, isopropyl (also referred to interchangeably herein as 2-propyl, iPr, i Pr and i-Pr), butyl, isobutyl (also referred to interchangeably herein as 2-butyl, iBu, i Bu and i-Bu) and tert-butyl (also referred to interchangeably herein as 2-methyl-2-butyl, tBu, t Bu and t-Bu).
  • alkenyl refers to a C 2-12 straight or branched partially unsaturated aliphatic group comprising at least one unsaturated carbon carbon double bond.
  • alkenyl refers to a C 2-8 or a C 2-6 straight or branched partially unsaturated aliphatic group comprising at least one unsaturated carbon carbon double bond.
  • lower alkenyl refers to a C 2-4 straight or branched partially unsaturated aliphatic group comprising at least one unsaturated carbon carbon double bond.
  • Alkenyl groups include both cis (Z) and trans (E) regioisomers.
  • alkynyl refers to a C 2-12 straight or branched partially unsaturated aliphatic group comprising at least one unsaturated carbon carbon triple bond. In certain instances, alkynyl refers to a C 2-8 or a C 2-6 straight or branched partially unsaturated aliphatic group comprising at least one unsaturated carbon carbon triple bond.
  • lower alkynyl refers to a C 2-4 straight or branched partially unsaturated aliphatic group comprising at least one unsaturated carbon carbon triple bond.
  • Exemplary lower alkynyl groups are ethynyl, 1-propynyl, 2-propynyl, 1- butynyl, 2-butynyl, and 3-butynyl.
  • haloalkyl refers to a straight or branched alkyl group that is substituted with one or more halogen atoms.
  • lower haloalkyl refers to a C 1-4 straight or branched alkyl group that is substituted with one or more halogen atoms.
  • heteroatom means one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon (including, any oxidized form of nitrogen, sulfur, phosphorus, or silicon; the quaternized form of any basic nitrogen or; a substitutable nitrogen of a heterocyclic ring, for example N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or NR + (as in N-substituted pyrrolidinyl).
  • unsaturated as used herein, means that a moiety has one or more units of unsaturation.
  • the term “bivalent C 1-8 (or C 1-6 ) saturated or unsaturated, straight or branched, hydrocarbon chain,” refers to bivalent alkylene, alkenylene, and alkynylene chains that are straight or branched as defined herein.
  • the term “bivalent,” to describe a cyclic (and noncyclic) group refers to, for example, bivalent carbocyclylene, phenylene, heterocyclylene, and heteroarylene that are bivalent cyclic moieties of carbocycles, phenyls, heterocycles, and heteroaryls described herein. Non-limiting examples include .
  • Carbocyclylene refers to a carbocyclic or cycloalkyl moiety that is bivalent as described above (i.e., attached at two different points to the rest of the compound).
  • a carbocyclylene may be multi-cyclic, for example, bicyclic or tricyclic. Such multi- cyclic carbocyclylene systems may be saturated or partially unsaturated (while one ring of the bicyclic system may be aromatic it is to be understood that multi-cyclic ring systems that are not in their entirety aromatic may also fall under the definition of carbocyclylene). The rings may form bridged, fused, or spiro systems.
  • Heterocyclylene refers to a heterocyclic or heterocyclyl moiety that is bivalent as described above (i.e., attached at two different points to the rest of the compound) and may also be saturated or partially unsaturated. Non-limiting examples include those shown below. Heterocyclylene is understood to include bicyclic heterocyclylene systems. Non-limiting examples of bicyclic heterocyclylene moieties are also shown below and said bicyclic systems may be spirocyclic, fused, or bridged and may be saturated or partially unsaturated.
  • Phenylene refers to a phenyl moiety that is bivalent as described above (i.e., attached at two different points to the rest of the compound). Examples of phenylene include attachment points that are arranged ortho, meta, and para. at [0033] “Arylene” as used herein refers to an mono or multi-cyclic aryl (i.e., phenyl or a multi- cyclic aryl) moiety that is bivalent as described above (i.e., attached at two different points to the rest of the compound), wherein the arylene group contains no heteroatoms.
  • Heteroarylene refers to a mono or multi-cyclic aryl ring system that contains at least one heteroatom wherein the ring system is bivalent as described above (i.e., attached at two different points to the rest of the compound).
  • alkylene refers to a bivalent alkyl group.
  • An “alkylene chain” is a polymethylene group, i.e., –(CH 2 ) n –, wherein n is a positive integer, preferably from 1 to 6, from 1 to 4, from 1 to 3, from 1 to 2, or from 2 to 3.
  • a substituted alkylene chain is a polymethylene group in which one or more methylene hydrogen atoms are replaced with a substituent.
  • Suitable substituents include those described below for a substituted aliphatic group.
  • alkenylene refers to a bivalent alkenyl group.
  • a substituted alkenylene chain is a polymethylene group containing at least one double bond in which one or more hydrogen atoms are replaced with a substituent.
  • Suitable substituents include those described below for a substituted aliphatic group.
  • halogen means F, Cl, Br, or I.
  • aryl used alone or as part of a larger moiety as in “aralkyl,” “aralkoxy,” or “aryloxyalkyl,” refers to monocyclic or bicyclic ring systems having a total of five to fourteen ring members, wherein at least one ring in the system is aromatic and wherein each ring in the system contains 3 to 7 ring members.
  • aryl may be used interchangeably with the term “aryl ring.”
  • aryl refers to an aromatic ring system which includes, but not limited to, phenyl, biphenyl, naphthyl, anthracyl and the like, which may bear one or more substituents.
  • aryl is a group in which an aromatic ring is fused to one or more non–aromatic rings, such as indanyl, phthalimidyl, naphthimidyl, phenanthridinyl, or tetrahydronaphthyl, and the like.
  • heteroaryl and “heteroar—,” used alone or as part of a larger moiety, e.g., “heteroaralkyl,” or “heteroaralkoxy,” refer to groups having 5 to 10 ring atoms, preferably 5, 6, 9 or 10 ring atoms; having 6, 10, or 14 electrons shared in a cyclic array; and having, in addition to carbon atoms, from one to five heteroatoms.
  • heteroatom refers to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur, and any quaternized form of a basic nitrogen.
  • Heteroaryl groups include, without limitation, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, triazinyl, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl (i.e., 1,2,3-triazolyl), 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, indolizinyl, purinyl, naphthyridinyl, and pteridinyl.
  • heteroaryl and “heteroar—,” as used herein, also include groups in which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic, or heterocyclyl rings, where unless otherwise specified, the radical or point of attachment is on the heteroaromatic ring or on one of the rings to which the heteroaromatic ring is fused.
  • Nonlimiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, indolizinyl, isoindolin-1-only, 1,2-dihydro-3H- pyrrolo[3,4-c]pyridin-3-onyl, 2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-only, imidazo[1,2- a]pyridyl, imidazo[1,5-a]pyridyl, pyrazolo[1,5-a]pyridyl, pyrrolo[1,2-b]pyridazinyl, pyrrolo[1,2- a]pyrimidinyl, imidazo[1,2-b]pyridazinyl, imidazo[1,2-a]pyrimidinyl, benzimidazolyl, benzthiazolyl, quinolyl, isoquinolyl, cinn
  • heteroaryl group may be mono– or bicyclic.
  • heteroaryl may be used interchangeably with the terms “heteroaryl ring,” “heteroaryl group,” or “heteroaromatic,” any of which terms include rings that are optionally substituted.
  • heteroarylkyl refers to an alkyl group substituted by a heteroaryl, wherein the alkyl and heteroaryl portions independently are optionally substituted.
  • heterocycle As used herein, the terms “heterocycle,” “heterocyclyl,” “heterocyclic radical,” and “heterocyclic ring” are used interchangeably and refer to a stable 5– to 7–membered monocyclic or 7–10–membered bicyclic heterocyclic moiety that is either saturated or partially unsaturated, and having, in addition to carbon atoms, one or more, preferably one to four, heteroatoms, as defined above.
  • nitrogen includes a substituted nitrogen.
  • the nitrogen may be N (as in 3,4–dihydro– 2H–pyrrolyl), NH (as in pyrrolidinyl), or + NR (as in N–substituted pyrrolidinyl).
  • a heterocyclic ring can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure and any of the ring atoms can be optionally substituted.
  • saturated or partially unsaturated heterocyclic radicals include, without limitation, oxetanyl, azetidinyl, tetrahydrofuranyl, tetrahydrothiophenyl pyrrolidinyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, 2-oxa-6- azaspiro[3.3]heptane, and quinuclidinyl.
  • heterocycle used interchangeably herein, and also include groups in which a heterocyclyl ring is fused to one or more aryl, heteroaryl, or cycloaliphatic rings, such as indolinyl, 3H–indolyl, chromanyl, phenanthridinyl, or tetrahydroquinolinyl.
  • a heterocyclyl group may be mono– or bicyclic.
  • heterocyclylalkyl refers to an alkyl group substituted by a heterocyclyl, wherein the alkyl and heterocyclyl portions independently are optionally substituted.
  • the term “partially unsaturated” refers to a ring moiety that includes at least one double or triple bond.
  • the term “partially unsaturated” is intended to encompass rings having multiple sites of unsaturation, but is not intended to include aryl or heteroaryl moieties, as herein defined.
  • the phrase “the left-hand is attached to R 6 ” is intended to refer to Ring A, (i.e., This phrase indicates that the marked with an arrow in attaches to R 6 as shown in Formula I with the same arrow at the same site of attachment to R 6 “Left-hand” as it refers to , or any specific drawings of said generic variable such as , refers to the left-side of the page as viewed by the reader.
  • compounds of the invention may contain “optionally substituted” moieties.
  • substituted means that one or more hydrogens of the designated moiety are replaced with a suitable substituent.
  • an “optionally substituted” group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position.
  • Combinations of substituents envisioned by this invention are preferably those that result in the formation of stable or chemically feasible compounds.
  • Suitable monovalent substituents on a substitutable carbon atom of an “optionally substituted” group are independently halogen; –(CH 2 ) 0–4 B(OR° ) 2 ; –(CH 2 ) 0–4 R° ; –(CH 2 ) 0–4 OR° ; - O(CH 2 ) 0-4 R o ; –O–(CH 2 ) 0–4 C(O)OR°; –(CH 2 ) 0–4 CH(OR° ) 2 ; –(CH 2 ) 0–4 SR° ; –(CH 2 ) 0–4 Ph, which may be substituted with R°; –(CH 2 ) 0–4 O(CH 2 )
  • Suitable monovalent substituents on R are independently halogen, —(CH 2 )0– 2 R ⁇ , –(haloR ⁇ ), –(CH 2 ) 0–2 OH, –(CH 2 ) 0–2 OR ⁇ , –(CH 2 ) 0–2 CH(OR ⁇ ) 2 ; –O(haloR ⁇ ), –CN, –N 3 , –(CH 2 ) 0– 2 C(O)R ⁇ , –(CH 2 )0–2C(O)OH, –(CH 2 )0–2C(O)OR ⁇ , –(CH 2 )0–2SR ⁇ , –(CH 2 )0–2SH, –(CH 2 )0–2NH 2 , – (CH 2 ) 0–2 NR ⁇ , –
  • Suitable divalent substituents that are bound to vicinal substitutable carbons of an “optionally substituted” group include: –O(CR * 2 ) 2–3 O–, wherein each independent occurrence of R * is selected from hydrogen, C 1–6 aliphatic which may be substituted as defined below, or an unsubstituted 5–6–membered saturated, partially unsaturated, or aryl ring having 0– 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • Suitable substituents on the aliphatic group of R * include halogen, –R ⁇ , -(haloR ⁇ ), -OH, –OR ⁇ , –O(haloR ⁇ ), –CN, –C(O)OH, –C(O)OR ⁇ , –NH 2 , –NR ⁇ , –NR 2, or –NO 2 , wherein each R ⁇ is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C 1–4 aliphatic, –CH 2 Ph, –O(CH 2 ) 0–1 Ph, or a 5–6– membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • Suitable substituents on a substitutable nitrogen of an “optionally substituted” group include –R ⁇ , –NR ⁇ 2 , –C(O)R ⁇ , –C(O)OR ⁇ , –C(O)C(O)R ⁇ , –C(O)CH 2 C(O)R ⁇ , -S(O) 2 R ⁇ , -S(O) 2 NR ⁇ 2 , –C(S)NR ⁇ 2 , –C(NH)NR ⁇ 2 , or –N(R ⁇ )S(O) 2 R ⁇ ; wherein each R ⁇ is independently hydrogen, C 1–6 aliphatic which may be substituted as defined below, unsubstituted –OPh, or an unsubstituted 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition
  • Suitable substituents on the aliphatic group of R ⁇ are independently halogen, –R ⁇ , -(haloR ⁇ ), –OH, –OR ⁇ , –O(haloR ⁇ ), –CN, –C(O)OH, –C(O)OR ⁇ , –NH 2 , –NR ⁇ , –NR ⁇ 2 , or –NO 2 , wherein each R ⁇ is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C 1–4 aliphatic, –CH 2 Ph, –O(CH 2 ) 0–1 Ph, or a 5–6– membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • the term “pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio.
  • Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1–19.
  • Pharmaceutically acceptable salts of the compounds of this invention include those derived from suitable inorganic and organic acids and bases.
  • Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid
  • organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange.
  • salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2– hydroxy–ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2–naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pec
  • Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N + (C 1–4 alkyl) 4 salts.
  • Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.
  • Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, loweralkyl sulfonate and aryl sulfonate.
  • structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example, the R and S configurations for each asymmetric center, Z and E double bond isomers, Z and E conformational isomers and Ra (or M) and Sa (or P) atropisomers. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present compounds are within the scope of the invention. Unless otherwise stated, all tautomeric forms of the compounds of the invention are within the scope of the invention.
  • structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms.
  • compounds having the present structures including the replacement of hydrogen by deuterium or tritium, or the replacement of a carbon by a 13 C- or 14 C-enriched carbon are within the scope of this invention.
  • Such compounds are useful, for example, as analytical tools, as probes in biological assays, or as therapeutic agents in accordance with the present invention.
  • a warhead moiety of a provided compound comprises one or more deuterium atoms.
  • Ring A of a provided compound may be substituted with one or more deuterium atoms. 3.
  • the disclosure provides a compound, or pharmaceutically acceptable salt thereof, according to the Formula I: wherein Ring A is a bivalent cyclic group selected from: a 3-8 membered saturated or partially unsaturated monocyclic carbocyclylene, phenylene, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroarylene having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an 8-10 membered bicyclic heteroarylene ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 7-12 membered saturated or partially unsaturated bicyclic heterocyclylene having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-12 membered saturated or partially unsaturated bicyclic carbocyclylene that is optionally bridged or spirocyclic, and a 5-12 membered saturated saturated or partially unsaturated bicyclic carbocyclylene that is
  • Ring A is a bivalent cyclic group selected from: a 3-8 membered saturated or partially unsaturated monocyclic carbocyclylene, phenylene, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroarylene having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an 8-10 membered bicyclic heteroarylene ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 7-12 membered saturated or partially unsaturated bicyclic heterocyclylene having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-12 membered saturated or partially unsaturated bicyclic carbocyclylene that is optionally bridged or spirocyclic, and a 5-12 membered saturated or partially unsaturated bicyclic heterocyclylene that is optionally bridged or spirocyclic having 1-4 heteroatom
  • Ring A is an optionally substituted bivalent phenylene substituted with x instances of R 5 .
  • Ring A is an optionally substituted bivalent cyclic group selected from: a 3-8 membered saturated or partially unsaturated monocyclic carbocyclylene, phenylene, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroarylene having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an 8-10 membered bicyclic heteroarylene ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 7-12 membered saturated or partially unsaturated bicyclic heterocyclylene having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-12 membered saturated or partially unsaturated bicyclic carbocyclylene that is optionally bridged or spirocyclic, a 5-12 membere
  • Ring A is an optionally substituted bivalent 3-8 membered saturated or partially unsaturated monocyclic carbocyclylene substituted with x instances of R 5 .
  • Ring A is an optionally substituted bivalent 4-8 membered saturated or partially unsaturated monocyclic heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur substituted with x instances of R 5 .
  • Ring A is an optionally substituted bivalent 5-6 membered monocyclic heteroarylene having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur substituted with x instances of R 5 .
  • Ring A is an optionally substituted bivalent 8-10 membered bicyclic heteroarylene ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur substituted with x instances of R 5 .
  • Ring A is an optionally substituted bivalent 7-12 membered saturated or partially unsaturated bicyclic heterocyclylene having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur substituted with x instances of R 5 .
  • Ring A is an optionally substituted bivalent 5-12 membered saturated or partially unsaturated bicyclic carbocyclylene that is optionally bridged or spirocyclic substituted with x instances of R 5 .
  • Ring A is an optionally substituted bivalent 5-12 membered saturated or partially unsaturated bicyclic heterocyclylene that is optionally bridged or spirocyclic having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur substituted with x instances of R 5 .
  • Ring A is bivalent phenylene.
  • Ring A is an optionally substituted bivalent phenylene substituted with 1 instance of R 5 .
  • Ring A is an optionally substituted bivalent phenylene substituted with 2 instances of R 5 .
  • Ring A is an optionally substituted bivalent phenylene substituted with 3 instances of R 5 .
  • Ring A is an optionally substituted bivalent phenylene substituted with 4 instances of R 5 .
  • Ring A and its x R 5 substituents :
  • Ring A is as selected from one of the substituents of Table 1.
  • R 1 is hydrogen, halogen, -CN, or an optionally substituted C 1-6 aliphatic.
  • R 1 is hydrogen or a C 1-6 aliphatic.
  • R 1 is hydrogen or halogen.
  • R 1 is a C 1-6 aliphatic or halogen.
  • R 1 is hydrogen.
  • R 1 is halogen.
  • R 1 is a C 1-6 aliphatic.
  • R 1 is -CH 2 OH.
  • R 1 is fluoro. In some embodiments, R 1 is chloro. In some embodiments, R 1 is -CH 3 . In some embodiments, R 1 is as selected from one of the substituents of Table 1.
  • R 2 is a C 1-6 aliphatic group, a C 1-6 aliphatic-Cy’ group, or a cyclic group selected from: a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, a 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 7-12 membered saturated or partially unsaturated bicyclic heterocycl
  • R 2 is an optionally substituted cyclic group selected from: a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, a 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-12 membered saturated or partially unsaturated bicyclic carbocyclic ring that is optionally bridged or spirocyclic, and a 5-12 membered saturated or partially unsaturated bicyclic heterocyclic ring that is optionally bridged or spirocyclic, and
  • R 2 is optionally substituted phenyl.
  • R 2 is a C 1-6 aliphatic-Cy’ group substituted with y instances of R A .
  • R 2 is a -CH 2 -Cy’ group.
  • R 2 is
  • R 2 is as selected from one of the substituents of Table 1.
  • R 3 is independently selected at each occurrence from hydrogen, halogen, –CN, –NO 2 , –OR, -SR, -NR 2 , - NRC(O)R-S(O) 2 R, -S(O) 2 NR 2 , -S(O)R, -S(O)NR 2 , -C(O)R, -C(O)OR, – C(O)NR 2 , -C(O)N(R)OR, -OC(O)R, -OC(O)NR 2 , - N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR 2 , -N(R)C(O)NR 2 , -N(R)S(O) 2 NR 2 , –N(R)S(O) 2 R
  • R 3 is hydrogen. In some embodiments, R 3 is independently selected at each occurrence from halogen, –CN, –NO 2 , –OR, -SR, -NR 2 , - NRC(O)R-S(O) 2 R, -S(O) 2 NR 2 , -S(O)R, -S(O)NR 2 , -C(O)R, -C(O)OR, – C(O)NR 2 , -C(O)N(R)OR, -OC(O)R, -OC(O)NR 2 , - N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR 2 , -N(R)C(O)NR 2 , -N(R)S(O) 2 NR 2 , –N(R)S(O) 2 R, a C 1-6 aliphatic group optionally substituted with
  • R 3 is independently selected at each occurrence from halogen; a C 1-6 aliphatic group optionally substituted with -C(O)NR 2 or NR 2 , -OR, and Cy’’. [0072] In some embodiments, R 3 is independently selected at each occurrence from halogen, a C 1-6 aliphatic group, –C(O)NR 2 , -NR 2 , or -OR.
  • R 3 is independently selected at each occurrence from -CH 3 , fluoro, -C(O)N(CH 3 ) 2 , -C(O)N(CH 2 CH 3 ) 2 , - OCH 3 , -OCH 2 CH 3 , -OCF2CH 3 , -OCH 2 CH 2 CH 3 , or
  • m is 1
  • R 4 is hydrogen
  • R 3 is halogen, a C 1-6 aliphatic group, –C(O)NR 2 , -NR 2 , or -OR.
  • m is 1, R 4 is hydrogen, and R 3 is -CH 3 , fluoro, -C(O)N(CH 3 ) 2 , -C(O)N(CH 2 CH 3 ) 2 , ,-OCH 3 , -OCH 2 CH 3 , -OCF2CH 3 , -OCH 2 CH 2 CH 3 , or [0073]
  • R 3 is as selected from one of the substituents of Table 1.
  • R 4 is independently selected at each occurrence from hydrogen, halogen, –CN, –NO 2 , –OR, -SR, -NR 2 , - NRC(O)R-S(O) 2 R, -S(O) 2 NR 2 , -S(O)R, -S(O)NR 2 , -C(O)R, -C(O)OR, – C(O)NR 2 , -C(O)N(R)OR, -OC(O)R, -OC(O)NR 2 , - N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR 2 , -N(R)C(NR 2 , -N(R)S(O) 2 NR 2 , –N(R)S(O) 2 R, a C 1-6 aliphatic group optionally substituted with -C(O)NR 2
  • R 4 is hydrogen. In some embodiments, R 4 is independently selected at each occurrence from hydrogen and halogen. In some embodiments, R 4 is independently selected at each occurrence from halogen, –CN, –NO 2 , –OR, -SR, -NR 2 , - NRC(O)R-S(O) 2 R, -S(O) 2 NR 2 , -S(O)R, -S(O)NR 2 , -C(O)R, -C(O)OR, – C(O)NR 2 , -C(O)N(R)OR, -OC(O)R, -OC(O)NR 2 , - N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR 2 , -N(R)C(O)NR 2 , -N(R)S(O) 2 NR 2 , –N(R)S(O) 2 NR 2
  • R 4 is independently selected at each occurrence from halogen, –CN, –NO 2 , –OR, -SR, -NR 2 , -NRC(O)R-S(O) 2 R, -S(O) 2 NR 2 , -S(O)R, -S(O)NR 2 , -C(O)R, -C(O)OR, – C(O)NR 2 , -C(O)N(R)OR, -OC(O)R, -OC(O)NR 2 , - N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR 2 , -N(R)C(NR 2 , -N(R)S(O) 2 NR 2 , –N(R)S(O) 2 R, and a C 1-6 aliphatic group optionally substituted with -C(O)NR 2 or NR 2 R, and a C
  • R 4 is as selected from one of the substituents of Table 1.
  • m is 2 and the two adjacent instances of CR 3 R 4 are optionally combined to form a carbon carbon double bond of the formula
  • m is 2 and the two adjacent instances of CR 3 R 4 are combined to form a carbon carbon double bond of the formula .
  • m is 2 and the two adjacent instances of CR 3 R 4 are combined to form a carbon carbon double bond of the formula [0077] In some embodiments, m is 3 and the three instances of CR 3 R 4 are combined to form In some embodiments, m is 3 and the three instances of CR 3 R 4 are combined to form . In some embodiments, m is 3 and the three instances of CR 3 R 4 are combined to form . In some embodiments, m is 3 and the three instances of CR 3 R 4 are combined to form . In some embodiments, m is 3 and the three instances of CR 3 R 4 are combined to form . In some embodiments, m is 3 and the three instances of CR 3 R 4 are combined to form .
  • R 4 is hydrogen and R 3 is independently selected at each occurrence from halogen, a C 1-6 aliphatic group, –C(O)NR 2 , -NR 2 , or -OR.
  • R 4 is hydrogen and R 3 is independently selected at each occurrence from -CH 3 , fluoro, - C(O)N(CH 3 )2, -C(O)N(CH 2 CH 3 )2, -OCH 3 , -OCH 2 CH 3 , -OCF2CH 3 , -OCH 2 CH 2 CH 3 , or [0079]
  • R 4 is hydrogen, m is 1, and R 3 is halogen, a C 1-6 aliphatic group, –C(O)NR 2 , -NR 2 , or -OR.
  • R 4 is hydrogen, m is 1, and R 3 is -CH 3 , fluoro, - C(O)N(CH 3 ) 2 , -C(O)NH(CH 3 ), -C(O)N(CH 2 CH 3 ) 2 , , , -OCH 3 , -SCH 3 , -CH 2 OCH 3 , -OCH 2 CH 3 , -OCF 2 CH 3 , -OCH 2 CH 2 CH 3 , [0080]
  • R 4 and R 3 are each independently selected from a halogen.
  • R 4 and R 3 are each fluoro.
  • each instance of R 5 is independently selected from hydrogen, halogen, –CN, –NO 2 , –OR, - SR, -NR 2 , -S(O) 2 R, -S(O) 2 NR 2 , -S(O)R, -S(O)NR 2 , -C(O)R, -C(O)OR, –C(O)NR 2 , -C(O)N(R)OR, -OC(O)R, -OC(O)NR 2 , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR 2 , -N(R)C(O)NR 2 , -N(R)S(O) 2 NR 2 , –N(R)S(O) 2 R, a C 1-6 aliphatic group substituted with z instances of R B , a C 1-6 aliphatic group substituted with z instances of
  • R 5 is hydrogen. [0083] In some embodiments, each instance of R 5 is independently halogen - CN, -NO 2 , -OR, -SR, -NR 2 , -S(O) 2 R, -S(O) 2 NR 2 , -S(O)R, -S(O)NR 2 , -C(O)R, -C(O)OR, -C(O)N R 2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR 2 , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR 2 , -N(R)C (NR 2 , -N(R)C (NR)NR 2 , -N(R)S(O) 2 NR 2 , –N(R)S(O) 2 R, a C 1-6 aliphatic group substituted with z instances of R
  • each instance of R 5 is independently halogen, – CN, -NO 2 , -OR, -SR, -NR 2 , -S(O) 2 R, -S(O) 2 NR 2 , -S(O)R, -S(O)NR 2 , -C(O)R, -C(O)OR, or – C(O)NR 2 .
  • each instance of R 5 is independently -N(R)S(O) 2 NR 2 or – N(R)S(O) 2 R.
  • R 5 is -N(R)S(O) 2 NR 2 .
  • R 5 is – N(R)S(O) 2 R.
  • R 5 is halogen. In some embodiments, R 5 is halogen and x is 1. In some embodiments, R 5 is halogen and x is 2. In some embodiments, R 5 is fluoro. In some embodiments, R 5 is fluoro and x is 1. In some embodiments, R 5 is fluoro and x is 2. [0085] In some embodiments, R 5 is as selected from one of the substituents of Table 1. [0086] In some embodiments, Ring A is phenylene and R 5 is halogen. In some embodiments, Ring A is phenylene, R 5 is halogen, and x is 1. In some embodiments, Ring A is phenylene, R 5 is halogen, and x is 2.
  • Ring A is phenylene, R 5 is fluoro. In some embodiments, Ring A is phenylene, R 5 is fluoro and x is 1. In some embodiments, Ring A is phenylene, R 5 is fluoro, and x is 2.
  • R 6 is hydrogen, halogen, a C 1-6 aliphatic group, -SF 5 , – OR, –SR, -S(O) 2 NR 2 , -NR 2 , -S(O) 2 R, -SiR 3 or a cyclic group selected from: a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, a 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-12 membered saturated or partially unsaturated bicyclic carbocyclic ring that is optionally bridged or spirocyclic, and a 5-12
  • R 6 is halogen, a C 1-6 aliphatic group, -SF 5 , –OR, – SR, -S(O) 2 NR 2 , -NR 2 , -S(O) 2 R, -SiR 3 or a cyclic group selected from: a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, a 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-12 membered saturated or partially unsaturated bicyclic carbocyclic ring that is optionally bridged or spirocyclic, and a 5-12 member
  • R 6 is halogen.
  • R 6 is a C 1-6 aliphatic group, -SF 5 , –OR, –SR, -S(O) 2 NR 2 , -S(O) 2 R, or a cyclic group selected from: a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, a 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-12 membered saturated or partially unsaturated bicyclic carbocyclic ring that is optionally bridged or spirocyclic, and a 5-12 membered saturated or partially
  • R 6 is a cyclic group selected from: a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, a 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the cyclic group is substituted with z instances of R B .
  • R 6 is a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring substituted with z instances of R B .
  • R 6 is a phenyl substituted with z instances of R B .
  • R 6 is a 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur substituted with z instances of R B .
  • R 6 is a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur substituted with z instances of R B .
  • R 6 is phenyl substituted with z instances of R B .
  • R 6 is fluoro substituted phenyl.
  • R 6 is -SF 5 .
  • Ring A is phenylene substituted with x instances of R 5 and R 6 is phenyl substituted with z instances of R B . In some embodiments, Ring A is phenylene substituted with x instances of R 5 and R 6 is fluoro substituted phenyl. In some embodiments, Ring A is phenylene substituted with x instances of R 5 and R 6 is -SF 5 . [0093] In some embodiments, R 6 is a 5-membered heteroaryl substituted with z instances of R B . In some embodiments, R 6 pyrrole substituted with z instances of R B . In some embodiments, R 6 pyrrole substituted with -CH 3 .
  • R 6 is isopropyl, sec-butyl, -CF 3 , -SF 5 , -CH 2 CF 3 , or -OCF 3 . In some embodiments, R 6 is -SF 5 . In some embodiments, R 6 is -CF 3 . [0095] In some embodiments, Ring A is bicyclic, m is greater than 0, and R 6 is hydrogen. In some embodiments, R 6 is not hydrogen.
  • R 6 is -F, -Br, -Cl, -SF 5 , -CF 3 , -CH 3 , -CH 2 CF 3 , -OCF 3 , -OCH 3 , - SCH 3 , ,
  • R 6 is as selected from one of the substituents of Table 1.
  • each instance of R A is independently selected from hydrogen; a C 1-6 aliphatic group optionally substituted with 1, 2, or 3 groups independently selected from halogen, -CN, -NR 2 , and -OR; halogen; –CN; –NO 2 ; –OR; - SR; -NR 2 ; -S(O) 2 R; -S(O) 2 NR 2 ; -S(O)R; -S(O)NR 2 ; -C(O)R; -C(O)OR; – C(O)NR 2 ; -C(O)N(R)OR; -OC(O)R; -OC(O)NR 2 ; -N(R)C(O)OR; -N(R)C(O)R; -N(R)C(O)OR; -N(R)C(O)R; -N(R)C(O)OR;
  • R A is hydrogen.
  • each instance of R A is independently selected from a C 1-6 aliphatic group optionally substituted with 1, 2, or 3 groups independently selected from halogen, -CN, -NR 2 , and -OR; halogen; –CN; –NO 2 ; –OR; - SR; -NR 2 ; -S(O) 2 R; -S(O) 2 NR 2 ; -S(O)R; -S(O)NR 2 ; -C(O)R; -C(O)OR; – C(O)NR 2 ; -C(O)N(R)OR; -OC(O)R; -OC(O)NR 2 ; -N(R)C(O)OR; -N(R)C(O)R; -N(R)C(O)OR; -N(R)C(O)R; -N(R)C(O)OR; -N(R)C(O)R;
  • each instance of R B is independently selected from hydrogen; a C 1-6 aliphatic group optionally substituted with 1, 2, or 3 groups independently selected from halogen, -CN, -NR 2 , and -OR; halogen; –CN; –NO 2 ; –OR; - SR; -NR 2 ; -S(O) 2 R; -S(O) 2 NR 2 ; -S(O)R; -S(O)NR 2 ; -C(O)R; -C(O)OR; – C(O)NR 2 ; -C(O)N(R)OR; -OC(O)R; -OC(O)NR 2 ; -N(R)C(O)OR; -N(R)C(O)R; -N(R)C(O)OR; -N(R)C(O)R; -N(R)C(O)OR; -N(R)C(O)R; -N(R
  • R B is hydrogen.
  • each instance of R B is independently selected a C 1-6 aliphatic group optionally substituted with 1, 2, or 3 groups independently selected from halogen, -CN, -NR 2 , and -OR; halogen; –CN; –NO 2 ; –OR; - SR; -NR 2 ; -S(O) 2 R; -S(O) 2 NR 2 ; -S(O)R; -S(O)NR 2 ; -C(O)R; -C(O)OR; – C(O)NR 2 ; -C(O)N(R)OR; -OC(O)R; -OC(O)NR 2 ; -N(R)C(O)OR; -N(R)C(O)R; -N(R)C(O)OR; -N(R)C(O)R; -N(R)C(O)OR; -N(R)C(O)R;
  • each instance of R B is independently selected a C 1-6 aliphatic group optionally substituted with 1, 2, or 3 groups independently selected from halogen, -CN, -NR 2 , and -OR. In some embodiments, each instance of R B is independently a halogen. [00104] In some embodiments, R B is as selected from one of the substituents of Table 1. [00105] In some embodiments, R 6 is a cyclic group substituted with three instances of R B , wherein R B is fluoro. In some embodiments, R 6 is a cyclic group substituted with two instances of R B , wherein R B is fluoro.
  • R 6 is a cyclic group substituted with one instance of R B , wherein R B is fluoro.
  • R 6 is a cyclic group substituted with three instances of R B , wherein R B is chloro.
  • R 6 is a cyclic group substituted with two instances of R B , wherein R B is chloro.
  • R 6 is a cyclic group substituted with one instance of R B , wherein R B is chloro.
  • R 6 is a cyclic group substituted with two instances of R B , wherein R B is -CH 3 .
  • R 4 is hydrogen and R B is independently selected at each occurrence from halogen; a C 1-6 aliphatic group optionally substituted with 1, 2, or 3 groups independently selected from halogen, -CN, -NR 2 , and -OR; -CN; -OH; -SR; and -OR.
  • R 4 is hydrogen and R B is independently selected at each occurrence from -CH 3 , - CH 2 CH 3 , isopropyl, cyclopropyl, trifluoromethyl, fluoro, chloro, OH, -CN, -OR, SR, or .
  • R 4 is hydrogen, m is 1, and R B is halogen; a C 1-6 aliphatic group optionally substituted with 1, 2, or 3 groups independently selected from halogen, -CN, -NR 2 , and -OR; -CN; -OH; -SR; and -OR.
  • R 4 is hydrogen, m is 1, and R B is -CH 3 , - CH 2 CH 3 , isopropyl, cyclopropyl, trifluoromethyl, fluoro, chloro, OH, -CN, OR, SR, or .
  • Cy’ is an optionally substituted cyclic group selected from: a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, a 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-12 membered saturated or partially unsaturated bicyclic carbocyclic ring that is optionally bridged or spirocyclic, a 5-12 membered saturated or partially unsaturated bicyclic heterocyclic ring that is optionally bridged or spirocyclic having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and an 8-10 membered bicyclic aromatic carbocyclic ring
  • Cy’ is an optionally substituted 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring. In some embodiments, Cy’ is an optionally substituted phenyl. In some embodiments, Cy’ is an optionally substituted 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Cy’ is an optionally substituted 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Cy’ is an optionally substituted 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • Cy’ is an optionally substituted 5-12 membered saturated or partially unsaturated bicyclic carbocyclic ring that is optionally bridged or spirocyclic. In some embodiments, Cy’ is an optionally substituted 5-12 membered saturated or partially unsaturated bicyclic heterocyclic ring that is optionally bridged or spirocyclic having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Cy’ is an optionally substituted 8-10 membered bicyclic aromatic carbocyclic ring. [00113] In some embodiments, Cy’ is an optionally substituted 5 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • Cy’ is an optionally substituted 5 membered monocyclic heteroaromatic ring having a sulfur atom and a nitrogen atom.
  • Cy’ is optionally substituted thiazolyl.
  • Cy’ is thiazolyl optionally substituted with 3-5 membered carbocyclyl, -CH 3 , hydroxyl substituted C 1-4 aliphatic, pyridinyl, pyrrolyl, trifluoromethyl, -CH 2 CF 3 , or the thiazolyl is substituted at two adjacent carbon atoms with two independent occurrences of R that are taken together with their intervening atoms to form a 5-6 membered saturated, partially unsaturated, or aryl ring fused to the thiazolyl, wherein the 5-6 membered ring comprises 0-2 oxygen atoms.
  • Cy’ is an optionally substituted 6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Cy’ is an optionally substituted pyridinyl.
  • Cy’ is a pyridinyl substituted with hydroxyl substituted C 1-4 aliphatic, hydroxyl substituted 3-6 membered carbocyclyl, -OCH 3 , -OCH 2 CF 3 , -OCH 2 CH 3 , -N(CH 3 )2; or the pyridinyl is substituted at two adjacent carbon atoms with two independent occurrences of R that are taken together with their intervening atoms to form a 5-6 membered saturated or partially unsaturated ring fused to the pyridinyl, wherein the 5-6 membered saturated or partially unsaturated ring is substituted with hydroxyl.
  • Cy’ is as selected from one of the substituents of Table 1.
  • Cy’’ is an optionally substituted cyclic group selected from: a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, a 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-12 membered saturated or partially unsaturated bicyclic carbocyclic ring that is optionally bridged or spirocyclic, a 5-12 membered saturated or partially unsaturated bicyclic heterocyclic ring that is optionally bridged or spirocyclic having 1-4 heteroatoms independently selected
  • Cy’’ is optionally substituted 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring. In some embodiments, Cy’’ is optionally substituted phenyl. In some embodiments, Cy’’ is optionally substituted 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Cy’’ is an optionally substituted 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Cy’’ is an optionally substituted 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • Cy’’ is an optionally substituted 5-12 membered saturated or partially unsaturated bicyclic carbocyclic ring that is optionally bridged or spirocyclic. In some embodiments, Cy’’ is an optionally substituted 5-12 membered saturated or partially unsaturated bicyclic heterocyclic ring that is optionally bridged or spirocyclic having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Cy’’ is an optionally substituted 8-10 membered bicyclic aromatic carbocyclic ring. [00118] In some embodiments, Cy’’ is as selected from one of the substituents of Table 1.
  • Cy’’’ is an optionally substituted cyclic group selected from: a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, a 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-12 membered saturated or partially unsaturated bicyclic carbocyclic ring that is optionally bridged or spirocyclic, a 5-12 membered saturated or partially unsaturated bicyclic heterocyclic ring that is optionally bridged or spirocyclic having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and an 8-10 membered bicyclic aromatic carbocyclic
  • Cy’’’ is an optionally substituted 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Cy’’’ is an optionally substituted 5-12 membered saturated or partially unsaturated bicyclic carbocyclic ring that is optionally bridged or spirocyclic. In some embodiments, Cy’’’ is an optionally substituted 5-12 membered saturated or partially unsaturated bicyclic heterocyclic ring that is optionally bridged or spirocyclic having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Cy’’’ is an optionally substituted 8-10 membered bicyclic aromatic carbocyclic ring.
  • Cy’’’ is as selected from one of the substituents of Table 1.
  • each R is independently hydrogen, -C(O)N(CH 3 ) 2 , - C(O) 2 CH 3 , -C(O) 2 C(CH 3 ) 3 , -C(O) 2 CH(CH 3 ) 2 , -S(O) 2 CH 3 , an optionally substituted C 1-6 aliphatic group, an optionally substituted cyclic group selected from: phenyl, an optionally substituted 3-7 membered saturated or partially unsaturated carbocyclic ring, an optionally substituted 3-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an optionally substituted 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and/or two R groups on the same atom are taken together with the same atom to form
  • each R is hydrogen. In some embodiments each R is independently -C(O)N(CH 3 ) 2 , -C(O) 2 CH 3 , -C(O) 2 C(CH 3 ) 3 , -C(O) 2 CH(CH 3 ) 2 , or -S(O) 2 CH 3 .
  • each R is independently an optionally substituted C 1-6 aliphatic group or an optionally substituted cyclic group selected from: an optionally substituted phenyl, an optionally substituted 3-7 membered saturated or partially unsaturated carbocyclic ring, an optionally substituted 3-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an optionally substituted 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • two R groups on the same atom are taken together with the same atom to form a cyclic group selected from: an optionally substituted 4-7 membered saturated or partially unsaturated carbocycyl, an optionally substituted 4-7 membered saturated or partially unsaturated heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and an optionally substituted 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • each R is as selected from the substituents of Table 1.
  • x is 0, 1, 2, 3, or 4. In some embodiments, x is 0. In some embodiments, x is 1.
  • x is 2. In some embodiments, x is 3. In some embodiments, x is 4. In some embodiments, x is as selected from one of the substituents of Table 1. [00127] As described generally above, m is 0, 1, 2, or 3. In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, m is as selected from one of the substituents of Table 1. [00128] As described generally above, n is 1 or 2. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is as selected from one of the substituents of Table 1. [00129] In some embodiments, n is 1 and m is 0.
  • the compound of Formula I is a compound of Formula IIIa or IIIb: wherein Ring A, Cy’, R 3 , R 4 , R 5 , R 6 , m, and x are as defined herein, both singly and in combination, and wherein R 8 is hydrogen, optionally substituted C 1-6 aliphatic group, halogen, –CN, –NO 2 , – OR, -SR, -NR 2 , -S(O) 2 R, -S(O) 2 NR 2 , -S(O)R, -S(O)NR 2 , -C(O)R, -C(O)OR, – C(O)NR 2 , -C(O)N(R)OR, -OC(O)R, -OC(O)NR 2 , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)OR, -N(R)C(O)R, -
  • the compound of Formula IVa or IVb includes compounds in which R 8 is hydrogen, -CH 3 or -CH 2 CH 3 .
  • the compound of Formula I is a compound of Formula Va or Vb: wherein Cy’, R 3 , R 4 , R 6 , and m are as defined herein, both singly and in combination, and wherein R 8 is hydrogen, optionally substituted C 1-6 aliphatic group, halogen, –CN, –NO 2 , –OR, - SR, -NR 2 , -S(O) 2 R, -S(O) 2 NR 2 , -S(O)R, -S(O)NR 2 , -C(O)R, -C(O)OR, – C(O)NR 2 , -C(O)N(R)OR, -OC(O)R, -OC(O)NR 2 , -N(R)C(O)OR, -N(N(R)OR, -OC(O
  • the compound of Formula Va or Vb includes compounds in which R 8 is hydrogen, -CH 3 or -CH 2 CH 3 .
  • the compound is of Formula Va or Vb and m is 0.
  • the compound is of Formula Va or Vb and m is 1.
  • the compound of Formula I is selected from Table 1. Table 1 identifies compounds by their IUPAC name and Table 2 lists the same compounds and shows their chemical structure. In the event of any discrepancy between Table 1’s name for a compound and Table 2’s structure for that same compound, Table 2’s compound structures will identify the compound corresponding to each respective compound number (I-#) in Table 1.
  • the disclosure provides a biotinylated compound selected from or a pharmaceutically acceptable salt thereof. It is to be understood that all compositions, methods of treatment, methods of administration of compounds, uses as medicaments, described infra which reference “compounds of the invention” or compounds of Formula I, also may include the biotinylated compounds shown supra. 4. Pharmaceutical compositions, methods of treatment and uses of compounds [00140] In another aspect, the present invention provides a pharmaceutical composition comprising a compound of the present invention, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • the pharmaceutical compositions are tablets or gelatin capsules comprising the active ingredient together with one or more of: g) diluents, e.g., lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine; h) lubricants, e.g., silica, talcum, stearic acid, its magnesium or calcium salt and/or polyethyleneglycol; for tablets also i) binders, e.g., magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone; if desired j) disintegrants, e.g., starches, agar, alginic acid or its sodium salt, or effervescent mixtures; and k) absorbents, colorants, flavors and sweeteners.
  • diluents e.g., lactose, dextrose
  • Typical approaches to solubilize compounds for parenteral administration are the optimization of the pH or the use of co-solvents (e.g. PEG300, PEG400, propylene glycol, or ethanol). If these approaches are, for any reason, not feasible, the use of surfactants may be considered (e.g. Tween® 80 or Cremophor EL®). Cyclodextrins are established as safe solubilizing agents. Compounds with a high solubility in natural oils may be solubilized in parenteral fat emulsions. [00142] There is also provided a pharmaceutical composition comprising a compound of Formula I as described herein, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers.
  • co-solvents e.g. PEG300, PEG400, propylene glycol, or ethanol.
  • surfactants e.g. Tween® 80 or Cremophor EL®
  • Cyclodextrins are established as safe solubilizing agents.
  • the compounds of Formula I of the present invention in free form or in pharmaceutically acceptable salt form, exhibit valuable pharmacological properties, e.g. WRN inhibiting properties, e.g. as indicated in vitro tests as provided in the next sections, and are therefore indicated for therapy, or for use as research chemicals, e.g. as a chemical probe, and as tool compounds.
  • WRN inhibiting properties e.g. as indicated in vitro tests as provided in the next sections
  • research chemicals e.g. as a chemical probe
  • tool compounds e.g. as a chemical probe
  • a compound of Formula I in particular II, IIIa, IIIb, IVa, IVb, Va, or Vb, as described herein.
  • Said compound can be used as a research chemical, a compound herein comprising an added biotin moeity, for example a tool compound or chemical probe, in particular for research on WRN.
  • a compound of Formula I in particular II, IIIa, IIIb, IVa, IVb, Va, or Vb, as described herein, as a research chemical, for example tool compound or chemical probe, in particular for research on WRN.
  • Cancers that may be treated by WRN inhibition include cancers that are characterized as microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR).
  • a compound of Formula I as described herein, or a pharmaceutically acceptable salt thereof may be useful in the treatment of a cancer that is characterized as microsatellite instability- high (MSI-H) or mismatch repair deficient (dMMR).
  • MSI-H microsatellite instability- high
  • dMMR mismatch repair deficient
  • said use is: for the treatment of a disease that is treated by WRN inhibition, for the treatment of cancer, for the treatment of cancer that is characterized as microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR), for the treatment of cancer that is characterized as microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR), such as colorectal, gastric, prostate, endometrial, adrenocortical, uterine, cervical, esophageal, breast, kidney and ovarian cancer, for the treatment of cancer that is characterized as microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) is selected from colorectal, gastric, prostate and endometrial cancer, or for the treatment of cancer wherein the cancer characterized as microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) is selected from uterine corpus endometrial carcinoma, colon a
  • a method of modulating WRN activity in a subject, wherein the method comprises administering to the subject a therapeutically effective amount of the compound of Formula I as described herein, in particular II, IIIa, IIIb, IVa, IVb, Va, or Vb, or a pharmaceutically acceptable salt thereof, inhibiting WRN in a subject, wherein the method comprises administering to the subject a therapeutically effective amount of the compound of Formula I as described herein, in particular II, IIIa, IIIb, IVa, IVb, Va, or Vb, or a pharmaceutically acceptable salt thereof, treating a disorder or disease which can be treated by WRN inhibition in a subject, comprising administering to the subject a therapeutically effective amount of the compound of Formula I as described herein, in particular II, IIIa, IIIb, IVa, IVb, Va, or Vb, or a pharmaceutically acceptable salt thereof, treating cancer in a subject, comprising administering to the subject a therapeutically effective amount of the compound of Formula I as described herein, in
  • the cancer characterized as microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) is selected from colorectal, gastric, prostate, endometrial, adrenocortical, uterine, cervical, esophageal, breast, kidney and ovarian cancer. More particularly, the cancer characterized as microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) is selected from colorectal, gastric, prostate and endometrial cancer.
  • Examples include uterine corpus endometrial carcinoma, colon adenocarcinoma, stomach adenocarcinoma, rectal adenocarcinoma, adrenocortical carcinoma, uterine carcinosarcoma, cervical squamous cell carcinoma, endocervical adenocarcinoma, esophageal carcinoma, breast carcinoma, kidney renal clear cell carcinoma, prostate cancer and ovarian serous cystadenocarcinoma.
  • said cancer is characterized as microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR), in the manufacture of a medicament for treatment of a disease which may be treated by WRN inhibition, wherein in particular, the cancer is characterized by microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR), for example colorectal, gastric, prostate, endometrial, adrenocortical, uterine, cervical, esophageal, breast, kidney and ovarian cancer, in particular, colorectal, gastric, prostate or endometrial cancer, or uterine corpus endometrial carcinoma, colon adenocarcinoma, stomach adenocarcinoma, rectal adenocarcinoma, adrenocortical carcinoma, uterine carcinosarcoma, cervical squamous cell carcinoma, endocervical adenocarcinoma, esophageal carcinoma, breast carcinoma
  • the subject has or is identified as having a microsatellite instable (MSI-H) cancer, e.g., in reference to a control, e.g., a normal, subject.
  • MSI-H microsatellite instable
  • the subject has MSI-H advanced solid tumors, a colorectal cancer (CRC), endometrial, uterine, stomach or other MSI-H cancer.
  • CRC colorectal
  • endometrial or stomach cancer which cancer has or is identified as having a microsatellite instability (MSI-H), e.g., in reference to a control, e.g., a normal, subject.
  • MSI-H microsatellite instable
  • the compounds can be present in the form of one of the possible stereoisomers or as mixtures thereof, for example as pure optical isomers, or as stereoisomer mixtures, such as racemates and diastereoisomer mixtures, depending on the number of asymmetric carbon atoms.
  • the present invention is meant to include all such possible stereoisomers, including racemic mixtures, diasteriomeric mixtures and optically pure forms.
  • Optically active (R)- and (S)-stereoisomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. If the compound contains a double bond, the substituent may be E or Z configuration.
  • the cycloalkyl substituent may have a cis- or trans-configuration. All tautomeric forms are also intended to be included. [00151] Any formula given herein is intended to represent unlabeled forms as well as isotopically labeled forms of the compounds, in addition to the deuteration specifically claimed in Formula I. Isotopically labeled compounds have structures depicted by the formulae given herein except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Isotopes that can be incorporated into compounds of the invention include, for example, isotopes of hydrogen.
  • isotopes particularly deuterium (i.e., 2H or D) may afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements or an improvement in therapeutic index or tolerability.
  • deuterium in this context is regarded as a substituent of a compound of the present invention.
  • concentration of deuterium may be defined by the isotopic enrichment factor.
  • isotopic enrichment factor as used herein means the ratio between the isotopic abundance and the natural abundance of a specified isotope.
  • a substituent in a compound of this invention is denoted as being deuterium, such compound has an isotopic enrichment factor for each designated deuterium atom of at least 3500 (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation).
  • isotopic enrichment factor can be applied to any isotope in the same manner as described for deuterium.
  • isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, and chlorine, such as 3H, 11C, 13C, 14C, 15N, 18F 31P, 32P, 35S, 36CI, 123I, 124I, 125I respectively.
  • the invention includes compounds that incorporate one or more of any of the aforementioned isotopes, including for example, radioactive isotopes, such as 3H and 14C, or those into which non-radioactive isotopes, such as 2H and 13C are present.
  • isotopically labelled compounds are useful in metabolic studies (with 14C), reaction kinetic studies (with, for example 2H or 3H), detection or imaging techniques, such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT) including drug or substrate tissue distribution assays, or in radioactive treatment of patients.
  • PET positron emission tomography
  • SPECT single-photon emission computed tomography
  • an 18F or labeled compound may be particularly desirable for PET or SPECT studies.
  • Isotopically-labeled compounds of the present invention can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples and Preparations using an appropriate isotopically-labeled reagents in place of the non- labeled reagent previously employed.
  • a “compound of the present invention” or a “compound of Formula I” includes a zwitterion thereof, a non-zwitterion thereof (non-charged form), or a pharmaceutically acceptable salt of said zwitterionic or non-zwitterionic form thereof.
  • “zwitterion” or “zwitterionic form” means a compound containing both positive and negatively charged functional groups.
  • cancer refers to a disease characterized by the rapid and uncontrolled growth of aberrant cells. Cancer cells can spread locally or through the bloodstream and lymphatic system to other parts of the body. Examples of various cancers are described herein and include but are not limited to colorectal, gastric, endometrial, prostate, adrenocortical, uterine, cervical, esophageal, breast, kidney, ovarian cancer and the like. [00156]
  • tumor and cancer are used interchangeably herein, e.g., both terms encompass solid and liquid, e.g., diffuse or circulating, tumors.
  • WRN inhibitor or “WRN helicase inhibitor” as used herein means a compound that inhibits Werner Syndrome RecQ DNA helicase (WRN).
  • WRN refers to the protein of Werner Syndrome RecQ DNA helicase.
  • WRN includes mutants, fragments, variants, isoforms, and homologs of full-length wild-type WRN.
  • the protein is encoded by the WRN gene (Entrez gene ID 7486; Ensembl ID ENSG00000165392).
  • WRN sequences are available at the Uniprot database under accession number Q14191.
  • Disease or condition mediated by WRN includes a disease or condition, such as cancer, which is treated by WRN inhibition. In particular this can include cancers characterized as microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR).
  • MSI-H microsatellite instability-high
  • dMMR mismatch repair deficient
  • MSI-H or dMMR tumor status for patients can be performed using, e.g., polymerase chain reaction (PCR) tests for MSI-H status or immunohistochemistry (IHC) tests for dMMR.
  • PCR polymerase chain reaction
  • IHC immunohistochemistry
  • Microsatellite instability can be found in colorectal cancer, gastric cancer and endometrial cancer in particular, but also in adrenocortical, uterine, cervical, esophageal, breast, kidney, prostate and ovarian cancers.
  • microsatellite high cancers include uterine corpus endometrial carcinoma, colon adenocarcinoma, stomach adenocarcinoma, rectal adenocarcinoma, adrenocortical carcinoma, uterine carcinosarcoma, cervical squamous cell carcinoma, endocervical adenocarcinoma, esophageal carcinoma, breast carcinoma, kidney renal clear cell carcinoma and ovarian serous cystadenocarcinoma.
  • a cancer that has “defective mismatch repair” (dMMR) or “dMMR character” includes cancer types associated with documented MLH1, PMS2, MSH2, MSH3, MSH6, MLH3, and PMS1 mutations or epigenetic silencing, microsatellite fragile sites, or other gene inactivation mechanisms, including but not limited to cancers of the lung, breast, kidney, large intestine, ovary, prostate, upper aerodigestive tract, stomach, endometrium, liver, pancreas, haematopoietic and lymphoid tissue, skin, thyroid, pleura, autonomic ganglia, central nervous system, soft tissue, pediatric rhabdoid sarcomas, melanomas and other cancers.
  • dMMR defective mismatch repair
  • a cell or cancer with “defective” mismatch repair has a significantly reduced (e.g., at least about 25%, 30%, 40%, 50%, 60%, 70%, 80% or 90% decrease) amount of mismatch repair. In some cases, a cell or cancer which is defective in mismatch repair will perform no mismatch repair.
  • pharmaceutical composition refers to a compound of the invention, or a pharmaceutically acceptable salt thereof, together with at least one pharmaceutically acceptable carrier, in a form suitable for oral or parenteral administration.
  • the term “pharmaceutically acceptable carrier” refers to a substance useful in the preparation or use of a pharmaceutical composition and includes, for example, suitable diluents, solvents, dispersion media, surfactants, antioxidants, preservatives, isotonic agents, buffering agents, emulsifiers, absorption delaying agents, salts, drug stabilizers, binders, excipients, disintegration agents, lubricants, wetting agents, sweetening agents, flavoring agents, dyes, and combinations thereof, as would be known to those skilled in the art (see, for example, Remington The Science and Practice of Pharmacy, 22nd Ed. Pharmaceutical Press, 2013, pp. 1049-1070).
  • a therapeutically effective amount of a compound of the present invention refers to an amount of the compound of the present invention that will elicit the biological or medical response of a subject, for example, reduction or inhibition of an enzyme or a protein activity, or ameliorate symptoms, alleviate conditions, slow or delay disease progression, or prevent a disease, etc.
  • the methods of the invention comprise administration of a therapeutically effective amount of a compound herein.
  • a therapeutically effective amount refers to the amount of the compound of the present invention that, when administered to a subject, is effective to (1) at least partially alleviate, prevent and/or ameliorate a condition, or a disorder or a disease (i) mediated by WRN, or (ii) associated with WRN activity, or (iii) characterized by activity (normal or abnormal) of WRN; or (2) reduce or inhibit the activity of WRN.
  • the term “a therapeutically effective amount” refers to the amount of the compound of the present invention that, when administered to a cell, or a tissue, or a non-cellular biological material, or a medium, is effective to at least partially reducing or inhibiting the activity of WRN, or reducing WRN protein levels.
  • the term “subject” refers to primates (e.g., humans, male or female), dogs, rabbits, guinea pigs, pigs, rats and mice. In certain embodiments, the subject is a primate, a rat or a mouse. In yet other embodiments, the subject is a human.
  • the term “inhibit,” “inhibition” or “inhibiting” refers to the reduction or suppression of a given condition, symptom, or disorder, or disease, or a significant decrease in the baseline activity of a biological activity or process.
  • the term “treat,” “treating” or “treatment” of any disease or disorder refers to alleviating or ameliorating the disease or disorder (i.e., slowing or arresting the development of the disease or at least one of the clinical symptoms thereof); or alleviating or ameliorating at least one physical parameter or biomarker associated with the disease or disorder, including those which may not be discernible to the patient.
  • the term “prevent,” “preventing” or “prevention” of any disease or disorder refers to the prophylactic treatment of the disease or disorder; or delaying the onset or progression of the disease or disorder.
  • a subject is “in need of” a treatment if such subject would benefit biologically, medically or in quality of life from such treatment.
  • the term “a,” “an,” “the” and similar terms used in the context of the present invention are to be construed to cover both the singular and plural unless otherwise indicated herein or clearly contradicted by the context.
  • May join means joins or does not join.
  • Any asymmetric atom (e.g., carbon or the like) of the compound(s) of the present invention can be present in racemic or enantiomerically enriched, for example the (R)-, (S)- or (R, S)-configuration.
  • each asymmetric atom has at least 50 % enantiomeric excess, at least 60 % enantiomeric excess, at least 70 % enantiomeric excess, at least 80 % enantiomeric excess, at least 90 % enantiomeric excess, at least 95 % enantiomeric excess, or at least 99 % enantiomeric excess in the (R)- or (S)- configuration.
  • Substituents at atoms with unsaturated double bonds may, if possible, be present in cis-(Z)- or trans- (E)- form.
  • a compound of the present invention can be in the form of one of the possible stereoisomers, rotamers, atropisomers, tautomers or mixtures thereof, for example, as substantially pure geometric (cis or trans) stereoisomers, diastereomers, optical isomers (antipodes), racemates or mixtures thereof.
  • Any resulting mixtures of stereoisomers can be separated on the basis of the physicochemical differences of the constituents, into the pure or substantially pure geometric or optical isomers, diastereomers, racemates, for example, by chromatography and/or fractional crystallization.
  • any resulting racemates of compounds of the present invention or of intermediates can be resolved into the optical antipodes by known methods, e.g., by separation of the diastereomeric salts thereof, obtained with an optically active acid or base, and liberating the optically active acidic or basic compound.
  • a basic moiety may thus be employed to resolve the compounds of the present invention into their optical antipodes, e.g., by fractional crystallization of a salt formed with an optically active acid, e.g., tartaric acid, dibenzoyl tartaric acid, diacetyl tartaric acid, di-O,O’-p-toluoyl tartaric acid, mandelic acid, malic acid or camphor-10-sulfonic acid.
  • Racemic compounds of the present invention or racemic intermediates can also be resolved by chiral chromatography, e.g., high pressure liquid chromatography (HPLC) using a chiral adsorbent.
  • HPLC high pressure liquid chromatography
  • compounds of Formula I that contain groups capable of acting as donors and/or acceptors for hydrogen bonds may be capable of forming co-crystals with suitable co-crystal formers.
  • These co-crystals may be prepared from compounds of Formula I by known co-crystal forming procedures. Such procedures include grinding, heating, co- subliming, co-melting, or contacting in solution compounds of Formula I with the co-crystal former under crystallization conditions and isolating co-crystals thereby formed.
  • Suitable co- crystal formers include those described in WO 2004/078163. Hence the invention further provides co-crystals comprising a compound of Formula I.
  • the compounds of the present invention can also be obtained in the form of their hydrates, or include other solvents used for their crystallization.
  • the compounds of the present invention may inherently or by design form solvates with pharmaceutically acceptable solvents (including water); therefore, it is intended that the invention embrace both solvated and unsolvated forms.
  • solvate refers to a molecular complex of a compound of the present invention (including pharmaceutically acceptable salts thereof) with one or more solvent molecules.
  • solvent molecules are those commonly used in the pharmaceutical art, which are known to be innocuous to the recipient, e.g., water, ethanol, and the like.
  • hydrate refers to the complex where the solvent molecule is water.
  • compositions or combination of the present invention may, for example, be in unit dosage of about 1-1000 mg of active ingredient(s) for a subject of about 50-70 kg.
  • Combinations refers to either a fixed combination in one dosage unit form, or a combined administration where a compound of Formula I, or a pharmaceutically acceptable salt thereof, and a combination partner (e.g. another drug as explained below, also referred to as “therapeutic agent” or “co-agent”) may be administered independently at the same time or separately within time intervals, especially where these time intervals allow that the combination partners show a cooperative, e.g. synergistic effect.
  • the single components may be packaged in a kit or separately.
  • One or both of the components may be reconstituted or diluted to a desired dose prior to administration.
  • co-administration or “combined administration” or the like as utilized herein are meant to encompass administration of the selected combination partner to a single subject in need thereof (e.g. a patient), and are intended to include treatment regimens in which the agents are not necessarily administered by the same route of administration or at the same time.
  • pharmaceutical combination as used herein means a product that results from the mixing or combining of more than one therapeutic agent and includes both fixed and non-fixed combinations of the therapeutic agents.
  • fixed combination means that the therapeutic agents, e.g.
  • non-fixed combination means that the therapeutic agents, e.g. a compound of the present invention and a combination partner, are both administered to a patient as separate entities either simultaneously, concurrently or sequentially with no specific time limits, wherein such administration provides therapeutically effective levels of the two compounds in the body of the patient.
  • cocktail therapy e.g. the administration of three or more therapeutic agents.
  • the combinations described herein can include a compound of Formula I and one or more additional therapeutic agents, e.g., one or more anti-cancer agents, cytotoxic or cytostatic agents, hormone treatment, vaccines, and/or other immunotherapies.
  • the combination is further administered or used in combination with other therapeutic treatment modalities, including surgery, radiation, cryosurgery, and/or thermotherapy.
  • Such combination therapies may advantageously utilize lower dosages of the administered therapeutic agents, thus avoiding possible toxicities or complications associated with the treatment.
  • a combination comprising a compound of Formula I as described herein, in particular II, IIIa, IIIb, IVa, IVb, Va, or Vb, or a pharmaceutically acceptable salt thereof, as described herein, and one or more additional therapeutically active agents.
  • the additional therapeutic agent is, for example, a chemical compound, peptide, antibody, antibody fragment or nucleic acid, which is therapeutically active or enhances the therapeutic activity when administered to a patient in combination with a compound of the present disclosure.
  • an additional therapeutically active agent is: an anti-cancer agent, a chemotherapy, a chemotherapy selected from anastrozole (Arimidex®), bicalutamide (Casodex®), bleomycin sulfate (Blenoxane®), busulfan (Myleran®), busulfan injection (Busulfex®), capecitabine (Xeloda®), N4-pentoxycarbonyl-5-deoxy-5- fluorocytidine, carboplatin (Paraplatin®), carmustine (BiCNU®), chlorambucil (Leukeran®), cisplatin (Platinol®), cladribine (Leustatin®), cyclophosphamide (Cytoxan® or Neosar®), cytarabine, cytosine arabinoside (Cytosar-U®), cytarabine liposome injection (DepoCyt®), dacarbazine (Arim
  • a PD-1 inhibitor an anti-PD-1 antibody molecule, a PD-1 inhibitor selected from spartalizumab (Novartis), nivolumab (Bristol-Myers Squibb), pembrolizumab (Merck & Co), pidilizumab (CureTech), MED10680 (Medimmune), cemiplimab (REGN2810, Regeneron), dostarlimab (TSR-042, Tesaro), PF-06801591 (Pfizer), tislelizumab (BGB-A317, Beigene), BGB-108 (Beigene), INCSHR1210 (Incyte), balstilimab (AGEN2035, Agenus), sintilimab (InnoVent), toripalimab (Shanghai Junshi Bioscience), camrelizumab (Jiangsu Hengrui Medicine Co.), AMP-224 (Amplimmune), penpulimab (A
  • the additional therapeutically active agent is the chemotherapy irinotecan (Camptosar®).
  • the additional therapeutically active agent is an inhibitor of PD-1, e.g., human PD-1.
  • the immunomodulator is an inhibitor of PD-L1, e.g., human PD-L1.
  • the inhibitor of PD-1 or PD-L1 is an antibody molecule to PD-1 or PD-L1.
  • the additional therapeutically active agent is an anti- PD-1 antibody molecule.
  • the PD-1 inhibitor is an anti-PD-1 antibody molecule as described in US 2015/0210769, published on July 30, 2015, entitled “Antibody Molecules to PD- 1 and Uses Thereof.”
  • a combination of a compound of Formula I or a pharmaceutically acceptable salt thereof, and a chemotherapy, and a PD-1 inhibitor are selected from those described above.
  • the chemotherapy and PD-1 inhibitor are selected from those described above.
  • the invention provides a product comprising a compound of the present invention and at least one other therapeutic agent as a combined preparation for simultaneous, separate or sequential use in therapy.
  • the therapy is the treatment of a disease or condition mediated by WRN.
  • Products provided as a combined preparation include a composition comprising the compound of Formula I and the other therapeutic agent(s) together in the same pharmaceutical composition, or the compound of the present invention and the other therapeutic agent(s) in separate form, e.g. in the form of a kit.
  • the invention provides a kit comprising two or more separate pharmaceutical compositions, at least one of which contains a compound of the present invention.
  • the kit comprises means for separately retaining said compositions, such as a container, divided bottle, or divided foil packet.
  • a kit is a blister pack, as typically used for the packaging of tablets, capsules and the like.
  • the kit of the invention may be used for administering different dosage forms, for example, oral and parenteral, for administering the separate compositions at different dosage intervals, or for titrating the separate compositions against one another. To assist compliance, the kit of the invention typically comprises directions for administration.
  • the compound of the present invention and the other therapeutic agent may be manufactured and/or formulated by the same or different manufacturers.
  • the compound of the present invention and the other therapeutic may be brought together into a combination therapy: (i) prior to release of the combination product to physicians (e.g. in the case of a kit comprising the compound of the present invention and the other therapeutic agent); (ii) by the physician themselves (or under the guidance of the physician) shortly before administration; (iii) in the patient themselves, e.g. during sequential administration of the compound of the present invention and the other therapeutic agent.
  • the invention provides the use of a compound of the present invention for treating a disease or condition mediated by WRN, wherein the medicament is prepared for administration with another therapeutic agent.
  • the invention also provides the use of another therapeutic agent for treating a disease or condition mediated by WRN, wherein the medicament is administered with a compound of the present invention.
  • the invention also provides a compound of the present invention for use in treating a disease or condition mediated by WRN, wherein the compound of the present invention is prepared for administration with another therapeutic agent.
  • the invention also provides another therapeutic agent for use in treating a disease or condition mediated by WRN, wherein the other therapeutic agent is prepared for administration with a compound of the present invention.
  • the invention also provides a compound of the present invention for use in treating a disease or condition mediated by WRN, wherein the compound of the present invention is administered with another therapeutic agent.
  • the invention also provides another therapeutic agent for use in a method of treating a disease or condition mediated by WRN, wherein the other therapeutic agent is administered with a compound of the present invention.
  • the invention also provides the use of a compound of the present invention for treating a disease or condition mediated by WRN, wherein the patient has previously (e.g. within 24 hours) been treated with another therapeutic agent.
  • the invention also provides the use of another therapeutic agent for treating a disease or condition mediated by WRN, wherein the patient has previously (e.g. within 24 hours) been treated with compound of the present invention. 5.
  • General synthetic methods of producing compounds of the disclosure [00202] Compounds of the present disclosure, in general, may be prepared by amide coupling methods known to those of skill in the art.
  • Carboxylic acid coupling partner A of Scheme 1 may be prepared according to simple methods known in the art. For example, see syntheses of intermediates 4, 15, 20, 22, and 25 infra. Those having ordinary skill in the art will be able to adapt such synthetic procedures to afford variably substituted carboxylic acids A for synthesis of the compounds of the disclosure.
  • EXAMPLES [00205] As depicted in the Examples below, in certain exemplary embodiments, compounds are prepared according to the procedures provided herein. It will be appreciated that, although the methods depict the synthesis of certain compounds of the present disclosure, the methods, and other methods known to one of ordinary skill in the art, can be applied to all compounds and subclasses and species of each of these compounds, as described herein.
  • Step 1 Synthesis of diethyl 2-(2-bromo-4-nitrophenyl)-2-methylmalonate: To a eq) in THF (20 mL) was added NaH (252 mg, 6.31 mmol, 60% dispersion in mineral oil, 1.1 eq) at 0 °C. The resulting mixture was warmed to room temperature and stirred for 0.5 hr. Then, the reaction was cooled to 0°C, 2- bromo-1-fluoro-4-nitrobenzene (1.26 g, 5.74 mmol, 1 eq) was added at 0°C. After addition, the reaction mixture was allowed to warm to room temperature and stirred for 2hrs. LCMS showed desired mass was detected.
  • Step 3 Synthesis of diethyl 2-(2-bromo-4-(lH-pyrrol-l-yl)phenyl)-2-methylmalonate: To a solution of diethyl 2-(4-amino-2-bromophenyl)-2-methylmalonate (100 mg, 291 ⁇ mol, 1 eq) in AcOH (2 mL) was added 2,5-dimethoxytetrahydrofuran (42 mg, 320 ⁇ mol 1.1 eq) at room temperature. The mixture was then irradiated under microwave at 150 °C for 15 mins. LCMS showed desired mass was detected. The mixture was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (Eluent of EtOAc/Petroleum ether) to afford the title compound. LCMS: 396.0[M+H]+.
  • Step 4 Synthesis of diethyl 3-(lH-pyrrol-l-yl)bicyclo[4.2.0]octa-l,3,5-triene-7,7- dicarboxylate: A mixture of diethyl 2-(2-bromo-4-(lH-pyrrol-l-yl)phenyl)-2-methylmalonate (30 mg, 76.09 ⁇ mol, 1 eq), diacetoxypalladium (2 mg, 8 pmol, 0.1 eq), [(t-Bu) 3 PH]BF 4 (4 mg, 15 ⁇ mol, 0.2 eq) and K 2 CO 3 (32 m g , 228 ⁇ mol, 3 eq) in DMF (1 mL) was stirred at 140 °C for 2 hrs under N 2 atmosphere.
  • Step 5 Synthesis of 3-(lH-pyrrol-l-yl)bicyclo[4.2.0]octa-l,3,5-triene-7-carboxylic acid: To a mixture of diethyl 3-(lH-pyrrol-l-yl)bicyclo[4.2.0]octa-l,3,5-triene-7,7-dicarboxylate (40 mg, 128 ⁇ mol, 1 eq) in DMSO (1 mL) was added KCN (10 mg, 153 ⁇ mol, 1.20 eq) at room temperature. Then, the resulting solution was then heated to 130 °C and stirred at 130 °C for 12 hrs. LCMS showed desired mass was detected.
  • Step 6 Synthesis of N-(l,l-dioxido-2,3-dihydrothiophen-3-yl)-N-(pyridin-4- ylmethyl)-3-(lH-pyrrol-l-yl)bicyclo[4.2.0]octa-l(6),2,4-triene-7-carboxamide: To amixture of 3- (lH-pyrrol-l-yl)bicyclo[4.2.0]octa-l,3,5-triene-7-carboxylic acid (30 mg, 141 ⁇ mol, 1 eq) and 3- ((pyridin-4-ylmethyl)amino)-2,3-dihydrothiophene 1,1-dioxide (38 mg, 169 ⁇ mol, 1.2 eq) in pyridine (1 mL) was added EDCI (54 mg, 281 ⁇ mol, 2 eq) at room temperature and then it was stirred at room temperature for 2 hrs.
  • EDCI 54 mg, 281
  • Step 3 Synthesis of (4-((2-(4-(1H-pyrrol-1-yl)phenyl)-N-(1,1-dioxido-2,3- dihydrothiophen-3-yl)acetamido)methyl)phenyl)boronic acid: A solution of 2-(4-(1H-pyrrol-1- yl)phenyl)-N-(1,1-dioxido-2,3-dihydrothiophen-3-yl)-N-(4-(4,4,5,5-tetramethyl-1,3,2- under N2 atmosphere.
  • Step 3 Synthesis of 3-(((2-(1-hydroxycyclobutyl)pyridin-4-yl)methyl)amino)-2,3- dihydrothiophene 1,1-dioxide: To a stirred mixture of 3,4-dibromotetrahydrothiophene 1,1- dioxide (2.23 g, 8.04 mmol, 2.00 eq) in MeOH (20.0 mL) was added TEA (2.03 g, 20.1 mmol, 5.00 eq) at 0 °C under N2 atmosphere. The resulting mixture was stirred for 40 min at 0 °C.
  • Step 4 Synthesis of N-(l,l-dioxido-2,3-dihydrothiophen-3-yl)-2-(2-fluoro-4-(2- methyl-lH-pyrrol-l-yl)phenyl)-N-((2-(l-hydroxycyclobutyl)pyridin-4-yl)methyl)acetamide: To a stirred mixture of 3-(((2-(l-hydroxycyclobutyl)pyridin-4-yl)methyl)amino)-2,3-dihydrothiophene 1,1-dioxide (87 mg, 296 ⁇ mol, 1.00 eq) and [2-fhuoro-4-(2-methylpyrrol-l-yl)phenyl]acetic acid (Intermediate-4) (83 mg, 355 ⁇ mol, 1.20 eq) in THF (10.0 mL) were added pyridine (94 mg, 1.18 mmol, 4.00 eq) and HATU (169 mg,
  • Step 1 Synthesis of N 1 -(1,1-dioxido-2,3-dihydrothiophen-3-yl)-2-(4'-fluoro-[1,1'- biphenyl]-4-yl)-N1-((2-(2-hydroxypropan-2-yl)pyridin-4-yl)methyl)-N3,N3-dimethylmalonamide: To a stirred mixture of 3-(dimethylamino)-2-(4'-fluoro-[1,1'-biphenyl]-4-yl)-3-oxopropanoic acid 3-(((2-(2-hydroxypropan-2-yl)pyridin-4- yl)methyl)amino)-2,3-dihydrothiophene 1,1-dioxide (Intermediate-9) (352 mg, 1.25 mmol, 2.50 eq) in DMF (8.00 mL) were added pyridine (787 mg, 9.97 mmol, 20.0 eq
  • Step 1 Synthesis of 1-(tert-butyl) 3-methyl 2-(5-bromo-3-fluoropyridin-2-yl)malonate : To a solution of 1-tert-butyl 3-methyl propanedioate (900 mg, 5.17 mmol, 1.00 eq) in THF (15. 0 mL) was added NaH (414 mg, 10.3 mmol, 2.00 eq, 60% dispersion in mineral oil) in portions o ver 30 min at 0 °C, followed by the addition of 5-bromo-2,3-difluoropyridine (1.00 g, 5.16 mmol , 1.00 eq) at 0 °C. The resulting mixture was stirred for overnight at room temperature.
  • Step 3 Synthesis of methyl 2-(5-(3,4-difluorophenyl)-3-fluoropyridin-2-yl)acetate: To 1.00 eq) and 3,4-difluorophenylboronic acid (112 mg, 710 jimol, 1.00 eq) in 1,4-dioxane (10.0 mL) and H 2 O (1.00 mL) was added K 2 CO 3 (294 mg, 2.13 mmol, 3.00 eq) and Pd(DtBPF)Cl (46 mg, 71 ⁇ mol, 0.10 eq) at room temperature under N 2 atmosphere. The mixture was stirred for 1 h at room temperature and concentrated under vacuum. The residue was purified by flash silica gel chromatography (Eluent of EtOAc/PE) to afford the title compound. LCMS: 282.1 [M+H] +
  • Step 4 Synthesis of 2-(5-(3,4-difluorophenyl)-3-fluoropyridin-2-yl)acetic acid: To a solution of methyl 2-[5-(3,4-difluorophenyl)-3-fluoropyridin-2-yl]acetate (650 mg, 2.31 mmol, 1.00 eq) in THF (10.0 mL) and H2O (2.00 mL) was added LiOH (166 mg, 6.93 mmol, 3.00 eq) at room temperature. The resulting mixture was stirred for 1 h at room temperature. The mixture was diluted with H 2 O and acidified to pH 2 ⁇ 3 with 1 N HC1 (aq.).
  • Step 5 Synthesis of 2-(5-(3,4-difluorophenyl)-3-fluoropyridin-2-yl)-N-(l,l-dioxido-2 ,3-dihydrothiophen-3-yl)-N-((2-(2-hydroxypropan-2-yl)pyridin-4-yl)methyl)acetamide: To a solu tion of [5-(3,4-difluorophenyl)-3-fluoropyridin-2-yl]acetic acid (340 mg, 1.27 mmol, 1.00 eq) an d 3-(((2-(2-hydroxypropan-2-yl)pyridin-4-yl)methyl)amino)-2,3-dihydrothiophene 1,1-dioxide (I ntermediate-9) (359 mg, 1.27 mmol, 1.00 eq) in pyridine (5.00 mL) was added HATH (967 mg, 2 .54 m
  • Step 1 Synthesis of 7-((tert-butyldimethylsilyl)oxy)-4-chloro-6,7-dihydro-5H- cyclopenta[b]pyridine: To a solution of 4-chloro-6,7-dihydro-5H-cyclopenta[b]pyridin-7-ol (200 mg, 1.18 mmol, 1.00 eq) and imidazole (322 mg, 4.73 mmol, 4.00 eq) in DCM (5.00 mL) was added TBSCl (713 mg, 4.73 mmol, 4.00 eq) at 0 °C. After addition, the resulting mixture was heated to 60 °C and stirred at 60 °C for 4 h.
  • Step 1 Synthesis of methyl 2-(1H-pyrazol-1-yl)-2-(3,3',4'-trifluoro-[1,1'-biphenyl]-4- yl)acetate: A mixture of 1H-pyrazole (193 mg, 2.84 mmol, 3.00 eq) and K2CO3 (393 mg, 2.84 mmol, 3.00 eq) in DMF (8.00 mL) was stirred for 30 min at room temperature.
  • Step 2 Synthesis of 2-(1H-pyrazol-1-yl)-2-(3,3',4'-trifluoro-[1,1'-biphenyl]-4-yl)acetic acid: To a solution of methyl 2-(1H-pyrazol-1-yl)-2-(3,3',4'-trifluoro-[1,1'-biphenyl]-4-yl)acetate eq) in THF (5.00 mL) and H 2 O (1.00 mL) was added LiOH (29 mg, 1.21 mmol, 3.00 eq) at 0 °C. The resulting mixture was stirred for 1 h at room temperature.
  • Step 1 Synthesis of 2-(3,4'-difluoro-[1,1'-biphenyl]-4-yl)-N-(1,1-dioxido-2,3- dihydrothiophen-3-yl)-N-((4-(2-hydroxypropan-2-yl)thiazol-2-yl)methyl)acetamide: To a solution of 3-(((4-(2-hydroxypropan-2-yl)thiazol-2-yl)methyl)amino)-2,3-dihydrothiophene 1,1- eq) and 2-(3,4'-difluoro-[1,1'-biphenyl]-4- for 1 h at room temperature and concentrated under reduced pressure.
  • Step 2 Synthesis of methyl 2,2-difluoro-2-(3,3',4'-trifluoro-[1,1'-biphenyl]-4-yl)acetat ol, 1.00 eq) in DCM (8.00 mL) was added DAST (263 mg, 1.63 mmol, 2.00 eq) at room temp. un der N 2 atmosphere. The mixture was stirred for 1 h at room temperature. The resulting mixture w as concentrated under reduced pressure. The residue was purified by Prep-TLC (Eluent of EtOAc /PE) to afford the title compound. [00291] Step 3.
  • Step 1 Synthesis of N-((4-cyclopropylthiazol-2-yl)methyl)-2-(4-(3,4-difluorophenyl)- 1H-pyrazol-1-yl)-N-(1,1-dioxido-2,3-dihydrothiophen-3-yl)acetamide: To a solution of [4-(3,4- cyclopropylthiazol-2-yl)methyl)amino)-2,3-dihydrothiophene 1,1-dioxide (Intermediate-21) (227 room temperature under N2 atmosphere. The resulting mixture was stirred for 1 h at room temperature and concentrated under reduced pressure.
  • Step 2 Synthesis of ethyl 5-(2-methyl-1H-pyrrol-1-yl)-2,3-dihydrobenzofuran-2- carboxylate: To a mixture of ethyl 5-amino-2,3-dihydrobenzofuran-2-carboxylate (400 mg, 1.93 mmol, 1.00 eq) and 4-oxopentanal (289 mg, 2.90 mmol, 1.50 eq) in AcOH (1.00 mL) and H 2 O (4.00 mL) was added anhydrous NaOAc (158 mg, 1.93 mmol, 1.00 eq) at room temperature.
  • 6-sulfaneyl)phenyl)acetate (1.00 g, 3.14 mmol, 1.00 eq) and 4-methylbenzenesulfonyl azide (743 mg, 3.77 mmol, 1.20 eq) in ACN (10.0 mL) was added DBU (717 mg, 4.71 mmol, 1.50 eq) at 0°C, then the mixture was stirred at room temperature for 16 h. The reaction mixture was quenched with saturated NH 4 Cl (aq.) solution (50 mL), extracted with EtOAc (2 x 50 mL).
  • 6 -sulfaneyl)phenyl)acetic acid A 6-sulfaneyl)phenyl)acetate (688 mg, 1.98 mmol, 1.00 eq) in FA (5.00 mL) was stirred at room temperature for 2 h. The reaction was concentrated under vacuum, then the residue was dissolved in saturated NaHCO3 solution (50 mL). The resulting mixture was washed with EtOAc (2 x 30 mL). The aqueous phase was adjusted to pH around 2 with 1 N HCl (aq.), then extracted with EtOAc (2 x 30 mL).
  • Step 1 Synthesis of N-(1,1-dioxido-2,3-dihydrothiophen-3-yl)-2-(4-(4-fluorophenyl)- 2-oxopyridin-1(2H)-yl)-N-(pyridin-4-ylmethyl)acetamide: To a mixture of 2-(4-(4-fluorophenyl)- eq) in pyridine (2.00 mL) was added EDCI (232 mg, 1.21 mmol, 2.00 eq) at room temperature. The mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated under vacuum.
  • Step 1 Synthesis of methyl 6-(4-fluorophenyl)-1H-indole-3-carboxylate: To a mixture of methyl 6-bromo-1H-indole-3-carboxylate (5.00 g, 19.7 mmol, 1.00 eq) and (4- fluorophenyl)boronic acid (5.51 g, 39.4 mmol, 2.00 eq) in 1,4-dioxane (50.0 mL) and H 2 O (5.00 mL) were added KF (3.43 g, 59.0 mmol, 3.00 eq) and Pd(amphos)Cl 2 (1.39 g, 1.97 mmol, 0.10 eq) at room temperature.
  • KF 3.43 g, 59.0 mmol, 3.00 eq
  • Pd(amphos)Cl 2 (1.39 g, 1.97 mmol, 0.10 eq
  • Step 2 Synthesis of 1-(tert-butyl) 3-methyl 6-(4-fluorophenyl)-1H-indole-1,3- dicarboxylate: To a mixture of methyl 6-(4-fluorophenyl)-1H-indole-3-carboxylate (5.30 g, 19.7 mmol, 1.00 eq) and (Boc)2O (4.73 g, 21.6 mmol, 1.10 eq) in DCM (50.0 mL) was added TEA mixture was stirred at room temperature for 1 h. The reaction mixture was poured into ice-water (100 mL) and extracted with EtOAc (3 x 80 mL).
  • Step 3 Synthesis of 1-(tert-butyl) 3-methyl 6-(4-fluorophenyl)indoline-1,3- dicarboxylate: To a mixture of 1-(tert-butyl) 3-methyl 6-(4-fluorophenyl)-1H-indole-1,3- dicarboxylate (6.50 g, 17.6 mmol, 1.00 eq) in EtOAc (30.0 mL) and MeOH (40.0 mL) was added dry Pd/C (2.00 g, 5%). The mixture was degassed and purged with H 2 gas (15 psi). Then it was stirred at 30 °C for 15 h. The mixture was filtered, and the filtrate was concentrated under vacuum.
  • Step 4 Synthesis of 1-(tert-butoxycarbonyl)-6-(4-fluorophenyl)indoline-3-carboxylic acid: To a mixture of 1-(tert-butyl) 3-methyl 6-(4-fluorophenyl)indoline-1,3-dicarboxylate (1.40 g, 3.77 mmol, 1.00 eq) in THF (10.0 mL), MeOH (5.00 mL) and H 2 O (5.00 mL) was added LiOH*H 2 O (316 mg, 7.54 mmol, 2.00 eq) at room temperature.
  • Step 6 Synthesis of N-(1,1-dioxido-2,3-dihydrothiophen-3-yl)-6-(4-fluorophenyl)-N- ((2-methoxypyridin-4-yl)methyl)indoline-3-carboxamide: To a mixture of tert-butyl 3-((1,1- dioxido-2,3-dihydrothiophen-3-yl)((2-methoxypyridin-4-yl)methyl)carbamoyl)-6-(4- 2 atmosphere. The mixture was then stirred at room temperature for 1 h. The reaction mixture was diluted with ice-water (10 mL) and extracted with DCM (3 x 10 mL).
  • Step 1 Synthesis of ethyl 2-(4-bromo-2-oxopyridin-1(2H)-yl)acetate: To a mixture of 4-bromopyridin-2(1H)-one (2.00 g, 11.5 mmol, 1.00 eq) and ethyl 2-bromoacetate (2.11 g, 12.6 mmol, 1.40 mL, 1.10 eq) in DMF (20.0 mL) was added K2CO3 (4.77 g, 34.5 mmol, 3.00 eq) at 30 °
  • Step 2 Synthesis of ethyl 2-(4-(3,4-difluorophenyl)-2-oxopyridin-1(2H)-yl)acetate: To a mixture of ethyl 2-(4-bromo-2-oxopyridin-1(2H)-yl)acetate (500 mg, 1.92 mmol, 1.00 eq) and (3,4-difluorophenyl)boronic acid (304 mg, 1.92 mmol, 1.00 eq) in dioxane (10.0 mL) and H 2 O (1.00 mL) was added Pd(amphos)Cl 2 3.00 eq) at room temperature under Ar atmosphere, then the reaction was stirred at 50 °C for 12 h.
  • Step 3 Synthesis of 2-(4-(3,4-difluorophenyl)-2-oxopyridin-1(2H)-yl)acetic acid: To a mixture of ethyl 2-(4-(3,4-difluorophenyl)-2-oxopyridin-1(2H)-yl)acetate (500 mg, 1.70 mmol, 1.00 eq) in H 2 O (6.00 mL), MeOH (3.00 mL) and THF (3.00 mL) was added 1 N NaOH (aq.) solution (6.00 mL, 6 mmol, 3.53 eq) at room temperature and the resulting mixture was stirred at room temperature for 1 h.
  • Step 4 Synthesis of (R)-2-(4-(3,4-difluorophenyl)-2-oxopyridin-1(2H)-yl)-N-(1,1- dioxido-2,3-dihydrothiophen-3-yl)-N-((2-(2-hydroxypropan-2-yl)pyridin-4-yl)methyl)acetamide: 1.00 eq) and (R)-3-(((2-(2-hydroxypropan-2-yl)pyridin-4-yl)methyl)amino)-2,3-dihydrothiophene for 1 h.
  • Step 2 Synthesis of 3-(benzylamino)-5-bromo-2,3-dihydrothiophene 1,1-dioxide: To a solution of 4-(benzylamino)-2,3-dibromotetrahydrothiophene 1,1-dioxide (1.50 g, 3.92 mmol, 1.00 eq) in EtOAc (30.0 mL) was added TEA (435 mg, 4.31 mmol, 1.10 eq) dropwise at 0 °C and then stirred for 30 min at 0 °C.
  • Step 1 Synthesis of 3-(((2-methoxypyridin-4-yl)methyl)amino)-2,3-dihydrothiophene 1,1-dioxide: To a solution of 3,4-dibromotetrahydrothiophene 1,1-dioxide (3.00 g, 10.8 mmol, 1.30 eq) in MeOH (45.0 mL) was added TEA (4.20 g, 41.5 mmol, 5.00 eq) and 1-(2- methoxypyridin-4-yl)methanamine (1.14 g, 8.30 mmol, 1.00 eq) at 0 °C under N 2 atmosphere.
  • Step 1 Synthesis of methyl 2-(4-bromophenyl)-3-(dimethylamino)-3-oxopropanoate: To a solution of methyl 2-(4-bromophenyl)acetate (2.00 g, 8.73 mmol, 1.00 eq) and dimethylcarbamyl chloride (1.13 g, 10.5 mmol, 1.20 eq) in THF (30.0 mL) were added a solution of LiHMDS in THF (26.0 mL, 26.0 mmol, 3.00 eq, 1 M) dropwise at -78 °C under N 2 atmosphere.
  • Step 1 Synthesis of tert-butyl ((4-(2-hydroxypropan-2-yl)thiazol-2- yl)methyl)carbamate: A solution of ethyl 2- ⁇ [(tert-butoxycarbonyl)amino]methyl ⁇ -1,3-thiazole-4- carboxylate (5.00 g, 17.5 mmol, 1.00 eq) in THF (70.0 mL) was degassed three times with N 2 , and then was cooled to -78 °C. To the solution was added a solution of MeMgBr in THF (65 mL, 65 mmol, 3.70 eq, 1 M) dropwise at -78 °C.
  • MeMgBr MeMgBr in THF
  • Step 3 Synthesis of 3-(((4-(2-hydroxypropan-2-yl)thiazol-2-yl)methyl)amino)-2,3- dihydrothiophene 1,1-dioxide: To a solution of 3,4-dibromotetrahydrothiophene 1,1-dioxide (3.43 g, 12.3 mmol, 1.20 eq) in MeOH (20.0 mL) was added TEA (5.20 g, 51.4 mmol, 5.00 eq) at 0 °C.
  • Step 1 Synthesis of 3,3',4'-trifluoro-[1,1'-biphenyl]-4-carbaldehyde: To a mixture of 4-bromo-2-fluorobenzaldehyde (15.0 g, 73.9 mmol, 1.00 eq) and 3,4-difluorophenylboronic acid (11.7 g, 73.9 mmol, 1.00 eq) in 1,4-dioxane (150 mL) and H 2 O (15.0 mL) were added Pd(DtBPF)Cl 2 (4.82 g, 7.39 mmol, 0.10 eq) and K 2 CO 3 (30.6 g, 222 mmol, 3.00 eq) at room temperature.
  • Pd(DtBPF)Cl 2 4.82 g, 7.39 mmol, 0.10 eq
  • K 2 CO 3 30.6 g, 222 mmol, 3.00 eq
  • Step 3 Synthesis of methyl 2-hydroxy-2-(3,3',4'-trifluoro-[1,1'-biphenyl]-4-yl)acetate : To a stirred mixture of 2-hydroxy-2-(3,3',4'-trifluoro-[1,1'-biphenyl]-4-yl)acetic acid (10.8 g, 38.3 mmol, 1.00 eq) in MeOH (100 mL) was added SOCl 2 (6.83 g, 57.4 mmol, 1.50 eq) in 10 min at 0 °C.
  • Step1 Synthesis of tert-butyl ((4-cyclopropylthiazol-2-yl)methyl)carbamate: To a mixture of tert-butyl (2-amino-2-thioxoethyl)carbamate (5.00 g, 26.28 mmol, 1.00 eq) in EtOH (50 mL) was added 2-bromo-1-cyclopropylethan-1-one (5.57 g, 34.2 mmol, 1.30 eq) and Na 2 CO 3 (2.79 g, 26.3 mmol, 1.00 eq) at room temperature. Then the reaction was heated to 80 °C and stirred at 80 °C for 15 hours.
  • 2-bromo-1-cyclopropylethan-1-one 5.57 g, 34.2 mmol, 1.30 eq
  • Na 2 CO 3 2.79 g, 26.3 mmol, 1.00 eq
  • Step 2 Synthesis of 4-cyclopropylthiazol-2-yl)methanamine, hydrochloride acid: To a solution of tert-butyl ((4-cyclopropylthiazol-2-yl)methyl)carbamate (5.30 g, 20.8 mmol, 1.00 eq) in DCM (5 mL) was added 4 M HCl solution in 1,4-dioxane (15 mL) at room temperature. The mixture was stirred at room temperature for 2 hours. After completion, the mixture was concentrated in vacuum to afford the title compound, which was used in the next step without further purification. LCMS: 155.1 [M+1] + .
  • Step 3 Synthesis of 3-(((4-cyclopropylthiazol-2-yl)methyl)amino)-2,3- dihydrothiophene 1,1-dioxide: To a mixture of 3-bromo-2,3-dihydrothiophene 1,1-dioxide (Intermediate-26) (2.50 g, 12.7 mmol, 1.00 eq) and (4-cyclopropylthiazol-2-yl)methanamine (1.96 g, 12.7 mmol, 1.00 eq) in MeOH (30 mL) was added TEA (3.85 g, 38.1 mmol, 5.30 mL, 3.00 eq) at room temperature.
  • Step 1 Synthesis of 1-(tert-butyl) 3-methyl 2-(3,3',4'-trifluoro-[1,1'-biphenyl]-4- yl)malonate: To a stirred mixture of methyl 2-(3,3',4'-trifluoro-[1,1'-biphenyl]-4-yl)acetate (Intermediate-12) (10.0 g, 35.7 mmol, 1.00 eq) in THF (60.0 mL) was added a solution of LiHMDS in THF (84.0 mL, 84.0 mmol, 2.35 eq, 1M) dropwise at -78 °C under N 2 atmosphere.
  • Step 1 Synthesis of (S)-1,1-dioxido-2,3-dihydrothiophen-3-yl (4-nitrophenyl) carbonate (single isomer): To a solution of (S)-3-hydroxy-2,3-dihydrothiophene 1,1-dioxide (Intermediate-27) (54.0 g, 402 mmol, 1.00 eq) in DCM (1000 mL) was added 4-nitrophenyl then the mixture was filtered, and the filter cake was collected and stirred in H 2 O (3 volumes) at room temperature. The residue was purified by recrystallization by acetone (5 volumes) to afford the title compound. LCMS: 321.9 [M+Na] + .
  • 2-(2-hydroxypropan-2-yl)isonicotinonitrile To a solution of 2- acetylisonicotinonitrile (30.0 g, 205 mmol, 1.00 eq) in THF (300 mL) was added MeMgBr in THF (75.3 mL, 226 mmol, 1.10 eq, 3 M) dropwise at -42 ⁇ -38°C during 1 h. The reaction mixture was stirred at -40°C for another 4 h, then quenched by saturated NH4Cl (300 mL) at -40°C and extracted with EtOAc (200 mL*2).
  • DNA duplex was synthesized at BGI (Shenzhen, China) and was composed of strand 1 with the sequence 5’- GCACTGGCCGTCGTTTTACGGTCG-3’ (SEQ ID NO.: 1) and strand 2 with the sequence 5’- TCCAAGTAAAACGACGGCCAGTGC-3’ (SEQ ID NO.: 2).
  • DNA strands were annealed by heating to 95 o C for 5 minutes followed by slow cooling to room temperature.
  • Compounds in 100% DMSO (0.1 l) were spotted into a 384-well white polystyrene Optiplate-384 (Perkin Elmer) assay plate using a LabCyte Echo 550 (Agilent).
  • DMSO 0.1 l was added to columns 12, rows A-H and column 24, rows I-P for the maximum signal control.
  • Compound NSC-617145 0.1 l was added to columns 12, rows I-P and 24, rows A-H for the minimum signal control (100% inhibition).
  • the reaction was initiated by the addition of 5 l 2X substrate mixture in assay buffer and incubated for 60 minutes at 25 o C.
  • the final concentrations of the assay components were 0.15 nM WRN, 5 M ATP, and 0.1 nM DNA duplex.
  • the final DMSO concentration was 1% and the reference compound concentration (NSC-617145) used for the minimal signal control was 20 M.
  • the reaction was stopped by the addition of the ADP-Glo Kit components (Promega) as directed and the relative luminescence units (RLU) were read on an Envision 2104 (Perkin Elmer).
  • WRN protein production [00436] Molecular Biology and virus production.
  • the DNA encoding human Werner helicase (Uniprot Q14191, amino acids 517-1235 with L1074F point mutation) was generated with codon- optimization for E.coli expression and subcloned into the pFastBac vector with a TEV cleavable 8xHis tag (WRN-BV08).
  • the baculovirus from the expression plasmid WRN-BV08 was generated from transfection and amplification following the manufacturer’s instructions.
  • the WRN protein was purified using the following protocol.
  • the cell pellets were thawed and resuspended in buffer A (50 mM Tris, pH 7.5, 500 mM NaCl, 1 mM TCEP, 10% Glycerol) supplemented with 0.5% CHAPS, 1mM PMSF, 1 ⁇ g/mL Leupeptin, 1 ⁇ g/mL Pepstatin, and the Pierce Universal Nuclease and cocktail tablet. Cleared lysates were loaded onto a Ni Sepharose TM excel column and washed with buffer A and bound protein was eluted with buffer A supplemented with 300 mM imidazole.
  • the eluted protein was dialyzed against buffer A and digested by His-tagged TEV (1:5 ratio) overnight at 4°C. ZnCl 2 was added into the sample at final 15 M before loading onto a second Ni Sepharose TM excel column.
  • Untagged WRN protein was eluted from the column with buffer A supplemented with 20 mM imidazole, dialyzed overnight into buffer B (50 mM Tris, pH 7.5, 1 mM TCEP, 10% Glycerol) supplemented with 150 mM NaCl and loaded onto a Heparin column. Proteins were eluted with a step gradient of buffer B supplemented with 150 mM, 200 mM, 300 mM and 500 mM NaCl.
  • Compounds with an IC 50 less than or equal to 0.5 ⁇ M are designated as “A.” Compounds with an IC 50 greater than 0.5 ⁇ M and less than or equal to 5.0 ⁇ M are designated as “B.” Compounds with an IC50 greater than 5.0 ⁇ M and less than or equal to 10.0 ⁇ M are designated as “C.” Compounds with an IC 50 greater than 10.0 ⁇ M and less than or equal to 50.0 ⁇ M are designated as “D.” Compounds with an IC 50 greater than 50.0 ⁇ M are designated as “E.” Table 3

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Abstract

La présente invention concerne des composés contenant une sulfone cyclique, notamment des composés de formule I : (I) des sels pharmaceutiquement acceptables de ceux-ci, et des compositions de ceux-ci, ainsi que des méthodes de traitement de cancers tels que ceux impliquant une protéine WRN.
PCT/US2024/024124 2023-04-11 2024-04-11 Inhibiteurs de wrn à base de sulfone vinylique cyclique Pending WO2024215923A2 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2025215527A2 (fr) 2024-04-10 2025-10-16 Novartis Ag Combinaisons pharmaceutiques et leurs utilisations

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EP2061797A4 (fr) * 2006-08-29 2010-07-28 Univ Boston Procédés thérapeutiques utilisant des molécules se liant à wrn
US20210371855A1 (en) * 2018-06-15 2021-12-02 Ideaya Biosciences, Inc. Methods of inhibiting proliferative cells
WO2023062575A1 (fr) * 2021-10-14 2023-04-20 Ideaya Biosciences, Inc. Composés de sulfone de vinyle cyclique utilisés en tant qu'inhibiteurs de wrn

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2025215527A2 (fr) 2024-04-10 2025-10-16 Novartis Ag Combinaisons pharmaceutiques et leurs utilisations

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