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WO2024229121A1 - Compounds for treating cancer - Google Patents

Compounds for treating cancer Download PDF

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Publication number
WO2024229121A1
WO2024229121A1 PCT/US2024/027254 US2024027254W WO2024229121A1 WO 2024229121 A1 WO2024229121 A1 WO 2024229121A1 US 2024027254 W US2024027254 W US 2024027254W WO 2024229121 A1 WO2024229121 A1 WO 2024229121A1
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alkyl
optionally substituted
compound
independently selected
cycloalkyl
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French (fr)
Inventor
Brett Busch
Brandon REINUS
William F. Vernier
Martin INDARTE
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GENESIS THERAPEUTICS Inc
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GENESIS THERAPEUTICS Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/44—Iso-indoles; Hydrogenated iso-indoles
    • C07D209/46—Iso-indoles; Hydrogenated iso-indoles with an oxygen atom in position 1
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
    • C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
    • C07D407/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
    • C07D407/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 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

Definitions

  • This disclosure provides compounds of Formula (I) and pharmaceutically acceptable salts thereof, that inhibit phosphatidylinositol 4, 5 -bisphosphate 3-kinase (PI3K) isoform alpha (PI3Ka).
  • PI3K phosphatidylinositol 4, 5 -bisphosphate 3-kinase
  • Phosphatidylinositol 4,5-bisphosphate 3-kinase (PI3K) isoform alpha (PI3Ka), encoded by the PIK3CA gene is a part of the PI3K/AKT/T0R signaling network and is altered in several human cancers.
  • PI3K pathway Activation of the PI3K pathway occurs in approximately 30-50% human cancers and contributes to resistance to various anti-cancer therapies.
  • PI3K inhibitors have been problematic for several reasons, in particular, inability to specifically inhibit signaling by mutant PI3Ka while sparing wild-type PI3Ka, and the related dose-limiting toxicities that prevent sustained PI3K pathway suppression.
  • Hanker et al., Cancer Discovery, April 2019;9: 482-491. See, Hanker et al., Cancer Discovery, April 2019;9: 482-491.
  • selectively targeting PI3Ka represents an approach for the treatment of proliferative disorders such as cancer.
  • Some embodiments provide a compound of Formula (I): or a pharmaceutically acceptable salt thereof, wherein:
  • R 1 is hydrogen, cyano, C3-C6 cycloalkyl, C1-C6 alkyl optionally substituted with phenyl optionally substituted with halogen, C1-C6 thioalkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C1-C6 alkoxy alkyl;
  • R 1 is hydrogen or C1-C6 alkyl; or R 1 and R 1 , together with the carbon atom to which they are attached form a C3-C10 cycloalkyl;
  • each R A and R B is independently selected from hydrogen, hydroxyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C2-C6 alkenyl, cyano, 4-10 membered heterocyclyl, and C1-C6 alkyl optionally substituted with hydroxyl or C1-C6 alkoxy, orR A and R B together with the nitrogen
  • R 4 is hydrogen, C1-C6 alkyl, or acrylamido
  • R 5A and R 5B are independently selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, and C1-C6 hydroxyalkyl;
  • R 6 is hydrogen, halogen, or C1-C6 alkyl
  • R Y1 is -SO2(C1-C6 alkyl), hydroxyl, or C1-C6 alkyl optionally substituted with oxo; and each R F and R G is independently selected from hydrogen, phenyl, and C1-C6 alkyl optionally substituted with oxo or -NR A R B .
  • composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.
  • a method for treating cancer in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as provided herein.
  • a method for treating cancer in a subject in need thereof comprising (a) determining that the cancer is associated with a dysregulation of a PIK3CA gene, a PI3Ka protein, or expression or activity or level of any of the same; and (b) administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as provided herein.
  • a method of treating a PI3Ka-associated disease in a subject comprising administering to a subject identified or diagnosed as having a PI3Ka-associated disease a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as provided herein.
  • This disclosure also provides a method of treating a PI3Ka-associated disease in a subject, comprising: determining that the cancer in the subject is a PI3Ka-associated disease; and administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as provided herein.
  • a method of treating a PI3Ka-associated cancer in a subject comprising administering to a subject identified or diagnosed as having a PI3Ka-associated cancer a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as provided herein.
  • This disclosure also provides a method of treating a PI3Ka-associated cancer in a subject, comprising: determining that the cancer in the subject is a PI3Ka-associated cancer; and administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as provided herein.
  • a method of treating a subject comprising administering a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as provided herein, to a subject having a clinical record that indicates that the subject has a dysregulation of &PIK3CA gene, a PI3Ka protein, or expression or activity or level of any of the same.
  • This disclosure also provides a method for inhibiting PI3Ka in a mammalian cell, comprising contacting the mammalian cell with an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.
  • inhibitor or “inhibition of' means to reduce by a measurable amount, or to prevent entirely (e.g., 100% inhibition).
  • terapéuticaally effective amount means an amount of compound that, when administered to a subject in need of such treatment, is sufficient to (i) treat a PI3Ka protein- associated disease, (ii) attenuate, ameliorate, or eliminate one or more symptoms of the particular disease, or (iii) delay the onset of one or more symptoms of the particular disease described herein.
  • pharmaceutically acceptable salt refers to a formulation of a compound that does not cause significant irritation to an organism to which it is administered and does not abrogate the biological activity and properties of the compound.
  • the term “subject” refer to any animal, including mammals such as primates (e g., humans), mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, primates, and humans.
  • the subject is a human.
  • the subject has experienced and/or exhibited at least one symptom of the disease to be treated and/or prevented.
  • treat or “treatment” refer to therapeutic or palliative measures.
  • Beneficial or desired clinical results include, but are not limited to, alleviation, in whole or in part, of symptoms associated with a disease, diminishment of the extent of disease, stabilized (i.e., not worsening) state of disease, delay or slowing of disease progression, amelioration or palliation of the disease state (e.g., one or more symptoms of the disease), and remission (whether partial or total), whether detectable or undetectable.
  • Treatment can also mean prolonging survival as compared to expected survival if not receiving treatment.
  • halogen refers to fluoro (F), chloro (Cl), bromo (Br), or iodo (I).
  • hydroxyl refers to an -OH radical.
  • cyano refers to a -CN radical.
  • alkyl refers to a saturated acyclic hydrocarbon radical that may be a straight chain or branched chain, containing the indicated number of carbon atoms.
  • Ci-io indicates that the group may have from 1 to 10 (inclusive) carbon atoms in it.
  • Non-limiting examples include methyl, ethyl, z.w-propyl, tert-butyl, n-hexyl.
  • saturated as used in this context means only single bonds present between constituent carbon atoms and other available valences occupied by hydrogen and/or other substituents as defined herein.
  • haloalkyl refers to an alkyl, in which one or more hydrogen atoms is/are replaced with an independently selected halogen.
  • alkoxy refers to an -O-alkyl radical (e.g., -OCH3).
  • alkoxyalkyl refers to an -alkyl-O-alkyl radical (e.g., -CH2CH2OCH3)
  • thioalkyl refers to an -S-alkyl radical (e.g., -SCH3) or an -alkyl- S-alkyl radical (e.g., -CH2CH2SCH3).
  • hydroxyalkyl refers to an alkyl, in which one or more hydrogen atoms is/are replaced with hydroxyl.
  • aryl refers to a 6-20 membered all carbon ring system wherein at least one ring in the system is aromatic (e.g., 6-carbon monocyclic, 10-carbon bicyclic, or 14-carbon tricyclic aromatic ring system).
  • aromatic e.g., 6-carbon monocyclic, 10-carbon bicyclic, or 14-carbon tricyclic aromatic ring system.
  • aryl groups include phenyl, naphthyl, tetrahydronaphthyl, 2,3- dihydro-lH-indene, and the like.
  • cycloalkyl refers to cyclic saturated hydrocarbon groups having, e.g., 3 to 20 ring carbons, preferably 3 to 16 ring carbons, and more preferably 3 to 12 ring carbons or 3-10 ring carbons or 3-6 ring carbons.
  • Examples of cycloalkyl groups include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
  • Cycloalkyl may include multiple fused and/or bridged rings.
  • Non-limiting examples of fused/bridged cycloalkyl includes: bicyclofl.1.0]butane, bicyclo[2.1.0]pentane, bicyclofl. l. l]pentane, bicyclo[3.1.0]hexane, bicyclo[2.1.1]hexane, bicyclo[3.2.0]heptane, bicyclo[4.1.0]heptane, bicyclo[2.2.1]heptane, bicyclo[3.1.1]heptane, bicyclo[4.2.0]octane, bicyclo[3.2. l]octane, bicyclo[2.2.2]octane, and the like.
  • Cycloalkyl also includes spirocyclic rings (e.g., spirocyclic bicycle wherein two rings are connected through just one atom).
  • spirocyclic cycloalkyls include spiro[2.2]pentane, spiro[2.5]octane, spiro[3.5]nonane, spiro[3.5]nonane, spiro[3.5]nonane, spiro[4.4]nonane, spiro[2.6]nonane, spiro[4.5]decane, spiro[3.6]decane, spiro[5.5]undecane, and the like.
  • saturated as used in this context means only single bonds present between constituent carbon atoms.
  • heteroaryl refers to a ring system having 5 to 20 ring atoms, such as 5, 6, 9, 10, or 14 ring atoms; wherein at least one ring in the system contains one or more heteroatoms independently selected from the group consisting of N, O, S, Si, and B, and at least one ring in the system is aromatic (but does not have to be a ring which contains a heteroatom, e.g. tetrahydroisoquinolinyl, e.g., tetrahydroquinolinyl).
  • Heteroaryl groups can include monocyclic, bridged, fused, and spiro ring systems, so long as one ring in the system is aromatic.
  • heteroaryl examples include thienyl, pyridinyl, furyl, oxazolyl, oxadiazolyl, pyrrolyl, imidazolyl, triazolyl, thiodiazolyl, pyrazolyl, isoxazolyl, thiadiazolyl, pyranyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, thiazolyl benzothienyl, benzoxadiazolyl, benzofuranyl, benzimidazolyl, benzotriazolyl, cinnolinyl, indazolyl, indolyl, isoquinolinyl, isothiazolyl, naphthyridinyl, purinyl, thienopyridinyl, pyrido[2,3-J]pyrimidinyl, pyrrolo[2,3-/>]pyridinyl, quinazoliny
  • the heteroaryl is selected from thienyl, pyridinyl, furyl, pyrazolyl, imidazolyl, isoindolinyl, pyranyl, pyrazinyl, and pyrimidinyl.
  • heteroaryl also includes aromatic lactams, aromatic cyclic ureas, or vinylogous analogs thereof, in which each ring nitrogen adjacent to a carbonyl is tertiary (i.e., all three valences are occupied by non-hydrogen substituents), such as one or more
  • heterocyclyl refers to a saturated or partially unsaturated ring systems with 3- 16 ring atoms (e.g., 3-8 membered monocyclic, 5-12 membered bicyclic, or 10-14 membered tricyclic ring system) having at least one heteroatom selected from O, N, S, Si, and B, wherein one or more ring atoms may be substituted by 1-3 oxo (forming, e.g., a lactam) and one or more N or S atoms may be substituted by 1-2 oxido (forming, e.g., an N-oxide, an S-oxide, or an S,S-dioxide), valence permitting.
  • Heterocyclyl groups include monocyclic, bridged, fused, and spiro ring systems.
  • heterocyclyl groups include piperazinyl, pyrrolidinyl, dioxanyl, morpholinyl, tetrahydrofuranyl, tetrahydropyridyl, dihydropyrazinyl, dihydropyridyl, dihydropyrrolyl, dihydrofuranyl, dihydrothiophenyl, and the like.
  • Heterocyclyl may include multiple fused and bridged rings.
  • Non-limiting examples of fused/bridged heteorocyclyl includes: 2-azabicyclo[ 1.1.0]butane, 2-azabicyclo[2.1.0]pentane, 2-azabicyclo[l.l.l]pentane, 3- azabicyclo[3.1.0]hexane, 5-azabicyclo[2.1.
  • Heterocyclyl also includes spirocyclic rings (e.g., spirocyclic bicycle wherein two rings are connected through just one atom).
  • spirocyclic heterocyclyls include 2-azaspiro[2.2]pentane, 4-azaspiro[2.5]octane, 1- azaspiro[3.5]nonane, 2-azaspiro[3.5]nonane, 7-azaspiro[3.5]nonane, 2-azaspiro[4.4]nonane, 6- azaspiro[2.6]nonane, l,7-diazaspiro[4.5]decane, 7-azaspiro[4.5]decane 2,5- diazaspiro[3.6]decane, 3-azaspiro[5.5]undecane, 2-oxaspiro[2.2]pentane, 4-oxaspiro[2.5]octane, l-oxaspiro[3.5]n
  • heterocyclyloxy refers to an -O-heterocyclyl radical (e.g., ).
  • aralkyl refers to an aryl group, as defined herein, connected to the remainder of the molecule via a divalent C1-C6 alkyl group, as described herein.
  • Non-limiting examples of an aralkyl group are benzyl, ethylphenyl, methylnaphthyl, and the like.
  • heteroarylkyl refers to a heteroaryl group, as defined herein, connected to the remainder of the molecule via a divalent C1-C6 alkyl group, as described herein.
  • Non-limiting examples of an aralkyl group are methylpyridyl, ethylpyrimidinyl, methylimidazolyl, and the like.
  • aromatic rings include: benzene, pyridine, pyrimidine, pyrazine, pyridazine, pyridone, pyrrole, pyrazole, oxazole, thioazole, isoxazole, isothiazole, and the like.
  • a ring when a ring is described as being “partially unsaturated”, it means said ring has one or more additional degrees of unsaturation (in addition to the degree of unsaturation attributed to the ring itself; e.g., one or more double or tirple bonds between constituent ring atoms), provided that the ring is not aromatic.
  • additional degrees of unsaturation in addition to the degree of unsaturation attributed to the ring itself; e.g., one or more double or tirple bonds between constituent ring atoms
  • examples of such rings include: cyclopentene, cyclohexene, cycloheptene, dihydropyridine, tetrahydropyridine, dihydropyrrole, dihydrofuran, dihydrothiophene, and the like.
  • rings and cyclic groups e.g., aryl, heteroaryl, heterocyclyl, cycloalkyl, and the like described herein
  • rings and cyclic groups encompass those having fused rings, including those in which the points of fusion are located (i) on adjacent ring atoms (e.g., [x.x.O] ring systems, in which 0 represents a zero atom bridge (e.g., single ring atom (spiro-fused ring systems) ( r (iii) a contiguous array of ring atoms (bridged ring systems having all bridge lengths > 0) (e.g.,
  • atoms making up the compounds of the present embodiments are intended to include all isotopic forms of such atoms.
  • Isotopes include those atoms having the same atomic number but different mass numbers.
  • isotopes of hydrogen include tritium and deuterium
  • isotopes of carbon include 13 C and 14 C.
  • a compound containing the moiety encompasses the tautomeric form containing the moiety: pyridinyl or pyrimidinyl moiety that is described to be optionally substituted with hydroxyl encompasses pyridone or pyrimidone tautomeric forms.
  • each center may independently be of R-configuration or S-configuration or a mixture thereof.
  • the compounds provided herein may be enantiomerically pure, enantiomerically enriched, racemic mixture, diastereomerically pure, diastereomerically enriched, or a stereoisomeric mixture.
  • each double bond may independently be E or Z a mixture thereof.
  • This disclosure provides compounds of Formula (I) and pharmaceutically acceptable salts thereof, that inhibit phosphatidylinositol 4,5 -bisphosphate 3-kinase (PI3K) isoform alpha (PI3Ka). These compounds are useful for treating a disease in which increased PI3Ka activation contributes to the pathology, symptoms, and/or progression of the disease (e.g., cancer) in a subject.
  • PI3K phosphatidylinositol 4,5 -bisphosphate 3-kinase
  • PI3Ka phosphatidylinositol 4,5 -bisphosphate 3-kinase
  • Some embodiments provide a compound of Formula (I): or a pharmaceutically acceptable salt thereof, wherein:
  • R 1 is hydrogen, cyano, C3-C6 cycloalkyl, C1-C6 alkyl optionally substituted with phenyl optionally substituted with halogen, C1-C6 thioalkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C1-C6 alkoxy alkyl;
  • R 1 is hydrogen or C1-C6 alkyl; or R 1 and R 1 , together with the carbon atom to which they are attached form a C3-C10 cycloalkyl;
  • each R A and R B is independently selected from hydrogen, hydroxyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C2-C6 alkenyl, cyano, 4-10 membered heterocyclyl, and C1-C6 alkyl optionally substituted with hydroxyl or C1-C6 alkoxy, orR A and R B together with the nitrogen
  • R 4 is hydrogen, C1-C6 alkyl, or acrylamido
  • R ?A and R 5B are independently selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, and
  • R 6 is hydrogen, halogen, or C1-C6 alkyl
  • R Y1 is -SO 2 (C1-C6 alkyl), hydroxyl, or C1-C6 alkyl optionally substituted with oxo; and each R F and R G is independently selected from hydrogen, phenyl, and C1-C6 alkyl optionally substituted with oxo or -NR A R B .
  • the compound of Formula (I) or a pharmaceutically acceptable salt thereof is a compound of Formula (I- A): or a pharmaceutically acceptable salt thereof, wherein:
  • R 1 is hydrogen, cyano, C3-C6 cycloalkyl, C1-C6 alkyl optionally substituted with phenyl optionally substituted with halogen, C1-C6 thioalkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C1-C6 alkoxy alkyl;
  • R 4 is hydrogen, C1-C6 alkyl, or acrylamido
  • R 5A and R 5B are independently selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, and C1-C6 hydroxyalkyl;
  • R 6 is hydrogen, halogen, or C1-C6 alkyl
  • R Y1 is -SO2(C1-C6 alkyl) or C1-C6 alkyl optionally substituted with oxo; and each R F and R G is independently selected from hydrogen, phenyl, and C1-C6 alkyl optionally substituted with oxo or -NR A R B .
  • R 1 is hydrogen
  • R 1 is cyano
  • R 1 is C3-C6 cycloalkyl. In some embodiments, R 1 is cyclopropyl or cyclobutyl.
  • R 1 is C1-C6 alkyl optionally substituted with phenyl optionally substituted with halogen. In some embodiments, R 1 is C1-C6 alkyl substituted with phenyl optionally substituted with halogen. In some embodiments, R 1 is C1-C6 alkyl substituted with phenyl substituted with halogen. In some embodiments, R 1 is para-fluorobenzyl. In some embodiments, R 1 is C1-C6 alkyl substituted with phenyl. In some embodiments, R 1 is benzyl. In some embodiments, R 1 is ethyl- 1 -phenyl or ethyl-2-phenyl. In some embodiments, R 1 is C1-C6 alkyl. In some embodiments, R 1 is methyl, ethyl, or isopropyl. In some embodiments, R 1 is methyl.
  • R 1 is C1-C6 thioalkyl. In some embodiments, R 1 is C1-C3 thioalkyl. In some embodiments, R 1 is thiomethyl, thioethyl, or thiopropyl. In some embodiments, R 1 is methyl-thiomethyl, methyl-thioethyl, or ethyl-thiom ethyl. In some embodiments, R 1 is thiomethyl.
  • R 1 is C1-C6 haloalkyl. In some embodiments, R 1 is C1-C3 haloalkyl. In some embodiments, R 1 is C1-C3 fluoroalkyl. In some embodiments, R 1 is CF3. In some embodiments, R 1 is CHF2.
  • R 1 is C1-C6 alkoxy. In some embodiments, R 1 is C1-C3 alkoxy. In some embodiments, R 1 is -OCH3, -OCH2CH3, or -OCH2CH2CH3. In some embodiments, R 1 is - OCH3.
  • R 1 is C1-C6 alkoxyalkyl. In some embodiments, R 1 is C1-C3 alkoxyalkyl. In some embodiments, R 1 is -CH2OCH3, -CH2OCH2CH3, or -CH2CH2OCH3. In some embodiments, R 1 is CH2OCH3.
  • R 1 is hydrogen
  • R 1 is C1-C6 alkyl. In some embodiments, R 1 is methyl. In some embodiments, R 1 and R 1 , together with the carbon atom to which they are attached form a C3-C10 cycloalkyl. In some embodiments, R 1 and R 1 , together with the carbon atom to which they are attached form a cyclopropyl.
  • R 2 is C6-C12 aryl optionally substituted with 1-4 independently selected R 2A . In some embodiments, R 2 is phenyl optionally substituted with 1-4 independently selected R 2A . In some embodiments, R 2 is phenyl substituted with 1 or 2 independently selected R 2A . In some embodiments, R 2 is phenyl substituted with 1 R 2A . In some embodiments, R 2 is phenyl substituted with 2 independently selected R 2A . In some embodiments, R 2 is phenyl optionally substituted with 3 independently selected R 2A . In some embodiments, R 2 is phenyl.
  • R 2 is 2,3-dihydro-lH-indenyl optionally substituted with 1-4 independently selected R 2A . In some embodiments, R 2 is 2,3-dihydro-lH-indenyl substituted with 1 or 2 independently selected R 2A . In some embodiments, R 2 is 2,3-dihydro-lH-indenyl substituted with 1 R 2A . In some embodiments, R 2 is 2,3-dihydro-lH-indenyl substituted with 2 independently selected R 2A . In some embodiments, R 2 is 2,3-dihydro-lH-indenyl optionally substituted with 3 independently selected R 2A . In some embodiments, R 2 is 2,3-dihydro-lH- indenyl.
  • R 2 is 5-10 membered heteroaryl optionally substituted with 1-4 independently selected R 2A . In some embodiments, R 2 is 5-10 membered heteroaryl substituted with 1 or 2 independently selected R 2A . In some embodiments, R 2 is 5-10 membered heteroaryl substituted with 1 R 2A . In some embodiments, R 2 is 5-10 membered heteroaryl substituted with 2 independently selected R 2A . In some embodiments, R 2 is 5-10 membered heteroaryl optionally substituted with 3 independently selected R 2A . In some embodiments, R 2 is 5-10 membered heteroaryl.
  • R 2 is 6 membered heteroaryl optionally substituted with 1-4 independently selected R 2A . In some embodiments, R 2 is 6 membered heteroaryl substituted with 1 or 2 independently selected R 2A . In some embodiments, R 2 is 6 membered heteroaryl substituted with 1 R 2A . In some embodiments, R 2 is 6 membered heteroaryl substituted with 2 independently selected R 2A . In some embodiments, R 2 is 6 membered heteroaryl optionally substituted with 3 independently selected R 2A . In some embodiments, R 2 is 6 membered heteroaryl.
  • R 2 is 9 membered heteroaryl optionally substituted with 1-4 independently selected R 2A . In some embodiments, R 2 is 9 membered heteroaryl substituted with 1 or 2 independently selected R 2A . In some embodiments, R 2 is 9 membered heteroaryl substituted with 1 R 2A . In some embodiments, R 2 is 9 membered heteroaryl substituted with 2 independently selected R 2A . In some embodiments, R 2 is 9 membered heteroaryl optionally substituted with 3 independently selected R 2A . In some embodiments, R 2 is 9 membered heteroaryl.
  • the heteroaryl of R 2 is pyridinyl, pyrimidinyl, pyridazinyl, indole, indazole, azaindole, azaindazole, indoline, azaindoline, isoindoline, azaisoindoline, benzimidazolyl, benzoxazolyl, benzothiazolyl, benzoisoxazolyl, benzisothiazolyl, quinolinyl, 6,7- dihydro-5H-cyclopenta[c]pyridinyl, 6,7-dihydro-5H-cyclopenta[b]pyridinyl, chromanyl, 3,4- dihydro-2H-112-quinolinyl, 5,6,7,8-tetrahydroquinazolinyl, 6,7-dihydro-5H- cyclopenta[c]pyridinyl, 3,4-dihydro-2H-pyr
  • the heteroaryl of R 2 is pyridinyl or pyrimidinyl. In some embodiments, the heteroaryl of R 2 is indole, indazole, azaindole, azaindazole, indoline, azaindoline, isoindoline, or azaisoindoline.
  • the heteroaryl of R 2 is 6,7-dihydro-5H-cyclopenta[c]pyridinyl, 6,7-dihydro-5H- cyclopenta[b]pyridinyl, chromanyl, 3,4-dihydro-2H-112-quinolinyl, 5,6,7,8- tetrahydroquinazolinyl, 6,7-dihydro-5H-cyclopenta[c]pyridinyl, 3,4-dihydro-2H-pyrano[2,3- b]pyridinyl, 3,4-dihydro-2H-pyrano[2,3-c]pyridinyl, 3,4-dihydro-2H-pyrano[3,2-b]pyridinyl, 7,8- dihydro-6H-pyrano[3,2-d]pyrimidinyl, or 5,6,7,8-tetrahydroquinazolinyl.
  • the heteroaryl of R 2 is 6,7-dihydro-5H-cyclopenta[c]pyridinyl. In some embodiments, the heteroaryl of R 2 is 6,7-dihydro-5H-cyclopenta[b]pyridinyl. In some embodiments, the heteroaryl of R 2 is chromanyl. In some embodiments, the heteroaryl of R 2 is 3,4-dihydro-2H-112-quinolinyl, 5,6,7,8-tetrahydroquinazolinyl, or 6,7-dihydro-5H-cyclopenta[c]pyridinyl.
  • the heteroaryl of R 2 is 3,4-dihydro-2H-112-quinolinyl. In some embodiments, the heteroaryl of R 2 is 5,6,7,8-tetrahydroquinazolinyl. In some embodiments, the heteroaryl of R 2 is 6,7-dihydro-5H- cyclopenta[c]pyridinyl. In some embodiments, the heteroaryl of R 2 is 4-dihydro-2H-pyrano[2,3- b]pyridinyl.
  • the heteroaryl of R 2 is 3,4-dihydro-2H-pyrano[2,3-c]pyridinyl, or 5,6,7,8-tetrahydroquinazolinyl, In some embodiments, the heteroaryl of R 2 is 3,4-dihydro-2H- pyrano[3,2-b]pyridinyl. In some embodiments, the heteroaryl of R 2 is 7,8-dihydro-6H-pyrano[3,2- d]pyrimidinyl, In some embodiments, the heteroaryl of R 2 is 5,6,7,8-tetrahydroquinazolinyl.
  • R 2 is 4-10 membered heterocyclyl optionally substituted with 1-4 independently selected R 2A . In some embodiments, R 2 is 4-10 membered heterocyclyl substituted with 1 or 2 independently selected R 2A . In some embodiments, R 2 is 4-10 membered heterocyclyl substituted with 1 R 2A . In some embodiments, R 2 is 4-10 membered heterocyclyl substituted with 2 independently selected R 2A . In some embodiments, R 2 is 4-10 membered heterocyclyl optionally substituted with 3 independently selected R 2A . In some embodiments, R 2 is 4-10 membered heterocyclyl.
  • R 2 is 5-8 membered heterocyclyl optionally substituted with 1-4 independently selected R 2A . In some embodiments, R 2 is 5-8 membered heterocyclyl substituted with 1 or 2 independently selected R 2A . In some embodiments, R 2 is 5-8 membered heterocyclyl substituted with 1 R 2A . In some embodiments, R 2 is 5-8 membered heterocyclyl substituted with 2 independently selected R 2A . In some embodiments, R 2 is 5-8 membered heterocyclyl optionally substituted with 3 independently selected R 2A . In some embodiments, R 2 is 5-8 membered heterocyclyl.
  • the heterocyclyl of R 2 is piperidinyl, piperazinyl, octahydrocyclopenta[c]pyranyl, octahydrocyclopenta[b]pyranyl, 2-oxabicyclo[2.1.1]hexanyl, 2- oxabicyclo[3.1.1]heptanyl, or morpholinyl.
  • the heterocyclyl of R 2 is octahydrocyclopenta[c]pyranyl.
  • the heterocyclyl of R 2 is octahydrocyclopenta[b]pyranyl.
  • the heterocyclyl of R 2 is 2- oxabicyclo[2.1.1]hexanyl.
  • the heterocyclyl of R 2 is 2- oxabicyclo[3.1.1]heptanyl.
  • R 2 is C4-C10 cycloalkyl optionally substituted with 1-4 independently selected R 2A . In some embodiments, R 2 is C4-C10 cycloalkyl substituted with 1 or 2 independently selected R 2A . In some embodiments, R 2 is C4-C10 cycloalkyl substituted with 1 R 2A . In some embodiments, R 2 is C4-C10 cycloalkyl substituted with 2 independently selected R 2A . In some embodiments, R 2 is C4-C10 cycloalkyl optionally substituted with 3 independently selected R 2A . In some embodiments, R 2 is C4-C10 cycloalkyl.
  • R 2 is C5-C7 cycloalkyl optionally substituted with 1-4 independently selected R 2A . In some embodiments, R 2 is C5-C7 cycloalkyl substituted with 1 or 2 independently selected R 2A . In some embodiments, R 2 is 5C5-C7 cycloalkyl substituted with 1 R 2A . In some embodiments, R 2 is C5-C7 cycloalkyl substituted with 2 independently selected R 2A . In some embodiments, R 2 is C5-C7 cycloalkyl optionally substituted with 3 independently selected R 2A . In some embodiments, R 2 is C5-C7 cycloalkyl.
  • the cycloalkyl of R 2 is cyclopentyl, [1.1. l]bicyclopentyl, octahydro-
  • the cycloalkyl of R 2 is octahydro- IH-indenyl. In some embodiments, the cycloalkyl of R 2 is bicyclo[2.1.1]hexanyl. In some embodiments, the cycloalkyl of R 2 is bicyclo[3.1.0]hexanyl.
  • R 2 is C1-C6 aralkyl optionally substituted with 1-4 independently selected R 2A . In some embodiments, R 2 is C1-C6 aralkyl. In some embodiments, R 2 is C1-C6 aralkyl substituted with 1-4 independently selected R 2A . In some embodiments, R 2 is benzyl substituted with 1-4 independently selected R 2A .
  • 1, 2, 3, or 4 of R 2A are independently halogen. In some embodiments, 1, 2, or 3 of R 2A are independently fluoro or chloro. In some embodiments, 1 or 2 of R 2A are independently fluoro or chloro.
  • 1, 2, 3, or 4 of R 2A are independently cyano. In some embodiments, 1 or 2 of R 2A are cyano.
  • 1, 2, 3, or 4 of R 2A are independently hydroxyl. In some embodiments, 1 or 2 of R 2A are hydroxyl.
  • R 2A are independently -NR A R B . In some embodiments, 1 or 2 of R 2A are independently -NR A R B .
  • 1, 2, 3, or 4 of R 2A are independently O in some embodiments.
  • R 2A 1, 2, 3, or 4 of R 2A are independently -SC>2R F . In some embodiments, 1 or 2 of R 2A are independently -SC>2R F .
  • R 2A are independently -NHSChR F . In some embodiments, 1 or 2 of R 2A are independently -NHSC>2R F .
  • R 2A are independently -S02NR F R G . In some embodiments, 1 or 2 of R 2A are independently -SO2NR F R G .
  • R 2A are independently C1-C6 haloalkyl. In some embodiments, 1 or 2 of R 2A are independently C1-C3 haloalkyl. In some embodiments, 1 or 2 of R 2A are trifluoromethyl.
  • 1, 2, 3, or 4 of R 2A are independently C1-C6 hydroxyalkyl. In some embodiments, 1 or 2 of R 2A are independently C1-C3 hydroxyalkyl.
  • 1, 2, 3, or 4 of R 2A are independently 5-10 membered heteroaryl.
  • 1 of R 2A is 5-6 membered heteroaryl.
  • 1, 2, 3, or 4 of R 2A are independently 4-10 membered heterocyclyl. In some embodiments, 1 of R 2A is 4-10 membered heterocyclyl.
  • 1, 2, 3, or 4 of R 2A are independently C1-C6 alkyl. In some embodiments, 1, 2, or 3 of R 2A are independently C1-C3 alkyl. In some embodiments, 1, 2, or 3 of R 2A are methyl. In some embodiments, 1 or 2 of R 2A are independently C1-C6 alkyl. In some embodiments, 1 or 2 of R 2A are independently C1-C3 alkyl. In some embodiments, 1 or 2 of R 2A are methyl.
  • 1, 2, 3, or 4 of R 2A are independently C1-C6 alkoxy substituted with -NR A R B or 4-10 membered heterocyclyl.
  • 1, 2, 3, or 4 of R 2A are independently C1-C6 alkoxy.
  • 1, 2, 3, or 4 of R 2A are independently C3-C6 cycloalkyl optionally substituted with 4-10 membered heterocyclyl optionally substituted with C1-C6 alkyl.
  • 1, 2, 3, or 4 of R 2A are independently C3-C6 cycloalkyl substituted with 4-10 membered heterocyclyl optionally substituted with C1-C6 alkyl.
  • 1, 2, 3, or 4 of R 2A are independently C3-C6 cycloalkyl substituted with 4-10 membered heterocyclyl substituted with C1-C6 alkyl.
  • 1, 2, 3, or 4 of R 2A are independently C3-C6 cycloalkyl substituted with 4-10 membered heterocyclyl.
  • R 2A are independently C3-C6 cycloalkyl. In some embodiments, 1 or 2 of R 2A are independently C3-C6 cycloalkyl.
  • R 2 is substituted with 1 R 2A . In some embodiments, R 2 is substituted with 2 independently selected R 2A . In some embodiments, R 2 is substituted with 3 independently selected R 2A . In some embodiments, R 2 is substituted with 4 independently selected R 2A .
  • R 2 is piperidinyl substituted with 1-2 independently selected R 2A . In some embodiments, R 2 is piperidinyl substituted with 2-4 independently selected R 2A . In some embodiments, R 2 is morpholinyl substituted with 2-4 independently selected R 2A . In some embodiments, R 2 is morpholinyl. In some embodiments, R 2 is piperazinyl substituted with 1-2 independently selected R 2A .
  • R 2 is phenyl substituted with 1-2 independently selected R 2A . In some embodiments, R 2 is pyridinyl substituted with 1-2 independently selected R 2A .
  • R 2 is indolyl substituted with 1-2 independently selected R 2A . In some embodiments, R 2 is indazolyl substituted with 1-2 independently selected R 2A . In some embodiments, R 2 is 7-azaindolyl substituted with 1-2 independently selected R 2A . In some embodiments, R 2 is 7-azaindazolyl substituted with 1-2 independently selected R 2A . In some embodiments, R 2 is l,2-dihydro-3H-indazol-3-one substituted with 1-2 independently selected R 2A . In some embodiments, R 2 is isoindolinyl substituted with 1-2 independently selected R 2A . In some embodiments, R 2 is isoindolinyl.
  • R 2 is 2-indolinone substituted with 1-2 independently selected R 2A .
  • R 2 is beznimidazolyl substituted with 1-2 independently selected R 2A .
  • R 2 is imidazopyridinyl substituted with 1-2 independently selected R 2A .
  • R 2 is l,3-dihydro-2H-benzo[d]imidazol-2- onyl substituted with 1-2 independently selected R 2A .
  • R 2 is [l,2,4]triazolo[l,5-a]pyridine substituted with 1-2 independently selected R 2A .
  • one R 2A is C1-C6 alkyl, C1 -C6 haloalkyl, C1-C6 hydroxyalkyl, cyano, or hydroxyl
  • X is a bond
  • X is CH2.
  • X is CH(CH3).
  • X is C(CH3)2.
  • one of R 3A and R 3B is hydrogen and the other of R 3A and R 3B is Cl- C6 alkyl. In some embodiments, one of R 3A and R 3B is hydrogen and the other of R 3A and R 3B is methyl. In some embodiments, each of R 3A and R 3B is hydrogen. In some embodiments, each of R 3A and R 3B is an independently selected C1-C6 alkyl. In some embodiments, each of R 3A and R 3B is methyl.
  • one of R 3A and R 3B is hydrogen and the other of R 3A and R 3B is C 1- C6 alkoxy. In some embodiments, one of R 3A and R 3B is C1-C6 alkyl and the other of R 3A and R 3B is C1-C6 alkoxy. In some embodiments, R 3A is C1-C6 alkoxy. In some embodiments, R 3A is Cl- C3 alkoxy. In some embodiments, R 3A is -OCH3, -OCH2CH3, or -OCH2CH2CH3. In some embodiments, R 3A is -OCH3.
  • one of R 3A and R 3B is hydrogen and the other of R 3A and R 3B is Cl- C6 haloalkyl. In some embodiments, one of R 3A and R 3B is C1-C6 alkyl and the other of R 3A and R 3B is C1-C6 haloalkyl. In some embodiments, R 3A is C1-C6 haloalkyl. In some embodiments, R 3A is C1-C3 haloalkyl. In some embodiments, R 3A is C1-C3 fluoroalkyl. In some embodiments, R 3A is CF3. In some embodiments, R 3A is -CHF2.
  • R 3A and R 3B together with the carbon and nitrogen atoms, respectively, to which they are attached together form a 4-8 membered heterocyclyl group. In some embodiments, R 3A and R 3B , together with the carbon and nitrogen atoms, respectively, to which they are attached together form a 5-6 membered heterocyclyl group.
  • Y is phenyl optionally substituted with R ⁇ naphthyl substituted with R Y , or 5-10 membered heteroaryl substituted with R Y .
  • Y is phenyl optionally substituted with 1-3 independently selected R Y . In some embodiments, Y is phenyl substituted with 1 or 2 independently selected R Y . In some embodiments, Y is phenyl substituted with 1 R Y . In some embodiments, Y is phenyl substituted with 2 independently selected R Y . In some embodiments, Y is phenyl optionally substituted with 3 independently selected R Y . In some embodiments, Y is phenyl.
  • Y is naphthyl optionally substituted with 1-3 independently selected R 3 . In some embodiments, Y is naphthyl substituted with 1 or 2 independently selected R Y . In some embodiments, Y is naphthyl substituted with 1 R Y . In some embodiments, Y is naphthyl substituted with 2 independently selected R Y . In some embodiments, Y is naphthyl optionally substituted with 3 independently selected R ⁇ In some embodiments, Y is naphthyl.
  • Y is 5-10 membered heteroaryl optionally substituted with 1-3 independently selected R Y . In some embodiments, Y is 5-10 membered heteroaryl substituted with 1 or 2 independently selected R ⁇ In some embodiments, Y is 5-10 membered heteroaryl substituted with 1 R Y . In some embodiments, Y is 5-10 membered heteroaryl substituted with 2 independently selected R Y . In some embodiments, Y is 5-10 membered heteroaryl optionally substituted with 3 independently selected RV In some embodiments, Y is 5-10 membered heteroaryl.
  • Y is 6 membered heteroaryl optionally substituted with 1-3 independently selected R ⁇ In some embodiments, Y is 6 membered heteroaryl substituted with 1 or 2 independently selected R Y . In some embodiments, Y is 6 membered heteroaryl substituted with 1 R Y . In some embodiments, Y is 6 membered heteroaryl substituted with 2 independently selected R Y . In some embodiments, Y is 6 membered heteroaryl optionally substituted with 3 independently selected R Y . In some embodiments, Y is 6 membered heteroaryl. In some embodiments, the 6 membered heteroaryl of Y is pyridyl (e.g., 3-pyridyl).
  • Y is 9 membered heteroaryl optionally substituted with 1-3 independently selected R ⁇ In some embodiments, Y is 9 membered heteroaryl substituted with 1 or 2 independently selected R Y . In some embodiments, Y is 9 membered heteroaryl substituted with 1 R ⁇ Tn some embodiments, Y is 9 membered heteroaryl substituted with 2 independently selected R Y . In some embodiments, Y is 9 membered heteroaryl optionally substituted with 3 independently selected R Y . In some embodiments, Y is 9 membered heteroaryl.
  • 1, 2, or 3 of R y is independently halogen. In some embodiments, 1, 2, or 3 of R Y is independently chloro or fluoro. In some embodiments, 1 or 2 of R Y is independently chloro or fluoro.
  • R Y is hydroxyl. In some embodiments, 1 or 2 of R Y is hydroxyl.
  • R Y is cyano. In some embodiments, 1 or 2 of R' is cyano.
  • 1, 2, or 3 of R? is independently C1-C6 haloalkyl. In some embodiments, 1 or 2 of R? is independently C1-C3 haloalkyl. In some embodiments, 1 or 2 ofR 4 is trifluorom ethyl.
  • R Y is independently C1-C6 alkoxy. In some embodiments, 1 or 2 of R y is independently C1-C3 alkoxy. In some embodiments, 1 or 2 of R Y is methoxy.
  • R Y is independently C1-C6 haloalkoxy. In some embodiments, 1 or 2 of R Y is independently C1-C3 haloalkoxy. In some embodiments, 1 or 2 of R Y is trifluoromethoxy.
  • 1, 2, or 3 of R 4 is independently C1-C6 hydroxyalkyl. In some embodiments, 1 or 2 of R Y is independently C1-C3 hydroxyalkyl. In some embodiments, 1 or 2 of R Y is independently mono-hydroxyl C1-C3 alkyl. In some embodiments, 1 or 2 of R Y is independently di-hydroxyl C2-C3 alkyl.
  • R Y is independently -CO2R 4 . In some embodiments, 1 or 2 of R Y is independently -CChR A . In some embodiments, 1 of R 1 is -CO2R A . In some embodiments, Y is substituted with 1 R Y , and R 1 is -CChR A In some embodiments, Y is substituted with 1 R Y , and R Y is -CO2H.
  • R Y is independently -SO2NR F R G . In some embodiments, 1 or 2 of R y is independently -SO2NR F R G . In some embodiments, 1 of R Y is -SO2NR F R G . In some embodiments, Y is substituted with 1 R Y , and R Y is -SO2NR F R G .
  • R Y is independently -NHS02R F . In some embodiments, 1 or 2 of R? is independently -NHS02R F . In some embodiments, 1 ofR Y is -NHSO2R F . In some embodiments, Y is substituted with 1 R Y , and R Y is -NHSO2R F .
  • 1, 2, or 3 of R y is independently -SO2(C1-C6 alkyl). In some embodiments, 1 or 2 of R Y is independently -SO2(C1-C6 alkyl). In some embodiments, 1 of R Y is -SO2(C1-C6 alkyl). In some embodiments, 1 or 2 of R Y is -SO2CH3. In some embodiments, 1 of R Y is -SO2CH3. In some embodiments, Y is substituted with 1 R Y , and R y is -SO2CH3.
  • 1, 2, or 3 of R Y is independently 5-6 membered heteroaryl. In some embodiments, 1 of R? is 5-6 membered heteroaryl. In some embodiments, Y is substituted with 1 R Y , and R Y is 5-6 membered heteroaryl.
  • 1, 2, or 3 of R Y is independently heteroaralkyl. In some embodiments, 1 of R Y is independently heteroaralkyl.
  • 1, 2, or 3 of R Y is independently C1-C6 alkyl optionally substituted with -CO2R A or 5-6 membered heteroaryl optionally substituted with R Y1 . In some embodiments, 1, 2, or 3 of R Y is independently C 1-C6 alkyl substituted with -CO2R A or 5-6 membered heteroaryl optionally substituted with R Y1 . In some embodiments, 1, 2, or 3 of R Y is independently C1-C6 alkyl substituted with -CChR A or 5-6 membered heteroaryl substituted with R Y1 .
  • 1, 2, or 3 of R‘ is independently C1-C6 alkyl substituted with CC>2R A or 5-6 membered heteroaryl.
  • Y is substituted with 1 R ⁇ and R Y is C1-C6 alkyl substituted with -CChR A .
  • Y is substituted with 1 R Y , and R Y is C1-C6 alkyl substituted with -CO2H.
  • 1 or 2 of R ⁇ is independently C1-C6 alkyl optionally substituted with -C02R A or 5-6 membered heteroaryl optionally substituted with R y h
  • 1 or 2 of R Y is independently C1-C6 alkyl substituted with -C02R A or 5-6 membered heteroaryl optionally substituted with R Y1 .
  • 1 or 2 of R Y is independently C1-C6 alkyl substituted with -C02R A or 5-6 membered heteroaryl substituted with R Y1 .
  • 1 or 2 of R Y is independently C1-C6 alkyl substituted with -CChR A or 5-6 membered heteroaryl.
  • 1 or 2 of R' is independently C1-C6 alkyl substituted with -CChR A .
  • 1 or 2 of R Y is independently C1-C6 alkyl substituted 5-6 membered heteroaryl optionally substituted with R Y1 .
  • 1 or 2 of R Y is independently C1-C6 alkyl substituted with 5-6 membered heteroaryl substituted with R Y1 .
  • 1 or 2 of R Y is independently C1-C6 alkyl substituted with 5-6 membered heteroaryl.
  • R' 1 is independently C1-C6 alkyl.
  • 1 or 2 of R Y is independently C1-C3 alkyl.
  • 1, 2, or 3 of R ⁇ is methyl.
  • R Y1 is -SO2(C1-C6 alkyl). In some embodiments, R Y1 is -SO2CH3.
  • R A 1 is hydroxyl
  • R y i is C1-C6 alkyl optionally substituted with oxo. In some embodiments, R Y1 is C1-C6 alkyl substituted with oxo. In some embodiments, R Y1 is acetyl, 1- oxoethyl, or 1 -oxopropyl. In some embodiments, R Y1 is C1-C6 alkyl. In some embodiments, R Y1 is methyl.
  • R 4 is hydrogen
  • R 4 is C1-C6 alkyl. In some embodiments, R 4 is methyl or ethyl. In some embodiments, R 4 is methyl.
  • R 4 is acrylamido
  • R 3 is hydrogen
  • R 5 is C1-C6 alkyl. In some embodiments, R 5 is methyl or ethyl. In some embodiments, R 5 is methyl. In some embodiments, R 5 is halogen. In some embodiments, R 5 is fluoro or chloro. In some embodiments, R 5 is fluoro. In some embodiments, R 5 is chloro.
  • R 5 is C1-C6 haloalkyl. In some embodiments, R 5 is trifluoromethyl.
  • R 5 is C3-C6 cycloalkyl. In some embodiments, R 5 is cyclopropyl.
  • R 5 is cyano
  • R 5 is -NR 5A R 5B .
  • one of R 5A and R 5B is hydrogen and the other of R 5A and R ⁇ B is Cl- C6 alkyl, C2-C6 alkenyl, or C1-C6 hydroxyalkyl.
  • one of R 5A and R 5B is C1-C6 alkyl and the other of R 5A and R 5B is C1-C6 alkyl, C2-C6 alkenyl, or C1-C6 hydroxyalkyl.
  • each of R 5A and R 5B is hydrogen.
  • each of R 5A and R 5B is an independently selected C1-C6 alkyl.
  • each of R 5A and R 5B is methyl.
  • the C1-C6 hydroxyalkyl of R 5A and R 5B is hydroxymethyl, 1- hydroxy ethyl, 2-hydroxy ethyl, dihydroxypropyl or dihydroxybutyl.
  • R 5 is acrylamido
  • R 6 is hydrogen
  • R 6 is halogen. In some embodiments, R 6 is fluoro. In some embodiments, R 6 is chloro.
  • R 6 is C1-C6 alkyl. In some embodiments, R 6 is methyl.
  • each of R A and R B are independently selected from hydrogen, hydroxyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C2-C6 alkenyl, cyano, 4-10 membered heterocyclyl, and C1-C6 alkyl optionally substituted with hydroxyl or C1-C6 alkoxy.
  • each of R A and R B are independently selected from hydrogen, hydroxyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C2-C6 alkenyl, and C1-C6 alkyl optionally substituted with hydroxyl or C1-C6 alkoxy.
  • one of R A and R B is hydrogen and the other of R A and R B is hydroxyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C2-C6 alkenyl, or C1-C6 alkyl optionally substituted with hydroxyl or C1-C6 alkoxy.
  • one of R A and R B is hydrogen and the other of R A and R B is hydroxyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C2-C6 alkenyl, or C1-C6 alkyl substituted with hydroxyl or C1-C6 alkoxy.
  • one of R A and R B is hydrogen and the other of R A and R B is hydroxyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C2-C6 alkenyl, or C1-C6 alkyl.
  • one of R A and R B is hydrogen and the other of R A and R B is hydroxyl. In some embodiments, one of R A and R B is hydrogen and the other of R A and R B is C 1- C6 alkoxy. In some embodiments, one of R A and R B is hydrogen and the other of R A and R B is C3-C6 cycloalkyl. In some embodiments, one of R A and R B is hydrogen and the other of R A and R B is C2-C6 alkenyl. In some embodiments, one of R A and R B is hydrogen and the other of R A and R B is C1-C6 alkyl optionally substituted with hydroxyl or C1-C6 alkoxy.
  • one of R A and R B is hydrogen and the other of R A and R B is C1-C6 alkyl substituted with hydroxyl. In some embodiments, one of R A and R B is hydrogen and the other of R A and R B is C1-C6 alkyl substituted with C1-C6 alkoxy. In some embodiments, one of R A and R B is hydrogen and the other of R A and R B is 4-10 membered heterocyclyl .
  • one of R A and R B is hydrogen and the other of R A and R B is C1-C6 alkyl. In some embodiments, each of R A and R B are hydrogen. In some embodiments, each of R A and R B are an independently selected C1-C6 alkyl optionally substituted with hydroxyl or C1-C6 alkoxy. In some embodiments, each of R A and R B are an independently selected C1-C6 alkyl. In some embodiments, each of R A and R B are methyl.
  • R A and R B together with the nitrogen atom to which they are attached form a 4-10 membered heterocyclyl substituted with 1-2 substitutents independently selected from fluoro, hydroxyl, methyl, and acetyl.
  • R A and R B together with the nitrogen atom to which they are attached form a 4-10 membered heterocyclyl. In some embodiments, R A and R B together with the nitrogen atom to which they are attached form a 4-6 membered heterocyclyl.
  • R D is selected from hydrogen, hydroxyl, C1-C6 alkyl, phenyl, 4-10 membered heterocyclyl, C1-C6 alkoxy, and C3-C6 cycloalkyl, wherein the C1-C6 alkyl, 4-10 membered heterocyclyl, and phenyl are optionally substituted with 4-10 membered heterocyclyl, C3-C6 cycloalkyl, or cyano, and the C3-C6 cycloalkyl is optionally substituted with C1-C6 alkyl optionally substituted with hydroxyl or C1-C6 alkoxy.
  • R D is hydrogen
  • R D is hydroxyl
  • R D is C1-C6 alkyl optionally substituted with 4-10 membered heterocyclyl, C3-C6 cycloalkyl, or cyano. In some embodiments, R D is unsubstituted C1-C6 alkyl. In some embodiments, R D is C1-C6 alkyl substituted with 4-10 membered heterocyclyl, C3-C6 cycloalkyl, or cyano. In some embodiments, R D is C1-C6 alkyl substituted with 4-10 membered heterocyclyl. Tn some embodiments, R D is C1-C6 alkyl substituted with C3-C6 cycloalkyl. In some embodiments, R D is C1-C6 alkyl substituted with cyano.
  • R D is 4-10 membered heterocyclyl optionally substituted with 4-10 membered heterocyclyl, C3-C6 cycloalkyl, or cyano. In some embodiments, R D is unsubstituted 4-10 membered heterocyclyl. In some embodiments, R D is 4-10 membered heterocyclyl substituted with 4-10 membered heterocyclyl, C3-C6 cycloalkyl, or cyano. In some embodiments, R D is 4-10 membered heterocyclyl substituted with 4-10 membered heterocyclyl. In some embodiments, R D is 4-10 membered heterocyclyl substituted with C3-C6 cycloalkyl. In some embodiments, R D is 4-10 membered heterocyclyl substituted with cyano.
  • R D is phenyl optionally substituted with 4-10 membered heterocyclyl, C3-C6 cycloalkyl, or cyano. In some embodiments, R D is unsubstituted phenyl. In some embodiments, R D is phenyl substituted with 4-10 membered heterocyclyl, C3-C6 cycloalkyl, or cyano. In some embodiments, R D is phenyl substituted with 4-10 membered heterocyclyl. In some embodiments, R D is phenyl substituted with C3-C6 cycloalkyl. In some embodiments, R D is phenyl substituted with cyano.
  • R D is C3-C6 cycloalkyl optionally substituted with C1-C6 alkyl optionally substituted with hydroxyl or C1-C6 alkoxy. In some embodiments, R D is unsubstituted C3-C6 cycloalkyl. In some embodiments, R D is C3-C6 cycloalkyl substituted with C1-C6 alkyl optionally substituted with hydroxyl or C1-C6 alkoxy. In some embodiments, R D is C3-C6 cycloalkyl substituted with C1-C6 alkyl. In some embodiments, R D is C3-C6 cycloalkyl substituted with C1-C6 alkyl substituted with hydroxyl. In some embodiments, R D is C3-C6 cycloalkyl substituted with C1-C6 alkyl substituted with C1-C6 alkoxy.
  • R u is C1-C6 alkoxy.
  • R D is C3-C6 cycloalkyl.
  • R E is selected from hydrogen, hydroxyl, C1-C6 alkyl, phenyl, 4-10 membered heterocyclyl, C1-C6 alkoxy, and C3-C6 cycloalkyl, wherein the C1-C6 alkyl, 4-10 membered heterocyclyl, and phenyl are optionally substituted with 4-10 membered heterocyclyl, C3-C6 cycloalkyl, or cyano, and the C3-C6 cycloalkyl is optionally substituted with C1-C6 alkyl optionally substituted with hydroxyl or C1-C6 alkoxy.
  • R E is hydrogen
  • R E is hydroxyl. In some embodiments, R E is C1-C6 alkyl optionally substituted with 4-10 membered heterocyclyl, C3-C6 cycloalkyl, or cyano. In some embodiments, R E is unsubstituted C1-C6 alkyl. In some embodiments, R E is C1-C6 alkyl substituted with 4-10 membered heterocyclyl, C3-C6 cycloalkyl, or cyano. In some embodiments, R E is C1-C6 alkyl substituted with 4-10 membered heterocyclyl. In some embodiments, R E is C1-C6 alkyl substituted with C3-C6 cycloalkyl. In some embodiments, R E is C1-C6 alkyl substituted with cyano.
  • R E is 4-10 membered heterocyclyl optionally substituted with 4-10 membered heterocyclyl, C3-C6 cycloalkyl, or cyano. In some embodiments, R E is unsubstituted 4-10 membered heterocyclyl. In some embodiments, R E is 4-10 membered heterocyclyl substituted with 4-10 membered heterocyclyl, C3-C6 cycloalkyl, or cyano. In some embodiments, R E is 4-10 membered heterocyclyl substituted with 4-10 membered heterocyclyl. In some embodiments, R E is 4-10 membered heterocyclyl substituted with C3-C6 cycloalkyl. In some embodiments, R E is 4-10 membered heterocyclyl substituted with cyano.
  • R E is phenyl optionally substituted with 4-10 membered heterocyclyl, C3-C6 cycloalkyl, or cyano. In some embodiments, R E is unsubstituted phenyl. In some embodiments, R E is phenyl substituted with 4-10 membered heterocyclyl, C3-C6 cycloalkyl, or cyano. In some embodiments, R E is phenyl substituted with 4-10 membered heterocyclyl. In some embodiments, R E is phenyl substituted with C3-C6 cycloalkyl. In some embodiments, R E is phenyl substituted with cyano.
  • R E is C3-C6 cycloalkyl optionally substituted with C1-C6 alkyl optionally substituted with hydroxyl or C1-C6 alkoxy. In some embodiments, R E is unsubstituted C3-C6 cycloalkyl. In some embodiments, R E is C3-C6 cycloalkyl substituted with C1-C6 alkyl optionally substituted with hydroxyl or C1-C6 alkoxy. In some embodiments, R E is C3-C6 cycloalkyl substituted with C1-C6 alkyl. In some embodiments, R E is C3-C6 cycloalkyl substituted with C1-C6 alkyl substituted with hydroxyl. In some embodiments, R E is C3-C6 cycloalkyl substituted with C1-C6 alkyl substituted with C1-C6 alkoxy.
  • R E is C1-C6 alkoxy.
  • R E is C3-C6 cycloalkyl.
  • one of R D and R E is hydrogen and the other of R D and R E is hydrogen, hydroxyl, C1-C6 alkyl, phenyl, 4-10 membered heterocyclyl, C 1-C6 alkoxy, and C3- C6 cycloalkyl optionally substituted with C1-C6 alkyl optionally substituted with hydroxyl or Cl - C6 alkoxy.
  • one of R D and R E is hydrogen and the other of R D and R E is hydroxyl, C1-C6 alkyl, or C1-C6 alkoxy. In some embodiments, one of R D and R E is hydrogen and the other of R D and R E is hydroxyl. In some embodiments, one of R D and R E is hydrogen and the other of R D and R E is C1-C6 alkyl. In some embodiments, one of R D and R E is hydrogen and the other of R D and R E is C1-C6 alkoxy. In some embodiments, one of R D and R E is hydrogen and the other of R D and R E is hydroxyl, methyl, or methoxy. In some embodiments, each of R D and R E is hydrogen. In some embodiments, each of R D and R E is an independently selected C1-C6 alkyl. In some embodiments, each of R D and R E is methyl.
  • one of R E and R G is hydrogen and the other of R E and R G is phenyl or C1-C6 alkyl optionally substituted with oxo or -NR A R B .
  • one of R F and R G is hydrogen and the other of R E and R G is phenyl or C1-C6 alkyl substituted with oxo or -NR A R B .
  • one of R F and R G is hydrogen and the other of R F and R G is phenyl or C1-C6 alkyl.
  • one of R E and R G is hydrogen and the other of R E and R G is phenyl.
  • one of R F and R G is hydrogen and the other of R F and R G is C1-C6 alkyl optionally substituted with oxo or -NR A R B . In some embodiments, one of R F and R G is hydrogen and the other of R F and R G is C1-C6 alkyl substituted with oxo or -NR A R B . In some embodiments, each of R F and R G is hydrogen. In some embodiments, each of R F and R G is an independently selected C1-C6 alkyl. In some embodiments, each of R F and R G is methyl.
  • the compound of Formula (I), or a pharmaceutically acceptable salt thereof is a compound of Formula (I-A1A): or a pharmaceutically acceptable salt thereof.
  • the compound of Formula (I), or a pharmaceutically acceptable salt thereof is a compound of Formula (I-A2): or a pharmaceutically acceptable salt thereof.
  • the compound of Formula (I), or a pharmaceutically acceptable salt thereof is a compound of Formula (I- A3): or a pharmaceutically acceptable salt thereof.
  • the compound of Formula (I), or a pharmaceutically acceptable salt thereof is a compound of Formula (I-A4): or a pharmaceutically acceptable salt thereof.
  • the compound of Formula (I), or a pharmaceutically acceptable salt thereof is a compound of Formula (I-A5):
  • the compound of Formula (I), or a pharmaceutically acceptable salt thereof is a compound of Formula (I-A6): or a pharmaceutically acceptable salt thereof.
  • the compound of Formula (I), or a pharmaceutically acceptable salt thereof is a compound of Formula (I-A7): or a pharmaceutically acceptable salt thereof.
  • the compound of Formula (I), or a pharmaceutically acceptable salt thereof is a compound of Formula (I-A8): or a pharmaceutically acceptable salt thereof, wherein:
  • Ring A is a 5-6 membered heterocyclyl, C5-C6 cycloalkyl, or 5-6 membered heteroaryl; and m is 0, 1, 2, or 3; n is 0, 1, or 2; and m+n is 0, 1, 2, or 3.
  • Ring A is pyridyl, tetrahydropyranyl, or cyclohexyl. In some embodiments, Ring A is pyridyl. In some embodiments, Ring A is tetrahydropyranyl. In some embodiments, Ring A is cyclohexyl.
  • the compound of Formula (I), or a pharmaceutically acceptable salt thereof is a compound of Formula (I-A9): or a pharmaceutically acceptable salt thereof, wherein: m is 0, 1, 2, or 3; n is 0, 1 , or 2; and m+n is 0, 1 , 2, or 3.
  • the compound of Formula (I), or a pharmaceutically acceptable salt thereof is a compound of Formula (I-A10): or a pharmaceutically acceptable salt thereof, wherein:
  • Q is CH, NH, or O
  • Ring A is phenyl or 5-6 membered heteroaryl; and m is 0, 1, 2, or 3; n is 0, 1, or 2; and m+n is 0, 1, 2, or 3.
  • Q is CH.
  • Q is NH.
  • Ring A is phenyl
  • Ring A is pyridyl or pyrimidinyl.
  • the compound is selected from the group consisting of the compounds in Example 1 (e.g., Compound 1), or a pharmaceutically acceptable salt thereof.
  • the compound is selected from the group consisting of the compounds delineated in Table A, or a pharmaceutically acceptable salt thereof.
  • Some embodiments provide a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.
  • a “PI3Ka inhibitor” as used herein includes any compound exhibiting PI3Ka inactivation activity (e.g., inhibiting or decreasing).
  • a PI3Ka inhibitor can be selective for a P13Ka having one or more mutations.
  • test compounds to act as inhibitors of PI3Ka may be demonstrated by assays known in the art.
  • the activity of the compounds and compositions provided herein as PT3Ka inhibitors can be assayed in vitro, in vivo, or in a cell line.
  • In vitro assays include assays that determine inhibition of the kinase.
  • Alternate in vitro assays quantitate the ability of the inhibitor to bind to the protein kinase and can be measured either by radio labeling the compound prior to binding, isolating the compound/kinase complex and determining the amount of radio label bound, or by running a competition experiment where new compounds are incubated with the kinase bound to known radio ligands.
  • Potency of a PI3Ka inhibitor as provided herein can be determined by ECso value.
  • Potency of a PI3Ka inhibitor as provided herein can also be determined by IC50 value.
  • a compound with a lower IC50 value, as determined under substantially similar conditions, is a more potent inhibitor relative to a compound with a higher ICso value.
  • the substantially similar conditions comprise determining a PI3Ka-dependent phosphorylation level, in vitro or in vivo.
  • the selectivity between wild type PI3Ka and PI3Ka containing one or more mutations as described herein can also be measured using in vitro assays such as surface plasmon resonance and fluorence-based binding assays, and cellular assays such as the levels of pAKT, a biomarker of PI3Ka activity, and/or proliferation assays where cell proliferation is dependent on mutant PI3Ka kinase activity.
  • in vitro assays such as surface plasmon resonance and fluorence-based binding assays, and cellular assays such as the levels of pAKT, a biomarker of PI3Ka activity, and/or proliferation assays where cell proliferation is dependent on mutant PI3Ka kinase activity.
  • the compounds provided herein can exhibit potent and selective inhibition of PI3Ka.
  • the compounds provided herein can bind to the helical phosphatidylinositol kinase homology domain catalytic domain of PI3Ka.
  • the compounds provided herein can exhibit nanomolar potency against a PI3Ka kinase including one or more mutations, for example, the mutations in Table 1.
  • the compounds of Formula (I), or a pharmaceutically acceptable salt thereof can selectively target PI3Ka.
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof can selectively target PI3Ka over another kinase or nonkinase target.
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof can exhibit greater inhibition of PI3Ka containing one or more mutations as described herein (e.g., one or more mutations as described in Table 1) relative to inhibition of wild type PI3Ka.
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof can exhibit at least 2-fold, 3-fold, 5-fold, 10-fold, 25-fold, 50-fold or 100-fold greater inhibition of PI3Ka containing one or more mutations as described herein relative to inhibition of wild type PI3Ka.
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof can exhibit up to 1,000-fold greater inhibition of P 13 Ku.
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof can exhibit up to 10,000-fold greater inhibition of PI3Ka having a combination of mutations described herein relative to inhibition of wild type PI3Ka.
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof can exhibit from about 2-fold to about 10-fold greater inhibition of PI3Ka containing one or more mutations as described herein relative to inhibition of wild type PI3Ka. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can exhibit from about 10-fold to about 100-fold greater inhibition of PI3Ka containing one or more mutations as described herein relative to inhibition of wild type PI3Ka.
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof can exhibit from about 100-fold to about 1,000-fold greater inhibition of PI3Ka containing one or more mutations as described herein relative to inhibition of wild type PI3KOL In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can exhibit from about 1000-fold to about 10,000-fold greater inhibition of PI3Ka containing one or more mutations as described herein relative to inhibition of wild type PI3Ka.
  • PI3Ku inhibitors are useful for treating diseases which can be treated with a PI3Ku inhibitor, such as PI3Ka-associated diseases, e.g., proliferative disorders such as cancers, including hematological cancers and solid tumors (e.g., advanced or metastatic solid tumors).
  • PI3Ka-associated diseases e.g., proliferative disorders such as cancers, including hematological cancers and solid tumors (e.g., advanced or metastatic solid tumors).
  • the subject has been identified or diagnosed as having a cancer with a dysregulation of a PIK3CA gene, a PI3Ka protein, or expression or activity, or level of any of the same (a PI3Ka-associated cancer), for example, as determined using a regulatory agency- approved, e.g., FDA-approved, assay or kit.
  • the subject has a tumor that is positive for a dysregulation of a PIK3CA gene, a PI3Ka protein, or expression or activity, or level of any of the same (e.g., as determined using a regulatory agency-approved assay or kit).
  • the subject has a tumor that is positive for a mutation as described in Table 1.
  • the subject can be a subject with a tumor(s) that is positive for a dysregulation of a PIK3CA gene, a PI3Ka protein, or expression or activity, or level of any of the same (e.g., identified as positive using a regulatory agency-approved, e.g., FDA-approved, assay or kit).
  • the subject can be a subject whose tumors have a dysregulation of a PIK3CA gene, a PI3Ka protein, or expression or activity, or a level of the same (e.g., where the tumor is identified as such using a regulatory agency-approved, e.g., FDA-approved, kit or assay).
  • the subject is suspected of having a PI3Ka -associated cancer.
  • the subject has a clinical record indicating that the subject has a tumor that has a dysregulation of a PIK3CA gene, a PI3Ka protein, or expression or activity, or level of any of the same (and optionally the clinical record indicates that the subject should be treated with any of the compositions provided herein).
  • compounds of Formula (I), or pharmaceutically acceptable salts thereof are useful for preventing diseases as defined herein such as cancer.
  • preventing means to delay the onset, recurrence or spread, in whole or in part, of the disease as described herein, or a symptom thereof.
  • PI3Ka-associated disease refers to diseases associated with or having a dysregulation of a PIK3CA gene, a PI3Ka protein, or the expression or activity or level of any (e.g., one or more) of the same (e.g., any of the types of dysregulation of a PIK3CA gene, or a PI3Ka protein, or the expression or activity or level of any of the same described herein).
  • Nonlimiting examples of a PI3Ka-associated disease include, for example, proliferative disorders such as cancer (e.g., PI3Ka-associated cancer).
  • PI3Ka-associated cancer refers to cancers associated with or having a dysregulation of a PIK3CA gene, a PI3Ka protein, or expression or activity, or level of any of the same. Non-limiting examples of PI3Ka-associated cancer are described herein.
  • the phrase “dysregulation of a PIK3CA gene, a PI3Ka protein, or the expression or activity or level of any of the same” refers to a genetic mutation (e.g., a mutation in a PIK3CA gene that results in the expression of a PI3Ka that includes a deletion of at least one amino acid as compared to a wild type PI3Ka, a mutation in a PIK3CA gene that results in the expression of PI3Ka with one or more point mutations as compared to a wild type PI3Ka, a mutation in a PIK3CA gene that results in the expression of PI3Ka with at least one inserted amino acid as compared to a wild type PI3Ka, a gene duplication that results in an increased level of PI3Ka in a cell, or a mutation in a regulatory sequence (e.g., a promoter and/or enhancer) that results in an increased level of PI3Ka in a cell
  • a dysregulation of a PIK3CA gene, a PI3Ka protein, or expression or activity, or level of any of the same can be a mutation in &PIK3CA gene that encodes a PI3Ka that is constitutively active or has increased activity as compared to a protein encoded by a PIK3CA gene that does not include the mutation.
  • Non-limiting examples of PI3Ka point mutations/substitutions/insertions/deletions are described in Table 1.
  • wild type describes a nucleic acid (e.g., a PIK3CA gene or a PI3Ka mRNA) or protein (e.g., a PI3Ka) sequence that is typically found in a subject that does not have a disease related to the reference nucleic acid or protein.
  • a nucleic acid e.g., a PIK3CA gene or a PI3Ka mRNA
  • protein e.g., a PI3Ka sequence that is typically found in a subject that does not have a disease related to the reference nucleic acid or protein.
  • wild type PI3Ka or “wild-type PI3Ka” describes a normal PI3Ka nucleic acid (e.g., &PIK3CA or PI3Ka mRNA) or protein that is found in a subject that does not have a PI3Ka- associated disease, e.g., a PI3Ka -associated cancer (and optionally also does not have an increased risk of developing a PI3Ka -associated disease and/or is not suspected of having a PI3Ka- associated disease), or is found in a cell or tissue from a subject that does not have a PI3Ka- associated disease, e.g., a PI3Ka -associated cancer (and optionally also does not have an increased risk of developing a PI3Ka -associated disease and/or is not suspected of having a PI3Ka- associated disease).
  • a PI3Ka-associated cancer e.g., a PI3Ka -associated cancer
  • a method of treating cancer comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.
  • methods for treating PI3Koi-associated cancer in a subject in need thereof comprising a) detecting a dysregulation of PIK3CA gene, a PI3Ka protein, or the expression or activity or level of any of the same in a sample from the subj ect; and b) administering a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.
  • the dysregulation of a PIK3CA gene, a PI3Ka protein, or the expression or activity or level of any of the same includes one or more a PI3Ka protein substitutions/point mutations/insertions.
  • PI3Ka protein substitutions/insertions/deletions are described in Table 1.
  • the PI3Ka protein substitution/insertion/deletion is selected from the group consisting of E542A, E542G, E542K, E542Q, E542V, E545A, E545D, E545G, E545K, E545Q, M1043I, M1043L, M1043T, M1043V, H1047L, H1047Q, H1047R, H1047Y, G1049R, and combinations thereof.
  • the PI3Ka protein substitution / insertion / deletion is H1047X, where X is any amino acid other than H.
  • the PI3Ka protein substitution / insertion / deletion is E542X, where X is any amino acid other than E. In some embodiments, the PI3Ka protein substitution / insertion / deletion is E545X, where X is any amino acid other than E.
  • the dysregulation of & PIK3CA gene, a PI3Ka protein, or expression or activity or level of any of the same includes a splice variation in a PI3Ka mRNA which results in an expressed protein that is an alternatively spliced variant of PI3Ka having at least one residue deleted (as compared to the wild type PI3Ka protein) resulting in a constitutive activity of a PI3Ka protein domain.
  • the dysregulation of &PIK3CA gene, a PI3Ka protein, or expression or activity or level of any of the same includes at least one point mutation in a PIK3CA gene that results in the production of a PI3Ka protein that has one or more amino acid substitutions or insertions or deletions in a PJK3CA gene that results in the production of a PI3Ka protein that has one or more amino acids inserted or removed, as compared to the wild type PI3Ka protein.
  • the resulting mutant PI3Ka protein has increased activity, as compared to a wild type PI3Kcc protein or a PI3Ka protein not including the same mutation.
  • the compounds described herein selectively inhibit the resulting mutant PI3Ka protein relative to a wild type PI3Ka protein or a PI3Ka protein not including the same mutation.
  • the cancer e.g., PI3Ka-associated cancer
  • the cancer is selected from a hematological cancer and a solid tumor.
  • the cancer e.g., PI3Ka-associated cancer
  • breast cancer including both HER2 + and HER2' breast cancer, ER + breast cancer, and triple negative breast cancer
  • uterine cancer including endometrial cancer
  • lung cancer including small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLS, including adenocarcinoma lung cancer and squamous cell lung carcinoma)
  • esophageal squamous cell carcinoma ovarian cancer, colorectal cancer, esophagastric adenocarcinoma, bladder cancer, head and neck cancer (including head and neck squamous cell cancers such as oropharyngeal squamous cell carcinoma), thyroid cancer, glioma, cervical cancer, lymphangioma, meningioma, melanoma (including uveal melanoma), kidney cancer, pancreatic neuroendocine neo
  • breast cancer including both HER2 + and HER2' breast cancer
  • the cancer e.g., PI3Ka-associated cancer
  • breast cancer including both HER2 + and HER.2 breast cancer, ER + breast cancer, and triple negative breast cancer
  • colon cancer rectal cancer, colorectal cancer, ovarian cancer, lymphangioma, meningioma, head and neck squamous cell cancer (including oropharyngeal squamous cell carcinoma), melanoma (including uveal melanoma), kidney cancer, pancreatic neuroendocine neoplasms (pNETs), stomach cancer, esophageal cancer, acute myeloid leukemia, relapsed and refractory multiple myeloma, pancreatic cancer, lung cancer (including adenocarcinoma lung cancer and squamous cell lung carcinoma), and endometrial cancer.
  • breast cancer including both HER2 + and HER.2 breast cancer, ER + breast cancer, and triple negative breast cancer
  • rectal cancer colorectal cancer
  • the cancer e.g., PI3Ka-associated cancer
  • the cancer is selected from breast cancer, SCLC, NSCLC, endometrial cancer, esophageal squamous cell carcinoma, ovarian cancer, colorectal cancer, esophagastric adenocarcinoma, bladder cancer, head and neck cancer, thyroid cancer, glioma, and cervical cancer.
  • the PI3Ka-associated cancer is breast cancer. In some embodiments of any of the methods or uses described herein, the PI3Ka-associated cancer is colorectal cancer. In some embodiments of any of the methods or uses described herein, the PI3Ka-associated cancer is endometrial cancer. In some embodiments of any of the methods or uses described herein, the PI3Ka-associated cancer is lung cancer.
  • the PI3Ka-associated cancer is selected from the cancers described in Table 1.
  • VIEPVGNREE KILNREIGFA IGMPVCEFDM VKDPEVQDFR RNILNVCKEA VDLRDLNSPH SRAMYVYPPN VESSPELPKH IYNKLDKGQI IVVIWVIVSP NNDKQKYTLK INHDCVPEQV IAEAIRKKTR SMLLSSEQLK LCVLEYQGKY ILKVCGCDEY FLEKYPLSQY KYIRSCIMLG RMPNLMLMAK ESLYSQLPMD CFTMPSYSRR ISTATPYMNG ETSTKSLWVI NSALRIKILC ATYVNVNIRD IDKIYVRTGI YHGGEPLCDN VNTQRVPCSN PRWNEWLNYD IYIPDLPRAA RLCLSICSVK GRKGAKEEHC PLAWGNINLF DYTDTLVSGK MALNLWPVPH GLEDLLNPIG VTGSNPNKET PCLELEFDWF SSVVKFPDMS VIEEHANWSV SREAGFSYSH A
  • a method for inhibiting PI3Ka activity in a cell comprising contacting the cell with a compound of Formula (I), or a pharmaceutically acceptable salt thereof.
  • the contacting is in vitro.
  • the contacting is in vivo.
  • the contacting is in vivo, wherein the method comprises administering an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, to a subject having a cell having aberrant PI3Ka activity.
  • the cell is a cancer cell.
  • the cancer cell is any cancer as described herein.
  • the cancer cell is a PI3Koi-associated cancer cell.
  • contacting refers to the bringing together of indicated moieties in an in vitro system or an in vivo system.
  • "contacting" a PI3Ka protein with a compound provided herein includes the administration of a compound provided herein to an individual or subject, such as a human, having a PI3Ka protein, as well as, for example, introducing a compound provided herein into a sample containing a cellular or purified preparation containing the PI3Ka protein.
  • Also provided herein is a method of inhibiting cell proliferation, in vitro or in vivo, comprising contacting a cell with an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof as defined herein.
  • a method of increase cell death in vitro or in vivo, comprising contacting a cell with an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof as defined herein.
  • a method of increasing tumor cell death in a subject comprising administering to the subject an effective compound of Formula (I), or a pharmaceutically acceptable salt thereof, in an amount effective to increase tumor cell death.
  • the PI3Ka is human PI3Ka. In some embodiments, the PI3Ka has one or more point mutations in the PIK3CA gene. In some embodiments, the point mtations include a substitution at amino acid position 1047 of a human PI3Ka protein. In some embodiments, the substitution is H1047R.
  • the compounds of Formula (I), including pharmaceutically acceptable salts thereof can be administered in the form of pharmaceutical compositions as described herein.
  • the starting materials used for the syntheses are either synthesized or obtained from commercial sources, such as, but not limited to, Sigma-Aldrich, Fluka, Acros Organics, Alfa Aesar, Enamine, Strem, VWR Scientific, and the like.
  • Nuclear Magnetic Resonance (NMR) analysis was conducted using a Bruker AVANCE III HD (300 or 400) MHz spectrometer or Bruker AVANCE NEO 400 MHz spectrometer with an appropriate deuterated solvent.
  • Step 4 Synthesis of 4-bromo-2-(5-chloro-2,3-dihydro-LH-inden-2-yl)-6- methylisoindolin-l-one
  • Step 5 Synthesis of 2-(5-chloro-2,3-dihydro-lH-inden-2-yl)-4-(l-ethoxyvinyl)-6- methylisoindolin-l-one
  • Step 6 Synthesis of 4-acetyl-2-(5-chloro-2,3-dihydro-LH-inden-2-yl)-6- methylisoindolin-l-one
  • Step 7 Synthesis of 4-(l-aminoethyl)-2-(5-chloro-2,3-dihydro-LH-inden-2-yl)-6- methylisoindolin-l-one
  • Step 8 Synthesis of tert-butyl 2-((l-(2-(5-chloro-2.3-dihydro-l//-inden-2-yl)-6- methyl-l-oxoisoindolin-4-yl)ethyl)amino)benzoate
  • Step 9 Synthesis of tert-butyl 2-((l-(2-(2,3-dihydro-l/Z-inden-2-yl)-6-methyl-l- oxoisoindolin-4-yl)ethyl)amino)benzoate
  • Step 10 Synthesis of 2-((l-(2-(2,3-dihydro-l//-inden-2-yl)-6-methyl-l-oxoisoindolin- 4-yl)ethyl)amino)benzoic acid
  • Step 1 Synthesis of 2-(5-chloro-2,3-dihydro-TH-inden-2-yl)-4-(l-hydroxyethyl)-6- methylisoindolin-l-one:
  • Step 3 Synthesis of 2-((l-(2-(5-chloro-2.3-dihydro-l//-inden-2-yl)-6-methyl-l- oxoisoindolin-4-yl)ethyl)amino)benzenesulfonamide:
  • Step 4 Synthesis of 2-((l-(2-(2,3-dihydro-17/-inden-2-yl)-6-methyl-l-oxoisoindolin- 4-yl)ethyl)amino)benzenesulfonamide:
  • Step 5 Synthesis of (/?)-2-((l-(2-(2.3-dihydro-l//-inden-2-yl)-6-methyl-l- oxoisoindolin-4-yl (ethyl (amino Jbenzenesulfonamide & GS')-2 -( ( 1 -( 2 - ( 2.3-d i hy d r o- 1 //- i n d e 11- 2-y I )-6-meth yl- 1 -oxoisoindol in-4-yl Jet hy 1 (a m in o (benzenesul t'oiiam ide:
  • Stepl - Synthesis of 4-bromo-2-(isochroman-4-yl)-6-methylisoindolin-l-one A mixture of methyl 3-bromo-2-(bromomethyl)-5-methylbenzoate (200 mg, 621 pmol), isochroman-4-amine (111 mg, 745 pmol) and K2CO3 (138 mg, 1.86 mmol) in EtOH (3 mL) was stirred at 60 °C for 1 h. After cooling to room temperature, the reaction was diluted with DCM (5 mL) and filtered, the filtrate was concentrated in vacuo.
  • Step 2 Synthesis of 4-(l-ethoxyvinyl)-2-(isochroman-4-yl)-6-methyIisoindolin-l-one:
  • Step 4 Synthesis of 4-(l-aminoethyl)-2-(isochroman-4-yl)-6-methylisoindolin-l-one: A mixture of 4-acetyl-2-(isochroman-4-yl)-6-methylisoindolin-l-one (122 mg, 380 pmol), NH4OAC (439 mg, 5.69 mmol) and AcOH (46 mg, 759 pmol) in MeOH (4 mL) was stirred at room temperature for 1 h. Then NaBHsCN (72 mg, 1.14 pmol) was added to the reaction mixture. After the addition, the reaction mixture was stirred at 60 °C for 16 h.
  • Step 5 Synthesis of tert-butyl 2-((l-(2-(isochroman-4-yl)-6-methyl-l-oxoisoindolin- 4-yl)ethyl)amino)benzoate:
  • Step 6 Synthesis of 2-((l-(2-(isochroman-4-yl)-6-methyl-l-oxoisoindolin-4- yl)ethyl)amino)benzoic acid:
  • Step 1 Synthesis of (H?,3r,55)-tert-butyl 3-((2-bromo-6-chloro-4- methylbenzyl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylate & tert-butyl (1/?,3s,55)-3-((2- bromo-6-chloro-4-methylbenzyl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylate:
  • Step 2 Synthesis of tert-butyl (H?,3s 9 55)-3-(4-chloro-6-methyl-l-oxoisoindolin-2-yl)- 8-azabicyclo[3.2.1]octane-8-carboxylate: A mixture of tert-butyl (17?,3.v,55)-3-((2-bromo-6-chloro-4-methylbenzyl)amino)-8- azabicyclo[3.2.1]octane-8-carboxylate (4.8 g, 10.82 mmol), Pd(dppf)C12 (2.37 g, 3.24 mmol) and DIPEA (4.19 g, 32.45 mmol, 5.65 mL) in DMF (100 mL) was stirred at 80 °C for 16 h under CO atmosphere (50 psi).
  • Step 3 Synthesis of tert-butyl (llf,3.$,55)-3-(4-acetyl-6-niethyl-l-oxoisoindolin-2-yl)- 8-azabicyclo[3.2.1]octane-8-carboxylate:
  • reaction mixture was added 1 M HC1 (10 mL) and stirred at room temperature for 0.5 h.
  • the reaction mixture was added 50 mL 10% KF solution, stirred at room temperature over 2 h.
  • the mixture was extracted with EtOAc (200 mL x 2).
  • the combined organic phase was washed with brine (200 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo.
  • the crude residue was purified by silica gel chromatography (solvent gradient: 0 - 30% EtOAc in petroleum ether) to give the title compound (1.4 g, 60%) as a yellow solid.
  • Step 4 Synthesis of tert-butyl (17?,3'S5»£)-3-(4-(l-aniinoethyl)-6-niethyl-l- oxoisoindolin-2-yl)-8-azabicyclo [3.2. l]octane-8-carboxylate:
  • Step 6 Synthesis of methyl 2-((l-(2-((ll?,3.s,55')-8-azabicyclo[3.2.1]octan-3-yl)-6- methyl-l-oxoisoindolin-4-yl)ethyl)amino)benzoate hydrochloride:
  • Step 7 Synthesis of methyl 2-((l-(2-((llf,3s,55)-8-acetyl-8-azabicyclo[3.2.1]octan-3- yl)-6-methyl-l-oxoisoindolin-4-yl)ethyl)amino)benzoate:
  • Step 8 Synthesis of 2-((l-(2-((H?,3s,55)-8-acetyl-8-azabicyclo[3.2.1]octan-3-yl)-6- methyl-l-oxoisoindolin-4-yl)ethyl)amino)benzoic acid:
  • Step 1 Synthesis of 4-bromo-6-methyl-2-(5,6,7,8-tetrahydroquinolin-7-yl)isoindolin- 1-one:
  • Step 2 Synthesis of 4-acetyl-6-methyl-2-(5,6,7,8-tetrahydroquinolin-7-yl)isoindolin- 1-one:
  • Step 3 Synthesis of 4-(l-aminoethyl)-6-methyl-2-(5,6,7,8-tetrahydroquinolin-7- yl)isoindolin-l-one:
  • Step 4 Synthesis of tert-butyl 2-((l-(6-methyl-l-oxo-2-(5,6,7,8-tetrahydroquinolin-7- yl)isoindolin-4-yl)ethyl)amino)benzoate:
  • Step 5 Synthesis of 2-((l-(6-methyl-l-oxo-2-(5,6,7,8-tetrahydroquinolin-7- yl)isoindolin-4-yl)ethyl)amino)benzoic acid :
  • the reaction mixture was added 20 mL 10% KF aqueous solution, stirred at room temperature for 2 h.
  • the mixture was extracted with EtOAc (20 mL x 3).
  • the combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated.
  • the crude residue was purified by silica gel chromatography (solvent gradient: 0 - 20% EtOAc in petroleum ether) to give the title compound (330 mg, 76%) as a white solid.
  • Step 3 Synthesis of tert- butyl JV-(2-(4-acetyl-6-methyl-l-oxo-isoindolin-2-yl)indan-5- yl)sulfonyl-N-tert-butoxycarbonyl-carbamate:
  • Step 4 Synthesis of tert-butyl /V-(2-[4-(l-aminoethyl)-6-methyl-l-oxo-isoindolin-2- yl]indan-5-yl)sulfonyl-/V-tert-butoxycarbonyl-carbamate:
  • Step 5 Synthesis of tert-butyl 2-(l-(2-(5-(bis(tert-butoxycarbonyl)sulfamoyl)indan- 2-yl)-6-methyl-l-oxo-isoindolin-4-yl)ethylamino)benzoate:
  • Step 6 Synthesis of 2-((l-(6-methyl-l-oxo-2-(5-sulfamoyl-2,3-dihydro-lH-inden-2- yl)isoindolin-4-yl)ethyl)amino)benzoic acid : To a mixture of tert-butyl 2-(l-(2-(5-(bis(tert-butoxycarbonyl)sulfamoyl)indan-2-yl)-6- methyl-l-oxo-isoindolin-4-yl)ethylamino)benzoate (25 mg, 32 umol) in DCM (1 mL) was added TFA (0.5 mL, 6.9 mmol).
  • reaction mixture was stirred at room temperature for 16 h.
  • the mixture was concentrated and the residue was purified by reverse phase chromatography (acetonitrile 39% - 69% / 0.225% formic acid in water) to give the title compound (2 mg, 16%) as a white solid.
  • Step 1 Synthesis of tert-butyl 2-((l-(2-(chroman-3-yl)-5,6-dimethyl-l-oxoisoindolin- 4-yl)ethyl)amino)benzoate:
  • Step 2 Synthesis of 2-((l-(2-(chroman-3-yl)-5,6-dimethyl-l-oxoisoindolin-4- yl)ethyl)amino)benzoic acid:
  • Step 1 Synthesis of tert-butyl 7-((2-bromo-6-chloro-4-methylbenzyl)amino)-2- azaspiro[3.5]nonane-2-carboxylate:
  • Step 2 Synthesis of tert-butyl 7-(4-chloro-6-methyl-l-oxoisoindolin-2-yl)-2- azaspiro[3.5]nonane-2-carboxylate:
  • Step 4 Synthesis of tert-butyl 7-(4-(l-aminoethyl)-6-methyl-l-oxoisoindolin-2-yl)-2- azaspiro[3.5]nonane-2-carboxylate:
  • Step 5 Synthesis of tert-butyl 7-(4-(l-((2-(methoxycarbonyl)phenyl)amino)ethyl)-6- methyl-l-oxoisoindolin-2-yl)-2-azaspiro[3.5]nonane-2-carboxylate: A mixture of Zc/7-butyl 7-(4-(l -((2-(methoxycarbonyl)phenyl)arnino)ethyl)-6-rnethyl-l - oxoisoindolin-2-yl)-2-azaspiro[3.5]nonane-2-carboxylate (1.48 g, 3.58 mmol), methyl 2- iodobenzoate (1.41 g, 5.37 mmol), CS2CO3 (3.50 g, 10.74 mmol), Pd2(dba)3 (328 mg, 0.36 mmol) and Xantphos (414 mg, 0.
  • Step 6 Synthesis of methyl 2-((l-(6-methyl-l-oxo-2-(2-azaspiro[3.5]nonan-7- yl)isoindolin-4-yl)ethyl)amino)benzoate trichloroacetate:
  • Step 7 Synthesis of methyl 2-((l-(2-(2-acetyl-2-azaspiro[3.5]nonan-7-yl)-6-methyl-l- oxoisoindolin-4-yl)ethyl)amino)benzoate:
  • Step 8 Synthesis of 2-((l-(2-(2-acetyl-2-azaspiro[3.5]nonan-7-yI)-6-methyl-l- oxoisoindolin-4-yl)ethyl)amino)benzoic acid:
  • Step 1 Synthesis of tert-butyl 6-chloro-3-((l-(2-(chroman-3-yl)-6-methyl-l- oxoisoindolin-4-yl)ethyl)amino)picolinate:
  • Step 2 Synthesis of 6-chloro-3-((l-(2-(chroman-3-yl)-6-methyl-l-oxoisoindolin-4- yl)ethyl)amino)picolinic acid:
  • Step 1 Synthesis of 4-bromo-2-(6-chlorochroman-3-yl)-6-methylisoindolin-l-one:
  • Step 5 Synthesis of methyl 2-((l-(2-(6-chlorochroman-3-yl)-6-methyl-l- oxoisoindolin-4-yl)ethyl)amino)benzoate:
  • Step 7 Synthesis of 2-((l-(6-methyl-2-(6-(oxetan-3-ylamino)chroman-3-yl)-l- oxoisoindolin-4-yl)ethyl)amino)benzoic acid:
  • Step 4 Synthesis of 4-bromo-6-chloro-2-(2,3-dihydro-lH-inden-2-yl)isoindolin-l- one:
  • Step 5 Synthesis of 6-chlor()-2-(2.3-dihydro-l//-inden-2-yl)-4-(l- ethoxyvinyl)isoindolin-l-one:
  • Step 7 Synthesis of 4-(l-aminoethyl)-6-chloro-2-(2,3-dihydro-l//-inden-2- yl)isoindolin-l-one:
  • Step 8 Synthesis of tert-butyl 2-((l-(6-chloro-2-(2,3-dihydro-LH-inden-2-yl)-l- oxoisoindolin-4-yl)ethyl)amino)benzoate:
  • Step 2 Synthesis of 2-((l-(2-(l-(2-oxabicyclo[3.1.1]heptane-l-carbonyl)azepan-4-yl)- 6-methyl-l-oxoisoindolin-4-yl)ethyl)amino)benzoic acid:
  • Step 3 Synthesis of 4-(l-aminoethyl)-2-(chroman-4-yl)-6-methylisoindolin-l-one:
  • Step 5 Synthesis of tert-butyl 2-((l-(2-(chroman-4-yl)-6-methyl-l-oxoisoindolin-4- yl)ethyl)amino)benzoate: A mixture of 4-(l -aminoethyl)-2-(chroman-4-yl)-6-methylisoindolin-l -one (250 mg, 775 pmol), tert-butyl 2-iodobenzoate (236 mg, 775 pmol), Pd2(dba)a (71 mg, 78 pmol), Xantphos (90 mg, 155 pmol) and CS2CO3 (758 mg, 2.33 mmol) in dioxane (10 mL).
  • reaction mixture was stirred at 100 °C for 16 h under N2 atmosphere. After cooling to room temperature, the reaction was filtered and the filtrate was concentrated. The crude residue was purified by silica gel chromatography (solvent gradient: 0 - 15% EtOAc in petroleum ether) to give the title compound (165 mg, 43%) as colorless oil.
  • Step 6 Synthesis of 2-((l-(2-(chroman-4-yl)-6-methyl-l-oxoisoindolin-4- yl)ethyl)amino)benzoic acid:
  • SKBR3 or T47D cells are seeded in DMEM containing 10% FBS at 25k cells/well into 96- well cell culture format. Cells are incubated overnight at 37°C in a 5% CO2 incubator and the following day cell media is aspirated, adherent cells are washed IX with room temperature PBS prior to serum-free media application. Cells are returned to 37°C 5% CO2 incubator and incubated a further 16hrs. Compounds are added to serum starved adherent cells with a top dose of 10,000nM and 3x multiple dose reductions for a minimum dose of 0.5nM diluted in DMSO.
  • T47D pAKT IC50 (nM): A denotes ⁇ 750 nM; B denotes 750 nM ⁇ IC50 ⁇ 2,000 nM; C denotes > 2,000 nM. ND denotes value not determined with that assay for the specified compound; and for T47D (H1047R) selectivity over SKBR3 (WT): A denotes > 20-fold; B denotes 20-fold
  • ND denotes value not determined with that assay for the specified compound
  • ND denotes value not determined with that assay for the specified compound.
  • Embodiment 1 A compound of Formula (I): or a pharmaceutically acceptable salt thereof, wherein:
  • R 1 is hydrogen, cyano, C3-C6 cycloalkyl, C1-C6 alkyl optionally substituted with phenyl optionally substituted with halogen, C1-C6 thioalkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C1-C6 alkoxy alkyl;
  • R 1 is hydrogen or C1-C6 alkyl; or R 1 and R 1 , together with the carbon atom to which they are attached form a C3-C10 cycloalkyl;
  • each R A and R B is independently selected from hydrogen, hydroxyl, Cl -C6 alkoxy, C3-C6 cycloalkyl, C2-C6 alkenyl, cyano, 4-10 membered heterocyclyl, and C1-C6 alkyl optionally substituted with hydroxyl or C1-C6 alkoxy, orR A and R B together with the
  • R 4 is hydrogen, C1-C6 alkyl, or acrylamido
  • R 5A and R 5B are independently selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, and C1-C6 hydroxyalkyl;
  • R 6 is hydrogen, halogen, or C1-C6 alkyl
  • X is a bond, CH 2 , CH(CH 3 ), C(CH 3 ) 2 , or ⁇ ;
  • R Y1 is -SO2(C1-C6 alkyl), hydroxyl, or C1-C6 alkyl optionally substituted with oxo; and each R F and R G is independently selected from hydrogen, phenyl, and C1-C6 alkyl optionally substituted with oxo or -NR A R B .
  • Embodiment 2 The compound of Embodiment 1, wherein R 1 is hydrogen.
  • Embodiment 3 The compound of Embodiment 1, wherein R 1 cyano.
  • Embodiment 4 The compound of Embodiment 1, wherein R 1 is C3-C6 cycloalkyl.
  • Embodiment 5 The compound of Embodiment 1, wherein R 1 is C1-C6 alkyl optionally substituted with phenyl optionally substituted with halogen.
  • Embodiment 6 The compound of Embodiment 1, wherein R 1 is C1-C6 alkyl substituted with phenyl optionally substituted with halogen.
  • Embodiment 7 The compound of Embodiment 1 or 6, wherein R 1 is C1-C6 alkyl substituted with phenyl substituted with halogen.
  • Embodiment 8 The compound of Embodiment 1 or 6, wherein R 1 is C1-C6 alkyl substituted with phenyl.
  • Embodiment 9 The compound of Embodiment 1 or 6, wherein R 1 is C1-C6 alkyl.
  • Embodiment 10 The compound of any one of Embodiments 1, 6, or 9, wherein R 1 is
  • Embodiment 11 The compound of Embodiment 1, wherein R 1 is C1-C6 thioalkyl.
  • Embodiment 12 The compound of Embodiment 1, wherein R 1 is C1-C6 haloalkyl.
  • Embodiment 13 The compound of Embodiment 1, wherein R 1 is C1-C6 alkoxy.
  • Embodiment 14 The compound of Embodiment 1, wherein R 1 is C1-C6 alkoxyalkyl.
  • Embodiment 15 The compound of any one of Embodiments 1-14, wherein R 1 is hydrogen.
  • Embodiment 16 The compound of any one of Embodiments 1-14, wherein R 1 is Cl-
  • Embodiment 17 The compound of any one of Embodiments 1-14, wherein R 1 is Cl-
  • Embodiment 18 The compound of Embodiment 1, wherein R 1 and R 1 , together with the carbon atom to which they are attached form a C3-C10 cycloalkyl.
  • Embodiment 19 The compound of any one of Embodiments 1-18, wherein R 2 is C6- C12 aryl optionally substituted with 1-3 independently selected R 2A .
  • Embodiment 20 The compound of any one of Embodiments 1-19, wherein R 2 is phenyl optionally substituted with 1-3 independently selected R 2A .
  • Embodiment 21 The compound of any one of Embodiments 1-19, wherein R 2 is 2,3- dihydro-lH-indenyl optionally substituted with 1-3 independently selected R 2A .
  • Embodiment 22 The compound of any one of Embodiments 1-18, wherein R 2 is 5- 10 membered heteroaryl optionally substituted with 1-3 independently selected R 2A .
  • Embodiment 23 The compound of any one of Embodiments 1-18, wherein R 2 is 4- 10 membered heterocyclyl optionally substituted with 1-3 independently selected R 2A .
  • Embodiment 24 The compound of any one of Embodiments 1-18, wherein R 2 is C4- C10 cycloalkyl optionally substituted with 1-3 independently selected R 2A .
  • Embodiment 25 The compound of any one of Embodiments 1-18, wherein R 2 is Cl- C6 aralkyl optionally substituted with 1-4 independently selected R 2A .
  • Embodiment 26 The compound of any one of Embodiments 1-18, wherein R 2 is Cl- C6 aralkyl substituted with 1-4 independently selected R 2A .
  • Embodiment 27 The compound of any one of Embodiments 1-18 or 25, wherein R 2 is C1-C6 aralkyl.
  • Embodiment 28 The compound of any one of Embodiments 1-27, wherein 1, 2, or 3 of R 2A are independently halogen.
  • Embodiment 29 The compound of any one of Embodiments 1-28, wherein 1, 2, or 3 of R 2A are independently cyano.
  • Embodiment 30 The compound of any one of Embodiments 1-29, wherein 1, 2, or 3 of R 2A are independently hydroxyl.
  • Embodiment 31 The compound of any one of Embodiments 1-30, wherein 1, 2, or 3 of R 2A are independently -NR A R B .
  • Embodiment 33 The compound of any one of Embodiments 1-32, wherein 1, 2, or 3 of R 2A are independently Embodiment 34.
  • the compound of any one of Embodiments 1-33, wherein 1, 2, or 3 of R 2A are independently -NHC( O)R c .
  • Embodiment 37 The compound of any one of Embodiments 1-36, wherein 1, 2, or 3 of R 2A are independently -SO2R F
  • Embodiment 38 The compound of any one of Embodiments 1-37, wherein 1, 2, or 3 of R 2A are independently -NHS02R F .
  • Embodiment 39 The compound of any one of Embodiments 1-38, wherein 1, 2, or 3 of R 2A are independently -SO2NR F R G .
  • Embodiment 42 The compound of any one of Embodiments 1-41, wherein 1, 2, or 3 of R 2A are independently C1-C6 haloalkyl.
  • Embodiment 43 The compound of any one of Embodiments 1-42, wherein 1, 2, or 3 of R 2A are independently C1-C6 hydroxy alkyl.
  • Embodiment 44 The compound of any one of Embodiments 1-43, wherein 1, 2, or 3 of R 2A are independently 5-10 membered heteroaryl optionally substituted with 1-3 substituents independently selected from C1-C6 alkyl and -NR A R B .
  • Embodiment 45 The compound of any one of Embodiments 1-44, wherein 1, 2, or 3 of R 2A are independently 5-10 membered heteroaryl substituted with 1-3 substituents independently selected from C1-C6 alkyl and -NR A R B .
  • Embodiment 46 The compound of any one of Embodiments 1-45, wherein 1, 2, or 3 of R 2A are independently 5-10 membered heteroaryl.
  • Embodiment 51 The compound of any one of Embodiments 1-50, wherein 1, 2, or 3 of R 2A are independently 4-10 membered heterocyclyl.
  • Embodiment 56 The compound of any one of Embodiments 1-55, wherein 1, 2, or 3 of R 2A are independently C1-C6 alkyl.
  • Embodiment 60 The compound of any one of Embodiments 1-59, wherein 1, 2, or 3 of R 2A are independently C1-C6 alkoxy substituted with -NR A R B or 4-10 membered heterocyclyl.
  • Embodiment 61 The compound of any one of Embodiments 1-60, wherein 1, 2, or 3 of R 2A are independently C1-C6 alkoxy.
  • Embodiment 62 The compound of any one of Embodiments 1-61, wherein 1, 2, or 3 of R 2A are independently C3-C6 cycloalkyl optionally substituted with 4-10 membered heterocyclyl optionally substituted with C1-C6 alkyl.
  • Embodiment 63 The compound of any one of Embodiments 1-62, wherein 1, 2, or 3 of R 2A are independently C3-C6 cycloalkyl substituted with 4-10 membered heterocyclyl optionally substituted with C1-C6 alkyl.
  • Embodiment 64 The compound of any one of Embodiments 1-63, wherein 1, 2, or 3 of R 2A are independently C3-C6 cycloalkyl substituted with 4-10 membered heterocyclyl substituted with C1-C6 alkyl.
  • Embodiment 65 The compound of any one of Embodiments 1-64, wherein 1, 2, or 3 of R 2A are independently C3-C6 cycloalkyl substituted with 4-10 membered heterocyclyl.
  • Embodiment 66 The compound of any one of Embodiments 1-58, wherein 1, 2, or 3 of R 2A are independently C3-C6 cycloalkyl.
  • Embodiment 67 The compound of any one of Embodiments 1-18, wherein R 2 is Cl-
  • Embodiment 69 The compound of any one of Embodiments 1-18 or 67, wherein R 2 is C1-C6 alkoxy.
  • Embodiment 70 The compound of any one of Embodiments 1-18, wherein R 2 is Cl-
  • Embodiment 71 The compound of any one of Embodiments 1-18, wherein R 2 is Cl-
  • Embodiment 72 The compound of any one of Embodiments 1-71, wherein X is a bond.
  • Embodiment 73 The compound of any one of Embodiments 1-71, wherein X is CH2.
  • Embodiment 74 The compound of any one of Embodiments 1-71, wherein X is
  • Embodiment 75 The compound of any one of Embodiments 1-71, wherein X is
  • Embodiment 76 The compound of any one of Embodiments 1-71, wherein X is
  • Embodiment 77 The compound of any one of Embodiments 1-76, wherein one of R 3A and R 3B is hydrogen and the other of R 3A and R 3B is C1-C6 alkyl.
  • Embodiment 78 The compound of any one of Embodiments 1-77, wherein one of R 3A and R 3B is hydrogen and the other of R 3A and R 3B is methyl.
  • Embodiment 79 The compound of any one of Embodiments 1-76, wherein each of R 3A and R 3B is hydrogen.
  • Embodiment 80 The compound of any one of Embodiments 1-76, wherein each of R 3A and R 3B is an independently selected C1-C6 alkyl.
  • Embodiment 81 The compound of any one of Embodiments 1-76 or 80, wherein each of R 3A and R 3B is methyl.
  • Embodiment 82 The compound of any one of Embodiments 1-76, wherein one of R 3A and R 3B is hydrogen and the other of R 3A and R 3B is C1-C6 alkoxy.
  • Embodiment 83 The compound of any one of Embodiments 1-76, wherein one of R 3A and R 3B is C1-C6 alkyl and the other of R 3A and R 3B is C1-C6 alkoxy.
  • Embodiment 84 The compound of any one of Embodiments 1-76, wherein each of R 3A and R 3B is C1-C6 alkoxy.
  • Embodiment 85 The compound of any one of Embodiments 1-76, wherein one of R 3A and R 3B is hydrogen and the other of R 3A and R 3B is C1-C6 haloalkyl.
  • Embodiment 86 The compound of any one of Embodiments 1-76, wherein one of R 3A and R 3B is C1-C6 alkyl and the other of R 3A and R 3B is C1-C6 haloalkyl.
  • Embodiment 87 The compound of any one of Embodiments 1-76, wherein each of R 3A and R 3B is C1-C6 haloalkyl.
  • Embodiment 88 The compound of any one of Embodiments 1-76, wherein R 3A and R 3B , together with the carbon and nitrogen atoms, respectively, to which they are attached together form a 4-8 membered heterocyclyl group.
  • Embodiment 89 The compound of any one of Embodiments 1-88, wherein Y is phenyl optionally substituted with 1-3 independently selected R Y .
  • Embodiment 90 The compound of any one of Embodiments 1-88, wherein Y is naphthyl optionally substituted with 1-3 independently selected R ⁇
  • Embodiment 91 The compound of any one of Embodiments 1-88, wherein Y is 5-10 membered heteroaryl optionally substituted with 1-3 independently selected R Y .
  • Embodiment 92 The compound of any one of Embodiments 1-91, wherein 1, 2, or 3 of R Y is independently halogen.
  • Embodiment 93 The compound of any one of Embodiments 1-92, wherein 1, 2, or 3 of R Y is hydroxyl.
  • Embodiment 94 The compound of any one of Embodiments 1-93, wherein 1, 2, or 3 of R Y is cyano.
  • Embodiment 95 The compound of any one of Embodiments 1-94, wherein 1, 2, or 3 of R Y is independently C1-C6 haloalkyl.
  • Embodiment 96 The compound of any one of Embodiments 1-95, wherein 1, 2, or 3 of R Y is independently C1-C6 alkoxy.
  • Embodiment 97 The compound of any one of Embodiments 1-96, wherein 1, 2, or 3 of R Y is independently C1-C6 haloalkoxy.
  • Embodiment 98 The compound of any one of Embodiments 1-97, wherein 1, 2, or 3 of R Y is independently C1-C6 hydroxyalkyl.
  • Embodiment 101 The compound of any one of Embodiments 1-100, wherein 1, 2, or 3 of R Y is independently -CO2R A .
  • Embodiment 102 The compound of any one of Embodiments 1-101, wherein 1, 2, or 3 of R Y is independently -SO2NR F R G .
  • Embodiment 103 The compound of any one of Embodiments 1-102, wherein 1, 2, or 3 of R Y is independently -NHSO2R F .
  • Embodiment 105 The compound of any one of Embodiments 1-104, wherein 1, 2, or 3 of R Y is independently -SCh(Cl-C6 alkyl).
  • Embodiment 107 The compound of any one of Embodiments 1-106, wherein 1, 2, or 3 of R Y is independently 5-6 membered heteroaryl.
  • Embodiment 108 The compound of any one of Embodiments 1-107, wherein 1, 2, or 3 of R' is independently heteroaralkyl.
  • Embodiment 109 The compound of any one of Embodiments 1-108, wherein 1, 2, or 3 of R Y is independently C1-C6 alkyl optionally substituted with -CO2R 4 or 5-6 membered heteroaryl optionally substituted with R' 1 .
  • Embodiment 1 10. The compound of any one of Embodiments 1-109, wherein 1, 2, or 3 of R Y is independently C1-C6 alkyl substituted with -CO2R A or 5-6 membered heteroaryl optionally substituted with R Y1 .
  • Embodiment 111 The compound of any one of Embodiments 1-110, wherein 1, 2, or 3 of R Y is independently C1-C6 alkyl substituted with -CChR A or 5-6 membered heteroaryl substituted with R Y1 .
  • Embodiment 112 The compound of any one of Embodiments 1-109, wherein 1, 2, or 3 of R Y is independently C1-C6 alkyl substituted with -CChR A or 5-6 membered heteroaryl.
  • Embodiment 113 The compound of any one of Embodiments 1-109, wherein 1, 2, or 3 of R Y is independently C1-C6 alkyl.
  • Embodiment 114 The compound of any one of Embodiments 1-91 or 109-111, wherein R Y1 is -SO2(C1-C6 alkyl).
  • Embodiment 115 The compound of any one of Embodiments 1-91 or 109-111, wherein R? 1 is C1-C6 alkyl optionally substituted with oxo.
  • Embodiment 116 The compound of any one of Embodiments 1-115, wherein R 4 is hydrogen.
  • Embodiment 117 The compound of any one of Embodiments 1-115, wherein R 4 is Cl- C6 alkyl.
  • Embodiment 118 The compound of any one of Embodiments 1-115, wherein R 4 is acrylamido.
  • Embodiment 119 The compound of any one of Embodiments 1-118, wherein R 5 is hydrogen.
  • Embodiment 120 The compound of any one of Embodiments 1-118, wherein R 5 is Cl- C6 alkyl.
  • Embodiment 121 The compound of any one of Embodiments 1-118, wherein R 5 is halogen.
  • Embodiment 122 The compound of any one ofEmbodiments 1-118, whereinR 5 is Cl- C6 haloalkyl.
  • Embodiment 123 The compound of any one ofEmbodiments 1-118, whereinR 5 is C3-
  • Embodiment 124 The compound of any one of Embodiments 1-118, wherein R 5 is cyano.
  • Embodiment 125 The compound of any one of Embodiments 1-118, wherein R 5 is -
  • Embodiment 128 The compound of any one of Embodiments 1-118 or 125-127, wherein one of R 5A and R 5B is hydrogen and the other of R 3A and R 5B is C1-C6 alkyl, C2-C6 alkenyl, or C1-C6 hydroxyalkyl.
  • Embodiment 129 The compound of any one of Embodiments 1-118 or 125-127, wherein one of R 5A and R 5B is C1-C6 alkyl and the other of R 5A and R 5B is C1-C6 alkyl, C2-C6 alkenyl, or C1-C6 hydroxyalkyl.
  • Embodiment 130 The compound of any one of Embodiments 1-118 or 125-127, wherein each of R 5A and R 5B is hydrogen.
  • Embodiment 131 The compound of any one of Embodiments 1-118 or 125-127, wherein each of R 5A and R 5B is an independently selected C1-C6 alkyl.
  • Embodiment 132 The compound of any one of Embodiments 1-131, wherein R 6 is hydrogen.
  • Embodiment 133 The compound of any one of Embodiments 1-131, wherein R 6 is halogen.
  • Embodiment 134 The compound of any one of Embodiments 1-131, wherein R 6 is Cl- C6 alkyl.
  • Embodiment 135. The compound of any one of Embodiments 1-134, wherein each of
  • R A and R B are independently selected from hydrogen, hydroxyl, C1-C6 alkoxy, C3-C6 cycloalkyl,
  • C2-C6 alkenyl, cyano, and C1-C6 alkyl optionally substituted with hydroxyl or C1-C6 alkoxy.
  • Embodiment 136 The compound of any one of Embodiments 1-135, wherein one of R A and R B is hydrogen and the other of R A and R B is hydroxyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C2-C6 alkenyl, cyano, or C1-C6 alkyl optionally substituted with hydroxyl or C1-C6 alkoxy.
  • Embodiment 137 Embodiment 137.
  • Embodiment 138 The compound of any one of Embodiments 1-136, wherein one of R A and R B is hydrogen and the other of R A and R B is hydroxyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C2-C6 alkenyl, or C1-C6 alkyl.
  • Embodiment 141 The compound of any one of Embodiments 1-134 or 139, wherein R A and R B together with the nitrogen atom to which they are attached form a 4-10 membered heterocyclyl.
  • Embodiment 146 The compound of any one of Embodiments 1-145, wherein each R D is hydrogen, hydroxyl, or C1-C6 alkoxy.
  • Embodiment 147 The compound of any one of Embodiments 1 -145, wherein each R D is C1-C6 alkyl, 4-10 membered heterocyclyl, or phenyl.
  • Embodiment 148 The compound of any one of embodiments 1-145, wherein each R D is C1-C6 alkyl, 4-10 membered heterocyclyl, or phenyl optionally substituted with 4-10 membered heterocyclyl, C3-C6 cycloalkyl, or cyano.
  • Embodiment 149 The compound of any one of embodiments 1-145, wherein each R D is C3-C6 cycloalkyl.
  • Embodiment 150 The compound of any one of embodiments 1-145, wherein each R D is C3-C6 cycloalkyl optionally substituted with C1-C6 alkyl optionally substituted with hydroxyl or Cl -C 6 alkoxy.
  • Embodiment 151 compound of any one of embodiments 1-150, wherein each R E is hydrogen, hydroxyl, or C1-C6 alkoxy.
  • Embodiment 152 The compound of any one of embodiments 1-150, wherein each R E is C1-C6 alkyl, 4-10 membered heterocyclyl, or phenyl.
  • Embodiment 153 The compound of any one of embodiments 1-150, wherein each R E is C1-C6 alkyl, 4-10 membered heterocyclyl, or phenyl optionally substituted with 4-10 membered heterocyclyl, C3-C6 cycloalkyl, or cyano.
  • Embodiment 154 The compound of any one of embodiments 1-150, wherein each R E is C3-C6 cycloalkyl.
  • Embodiment 155 The compound of any one of embodiments 1-150, wherein each R E is C3-C6 cycloalkyl optionally substituted with C1-C6 alkyl optionally substituted with hydroxyl or C1-C6 alkoxy.
  • Embodiment 156 The compound of any one of Embodiments 1-145, wherein one of R D and R E is hydrogen and the other of R D and R E is hydroxyl, C1-C6 alkyl, or C1-C6 alkoxy.
  • Embodiment 157 The compound of any one of Embodiments 1-145, wherein each of R D and R E is hydrogen.
  • Embodiment 158 The compound of any one of Embodiments 1-145, wherein each of R D and R E is an independently selected C1-C6 alkyl.
  • Embodiment 159 The compound of any one of Embodiments 1-158, wherein one of R F and R G is hydrogen and the other of R E and R G is phenyl or C1-C6 alkyl optionally substituted with oxo or -NR A R B .
  • Embodiment 160 The compound of any one of Embodiments 1-158, wherein one of R F and R G is hydrogen and the other of R F and R G is phenyl or C1-C6 alkyl substituted with oxo or -NR A R B .
  • Embodiment 161 The compound of any one of Embodiments 1-158, wherein one of R F and R G is hydrogen and the other of R F and R G is phenyl or C1-C6 alkyl.
  • Embodiment 162 The compound of any one of Embodiments 1-158, wherein each of R F and R G is hydrogen.
  • Embodiment 163 The compound of any one of Embodiments 1-158, wherein each of R F and R G is an independently selected C1-C6 alkyl.
  • Embodiment 164 The compound of Embodiment 1, wherein, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is a compound of Formula (I-A2): or a pharmaceutically acceptable salt thereof.
  • Embodiment 165 A compound selected from the group consisting of the compounds in Table A, or a pharmaceutically acceptable salt thereof.
  • Embodiment 166 A pharmaceutical composition comprising a compound of any one of Embodiments 1-165, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.
  • Embodiment 167 A method for treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of any one of Embodiments 1-165, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of Embodiment 166.
  • Embodiment 168 A method for treating cancer in a subject in need thereof, the method comprising (a) determining that the cancer is associated with a dysregulation of a PIK3CA gene, a PI3Ka protein, or expression or activity or level of any of the same; and (b) administering to the subject a therapeutically effective amount of a compound of any one of Embodiments 1-165, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of Embodiment 166.
  • Embodiment 169 Embodiment 169.
  • a method of treating a PI3Ka-associated cancer in a subject comprising administering to a subject identified or diagnosed as having a PI3Ka-associated cancer a therapeutically effective amount of a compound of any one of Embodiments 1-165 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of Embodiment 166.
  • Embodiment 170 A method for inhibiting mutant PI3Ka activity in a mammalian cell, the method comprising contacting the mammalian cell with an effective amount of a compound of any one of Embodiments 1-165, or a pharmaceutically acceptable salt thereof.

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Abstract

This disclosure provides compounds of Formula (I) and pharmaceutically acceptable salts thereof, that inhibit phosphatidylinositol 4,5-bisphosphate 3-kinase (PI3K) isoform alpha (PI3Kα).

Description

Compounds for Treating Cancer
CROSS-REFERENCE TO RELATED APPLICATIONS
This application claims the benefit of priority to U.S. Application No. 63/463,353 filed on May 2, 2023, the contents of which are hereby incorporated by reference.
TECHNICAL FIELD
This disclosure provides compounds of Formula (I) and pharmaceutically acceptable salts thereof, that inhibit phosphatidylinositol 4, 5 -bisphosphate 3-kinase (PI3K) isoform alpha (PI3Ka).
BACKGROUND
Phosphatidylinositol 4,5-bisphosphate 3-kinase (PI3K) isoform alpha (PI3Ka), encoded by the PIK3CA gene is a part of the PI3K/AKT/T0R signaling network and is altered in several human cancers.
Activation of the PI3K pathway occurs in approximately 30-50% human cancers and contributes to resistance to various anti-cancer therapies. (See, Bauer, T.M. et al., Pharmacol. Ther. 2015, 146, 53-60.) However, development of PI3K inhibitors has been problematic for several reasons, in particular, inability to specifically inhibit signaling by mutant PI3Ka while sparing wild-type PI3Ka, and the related dose-limiting toxicities that prevent sustained PI3K pathway suppression. (See, Hanker et al., Cancer Discovery, April 2019;9: 482-491.)
Thus, selectively targeting PI3Ka represents an approach for the treatment of proliferative disorders such as cancer.
SUMMARY
Some embodiments provide a compound of Formula (I):
Figure imgf000002_0001
or a pharmaceutically acceptable salt thereof, wherein:
R1 is hydrogen, cyano, C3-C6 cycloalkyl, C1-C6 alkyl optionally substituted with phenyl optionally substituted with halogen, C1-C6 thioalkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C1-C6 alkoxy alkyl;
R1 is hydrogen or C1-C6 alkyl; or R1 and R1 , together with the carbon atom to which they are attached form a C3-C10 cycloalkyl;
R2 is C6-C12 aryl optionally substituted with 1-4 independently selected R2A, 5-10 membered heteroaryl optionally substituted with 1-4 independently selected R2A, 4-10 membered heterocyclyl optionally substituted with 1-4 independently selected R2A, C4-C10 cycloalkyl optionally substituted with 1-4 independently selected R2A, C1-C6 alkoxyalkyl optionally substituted with -C(=O)NRARc, C1-C6 aralkyl optionally substituted with 1-4 independently selected R2A, or C1-C6 alkoxy optionally substituted with -C(=O)NRARc; each R2A is independently selected from:
(i) halogen,
(ii) cyano,
(iii) hydroxyl,
(iv) -NRARB,
(v) -C(=O)NRARB,
Figure imgf000003_0002
(vii) -NHC(=O)Rc,
(viii) -C(=O)RD,
Figure imgf000003_0001
(xii) -SO2NRFRG,
(xiii) -NHC(=O)C1-C6 alkyl optionally substituted with NRARB,
(xiv) C1-C6 haloalkyl,
(xv) C1-C6 hydroxyalkyl,
(xvi) 5-10 membered heteroaryl optionally substituted with 1-3 substituents independently selected from C1-C6 alkyl, -C(=O)NRARB, C1-C6 haloalkyl, and -NRARB, (xvii) 4-10 membered heterocyclyl optionally substituted with 1-3 substituents independently selected from hydroxyl, C1-C6 haloalkyl, -C(=O)C1-C6 alkyl, -SO2(C1-C6 alkyl), -SO2NRFRG, C6-C12 aryl, C1-C6 alkyl optionally substituted with C1-C6 alkoxy, -C(=O)NRARB, or -NHC(=O)C1-C6 alkyl optionally substituted with -NRARB,
(xviii) C1-C6 alkyl optionally substituted with 1-3 substituents independently selected from hydroxyl, oxo, -NRARB, -C(=O)NRARB, C1-C6 alkoxy, C3-C10 cycloalkyl, phenyl, and 4- 10 membered heterocyclyl optionally substituted with hydroxyl, C1-C6 alkyl, aralkyl, heteroaralkyl, -C(=O)NRARB, or -C(=O)C3-C6 cycloalkyl,
(xix) C1-C6 alkoxy optionally substituted with -NRARB or 4-10 membered heterocyclyl optionally substituted with C1-C6 alkyl, hydroxyl, aralkyl, heteroaralkyl, or -C(=O)C3-C6 cycloalkyl,
(xx) C3-C6 cycloalkyl optionally substituted with 4-10 membered heterocyclyl optionally substituted with C1-C6 alkyl;
(xxi) C6-C12 aryl optionally substituted with 1-3 substituents independently selected from hydroxyl, cyano, C1-C6 haloalkyl, -ORE, -C(=O)C1-C6 alkyl, -SO2(C1-C6 alkyl), -SO2NRFRG, 4- 10 membered heterocyclyl, or C1-C6 alkyl optionally substituted with C1-C6 alkoxy, hydroxyl, or -C(=O)NRARB; and
(xxii) 4-10 membered heterocyclyloxy optionally substituted with 1-3 substituents independently selected from hydroxyl, C1-C6 haloalkyl, -C(=O)C1-C6 alkyl, -SO2(C1-C6 alkyl), -SO2NRFRG, C6-C12 aryl, C1-C6 alkyl optionally substituted with C1-C6 alkoxy, -C(=O)NRARB, or -NHC(=O)C1-C6 alkyl optionally substituted with -NRARB; each RA and RB is independently selected from hydrogen, hydroxyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C2-C6 alkenyl, cyano, 4-10 membered heterocyclyl, and C1-C6 alkyl optionally substituted with hydroxyl or C1-C6 alkoxy, orRA and RB together with the nitrogen atom to which they are attached form a 4-10 membered heterocyclyl optionally substituted with 1-2 substituents independently selected from halogen, hydroxyl, C1-C6 alkyl, and -C(=O)C1-C6 alkyl; each Rc is independently selected from C3-C6 cycloalkyl, -C(=O)NHRY1, C2-C6 alkenyl, or a C1-C6 alkyl optionally substituted with -NRARB or with 4-10 membered heterocyclyl optionally substituted with C1-C6 alkyl or with C1-C6 hydroxylalkyl; each RD and RE is independently selected from hydrogen, hydroxyl, C1-C6 alkyl, phenyl, 4-10 membered heterocyclyl, C1-C6 alkoxy, and C3-C6 cycloalkyl, wherein the C1-C6 alkyl, 4- 10 membered heterocyclyl, and phenyl are optionally substituted with 4-10 membered heterocyclyl, C3-C6 cycloalkyl, or cyano, and the C3-C6 cycloalkyl is optionally substituted with C1-C6 alkyl optionally substituted with hydroxyl or C1-C6 alkoxy; each R3A and R3B is independently selected from hydrogen C1-C6 alkyl, C1-C6 alkoxy, and C1-C6 haloalkyl, or R3A and R3B, together with the carbon and nitrogen atoms, respectively, to which they are attached together form a 4-8 membered heterocyclyl group;
R4 is hydrogen, C1-C6 alkyl, or acrylamido;
R5 is hydrogen, C1-C6 alkyl, halogen, C1-C6 haloalkyl, C3-C6 cycloalkyl, cyano, - NR5AR5B, -NR5AC(=O)R5B, or -C(=O)NR5AR5B;
R5A and R5B are independently selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, and C1-C6 hydroxyalkyl;
R6 is hydrogen, halogen, or C1-C6 alkyl;
X is a bond,
Figure imgf000005_0001
Y is phenyl optionally substituted with 1-3 independently selected R\ naphthyl optionally substituted with 1-3 independently selected RY, or 5-10 membered heteroaryl optionally substituted with 1-3 independently selected RY; each Ry is independently selected from: halogen, cyano, hydroxyl, C1-C6 haloalkyl, Cl- C6 alkoxy, C1-C6 haloalkoxy, C1-C6 hydroxyalkyl, -NHC(=0)Rc, -C(=O)NHRY1, -CO2RA, -SO2NRFRG, -NHSO2RF, -S(=O)(=NRF)RG, -SO2(C1-C6 alkyl), -C(=O)NRARB, 5-6 membered heteroaryl, heteroaralkyl, and C1-C6 alkyl optionally substituted with -CO2RA or 5-6 membered heteroaryl optionally substituted with R^ ’;
RY1 is -SO2(C1-C6 alkyl), hydroxyl, or C1-C6 alkyl optionally substituted with oxo; and each RF and RG is independently selected from hydrogen, phenyl, and C1-C6 alkyl optionally substituted with oxo or -NRARB.
Also provided herein is a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.
Provided herein is a method for treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as provided herein. Also provided herein is a method for treating cancer in a subject in need thereof, comprising (a) determining that the cancer is associated with a dysregulation of a PIK3CA gene, a PI3Ka protein, or expression or activity or level of any of the same; and (b) administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as provided herein.
Provided herein is a method of treating a PI3Ka-associated disease in a subject, comprising administering to a subject identified or diagnosed as having a PI3Ka-associated disease a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as provided herein.
This disclosure also provides a method of treating a PI3Ka-associated disease in a subject, comprising: determining that the cancer in the subject is a PI3Ka-associated disease; and administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as provided herein.
Further provided herein is a method of treating a PI3Ka-associated cancer in a subject, comprising administering to a subject identified or diagnosed as having a PI3Ka-associated cancer a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as provided herein.
This disclosure also provides a method of treating a PI3Ka-associated cancer in a subject, comprising: determining that the cancer in the subject is a PI3Ka-associated cancer; and administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as provided herein.
Provided herein is a method of treating a subject, comprising administering a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as provided herein, to a subject having a clinical record that indicates that the subject has a dysregulation of &PIK3CA gene, a PI3Ka protein, or expression or activity or level of any of the same.
This disclosure also provides a method for inhibiting PI3Ka in a mammalian cell, comprising contacting the mammalian cell with an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.
Other embodiments include those described in the Detailed Description and/or in the claims. Additional Definitions
To facilitate understanding of the disclosure set forth herein, a number of additional terms are defined below. Generally, the nomenclature used herein and the laboratory procedures in organic chemistry, medicinal chemistry, and pharmacology described herein are those well-known and commonly employed in the art. Unless defined otherwise, all technical and scientific terms used herein generally have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Each of the patents, applications, published applications, and other publications that are mentioned throughout the specification and the attached appendices are incorporated herein by reference in their entireties.
The term “about” when referring to a number or a numerical range means that the number or numerical range referred to is an approximation, for example, within experimental variability and/or statistical experimental error, and thus the number or numerical range may vary up to ±10% of the stated number or numerical range.
The term “acceptable” with respect to a formulation, composition or ingredient, as used herein, means having no persistent detrimental effect on the general health of the subject being treated.
The term "inhibit" or "inhibition of' means to reduce by a measurable amount, or to prevent entirely (e.g., 100% inhibition).
The phrase "therapeutically effective amount" means an amount of compound that, when administered to a subject in need of such treatment, is sufficient to (i) treat a PI3Ka protein- associated disease, (ii) attenuate, ameliorate, or eliminate one or more symptoms of the particular disease, or (iii) delay the onset of one or more symptoms of the particular disease described herein.
The term “pharmaceutically acceptable salt” refers to a formulation of a compound that does not cause significant irritation to an organism to which it is administered and does not abrogate the biological activity and properties of the compound.
As used herein, the term “subject” refer to any animal, including mammals such as primates (e g., humans), mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, primates, and humans. In some embodiments, the subject is a human. In some embodiments, the subject has experienced and/or exhibited at least one symptom of the disease to be treated and/or prevented.
As used herein, terms “treat” or “treatment” refer to therapeutic or palliative measures. Beneficial or desired clinical results include, but are not limited to, alleviation, in whole or in part, of symptoms associated with a disease, diminishment of the extent of disease, stabilized (i.e., not worsening) state of disease, delay or slowing of disease progression, amelioration or palliation of the disease state (e.g., one or more symptoms of the disease), and remission (whether partial or total), whether detectable or undetectable. “Treatment” can also mean prolonging survival as compared to expected survival if not receiving treatment.
The term “halogen” refers to fluoro (F), chloro (Cl), bromo (Br), or iodo (I).
The term “oxo” refers to a divalent doubly bonded oxygen atom (i.e., “=O”). As used herein, oxo groups are attached to carbon atoms to form carbonyls.
The term “hydroxyl” refers to an -OH radical.
The term “cyano” refers to a -CN radical.
The term “alkyl” refers to a saturated acyclic hydrocarbon radical that may be a straight chain or branched chain, containing the indicated number of carbon atoms. For example, Ci-io indicates that the group may have from 1 to 10 (inclusive) carbon atoms in it. Non-limiting examples include methyl, ethyl, z.w-propyl, tert-butyl, n-hexyl. The term “saturated” as used in this context means only single bonds present between constituent carbon atoms and other available valences occupied by hydrogen and/or other substituents as defined herein.
The term “haloalkyl” refers to an alkyl, in which one or more hydrogen atoms is/are replaced with an independently selected halogen.
The term “alkoxy” refers to an -O-alkyl radical (e.g., -OCH3).
The term “alkoxyalkyl” refers to an -alkyl-O-alkyl radical (e.g., -CH2CH2OCH3)
The term “thioalkyl” refers to an -S-alkyl radical (e.g., -SCH3) or an -alkyl- S-alkyl radical (e.g., -CH2CH2SCH3).
The term “hydroxyalkyl” refers to an alkyl, in which one or more hydrogen atoms is/are replaced with hydroxyl.
The term “aryl” refers to a 6-20 membered all carbon ring system wherein at least one ring in the system is aromatic (e.g., 6-carbon monocyclic, 10-carbon bicyclic, or 14-carbon tricyclic aromatic ring system). Examples of aryl groups include phenyl, naphthyl, tetrahydronaphthyl, 2,3- dihydro-lH-indene, and the like.
The term “cycloalkyl” as used herein refers to cyclic saturated hydrocarbon groups having, e.g., 3 to 20 ring carbons, preferably 3 to 16 ring carbons, and more preferably 3 to 12 ring carbons or 3-10 ring carbons or 3-6 ring carbons. Examples of cycloalkyl groups include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Cycloalkyl may include multiple fused and/or bridged rings. Non-limiting examples of fused/bridged cycloalkyl includes: bicyclofl.1.0]butane, bicyclo[2.1.0]pentane, bicyclofl. l. l]pentane, bicyclo[3.1.0]hexane, bicyclo[2.1.1]hexane, bicyclo[3.2.0]heptane, bicyclo[4.1.0]heptane, bicyclo[2.2.1]heptane, bicyclo[3.1.1]heptane, bicyclo[4.2.0]octane, bicyclo[3.2. l]octane, bicyclo[2.2.2]octane, and the like. Cycloalkyl also includes spirocyclic rings (e.g., spirocyclic bicycle wherein two rings are connected through just one atom). Non-limiting examples of spirocyclic cycloalkyls include spiro[2.2]pentane, spiro[2.5]octane, spiro[3.5]nonane, spiro[3.5]nonane, spiro[3.5]nonane, spiro[4.4]nonane, spiro[2.6]nonane, spiro[4.5]decane, spiro[3.6]decane, spiro[5.5]undecane, and the like. The term “saturated” as used in this context means only single bonds present between constituent carbon atoms.
The term “heteroaryl”, as used herein, refers to a ring system having 5 to 20 ring atoms, such as 5, 6, 9, 10, or 14 ring atoms; wherein at least one ring in the system contains one or more heteroatoms independently selected from the group consisting of N, O, S, Si, and B, and at least one ring in the system is aromatic (but does not have to be a ring which contains a heteroatom, e.g. tetrahydroisoquinolinyl, e.g., tetrahydroquinolinyl). Heteroaryl groups can include monocyclic, bridged, fused, and spiro ring systems, so long as one ring in the system is aromatic. Examples of heteroaryl include thienyl, pyridinyl, furyl, oxazolyl, oxadiazolyl, pyrrolyl, imidazolyl, triazolyl, thiodiazolyl, pyrazolyl, isoxazolyl, thiadiazolyl, pyranyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, thiazolyl benzothienyl, benzoxadiazolyl, benzofuranyl, benzimidazolyl, benzotriazolyl, cinnolinyl, indazolyl, indolyl, isoquinolinyl, isothiazolyl, naphthyridinyl, purinyl, thienopyridinyl, pyrido[2,3-J]pyrimidinyl, pyrrolo[2,3-/>]pyridinyl, quinazolinyl, quinolinyl, thieno[2,3- c]pyridinyl, pyrazolo[3,4-Z>]pyridinyl, pyrazolo[3,4-c]pyridinyl, pyrazolo[4,3-c]pyridine, pyrazolo[4,3-Z>]pyridinyl, tetrazolyl, chromane, 2,3-dihydrobenzo[Z>][l,4]dioxine, benzo[d][l,3]dioxole, 2,3 -dihydrobenzofuran, tetrahydroquinoline, 2,3- dihydrobenzo[/>][l,4]oxathiine, isoindoline, and others. In some embodiments, the heteroaryl is selected from thienyl, pyridinyl, furyl, pyrazolyl, imidazolyl, isoindolinyl, pyranyl, pyrazinyl, and pyrimidinyl. For purposes of clarification, heteroaryl also includes aromatic lactams, aromatic cyclic ureas, or vinylogous analogs thereof, in which each ring nitrogen adjacent to a carbonyl is tertiary (i.e., all three valences are occupied by non-hydrogen substituents), such as one or more
Figure imgf000010_0002
Figure imgf000010_0003
imidazolone (e.g.
Figure imgf000010_0004
, ), wherein each ring nitrogen adjacent to a carbonyl is tertiary (i.e., the oxo group (i.e., “=O”) herein is a constituent part of the heteroaryl ring).
The term “heterocyclyl” refers to a saturated or partially unsaturated ring systems with 3- 16 ring atoms (e.g., 3-8 membered monocyclic, 5-12 membered bicyclic, or 10-14 membered tricyclic ring system) having at least one heteroatom selected from O, N, S, Si, and B, wherein one or more ring atoms may be substituted by 1-3 oxo (forming, e.g., a lactam) and one or more N or S atoms may be substituted by 1-2 oxido (forming, e.g., an N-oxide, an S-oxide, or an S,S-dioxide), valence permitting. Heterocyclyl groups include monocyclic, bridged, fused, and spiro ring systems. Examples of heterocyclyl groups include piperazinyl, pyrrolidinyl, dioxanyl, morpholinyl, tetrahydrofuranyl, tetrahydropyridyl, dihydropyrazinyl, dihydropyridyl, dihydropyrrolyl, dihydrofuranyl, dihydrothiophenyl, and the like. Heterocyclyl may include multiple fused and bridged rings. Non-limiting examples of fused/bridged heteorocyclyl includes: 2-azabicyclo[ 1.1.0]butane, 2-azabicyclo[2.1.0]pentane, 2-azabicyclo[l.l.l]pentane, 3- azabicyclo[3.1.0]hexane, 5-azabicyclo[2.1. l]hexane, 3 -azabicy clo[3.2.0]heptane, octahydrocyclopenta[c]pyrrole, 3-azabicyclo[4.1.0]heptane, 7-azabicyclo[2.2.1]heptane, 6- azabicy clo[3.1.1 ]heptane, 7-azabicyclo[4.2.0]octane, 2-azabicyclo[2.2.2]octane,
Figure imgf000010_0001
azabicyclo[3.2.1]octane, 2-oxabicyclo[l .1.0]butane, 2-oxabicyclo[2.1.0]pentane, 2- oxabicyclo[ 1.1. l]pentane, 3-oxabicyclo[3.1.0]hexane, 5-oxabicyclo[2.1.1 ]hexane, 3- oxabicyclo[3.2.0]heptane, 3-oxabicyclo[4.1.0]heptane, 7-oxabicyclo[2.2.1]heptane, 6- oxabi cyclo[3.1 .1 ]heptane, 7-oxabicyclo[4.2.0]octane, 2-oxabicyclo[2.2.2]octane, 3- oxabicyclo[3.2.1]octane, and the like. Heterocyclyl also includes spirocyclic rings ( (e.g., spirocyclic bicycle wherein two rings are connected through just one atom). Non-limiting examples of spirocyclic heterocyclyls include 2-azaspiro[2.2]pentane, 4-azaspiro[2.5]octane, 1- azaspiro[3.5]nonane, 2-azaspiro[3.5]nonane, 7-azaspiro[3.5]nonane, 2-azaspiro[4.4]nonane, 6- azaspiro[2.6]nonane, l,7-diazaspiro[4.5]decane, 7-azaspiro[4.5]decane 2,5- diazaspiro[3.6]decane, 3-azaspiro[5.5]undecane, 2-oxaspiro[2.2]pentane, 4-oxaspiro[2.5]octane, l-oxaspiro[3.5]nonane, 2-oxaspiro[3.5]nonane, 7-oxaspiro[3.5]nonane, 2-oxaspiro[4.4]nonane, 6- oxaspiro[2.6]nonane, l,7-dioxaspiro[4.5]decane, 2,5-dioxaspiro[3.6]decane, 1- oxaspiro[5.5]undecane, 3-oxaspiro[5.5]undecane, 3-oxa-9-azaspiro[5.5]undecane and the like.
A "heterocyclyloxy” refers to an -O-heterocyclyl radical (e.g.,
Figure imgf000011_0001
).
An “aralkyl” refers to an aryl group, as defined herein, connected to the remainder of the molecule via a divalent C1-C6 alkyl group, as described herein. Non-limiting examples of an aralkyl group are benzyl, ethylphenyl, methylnaphthyl, and the like.
A “heteroaralkyl” refers to a heteroaryl group, as defined herein, connected to the remainder of the molecule via a divalent C1-C6 alkyl group, as described herein. Non-limiting examples of an aralkyl group are methylpyridyl, ethylpyrimidinyl, methylimidazolyl, and the like.
As used herein, examples of aromatic rings include: benzene, pyridine, pyrimidine, pyrazine, pyridazine, pyridone, pyrrole, pyrazole, oxazole, thioazole, isoxazole, isothiazole, and the like.
As used herein, when a ring is described as being “partially unsaturated”, it means said ring has one or more additional degrees of unsaturation (in addition to the degree of unsaturation attributed to the ring itself; e.g., one or more double or tirple bonds between constituent ring atoms), provided that the ring is not aromatic. Examples of such rings include: cyclopentene, cyclohexene, cycloheptene, dihydropyridine, tetrahydropyridine, dihydropyrrole, dihydrofuran, dihydrothiophene, and the like.
For the avoidance of doubt, and unless otherwise specified, for rings and cyclic groups (e.g., aryl, heteroaryl, heterocyclyl, cycloalkyl, and the like described herein) containing a sufficient number of ring atoms to form bicyclic or higher order ring systems (e.g., tricyclic, polycyclic ring systems), it is understood that such rings and cyclic groups encompass those having fused rings, including those in which the points of fusion are located (i) on adjacent ring atoms (e.g., [x.x.O] ring systems, in which 0 represents a zero atom bridge (e.g.,
Figure imgf000012_0001
single ring atom (spiro-fused ring systems) (
Figure imgf000012_0002
r (iii) a contiguous array of ring atoms (bridged ring systems having all bridge lengths > 0) (e.g.,
Figure imgf000012_0003
Figure imgf000012_0004
In addition, atoms making up the compounds of the present embodiments are intended to include all isotopic forms of such atoms. Isotopes, as used herein, include those atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include tritium and deuterium, and isotopes of carbon include 13C and 14C.
In addition, the compounds generically or specifically disclosed herein are intended to include all tautomeric forms. Thus, by way of example, a compound containing the moiety:
Figure imgf000012_0006
encompasses the tautomeric form containing the moiety:
Figure imgf000012_0005
pyridinyl or pyrimidinyl moiety that is described to be optionally substituted with hydroxyl encompasses pyridone or pyrimidone tautomeric forms.
The term “compound,” as used herein is meant to include all stereoisomers, geometric isomers, tautomers, and isotopically enriched variants of the structures depicted. Compounds herein identified by name or structure as one particular tautomeric form are intended to include other tautomeric forms unless otherwise specified.
It is understood that, in any compound described herein having one or more chiral centers, if an absolute stereochemistry is not expressly indicated, then each center may independently be of R-configuration or S-configuration or a mixture thereof. Thus, the compounds provided herein may be enantiomerically pure, enantiomerically enriched, racemic mixture, diastereomerically pure, diastereomerically enriched, or a stereoisomeric mixture. In addition it is understood that, in any compound described herein having one or more double bond(s) generating geometrical isomers that can be defined as E or Z, each double bond may independently be E or Z a mixture thereof.
The details of one or more embodiments of this disclosure are set forth in the accompanying drawings and the description below. Other features and advantages of the present disclosure will be apparent from the description and drawings, and from the claims.
DETAILED DESCRIPTION
This disclosure provides compounds of Formula (I) and pharmaceutically acceptable salts thereof, that inhibit phosphatidylinositol 4,5 -bisphosphate 3-kinase (PI3K) isoform alpha (PI3Ka). These compounds are useful for treating a disease in which increased PI3Ka activation contributes to the pathology, symptoms, and/or progression of the disease (e.g., cancer) in a subject.
Formulae (I) Compounds
Some embodiments provide a compound of Formula (I):
Figure imgf000013_0001
or a pharmaceutically acceptable salt thereof, wherein:
R1 is hydrogen, cyano, C3-C6 cycloalkyl, C1-C6 alkyl optionally substituted with phenyl optionally substituted with halogen, C1-C6 thioalkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C1-C6 alkoxy alkyl;
R1 is hydrogen or C1-C6 alkyl; or R1 and R1 , together with the carbon atom to which they are attached form a C3-C10 cycloalkyl;
R2 is C6-C12 aryl optionally substituted with 1-4 independently selected R2A, 5-10 membered heteroaryl optionally substituted with 1-4 independently selected R2A, 4-10 membered heterocyclyl optionally substituted with 1-4 independently selected R2A, C4-C10 cycloalkyl optionally substituted with 1-4 independently selected R2A, C1-C6 alkoxyalkyl optionally substituted with -C(=O)NRARc, C1-C6 aralkyl optionally substituted with 1-4 independently selected R2A, or C1-C6 alkoxy optionally substituted with -C(=O)NRARc; each R2A is independently selected from:
(i) halogen,
(ii) cyano,
(iii) hydroxyl,
(iv) -NRARB,
(v) -C(=O)NRARB,
^Y^NRARB
(vi) O
(vii) -NHC(=O)Rc,
(viii) -C(=O)RD,
Figure imgf000014_0001
(xii) -SO2NRFRG,
(xiii) -NHC(=O)C1-C6 alkyl optionally substituted with NRARB,
(xiv) C1-C6 haloalkyl,
(xv) C1-C6 hydroxyalkyl,
(xvi) 5-10 membered heteroaryl optionally substituted with 1-3 substituents independently selected from C1-C6 alkyl, C1-C6 haloalkyl, -C(=O)NRARB, and -NRARB,
(xvii) 4-10 membered heterocyclyl optionally substituted with 1-3 substituents independently selected from hydroxyl, C1-C6 haloalkyl, -C(=O)C1-C6 alkyl, -SO2(C1-C6 alkyl), -SO2NRFRG, C6-C12 aryl, C1-C6 alkyl optionally substituted with C1-C6 alkoxy, -C(=O)NRARB, or -NHC(=O)C1-C6 alkyl optionally substituted with -NRARB,
(xviii) C1-C6 alkyl optionally substituted with 1-3 substituents independently selected from hydroxyl, oxo, -NRARB, -C(=O)NRARB, C1-C6 alkoxy, C3-C10 cycloalkyl, phenyl, and 4- 10 membered heterocyclyl optionally substituted with hydroxyl, C1-C6 alkyl, aralkyl, heteroaralkyl, -C(=O)NRARB, or -C(=O)C3-C6 cycloalkyl, (xix) C1-C6 alkoxy optionally substituted with -NRARB or 4-10 membered heterocyclyl optionally substituted with C1-C6 alkyl, hydroxyl, aralkyl, heteroaralkyl, or -C(=O)C3-C6 cycloalkyl,
(xx) C3-C6 cycloalkyl optionally substituted with 4-10 membered heterocyclyl optionally substituted with C1-C6 alkyl;
(xxi) C6-C12 aryl optionally substituted with 1-3 substituents independently selected from hydroxyl, cyano, C1-C6 haloalkyl, -ORE, -C(=O)C1-C6 alkyl, -SO2(C1-C6 alkyl), -SChNRFRG, 4- 10 membered heterocyclyl, or C1-C6 alkyl optionally substituted with C1-C6 alkoxy, hydroxyl, or -C(=O)NRARB; and
(xxii) 4-10 membered heterocyclyloxy optionally substituted with 1-3 substituents independently selected from hydroxyl, C1-C6 haloalkyl, -C(=O)C1-C6 alkyl, -SO2(C1-C6 alkyl), -SO2NRFRG, C6-C12 aryl, C1-C6 alkyl optionally substituted with C1-C6 alkoxy, -C(=O)NRARB, or -NHC(=O)C1-C6 alkyl optionally substituted with -NRARB; each RA and RB is independently selected from hydrogen, hydroxyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C2-C6 alkenyl, cyano, 4-10 membered heterocyclyl, and C1-C6 alkyl optionally substituted with hydroxyl or C1-C6 alkoxy, orRA and RB together with the nitrogen atom to which they are attached form a 4-10 membered heterocyclyl optionally substituted with 1-2 substituents independently selected from halogen, hydroxyl, C1-C6 alkyl, and -C(=O)C1-C6 alkyl; each Rc is independently selected from C3-C6 cycloalkyl, -C(=O)NHRY1, C2-C6 alkenyl, or a C1-C6 alkyl optionally substituted with -NRARB or with 4-10 membered heterocyclyl optionally substituted with C1-C6 alkyl or with C1-C6 hydroxylalkyl; each RD and RE is independently selected from hydrogen, hydroxyl, C1-C6 alkyl, phenyl, 4-10 membered heterocyclyl, C1-C6 alkoxy, and C3-C6 cycloalkyl, wherein the C1-C6 alkyl, 4- 10 membered heterocyclyl, and phenyl are optionally substituted with 4-10 membered heterocyclyl, C3-C6 cycloalkyl, or cyano, and the C3-C6 cycloalkyl is optionally substituted with C1-C6 alkyl optionally substituted with hydroxyl or C1-C6 alkoxy; each R3A and R3B is independently selected from hydrogen C1-C6 alkyl, C1-C6 alkoxy, and C1-C6 haloalkyl, or R3A and R3B, together with the carbon and nitrogen atoms, respectively, to which they are attached together form a 4-8 membered heterocyclyl group;
R4 is hydrogen, C1-C6 alkyl, or acrylamido; R5 is hydrogen, C1-C6 alkyl, halogen, C1-C6 haloalkyl, C3-C6 cycloalkyl, cyano, - NR5AR5B, -NR5AC(=O)R5B, or -C(=O)NR5AR5B;
R?A and R5B are independently selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, and
C1-C6 hydroxyalkyl;
R6 is hydrogen, halogen, or C1-C6 alkyl;
X is a bond,
Figure imgf000016_0001
Y is phenyl optionally substituted with 1-3 independently selected RY, naphthyl optionally substituted with 1-3 independently selected R\ or 5-10 membered heteroaryl optionally substituted with 1-3 independently selected Ry; each RY is independently selected from: halogen, cyano, hydroxyl, C1-C6 haloalkyl, Cl- C6 alkoxy, C1-C6 haloalkoxy, C1-C6 hydroxyalkyl, -NHC(=O)Rc, -C(=O)NHRY1, -CO2RA, -SO2NRFRG, -NHSO2RF, -S(=O)(=NRF)RG, -SO2(C1-C6 alkyl), -C(=O)NRARB, 5-6 membered heteroaryl, heteroaralkyl, and C1-C6 alkyl optionally substituted with -CO2RA or 5-6 membered heteroaryl optionally substituted with R'1 1;
RY1 is -SO2(C1-C6 alkyl), hydroxyl, or C1-C6 alkyl optionally substituted with oxo; and each RF and RG is independently selected from hydrogen, phenyl, and C1-C6 alkyl optionally substituted with oxo or -NRARB.
In some embodiments, the compound of Formula (I) or a pharmaceutically acceptable salt thereof, is a compound of Formula (I- A):
Figure imgf000016_0002
or a pharmaceutically acceptable salt thereof, wherein:
R1 is hydrogen, cyano, C3-C6 cycloalkyl, C1-C6 alkyl optionally substituted with phenyl optionally substituted with halogen, C1-C6 thioalkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C1-C6 alkoxy alkyl;
R2 is aryl optionally substituted with 1-4 independently selected R2A, 5-10 membered heteroaryl optionally substituted with 1-4 independently selected R2A, 4-10 membered heterocyclyl optionally substituted with 1 -4 independently selected R2A, C4-C10 cycloalkyl optionally substituted with 1-4 independently selected R2A, C1-C6 alkoxyalkyl optionally substituted with -C(=O)NRARc, or C1-C6 alkoxy optionally substituted with -C(=O)NRARc; each R2A is independently selected from:
(i) halogen,
(ii) cyano,
(iii) hydroxyl,
(iv) -NRARB,
(v) -C(=O)NRARB,
Figure imgf000017_0001
(vii) -NHC(=O)Rc,
(viii) -C(=O)NRDRE,
(ix) -C(=O)ORF,
(x) -SO2RF,
(xi) -NHSO2RF,
(xii) -SO2NRFRG,
(xiii) -NHC(=O)C1-C6 alkyl optionally substituted with NRARB,
(xiv) C1-C6 haloalkyl,
(xv) C1-C6 hydroxyalkyl,
(xvi) 5-10 membered heteroaryl optionally substituted with 1-3 substituents independently selected from C1-C6 alkyl and -NRARB,
(xvii) 4-10 membered heterocyclyl optionally substituted with 1-3 substituents independently selected from hydroxyl, C1-C6 haloalkyl, -C(=O)C1-C6 alkyl, -SO2(C1-C6 alkyl), -SO2NRFRG, C1-C6 alkyl optionally substituted with C1-C6 alkoxy, -C(=O)NRARB, or -NHC(=O)C1-C6 alkyl optionally substituted with -NRARB,
(xviii) C1-C6 alkyl optionally substituted with 1-3 substituents independently selected from hydroxyl, oxo, -NRARB, -C(=O)NRARB, C1-C6 alkoxy, and 4-10 membered heterocyclyl optionally substituted with hydroxyl, C1-C6 alkyl, aralkyl, heteroaralkyl, -C(=O)NRARB, or - C(=O)C3-C6 cycloalkyl, (xix) C1-C6 alkoxy optionally substituted with -NRARB or 4-10 membered heterocyclyl optionally substituted with C1-C6 alkyl, aralkyl, heteroaralkyl, or -C(=O)C3-C6 cycloalkyl, and
(xx) C3-C6 cycloalkyl optionally substituted with 4-10 membered heterocyclyl optionally substituted with C1-C6 alkyl; each RA and RB is independently selected from hydrogen, hydroxyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C2-C6 alkenyl, cyano, and C1-C6 alkyl optionally substituted with hydroxyl or C1-C6 alkoxy, or RA and RB together with the nitrogen atom to which they are attached form a 4-10 membered heterocyclyl optionally substituted with 1-2 substituents independently selected from halogen, C1-C6 alkyl, and -C(=O)C1-C6 alkyl; each Rc is independently selected from C3-C6 cycloalkyl, -C(=O)NHRY1, C2-C6 alkenyl, or a C1-C6 alkyl optionally substituted with -NRARB or with 4-10 membered heterocyclyl optionally substituted with C1-C6 alkyl or with C1-C6 hydroxylalkyl; each RD and RE is independently selected from hydrogen, hydroxyl, C1-C6 alkyl, and Cl- C6 alkoxy; each R3A and R3B is independently selected from hydrogen C1-C6 alkyl, C1-C6 alkoxy, and C1-C6 haloalkyl, or R3A and R3B, together with the carbon and nitrogen atoms, respectively, to which they are attached together form a 4-8 membered heterocyclyl group;
R4 is hydrogen, C1-C6 alkyl, or acrylamido;
R5 is hydrogen, C1-C6 alkyl, halogen, C1-C6 haloalkyl, C3-C6 cycloalkyl, cyano, - NR5AR5B, -NR5AC(=O)R5B, or -C(=O)NR5AR5B;
R5A and R5B are independently selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, and C1-C6 hydroxyalkyl;
R6 is hydrogen, halogen, or C1-C6 alkyl;
X is a bond,
Figure imgf000018_0001
Y is phenyl optionally substituted with 1 -3 independently selected R\ naphthyl optionally substituted with 1-3 independently selected RY, or 5-10 membered heteroaryl optionally substituted with 1-3 independently selected RY; each Ry is independently selected from: halogen, cyano, hydroxyl, C1-C6 haloalkyl, Cl- C6 alkoxy, C1-C6 haloalkoxy, C1-C6 hydroxyalkyl, -NHC(=O)Rc, -C(=O)NHRY1, -CO2RA, -SO2NRFRG, -NHSO2Rr, -S(=O)(=NRF)RG, -SO2(C1-C6 alkyl), -C(=O)NRARB, 5-6 membered heteroaryl, heteroaralkyl, and C1-C6 alkyl optionally substituted with -CChRA or 5-6 membered heteroaryl optionally substituted with R?1;
RY1 is -SO2(C1-C6 alkyl) or C1-C6 alkyl optionally substituted with oxo; and each RF and RG is independently selected from hydrogen, phenyl, and C1-C6 alkyl optionally substituted with oxo or -NRARB.
In some embodiments, R1 is hydrogen.
In some embodiments, R1 is cyano.
In some embodiments, R1 is C3-C6 cycloalkyl. In some embodiments, R1 is cyclopropyl or cyclobutyl.
In some embodiments, R1 is C1-C6 alkyl optionally substituted with phenyl optionally substituted with halogen. In some embodiments, R1 is C1-C6 alkyl substituted with phenyl optionally substituted with halogen. In some embodiments, R1 is C1-C6 alkyl substituted with phenyl substituted with halogen. In some embodiments, R1 is para-fluorobenzyl. In some embodiments, R1 is C1-C6 alkyl substituted with phenyl. In some embodiments, R1 is benzyl. In some embodiments, R1 is ethyl- 1 -phenyl or ethyl-2-phenyl. In some embodiments, R1 is C1-C6 alkyl. In some embodiments, R1 is methyl, ethyl, or isopropyl. In some embodiments, R1 is methyl.
In some embodiments, R1 is C1-C6 thioalkyl. In some embodiments, R1 is C1-C3 thioalkyl. In some embodiments, R1 is thiomethyl, thioethyl, or thiopropyl. In some embodiments, R1 is methyl-thiomethyl, methyl-thioethyl, or ethyl-thiom ethyl. In some embodiments, R1 is thiomethyl.
In some embodiments, R1 is C1-C6 haloalkyl. In some embodiments, R1 is C1-C3 haloalkyl. In some embodiments, R1 is C1-C3 fluoroalkyl. In some embodiments, R1 is CF3. In some embodiments, R1 is CHF2.
In some embodiments, R1 is C1-C6 alkoxy. In some embodiments, R1 is C1-C3 alkoxy. In some embodiments, R1 is -OCH3, -OCH2CH3, or -OCH2CH2CH3. In some embodiments, R1 is - OCH3.
In some embodiments, R1 is C1-C6 alkoxyalkyl. In some embodiments, R1 is C1-C3 alkoxyalkyl. In some embodiments, R1 is -CH2OCH3, -CH2OCH2CH3, or -CH2CH2OCH3. In some embodiments, R1 is CH2OCH3.
In some embodiments, R1 is hydrogen.
In some embodiments, R1 is C1-C6 alkyl. In some embodiments, R1 is methyl. In some embodiments, R1 and R1 , together with the carbon atom to which they are attached form a C3-C10 cycloalkyl. In some embodiments, R1 and R1 , together with the carbon atom to which they are attached form a cyclopropyl.
In some embodiments, R2 is C6-C12 aryl optionally substituted with 1-4 independently selected R2A. In some embodiments, R2 is phenyl optionally substituted with 1-4 independently selected R2A. In some embodiments, R2 is phenyl substituted with 1 or 2 independently selected R2A. In some embodiments, R2 is phenyl substituted with 1 R2A. In some embodiments, R2 is phenyl substituted with 2 independently selected R2A. In some embodiments, R2 is phenyl optionally substituted with 3 independently selected R2A. In some embodiments, R2 is phenyl.
In some embodiments, R2 is 2,3-dihydro-lH-indenyl optionally substituted with 1-4 independently selected R2A. In some embodiments, R2 is 2,3-dihydro-lH-indenyl substituted with 1 or 2 independently selected R2A. In some embodiments, R2 is 2,3-dihydro-lH-indenyl substituted with 1 R2A. In some embodiments, R2 is 2,3-dihydro-lH-indenyl substituted with 2 independently selected R2A. In some embodiments, R2 is 2,3-dihydro-lH-indenyl optionally substituted with 3 independently selected R2A. In some embodiments, R2 is 2,3-dihydro-lH- indenyl.
In some embodiments, R2 is 5-10 membered heteroaryl optionally substituted with 1-4 independently selected R2A. In some embodiments, R2 is 5-10 membered heteroaryl substituted with 1 or 2 independently selected R2A. In some embodiments, R2 is 5-10 membered heteroaryl substituted with 1 R2A. In some embodiments, R2 is 5-10 membered heteroaryl substituted with 2 independently selected R2A. In some embodiments, R2 is 5-10 membered heteroaryl optionally substituted with 3 independently selected R2A. In some embodiments, R2 is 5-10 membered heteroaryl.
In some embodiments, R2 is 6 membered heteroaryl optionally substituted with 1-4 independently selected R2A. In some embodiments, R2 is 6 membered heteroaryl substituted with 1 or 2 independently selected R2A. In some embodiments, R2 is 6 membered heteroaryl substituted with 1 R2A. In some embodiments, R2 is 6 membered heteroaryl substituted with 2 independently selected R2A. In some embodiments, R2 is 6 membered heteroaryl optionally substituted with 3 independently selected R2A. In some embodiments, R2 is 6 membered heteroaryl.
In some embodiments, R2 is 9 membered heteroaryl optionally substituted with 1-4 independently selected R2A. In some embodiments, R2 is 9 membered heteroaryl substituted with 1 or 2 independently selected R2A. In some embodiments, R2 is 9 membered heteroaryl substituted with 1 R2A. In some embodiments, R2 is 9 membered heteroaryl substituted with 2 independently selected R2A. In some embodiments, R2 is 9 membered heteroaryl optionally substituted with 3 independently selected R2A. In some embodiments, R2 is 9 membered heteroaryl.
In some embodiments, the heteroaryl of R2 is pyridinyl, pyrimidinyl, pyridazinyl, indole, indazole, azaindole, azaindazole, indoline, azaindoline, isoindoline, azaisoindoline, benzimidazolyl, benzoxazolyl, benzothiazolyl, benzoisoxazolyl, benzisothiazolyl, quinolinyl, 6,7- dihydro-5H-cyclopenta[c]pyridinyl, 6,7-dihydro-5H-cyclopenta[b]pyridinyl, chromanyl, 3,4- dihydro-2H-112-quinolinyl, 5,6,7,8-tetrahydroquinazolinyl, 6,7-dihydro-5H- cyclopenta[c]pyridinyl, 3,4-dihydro-2H-pyrano[2,3-b]pyridinyl, 3,4-dihydro-2H-pyrano[2,3- c]pyridinyl, 3,4-dihydro-2H-pyrano[3,2-b]pyridinyl, 7,8-dihydro-6H-pyrano[3,2-d]pyrimidinyl, 5,6,7,8-tetrahydroquinazolinyl, or isoquinolinyl. In some embodiments, the heteroaryl of R2 is pyridinyl or pyrimidinyl. In some embodiments, the heteroaryl of R2 is indole, indazole, azaindole, azaindazole, indoline, azaindoline, isoindoline, or azaisoindoline. In some embodiments, the heteroaryl of R2 is 6,7-dihydro-5H-cyclopenta[c]pyridinyl, 6,7-dihydro-5H- cyclopenta[b]pyridinyl, chromanyl, 3,4-dihydro-2H-112-quinolinyl, 5,6,7,8- tetrahydroquinazolinyl, 6,7-dihydro-5H-cyclopenta[c]pyridinyl, 3,4-dihydro-2H-pyrano[2,3- b]pyridinyl, 3,4-dihydro-2H-pyrano[2,3-c]pyridinyl, 3,4-dihydro-2H-pyrano[3,2-b]pyridinyl, 7,8- dihydro-6H-pyrano[3,2-d]pyrimidinyl, or 5,6,7,8-tetrahydroquinazolinyl. In some embodiments, the heteroaryl of R2 is 6,7-dihydro-5H-cyclopenta[c]pyridinyl. In some embodiments, the heteroaryl of R2 is 6,7-dihydro-5H-cyclopenta[b]pyridinyl. In some embodiments, the heteroaryl of R2 is chromanyl. In some embodiments, the heteroaryl of R2 is 3,4-dihydro-2H-112-quinolinyl, 5,6,7,8-tetrahydroquinazolinyl, or 6,7-dihydro-5H-cyclopenta[c]pyridinyl. In some embodiments, the heteroaryl of R2 is 3,4-dihydro-2H-112-quinolinyl. In some embodiments, the heteroaryl of R2 is 5,6,7,8-tetrahydroquinazolinyl. In some embodiments, the heteroaryl of R2 is 6,7-dihydro-5H- cyclopenta[c]pyridinyl. In some embodiments, the heteroaryl of R2 is 4-dihydro-2H-pyrano[2,3- b]pyridinyl. In some embodiments, the heteroaryl of R2 is 3,4-dihydro-2H-pyrano[2,3-c]pyridinyl, or 5,6,7,8-tetrahydroquinazolinyl, In some embodiments, the heteroaryl of R2 is 3,4-dihydro-2H- pyrano[3,2-b]pyridinyl. In some embodiments, the heteroaryl of R2 is 7,8-dihydro-6H-pyrano[3,2- d]pyrimidinyl, In some embodiments, the heteroaryl of R2 is 5,6,7,8-tetrahydroquinazolinyl. In some embodiments, R2 is 4-10 membered heterocyclyl optionally substituted with 1-4 independently selected R2A. In some embodiments, R2 is 4-10 membered heterocyclyl substituted with 1 or 2 independently selected R2A. In some embodiments, R2 is 4-10 membered heterocyclyl substituted with 1 R2A. In some embodiments, R2 is 4-10 membered heterocyclyl substituted with 2 independently selected R2A. In some embodiments, R2 is 4-10 membered heterocyclyl optionally substituted with 3 independently selected R2A. In some embodiments, R2 is 4-10 membered heterocyclyl.
In some embodiments, R2 is 5-8 membered heterocyclyl optionally substituted with 1-4 independently selected R2A. In some embodiments, R2 is 5-8 membered heterocyclyl substituted with 1 or 2 independently selected R2A. In some embodiments, R2 is 5-8 membered heterocyclyl substituted with 1 R2A. In some embodiments, R2 is 5-8 membered heterocyclyl substituted with 2 independently selected R2A. In some embodiments, R2 is 5-8 membered heterocyclyl optionally substituted with 3 independently selected R2A. In some embodiments, R2 is 5-8 membered heterocyclyl.
In some embodiments, the heterocyclyl of R2 is piperidinyl, piperazinyl, octahydrocyclopenta[c]pyranyl, octahydrocyclopenta[b]pyranyl, 2-oxabicyclo[2.1.1]hexanyl, 2- oxabicyclo[3.1.1]heptanyl, or morpholinyl. In some embodiments, the heterocyclyl of R2 is octahydrocyclopenta[c]pyranyl. In some embodiments, the heterocyclyl of R2 is octahydrocyclopenta[b]pyranyl. In some embodiments, the heterocyclyl of R2 is 2- oxabicyclo[2.1.1]hexanyl. In some embodiments, the heterocyclyl of R2 is 2- oxabicyclo[3.1.1]heptanyl.
In some embodiments, R2 is C4-C10 cycloalkyl optionally substituted with 1-4 independently selected R2A. In some embodiments, R2 is C4-C10 cycloalkyl substituted with 1 or 2 independently selected R2A. In some embodiments, R2 is C4-C10 cycloalkyl substituted with 1 R2A. In some embodiments, R2 is C4-C10 cycloalkyl substituted with 2 independently selected R2A. In some embodiments, R2 is C4-C10 cycloalkyl optionally substituted with 3 independently selected R2A. In some embodiments, R2 is C4-C10 cycloalkyl.
In some embodiments, R2 is C5-C7 cycloalkyl optionally substituted with 1-4 independently selected R2A. In some embodiments, R2 is C5-C7 cycloalkyl substituted with 1 or 2 independently selected R2A. In some embodiments, R2 is 5C5-C7 cycloalkyl substituted with 1 R2A. In some embodiments, R2 is C5-C7 cycloalkyl substituted with 2 independently selected R2A. In some embodiments, R2 is C5-C7 cycloalkyl optionally substituted with 3 independently selected R2A. In some embodiments, R2 is C5-C7 cycloalkyl.
In some embodiments, the cycloalkyl of R2 is cyclopentyl, [1.1. l]bicyclopentyl, octahydro-
IH-indenyl, bicyclo[2.1.1]hexanyl, bicyclo[3.1.0]hexanyl, spiro[2.4]heptanyl, or cyclohexyl. In some embodiments, the cycloalkyl of R2 is octahydro- IH-indenyl. In some embodiments, the cycloalkyl of R2 is bicyclo[2.1.1]hexanyl. In some embodiments, the cycloalkyl of R2 is bicyclo[3.1.0]hexanyl.
In some embodiments, R2 is C1-C6 aralkyl optionally substituted with 1-4 independently selected R2A. In some embodiments, R2 is C1-C6 aralkyl. In some embodiments, R2 is C1-C6 aralkyl substituted with 1-4 independently selected R2A. In some embodiments, R2 is benzyl substituted with 1-4 independently selected R2A.
In some embodiments, R2 is C1-C6 alkoxyalkyl optionally substituted with - C(=O)NRARC. In some embodiments, R2 is C1-C6 alkoxyalkyl. In some embodiments, R2 is Cl- C3 alkoxyalkyl. In some embodiments, R2 is -CH2OCH3, -CH2OCH2CH3, or -CH2CH2OCH3. In some embodiments, R2 is -CH2OCH3.
In some embodiments, 1, 2, 3, or 4 of R2A are independently halogen. In some embodiments, 1, 2, or 3 of R2A are independently fluoro or chloro. In some embodiments, 1 or 2 of R2A are independently fluoro or chloro.
In some embodiments, 1, 2, 3, or 4 of R2A are independently cyano. In some embodiments, 1 or 2 of R2A are cyano.
In some embodiments, 1, 2, 3, or 4 of R2A are independently hydroxyl. In some embodiments, 1 or 2 of R2A are hydroxyl.
In some embodiments, 1, 2, 3, or 4 of R2A are independently -NRARB. In some embodiments, 1 or 2 of R2A are independently -NRARB.
In some embodiments, 1, 2, 3, or 4 of R2A are independently -C(=O)NRARB. In some embodiments, 1 or 2 of R2A are independently -C(=O)NRARB.
A/NRARB
In some embodiments, 1, 2, 3, or 4 of R2A are independently O in some
A/NRARB embodiments, 1 or 2 of R2A are independently 0 In some embodiments, 1 , 2, 3, or 4 of R2A are independently -NHC(=O)Rc. In some embodiments, 1 or 2 of R2A are independently -NHC(=O)Rc.
In some embodiments, 1, 2, 3, or 4 of R2A are independently -C(=O)RD. In some embodiments, 1 or 2 of R2A are independently -C(=O)RD.
In some embodiments, 1, 2, 3, or 4 of R2A are independently -C(=O)ORF. In some embodiments, 1 or 2 of R2A are independently -C(=O)ORE.
In some embodiments, 1, 2, 3, or 4 of R2A are independently -SC>2RF. In some embodiments, 1 or 2 of R2A are independently -SC>2RF.
In some embodiments, 1, 2, 3, or 4 of R2A are independently -NHSChRF. In some embodiments, 1 or 2 of R2A are independently -NHSC>2RF.
In some embodiments, 1, 2, 3, or 4 of R2A are independently -S02NRFRG. In some embodiments, 1 or 2 of R2A are independently -SO2NRFRG.
In some embodiments, 1, 2, 3, or 4 of R2A are independently -NHC(=O)C1-C6 alkyl optionally substituted with NRARB. In some embodiments, 1, 2, or 3 of R2A are independently -NHC(=O)C1-C6 alkyl substituted with NRARB. In some embodiments, 1, 2, or 3 of R2A are independently -NHC(=O)C 1 -C6 alkyl. In some embodiments, 1 or 2 of R2A are independently -NHC(=O)C1-C6 alkyl optionally substituted with NRARB. In some embodiments, 1 or 2 of R2A are independently -NHC(=O)C1-C6 alkyl substituted with NRARB. In some embodiments, 1 or 2 of R2A are independently -NHC(=O)C1-C6 alkyl.
In some embodiments, 1, 2, 3, or 4 of R2A are independently C1-C6 haloalkyl. In some embodiments, 1 or 2 of R2A are independently C1-C3 haloalkyl. In some embodiments, 1 or 2 of R2A are trifluoromethyl.
In some embodiments, 1, 2, 3, or 4 of R2A are independently C1-C6 hydroxyalkyl. In some embodiments, 1 or 2 of R2A are independently C1-C3 hydroxyalkyl.
In some embodiments, 1, 2, 3, or 4 of R2A are independently 5-10 membered heteroaryl optionally substituted with 1-3 substituents independently selected from C1-C6 alkyl, - C(=O)NRARB, C1-C6 haloalkyl, and -NRARB. In some embodiments, 1, 2, 3, or 4 of R2A are independently 5-10 membered heteroaryl substituted with 1-3 substituents independently selected from C1-C6 alkyl, -C(=O)NRARB, C1-C6 haloalkyl, and -NRARB. In some embodiments, 1, 2, 3, or 4 of R2A are independently 5-10 membered heteroaryl. In some embodiments, 1 of R2A is 5-6 membered heteroaryl optionally substituted with 1 - 3 substituents independently selected from C1-C6 alkyl, -C(=O)NRARB, C1-C6 haloalkyl, and - NRARB. In some embodiments, 1 of R2A is 5-6 membered heteroaryl substituted with 1-3 substituents independently selected from C1-C6 alkyl, -C(=O)NRARB, C1-C6 haloalkyl, and - NRARB. In some embodiments, 1 of R2A is 5-6 membered heteroaryl.
In some embodiments, 1, 2, 3, or 4 of R2A are independently 4-10 membered heterocyclyl optionally substituted with 1-3 substituents independently selected from hydroxyl, C1-C6 haloalkyl, -C(=O)C1-C6 alkyl, -SO2(C1-C6 alkyl), -SO2NRFRG, C6-C12 aryl, C1-C6 alkyl optionally substituted with C1-C6 alkoxy, -C(=O)NRARB, or -NHC(=O)C1-C6 alkyl optionally substituted with -NRARB. In some embodiments, 1 of R2A is 4-10 membered heterocyclyl optionally substituted with 1-3 substituents independently selected from hydroxyl, C1-C6 haloalkyl, -C(=O)C1-C6 alkyl, -SO2(C1-C6 alkyl), -SO2NRFRG, C6-C12 aryl, C1-C6 alkyl optionally substituted with C1-C6 alkoxy, -C(=O)NRARB, or -NHC(=O)C1-C6 alkyl optionally substituted with -NRARB.
In some embodiments, 1, 2, 3, or 4 of R2A are independently 4-10 membered heterocyclyl substituted with 1-3 substituents independently selected from hydroxyl, C1-C6 haloalkyl, -C(=O)C1-C6 alkyl, -SO2(C1-C6 alkyl), -SO2NRFRG, C6-C12 aryl, C1-C6 alkyl optionally substituted with C1-C6 alkoxy, -C(=O)NRARB, or -NHC(=O)C1-C6 alkyl optionally substituted with -NRARB. In some embodiments, 1 of R2A is 4-10 membered heterocyclyl substituted with 1- 3 substituents independently selected from hydroxyl, C1-C6 haloalkyl, -C(=O)C1-C6 alkyl, - SO2(C1-C6 alkyl), -SO2NRFRG, C6-C12 aryl, C1-C6 alkyl optionally substituted with C1-C6 alkoxy, -C(=O)NRARB, or -NHC(=O)C1-C6 alkyl optionally substituted with -NRARB.
In some embodiments, 1, 2, 3, or 4 of R2A are independently 4-10 membered heterocyclyl substituted with 1-3 substituents independently selected from hydroxyl, C1-C6 haloalkyl, -C(=O)C1-C6 alkyl, -SO2(C1-C6 alkyl), -SO2NRFRG, C1-C6 alkyl substituted with Cl -C6 alkoxy, -C(=O)NRARB, or -NHC(=O)C1-C6 alkyl substituted with -NRARB. In some embodiments, 1 of R2A is 4-10 membered heterocyclyl substituted with 1-3 substituents independently selected from hydroxyl, C1-C6 haloalkyl, -C(=O)C1-C6 alkyl, -SO2(C1-C6 alkyl), -SO2NRFRG, C1-C6 alkyl substituted with C1-C6 alkoxy, -C(=O)NRARB, or -NHC(=O)C1-C6 alkyl substituted with -NRARB y In some embodiments, 1, 2, 3, or 4 of R2A are independently 4-10 membered heterocyclyl substituted with 1-3 substituents independently selected from hydroxyl, C1-C6 haloalkyl, -C(=O)C1-C6 alkyl, -SO2(C1-C6 alkyl), -SO2NRFRG, C1-C6 alkyl, -C(=O)NRARB, or -NHC(=O)C1-C6 alkyl. In some embodiments, 1 of R2A is 4-10 membered heterocyclyl substituted with 1-3 substituents independently selected from hydroxyl, C1-C6 haloalkyl, -C(=O)C1-C6 alkyl, -SO2(C1-C6 alkyl), -SO2NRFRG, C1-C6 alkyl, -C(=O)NRARB, or -NHC(=O)C1-C6 alkyl.
In some embodiments, 1, 2, 3, or 4 of R2A are independently 4-10 membered heterocyclyl. In some embodiments, 1 of R2A is 4-10 membered heterocyclyl.
In some embodiments, 1, 2, or 3 of R2A are independently C1-C6 alkyl optionally substituted with 1-3 substituents independently selected from hydroxyl, oxo, -NRARB, -C(=O)NRARB, C3-C10 cycloalkyl, phenyl, and 4-10 membered heterocyclyl optionally substituted with hydroxyl, C1-C6 alkyl, aralkyl, heteroaralkyl, -C(=O)NRARB, or -C(=O)C3-C6 cycloalkyl.
In some embodiments, 1, 2, 3, or 4 of R2A are independently C1-C6 alkyl substituted with 1-3 substituents independently selected from hydroxyl, oxo, -NRARB, -C(=O)NRARB, C3-C10 cycloalkyl, phenyl, and 4-10 membered heterocyclyl optionally substituted with hydroxyl, C1-C6 alkyl, aralkyl, heteroaralkyl, -C(=O)NRARB, or -C(=O)C3-C6 cycloalkyl.
In some embodiments, 1, 2, 3, or 4 of R2A are independently C1-C6 alkyl substituted with 1-3 substituents independently selected from hydroxyl, oxo, -NRARB, -C(=O)NRARB, C3-C10 cycloalkyl, phenyl, and 4-10 membered heterocyclyl substituted with hydroxyl, C1-C6 alkyl, aralkyl, heteroaralkyl, -C(=O)NRARB, or -C(=O)C3-C6 cycloalkyl.
In some embodiments, 1, 2, 3, or 4 of R2A are independently C1-C6 alkyl substituted with 1-3 substituents independently selected from hydroxyl, oxo, -NRARB, -C(=O)NRARB, C3-C10 cycloalkyl, phenyl, and 4-10 membered heterocyclyl.
In some embodiments, 1, 2, 3, or 4 of R2A are independently C1-C6 alkyl. In some embodiments, 1, 2, or 3 of R2A are independently C1-C3 alkyl. In some embodiments, 1, 2, or 3 of R2A are methyl. In some embodiments, 1 or 2 of R2A are independently C1-C6 alkyl. In some embodiments, 1 or 2 of R2A are independently C1-C3 alkyl. In some embodiments, 1 or 2 of R2A are methyl. In some embodiments, 1 , 2, 3, or 4 of R2A are independently C1 -C6 alkoxy optionally substituted with -NRARB or 4-10 membered heterocyclyl optionally substituted with C1-C6 alkyl, hydroxyl, aralkyl, heteroaralkyl, or -C(=O)C3-C6 cycloalkyl.
In some embodiments, 1, 2, 3, or 4 of R2A are independently C1-C6 alkoxy substituted with -NRARB or 4-10 membered heterocyclyl optionally substituted with C1-C6 alkyl, hydroxyl, aralkyl, heteroaralkyl, or -C(=O)C3-C6 cycloalkyl.
In some embodiments, 1, 2, 3, or 4 of R2A are independently C1-C6 alkoxy substituted with -NRARB or 4-10 membered heterocyclyl substituted with C1-C6 alkyl, hydroxyl, aralkyl, heteroaralkyl, or -C(=O)C3-C6 cycloalkyl.
In some embodiments, 1, 2, 3, or 4 of R2A are independently C1-C6 alkoxy substituted with -NRARB or 4-10 membered heterocyclyl.
In some embodiments, 1, 2, 3, or 4 of R2A are independently C1-C6 alkoxy.
In some embodiments, 1, 2, 3, or 4 of R2A are independently C3-C6 cycloalkyl optionally substituted with 4-10 membered heterocyclyl optionally substituted with C1-C6 alkyl.
In some embodiments, 1, 2, 3, or 4 of R2A are independently C3-C6 cycloalkyl substituted with 4-10 membered heterocyclyl optionally substituted with C1-C6 alkyl.
In some embodiments, 1, 2, 3, or 4 of R2A are independently C3-C6 cycloalkyl substituted with 4-10 membered heterocyclyl substituted with C1-C6 alkyl.
In some embodiments, 1, 2, 3, or 4 of R2A are independently C3-C6 cycloalkyl substituted with 4-10 membered heterocyclyl.
In some embodiments, 1, 2, 3, or 4 of R2A are independently C3-C6 cycloalkyl. In some embodiments, 1 or 2 of R2A are independently C3-C6 cycloalkyl.
In some embodiments, 1, 2, 3, or 4 of R2A are independently C6-C12 aryl optionally substituted with 1-3 substituents independently selected from hydroxyl, cyano, C1-C6 haloalkyl, -ORE, -C(=O)C1-C6 alkyl, -SO2(C1 -C6 alkyl), -SO2NRFRG, 4-10 membered heterocyclyl, or Cl- C6 alkyl optionally substituted with C1-C6 alkoxy, hydroxyl, or -C(=O)NRARB. In some embodiments, 1 of R2A is C6-C12 aryl optionally substituted with 1-3 substituents independently selected from hydroxyl, cyano, C1-C6 haloalkyl, -ORE, -C(=O)C1-C6 alkyl, -SC>2(C1-C6 alkyl), - SC>2NRFRG, 4-10 membered heterocyclyl, or C1-C6 alkyl optionally substituted with C1-C6 alkoxy, hydroxyl, or -C(=O)NRARB. In some embodiments, 1, 2, 3, or 4 of R2A are independently 4-10 membered heterocyclyloxy optionally substituted with 1-3 substituents independently selected from hydroxyl, C1-C6 haloalkyl, -C(=O)C1-C6 alkyl, -SO2(C1-C6 alkyl), -SO2NRFRG, C6-C12 aryl, C1-C6 alkyl optionally substituted with C1-C6 alkoxy, -C(=O)NRARB, or -NHC(=O)C1-C6 alkyl optionally substituted with -NRARB. In some embodiments, 1 of R2A is 4-10 membered heterocyclyloxy optionally substituted with 1-3 substituents independently selected from hydroxyl, C1-C6 haloalkyl, -C(=O)C1-C6 alkyl, -SO2(C1-C6 alkyl), -SO2NRFRG, C6-C12 aryl, C1-C6 alkyl optionally substituted with C1-C6 alkoxy, -C(=O)NRARB, or -NHC(=O)C1-C6 alkyl optionally substituted with -NRARB.
In some embodiments, R2 is substituted with 1 R2A. In some embodiments, R2 is substituted with 2 independently selected R2A. In some embodiments, R2 is substituted with 3 independently selected R2A. In some embodiments, R2 is substituted with 4 independently selected R2A.
In some embodiments, R2 is piperidinyl substituted with 1-2 independently selected R2A. In some embodiments, R2 is piperidinyl substituted with 2-4 independently selected R2A. In some embodiments, R2 is morpholinyl substituted with 2-4 independently selected R2A. In some embodiments, R2 is morpholinyl. In some embodiments, R2 is piperazinyl substituted with 1-2 independently selected R2A.
In some embodiments, R2 is phenyl substituted with 1-2 independently selected R2A. In some embodiments, R2 is pyridinyl substituted with 1-2 independently selected R2A.
In some embodiments, R2 is indolyl substituted with 1-2 independently selected R2A. In some embodiments, R2 is indazolyl substituted with 1-2 independently selected R2A. In some embodiments, R2 is 7-azaindolyl substituted with 1-2 independently selected R2A. In some embodiments, R2 is 7-azaindazolyl substituted with 1-2 independently selected R2A. In some embodiments, R2 is l,2-dihydro-3H-indazol-3-one substituted with 1-2 independently selected R2A. In some embodiments, R2 is isoindolinyl substituted with 1-2 independently selected R2A. In some embodiments, R2 is isoindolinyl. In some embodiments, R2 is 2-indolinone substituted with 1-2 independently selected R2A. In some embodiments, R2 is beznimidazolyl substituted with 1-2 independently selected R2A. In some embodiments, R2 is imidazopyridinyl substituted with 1-2 independently selected R2A. In some embodiments, R2 is l,3-dihydro-2H-benzo[d]imidazol-2- onyl substituted with 1-2 independently selected R2A. In some embodiments, R2 is [l,2,4]triazolo[l,5-a]pyridine substituted with 1-2 independently selected R2A. In some embodiments, one R2A is C1-C6 alkyl, C1 -C6 haloalkyl, C1-C6 hydroxyalkyl, cyano, or hydroxyl, and the other R2A are independently selected from C1-C6 haloalkyl, C1-C6
Figure imgf000029_0001
hydroxyalkyl, cyano, hydroxyl, halogen, -NRARB, -C(=O)NRARB, O , -NHC(=O)Rc,
-C(=O)NRDRE, -C(=O)ORF, -SO2RF, -NHSO2RF, -SO2NRFRG, -NHC(=O)C1-C6 alkyl optionally substituted with NRARB, 5-10 membered heteroaryl optionally substituted with 1-3 substituents independently selected from C1-C6 alkyl and -NRARB, 4-10 membered heterocyclyl optionally substituted with 1-3 substituents independently selected from hydroxyl, C1-C6 haloalkyl, -C(=O)C1-C6 alkyl, -SO2(C1-C6 alkyl), -SO2NRFRG, C1-C6 alkyl optionally substituted with Cl- C6 alkoxy, -C(=O)NRARB, or -NHC(=O)C1-C6 alkyl optionally substituted with -NRARB, C1-C6 alkyl optionally substituted with 1-3 substituents independently selected from hydroxyl, oxo, -NRARB, -C(=O)NRARB, C1-C6 alkoxy, and 4-10 membered heterocyclyl optionally substituted with hydroxyl, C1-C6 alkyl, aralkyl, heteroaralkyl, -C(=O)NRARB, or -C(=O)C3-C6 cycloalkyl, C1-C6 alkoxy optionally substituted with -NRARB or 4-10 membered heterocyclyl optionally substituted with C1-C6 alkyl, aralkyl, heteroaralkyl, or -C(=O)C3-C6 cycloalkyl, and C3-C6 cycloalkyl optionally substituted with 4- 10 membered heterocyclyl optionally substituted with C 1 - C6 alkyl.
In some embodiments, each R2A is independently selected from halogen, methyl, ethyl, -NH2, -NHCH3, -N(CH3)2, -C(=O)NH2, -C(=O)NHCH3, -C(=O)N(CH3)2, -C(=O)NHOH, -SO2NH2, -SO2NHCH3, -SO2N(CH3)2, cyclopropyl, cyclobutyl, trifluoromethyl, 2,2,2- trifluoroethyl, and acetyl.
In some embodiments, 1, 2, or 3 R2A are independently selected from halogen, methyl, ethyl, -NIL, -NHCH3, -N(CH3)2, -C(=O)NH2, -C(=O)NHCH3, -C(=O)N(CH3)2, -C(=O)NHOH, -SO2NH2, -SO2NHCH3, -SO2N(CH3)2, cyclopropyl, cyclobutyl, trifluoromethyl, 2,2,2- trifluoroethyl, and acetyl.
In some embodiments, 1 or 2 R2A are independently selected from halogen, methyl, ethyl, -NH2, -NHCH3, -N(CH3)2, -C(=O)NH2, -C(=O)NHCH3, -C(=O)N(CH3)2, -C(=O)NHOH, -SO2NH2, -SO2NHCH3, -SO2N(CH3)2, cyclopropyl, cyclobutyl, trifluoromethyl, 2,2,2- trifluoroethyl, and acetyl. In some embodiments, R2 is C1-C6 alkoxy optionally substituted with -C(=O)NRARc. In some embodiments, R2 is C1-C6 alkoxy substituted with -C(=O)NRARc. In some embodiments, R2 is C3-C6 alkoxy substituted with -C(=O)NRARc. In some embodiments, R2 is C1-C6 alkoxy.
In some embodiments, R2 is C1-C6 alkylalkoxy optionally substituted with - C(=O)NRARC. In some embodiments, R2 is C1-C6 alkylalkoxy substituted with -C(=O)NRARc. In some embodiments, R2 is C3-C6 alkylalkoxy substituted with -C(=O)NRARc. In some embodiments, R2 is C1-C6 alkylalkoxy.
In some embodiments, X is a bond.
In some embodiments, X is CH2.
In some embodiments, X is CH(CH3).
In some embodiments, X is C(CH3)2.
In some embodiments,
Figure imgf000030_0001
In some embodiments, one of R3A and R3B is hydrogen and the other of R3A and R3B is Cl- C6 alkyl. In some embodiments, one of R3A and R3B is hydrogen and the other of R3A and R3B is methyl. In some embodiments, each of R3A and R3B is hydrogen. In some embodiments, each of R3A and R3B is an independently selected C1-C6 alkyl. In some embodiments, each of R3A and R3B is methyl.
In some embodiments, one of R3A and R3B is hydrogen and the other of R3A and R3B is C 1- C6 alkoxy. In some embodiments, one of R3A and R3B is C1-C6 alkyl and the other of R3A and R3B is C1-C6 alkoxy. In some embodiments, R3A is C1-C6 alkoxy. In some embodiments, R3A is Cl- C3 alkoxy. In some embodiments, R3A is -OCH3, -OCH2CH3, or -OCH2CH2CH3. In some embodiments, R3A is -OCH3.
In some embodiments, one of R3A and R3B is hydrogen and the other of R3A and R3B is Cl- C6 haloalkyl. In some embodiments, one of R3A and R3B is C1-C6 alkyl and the other of R3A and R3B is C1-C6 haloalkyl. In some embodiments, R3A is C1-C6 haloalkyl. In some embodiments, R3A is C1-C3 haloalkyl. In some embodiments, R3A is C1-C3 fluoroalkyl. In some embodiments, R3A is CF3. In some embodiments, R3A is -CHF2.
In some embodiments, R3A and R3B, together with the carbon and nitrogen atoms, respectively, to which they are attached together form a 4-8 membered heterocyclyl group. In some embodiments, R3A and R3B, together with the carbon and nitrogen atoms, respectively, to which they are attached together form a 5-6 membered heterocyclyl group.
In some embodiments, Y is phenyl optionally substituted with R\ naphthyl substituted with RY, or 5-10 membered heteroaryl substituted with RY.
In some embodiments, Y is phenyl optionally substituted with 1-3 independently selected RY . In some embodiments, Y is phenyl substituted with 1 or 2 independently selected RY . In some embodiments, Y is phenyl substituted with 1 RY. In some embodiments, Y is phenyl substituted with 2 independently selected RY. In some embodiments, Y is phenyl optionally substituted with 3 independently selected RY. In some embodiments, Y is phenyl.
In some embodiments, Y is naphthyl optionally substituted with 1-3 independently selected R3 . In some embodiments, Y is naphthyl substituted with 1 or 2 independently selected RY. In some embodiments, Y is naphthyl substituted with 1 RY. In some embodiments, Y is naphthyl substituted with 2 independently selected RY. In some embodiments, Y is naphthyl optionally substituted with 3 independently selected R\ In some embodiments, Y is naphthyl.
In some embodiments, Y is 5-10 membered heteroaryl optionally substituted with 1-3 independently selected RY. In some embodiments, Y is 5-10 membered heteroaryl substituted with 1 or 2 independently selected R\ In some embodiments, Y is 5-10 membered heteroaryl substituted with 1 RY. In some embodiments, Y is 5-10 membered heteroaryl substituted with 2 independently selected RY. In some embodiments, Y is 5-10 membered heteroaryl optionally substituted with 3 independently selected RV In some embodiments, Y is 5-10 membered heteroaryl.
In some embodiments, Y is 6 membered heteroaryl optionally substituted with 1-3 independently selected R\ In some embodiments, Y is 6 membered heteroaryl substituted with 1 or 2 independently selected RY. In some embodiments, Y is 6 membered heteroaryl substituted with 1 RY. In some embodiments, Y is 6 membered heteroaryl substituted with 2 independently selected RY. In some embodiments, Y is 6 membered heteroaryl optionally substituted with 3 independently selected RY. In some embodiments, Y is 6 membered heteroaryl. In some embodiments, the 6 membered heteroaryl of Y is pyridyl (e.g., 3-pyridyl).
In some embodiments, Y is 9 membered heteroaryl optionally substituted with 1-3 independently selected R\ In some embodiments, Y is 9 membered heteroaryl substituted with 1 or 2 independently selected RY. In some embodiments, Y is 9 membered heteroaryl substituted with 1 R\ Tn some embodiments, Y is 9 membered heteroaryl substituted with 2 independently selected RY. In some embodiments, Y is 9 membered heteroaryl optionally substituted with 3 independently selected RY. In some embodiments, Y is 9 membered heteroaryl.
In some embodiments, 1, 2, or 3 of Ry is independently halogen. In some embodiments, 1, 2, or 3 of RY is independently chloro or fluoro. In some embodiments, 1 or 2 of RY is independently chloro or fluoro.
In some embodiments, 1, 2, or 3 of RY is hydroxyl. In some embodiments, 1 or 2 of RY is hydroxyl.
In some embodiments, 1, 2, or 3 of RY is cyano. In some embodiments, 1 or 2 of R' is cyano.
In some embodiments, 1, 2, or 3 of R? is independently C1-C6 haloalkyl. In some embodiments, 1 or 2 of R? is independently C1-C3 haloalkyl. In some embodiments, 1 or 2 ofR4 is trifluorom ethyl.
In some embodiments, 1, 2, or 3 of RY is independently C1-C6 alkoxy. In some embodiments, 1 or 2 of Ry is independently C1-C3 alkoxy. In some embodiments, 1 or 2 of RY is methoxy.
In some embodiments, 1, 2, or 3 of RY is independently C1-C6 haloalkoxy. In some embodiments, 1 or 2 of RY is independently C1-C3 haloalkoxy. In some embodiments, 1 or 2 of RY is trifluoromethoxy.
In some embodiments, 1, 2, or 3 of R4 is independently C1-C6 hydroxyalkyl. In some embodiments, 1 or 2 of RY is independently C1-C3 hydroxyalkyl. In some embodiments, 1 or 2 of RY is independently mono-hydroxyl C1-C3 alkyl. In some embodiments, 1 or 2 of RY is independently di-hydroxyl C2-C3 alkyl.
In some embodiments, 1, 2, or 3 of RY is independently -NHC(=O)Rc. In some embodiments, 1 or 2 of Ry is independently -NHC(=O)Rc. In some embodiments, 1 of RY is -NHC(=O)Rc. In some embodiments, Y is substituted with 1 R\ and RY is -NHC(=O)Rc.
In some embodiments, 1, 2, or 3 of RY is independently -C(=O)NHRY1. In some embodiments, 1 or 2 of RY is independently -C(=O)NHRY1. In some embodiments, 1 of R' is -C(=O)NHRY1. In some embodiments, Y is substituted with 1 RY, and RY is -C(=O)NHRY1.
In some embodiments, 1, 2, or 3 of RY is independently -CO2R4. In some embodiments, 1 or 2 of RY is independently -CChRA. In some embodiments, 1 of R 1 is -CO2RA. In some embodiments, Y is substituted with 1 RY, and R 1 is -CChRA In some embodiments, Y is substituted with 1 RY, and RY is -CO2H.
In some embodiments, 1, 2, or 3 of RY is independently -SO2NRFRG. In some embodiments, 1 or 2 of Ry is independently -SO2NRFRG. In some embodiments, 1 of RY is -SO2NRFRG. In some embodiments, Y is substituted with 1 RY, and RY is -SO2NRFRG.
In some embodiments, 1, 2, or 3 of RY is independently -NHS02RF. In some embodiments, 1 or 2 of R? is independently -NHS02RF. In some embodiments, 1 ofRY is -NHSO2RF. In some embodiments, Y is substituted with 1 RY, and RY is -NHSO2RF.
In some embodiments, 1, 2, or 3 of R' is independently -S(=O)(=NRF)RG. In some embodiments, 1 or 2 of RY is independently -S(=O)(=NRF)RG. In some embodiments, 1 of RY is -S(=O)(=NRF)RG. In some embodiments, Y is substituted with 1 R\ and RY is -S(=O)(=NRF)RG.
In some embodiments, 1, 2, or 3 of Ry is independently -SO2(C1-C6 alkyl). In some embodiments, 1 or 2 of RY is independently -SO2(C1-C6 alkyl). In some embodiments, 1 of RY is -SO2(C1-C6 alkyl). In some embodiments, 1 or 2 of RY is -SO2CH3. In some embodiments, 1 of RY is -SO2CH3. In some embodiments, Y is substituted with 1 RY, and Ry is -SO2CH3.
In some embodiments, 1, 2, or 3 of RY is independently -C(=O)NRARB. In some embodiments, 1 or 2 of RY is independently -C(=O)NRARB. In some embodiments, 1 of RY is -C(=O)NRARB. In some embodiments, Y is substituted with 1 RY, and RY is -C(=O)NRARB.
In some embodiments, 1, 2, or 3 of RY is independently 5-6 membered heteroaryl. In some embodiments, 1 of R? is 5-6 membered heteroaryl. In some embodiments, Y is substituted with 1 RY, and RY is 5-6 membered heteroaryl.
In some embodiments, 1, 2, or 3 of RY is independently heteroaralkyl. In some embodiments, 1 of RY is independently heteroaralkyl.
In some embodiments, 1, 2, or 3 of RY is independently C1-C6 alkyl optionally substituted with -CO2RA or 5-6 membered heteroaryl optionally substituted with RY1. In some embodiments, 1, 2, or 3 of RY is independently C 1-C6 alkyl substituted with -CO2RA or 5-6 membered heteroaryl optionally substituted with RY1. In some embodiments, 1, 2, or 3 of RY is independently C1-C6 alkyl substituted with -CChRA or 5-6 membered heteroaryl substituted with RY1. In some embodiments, 1, 2, or 3 of R‘ is independently C1-C6 alkyl substituted with CC>2RA or 5-6 membered heteroaryl. In some embodiments, Y is substituted with 1 R\ and RY is C1-C6 alkyl substituted with -CChRA. In some embodiments, Y is substituted with 1 RY, and RY is C1-C6 alkyl substituted with -CO2H.
In some embodiments, 1 or 2 of R^ is independently C1-C6 alkyl optionally substituted with -C02RA or 5-6 membered heteroaryl optionally substituted with Ry h In some embodiments, 1 or 2 of RY is independently C1-C6 alkyl substituted with -C02RA or 5-6 membered heteroaryl optionally substituted with RY1. In some embodiments, 1 or 2 of RY is independently C1-C6 alkyl substituted with -C02RA or 5-6 membered heteroaryl substituted with RY1. In some embodiments, 1 or 2 of RY is independently C1-C6 alkyl substituted with -CChRA or 5-6 membered heteroaryl.
In some embodiments, 1 or 2 of R' is independently C1-C6 alkyl substituted with -CChRA. In some embodiments, 1 or 2 of RY is independently C1-C6 alkyl substituted 5-6 membered heteroaryl optionally substituted with RY1. In some embodiments, 1 or 2 of RY is independently C1-C6 alkyl substituted with 5-6 membered heteroaryl substituted with RY1. In some embodiments, 1 or 2 of RY is independently C1-C6 alkyl substituted with 5-6 membered heteroaryl.
In some embodiments, 1, 2, or 3 of R'1 is independently C1-C6 alkyl. In some embodiments, 1 or 2 of RY is independently C1-C3 alkyl. In some embodiments, 1, 2, or 3 of R^ is methyl.
In some embodiments, RY1 is -SO2(C1-C6 alkyl). In some embodiments, RY1 is -SO2CH3.
In some embodiments, RA 1 is hydroxyl.
In some embodiments, Ry i is C1-C6 alkyl optionally substituted with oxo. In some embodiments, RY1 is C1-C6 alkyl substituted with oxo. In some embodiments, RY1 is acetyl, 1- oxoethyl, or 1 -oxopropyl. In some embodiments, RY1 is C1-C6 alkyl. In some embodiments, RY1 is methyl.
In some embodiments, R4 is hydrogen.
In some embodiments, R4 is C1-C6 alkyl. In some embodiments, R4 is methyl or ethyl. In some embodiments, R4 is methyl.
In some embodiments, R4 is acrylamido.
In some embodiments, R3 is hydrogen.
In some embodiments, R5 is C1-C6 alkyl. In some embodiments, R5 is methyl or ethyl. In some embodiments, R5 is methyl. In some embodiments, R5 is halogen. In some embodiments, R5 is fluoro or chloro. In some embodiments, R5 is fluoro. In some embodiments, R5 is chloro.
In some embodiments, R5 is C1-C6 haloalkyl. In some embodiments, R5 is trifluoromethyl.
In some embodiments, R5 is C3-C6 cycloalkyl. In some embodiments, R5 is cyclopropyl.
In some embodiments, R5 is cyano.
In some embodiments, R5 is -NR5AR5B.
In some embodiments, R5 is -NR3AC(=O)R5B.
In some embodiments, R5 is -C(=O)NR5AR5B.
In some embodiments, one of R5A and R5B is hydrogen and the other of R5A and R~B is Cl- C6 alkyl, C2-C6 alkenyl, or C1-C6 hydroxyalkyl. In some embodiments, one of R5A and R5B is C1-C6 alkyl and the other of R5A and R5B is C1-C6 alkyl, C2-C6 alkenyl, or C1-C6 hydroxyalkyl. In some embodiments, each of R5A and R5B is hydrogen. In some embodiments, each of R5A and R5B is an independently selected C1-C6 alkyl. In some embodiments, each of R5A and R5B is methyl. In some embodiments, the C1-C6 hydroxyalkyl of R5A and R5B is hydroxymethyl, 1- hydroxy ethyl, 2-hydroxy ethyl, dihydroxypropyl or dihydroxybutyl.
In some embodiments, R5 is acrylamido.
In some embodiments, R6 is hydrogen.
In some embodiments, R6 is halogen. In some embodiments, R6 is fluoro. In some embodiments, R6 is chloro.
In some embodiments, R6 is C1-C6 alkyl. In some embodiments, R6 is methyl.
In some embodiments, each of RA and RB are independently selected from hydrogen, hydroxyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C2-C6 alkenyl, cyano, 4-10 membered heterocyclyl, and C1-C6 alkyl optionally substituted with hydroxyl or C1-C6 alkoxy.
In some embodiments, RA and RB together with the nitrogen atom to which they are attached form a 4-10 membered heterocyclyl optionally substituted with 1-2 substituents independently selected from halogen, C1-C6 alkyl, hydroxyl, and -C(=O)C1-C6 alkyl.
In some embodiments, each of RA and RB are independently selected from hydrogen, hydroxyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C2-C6 alkenyl, and C1-C6 alkyl optionally substituted with hydroxyl or C1-C6 alkoxy. In some embodiments, one of RA and RB is hydrogen and the other of RA and RB is hydroxyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C2-C6 alkenyl, or C1-C6 alkyl optionally substituted with hydroxyl or C1-C6 alkoxy.
In some embodiments, one of RA and RB is hydrogen and the other of RA and RB is hydroxyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C2-C6 alkenyl, or C1-C6 alkyl substituted with hydroxyl or C1-C6 alkoxy.
In some embodiments, one of RA and RB is hydrogen and the other of RA and RB is hydroxyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C2-C6 alkenyl, or C1-C6 alkyl.
In some embodiments, one of RA and RB is hydrogen and the other of RA and RB is hydroxyl. In some embodiments, one of RA and RB is hydrogen and the other of RA and RB is C 1- C6 alkoxy. In some embodiments, one of RA and RB is hydrogen and the other of RA and RB is C3-C6 cycloalkyl. In some embodiments, one of RA and RB is hydrogen and the other of RA and RB is C2-C6 alkenyl. In some embodiments, one of RA and RB is hydrogen and the other of RA and RB is C1-C6 alkyl optionally substituted with hydroxyl or C1-C6 alkoxy. In some embodiments, one of RA and RB is hydrogen and the other of RA and RB is C1-C6 alkyl substituted with hydroxyl. In some embodiments, one of RA and RB is hydrogen and the other of RA and RB is C1-C6 alkyl substituted with C1-C6 alkoxy. In some embodiments, one of RA and RB is hydrogen and the other of RA and RB is 4-10 membered heterocyclyl .
In some embodiments, one of RA and RB is hydrogen and the other of RA and RB is C1-C6 alkyl. In some embodiments, each of RA and RB are hydrogen. In some embodiments, each of RA and RB are an independently selected C1-C6 alkyl optionally substituted with hydroxyl or C1-C6 alkoxy. In some embodiments, each of RA and RB are an independently selected C1-C6 alkyl. In some embodiments, each of RA and RB are methyl.
In some embodiments, RA and RB together with the nitrogen atom to which they are attached form a 4-10 membered heterocyclyl optionally substituted with 1-2 substituents independently selected from halogen, C1-C6 alkyl, hydroxyl, and -C(=O)C1-C6 alkyl.
In some embodiments, RA and RB together with the nitrogen atom to which they are attached form a 4-10 membered heterocyclyl substituted with 1-2 substituents independently selected from halogen, C1-C6 alkyl, hydroxyl, and -C(=O)C1-C6 alkyl.
In some embodiments, RA and RB together with the nitrogen atom to which they are attached form a 4-10 membered heterocyclyl substituted with halogen, C1-C6 alkyl, hydroxyl, or -C(=O)C1-C6 alkyl. In some embodiments, RA and RB together with the nitrogen atom to which they are attached form a 4-10 membered heterocyclyl substituted with 1-2 substitutents independently selected from fluoro, hydroxyl, methyl, and acetyl.
In some embodiments, RA and RB together with the nitrogen atom to which they are attached form a 4-10 membered heterocyclyl. In some embodiments, RA and RB together with the nitrogen atom to which they are attached form a 4-6 membered heterocyclyl.
In some embodiments, each Rc is independently C3-C6 cycloalkyl, -C(=O)NHRY1, or a C1-C6 alkyl substituted with -NRARB or with 4-10 membered heterocyclyl optionally substituted with C1-C6 alkyl or with C1-C6 hydroxylalkyl. In some embodiments, each Rc is independently C3-C6 cycloalkyl, -C(=O)NHRY1, or a C1-C6 alkyl substituted with -NRARB or with 4-10 membered heterocyclyl substituted with C1-C6 alkyl or with C1-C6 hydroxylalkyl. In some embodiments, each Rc is independently C3-C6 cycloalkyl, -C(=O)NHRY1, or a C1-C6 alkyl substituted with -NRARB or with 4-10 membered heterocyclyl. In some embodiments, each Rc is independently C3-C6 cycloalkyl, -C(=O)NHRY1, or a C1-C6 alkyl.
In some embodiments, each Rc is independently C3-C6 cycloalkyl. In some embodiments, each Rc is independently -C(=O)NHRY1. In some embodiments, each Rc is independently C1-C6 alkyl optionally substituted with -NRARB or with 4-10 membered heterocyclyl optionally substituted with C1-C6 alkyl or with C1-C6 hydroxylalkyl. In some embodiments, each Rc is independently C1-C6 alkyl substituted with -NRARB or with 4-10 membered heterocyclyl optionally substituted with C1-C6 alkyl or with C1-C6 hydroxylalkyl.
In some embodiments, RD is selected from hydrogen, hydroxyl, C1-C6 alkyl, phenyl, 4-10 membered heterocyclyl, C1-C6 alkoxy, and C3-C6 cycloalkyl, wherein the C1-C6 alkyl, 4-10 membered heterocyclyl, and phenyl are optionally substituted with 4-10 membered heterocyclyl, C3-C6 cycloalkyl, or cyano, and the C3-C6 cycloalkyl is optionally substituted with C1-C6 alkyl optionally substituted with hydroxyl or C1-C6 alkoxy.
In some embodiments, RD is hydrogen.
In some embodiments, RD is hydroxyl.
In some embodiments, RD is C1-C6 alkyl optionally substituted with 4-10 membered heterocyclyl, C3-C6 cycloalkyl, or cyano. In some embodiments, RD is unsubstituted C1-C6 alkyl. In some embodiments, RD is C1-C6 alkyl substituted with 4-10 membered heterocyclyl, C3-C6 cycloalkyl, or cyano. In some embodiments, RD is C1-C6 alkyl substituted with 4-10 membered heterocyclyl. Tn some embodiments, RD is C1-C6 alkyl substituted with C3-C6 cycloalkyl. In some embodiments, RD is C1-C6 alkyl substituted with cyano.
In some embodiments, RD is 4-10 membered heterocyclyl optionally substituted with 4-10 membered heterocyclyl, C3-C6 cycloalkyl, or cyano. In some embodiments, RD is unsubstituted 4-10 membered heterocyclyl. In some embodiments, RD is 4-10 membered heterocyclyl substituted with 4-10 membered heterocyclyl, C3-C6 cycloalkyl, or cyano. In some embodiments, RD is 4-10 membered heterocyclyl substituted with 4-10 membered heterocyclyl. In some embodiments, RD is 4-10 membered heterocyclyl substituted with C3-C6 cycloalkyl. In some embodiments, RD is 4-10 membered heterocyclyl substituted with cyano.
In some embodiments, RD is phenyl optionally substituted with 4-10 membered heterocyclyl, C3-C6 cycloalkyl, or cyano. In some embodiments, RD is unsubstituted phenyl. In some embodiments, RD is phenyl substituted with 4-10 membered heterocyclyl, C3-C6 cycloalkyl, or cyano. In some embodiments, RD is phenyl substituted with 4-10 membered heterocyclyl. In some embodiments, RD is phenyl substituted with C3-C6 cycloalkyl. In some embodiments, RD is phenyl substituted with cyano.
In some embodiments, RD is C3-C6 cycloalkyl optionally substituted with C1-C6 alkyl optionally substituted with hydroxyl or C1-C6 alkoxy. In some embodiments, RD is unsubstituted C3-C6 cycloalkyl. In some embodiments, RD is C3-C6 cycloalkyl substituted with C1-C6 alkyl optionally substituted with hydroxyl or C1-C6 alkoxy. In some embodiments, RD is C3-C6 cycloalkyl substituted with C1-C6 alkyl. In some embodiments, RD is C3-C6 cycloalkyl substituted with C1-C6 alkyl substituted with hydroxyl. In some embodiments, RD is C3-C6 cycloalkyl substituted with C1-C6 alkyl substituted with C1-C6 alkoxy.
In some embodiments, Ru is C1-C6 alkoxy.
In some embodiments, RD is C3-C6 cycloalkyl.
In some embodiments, RE is selected from hydrogen, hydroxyl, C1-C6 alkyl, phenyl, 4-10 membered heterocyclyl, C1-C6 alkoxy, and C3-C6 cycloalkyl, wherein the C1-C6 alkyl, 4-10 membered heterocyclyl, and phenyl are optionally substituted with 4-10 membered heterocyclyl, C3-C6 cycloalkyl, or cyano, and the C3-C6 cycloalkyl is optionally substituted with C1-C6 alkyl optionally substituted with hydroxyl or C1-C6 alkoxy.
In some embodiments, RE is hydrogen.
In some embodiments, RE is hydroxyl. In some embodiments, RE is C1-C6 alkyl optionally substituted with 4-10 membered heterocyclyl, C3-C6 cycloalkyl, or cyano. In some embodiments, RE is unsubstituted C1-C6 alkyl. In some embodiments, RE is C1-C6 alkyl substituted with 4-10 membered heterocyclyl, C3-C6 cycloalkyl, or cyano. In some embodiments, RE is C1-C6 alkyl substituted with 4-10 membered heterocyclyl. In some embodiments, RE is C1-C6 alkyl substituted with C3-C6 cycloalkyl. In some embodiments, RE is C1-C6 alkyl substituted with cyano.
In some embodiments, RE is 4-10 membered heterocyclyl optionally substituted with 4-10 membered heterocyclyl, C3-C6 cycloalkyl, or cyano. In some embodiments, RE is unsubstituted 4-10 membered heterocyclyl. In some embodiments, RE is 4-10 membered heterocyclyl substituted with 4-10 membered heterocyclyl, C3-C6 cycloalkyl, or cyano. In some embodiments, RE is 4-10 membered heterocyclyl substituted with 4-10 membered heterocyclyl. In some embodiments, RE is 4-10 membered heterocyclyl substituted with C3-C6 cycloalkyl. In some embodiments, RE is 4-10 membered heterocyclyl substituted with cyano.
In some embodiments, RE is phenyl optionally substituted with 4-10 membered heterocyclyl, C3-C6 cycloalkyl, or cyano. In some embodiments, RE is unsubstituted phenyl. In some embodiments, RE is phenyl substituted with 4-10 membered heterocyclyl, C3-C6 cycloalkyl, or cyano. In some embodiments, RE is phenyl substituted with 4-10 membered heterocyclyl. In some embodiments, RE is phenyl substituted with C3-C6 cycloalkyl. In some embodiments, RE is phenyl substituted with cyano.
In some embodiments, RE is C3-C6 cycloalkyl optionally substituted with C1-C6 alkyl optionally substituted with hydroxyl or C1-C6 alkoxy. In some embodiments, RE is unsubstituted C3-C6 cycloalkyl. In some embodiments, RE is C3-C6 cycloalkyl substituted with C1-C6 alkyl optionally substituted with hydroxyl or C1-C6 alkoxy. In some embodiments, RE is C3-C6 cycloalkyl substituted with C1-C6 alkyl. In some embodiments, RE is C3-C6 cycloalkyl substituted with C1-C6 alkyl substituted with hydroxyl. In some embodiments, RE is C3-C6 cycloalkyl substituted with C1-C6 alkyl substituted with C1-C6 alkoxy.
In some embodiments, RE is C1-C6 alkoxy.
In some embodiments, RE is C3-C6 cycloalkyl.
In some embodiments, one of RD and RE is hydrogen and the other of RD and RE is hydrogen, hydroxyl, C1-C6 alkyl, phenyl, 4-10 membered heterocyclyl, C 1-C6 alkoxy, and C3- C6 cycloalkyl optionally substituted with C1-C6 alkyl optionally substituted with hydroxyl or Cl - C6 alkoxy.
In some embodiments, one of RD and RE is hydrogen and the other of RD and RE is hydroxyl, C1-C6 alkyl, or C1-C6 alkoxy. In some embodiments, one of RD and RE is hydrogen and the other of RD and RE is hydroxyl. In some embodiments, one of RD and RE is hydrogen and the other of RD and RE is C1-C6 alkyl. In some embodiments, one of RD and RE is hydrogen and the other of RD and RE is C1-C6 alkoxy. In some embodiments, one of RD and RE is hydrogen and the other of RD and RE is hydroxyl, methyl, or methoxy. In some embodiments, each of RD and RE is hydrogen. In some embodiments, each of RD and RE is an independently selected C1-C6 alkyl. In some embodiments, each of RD and RE is methyl.
In some embodiments, one of RE and RG is hydrogen and the other of RE and RG is phenyl or C1-C6 alkyl optionally substituted with oxo or -NRARB. In some embodiments, one of RF and RG is hydrogen and the other of RE and RG is phenyl or C1-C6 alkyl substituted with oxo or -NRARB. In some embodiments, one of RF and RG is hydrogen and the other of RF and RG is phenyl or C1-C6 alkyl. In some embodiments, one of RE and RG is hydrogen and the other of RE and RG is phenyl. In some embodiments, one of RF and RG is hydrogen and the other of RF and RG is C1-C6 alkyl optionally substituted with oxo or -NRARB. In some embodiments, one of RF and RG is hydrogen and the other of RF and RG is C1-C6 alkyl substituted with oxo or -NRARB. In some embodiments, each of RF and RG is hydrogen. In some embodiments, each of RF and RG is an independently selected C1-C6 alkyl. In some embodiments, each of RF and RG is methyl.
In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is a compound of Formula (I-A1A):
Figure imgf000040_0001
or a pharmaceutically acceptable salt thereof.
In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is a compound of Formula (I-A2):
Figure imgf000041_0001
or a pharmaceutically acceptable salt thereof.
In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is a compound of Formula (I- A3):
Figure imgf000041_0002
or a pharmaceutically acceptable salt thereof.
In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is a compound of Formula (I-A4):
Figure imgf000041_0003
or a pharmaceutically acceptable salt thereof.
In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is a compound of Formula (I-A5):
Figure imgf000042_0001
or a pharmaceutically acceptable salt thereof.
In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is a compound of Formula (I-A6):
Figure imgf000042_0002
or a pharmaceutically acceptable salt thereof.
In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is a compound of Formula (I-A7):
Figure imgf000042_0003
or a pharmaceutically acceptable salt thereof.
In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is a compound of Formula (I-A8):
Figure imgf000043_0001
or a pharmaceutically acceptable salt thereof, wherein:
Ring A is a 5-6 membered heterocyclyl, C5-C6 cycloalkyl, or 5-6 membered heteroaryl; and m is 0, 1, 2, or 3; n is 0, 1, or 2; and m+n is 0, 1, 2, or 3.
In some embodiments, Ring A is pyridyl, tetrahydropyranyl, or cyclohexyl. In some embodiments, Ring A is pyridyl. In some embodiments, Ring A is tetrahydropyranyl. In some embodiments, Ring A is cyclohexyl.
In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is a compound of Formula (I-A9):
Figure imgf000043_0002
or a pharmaceutically acceptable salt thereof, wherein: m is 0, 1, 2, or 3; n is 0, 1 , or 2; and m+n is 0, 1 , 2, or 3.
In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is a compound of Formula (I-A10):
Figure imgf000043_0003
or a pharmaceutically acceptable salt thereof, wherein:
Q is CH, NH, or O;
Ring A is phenyl or 5-6 membered heteroaryl; and m is 0, 1, 2, or 3; n is 0, 1, or 2; and m+n is 0, 1, 2, or 3. In some embodiments, Q is CH. In some embodiments, Q is NH. In some embodiments,
Q is O.
In some embodiments, Ring A is phenyl.
In some embodiments, Ring A is pyridyl or pyrimidinyl.
Non-Limiting Exemplary Compounds
In some embodiments, the compound is selected from the group consisting of the compounds in Example 1 (e.g., Compound 1), or a pharmaceutically acceptable salt thereof.
In some embodiments, the compound is selected from the group consisting of the compounds delineated in Table A, or a pharmaceutically acceptable salt thereof.
Table A
Figure imgf000044_0001
Figure imgf000045_0001
Figure imgf000046_0001
Figure imgf000047_0001
Figure imgf000048_0001
Figure imgf000049_0001
Figure imgf000050_0001
Figure imgf000051_0001
Figure imgf000052_0001
Figure imgf000053_0001
Figure imgf000054_0001
Figure imgf000055_0001
Figure imgf000056_0001
Figure imgf000057_0001
Figure imgf000058_0001
Figure imgf000059_0001
Figure imgf000060_0001
Figure imgf000061_0001
Figure imgf000062_0001
Figure imgf000063_0001
Figure imgf000064_0001
Figure imgf000065_0001
Figure imgf000066_0001
Figure imgf000067_0001
Figure imgf000068_0001
Figure imgf000069_0001
Figure imgf000070_0001
Figure imgf000071_0001
\L
Figure imgf000072_0001
Figure imgf000073_0001
Figure imgf000074_0001
Figure imgf000075_0001
Figure imgf000076_0001
Figure imgf000077_0001
Figure imgf000078_0001
Figure imgf000079_0001
Figure imgf000080_0001
Figure imgf000081_0001
Figure imgf000082_0001
Pharmaceutical Compositions
Some embodiments provide a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.
Methods of Treatment
A “PI3Ka inhibitor” as used herein (e.g., compounds of Formula (I) and pharmaceutically acceptable salts thereof) includes any compound exhibiting PI3Ka inactivation activity (e.g., inhibiting or decreasing). In some embodiments, a PI3Ka inhibitor can be selective for a P13Ka having one or more mutations.
The ability of test compounds to act as inhibitors of PI3Ka may be demonstrated by assays known in the art. The activity of the compounds and compositions provided herein as PT3Ka inhibitors can be assayed in vitro, in vivo, or in a cell line. In vitro assays include assays that determine inhibition of the kinase. Alternate in vitro assays quantitate the ability of the inhibitor to bind to the protein kinase and can be measured either by radio labeling the compound prior to binding, isolating the compound/kinase complex and determining the amount of radio label bound, or by running a competition experiment where new compounds are incubated with the kinase bound to known radio ligands.
Potency of a PI3Ka inhibitor as provided herein can be determined by ECso value. A compound with a lower ECso value, as determined under substantially similar conditions, is a more potent inhibitor relative to a compound with a higher EC50 value.
Potency of a PI3Ka inhibitor as provided herein can also be determined by IC50 value. A compound with a lower IC50 value, as determined under substantially similar conditions, is a more potent inhibitor relative to a compound with a higher ICso value. In some embodiments, the substantially similar conditions comprise determining a PI3Ka-dependent phosphorylation level, in vitro or in vivo.
The selectivity between wild type PI3Ka and PI3Ka containing one or more mutations as described herein can also be measured using in vitro assays such as surface plasmon resonance and fluorence-based binding assays, and cellular assays such as the levels of pAKT, a biomarker of PI3Ka activity, and/or proliferation assays where cell proliferation is dependent on mutant PI3Ka kinase activity.
In some embodiments, the compounds provided herein can exhibit potent and selective inhibition of PI3Ka. For example, the compounds provided herein can bind to the helical phosphatidylinositol kinase homology domain catalytic domain of PI3Ka. In some embodiments, the compounds provided herein can exhibit nanomolar potency against a PI3Ka kinase including one or more mutations, for example, the mutations in Table 1.
In some embodiments, the compounds of Formula (I), or a pharmaceutically acceptable salt thereof, can selectively target PI3Ka. For example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can selectively target PI3Ka over another kinase or nonkinase target.
In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can exhibit greater inhibition of PI3Ka containing one or more mutations as described herein (e.g., one or more mutations as described in Table 1) relative to inhibition of wild type PI3Ka. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof can exhibit at least 2-fold, 3-fold, 5-fold, 10-fold, 25-fold, 50-fold or 100-fold greater inhibition of PI3Ka containing one or more mutations as described herein relative to inhibition of wild type PI3Ka. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can exhibit up to 1,000-fold greater inhibition of P 13 Ku. containing one or more mutations as described herein relative to inhibition of wild type PI3Ka. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can exhibit up to 10,000-fold greater inhibition of PI3Ka having a combination of mutations described herein relative to inhibition of wild type PI3Ka.
In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can exhibit from about 2-fold to about 10-fold greater inhibition of PI3Ka containing one or more mutations as described herein relative to inhibition of wild type PI3Ka. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can exhibit from about 10-fold to about 100-fold greater inhibition of PI3Ka containing one or more mutations as described herein relative to inhibition of wild type PI3Ka. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can exhibit from about 100-fold to about 1,000-fold greater inhibition of PI3Ka containing one or more mutations as described herein relative to inhibition of wild type PI3KOL In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can exhibit from about 1000-fold to about 10,000-fold greater inhibition of PI3Ka containing one or more mutations as described herein relative to inhibition of wild type PI3Ka.
Compounds of Formula (I), or pharmaceutically acceptable salts thereof, are useful for treating diseases which can be treated with a PI3Ku inhibitor, such as PI3Ka-associated diseases, e.g., proliferative disorders such as cancers, including hematological cancers and solid tumors (e.g., advanced or metastatic solid tumors).
In some embodiments, the subject has been identified or diagnosed as having a cancer with a dysregulation of a PIK3CA gene, a PI3Ka protein, or expression or activity, or level of any of the same (a PI3Ka-associated cancer), for example, as determined using a regulatory agency- approved, e.g., FDA-approved, assay or kit. In some embodiments, the subject has a tumor that is positive for a dysregulation of a PIK3CA gene, a PI3Ka protein, or expression or activity, or level of any of the same (e.g., as determined using a regulatory agency-approved assay or kit). For example, the subject has a tumor that is positive for a mutation as described in Table 1. The subject can be a subject with a tumor(s) that is positive for a dysregulation of a PIK3CA gene, a PI3Ka protein, or expression or activity, or level of any of the same (e.g., identified as positive using a regulatory agency-approved, e.g., FDA-approved, assay or kit). The subject can be a subject whose tumors have a dysregulation of a PIK3CA gene, a PI3Ka protein, or expression or activity, or a level of the same (e.g., where the tumor is identified as such using a regulatory agency-approved, e.g., FDA-approved, kit or assay). In some embodiments, the subject is suspected of having a PI3Ka -associated cancer. In some embodiments, the subject has a clinical record indicating that the subject has a tumor that has a dysregulation of a PIK3CA gene, a PI3Ka protein, or expression or activity, or level of any of the same (and optionally the clinical record indicates that the subject should be treated with any of the compositions provided herein).
In certain embodiments, compounds of Formula (I), or pharmaceutically acceptable salts thereof, are useful for preventing diseases as defined herein such as cancer. The term “preventing” as used herein means to delay the onset, recurrence or spread, in whole or in part, of the disease as described herein, or a symptom thereof.
The term “PI3Ka-associated disease” as used herein refers to diseases associated with or having a dysregulation of a PIK3CA gene, a PI3Ka protein, or the expression or activity or level of any (e.g., one or more) of the same (e.g., any of the types of dysregulation of a PIK3CA gene, or a PI3Ka protein, or the expression or activity or level of any of the same described herein). Nonlimiting examples of a PI3Ka-associated disease include, for example, proliferative disorders such as cancer (e.g., PI3Ka-associated cancer).
The term “PI3Ka-associated cancer” as used herein refers to cancers associated with or having a dysregulation of a PIK3CA gene, a PI3Ka protein, or expression or activity, or level of any of the same. Non-limiting examples of PI3Ka-associated cancer are described herein.
The phrase “dysregulation of a PIK3CA gene, a PI3Ka protein, or the expression or activity or level of any of the same” refers to a genetic mutation (e.g., a mutation in a PIK3CA gene that results in the expression of a PI3Ka that includes a deletion of at least one amino acid as compared to a wild type PI3Ka, a mutation in a PIK3CA gene that results in the expression of PI3Ka with one or more point mutations as compared to a wild type PI3Ka, a mutation in a PIK3CA gene that results in the expression of PI3Ka with at least one inserted amino acid as compared to a wild type PI3Ka, a gene duplication that results in an increased level of PI3Ka in a cell, or a mutation in a regulatory sequence (e.g., a promoter and/or enhancer) that results in an increased level of PI3Ka in a cell), an alternative spliced version of PI3Ka mRNA that results in PI3Ka having a deletion of at least one amino acid in the PI3Ka as compared to the wild type PI3Ka), or increased expression (e.g., increased levels) of a wild type PI3Ka in a mammalian cell due to aberrant cell signaling and/or dysregulated autocrine/paracrine signaling (e.g., as compared to a control non- cancerous cell). As another example, a dysregulation of a PIK3CA gene, a PI3Ka protein, or expression or activity, or level of any of the same, can be a mutation in &PIK3CA gene that encodes a PI3Ka that is constitutively active or has increased activity as compared to a protein encoded by a PIK3CA gene that does not include the mutation. Non-limiting examples of PI3Ka point mutations/substitutions/insertions/deletions are described in Table 1.
The term “wild type” describes a nucleic acid (e.g., a PIK3CA gene or a PI3Ka mRNA) or protein (e.g., a PI3Ka) sequence that is typically found in a subject that does not have a disease related to the reference nucleic acid or protein.
The term “wild type PI3Ka” or “wild-type PI3Ka” describes a normal PI3Ka nucleic acid (e.g., &PIK3CA or PI3Ka mRNA) or protein that is found in a subject that does not have a PI3Ka- associated disease, e.g., a PI3Ka -associated cancer (and optionally also does not have an increased risk of developing a PI3Ka -associated disease and/or is not suspected of having a PI3Ka- associated disease), or is found in a cell or tissue from a subject that does not have a PI3Ka- associated disease, e.g., a PI3Ka -associated cancer (and optionally also does not have an increased risk of developing a PI3Ka -associated disease and/or is not suspected of having a PI3Ka- associated disease).
Provided herein is a method of treating cancer (e.g., a PI3Ka-associated cancer) in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. For example, provided herein are methods for treating PI3Koi-associated cancer in a subject in need thereof, comprising a) detecting a dysregulation of PIK3CA gene, a PI3Ka protein, or the expression or activity or level of any of the same in a sample from the subj ect; and b) administering a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the dysregulation of a PIK3CA gene, a PI3Ka protein, or the expression or activity or level of any of the same includes one or more a PI3Ka protein substitutions/point mutations/insertions. Non-limiting examples of PI3Ka protein substitutions/insertions/deletions are described in Table 1.
In some embodiments, the PI3Ka protein substitution/insertion/deletion is selected from the group consisting of E542A, E542G, E542K, E542Q, E542V, E545A, E545D, E545G, E545K, E545Q, M1043I, M1043L, M1043T, M1043V, H1047L, H1047Q, H1047R, H1047Y, G1049R, and combinations thereof. In some embodiments, the PI3Ka protein substitution / insertion / deletion is H1047X, where X is any amino acid other than H. In some embodiments, the PI3Ka protein substitution / insertion / deletion is E542X, where X is any amino acid other than E. In some embodiments, the PI3Ka protein substitution / insertion / deletion is E545X, where X is any amino acid other than E.
In some embodiments, the dysregulation of & PIK3CA gene, a PI3Ka protein, or expression or activity or level of any of the same, includes a splice variation in a PI3Ka mRNA which results in an expressed protein that is an alternatively spliced variant of PI3Ka having at least one residue deleted (as compared to the wild type PI3Ka protein) resulting in a constitutive activity of a PI3Ka protein domain.
In some embodiments, the dysregulation of &PIK3CA gene, a PI3Ka protein, or expression or activity or level of any of the same, includes at least one point mutation in a PIK3CA gene that results in the production of a PI3Ka protein that has one or more amino acid substitutions or insertions or deletions in a PJK3CA gene that results in the production of a PI3Ka protein that has one or more amino acids inserted or removed, as compared to the wild type PI3Ka protein. In some cases, the resulting mutant PI3Ka protein has increased activity, as compared to a wild type PI3Kcc protein or a PI3Ka protein not including the same mutation. In some embodiments, the compounds described herein selectively inhibit the resulting mutant PI3Ka protein relative to a wild type PI3Ka protein or a PI3Ka protein not including the same mutation.
In some embodiments of any of the methods or uses described herein, the cancer (e.g., PI3Ka-associated cancer) is selected from a hematological cancer and a solid tumor.
In some embodiments of any of the methods or uses described herein, the cancer (e.g., PI3Ka-associated cancer) is selected from breast cancer (including both HER2+ and HER2' breast cancer, ER+ breast cancer, and triple negative breast cancer), uterine cancer (including endometrial cancer), lung cancer (including small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLS, including adenocarcinoma lung cancer and squamous cell lung carcinoma)), esophageal squamous cell carcinoma, ovarian cancer, colorectal cancer, esophagastric adenocarcinoma, bladder cancer, head and neck cancer (including head and neck squamous cell cancers such as oropharyngeal squamous cell carcinoma), thyroid cancer, glioma, cervical cancer, lymphangioma, meningioma, melanoma (including uveal melanoma), kidney cancer, pancreatic neuroendocine neoplasms (pNETs), stomach cancer, esophageal cancer, acute myeloid leukemia, relapsed and refractory multiple myeloma, hepatocellular carcinoma, prostate cancer, Malignant Peripheral Nerve Sheath Tumor (MPNST), glioblastoma, cholangiocarcinoma, and pancreatic cancer.
In some embodiments of any of the methods or uses described herein, the cancer (e.g., PI3Ka-associated cancer) is selected from breast cancer (including both HER2+ and HER.2 breast cancer, ER+ breast cancer, and triple negative breast cancer), colon cancer, rectal cancer, colorectal cancer, ovarian cancer, lymphangioma, meningioma, head and neck squamous cell cancer (including oropharyngeal squamous cell carcinoma), melanoma (including uveal melanoma), kidney cancer, pancreatic neuroendocine neoplasms (pNETs), stomach cancer, esophageal cancer, acute myeloid leukemia, relapsed and refractory multiple myeloma, pancreatic cancer, lung cancer (including adenocarcinoma lung cancer and squamous cell lung carcinoma), and endometrial cancer.
In some embodiments of any of the methods or uses described herein, the cancer (e.g., PI3Ka-associated cancer) is selected from breast cancer, SCLC, NSCLC, endometrial cancer, esophageal squamous cell carcinoma, ovarian cancer, colorectal cancer, esophagastric adenocarcinoma, bladder cancer, head and neck cancer, thyroid cancer, glioma, and cervical cancer.
In some embodiments of any of the methods or uses described herein, the PI3Ka-associated cancer is breast cancer. In some embodiments of any of the methods or uses described herein, the PI3Ka-associated cancer is colorectal cancer. In some embodiments of any of the methods or uses described herein, the PI3Ka-associated cancer is endometrial cancer. In some embodiments of any of the methods or uses described herein, the PI3Ka-associated cancer is lung cancer.
In some embodiments of any of the methods or uses described herein, the PI3Ka-associated cancer is selected from the cancers described in Table 1.
Table 1. PI3Ka Protein Amino Acid Substitutions/Insertions/DeletionsA
Figure imgf000089_0001
Figure imgf000090_0001
Figure imgf000091_0001
A Unless noted otherwise, the mutations of Table 1 are found in cBioPortal database derived from Cerami et al. The eBio Cancer Genomics Portal: An Open Platform for Exploring Multidimensional Cancer Genomics Data. Cancer Discovery. May 2012 2; 401; and Gao et al. Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal. Sci. Signal. 6, pH (2013). f Velho S, Oliveira C, Ferreira A, Ferreira AC, Suriano G, Schwartz S Jr, Duval A, Carneiro F, Machado JC, Hamelin R, Seruca R. The prevalence of PIK3CA mutations in gastric and colon cancer. Eur J Cancer. 2005 Jul;41(l 1): 1649-54. doi: 10.1016/j.ejca.2005.04.022. PMID: 15994075.
Exemplary Sequence of Human Phosphatidylinositol 4,5-bisphosphate 3-kinase isoform alpha (UniProtKB entry P42336) (SEQ ID NO: 1)
MPPRPSSGEL WGIHLMPPRI LVECLLPNGM IVTLECLREA TLITIKHELF KEARKYPLHQ LLQDESSYIF VSVTQEAERE EFFDETRRLC DLRLFQPFLK
VIEPVGNREE KILNREIGFA IGMPVCEFDM VKDPEVQDFR RNILNVCKEA VDLRDLNSPH SRAMYVYPPN VESSPELPKH IYNKLDKGQI IVVIWVIVSP NNDKQKYTLK INHDCVPEQV IAEAIRKKTR SMLLSSEQLK LCVLEYQGKY ILKVCGCDEY FLEKYPLSQY KYIRSCIMLG RMPNLMLMAK ESLYSQLPMD CFTMPSYSRR ISTATPYMNG ETSTKSLWVI NSALRIKILC ATYVNVNIRD IDKIYVRTGI YHGGEPLCDN VNTQRVPCSN PRWNEWLNYD IYIPDLPRAA RLCLSICSVK GRKGAKEEHC PLAWGNINLF DYTDTLVSGK MALNLWPVPH GLEDLLNPIG VTGSNPNKET PCLELEFDWF SSVVKFPDMS VIEEHANWSV SREAGFSYSH AGLSNRLARD NELRENDKEQ LKAISTRDPL SEITEQEKDF LWSHRHYCVT IPEILPKLLL SVKWNSRDEV AQMYCLVKDW PPIKPEQAME LLDCNYPDPM VRGFAVRCLE KYLTDDKLSQ YLIQLVQVLK YEQYLDNLLV RFLLKKALTN QRIGHFFFWH LKSEMHNKTV SQRFGLLLES YCRACGMYLK HLNRQVEAME KLINLTDILK QEKKDETQKV QMKFLVEQMR RPDFMDALQG FLSPLNPAHQ LGNLRLEECR IMSSAKRPLW LNWENPDIMS ELLFQNNEII FKNGDDLRQD MLTLQIIRIM ENIWQNQGLD LRMLPYGCLS IGDCVGLIEV VRNSHTIMQI QCKGGLKGAL QFNSHTLHQW LKDKNKGEIY DAAIDLFTRS CAGYCVATFI LGIGDRHNSN IMVKDDGQLF HIDFGHFLDH KKKKFGYKRE RVPFVLTQDF LIVISKGAQE CTKTREFERF QEMCYKAYLA IRQHANLFIN LFSMMLGSGM PELQSFDDIA YIRKTLALDK TEQEALEYFM KQMNDAHHGG WTTKMDWIFH TIKQHALN
Also provided is a method for inhibiting PI3Ka activity in a cell, comprising contacting the cell with a compound of Formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the contacting is in vitro. In some embodiments, the contacting is in vivo. In some embodiments, the contacting is in vivo, wherein the method comprises administering an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, to a subject having a cell having aberrant PI3Ka activity. In some embodiments, the cell is a cancer cell. In some embodiments, the cancer cell is any cancer as described herein. In some embodiments, the cancer cell is a PI3Koi-associated cancer cell. As used herein, the term "contacting" refers to the bringing together of indicated moieties in an in vitro system or an in vivo system. For example, "contacting" a PI3Ka protein with a compound provided herein includes the administration of a compound provided herein to an individual or subject, such as a human, having a PI3Ka protein, as well as, for example, introducing a compound provided herein into a sample containing a cellular or purified preparation containing the PI3Ka protein.
Also provided herein is a method of inhibiting cell proliferation, in vitro or in vivo, comprising contacting a cell with an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof as defined herein.
Further provided herein is a method of increase cell death, in vitro or in vivo, comprising contacting a cell with an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof as defined herein. Also provided herein is a method of increasing tumor cell death in a subject, comprising administering to the subject an effective compound of Formula (I), or a pharmaceutically acceptable salt thereof, in an amount effective to increase tumor cell death.
In some mebodiments, the PI3Ka is human PI3Ka. In some embodiments, the PI3Ka has one or more point mutations in the PIK3CA gene. In some embodiments, the point mtations include a substitution at amino acid position 1047 of a human PI3Ka protein. In some embodiments, the substitution is H1047R.
When employed as pharmaceuticals, the compounds of Formula (I), including pharmaceutically acceptable salts thereof, can be administered in the form of pharmaceutical compositions as described herein.
EXAMPLES
Example 1: Compound Preparation
The general methods for the preparation of the compounds of Formula (I) have been described in an illustrative manner and is intended to be description, rather than of limitation. Thus, it will be appreciated that conditions such as choice of solvent, temperature of reaction, volumes, reaction time may vary while still producing the desired compounds. In addition, it will be appreciated that many of the reagents provided in the following examples may be substituted with other suitable reagents. See, e.g., Smith & March, Advanced Organic Chemistry, 7th Ed. (2013). Such changes and modifications, including without limitation, those relating to the chemical structures, substituents, derivatives, intermediates, syntheses, formulations and / or methods of use provided herein, may be made without departing from the spirit and scope thereof.
The starting materials used for the syntheses are either synthesized or obtained from commercial sources, such as, but not limited to, Sigma-Aldrich, Fluka, Acros Organics, Alfa Aesar, Enamine, Strem, VWR Scientific, and the like. Nuclear Magnetic Resonance (NMR) analysis was conducted using a Bruker AVANCE III HD (300 or 400) MHz spectrometer or Bruker AVANCE NEO 400 MHz spectrometer with an appropriate deuterated solvent. LCMS spectra were obtained on a Shimadzu LCMS-2020 with electrospray ionization in positive ion detection mode with 20ADXR pump, SIL-20ACXR autosampler, CTO-20AC column oven, M20A PDA Detector and LCMS 2020 MS detector. Compound 25: (A)-2-((l-(2-(2,3-dihydro-l//-inden-2-yl)-6-methyl-l-oxoisoindolin-4- yl)ethyl)amino) benzoic acid
Figure imgf000094_0001
Step 1 - Synthesis of methyl 3-bromo-2-(bromomethyl)-5-methylbenzoate
To a mixture of methyl 3-bromo-2,5-dimethylbenzoate (2.1 g, 8.64 mmol, prepared according to the procedure in CN113004145) in CCh (20 mL) was added AIBN (142 mg, 864 umol) and NBS (1.54 g, 8.64 mmol). The mixture was stirred at 80 °C for 16 h. After cooling to room temperature, the reaction was quenched with aq. sat. NaHCOi (100 mL). The mixture was stirred for 10 min at room temperature. The aqueous phase was extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine (50 mL x 2), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (solvent gradient: 0 - 8% EtOAc in petroleum ether) to give the title compound (1 g, 36%) as colorless oil. 'H NMR (400 MHz, DMSO-tL) 8 7.81 (s, 1H), 7.69 (s, 1H), 5.01 (s, 2H), 3.88 (s, 3H), 2.35 (s, 3H).
Step 2 - Synthesis of tert-butyl (5-chloro-2,3-dihydro-LH-inden-2-yl)carbamate
A mixture of 5-chloro-l,3-dihydro-27/-inden-2-one (1 g, 6.0 mmol), NH4OAC (4.63 mg, 60.0 mmol) and AcOH (36 mg, 0.6 mmol) in MeOH (20 mL) was stirred at room temperature for 1 h. Then the mixture was added NaBHiCN (755 mg, 12.0 mmol) and stirred at 60 °C for 16 h. After cooling to room temperature, the reaction was added BOC2O (2.62 g, 12.0 mmol). The mixture was stirred at room temperature for another 2 h. The mixture was quenched with aq. sat. Nal ICO3 (50 mL), extracted with DCM (80 mL x 2). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (solvent gradient: 0 - 10% EtOAc in petroleum ether) to give the title compound (600 mg, 37%) as a brown soild. 'H NMR (400 MHz, CDCI3) 6 7.20 (s, 1H), 7.17 - 7.1 1 (m, 2H), 4.73 (s, 1H), 4.49 - 4.45 (m, 1H), 3.33 - 3.17 (m, 2H), 2.83 - 2.67 (m, 2H), 1.45 (s, 9H). MS: m/z 212.1 (M-56+H+).
Step 3 - Synthesis of 5-chloro-2,3-dihydro-l/7-inden-2-amine hydrochloride
To a solution of /c/V-butyl (5-chloro-2,3-dihydro-l//-inden-2-yl)carbamate (600 mg, 2.24 mmol) in DCM (10 mb) was added HC1 (5 mb, 4M in dioxane). After the addition, the reaction mixture was stirred at room temperature for 2 h. The mixture was concentrated to give the title compound (440 mg, crude) as a yellow solid that required no further purification.
Figure imgf000095_0001
NMR (400MHz, DMSO4) 5 8.29 (s, 3H), 7.37 (s, 1H), 7.32 - 7.27 (m, 1H), 7.27 - 7.22 (m, 1H), 4.06 - 3.93 (m, 1H), 3.32 - 3.20 (m, 2H), 3.01 - 2.91 (m, 2H). MS: m/z 168.1 (M+H+).
Step 4 - Synthesis of 4-bromo-2-(5-chloro-2,3-dihydro-LH-inden-2-yl)-6- methylisoindolin-l-one
A mixture of methyl methyl 3-bromo-2-(bromomethyl)-5-methylbenzoate (400 mg, 1.24 mmol), 5-chloro-2,3-dihydro-l//-inden-2-amine hydrochloride (273 mg, 1.34 mmol) and K2CO3 (515 mg, 3.73 mmol) in EtOH (10 mb) was stirred at 60 °C for 16 h. After cooling to room temperature, the reaction was diluted with EtOAc (30 mb) and filtered, the filtrate was concentrated in vacuo. The crude residue was purified by silica gel chromatography (solvent gradient: 0 - 20% EtOAc in petroleum ether) to give the title compound (160 mg, 34%) as a yellow solid. 'H NMR (400MHz, DMSO-tfc) 8 7.65 (s, 1H), 7.53 (s, 1H), 7.33 (s, 1H), 7.31 - 7.22 (m, 2H), 5.14 - 5.06 (m, 1H), 4.20 (s, 2H), 3.28 - 2.97 (m, 4H), 2.40 (s, 3H). MS: m/z 377.9 (M+H+).
Step 5 - Synthesis of 2-(5-chloro-2,3-dihydro-lH-inden-2-yl)-4-(l-ethoxyvinyl)-6- methylisoindolin-l-one
A mixture of 4-bromo-2-(5-chloro-2,3-dihydro-l/f-inden-2-yl)-6-methylisoindolin-l-one (160 mg, 424 mmol), tributyl(l-ethoxyvinyl)stannane (160 mg, 424 pmol) and Pd(dppf)Ch (307 mg, 849 pmol) in dioxane (3 mb) was stirred at 90 °C for 16 h under N2 atmosphere. After cooling to room temperature, the reaction was quenched with 10% KF solution (20 mL). The mixture was filtered and the filtrate was separated between EtOAc (30 mL) and H2O (20 mL). The organic layer was washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (solvent gradient: 0 - 30% EtOAc in petroleum ether) to give the title compound (87 mg, 57%) as an off-white solid. 1 H NMR (400MHz, CDCI3) 87.62 (s, 1H), 7.49 (s, 1H), 7.29 - 7.27 (m, 1H), 7.20 (s, 2H), 5.44 - 5.37 (m, 1H), 4.56 (d, J = 2.8 Hz, 1H), 4.22 (d, J = 2.8 Hz, 1H), 4.19 (d, J = 2.8 Hz, 2H), 3.81 - 3.74 (m, 2H), 3.40 - 3.31 (m, 2H), 3.03 - 2.92 (m, 2H), 2.44 (s, 3H), 1.10 (t, J= 7.2 Hz, 3H). MS: m/z 367.9 (M+H+).
Step 6 - Synthesis of 4-acetyl-2-(5-chloro-2,3-dihydro-LH-inden-2-yl)-6- methylisoindolin-l-one
To a solution of 2-(5-chloro-2,3-dihydro-l//-inden-2-yl)-4-(l-ethoxyvinyl)-6- methylisoindolin-l-one (87 mg, 236 pmol) in THF (2 mL) was added HC1 (1 mL, IM in water) at room temperature. The reaction mixture was stirred at room temperature for 1 h. The mixture was quenched with saturated NaHCCh (10 mL), extracted with EtOAc (30 mL x 2). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated to give the title compound (80 mg, crude) as a yellow solid that required no further purification. 'H NMR (400 MHz, DMSO-tL) 8 8.06 (s, 1H), 7.76 (s, 1H), 7.34 (s, 1H), 7.32 - 7.28 (m, 1H), 7.27 - 7.22 (m, 1H), 5.15 - 5.06 (m, 1H), 4.47 (s, 2H), 3.30 - 3.19 (m, 2H), 3.15 - 3.04 (m, 2H), 2.59 (s, 3H), 2.49 (s, 3H). MS: m/z 339.9 (M+H+).
Step 7 - Synthesis of 4-(l-aminoethyl)-2-(5-chloro-2,3-dihydro-LH-inden-2-yl)-6- methylisoindolin-l-one
A mixture of 4-acetyl-2-(5-chloro-2,3-dihydro-l/7-inden-2-yl)-6-methylisoindolin-l-one (80 mg, 235 pmol), ISTLiOAc (363 mg, 4.71 mmol) and AcOH (1.41 mg, 23.5 pmol) in MeOH (5 mL) was stirred at room temperature for 1 h. Then NaBHiCN (29.6 mg, 471 pmol) was added to the reaction mixture. After the addition, the reaction mixture was stirred at 60 °C for 16 h. After cooling to room temperature, the reaction mixture was diluted with DCM (30 mL). The mixture was washed with saturated NaHCOs solution (20 mL x 3), brine (20 mL), dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated to give the title compound (80 mg, crdue) as a brown solid that required no further purification. MS: m/z 363.1 (M+Na+).
Step 8 - Synthesis of tert-butyl 2-((l-(2-(5-chloro-2.3-dihydro-l//-inden-2-yl)-6- methyl-l-oxoisoindolin-4-yl)ethyl)amino)benzoate
A mixture of 4-(l-aminoethyl)-2-(5-chl oro-2, 3 -dihydro- l/7-inden-2-yl)-6- methylisoindolin-l-one (200 mg, 587 pmol), tert-butyl 2- iodobenzoate (357 mg, 1.17 mmol), CS2CO3 (574 mg, 1.76 mmol), Pd2(dba).3 (54 mg, 59 pmol) and Xantphos (68 mg, 117 pmol) in dioxane (5 mL), the reaction mixture was stirred at 100 °C for 16 h under N2 atmosphere. After cooling to room temperature, the reaction was filtered and the filtrate was concentrated. The crude residue was purified by silica gel chromatography (solvent gradient: 0 - 20% EtOAc in petroleum ether) to give the title compound (120 mg, 40%) as a yellow solid. JH NMR (400 MHz, DMSO- d6) 5 8.08 - 7.98 (m, 1H), 7.77- 7.73 (m, 1H), 7.38 (s, 2H), 7.33 - 7.26 (m, 2H), 7.23 - 7.15 (m, 2H), 6.56 - 6.51 (m, 1H), 6.47 - 6.42 (m, 1H), 5.12 - 5.00 (m, 1H), 4.77 - 4.68 (m, 2H), 4.32 - 4.24 (m, 1H), 3.21 - 3.09 (m, 3H), 3.05 - 2.94 (m, 1H), 2.36 (s, 3H), 1.53 (d, J= 6.8 Hz, 3H), 1.51 (s, 9H). MS: m/z 517.1 (M+H+).
Step 9 - Synthesis of tert-butyl 2-((l-(2-(2,3-dihydro-l/Z-inden-2-yl)-6-methyl-l- oxoisoindolin-4-yl)ethyl)amino)benzoate
To a solution of /crt-butyl 2-((l-(2-(5-chloro-2,3-dihydro-17/-inden-2-yl)-6-methyl-l- oxoisoindolin-4-yl)ethyl)amino)benzoate (100 mg, 193 pmol) and TEA (75 mg, 741 pmol) in MeOH (5 mL) was added wet Pd(OH)2 on carbon (50 mg, 20% Pd, 50% wet with water). The reaction was stirred at room temperature for 4 h under H2 atmosphere (15 psi). The reaction was filtered through diatomaceous earth and the filtrate was concentrated to afford the title compound (90 mg, crude) as a yellow solid that required no further purification. MS: m/z 483.2 (M+H+).
Step 10 - Synthesis of 2-((l-(2-(2,3-dihydro-l//-inden-2-yl)-6-methyl-l-oxoisoindolin- 4-yl)ethyl)amino)benzoic acid
To a mixture of tert-butyl 2-(( l-(2-(2, 3 -dihydro- l//-inden-2-yl)-6-methyl- 1- oxoisoindolin-4-yl)ethyl)amino)benzoate (100 mg, 207 umol) in DCM (3 mL) was added TFA (1 mL, 13.5 mmol). The reaction mixture was stirred at 40 °C for 16 h. After cooling to room temperature, the reaction mixture was concentrated and the residue was purified by reverse phase chromatography (acetonitrile 37% - 67% / 0.225% formic acid in water) to give the title compound (38 mg, 43%) as a white solid. JH NMR (400 MHz, DMSO-rL) 5 12.76 (s, 1H), 8.26 (s, 1H), 7.81 - 7.75 (m, 1H), 7.37 (s, 1H), 7.34 (s, 1H), 7.29 - 7.22 (m, 2H), 7.21 - 7.15 (m, 3H), 6.56 - 6.49 (m, 1H), 6.41 (d, J= 8.4 Hz, 1H), 5.10 - 4.99 (m, 1H), 4.76 - 4.63 (m, 2H), 4.35 - 4.31 (m, 1H), 3.22 - 3.17 (m, 2H), 3.17 - 3.03 (m, 2H), 2.37 - 2.33 (m, 1H), 2.35 (s, 2H), 1.50 (d, J= 6.8 Hz, 3H). MS: m/z 427.2 (M+H+).
Step 11 - Synthesis of (l?)-2-((l-(2-(2,3-dihydro-lH-inden-2-yl)-6-methyl-l- oxoisoindolin-4-yl)ethyl)amino)benzoic acid and (5)-2-((l-(2-(2,3-dihydro-l/f-inden-2-yl)-6- methyl-l-oxoisoindolin-4-yl)ethyl)amino)benzoic acid Racemic 2-((l-(2-(2,3-dihydro-17/-inden-2-yl)-6-methyl-l-oxoisoindolin-4- yl)ethyl)amino)benzoic acid (34 mg, 80 umol) was separated by using chiral SFC (DAICEL CHIRALPAK AD(250mm*30mm,10 urn); Supercritical CO2 / IPA+0.1% NH3*H2O = 30/70; 150 mL/min) to afford (7?)-2-((l-(2-(2,3-dihydro-l//-inden-2-yl)-6-methyl-l-oxoisoindolin-4- yl)ethyl)amino)benzoic acid (9.6 mg, first peak) and (5)-2-((l-(2-(2, 3 -dihydro- 177-inden-2-y l)-6- methyl-l-oxoisoindolin-4-yl)ethyl)amino)benzoic acid (8.9 mg, second peak) both as white solid. Absolute configuration was arbitrarily assigned to each enantiomer. Compound 25: 'H NMR (400 MHz, DMSO-tL) 6 12.75 (s, 1H), 8.32 (s, 1H), 7.79 - 7.76 (m, 1H), 7.37 (s, 1H), 7.34 (s, 1H), 7.28 - 7.21 (m, 2H), 7.21 - 7.15 (m, 3H), 6.56 - 6.49 (m, 1H), 6.41 (d, J= 8.4 Hz, 1H), 5.10 - 4.99 (m, 1H), 4.76 - 4.63 (m, 2H), 4.36 - 4.31 (m, 1H), 3.23 - 3.18 (m, 2H), 3.17 - 3.03 (m, 2H), 2.37 - 2.33 (m, 1H), 2.35 (s, 2H), 1.50 (d, J= 6.4 Hz, 3H). MS: m/z 427.1 (M+H+).
Compound 76: (A)-2-((l-(2-(2,3-dihydro-17/-inden-2-yl)-6-methyl-l-oxoisoindolin-4- yl)ethyl)amino)benzenesulfonamide
Figure imgf000098_0001
Step 1 - Synthesis of 2-(5-chloro-2,3-dihydro-TH-inden-2-yl)-4-(l-hydroxyethyl)-6- methylisoindolin-l-one:
To a solution of 4-acetyl-2-(5-chloro-2,3-dihydro-l//-inden-2-yl)-6-methylisoindolin-l- one (100 mg, 294 pmol) in MeOH (2 mL) was added NaBHi (10 mg, 264 pmol). The mixture was stirred at room temperature for 1 h. The reaction was quenched with sat. aq. NH4CI (5 mL), diluted with water (10 mL), extracted with EtOAc (15 mL x 2). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo to afford title compound (100 mg, crude) as a yellow solid that required no further purification. 'H NMR (400 MHz, DMSO-tA) 8 7.38 - 7.32 (m, 3H), 7.31 - 7.27 (m, 1H), 7.26 - 7.21 (m, 1H), 5.14 - 5.04 (m, 1H), 4.84 - 4.70 (m, 1H), 4.38 (s, 2H), 3.28 - 3.03 (m, 4H), 2.38 (s, 3H), 1.31 (d, J= 6.4 Hz, 3H). MS: m/z 342.1 (M+H+). Step 2 - Synthesis of 4-(l-bromoethyl)-2-(5-chloro-2.3-dihydro-l//-inden-2-yl)-6- methylisoindolin-l-one:
To a solution of 2-(5-chloro-2,3-dihydro-lH-inden-2-yl)-4-(l-hydroxyethyl)-6- methylisoindolin-l-one (100 mg, 293 pmol) in DCM (2 mL) was added PBn (87 mg, 322 pmol) at 0 °C. The reaction mixture was stirred at 0 °C for 1 h under N2 atmosphere. The mixture was concentrated in vacuo to afford title compound (500 mg, crude) as a yellow solid that required no further purification. 'H NMR (400 MHz, DMSO-tfc) 8 7.60 (s, 1H), 7.50 - 7.44 (m, 1H), 7.35 (s, 1H), 7.17 - 7.09 (m, 1H), 7.05 - 6.97 (m, 1H), 5.92 (s, 2H), 5.48 (m, 1H), 5.16 - 5.05 (m, 1H), 3.30 - 3.19 (m, 2H), 3.17 - 3.03 (m, 2H), 2.42 (s, 3H), 2.01 (d, J= 6.8 Hz, 3H).
Step 3 - Synthesis of 2-((l-(2-(5-chloro-2.3-dihydro-l//-inden-2-yl)-6-methyl-l- oxoisoindolin-4-yl)ethyl)amino)benzenesulfonamide:
To a solution of 4-(l-bromoethyl)-2-(5-chloro-2,3-dihydro-l//-inden-2-yl)-6- methylisoindolin-l-one (110 mg, 272 pmol) in dioxane (2 mL) was added 2- aminobenzenesulfonamide (140 mg, 815 pmol). The mixture was stirred at 100 °C for 16 h. After cooling to room temperature, the reaction mixture was added water (20 mL) and extracted with EtOAc (40 mL x 2). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na?SO4, filtered and concentrated in vacuo. The residue was purified by reverse phase chromatography (acetonitrile 55% - 85% / 0.225% formic acid in water) to give the title compound (60 mg, 28%) as a white solid. MS: m/z 496.0 (M+H+).
Step 4 - Synthesis of 2-((l-(2-(2,3-dihydro-17/-inden-2-yl)-6-methyl-l-oxoisoindolin- 4-yl)ethyl)amino)benzenesulfonamide:
To a solution of 2-((l-(2-(5-chloro-2,3-dihydro-17/-inden-2-yl)-6-methyl-l-oxoisoindolin- 4-yl)ethyl)amino)benzenesulfonamide (60 mg, 120 pmol) and TEA (37 mg, 363.0 pmol) in MeOH (3 mL) was added wet Pd(OH)2 on carbon (50 mg, 20% Pd, 50% wet with water). The reaction was stirred at room temperature for 2 h under H2 atmosphere (15 psi). The reaction was filtered through diatomaceous earth and the filtrate was concentrated in vacuo. The residue was purified by reverse phase chromatography (acetonitrile 46% - 76% / 0.225% formic acid in water) to give the title compound (25 mg, 43%) as a white solid. 'H NMR (400 MHz, DMSO-A) 8 7.65 - 7.61 (m, 1H), 7.56 (s, 2H), 7.47 (s, 1H), 7.38 (s, 1H), 7.30 - 7.23 (m, 2H), 7.22 - 7.13 (m, 3H), 6.68 - 6.60 (m, 1H), 6.46 (d, J= 8.4 Hz, 1H), 6.24 (d, J = 5.6 Hz, 1H), 5.08 - 5.02 (m, 1H), 4.80 - 4.64 (m, 2H), 4.49 - 4.44 (m, 1H), 3.24 - 3.10 (m, 4H), 2.35 (s, 3H), 1.52 (d, J= 6.8 Hz, 3H). MS: m/z 462.0 (M+H+).
Step 5 - Synthesis of (/?)-2-((l-(2-(2.3-dihydro-l//-inden-2-yl)-6-methyl-l- oxoisoindolin-4-yl (ethyl (amino Jbenzenesulfonamide & GS')-2 -( ( 1 -( 2 - ( 2.3-d i hy d r o- 1 //- i n d e 11- 2-y I )-6-meth yl- 1 -oxoisoindol in-4-yl Jet hy 1 (a m in o (benzenesul t'oiiam ide:
2-((l -(2-(2, 3 -dihydro- 177-inden-2-yl)-6-methyl- 1 -oxoisoindolin-4- yl)ethyl)amino)benzene sulfonamide (25 mg, 54 pmol) was separated by using chiral SFC (DAICEL CHIRALPAK AD (250mm*30mm, lOum); Supercritical CO2 / EtOH + 0.1% NH3«H2O = 60/40; 80 mL/min) to afford (7?)-2-((l-(2-(2,3-dihydro-l/7-inden-2-yl)-6-methyl-l- oxoisoindolin-4-yl)ethyl)amino)benzenesulfonamide (4.8 mg, first peak) and (5)-2-((l-(2-(2,3- dihydro-l/7-inden-2-yl)-6-methyl-l-oxoisoindolin-4-yl)ethyl)amino)benzenesulfonamide (2.4 mg, second peak) both as yellow solid. Absolute configuration was arbitrarily assigned to each enantiomer, (first peak): 'H NMR (400 MHz, DMSO-tA) 8 7.65 - 7.61 (m, 1H), 7.55 (s, 2H), 7.47 (s, 1H), 7.38 (s, 1H), 7.29 - 7.22 (m, 2H), 7.22 - 7.14 (m, 3H), 6.68 - 6.58 (m, 1H), 6.46 (d, J= 8.0 Hz, 1H), 6.23 (d, J= 5.2 Hz, 1H), 5.07 - 5.03 (m, 1H), 4.79 - 4.66 (m, 2H), 4.49 - 4.44 (m, 1H), 3.24 - 3.08 (m, 4H), 2.35 (s, 3H), 1.52 (d, J= 6.8 Hz, 3H). MS: m/z 462.0 (M+H+). Compound 76 (second peak): 'H NMR (400 MHz, DMSO-fifc) 8 7.65 - 7.61 (m, 1H), 7.55 (s, 2H), 7.47 (s, 1H), 7.38 (s, 1H), 7.29 - 7.23 (m, 2H), 7.21 - 7.15 (m, 3H), 6.64 (m, 1H), 6.46 (d, J= 8.4 Hz, 1H), 6.23 (d, J= 5.6 Hz, 1H), 5.07 - 5.03 (m, 1H), 4.78 - 4.65 (m, 2H), 4.49 - 4.44 (m, 1H), 3.23 - 3.08 (m, 4H), 2.35 (s, 3H), 1.52 (d, J= 6.8 Hz, 3H). MS: m/z 462.0 (M+H+).
Compound 61 2-((l-(2-(isochroman-4-yl)-6-methyl-l-oxoisoindolin-4- yl)ethyl)amino)benzoic acid
Figure imgf000100_0001
Stepl - Synthesis of 4-bromo-2-(isochroman-4-yl)-6-methylisoindolin-l-one: A mixture of methyl 3-bromo-2-(bromomethyl)-5-methylbenzoate (200 mg, 621 pmol), isochroman-4-amine (111 mg, 745 pmol) and K2CO3 (138 mg, 1.86 mmol) in EtOH (3 mL) was stirred at 60 °C for 1 h. After cooling to room temperature, the reaction was diluted with DCM (5 mL) and filtered, the filtrate was concentrated in vacuo. The crude residue was purified by silica gel chromatography (solvent gradient: 0 - 10% EtOAc in petroleum ether) to give the title compound (208 mg, 79%) as colourless oil. 'H NMR (400MHz, DMSO-tfc) 5 7.66 (s, 1H), 7.60 (s, 1H), 7.33 - 7.28 (m, 1H), 7.25 - 7.22 (m, 1H), 7.20 - 7.15 (m, 2H), 5.42 - 5.36 (m, 1H), 4.95 - 4.86 (m, 1H), 4.73 - 4.67 (m, 1H), 4.45 - 4.36 (m, 1H), 4.21 - 4.15 (m, 1H), 4.07 - 4.00 (m, 1H), 3.76 - 3.70 (m, 1H), 2.41 (s, 3H). MS: m/z 357.9 (M+H+).
Step 2 - Synthesis of 4-(l-ethoxyvinyl)-2-(isochroman-4-yl)-6-methyIisoindolin-l-one:
A mixture of 4-bromo-2-(isochroman-4-yl)-6-methylisoindolin-l-one (208 mg, 581 pmol), tributyl (1 -ethoxy vinyl )stannane (530 mg, 1.47 mmol) and Pd(dppf)Ch (43 mg, 58 pmol) in dioxane (2 mL) was stirred at 90 °C for 16 h under N2 atmosphere. After cooling to room temperature, the reaction was quenched with 10% KF solution (10 mL). The mixture was filtered and the filtrate was separated between EtOAc (40 mL) and H2O (20 mL). The organic layer was washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (solvent gradient: 0 - 20% EtOAc in petroleum ether) to give the title compound (133 mg, 66%) as yellow oil. 'H NMR (400 MHz, DMSO-t/e) 5 7.59 (s, 1H), 7.54 (s, 1H), 7.32 - 7.27 (m, 1H), 7.24 - 7.20 (m, 1H), 7.19 - 7.15 (m, 2H), 5.38 - 5.33 (m, 1H), 4.91 - 4.80 (m, 1H), 4.76 - 4.72 (m, 1H), 4.67 - 4.65 (m, 1H), 4.62 - 4.55 (m, 1H), 4.33 - 4.31 (m, 1H), 4.19 - 4.12 (m, 1H), 4.06 - 4.02 (m, 1H), 3.92 - 3.83 (m, 1H), 3.81 - 3.76 (m, 2H), 2.41 (s, 3H), 1.17 - 1.14 (m, 3H) MS: m/z 350.1 (M+H+).
Step 3 - Synthesis of 4-acetyl-2-(isochroman-4-yl)-6-methylisoindolin-l-one:
To a solution of 4-(l -ethoxy vinyl)-2-(isochroman-4-yl)-6-methylisoindolin-l -one (133 mg, 381 pmol) in THF (2 mL) was added HC1 (1 mL, IM in water) at room temperature. The reaction mixture was stirred at room temperature for 1 h. The mixture was quenched with saturated NaHCO.i (5 mL), extracted with EtOAc (10 mL x 2). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated to give the title compound (122 mg, crude) as a yellow solid that required no further purification. MS: m/z 322.0 (M+H+).
Step 4 - Synthesis of 4-(l-aminoethyl)-2-(isochroman-4-yl)-6-methylisoindolin-l-one: A mixture of 4-acetyl-2-(isochroman-4-yl)-6-methylisoindolin-l-one (122 mg, 380 pmol), NH4OAC (439 mg, 5.69 mmol) and AcOH (46 mg, 759 pmol) in MeOH (4 mL) was stirred at room temperature for 1 h. Then NaBHsCN (72 mg, 1.14 pmol) was added to the reaction mixture. After the addition, the reaction mixture was stirred at 60 °C for 16 h. After cooling to room temperature, the reaction mixture was diluted with DCM (30 mL). The mixture was washed with saturated NaHCCh solution (20 mL x 3), brine (20 mL), dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated to give the title compound (112 mg, crdue) as yellow oil that required no further purification. MS: m/z 345.0 (M+Na+).
Step 5 - Synthesis of tert-butyl 2-((l-(2-(isochroman-4-yl)-6-methyl-l-oxoisoindolin- 4-yl)ethyl)amino)benzoate:
A mixture of 4-(l-aminoethyl)-2-(isochroman-4-yl)-6-methylisoindolin-l-one (158 mg, 521 pmol), tert-butyl 2- iodobenzoate (322 mg, 347 pmol), CS2CO3 (453 mg, 1.39 mmol), Pd2(dba)3 (32 mg, 35 pmol) and Xantphos (20 mg, 35 pmol) in dioxane (2 mL), the reaction mixture was stirred at 100 °C for 2 h under N2 atmosphere. After cooling to room temperature, the reaction was filtered and the filtrate was concentrated. The crude residue was purified by silica gel chromatography (solvent gradient: 10 - 20% EtOAc in petroleum ether) to give the title compound (80 mg, 46%) as yellow oil. 'H NMR (400 MHz, DMSO-tfc) 5 7.94 - 7.85 (m, 1H), 7.77 - 7.64 (m, 1H), 7.45 (s, 1H), 7.37 (d, J= 3.2 Hz, 1H), 7.33 - 7.19 (m, 2H), 7.17 - 7.06 (m, 3H), 6.55 - 6.46 (m, 1H), 6.35 - 6.28 (m, 1H), 5.42 - 5.34 (m, 1H), 4.90 - 4.59 (m, 4H), 4.17 - 4.04 (m, 2H), 3.86 - 3.75 (m, 1H), 2.40 - 2.33 (m, 3H), 1.56 - 1.50 (m, 9H), 1.47 - 1.41 (m, 3H). MS: m/z 499.3 (M+H+).
Step 6 - Synthesis of 2-((l-(2-(isochroman-4-yl)-6-methyl-l-oxoisoindolin-4- yl)ethyl)amino)benzoic acid:
To a mixture of tert-butyl 2-(( l-(2-(2, 3 -dihydro- 177-inden-2-yl)-6-methyl-l- oxoisoindolin-4-yl)ethyl)amino)benzoate (25 mg, 50 umol) in DCM (0.9 mL) was added TFA (0.3 mL, 3.37 mmol). The reaction mixture was stirred at room temperature for 1 h. After cooling to room temperature, the reaction mixture was concentrated and the residue was purified by reverse phase chromatography (acetonitrile 41% - 71% / 0.225% formic acid in water) to give the title compound (1.85 mg, 8%) as a white solid. 'H NMR (400 MHz, DMSO-cL) 5 12.58 (s, 1H), 8.23 - 8.16 (m, 1H), 7.82 - 7.61 (m, 1H), 7.84 - 7.62 (m, 1H), 7.36 (d, J = 4.4 Hz, 1H), 7.33 - 6.92 (m, 5H), 6.54 - 6.40 (m, 1H), 6.30 (d, J= 8.4 Hz, 1H), 5.37 - 5.34 (m, 1H), 4.91 - 4.80 (m, 1H), 4.73 - 4.62 (tn, 2.5H), 4.42 - 4.38 (m, 0.5H), 4.15 - 3.97 (m, 2.5H), 3.71 - 3.69 (m, 0.5H), 2.39 - 2.35 (tn, 3H), 1.42 (d, J= 5.6 Hz, 3H). MS: m/z 443.1 (M+H+).
Compound 117: 2-((l-(2-((ll?,3.s,5A')-8-acetyl-8-azabicyclo[3.2.1]octan-3-yl)-6- methyl-l-oxoisoindolin-4-yl)ethyl)amino)benzoic acid
Figure imgf000103_0001
Step 1 - Synthesis of (H?,3r,55)-tert-butyl 3-((2-bromo-6-chloro-4- methylbenzyl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylate & tert-butyl (1/?,3s,55)-3-((2- bromo-6-chloro-4-methylbenzyl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylate:
To a solution of 2-bromo-6-chloro-4-methylbenzaldehyde (4.3 g, 18.42 mmol) and tertbutyl 3-amino-8-azabicyclo[3.2.1]octane-8-carboxylate (4.17 g, 18.42 mmol) in MeOH (120 mb) was added AcOH (2.21 g, 36.83 mmol) and NaBHsCN (1.74 g, 27.63 mmol). The reaction mixture was stirred at room temperature for 16 h. The mixture was quenched with sat. aq. NaHCCh (100 mL), extracted with EtOAc (100 mL x 2). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (solvent gradient: 0 - 20% EtOAc in petroleum ether) to give the first peak (2.1 g, 26%) and second peak (4.8 g, 59%) both as white solid, which were further confirmed by NOESY. First peak: 'H NVIR. (400 MHz, DMSO-cL) 5 7.45 (s, 1H), 7.32 (s, 1H), 4.66 - 4.64 (m, 1H), 3.99 - 3.93 (m, 2H), 3.86 (s, 2H), 2.90 - 2.87 (m, 1H), 2.27 (s, 3H), 2.13 - 2.08 (m, 2H), 1.89 - 1.79 (m, 2H), 1.78 - 1.72 (s, 2H), 1.71 - 1.59 (m, 2H), 1.38 (s, 9H). MS: m/z 443.2 (M+H+). Second peak: ‘H NMR (400 MHz, DMSO-tL) 8 7.44 (s, 1H), 7.31 (s, 1H), 4.07 - 4.02 (m, 2H), 3.87 (s, 2H), 3.03 - 2.89 (m, 1H), 2.27 (s, 3H), 1.88 - 1.73 (m, 4H), 1.65 - 1.53 (m, 2H), 1.39 (s, 9H), 1.36 - 1.25 (m, 2H). MS: m/z 443.2 (M+H+).
Step 2 - Synthesis of tert-butyl (H?,3s955)-3-(4-chloro-6-methyl-l-oxoisoindolin-2-yl)- 8-azabicyclo[3.2.1]octane-8-carboxylate: A mixture of tert-butyl (17?,3.v,55)-3-((2-bromo-6-chloro-4-methylbenzyl)amino)-8- azabicyclo[3.2.1]octane-8-carboxylate (4.8 g, 10.82 mmol), Pd(dppf)C12 (2.37 g, 3.24 mmol) and DIPEA (4.19 g, 32.45 mmol, 5.65 mL) in DMF (100 mL) was stirred at 80 °C for 16 h under CO atmosphere (50 psi). After cooling to room temperature, the reaction was quenched with water (200 mL), extracted with EtOAc (200 mL x 2). The combined organic layers were washed with brine (200 mL x 3), dried over anhydrous Na2SO4, fdtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (solvent gradient: 0 - 50% EtOAc in petroleum ether) to give the title compound (3.1 g, 73%) as a yellow solid. *HNMR (400 MHz, DMSO-de) 5 7.50 (s, 1H), 7.47 (s, 1H), 4.61 - 4.52 (m, 1H), 4.35 (s, 2H), 4.17 (s, 2H), 2.40 (s, 3H), 1.99 - 1.82 (m, 4H), 1.78 - 1.74 (m, 2H), 1.70 - 1.62 (m, 2H), 1.45 (s, 9H). MS: m/z 335.2 (M-56+H+).
Step 3 - Synthesis of tert-butyl (llf,3.$,55)-3-(4-acetyl-6-niethyl-l-oxoisoindolin-2-yl)- 8-azabicyclo[3.2.1]octane-8-carboxylate:
To a solution of tert-butyl (17?,3s,55)-3-(4-chloro-6-methyl-l-oxoisoindolin-2-yl)-8- azabicyclo[3.2.1]octane-8-carboxylate (3.1 g, 7.93 mmol) in toluene (50 mL) was added tributyl(l-ethoxyvinyl)stannane (4.3 g, 11.9 mmol), SPhos Pd G3 (619 mg, 793 pmol) and CsF (2.41 g, 15.86 mmol). The reaction was stirred at 100 °C for 16 h under N2 atmosphere. After cooling to room temperature, the reaction mixture was added 1 M HC1 (10 mL) and stirred at room temperature for 0.5 h. The reaction mixture was added 50 mL 10% KF solution, stirred at room temperature over 2 h. The mixture was extracted with EtOAc (200 mL x 2). The combined organic phase was washed with brine (200 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (solvent gradient: 0 - 30% EtOAc in petroleum ether) to give the title compound (1.4 g, 60%) as a yellow solid. 'H NMR (400 MHz, DMSO-de) 8 8.07 (s, 1H), 7.74 (s, 1H), 4.62 - 4.56 (m, 1H), 4.55 (s, 2H), 4.15 (s, 2H), 2.62 (s, 3H), 2.48 (s, 3H), 2.00 - 1.87 (m, 4H), 1.79 - 1.75 (m, 2H), 1.70 - 1.62 (m, 2H), 1.46 (s, 9H). MS: m/z 343.2 (M-56+H+).
Step 4 - Synthesis of tert-butyl (17?,3'S5ȣ)-3-(4-(l-aniinoethyl)-6-niethyl-l- oxoisoindolin-2-yl)-8-azabicyclo [3.2. l]octane-8-carboxylate:
To a solution of tert-butyl (l/?,3s,55)-3-(4-acetyl-6-methyl-l-oxoisoindolin-2-yl)-8- azabicyclo[3.2.1]octane-8-carboxylate (1.4 g, 3.51 mmol), NH4OAC (4.06 g, 52.70 mmol) and AcOH (211 mg, 3.51 mmol) in MeOH (35 mL) was degassed and stirred at room temperature for 1 h, then added NaBHsCN (662 mg, 10.54 mmol), the mixture was stirred at 60 °C for 16 h. After cooling to room temperature, the reaction mixture was diluted with DCM (150 mL). The mixture was washed with saturated NaHCCh solution (100 mL x 3), brine (100 mL), dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated to give the title compound (1.38 g, crude) as yellow oil that required no further purification. MS: m/z 344.2 (M-56+H+).
Step 5 - Synthesis of tert-butyl (H?,3s,5»S)-3-(4-(l-((2-
(methoxycarbonyl)phenyl)amino)ethyl)-6-methyl-l-oxoisoindolin-2-yl)-8- azabicyclo [3.2. l]octane-8-carboxylate:
To a solution of tert-butyl (lA,3s,55)-3-(4-(l-aminoethyl)-6-methyl-l-oxoisoindolin-2- yl)-8-azabicyclo[3.2.1]octane-8-carboxylate (1.38 g, 3.45 mmol), methyl 2 -iodobenzoate (1.36 g, 5.18 mmol), CS2CO3 (3.38 g, 10.36 mmol) and Xantphos (200 mg, 345 pmol) in dioxane (30 mL) was added Pd2(dba)3 (158 mg, 173 pmol). The reaction was stirred at 100 °C for 2 h under N2 atmosphere. After cooling to room temperature, the reaction was quenched with water (100 mL), extracted with EtOAc (100 mL x 2). The combined organic layers were washed with water (50 mL x 3) and brine (50 mL), dried over anhydrous Na2SC>4, filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (solvent gradient: 0 - 30% EtOAc in petroleum ether) to give the title compound (980 mg, 53%) as a yellow solid. MS: m/z 478.3 (M- 56+H+).
Step 6 - Synthesis of methyl 2-((l-(2-((ll?,3.s,55')-8-azabicyclo[3.2.1]octan-3-yl)-6- methyl-l-oxoisoindolin-4-yl)ethyl)amino)benzoate hydrochloride:
To a solution of /c/7-butyl (17?,35,55)-3-(4-(l-((2-(methoxycarbonyl)phenyl)amino)ethyl)- 6-methyl-l-oxoisoindolin-2-yl)-8-azabicyclo [3.2.1]octane-8-carboxylate (980 mg, 1.84 mmol) in DCM (3 mL) was added HC1 (5 mL, 4M in dioxane). The reaction was stirred at room temperature for 1 h under N2 atmosphere. The reaction mixture was concentrated to give the title compound (860 mg, crude) as a yellow solid that required no further purification. MS: m/z 434.3 (M+H+).
Step 7 - Synthesis of methyl 2-((l-(2-((llf,3s,55)-8-acetyl-8-azabicyclo[3.2.1]octan-3- yl)-6-methyl-l-oxoisoindolin-4-yl)ethyl)amino)benzoate:
To a solution of methyl 2-((l-(2-((17?,3s,55)-8-azabicyclo[3.2.1]octan-3-yl)-6-methyl-l- oxoisoindolin-4-yl)ethyl)amino)benzoate hydrochloride (100 mg, 213 pmol) and TEA (65 mg, 638 pmol) in DCM (4 mL) was added AC2O (26 mg, 255 pmol). The reaction was stirred at room temperature for 1 h. The reaction was quenched with NaHCOi (30 mL), extracted with DCM (30 mL x 2). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give the title compound (100 mg, 99%) as a yellow solid that required no further purification. MS: m/z 476.3 (M+H+).
Step 8 - Synthesis of 2-((l-(2-((H?,3s,55)-8-acetyl-8-azabicyclo[3.2.1]octan-3-yl)-6- methyl-l-oxoisoindolin-4-yl)ethyl)amino)benzoic acid:
To a solution of methyl 2-((l-(2-((lA,3.s-,55)-8-acetyl-8-azabicyclo[3.2.1]octan-3-yl)-6- methyl-l-oxoisoindolin-4-yl)ethyl)amino)benzoate (100 mg, 212 pmol) and KOH (119 mg, 2.12 mmol) in EtOH (5 mb) and H2O (0.1 mb) was stirred at 100 °C for 1 h. After cooling to room temperature, the mixture was adjusted to pH 4 with formic acid, the reaction mixture was concentrated and the residue was purified by reverse phase chromatography (acetonitrile 30% - 60% / 0.225% formic acid in water) to give the title compound (60 mg, 61%) as a white solid. 'H NMR (400 MHz, DMSO-t/6) 8 12.81 (s, 1H), 8.32 (s, 1H), 7.79 (d, J= 8.0 Hz, 1H), 7.35 (s, 1H), 7.31 (d, J= 4.0 Hz, 1H), 7.22 - 7.14 (m, 1H), 6.54 - 6.51 (m, 1H), 6.44 - 6.37 (m, 1H), 4.80 - 4.73 (m, 1H), 4.67 - 4.59 (m, 2H), 4.57 - 4.55 (m, 1H), 4.35 - 4.27 (m, 2H), 2.32 (s, 3H), 2.03 (s, 3H), 2.01 - 1.82 (m, 4H), 1.82 - 1.60 (m, 4H), 1.54 - 1.50 (m, 3H). MS: m/z 462.3 (M+H1 ).
Compound 126: 2-((l-(6-methyl-l-oxo-2-(5,6,7,8-tetrahydroquinolin-7-yI)isoindolin- 4-yl)ethyl)amino) benzoic acid
Figure imgf000106_0001
Step 1 - Synthesis of 4-bromo-6-methyl-2-(5,6,7,8-tetrahydroquinolin-7-yl)isoindolin- 1-one:
A mixture of 5,6,7,8-tetrahydroquinolin-7-amine (276 mg, 1.86 mmol) (prepared according to the procedure in Tetrahedron. Lett., 1991, 32, 6789), methyl 3-bromo-2- (bromomethyl)-5-methylbenzoate (300 mg, 932 pmol) and K2CO3 (386 mg, 2.80 mmol) in EtOH (5 mb) was stirred at 60 °C for 16 h. After cooling to room temperature, the reaction was diluted with EtOAc (15 mL) and filtered, the filtrate was concentrated in vacuo. The crude residue was purified by silica gel chromatography (solvent gradient: 0 - 13% (EtOAc/EtOH = 3/1) in petroleum ether) to give the title compound (183 mg, 49%) as a white solid. 'H NMR (400 MHz, DMSO-tfe) 8 8.34 (d, J= 3.6 Hz, 1H), 7.68 (s, 1H), 7.59 - 7.50 (tn, 2H), 7.21 - 7.13 (m, 1H), 4.56 - 4.46 (m, 2H), 4.43 - 4.36 (m, 1H), 3.25 - 3.15 (m, 1H), 3.06 - 2.98 (m, 1H), 2.98 - 2.89 (m, 2H), 2.42 (s, 3H), 2.11 - 2.02 (m, 2H). MS: m/z 357.1 (M+H+).
Step 2 - Synthesis of 4-acetyl-6-methyl-2-(5,6,7,8-tetrahydroquinolin-7-yl)isoindolin- 1-one:
A mixture of 4-bromo-6-methyl-2-(5,6,7,8-tetrahydroquinolin-7-yl)isoindolin-l-one (183 mg, 512 pmol), tributyl(l -ethoxy vinyl)stannane (450 mg, 1.25 mmol) and Pd(dppf)C12 (19 mg, 26 pmol) in dioxane (2 mL) was stirred at 90 °C for 16 h under N2 atmosphere. After cooling to room temperature, the reaction mixture was added IM HC1 (3 mL) and stirred at room temperature for 0.5 h. The reaction mixture was added 15 mL 10% KF solution, stirred at room temperature over 2 h. The mixture was extracted with EtOAc (30 mL x 2). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SC>4, filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (solvent gradient: 0 - 13% (EtOAc/EtOH = 3/1) in petroleum ether) to give the title compound (65 mg, 58%) as a white solid. 'H NMR (400 MHz, DMSO-t/e) 8 8.37 - 8.31 (m, 1H), 8.10 (s, 1H), 7.79 (s, 1H), 7.55 (d, J= 7.6 Hz, 1H), 7.21 - 7.15 (m, 1H), 4.87 - 4.63 (m, 2H), 4.57 - 4.44 (m, 1H), 3.25 - 3.14 (m, 1H), 3.09 - 2.98 (m, 1H), 2.98 - 2.87 (m, 2H), 2.69 - 2.53 (m, 3H), 2.49 - 2.38 (m, 3H), 2.12 - 2.02 (m, 2H). MS: m/z 321.2 (M+H+).
Step 3 - Synthesis of 4-(l-aminoethyl)-6-methyl-2-(5,6,7,8-tetrahydroquinolin-7- yl)isoindolin-l-one:
To a solution of 4-acetyl-6-methyl-2-(5,6,7,8-tetrahydroquinolin-7-yl)isoindolin-l-one (62 mg, 194 pmol), NH4OAC (149 mg, 1.94 mmol) and AcOH (3 mg, 52 ymol) in MeOH (2 mL) was added NaBHiCN (36 mg, 581 pmol). The reaction was heated to 60 °C for 16 h under N2 atmosphere. After cooling to room temperature, the reaction mixture was diluted with DCM (40 mL), washed with saturated NaHCCh solution (20 mL x 3) and brine (30 mL), dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated to give the title compound (62 mg, crude) as a brown solid that required no further purification. MS: m/z 322.3 (M+H+).
Step 4 - Synthesis of tert-butyl 2-((l-(6-methyl-l-oxo-2-(5,6,7,8-tetrahydroquinolin-7- yl)isoindolin-4-yl)ethyl)amino)benzoate:
A mixture of 4-(l-aminoethyl)-6-methyl-2-(5,6,7,8-tetrahydroquinolin-7-yl)isoindolin-l- one (62 mg, 193 pmol), tert-butyl 2-iodobenzoate (117 mg, 386 pmol), Xantphos (22 mg, 39 pmol), Pd2(dba)s (18 mg, 19 pmol,) and CS2CO3 (189 mg, 579 pmol) in dioxane (1 mL) was heated to 100 °C for 2 h under N2 atmosphere. After cooling to room temperature, the reaction was quenched with water (10 mL) and extracted with EtOAc (15 mL x 2). The combined organic layers were washed with brine (15 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash silica gel chromatography (0 - 18% (EtOAc/EtOH=3/l) in petroleum ether) to give the title compound (32 mg, 33%) as a yellow solid. rH NMR (400 MHz, DMSO-<A) 8 8.35 - 8.33 (m, 1H), 8.12 - 8.04 (m, 1H), 7.76 (d, J= 7.6 Hz, 1H), 7.54 (d, J= 7.6 Hz, 1H), 7.39 (s, 2H), 7.24 - 7.15 (m, 2H), 6.61 - 6.41 (m, 2H), 4.92 - 4.68 (m, 2H), 4.56 - 4.44 (m, 1H), 4.41 - 4.24 (m, 1H), 3.10 - 2.98 (m, 2H), 2.97 - 2.91 (m, 2H), 2.37 (s, 3H), 1.57 (d, J = 6.8 Hz, 3H), 1.52 - 1.49 (m, 9H), 1.25 - 1.21 (m, 2H). MS: m/z 498.0 (M+H+).
Step 5 - Synthesis of 2-((l-(6-methyl-l-oxo-2-(5,6,7,8-tetrahydroquinolin-7- yl)isoindolin-4-yl)ethyl)amino)benzoic acid :
To a solution of /c'/V-butyl 2-((l-(6-methyl-l-oxo-2-(5,6,7,8-tetrahydroquinolin-7- yl)isoindolin-4-yl)ethyl)amino)benzoate (32 mg, 64 pmol) in DCM (1.5 mL) was added TFA (0.5 mL, 6.8 mmol). The mixture was stirred at 40 °C for 16 h. After cooling to room temperature, the reaction mixture was concentrated in vacuo. The resulting residue was purified by reverse phase chromatography (acetonitrile 20% - 50% / 0.225% formic acid in water) to give the title compound (10 mg, 35%) as a white solid. rH NMR (400 MHz, DMSO-sfc) 8 8.66 - 8.40 (m, 1H), 8.37 - 8.31 (m, 1H), 7.79 (d, J = 8.0 Hz, 1H), 7.55 (d, J = 7.6 Hz, 1H), 7.40 - 7.35 (m, 2H), 7.22 - 7.11 (m, 2H), 6.52 - 6.49 (m, 1H), 6.47 - 6.40 (m, 1H), 4.91 - 4.64 (m, 2H), 4.54 - 4.34 (m, 2H), 3.11 - 3.03 (m, 1H), 3.03 - 2.97 (m, 1H), 2.97 - 2.89 (m, 2H), 2.36 (s, 3H), 2.17 - 2.03 (m, 1H), 2.00 - 1.94 (m, 1H), 1.54 (d, J= 6.4 Hz, 3H). MS: m/z 442.0 (M+H+).
Compound 150: 2-((l-(6-methyl-l-oxo-2-(5-sulfamoyl-2,3-dihydro-lH-inden-2- yl)isoindolin-4-yl)ethyl)amino)benzoic acid
Figure imgf000108_0001
Step 1 - Synthesis of 2-(4-bromo-6-methyl-l -oxoisoindolin-2-yl)-2,3-dihydro-1 H- indene-5-sulfonamide:
A solution of methyl 3-bromo-2-(bromomethyl)-5-methylbenzoate (100 mg, 0.31 mmol), 2-amino-2,3-dihydro-l//-indene-5-sulfonamide (77 mg, 0.31 mmol) (prepared according to the procedure in Bioorg. Med. Chem. Lett., 2004, 14, 5781) and K2CO3 (128 mg, 0.93 mmol) in EtOH (10 ml) was stirred at 60 °C for 1 h. After cooling to room temperature, the reaction was diluted with EtOAc (30 mL) and filtered, the filtrate was concentrated in vacuo. The residue was concentrated to give the title compound (100 mg, crude) as a yellow solid that required no further purification. MS: m/z 442.7 (M+Na+).
Step 2 - Synthesis of 2-(4-acetyl-6-methyl-l-oxoisoindolin-2-yl)-2,3-dihydro-LH- indene-5-sulfonamide:
A mixture of 2-(4-bromo-6-methyl-l-oxoisoindolin-2-yl)-2,3-dihydro-l//-indene-5- sulfonamide (620 mg, 1.47 mmol), tributyl(l -ethoxy vinyl)stannane (1.09 g, 3.02 mmol) and Pd(dppf)Ch (107 mg, 0.15 mmol) in dioxane (10 mL) was degassed and purged with N2 for 3 times. The reaction mixture was stirred at 90 °C for 16 h under N2 atmosphere. After cooling to room temperature, HC1 (4 mL, 1 M) was added. The mixture was stirred at room temperature for 0.5 h. The reaction mixture was added 20 mL 10% KF aqueous solution, stirred at room temperature for 2 h. The mixture was extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated. The crude residue was purified by silica gel chromatography (solvent gradient: 0 - 20% EtOAc in petroleum ether) to give the title compound (330 mg, 76%) as a white solid. rH NMR (400 MHz, DMSO-t/r,) 8 8.08 (s, 1H), 7.77 (s, 1H), 7.72 (s, 1H), 7.68 (d, J= 8.0 Hz, 1H), 7.46 (d, J =7.6 Hz, 1H), 7.31 (s, 2H), 5.19 - 5.11 (m, 1H), 4.52 (s, 2H), 3.26 - 3.14 (m, 4H), 2.59 (s, 3H), 2.48 (s, 3H) MS: m/z 385.1 (M+H+).
Step 3 - Synthesis of tert- butyl JV-(2-(4-acetyl-6-methyl-l-oxo-isoindolin-2-yl)indan-5- yl)sulfonyl-N-tert-butoxycarbonyl-carbamate:
To a mixture of BOC2O (450 mg, 2.06 mmol) and 2-(4-acetyl-6-methyl-l-oxo-isoindolin- 2-yl)indane-5-sulfonamide (330 mg, 858 pmol) in DCM (5 mL) was added DMAP (11 mg, 86 pmol). After the addition, the reaction mixture was stirred at room temperature for 1 h. The mixture was diluted with EtOAc (30 mL), washed with IM HC1 (20 mL) and brine (20 mL), dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo. The crude residue was purified by silica gel chromatography (solvent gradient: 0 - 50% EtOAc in petroleum ether) to give the title compound (150 mg, 28%) as a white soild. JH NMR (400 MHz, DMSO4) 8 8.07 (s, 1H), 7.88 (s, 1H), 7.84 (d, J= 8.0 Hz, 1H), 7.77 (s, 1H), 7.52 (d, J= 7.6 Hz, 1H), 5.20 - 5.13 (m, 1H), 4.49 (s, 2H), 3.39 - 3.35 (m, 2H), 3.26 - 3.18 (m, 2H), 2.58 (s, 3H), 1.47 (s, 9H), 1.42 (s, 9H). MS: m/z 429.1 (M-100-56+H+).
Step 4 - Synthesis of tert-butyl /V-(2-[4-(l-aminoethyl)-6-methyl-l-oxo-isoindolin-2- yl]indan-5-yl)sulfonyl-/V-tert-butoxycarbonyl-carbamate:
To a solution of tert-butyl A-(2-(4-acetyl-6-methyl- l-oxo-isoindolin-2-yl)indan-5- yl)sulfonyl-A-tert-butoxycarbonyl-carbamate (150 mg, 0.25 mmol), NH4OAC (296 mg, 3.85 mmol) in MeOH (3 mb) was added NaBHiCN (48 mg, 0.77 mmol). The reaction was heated to 60 °C for 16 h. After cooling to room temperature, the mixture was diluted with EtOAc (50 mL), washed with sat. aq. NaHCOa (20 mL x 2) and brine (20 mL). The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The residue was concentrated to give the title compound (110 mg, crude) as a yellow oil that required no further purification. MS: m/z 486.2 (M-100+H+).
Step 5 - Synthesis of tert-butyl 2-(l-(2-(5-(bis(tert-butoxycarbonyl)sulfamoyl)indan- 2-yl)-6-methyl-l-oxo-isoindolin-4-yl)ethylamino)benzoate:
A mixture of tert-butyl 7V-(2-(4-(l-aminoethyl)-6-methyl-l-oxo-isoindolin-2-yl)indan-5- yl)sulfonyl-A-tert-butoxycarbonyl-carbamate (100 mg, 0.17 mmol), tert-butyl 2-bromobenzoate (78 mg, 0.26 mmol), CS2CO3 (167 mg, 0.51 mmol), Pd2(dba)s (15 mg, 17 pmol) and Xantphos (19 mg, 34 pmol) in dioxane (0.5 mL) was stirred at 100 °C for 16 h under N2 atmosphere. After cooling to room temperature, the reaction was diluted with EtOAc (30 mL) and filtered, the filtrate was concentrated in vacuo. The crude residue was purified by silica gel chromatography (solvent gradient: 0 - 25% EtOAc in petroleum ether) to give the title compound (50 mg, 38%) as a white soild. 'H NMR (400 MHz, DMSO-t/6) 8 8.09 - 8.03 (m, 1H), 7.89 - 7.78 (m, 2H), 7.76 - 7.73 (m, 1H), 7.51 - 7.44 (m, 1H), 7.38 (s, 2H), 7.21 - 7.18 (m,lH), 6.55 - 6.53 (m 1H), 6.45 (d, J= 8.4 Hz, 1H), 5.14 - 5.10 (m, 1H), 4.81 - 4.68 (m, 2H), 4.33 - 4.27 (m, 1H), 3.29 - 3.26 (m, 2H), 3.24 - 3.07 (m, 2H), 2.36 (s, 3H), 1.55 - 1.49 (m, 12H), 1.47 (s, 9H), 1.40 (s, 9H). MS: m/z 684.3 (M- 100+Na+).
Step 6 - Synthesis of 2-((l-(6-methyl-l-oxo-2-(5-sulfamoyl-2,3-dihydro-lH-inden-2- yl)isoindolin-4-yl)ethyl)amino)benzoic acid : To a mixture of tert-butyl 2-(l-(2-(5-(bis(tert-butoxycarbonyl)sulfamoyl)indan-2-yl)-6- methyl-l-oxo-isoindolin-4-yl)ethylamino)benzoate (25 mg, 32 umol) in DCM (1 mL) was added TFA (0.5 mL, 6.9 mmol). The reaction mixture was stirred at room temperature for 16 h. The mixture was concentrated and the residue was purified by reverse phase chromatography (acetonitrile 39% - 69% / 0.225% formic acid in water) to give the title compound (2 mg, 16%) as a white solid. 'H NMR (400 MHz, DMSO-fifc) 8 12.76 (s, 1H), 8.34 - 8.24 (m, 1H), 7.82 - 7.77 (m, 1H), 7.73 - 7.69 (m, 1H), 7.69 - 7.64 (m, 1H), 7.46 - 7.42 (m, 1H), 7.38 (s, 1H), 7.34 (s, 1H), 7.29 (s, 2H), 7.23 - 7.16 (m, 1H), 6.54 - 6.52 (m, 1H), 6.43 (d, J = 8.4 Hz, 1H), 5.13 - 5.07 (m, 1H), 4.79 - 4.67 (m, 2H), 4.46 - 4.34 (m, 1H), 3.31 - 3.26 (m, 2H), 3.25 - 3.14 (m, 2H), 2.35 (s, 3H), 1.51 (d, J= 6.8 Hz, 3H). MS: m/z 528.0 (M+Na+).
Compound 45: 2-((l-(2-(chroman-3-yl)-5,6-dimethyl-l-oxoisoindolin-4- yl)ethyl)amino)benzoic acid
Figure imgf000111_0001
Step 1 - Synthesis of tert-butyl 2-((l-(2-(chroman-3-yl)-5,6-dimethyl-l-oxoisoindolin- 4-yl)ethyl)amino)benzoate:
To a solution of 4-(l-bromoethyl)-2-(chroman-3-yl)-5,6-dimethylisoindolin-l-one (80 mg, 200 pmol) in dioxane (1 mL) was added tert-butyl 2-aminobenzoate (77 mg, 400 pmol). The mixture was stirred at 100 °C for 16 h. After cooling to room temperature, the reaction mixture was concentrated in vacuo. The residue was purified by prep_TLC (petroleum ether /EtOAc = 2/1) to give the title compound (30 mg, 25%) as a white solid. MS: m/z 535.1 (M+Nal).
Step 2 - Synthesis of 2-((l-(2-(chroman-3-yl)-5,6-dimethyl-l-oxoisoindolin-4- yl)ethyl)amino)benzoic acid:
To a mixture of tert-butyl 2-((l-(2-(chroman-3-yl)-5,6-dimethyl-l-oxoisoindolin-4- yl)ethyl)amino)benzoate (30 mg, 59 pmol) in DCM (3 mL) was added TFA (1 mL, 13.46 mmol). The reaction mixture was stirred at room temperature for 16 h. The mixture was concentrated and the residue was purified by reverse phase chromatography (acetonitrile 47% - 77% / 0.225% formic acid in water) to give the title compound (4.92 mg, 18%) as a white solid. 'H NMR (400 MHz, DMSO-tL) 8 8.28 (s, 1H), 7.87 - 7.74 (m, 1H), 7.45 - 7.36 (m, 1H), 7.18 - 7.03 (m, 3H), 6.91 - 6.74 (m, 2H), 6.61 - 6.44 (m, 1H), 6.26 - 6.10 (m, 1H), 5.04 - 4.89 (m, 1H), 4.82 - 4.64 (m, 1H), 4.50 - 4.36 (m, 1H), 4.27 - 3.93 (m, 3H), 3.28 - 2.80 (m, 2H), 2.43 (s, 3H), 2.37 (s, 3H), 1.53 - 1.46 (m, 3H). MS: m/z 479.1 (M+Na+).
Compound 128: 2-((l-(2-(2-acetyl-2-azaspiro[3.5]nonan-7-yl)-6-methyl-l- oxoisoindolin-4-yl)ethyl)amino)benzoic acid
Figure imgf000112_0001
Step 1 - Synthesis of tert-butyl 7-((2-bromo-6-chloro-4-methylbenzyl)amino)-2- azaspiro[3.5]nonane-2-carboxylate:
A solution of (2-bromo-6-chloro-4-methyl-phenyl)methanamine (6.2 g, 26.44 mmol), tertbutyl 7-oxo-2-azaspiro[3.5]nonane-2-carboxylate (6.33 g, 26.44 mmol) and AcOH (1.51 mL, 26.44 mmol) in MeOH (60 mL) was stirred at room temperature for 30 min, and then NaBHsCN (4.98 g, 79.31 mmol) was added. The mixture was stirred at room temperature for 16 h under N2 atmosphere. The reaction was added water (100 mL) and extracted with EtOAc (200 mL x 2). The combined organic layers were washed with brine (200 mL), dried over anhydrous NazSCh, filtered and concentrated. The crude residue was purified by silica gel chromatography (solvent gradient: 0 - 100% EtOAc in petroleum ether) to give the title compound (10 g, 83%) as yellow oil. 'H NMR (400 MHz, DMSO-de) 8 7.30 (s, 1H), 7.15 (s, 1H), 4.03 (s, 2H), 3.60 (s, 2H), 3.55 (s, 2H), 2.51 - 2.37 (m, 1H), 2.28 (s, 3H), 1.91 - 1.83 (m, 4H), 1.66 - 1.64 (m, 2H), 1.43 (s, 9H), 1.26 - 1.16 (m, 2H). MS: m/z 457.1 (M+H+).
Step 2 - Synthesis of tert-butyl 7-(4-chloro-6-methyl-l-oxoisoindolin-2-yl)-2- azaspiro[3.5]nonane-2-carboxylate:
To a solution of tert-butyl 7-((2-bromo-6-chloro-4-methylbenzyl)amino)-2- azaspiro[3.5]nonane-2-carboxylate (2 g, 4.37 mmol) in DMF (10 mL) was added Pd(dppf)Ch (959 mg, 1.31 mmol) and DIPEA (2.28 mL, 13.11 mmol). The mixture was stirred at 80 °C for 12 h under CO (50 Psi) atmosphere. After cooling to room temperature, the reaction was diluted with water (50 mL), extracted with EtOAc (100 mL x 2). The combined organic layers were washed with brine (50 mL x 3), dried over anhydrous Na2SO4, filtered and concentrated. The crude residue was purified by silica gel chromatography (solvent gradient: 0 - 20% EtOAc in petroleum ether) to give the title compound (1.59 g, 90%) as a yellow solid. MS: m/z 405.2 (M+H+).
Step 3 - Synthesis of tert-butyl 7-(4-acetyl-6-methyl-l-oxoisoindolin-2-yl)-2- azaspiro[3.5]nonane-2-carboxylate:
A mixture of tert-butyl 7-(4-chloro-6-methyl-l-oxoisoindolin-2-yl)-2- azaspiro[3.5]nonane-2-carboxylate (1.59 g, 3.93 mmol), Sphos Pd Gi (306 mg, 393 pmol) and CsF (1.19 g, 7.85 mmol) in toluene (20 mL) was degassed and purged with N2 for 3 times, and then tributyl(l -ethoxy vinyl)stannane (3.12 g, 8.64 mmol) was added, the reaction was stirred at 100 °C for 16 h under N2 atmosphere. After cooling to room temperature, the reaction mixture was added 1 M HC1 in water (6 mL) and stirred at room temperature for 0.5 h. The reaction mixture was added 30 mL 10% KF solution, stirred at room temperature over 2 h. The mixture was filtered and extracted with EtOAc (50 mL x 3). The combined organic phase was washed with brine (30 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (solvent gradient: 0 - 50% EtOAc in petroleum ether) to give the title compound (1.5 g, 94%) as a white solid. MS: m/z 413.2 (M+H+).
Step 4 - Synthesis of tert-butyl 7-(4-(l-aminoethyl)-6-methyl-l-oxoisoindolin-2-yl)-2- azaspiro[3.5]nonane-2-carboxylate:
To a solution of te/7-butyl 7-(4-(l-aminoethyl)-6-methyl-l-oxoisoindolin-2-yl)-2- azaspiro[3.5]nonane-2-carboxylate (1.5 g, 3.64 mmol), NFLOAc (5.61 g, 72.72 mmol) and AcOH (219 mg, 3.64 mmol) in MeOH (10 mL) was added NaBFFCN (610 mg, 9.7 mmol). The mixture was stirred at 40 °C for 16 h under N2 atmosphere. After cooling to room temperature, the reaction mixture was diluted with EtOAc (100 mL). The mixture was washed with saturated NaHCOi solution (50 mL x 3), brine (50 mL), dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated to give the title compound (1.5 g, crude) as a yellow solid that required no further purification. MS: m/z 414.2 (M+H+).
Step 5 - Synthesis of tert-butyl 7-(4-(l-((2-(methoxycarbonyl)phenyl)amino)ethyl)-6- methyl-l-oxoisoindolin-2-yl)-2-azaspiro[3.5]nonane-2-carboxylate: A mixture of Zc/7-butyl 7-(4-(l -((2-(methoxycarbonyl)phenyl)arnino)ethyl)-6-rnethyl-l - oxoisoindolin-2-yl)-2-azaspiro[3.5]nonane-2-carboxylate (1.48 g, 3.58 mmol), methyl 2- iodobenzoate (1.41 g, 5.37 mmol), CS2CO3 (3.50 g, 10.74 mmol), Pd2(dba)3 (328 mg, 0.36 mmol) and Xantphos (414 mg, 0.72 mmol) in dioxane (15 mL) was stirred at 100 °C for 16 h under N2 atmosphere. After cooling to room temperature, the reaction was filtered and the filtrate was concentrated. The crude residue was purified by silica gel chromatography (solvent gradient: 0 - 30% EtOAc in petroleum ether) to give the title compound (1.96 g, 53%) as yellow oil. MS: m/z
548.3 (M+H+).
Step 6 - Synthesis of methyl 2-((l-(6-methyl-l-oxo-2-(2-azaspiro[3.5]nonan-7- yl)isoindolin-4-yl)ethyl)amino)benzoate trichloroacetate:
A solution of /c77-butyl 7-(4-(l-((2-(methoxycarbonyl)phenyl)amino)ethyl)-6-methyl-l- oxoisoindolin-2-yl)-2-azaspiro[3.5]nonane-2-carboxylate (206 mg, 376 pmol) in DCM (3 mL) was added TFA (1 mL, 1.35 mmol). The mixture was stirred at room temperature for 1 h. The reaction was concentrated to afford the title compound (200 mg, crude) as yellow oil that required no further purification. MS: m/z 448.2 (M+H+).
Step 7 - Synthesis of methyl 2-((l-(2-(2-acetyl-2-azaspiro[3.5]nonan-7-yl)-6-methyl-l- oxoisoindolin-4-yl)ethyl)amino)benzoate:
To a solution of methyl 2-((l-(6-methyl-l-oxo-2-(2-azaspiro[3.5]nonan-7-yl)isoindolin-4- yl)ethyl)amino)benzoate tri chloroacetate (168 mg, 375 pmol) in DCM (2 mL) was added TEA (114 mg, 1.13 mmol). The mixture was stirred at 0 °C for 5 min, acetyl chloride (30 mg, 375 pmol) was added. The mixture was stirred at 0 °C for 1 h under N2 atmosphere. The reaction was diluted with water (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic phase was washed with brine (20 mL x 2), dried over anhydrous Na2SO4, filtered and concentrated to give the title compound (156 mg, crude) as a white solid that required no further purification. MS: m/z
490.3 (M+H+).
Step 8 - Synthesis of 2-((l-(2-(2-acetyl-2-azaspiro[3.5]nonan-7-yI)-6-methyl-l- oxoisoindolin-4-yl)ethyl)amino)benzoic acid:
To a solution of methyl 2-((l-(2-(2-acetyl-2-azaspiro[3.5]nonan-7-yl)-6-methyl-l- oxoisoindolin-4-yl)ethyl)amino)benzoate (40 mg, 82 pmol) in H2O (0.1 mL), MeOH (0.2 mL) and THF (4 mL) was added LiOH.ELO (34 mg, 817 pmol). The mixture was stirred at 60 °C for 3 h. After cooling to room temperature, the mixture was concentrated and the residue was purified by reverse phase chromatography (acetonitrile 39% - 69% / 0.225% formic acid in water) to give the title compound (2.5 mg, 6%) as a white solid. 1HNMR (400 MHz, DMSO-de) 8 8.45 (s, 1H), 7.86
- 7.76 (m, 1H), 7.34 (s, 2H), 7.23 - 7.14 (m, 1H), 6.55 - 6.51 (m, 1H), 6.44 - 6.41 (m, 1H), 4.85 -
4.74 (m, 1H), 4.67 - 4.57 (m, 1H), 4.32 - 4.22 (m, 1H), 4.01 - 3.92 (m, 1H), 3.90 - 3.82 (m, 1H),
3.75 (s, 1H), 3.60 (s, 1H), 3.48 (s, 1H), 2.34 (s, 3H), 1.96 - 1.88 (m, 2H), 1.79 - 1.75 (m, 3H), 1.73
- 1.67 (m, 1H), 1.64 - 1.56 (m, 4H), 1.55 - 1.51 (m, 3H), 1.51 - 1.42 (m, 1H). MS: m/z 476.3 (M+H+).
Compound 47 : 6-chloro-3-((l-(2-(chroman-3-yl)-6-methyl-l-oxoisoindolin-4- yl)ethyl)amino)picolinic acid
Figure imgf000115_0001
Step 1 - Synthesis of tert-butyl 6-chloro-3-((l-(2-(chroman-3-yl)-6-methyl-l- oxoisoindolin-4-yl)ethyl)amino)picolinate:
A mixture of 4-(l-aminoethyl)-2-chroman-3-yl-6-methyl-isoindolin-l-one (50 mg, 155 pmol), tert-butyl 3-bromo-6-chloropicolinate (68 mg, 233 pmol), CS2CO3 (152 mg, 465 pmol), Pd2(dba)3 (14 mg, 16 pmol) and Xantphos (18 mg, 31 pmol) in dioxane (2 mL) was stirred at 100 °C for 16 h under N2 atmosphere. After cooling to room temperature, the reaction was filtered and the filtrate was concentrated. The crude residue was purified by silica gel chromatography (solvent gradient: 0 - 30% EtOAc in petroleum ether) to give the title compound (22 mg, 26%) as a yellow solid. MS: m/z 534.1 (M+H+).
Step 2 - Synthesis of 6-chloro-3-((l-(2-(chroman-3-yl)-6-methyl-l-oxoisoindolin-4- yl)ethyl)amino)picolinic acid:
To a solution of tert-butyl 6-chloro-3-((l-(2-(chroman-3-yl)-6-methyl-l-oxoisoindolin-4- yl)ethyl)amino)picolinate (62 mg, 116 umol) in DCM (1 mL) was added TFA (0.5 mL, 6.7 mmol). The reaction mixture was stirred at room temperature for 16 h. The mixture was concentrated and the residue was purified by reverse phase chromatography (acetonitrile 47% - 77% / 0.225% formic acid in water) to give the title compound (28 mg, 35%) as a white solid. 'H NMR (400 MHz, DMSO-tL) 8 13.10 (s, 1H), 8.32 - 8.22 (m, 1H), 7.42 (s, 1H), 7.37 - 7.33 (m, 1H), 7.32 - 7.27 (m, 1H), 7.14 - 7.08 (m, 2H), 7.00 - 6.94 (m, 1H), 6.92 - 6.84 (m, 1H), 6.82 - 6.72 (m, 1H), 4.78 - 4.68 (m, 2H), 4.59 - 4.50 (m, 1H), 4.38 - 4.36 (m, 1H), 4.32 - 4.13 (m, 2H), 3.23 - 3.05 (m, 2H), 2.36 (s, 3H), 1.51 (d, J= 5.2 Hz, 3H). MS: m/z 478.1 (M+H+).
Compound 83: (2-((l-(6-methyl-2-(6-(oxetan-3-ylamino)chroman-3-yl)-l- oxoisoindolin-4-yl)ethyI)amino)benzoic acid
Figure imgf000116_0001
Step 1 - Synthesis of 4-bromo-2-(6-chlorochroman-3-yl)-6-methylisoindolin-l-one:
To a mixture of 6-chlorochroman-3 -amine hydrochloride (376 mg, 1.71 mmol) and K2CO3 (858 mg, 6.21 mmol) in EtOH (9 mL) was added methyl 3-bromo-2-(bromomethyl)-5- methylbenzoate (500 mg, 1.55 mmol). After the addition, the reaction mixture was stirred at 60 °C for 16 h. After cooling to room temperature, the reaction was diluted with EtOAc (30 mL) and filtered, the filtrate was concentrated in vacuo. The crude residue was purified by silica gel chromatography (solvent gradient: 0 - 15% EtOAc in petroleum ether) to give the title compound (415 mg, 68%) as a white solid. ’H NMR (400 MHz, DMSO-tL) 8 7.66 (s, 1H), 7.56 (s, 1H), 7.21 (d, J = 2.4 Hz, 1H), 7.19 - 7.16 (m, 1H), 6.88 (d, J= 8.4 Hz, 1H), 4.63 - 4.57 (m, lH), 4.34 (s, 2H), 4.31 - 4.26 (m, 2H), 3.27 - 3.05 (m, 2H), 2.41 (s, 3H). MS: m/z 392.0 (M+H+).
Step 2 - Synthesis of 2-(6-chlorochroman-3-yl)-4-(l-ethoxyvinyl)-6-methylisoindolin- 1-one:
A mixture of 4-bromo-2-(6-chlorochroman-3-yl)-6-methylisoindolin-l-one (415 mg, 1.06 mmol), tributyl(l-ethoxyvinyl)stannane (900 mg, 2.49 mmol) and Pd(dppf)Ch (77 mg, 106 pmol) in dioxane (7 mL) was degassed with N2 for 3 times and stirred at 90 °C for 16 h. After cooling to room temperature, the reaction was quenched with 10% KF solution (20 mL). The mixture was filtered and the filtrate was separated between EtOAc (30 mL) and H2O (20 mL). The organic layer was washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The filtrate was concentrated to give the title compound (405 mg, crude) as a brown oil that required no further purification. MS: m/z 384.0 (M+H+).
Step 3 - Synthesis of 4-acetyl-2-(6-chlorochroman-3-yl)-6-methylisoindolin-l-one:
To a solution of 2-(6-chlorochroman-3-yl)-4-(l-ethoxyvinyl)-6-methylisoindolin-l-one (405 mg, 1.06 mmol) in THF (6 mL) was added HC1 (3 mL, IM in water) at room temperature. The reaction mixture was stirred at room temperature for 1 h. The mixture was quenched with saturated NaHCCh (20 mL), extracted with EtOAc (50 mL x 2). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4 and filtered. The crude residue was purified by silica gel chromatography (solvent gradient: 0 - 30% EtOAc in petroleum ether) to give the title compound (149 mg, 40%) as a yellow solid. MS: m/z 356.0 (M+H+).
Step 4 - Synthesis of 4-(l-aminoethyl)-2-(6-chlorochroman-3-yl)-6-methylisoindolin- 1-one:
To a solution of 4-(l-aminoethyl)-2-(6-chlorochroman-3-yl)-6-methylisoindolin-l-one (149 mg, 419 umol) and NELOAc (646 mg, 8.38 mmol) in MeOH (2 mL) was added NaBELCN (53 mg, 838 umol). The reaction was stirred at 60 °C for 16 h under N2 atmosphere. After cooling to room temperature, the reaction mixture was diluted with EtOAc (50 mL). The mixture was washed with saturated NaHCOi solution (20 mL) and brine (20 mL), dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated to give the title compound (148 mg, crude) as a yellow solid that required no further purification. MS: m/z 379.0 (M+Na+).
Step 5 - Synthesis of methyl 2-((l-(2-(6-chlorochroman-3-yl)-6-methyl-l- oxoisoindolin-4-yl)ethyl)amino)benzoate:
A mixture of 4-(l-aminoethyl)-2-(6-chlorochroman-3-yl)-6-methylisoindolin-l-one (220 mg, 617 pmol), methyl 2-iodobenzoate (323 mg, 1.23 mmol), CS2CO3 (603 mg, 1.85 mmol), Pd2(dba)3 (56 mg, 62 pmol) and Xantphos (71 mg, 123 pmol) in dioxane (4 mL), the reaction mixture was stirred at 100 °C for 16 h under N2 atmosphere. After cooling to room temperature, the reaction was filtered and the filtrate was concentrated. The crude residue was purified by silica gel chromatography (solvent gradient: 0 - 30% EtOAc in petroleum ether) to give the title compound (109 mg, 36%) as a yellow solid. MS: m/z 491.2 (M+H+). Step 6 - Synthesis of methyl 2-((l-(6-methyl-2-(6-(oxetan-3-ylamino)chroman-3-yl)- l-oxoisoindolin-4-yl)ethyl)amino)benzoate:
A mixture of methyl 2-((l-(2-(6-chlorochroman-3-yl)-6-methyl-l-oxoisoindolin-4- yl)ethyl)amino)benzoate (109 mg, 222 pmol), oxetan-3 -amine (32 mg, 444 pmol), /-BuONa (26 mg, 266 pmol), BrettPhos Pd G1 (18 mg, 22 pmol) and RuPhos (21 mg, 44 pmol) in dioxane (3 mL), the reaction mixture was stirred at 100 °C for 2 h under N2 atmosphere. After cooling to room temperature, the reaction was filtered and the filtrate was concentrated. The crude residue was purified by silica gel chromatography (solvent gradient: 0 - 30% EtOAc in petroleum ether) to give the title compound (27 mg, 23%) as a white solid. XH NMR (400 MHz, DMSO-t/s) 6 8.11 - 8.03 (m, 1H), 7.81 (d, J= 7.6 Hz, 1H), 7.40 (s, 1H), 7.36 (d, J= 6.8 Hz, 1H), 7.26 - 7.20 (m, 1H), 6.67 - 6.54 (m, 2H), 6.43 (d, J= 8.0 Hz, 1H), 6.36 - 6.27 (m, 1H), 6.23 - 6.15 (m, 1H), 5.95 - 5.87 (m, 1H), 4.83 - 4.77 (m, 2H), 4.75 - 4.69 (m, 2H), 4.55 - 4.32 (m, 5H), 4.23 - 4.08 (m, 2H), 3.86 - 3.84 (m, 3H), 3.18 - 3.09 (m, 1H), 3.02 - 2.89 (m, lH), 2.35 (s, 3H), 1.54 - 1.49 (m, 3H). MS: m/z 550.1 (M+Nal).
Step 7 - Synthesis of 2-((l-(6-methyl-2-(6-(oxetan-3-ylamino)chroman-3-yl)-l- oxoisoindolin-4-yl)ethyl)amino)benzoic acid:
A solution of methyl 2-((l-(6-methyl-2-(6-(oxetan-3-ylamino)chroman-3-yl)-l- oxoisoindolin-4-yl)ethyl)amino)benzoate (27 mg, 51 pmol) in EtOH (0.5 mL) and H2O (0.5 mL) was added KOH (29 mg, 512 pmol). The mixture was stirred at 100 °C for 0.5 h. After cooling to room temperature, the reaction mixture was adjusted to pH 6 with formic acid. The reaction mixture was concentrated and the residue was purified by reverse phase chromatography (acetonitrile 30% - 60% / 0.225% formic acid in water) to give the title compound (3.78 mg, 14%) as a white solid. 1 H NMR (400 MHz, DMSO4) 6 8.48 (s, 1H), 7.79 (d, J = 8.0 Hz, 1H), 7.38 (s, 1H), 7.36 - 7.34 (m, 1H), 7.19 - 7.10 (m, 1H), 6.65 - 6.60 (m, 1H), 6.54 - 6.47 (m, 1H), 6.42 - 6.27 (m, 2H), 6.23 - 6.16 (m, 1H), 5.94 - 5.86 (m, 1H), 4.85 - 4.75 (m, 2H), 4.75 - 4.62 (m, 2H), 4.54 - 4.31 (m, 5H), 4.23 - 3.93 (m, 2H), 3.14 - 3.01 (m, 1H), 3.00 - 2.86 (m, 1H), 2.35 (s, 3H), 1.49 (d, J = 5.2 Hz, 3H). MS: m/z 536.1 (M+Na+).
Compound 53: 2-((l-(6-chloro-2-(2,3-dihydro-l//-inden-2-yl)-l-oxoisoindolin-4- yl)ethyl)amino) benzoic acid
Figure imgf000119_0001
Step 1 - Synthesis of (2-bromo-4-chlorophenyl)methanamine:
A mixture of 2-bromo-4-chloro-benzonitrile (10 g, 46.20 mmol) in THF (150 mL) was added BH3.THF (46.20 mL, 46.20 mmol 1 M in THF) at room temperature under N2 atmosphere. The resulting mixture was stirred at 80 °C for 1 h. After cooling to 0 °C, IM HC1 (46 mL) was added dropwise and then added MeOH (30 mL). The mixture was adjusted to pH 8 with IM NaOH aqueous solution, extracted with DCM (200 mL x 3). The combined organic layers were washed with brine (200 mL), dried over anhydrous NazSCL, fdtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (solvent gradient: 0 - 30% EtOAc in petroleum ether) to give the title compound (8 g, 53%) as yellow oil. 1 H NMR (400MHz, CDCh) 5 7.57 (d, .7= 2.0 Hz, 1H), 7.35 (d, J= 8.0 Hz, 1H), 7.31 - 7.27 (m, 1H), 3.89 (s, 2H) MS: m/z 219.7 (M+H+).
Step 2 - Synthesis of /V-(2-bromo-4-chlorobenzyl)-2,3-dihydro-lH-inden-2-amine:
To a solution of indan-2-one (3.24 g, 24.49 mmol) and (2-bromo-4-chloro- phenyl)methanamine (6 g, 27.21 mmol) in DCM (30 mL) was added NaBHiCN (5.13 g, 81.63 mmol). The reaction mixture was stirred at room temperature for 16 h under N2 atmosphere. The reaction mixture was diluted with H2O (200 mL) and extracted with EtOAc (100 mL x 2). The combined organic layers were washed with brine (100 mL x 3), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (solvent gradient: 0 - 3% EtOAc in petroleum ether) to give the title compound (5.97 g, 65%) as yellow oil. 'H NMR (400 MHz, CDCh) 8 7.57 (d, J= 2.0 Hz, 1H), 7.39 (d, J= 8.4 Hz, 1H), 7.28 - 7.26 (m, 2H), 7.24 - 7.18 (m, 2H), 7.18 - 7.13 (m, 2H), 3.91 (s, 2H), 3.68 - 3.64 (m, 1H), 3.22 - 3.16 (m, 2H), 2.87 - 2.81 (m, 2H) MS: m/z 335.9 (M+H+).
Step 3 - Synthesis of ethyl (2-bromo-4-chlorobenzyl)(2,3-dihydro-LH-inden-2- yl)carbamate:
To a solution of N-(2 -bromo-4-chlorobenzyl)-2, 3 -dihydro- 17/-inden-2-amine (5.97 g, 17.73 mmol) in DCM (80 mL) was added TEA (7.40 mL, 53.20 mmol), and then ethyl carbonochloridate (4.15 g, 38.24 mmol, 3.7 mL) was added dropwise at 0 °C. The mixture was stirred at room temperature for 16 h. The resulting mixture was quenched with water (50 mL) and sat. aq. NaHCCh solution (50 mL), extracted with DCM (100 mL x 2). The combined organic layer was washed with brine (100 mL), dried over anhydrous Na?SO4, filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (solvent gradient: 0 - 3% EtOAc in petroleum ether) to give the title compound (6.33 g, 87%) as yellow oil. JH NMR (400 MHz, CDCh) 8 7.55 (d, J = 2.0 Hz, 1H), 7.29 - 7.34 (m, 1H), 7.17 - 7.13 (m, 5H), 5.22 - 4.85 (m, 1H), 4.48 (s, 2H), 4.28 - 4.09 (m, 2H), 3.17 - 3.04 (m, 2H), 2.96 - 2.89 (m, 2H), 1.27 - 1.14 (m, 3H). MS: m/z 407.9 (M+H+).
Step 4 - Synthesis of 4-bromo-6-chloro-2-(2,3-dihydro-lH-inden-2-yl)isoindolin-l- one:
To a solution of ethyl (2-bromo-4-chlorobenzyl)(2,3-dihydro-l//-inden-2-yl)carbamate (3.33 g, 8.15 mmol) in DCM (100 mL) was added P2O5 (11.56 g, 81.47 mmol) at 0°C under N2 atmosphere. The mixture was stirred at room temperature for 16 h. The reaction was quenched with IM NaOH solution carefully, and the mixture was extracted with DCM (100 mL><2). The combined organics were dried over Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by reverse phase chromatography (acetonitrile 61% - 91% / 0.225% formic acid in water) to give the title compound (500 mg, 11%) as a white solid. ’H NMR (400 MHz, DMSO-fifc) 8 7.97 (d, J= 1.6 Hz, 1H), 7.74 (d, J= 1.2 Hz, 1H), 7.31 - 7.24 (m, 2H), 7.23 - 7.17 (m, 2H), 5.13 - 5.04 (m, 1H), 4.24 (s, 2H), 3.28 - 3.20 (m, 2H), 3.18 - 3.11 (m, 2H). MS: m/z 361.8 (M+H+).
Step 5 - Synthesis of 6-chlor()-2-(2.3-dihydro-l//-inden-2-yl)-4-(l- ethoxyvinyl)isoindolin-l-one:
A mixture of 4-bromo-6-chloro-2-(2,3-dihydro-l//-inden-2-yl)isoindolin-l-one (565 mg, 1.56 mmol)? Pd(dppf)Ch (114 mg, 156 pmol) in dioxane (6 mL) was degassed and purged with N2 for 3 times, and then tributyl(l-ethoxyvinyl)stannane (730 mg, 2.02 mmol) was added, the final mixture was stirred at 90 °C for 16 h under N2 atmosphere. After cooling to room temperature, the reaction was quenched with 10% KF solution (20 mL). The mixture was filtered and the filtrate was separated between EtOAc (50 mL) and H2O (30 mL). The organic layer was washed with brine (30 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give the title compound (551 mg, crude) as yellow oil that required no further purification. MS: m/z 353.9 (M+H+). Step 6 - Synthesis of 4-acetyl-6-chloro-2-(2,3-dihydro-l/7-inden-2-yl)isoindolin-l- one:
To a solution of 6-chloro-2-(2,3-dihydro-17f-inden-2-yl)-4-(l-ethoxyvinyl)isoindolin-l- one (551 mg, 1.56 mmol) in THF (5 mL) was added HC1 (1 mL, IM in water) at room temperature. The reaction mixture was stirred at room temperature for 1 h. The mixture was quenched with saturated NaHCCh (10 mL), extracted with EtOAc (30 mL x 2). The combined organic layers were washed with brine (20 mL), dried over anhydrous NaiSCL and filtered. The crude residue was purified by silica gel chromatography (solvent gradient: 0 - 20% EtOAc in petroleum ether) to give the title compound (390 mg, 77%) as a yellow solid. !H NMR (400 MHz, DMSO-cL) 8 8.26 (d, J = 1.2 Hz, 1H), 7.95 (d, J= 1.2 Hz, 1H), 7.30 - 7.26 (m, 2H), 7.23 - 7.18 (m, 2H), 5.13 - 5.05 (m, 1H), 4.52 (s, 2H), 3.29 - 3.23 (m, 2H), 3.15 - 3.08 (m, 2H), 2.61 (s, 3H). MS: m/z 325.9 (M+H+).
Step 7 - Synthesis of 4-(l-aminoethyl)-6-chloro-2-(2,3-dihydro-l//-inden-2- yl)isoindolin-l-one:
A mixture of 4-acetyl-6-chloro-2-(2,3-dihydro-l//-inden-2-yl)isoindolin-l-one (380 mg, 1.17 mmol), NH4OAC (1.35 g, 17.50 mmol) and HOAc (70 mg, 1.17 mmol) in MeOH (15 mL) was stirred at room temperature for 1 h. Then NaBHiCN (220 mg, 3.50 mmol) was added to the reaction mixture. After the addition, the reaction mixture was stirred at 60 °C for 16 h. After cooling to room temperature, the reaction mixture was diluted with DCM (50 mL), washed with saturated NaHCCh solution (20 mL x 3), brine (20 mL), dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated to give the title compound (490 mg, crdue) as a yellow solid that required no further purification. MS: m/z 348.9 (M+Na+).
Step 8 - Synthesis of tert-butyl 2-((l-(6-chloro-2-(2,3-dihydro-LH-inden-2-yl)-l- oxoisoindolin-4-yl)ethyl)amino)benzoate:
A mixture of 4-(l-aminoethyl)-6-chloro-2-(2,3-dihydro-17/-inden-2-yl)isoindolin-l-one (450 mg, 1.38 mmol), tert-butyl 2-iodobenzoate (628 mg, 2.07 mmol), CS2CO3 (897 mg, 2.75 mmol), Pd2(dba)3 (126 mg, 138 pmol) and Xantphos (159 mg, 275 pmol) in dioxane (8 mL) was stirred at 100 °C for 16 h under N2 atmosphere. After cooling to room temperature, the reaction was filtered and the filtrate was concentrated. The crude residue was purified by silica gel chromatography (solvent gradient: 0 - 15% EtOAc in petroleum ether) to give the title compound (350 mg, 50%) as a yellow solid. MS: m/z 525.1 (M+Na+). Step 9 - Synthesis ol'2-(( l-(6-chloro-2-(2,3-dihydro-l //-inden-2-yl)-l-oxoisoindolin-4- yl)ethyl)amino)benzoic acid:
To a solution of /e/7-butyl 2-((l-(6-chloro-2-(2,3-dihydro-l/f-inden-2-yl)-l-oxoisoindolin- 4-yl)ethyl)amino)benzoate (100 mg, 199 pmol) in DCM (2 mb) was added TFA (0.8 mL, 10.77 mmol). The reaction mixture was stirred at 40 °C for 2 h. After cooling to room temperature, the reaction mixture was concentrated and the residue was purified by reverse phase chromatography (acetonitrile 58% - 88% / 0.225% formic acid in water) to give the title compound (73 mg, 82%) as a white solid. 'H NMR (400 MHz, DMSO-cL) 8 12.79 (s, 1H), 8.25 (s, 1H), 7.82 - 7.78 (m, 1H), 7.57 - 7.53 (m, 2H), 7.28 - 7.22 (m, 2H), 7.22 - 7.16 (m, 3H), 6.58 - 6.54 (m, 1H), 6.41 (d, J= 8.4 Hz, 1H), 5.08 - 5.02 (m, 1H), 4.83 - 4.72 (m, 2H), 4.41 - 4.36 (m, 1H), 3.25 - 3.20 (m, 2H), 3.19 - 3.09 (m, 2H), 1.53 (d, J= 6.8 Hz, 3H). MS: m/z 447.1 (M+H+).
Compound 102: 2-((l-(2-(l-(2-oxabicyclo[3.1.1]heptane-l-carbonyl)azepan-4-yl)-6- methyl-l-oxoisoindolin-4-yl)ethyl)amino)benzoic acid
Figure imgf000122_0001
Stepl Synthesis of methyl 2-((l-(2-(l-(2-oxabicyclo[3.1.1]heptane-l- carbonyl)azepan-4-yl)-6-methyl-l-oxoisoindolin-4-yl)ethyl)amino)benzoate:
To a solution of methyl 2-((l-(2-(azepan-4-yl)-6-methyl-l-oxoisoindolin-4- yl)ethyl)amino)benzoate hydrochloride (150 mg, 356 pmol), 2-oxabicyclo[3.1.1]heptane-l- carboxylic acid (61 mg, 427 pmol) and DIEA (138 mg, 1.07 mmol) in DMF (3 mL) was added HATU (162 mg, 427 pmol). The mixture was stirred at room temperature for 1 h. The reaction was quenched with H2O (10 mL), extracted with EtOAc (10 mL x 2). The combined organic layers were washed with brine (10 mL x 3), dried over anhydrous Na2SC>4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (solvent gradient: 0 - 30% EtOAc in petroleum ether) to give the title compound (145 mg, 75%) as colorless oil. 1 H NMR (400 MHz, DMSO-t/6) 8 8.13 - 8.06 (m, 1H), 7.81 (d, J = 8.0 Hz, 1H), 7.39 - 7.29 (m, 2H), 7.28 - 7.19 (m, 1H), 6.61 - 6.53 (m, 1H), 6.49 (d, J= 7.6 Hz, 1H), 4.86 - 4.76 (m, 1H), 4.69 - 4.57 (m, 1H), 4.34 - 4.20 (tn, 1H), 4.19 - 4.1 1 (m, 1H), 4.10 - 3.98 (tn, 4H), 3.90 - 3.82 (m, 3H), 3.81 - 3.45 (tn, 4H), 3.24 - 3.07 (m, 1H), 2.43 - 2.40 (m, 1H), 2.35 - 2.32 (m, 3H), 2.31 - 2.18 (m, 2H), 2.07 - 2.01 (m, 2H), 1.98 - 1.62 (m, 8H), 1.58 - 1.50 (m, 3H). MS: m/z 568.2 (M+Na+).
Step 2 - Synthesis of 2-((l-(2-(l-(2-oxabicyclo[3.1.1]heptane-l-carbonyl)azepan-4-yl)- 6-methyl-l-oxoisoindolin-4-yl)ethyl)amino)benzoic acid:
To a solution of methyl 2-((l-(2-(l-(2-oxabicyclo[3.1.1]heptane-l-carbonyl)azepan-4-yl)- 6-methyl-l-oxoisoindolin-4-yl)ethyl)amino)benzoate (20 mg, 37 pmol) in EtOH (0.5 mL) and H2O (0.5 mL) was added KOH (21 mg, 366 pmol). The reaction mixture was stirred at 100 °C for 1 h. After cooling to room temperature, the mixture was acidified to pH 3 with IM HC1, diluted with H2O (10 mL), extracted with EtOAc (10 mL x 2). The combined organic layers were washed with brine (10 mL), dried over Na2SO4 and filtered and concentrated in vacuo. The residue was purified by prep_TLC (DCM/MeOH = 9/1) to give the title compound (4.38 mg, 22%) as a white solid. 'H NMR (400 MHz, DMSO4) 8 12.76 (s, 1H), 8.32 (s, 1H), 7.79 (d, J= 7.6 Hz, 1H), 7.38 - 7.27 (m, 2H), 7.23 - 7.15 (m, 1H), 6.57 - 6.49 (m, 1H), 6.48 - 6.39 (m, 1H), 4.84 - 4.72 (m, 1H), 4.70 - 4.56 (m, 1H), 4.42 - 4.23 (m, 1H), 4.20 - 4.11 (m, 1H), 4.10 - 4.01 (m, 2H), 3.84 - 3.61 (m, 1H), 3.60 - 3.40 (m, 2H), 3.25 - 3.14 (m, 1H), 2.45 - 2.38 (m, 1H), 2.37 - 2.31 (m, 3H), 2.30 - 2.14 (m, 2H), 2.05 - 1.64 (m, 10H), 1.57 - 1.50 (m, 3H). MS: m/z 532.3 (M+H+).
Compound 141: 2-((l-(2-(chroman-4-yl)-6-methyl-l-oxoisoindolin-4- yl)ethyl)amino)benzoic acid
Figure imgf000123_0001
Step 1 - Synthesis of 4-bromo-2-(chroman-4-yl)-6-methylisoindolin-l-one:
To a solution of methyl 3-bromo-2-(bromomethyl)-5-methylbenzoate (1.30 g, 4.02 mmol) and chroman-4-amine (723 mg, 4.84 mmol) in EtOH (15 mL) was added K2CO3 (1.67 g, 12.09 mmol) at room temperature. The reaction was stirred at 60 °C for 16 h under N2 atmosphere. After cooling to room temperature, the reaction was quenched with water (30 mL), extracted with EtOAc (50 mL x 2). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (solvent gradient: 0 - 2% EtOAc in petroleum ether) to give the title compound (730 mg, 50%) as yellow oil. 'H NMR (400 MHz, DMSO-tL) 6 7.69 (s, 1H), 7.62 (s, 1H), 7.20 - 7.14 (m, 1H), 6.90 - 6.81 (m, 3H), 5.63-5.55 (m, 1H), 4.46 - 4.24 (m, 3H), 3.88 - 3.83 (m, 1H), 2.43 (s, 3H), 2.39 - 2.29 (m, 1H), 2.12-2.09 (m, 1H). MS: m/z 357.9 (M+H+).
Step 2 - Synthesis of 4-acetyl-2-(chroman-4-yl)-6-methylisoindolin-l-one:
To a solution of 4-bromo-2-(chroman-4-yl)-6-methylisoindolin-l-one (730 mg, 2.04 mmol) and tributyl(l -ethoxy vinyl)stannane (1.77 g, 4.90 mmol) in dioxane (15 mb) was added Pd(dppf)C12 (149 mg, 204 umol). The reaction was stirred at 90 °C for 16 h under N2 atmosphere. After cooling to room temperature, the reaction mixture was added 1 M HC1 in water (4 mL) and stirred at room temperature for 0.5 h. The reaction mixture was added 30 mL 10% KF solution, stirred at room temperature over 2 h. The mixture was filtered and extracted with EtOAc (30 mL x 3). The combined organic phase was washed with brine (30 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (solvent gradient: 0 - 10% EtOAc in petroleum ether) to give the title compound (488 mg, 68%) as yellow oil. ’H NMR (400 MHz, DMSO-cL) 8 7.94 (s, 1H), 7.86 (s, 1H), 7.18 - 7.12 (m, 1H), 6.91 - 6.85 (m, 2H), 6.82 - 6.77 (m, 1H), 5.82 - 5.81 (m, 1H), 4.64 - 4.62 (m, 1H), 4.43 - 4.38 (m, 2H), 4.34 - 4.25 (m, 1H), 2.61 (s, 3H), 2.55 (s, 3H), 2.43 - 2.31 (m, 1H), 2.28 - 2.18 (m, 1H). MS: m/z 322.0 (M+H+).
Step 3 - Synthesis of 4-(l-aminoethyl)-2-(chroman-4-yl)-6-methylisoindolin-l-one:
A mixture of 4-acetyl-2-(chroman-4-yl)-6-methylisoindolin-l-one (200 mg, 622 pmol), NH4OAC (720 mg, 9.34 mmol) and AcOH (4 mg, 6.5 pmol) in MeOH (10 mL) was stirred at room temperature for 0.5 h. Then NaBHsCN (117 mg, 1.87 pmol) was added to the reaction mixture. After the addition, the reaction mixture was stirred at 60 °C for 16 h. After cooling to room temperature, the reaction mixture was diluted with DCM (50 mL). The mixture was washed with saturated NaHCCh solution (20 mL x 3), brine (20 mL), dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated to give the title compound (250 mg, crdue) as a brown solid that required no further purification. MS: m/z 345 (M+Na+).
Step 5 - Synthesis of tert-butyl 2-((l-(2-(chroman-4-yl)-6-methyl-l-oxoisoindolin-4- yl)ethyl)amino)benzoate: A mixture of 4-(l -aminoethyl)-2-(chroman-4-yl)-6-methylisoindolin-l -one (250 mg, 775 pmol), tert-butyl 2-iodobenzoate (236 mg, 775 pmol), Pd2(dba)a (71 mg, 78 pmol), Xantphos (90 mg, 155 pmol) and CS2CO3 (758 mg, 2.33 mmol) in dioxane (10 mL). The reaction mixture was stirred at 100 °C for 16 h under N2 atmosphere. After cooling to room temperature, the reaction was filtered and the filtrate was concentrated. The crude residue was purified by silica gel chromatography (solvent gradient: 0 - 15% EtOAc in petroleum ether) to give the title compound (165 mg, 43%) as colorless oil. 'H NMR (400 MHz, DMSO-tfc) 8 8.07 (d, J= 4.4 Hz, 1H), 7.86 - 7.76 (m, 1H), 7.61(s, 1H), 7.35 (s, 1H), 7.20 - 7.06 (m, 2H) ,6.87 - 6.81 (m, 1H), 6.68 - 6.65 (m, 1H), 6.52 (d, J= 7.6 Hz, 1H), 6.26 - 6.20 (m, 1H), 5.79 - 5.75 (m, 1H), 4.77 - 4.73 (m, 1H), 4.56 - 4.51 (m, 1H), 4.38 - 4.26 (m, 3H), 4.22 - 4.18 (m, 1H), 2.44 (s, 3H), 2.35 - 2.13 (m, 2H), 1.59 - 1.53 (m, 12H). MS: m/z 499.1 (M+H+).
Step 6 - Synthesis of 2-((l-(2-(chroman-4-yl)-6-methyl-l-oxoisoindolin-4- yl)ethyl)amino)benzoic acid:
To a mixture of tert-butyl 2-((l-(2-(chroman-4-yl)-6-methyl-l-oxoisoindolin-4- yl)ethyl)amino)benzoate (30 mg, 60 pmol) in DCM (2 mL) was added TFA (1 mL, 13.5 mmol). The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was concentrated and the residue was purified by reverse phase chromatography (acetonitrile 50% - 80% / 0.225% formic acid in water) to give the title compound (2.6 mg, 10%) as a white solid. ’H NMR (400 MHz, DMSO-r/r,) 8 8.34 (s, 1H), 7.79 - 7.78 (m, 1H), 7.47 - 7.43 (m, 1H), 7.41 - 7.35 (m, 1H), 7.20 - 7.09 (m, 2H), 6.87 - 6.81 (m, 2H), 6.73 - 6.64 (m, 1H), 6.53 - 6.46 (m, 1H), 6.40 - 6.31 (m, 1H), 5.66 - 5.50 (m, 1H), 4.70 - 4.66 (m, 1H), 4.44 - 4.25 (m, 3H), 4.23 - 3.87 (m, 1H), 2.39 - 2.35 (m, 3H), 2.26 - 2.07 (m, 2H), 1.46 - 1.42 (m, 3H). MS: m/z 443.1 (M+H+).
The rest of the compounds in Table 1 were prepared using procedures analogous to those disclosed above with appropriate modifications within the purview of one skilled in the art.
Example 2: Biological Assays
PI3Ka cellular assay experimental procedure:
SKBR3 or T47D cells are seeded in DMEM containing 10% FBS at 25k cells/well into 96- well cell culture format. Cells are incubated overnight at 37°C in a 5% CO2 incubator and the following day cell media is aspirated, adherent cells are washed IX with room temperature PBS prior to serum-free media application. Cells are returned to 37°C 5% CO2 incubator and incubated a further 16hrs. Compounds are added to serum starved adherent cells with a top dose of 10,000nM and 3x multiple dose reductions for a minimum dose of 0.5nM diluted in DMSO. Cell/compound incubation continues for Ihr in a 37°C, 5% CO2 incubator prior to 10 minute PIK3CA stimulation with 20ng/ml EGF. Cells treated with 0.1% DMSO and 20ng/mL EGF are employed as negative control, cells treated with lOuM Alpelisib and 20ng/mL EGF are employed as a positive control. After 10 mins, plates are removed from incubator and cells are lysed with buffer and shaking 45 minutes. 20uL of lysate is transferred to an opti-384 plate and 2.5 pl of Phospho- AKT d2 antibody with 2.5 pl of Phospho- AKT Eu Cryptate solution in the detection buffer are added to each well. 384 well plate is left overnight at room temperature before reading HTRF on an Envision plate reader. The biological activity of certain compounds using the assays described above is shown in
Table 2. The ranges are as follows: for T47D pAKT IC50 (nM): A denotes < 750 nM; B denotes 750 nM < IC50 < 2,000 nM; C denotes > 2,000 nM. ND denotes value not determined with that assay for the specified compound; and for T47D (H1047R) selectivity over SKBR3 (WT): A denotes > 20-fold; B denotes 20-fold
> value > 5-fold; C denotes < 5-fold. ND denotes value not determined with that assay for the specified compound; ND denotes value not determined with that assay for the specified compound.
Table 2.
Figure imgf000127_0001
Figure imgf000128_0001
Figure imgf000129_0001
Figure imgf000130_0001
EMBODIMENTS
Embodiment 1. A compound of Formula (I):
Figure imgf000131_0001
or a pharmaceutically acceptable salt thereof, wherein:
R1 is hydrogen, cyano, C3-C6 cycloalkyl, C1-C6 alkyl optionally substituted with phenyl optionally substituted with halogen, C1-C6 thioalkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C1-C6 alkoxy alkyl;
R1 is hydrogen or C1-C6 alkyl; or R1 and R1 , together with the carbon atom to which they are attached form a C3-C10 cycloalkyl;
R2 is C6-C12 aryl optionally substituted with 1-4 independently selected R2A, 5-10 membered heteroaryl optionally substituted with 1-4 independently selected R2A, 4-10 membered heterocyclyl optionally substituted with 1-4 independently selected R2A, C4-C10 cycloalkyl optionally substituted with 1-4 independently selected R2A, C1-C6 alkoxyalkyl optionally substituted with -C(=O)NRARc, C1-C6 aralkyl optionally substituted with 1-4 independently selected R2A, or C1-C6 alkoxy optionally substituted with -C(=O)NRARc; each R2A is independently selected from:
(i) halogen,
(ii) cyano,
(iii) hydroxyl,
Figure imgf000131_0002
(vii)
(viii)
Figure imgf000131_0003
Figure imgf000132_0001
(xii) -SO2NRFRG,
(xiii) -NHC(=O)C1-C6 alkyl optionally substituted with NRARB,
(xiv) C1-C6 haloalkyl,
(xv) C1-C6 hydroxyalkyl,
(xvi) 5-10 membered heteroaryl optionally substituted with 1-3 substituents independently selected from C1-C6 alkyl, -C(=O)NRARB, C1-C6 haloalkyl, and -NRARB,
(xvii) 4-10 membered heterocyclyl optionally substituted with 1-3 substituents independently selected from hydroxyl, C1-C6 haloalkyl, -C(=O)C1-C6 alkyl, -SO2(C1-C6 alkyl), -SO2NRFRG, C6-C12 aryl, C1-C6 alkyl optionally substituted with C1-C6 alkoxy, -C(=O)NRARB, or -NHC(=O)C1-C6 alkyl optionally substituted with -NRARB,
(xviii) C1-C6 alkyl optionally substituted with 1-3 substituents independently selected from hydroxyl, oxo, -NRARB, -C(=O)NRARB, C1-C6 alkoxy, C3-C10 cycloalkyl, phenyl, and 4- 10 membered heterocyclyl optionally substituted with hydroxyl, C1-C6 alkyl, aralkyl, heteroaralkyl, -C(=O)NRARB, or -C(=O)C3-C6 cycloalkyl,
(xix) C1-C6 alkoxy optionally substituted with -NRARB or 4-10 membered heterocyclyl optionally substituted with C1-C6 alkyl, hydroxyl, aralkyl, heteroaralkyl, or -C(=O)C3-C6 cycloalkyl,
(xx) C3-C6 cycloalkyl optionally substituted with 4-10 membered heterocyclyl optionally substituted with C1-C6 alkyl;
(xxi) C6-C12 aryl optionally substituted with 1-3 substituents independently selected from hydroxyl, cyano, C1-C6 haloalkyl, -ORE, -C(=O)C1-C6 alkyl, -SO2(C1-C6 alkyl), -SO2NRFRG, 4- 10 membered heterocyclyl, or C1-C6 alkyl optionally substituted with C1-C6 alkoxy, hydroxyl, or -C(=O)NRARB; and
(xxii) 4-10 membered heterocyclyloxy optionally substituted with 1-3 substituents independently selected from hydroxyl, C1-C6 haloalkyl, -C(=O)C1-C6 alkyl, -SO2(C1-C6 alkyl), -SO2NRFRG, C6-C12 aryl, C1-C6 alkyl optionally substituted with C1-C6 alkoxy, -C(=O)NRARB, or -NHC(=O)C1-C6 alkyl optionally substituted with -NRARB; each RA and RB is independently selected from hydrogen, hydroxyl, Cl -C6 alkoxy, C3-C6 cycloalkyl, C2-C6 alkenyl, cyano, 4-10 membered heterocyclyl, and C1-C6 alkyl optionally substituted with hydroxyl or C1-C6 alkoxy, orRA and RB together with the nitrogen atom to which they are attached form a 4-10 membered heterocyclyl optionally substituted with 1-2 substituents independently selected from halogen, hydroxyl, C1-C6 alkyl, and -C(=O)C1-C6 alkyl; each Rc is independently selected from C3-C6 cycloalkyl, -C(=O)NHRY1, C2-C6 alkenyl, or a C1-C6 alkyl optionally substituted with -NRARB or with 4-10 membered heterocyclyl optionally substituted with C1-C6 alkyl or with C1-C6 hydroxylalkyl; each RD and RE is independently selected from hydrogen, hydroxyl, C1-C6 alkyl, phenyl, 4-10 membered heterocyclyl, -NRARB, C1-C6 alkoxy, and C3-C6 cycloalkyl, wherein the C1-C6 alkyl, 4-10 membered heterocyclyl, and phenyl are optionally substituted with 4-10 membered heterocyclyl, C3-C6 cycloalkyl, or cyano, and the C3-C6 cycloalkyl is optionally substituted with C1-C6 alkyl optionally substituted with hydroxyl or C1-C6 alkoxy; each R3A and R3B is independently selected from hydrogen C1-C6 alkyl, C1-C6 alkoxy, and C1-C6 haloalkyl, or R3A and R3B, together with the carbon and nitrogen atoms, respectively, to which they are attached together form a 4-8 membered heterocyclyl group;
R4 is hydrogen, C1-C6 alkyl, or acrylamido;
R5 is hydrogen, C1-C6 alkyl, halogen, C1-C6 haloalkyl, C3-C6 cycloalkyl, cyano, - NR5AR5B, -NR5AC(=O)R5B, or -C(=O)NR5AR5B;
R5A and R5B are independently selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, and C1-C6 hydroxyalkyl;
R6 is hydrogen, halogen, or C1-C6 alkyl;
JL
X is a bond, CH2, CH(CH3), C(CH3)2, or < ;
Y is phenyl optionally substituted with 1-3 independently selected RY, naphthyl optionally substituted with 1 -3 independently selected RY, or 5-10 membered heteroaryl optionally substituted with 1-3 independently selected RY; each RY is independently selected from: halogen, cyano, hydroxyl, C1-C6 haloalkyl, Cl- C6 alkoxy, C1-C6 haloalkoxy, C1-C6 hydroxyalkyl, -NHC(=O)Rc, -C(=O)NHRY1, -CO2RA, -SO2NRFRG, -NHSO2RF, -S(=O)(=NRF)RG, -SO2(C1-C6 alkyl), -C(=O)NRARB, 5-6 membered heteroaryl, heteroaralkyl, and C1-C6 alkyl optionally substituted with -CChRA or 5-6 membered heteroaryl optionally substituted with R?1;
RY1 is -SO2(C1-C6 alkyl), hydroxyl, or C1-C6 alkyl optionally substituted with oxo; and each RF and RG is independently selected from hydrogen, phenyl, and C1-C6 alkyl optionally substituted with oxo or -NRARB.
Embodiment 2. The compound of Embodiment 1, wherein R1 is hydrogen.
Embodiment 3. The compound of Embodiment 1, wherein R1 cyano.
Embodiment 4. The compound of Embodiment 1, wherein R1 is C3-C6 cycloalkyl.
Embodiment 5. The compound of Embodiment 1, wherein R1 is C1-C6 alkyl optionally substituted with phenyl optionally substituted with halogen.
Embodiment 6. The compound of Embodiment 1, wherein R1 is C1-C6 alkyl substituted with phenyl optionally substituted with halogen.
Embodiment 7. The compound of Embodiment 1 or 6, wherein R1 is C1-C6 alkyl substituted with phenyl substituted with halogen.
Embodiment 8. The compound of Embodiment 1 or 6, wherein R1 is C1-C6 alkyl substituted with phenyl.
Embodiment 9. The compound of Embodiment 1 or 6, wherein R1 is C1-C6 alkyl.
Embodiment 10. The compound of any one of Embodiments 1, 6, or 9, wherein R1 is
C1-C3 alkyl.
Embodiment 11. The compound of Embodiment 1, wherein R1 is C1-C6 thioalkyl.
Embodiment 12. The compound of Embodiment 1, wherein R1 is C1-C6 haloalkyl.
Embodiment 13. The compound of Embodiment 1, wherein R1 is C1-C6 alkoxy.
Embodiment 14. The compound of Embodiment 1, wherein R1 is C1-C6 alkoxyalkyl.
Embodiment 15. The compound of any one of Embodiments 1-14, wherein R1 is hydrogen.
Embodiment 16. The compound of any one of Embodiments 1-14, wherein R1 is Cl-
C6 alkyl.
Embodiment 17. The compound of any one of Embodiments 1-14, wherein R1 is Cl-
C3 alkyl.
Embodiment 18. The compound of Embodiment 1, wherein R1 and R1 , together with the carbon atom to which they are attached form a C3-C10 cycloalkyl. Embodiment 19. The compound of any one of Embodiments 1-18, wherein R2 is C6- C12 aryl optionally substituted with 1-3 independently selected R2A.
Embodiment 20. The compound of any one of Embodiments 1-19, wherein R2 is phenyl optionally substituted with 1-3 independently selected R2A.
Embodiment 21. The compound of any one of Embodiments 1-19, wherein R2 is 2,3- dihydro-lH-indenyl optionally substituted with 1-3 independently selected R2A.
Embodiment 22. The compound of any one of Embodiments 1-18, wherein R2 is 5- 10 membered heteroaryl optionally substituted with 1-3 independently selected R2A.
Embodiment 23. The compound of any one of Embodiments 1-18, wherein R2 is 4- 10 membered heterocyclyl optionally substituted with 1-3 independently selected R2A.
Embodiment 24. The compound of any one of Embodiments 1-18, wherein R2 is C4- C10 cycloalkyl optionally substituted with 1-3 independently selected R2A.
Embodiment 25. The compound of any one of Embodiments 1-18, wherein R2 is Cl- C6 aralkyl optionally substituted with 1-4 independently selected R2A.
Embodiment 26. The compound of any one of Embodiments 1-18, wherein R2 is Cl- C6 aralkyl substituted with 1-4 independently selected R2A.
Embodiment 27. The compound of any one of Embodiments 1-18 or 25, wherein R2 is C1-C6 aralkyl.
Embodiment 28. The compound of any one of Embodiments 1-27, wherein 1, 2, or 3 of R2A are independently halogen.
Embodiment 29. The compound of any one of Embodiments 1-28, wherein 1, 2, or 3 of R2A are independently cyano.
Embodiment 30. The compound of any one of Embodiments 1-29, wherein 1, 2, or 3 of R2A are independently hydroxyl.
Embodiment 31. The compound of any one of Embodiments 1-30, wherein 1, 2, or 3 of R2A are independently -NRARB.
Embodiment 32. The compound of any one of Embodiments 1-31, wherein 1, 2, or 3 of R2A are independently -C(=O)NRARB.
Embodiment 33. The compound of any one of Embodiments 1-32, wherein 1, 2, or 3 of R2A are independently
Figure imgf000135_0001
Embodiment 34. The compound of any one of Embodiments 1-33, wherein 1, 2, or 3 of R2A are independently -NHC(=O)Rc.
Embodiment 35. The compound of any one of Embodiments 1-34, wherein 1, 2, or 3 of R2A are independently -C(=O)NRDRE.
Embodiment 36. The compound of any one of Embodiments 1-35, wherein 1, 2, or 3 of R2A are independently -C(=O)ORF.
Embodiment 37. The compound of any one of Embodiments 1-36, wherein 1, 2, or 3 of R2A are independently -SO2RF
Embodiment 38. The compound of any one of Embodiments 1-37, wherein 1, 2, or 3 of R2A are independently -NHS02RF.
Embodiment 39. The compound of any one of Embodiments 1-38, wherein 1, 2, or 3 of R2A are independently -SO2NRFRG.
Embodiment 40. The compound of any one of Embodiments 1-39, wherein 1, 2, or 3 of R2A are independently -NHC(=O)C1-C6 alkyl optionally substituted with NRARB.
Embodiment 41. The compound of any one of Embodiments 1-40, wherein 1, 2, or 3 of R2A are independently -NHC(=O)C1-C6 alkyl substituted with NRARB.
Embodiment 42. The compound of any one of Embodiments 1-41, wherein 1, 2, or 3 of R2A are independently C1-C6 haloalkyl.
Embodiment 43. The compound of any one of Embodiments 1-42, wherein 1, 2, or 3 of R2A are independently C1-C6 hydroxy alkyl.
Embodiment 44. The compound of any one of Embodiments 1-43, wherein 1, 2, or 3 of R2A are independently 5-10 membered heteroaryl optionally substituted with 1-3 substituents independently selected from C1-C6 alkyl and -NRARB.
Embodiment 45. The compound of any one of Embodiments 1-44, wherein 1, 2, or 3 of R2A are independently 5-10 membered heteroaryl substituted with 1-3 substituents independently selected from C1-C6 alkyl and -NRARB.
Embodiment 46. The compound of any one of Embodiments 1-45, wherein 1, 2, or 3 of R2A are independently 5-10 membered heteroaryl.
Embodiment 47. The compound of any one of Embodiments 1-46, wherein 1, 2, or 3 of R2A are independently 4-10 membered heterocyclyl optionally substituted with 1-3 substituents independently selected from hydroxyl, C1-C6 haloalkyl, -C(=O)C1-C6 alkyl, -SO2(C1-C6 alkyl), -S02NRFRG, C1-C6 alkyl optionally substituted with C1-C6 alkoxy, -C(=O)NRARB, or -NHC(=O)C1-C6 alkyl optionally substituted with -NRARB.
Embodiment 48. The compound of any one of Embodiments 1-47, wherein 1, 2, or 3 of R2A are independently 4-10 membered heterocyclyl substituted with 1-3 substituents independently selected from hydroxyl, C1-C6 haloalkyl, -C(=O)C1-C6 alkyl, -SO2(C1-C6 alkyl), -SO2NRFRG, C1-C6 alkyl optionally substituted with C1-C6 alkoxy, -C(=O)NRARB, or - NHC(=O)C1-C6 alkyl optionally substituted with -NRARB.
Embodiment 49. The compound of any one of Embodiments 1-48, wherein 1, 2, or 3 of R2A are independently 4-10 membered heterocyclyl substituted with 1-3 substituents independently selected from hydroxyl, C1-C6 haloalkyl, -C(=O)C1-C6 alkyl, -SO2(C1-C6 alkyl), -SO2NRFRG, C1-C6 alkyl substituted with C1-C6 alkoxy, -C(=O)NRARB, or -NHC(=O)C1-C6 alkyl substituted with -NRARB.
Embodiment 50. The compound of any one of Embodiments 1-49, wherein 1, 2, or 3 of R2A are independently 4-10 membered heterocyclyl substituted with 1-3 substituents independently selected from hydroxyl, C1-C6 haloalkyl, -C(=O)C1-C6 alkyl, -SC>2(C1-C6 alkyl), -SO2NRFRG, C1-C6 alkyl, -C(=O)NRARB, or -NHC(=O)C1-C6 alkyl.
Embodiment 51. The compound of any one of Embodiments 1-50, wherein 1, 2, or 3 of R2A are independently 4-10 membered heterocyclyl.
Embodiment 52. The compound of any one of Embodiments 1-51, wherein 1, 2, or 3 of R2A are independently C1-C6 alkyl optionally substituted with 1-3 substituents independently selected from hydroxyl, oxo, -NRARB, -C(=O)NRARB, C1-C6 alkoxy, C3-C10 cycloalkyl, and 4- 10 membered heterocyclyl optionally substituted with hydroxyl, C1-C6 alkyl, aralkyl, heteroaralkyl, -C(=O)NRARB, or -C(=O)C3-C6 cycloalkyl.
Embodiment 53. The compound of any one of Embodiments 1-52, wherein 1, 2, or 3 of R2A are independently C1-C6 alkyl substituted with 1-3 substituents independently selected from hydroxyl, oxo, -NRARB, -C(=O)NRARB, C1-C6 alkoxy, C3-C10 cycloalkyl, and 4-10 membered heterocyclyl optionally substituted with hydroxyl, C1-C6 alkyl, aralkyl, heteroaralkyl, -C(=O)NRARB, or -C(=O)C3-C6 cycloalkyl.
Embodiment 54. The compound of any one of Embodiments 1-53, wherein 1, 2, or 3 of R2A are independently C1-C6 alkyl substituted with 1-3 substituents independently selected from hydroxyl, oxo, -NRARB, -C(=O)NRARB, C1-C6 alkoxy, C3-C10 cycloalkyl, and 4-10 membered heterocyclyl substituted with hydroxyl, C1 -C6 alkyl, aralkyl, heteroaralkyl, - C(=O)NRARB, or -C(=O)C3-C6 cycloalkyl.
Embodiment 55. The compound of any one of Embodiments 1-54, wherein 1, 2, or 3 of R2A are independently C1-C6 alkyl substituted with 1-3 substituents independently selected from hydroxyl, oxo, -NRARB, -C(=O)NRARB, C1-C6 alkoxy, C3-C10 cycloalkyl, and 4-10 membered heterocyclyl.
Embodiment 56. The compound of any one of Embodiments 1-55, wherein 1, 2, or 3 of R2A are independently C1-C6 alkyl.
Embodiment 57. The compound of any one of Embodiments 1-56, wherein 1, 2, or 3 of R2A are independently C1-C6 alkoxy optionally substituted with -NRARB or 4-10 membered heterocyclyl optionally substituted with C1-C6 alkyl, aralkyl, heteroaralkyl, or -C(=O)C3-C6 cycloalkyl.
Embodiment 58. The compound of any one of Embodiments 1-57, wherein 1, 2, or 3 of R2A are independently C1-C6 alkoxy substituted with -NRARB or 4-10 membered heterocyclyl optionally substituted with C1-C6 alkyl, aralkyl, heteroaralkyl, or -C(=O)C3-C6 cycloalkyl.
Embodiment 59. The compound of any one of Embodiments 1-58, wherein 1, 2, or 3 of R2A are independently C1-C6 alkoxy substituted with -NRARB or 4-10 membered heterocyclyl substituted with C1-C6 alkyl, aralkyl, heteroaralkyl, or -C(=O)C3-C6 cycloalkyl.
Embodiment 60. The compound of any one of Embodiments 1-59, wherein 1, 2, or 3 of R2A are independently C1-C6 alkoxy substituted with -NRARB or 4-10 membered heterocyclyl.
Embodiment 61. The compound of any one of Embodiments 1-60, wherein 1, 2, or 3 of R2A are independently C1-C6 alkoxy.
Embodiment 62. The compound of any one of Embodiments 1-61, wherein 1, 2, or 3 of R2A are independently C3-C6 cycloalkyl optionally substituted with 4-10 membered heterocyclyl optionally substituted with C1-C6 alkyl.
Embodiment 63. The compound of any one of Embodiments 1-62, wherein 1, 2, or 3 of R2A are independently C3-C6 cycloalkyl substituted with 4-10 membered heterocyclyl optionally substituted with C1-C6 alkyl.
Embodiment 64. The compound of any one of Embodiments 1-63, wherein 1, 2, or 3 of R2A are independently C3-C6 cycloalkyl substituted with 4-10 membered heterocyclyl substituted with C1-C6 alkyl. Embodiment 65. The compound of any one of Embodiments 1-64, wherein 1, 2, or 3 of R2A are independently C3-C6 cycloalkyl substituted with 4-10 membered heterocyclyl.
Embodiment 66. The compound of any one of Embodiments 1-58, wherein 1, 2, or 3 of R2A are independently C3-C6 cycloalkyl.
Embodiment 67. The compound of any one of Embodiments 1-18, wherein R2 is Cl-
C6 alkoxy optionally substituted with -C(=O)NRARc.
Embodiment 68. The compound of any one of Embodiments 1-18 or 67, wherein R2 is C1-C6 alkoxy substituted with -C(=O)NRARc.
Embodiment 69. The compound of any one of Embodiments 1-18 or 67, wherein R2 is C1-C6 alkoxy.
Embodiment 70. The compound of any one of Embodiments 1-18, wherein R2 is Cl-
C6 alkoxyalkyl optionally substituted with -C(=O)NRARc.
Embodiment 71. The compound of any one of Embodiments 1-18, wherein R2 is Cl-
C6 alkoxy alkyl.
Embodiment 72. The compound of any one of Embodiments 1-71, wherein X is a bond.
Embodiment 73. The compound of any one of Embodiments 1-71, wherein X is CH2.
Embodiment 74. The compound of any one of Embodiments 1-71, wherein X is
CH(CH3).
Embodiment 75. The compound of any one of Embodiments 1-71, wherein X is
C(CH3)2.
Embodiment 76. The compound of any one of Embodiments 1-71, wherein X is
Figure imgf000139_0001
Embodiment 77. The compound of any one of Embodiments 1-76, wherein one of R3A and R3B is hydrogen and the other of R3A and R3B is C1-C6 alkyl.
Embodiment 78. The compound of any one of Embodiments 1-77, wherein one of R3A and R3B is hydrogen and the other of R3A and R3B is methyl.
Embodiment 79. The compound of any one of Embodiments 1-76, wherein each of R3A and R3B is hydrogen. Embodiment 80. The compound of any one of Embodiments 1-76, wherein each of R3A and R3B is an independently selected C1-C6 alkyl.
Embodiment 81. The compound of any one of Embodiments 1-76 or 80, wherein each of R3A and R3B is methyl.
Embodiment 82. The compound of any one of Embodiments 1-76, wherein one of R3A and R3B is hydrogen and the other of R3A and R3B is C1-C6 alkoxy.
Embodiment 83. The compound of any one of Embodiments 1-76, wherein one of R3A and R3B is C1-C6 alkyl and the other of R3A and R3B is C1-C6 alkoxy.
Embodiment 84. The compound of any one of Embodiments 1-76, wherein each of R3A and R3B is C1-C6 alkoxy.
Embodiment 85. The compound of any one of Embodiments 1-76, wherein one of R3A and R3B is hydrogen and the other of R3A and R3B is C1-C6 haloalkyl.
Embodiment 86. The compound of any one of Embodiments 1-76, wherein one of R3A and R3B is C1-C6 alkyl and the other of R3A and R3B is C1-C6 haloalkyl.
Embodiment 87. The compound of any one of Embodiments 1-76, wherein each of R3A and R3B is C1-C6 haloalkyl.
Embodiment 88. The compound of any one of Embodiments 1-76, wherein R3A and R3B, together with the carbon and nitrogen atoms, respectively, to which they are attached together form a 4-8 membered heterocyclyl group.
Embodiment 89. The compound of any one of Embodiments 1-88, wherein Y is phenyl optionally substituted with 1-3 independently selected RY.
Embodiment 90. The compound of any one of Embodiments 1-88, wherein Y is naphthyl optionally substituted with 1-3 independently selected R\
Embodiment 91. The compound of any one of Embodiments 1-88, wherein Y is 5-10 membered heteroaryl optionally substituted with 1-3 independently selected RY.
Embodiment 92. The compound of any one of Embodiments 1-91, wherein 1, 2, or 3 of RY is independently halogen.
Embodiment 93. The compound of any one of Embodiments 1-92, wherein 1, 2, or 3 of RY is hydroxyl.
Embodiment 94. The compound of any one of Embodiments 1-93, wherein 1, 2, or 3 of RY is cyano. Embodiment 95. The compound of any one of Embodiments 1-94, wherein 1, 2, or 3 of RY is independently C1-C6 haloalkyl.
Embodiment 96. The compound of any one of Embodiments 1-95, wherein 1, 2, or 3 of RY is independently C1-C6 alkoxy.
Embodiment 97. The compound of any one of Embodiments 1-96, wherein 1, 2, or 3 of RY is independently C1-C6 haloalkoxy.
Embodiment 98. The compound of any one of Embodiments 1-97, wherein 1, 2, or 3 of RY is independently C1-C6 hydroxyalkyl.
Embodiment 99. The compound of any one of Embodiments 1-98, wherein 1, 2, or 3 of RY is independently -NHC(=O)Rc.
Embodiment 100. The compound of any one of Embodiments 1-99, wherein 1, 2, or 3 of RY is independently -C(=O)NHRY1.
Embodiment 101. The compound of any one of Embodiments 1-100, wherein 1, 2, or 3 of RY is independently -CO2RA.
Embodiment 102. The compound of any one of Embodiments 1-101, wherein 1, 2, or 3 of RY is independently -SO2NRFRG.
Embodiment 103. The compound of any one of Embodiments 1-102, wherein 1, 2, or 3 of RY is independently -NHSO2RF.
Embodiment 104. The compound of any one of Embodiments 1-103, wherein 1, 2, or 3 of R' is independently -S(=O)(=NRF)RG.
Embodiment 105. The compound of any one of Embodiments 1-104, wherein 1, 2, or 3 of RY is independently -SCh(Cl-C6 alkyl).
Embodiment 106. The compound of any one of Embodiments 1-105, wherein 1, 2, or 3 of RY is independently -C(=O)NRARB.
Embodiment 107. The compound of any one of Embodiments 1-106, wherein 1, 2, or 3 of RY is independently 5-6 membered heteroaryl.
Embodiment 108. The compound of any one of Embodiments 1-107, wherein 1, 2, or 3 of R' is independently heteroaralkyl.
Embodiment 109. The compound of any one of Embodiments 1-108, wherein 1, 2, or 3 of RY is independently C1-C6 alkyl optionally substituted with -CO2R4 or 5-6 membered heteroaryl optionally substituted with R'1. Embodiment 1 10. The compound of any one of Embodiments 1-109, wherein 1, 2, or 3 of RY is independently C1-C6 alkyl substituted with -CO2RA or 5-6 membered heteroaryl optionally substituted with RY1.
Embodiment 111. The compound of any one of Embodiments 1-110, wherein 1, 2, or 3 of RY is independently C1-C6 alkyl substituted with -CChRA or 5-6 membered heteroaryl substituted with RY1.
Embodiment 112. The compound of any one of Embodiments 1-109, wherein 1, 2, or 3 of RY is independently C1-C6 alkyl substituted with -CChRA or 5-6 membered heteroaryl.
Embodiment 113. The compound of any one of Embodiments 1-109, wherein 1, 2, or 3 of RY is independently C1-C6 alkyl.
Embodiment 114. The compound of any one of Embodiments 1-91 or 109-111, wherein RY1 is -SO2(C1-C6 alkyl).
Embodiment 115. The compound of any one of Embodiments 1-91 or 109-111, wherein R? 1 is C1-C6 alkyl optionally substituted with oxo.
Embodiment 116. The compound of any one of Embodiments 1-115, wherein R4 is hydrogen.
Embodiment 117. The compound of any one of Embodiments 1-115, wherein R4 is Cl- C6 alkyl.
Embodiment 118. The compound of any one of Embodiments 1-115, wherein R4 is acrylamido.
Embodiment 119. The compound of any one of Embodiments 1-118, wherein R5 is hydrogen.
Embodiment 120. The compound of any one of Embodiments 1-118, wherein R5 is Cl- C6 alkyl.
Embodiment 121. The compound of any one of Embodiments 1-118, wherein R5 is halogen.
Embodiment 122. The compound of any one ofEmbodiments 1-118, whereinR5 is Cl- C6 haloalkyl.
Embodiment 123. The compound of any one ofEmbodiments 1-118, whereinR5 is C3-
C6 cycloalkyl. Embodiment 124. The compound of any one of Embodiments 1-118, wherein R5 is cyano.
Embodiment 125. The compound of any one of Embodiments 1-118, wherein R5 is -
NR5AR5B.
Embodiment 126. The compound of any one of Embodiments 1-118, wherein R5 is -C(=O)NR5AR5B.
Embodiment 127. The compound of any one of Embodiments 1-118, wherein R5 is - NR5AC(=O)R5B.
Embodiment 128. The compound of any one of Embodiments 1-118 or 125-127, wherein one of R5A and R5B is hydrogen and the other of R3A and R5B is C1-C6 alkyl, C2-C6 alkenyl, or C1-C6 hydroxyalkyl.
Embodiment 129. The compound of any one of Embodiments 1-118 or 125-127, wherein one of R5A and R5B is C1-C6 alkyl and the other of R5A and R5B is C1-C6 alkyl, C2-C6 alkenyl, or C1-C6 hydroxyalkyl.
Embodiment 130. The compound of any one of Embodiments 1-118 or 125-127, wherein each of R5A and R5B is hydrogen.
Embodiment 131. The compound of any one of Embodiments 1-118 or 125-127, wherein each of R5A and R5B is an independently selected C1-C6 alkyl.
Embodiment 132. The compound of any one of Embodiments 1-131, wherein R6 is hydrogen.
Embodiment 133. The compound of any one of Embodiments 1-131, wherein R6 is halogen.
Embodiment 134. The compound of any one of Embodiments 1-131, wherein R6 is Cl- C6 alkyl.
Embodiment 135. The compound of any one of Embodiments 1-134, wherein each of
RA and RB are independently selected from hydrogen, hydroxyl, C1-C6 alkoxy, C3-C6 cycloalkyl,
C2-C6 alkenyl, cyano, and C1-C6 alkyl optionally substituted with hydroxyl or C1-C6 alkoxy.
Embodiment 136. The compound of any one of Embodiments 1-135, wherein one of RA and RB is hydrogen and the other of RA and RB is hydroxyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C2-C6 alkenyl, cyano, or C1-C6 alkyl optionally substituted with hydroxyl or C1-C6 alkoxy. Embodiment 137. The compound of any one of Embodiments 1-136, wherein one of RA and RB is hydrogen and the other of RA and RB is hydroxyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C2-C6 alkenyl, or C1-C6 alkyl substituted with hydroxyl or C1-C6 alkoxy.
Embodiment 138. The compound of any one of Embodiments 1-136, wherein one of RA and RB is hydrogen and the other of RA and RB is hydroxyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C2-C6 alkenyl, or C1-C6 alkyl.
Embodiment 139. The compound of any one of Embodiments 1-134, wherein RA and RB together with the nitrogen atom to which they are attached form a 4-10 membered heterocyclyl optionally substituted with 1-2 substituents independently selected from halogen, C1-C6 alkyl, and -C(=O)C1-C6 alkyl.
Embodiment 140. The compound of any one of Embodiments 1-134 or 139, wherein RA and RB together with the nitrogen atom to which they are attached form a 4-10 membered heterocyclyl substituted with 1-2 substituents independently selected from halogen, C1-C6 alkyl, and -C(=O)C1-C6 alkyl.
Embodiment 141. The compound of any one of Embodiments 1-134 or 139, wherein RA and RB together with the nitrogen atom to which they are attached form a 4-10 membered heterocyclyl.
Embodiment 142. The compound of any one of Embodiments 1-141, wherein each Rc is independently C3-C6 cycloalkyl, -C(=O)NHRY1, or a C1-C6 alkyl substituted with -NRARB or with 4-10 membered heterocyclyl optionally substituted with C1-C6 alkyl or with C1-C6 hydroxylalkyl.
Embodiment 143. The compound of any one of Embodiments 1-142, wherein each Rc is independently C3-C6 cycloalkyl, -C(=O)NHR^ 1, or a C1-C6 alkyl substituted with -NRARB or with 4-10 membered heterocyclyl substituted with C1-C6 alkyl or with C1-C6 hydroxylalkyl.
Embodiment 144. The compound of any one of Embodiments 1-142, wherein each Rc is independently C3-C6 cycloalkyl, -C(=O)NHR't l, or a C1-C6 alkyl substituted with -NRARB or with 4-10 membered heterocyclyl.
Embodiment 145. The compound of any one of Embodiments 1-142, wherein each Rc is independently C3-C6 cycloalkyl, -C(=O)NHRY1, or a C1-C6 alkyl.
Embodiment 146. The compound of any one of Embodiments 1-145, wherein each RD is hydrogen, hydroxyl, or C1-C6 alkoxy. Embodiment 147. The compound of any one of Embodiments 1 -145, wherein each RD is C1-C6 alkyl, 4-10 membered heterocyclyl, or phenyl.
Embodiment 148. The compound of any one of embodiments 1-145, wherein each RD is C1-C6 alkyl, 4-10 membered heterocyclyl, or phenyl optionally substituted with 4-10 membered heterocyclyl, C3-C6 cycloalkyl, or cyano.
Embodiment 149. The compound of any one of embodiments 1-145, wherein each RD is C3-C6 cycloalkyl.
Embodiment 150. The compound of any one of embodiments 1-145, wherein each RD is C3-C6 cycloalkyl optionally substituted with C1-C6 alkyl optionally substituted with hydroxyl or Cl -C 6 alkoxy.
Embodiment 151. compound of any one of embodiments 1-150, wherein each RE is hydrogen, hydroxyl, or C1-C6 alkoxy.
Embodiment 152. The compound of any one of embodiments 1-150, wherein each RE is C1-C6 alkyl, 4-10 membered heterocyclyl, or phenyl.
Embodiment 153. The compound of any one of embodiments 1-150, wherein each RE is C1-C6 alkyl, 4-10 membered heterocyclyl, or phenyl optionally substituted with 4-10 membered heterocyclyl, C3-C6 cycloalkyl, or cyano.
Embodiment 154. The compound of any one of embodiments 1-150, wherein each RE is C3-C6 cycloalkyl.
Embodiment 155. The compound of any one of embodiments 1-150, wherein each RE is C3-C6 cycloalkyl optionally substituted with C1-C6 alkyl optionally substituted with hydroxyl or C1-C6 alkoxy.
Embodiment 156. The compound of any one of Embodiments 1-145, wherein one of RD and RE is hydrogen and the other of RD and RE is hydroxyl, C1-C6 alkyl, or C1-C6 alkoxy.
Embodiment 157. The compound of any one of Embodiments 1-145, wherein each of RD and RE is hydrogen.
Embodiment 158. The compound of any one of Embodiments 1-145, wherein each of RD and RE is an independently selected C1-C6 alkyl.
Embodiment 159. The compound of any one of Embodiments 1-158, wherein one of RF and RG is hydrogen and the other of RE and RG is phenyl or C1-C6 alkyl optionally substituted with oxo or -NRARB. Embodiment 160. The compound of any one of Embodiments 1-158, wherein one of RF and RG is hydrogen and the other of RF and RG is phenyl or C1-C6 alkyl substituted with oxo or -NRARB.
Embodiment 161. The compound of any one of Embodiments 1-158, wherein one of RF and RG is hydrogen and the other of RF and RG is phenyl or C1-C6 alkyl.
Embodiment 162. The compound of any one of Embodiments 1-158, wherein each of RF and RG is hydrogen.
Embodiment 163. The compound of any one of Embodiments 1-158, wherein each of RF and RG is an independently selected C1-C6 alkyl.
Embodiment 164. The compound of Embodiment 1, wherein, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is a compound of Formula (I-A2):
Figure imgf000146_0001
or a pharmaceutically acceptable salt thereof.
Embodiment 165. A compound selected from the group consisting of the compounds in Table A, or a pharmaceutically acceptable salt thereof.
Embodiment 166. A pharmaceutical composition comprising a compound of any one of Embodiments 1-165, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.
Embodiment 167. A method for treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of any one of Embodiments 1-165, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of Embodiment 166.
Embodiment 168. A method for treating cancer in a subject in need thereof, the method comprising (a) determining that the cancer is associated with a dysregulation of a PIK3CA gene, a PI3Ka protein, or expression or activity or level of any of the same; and (b) administering to the subject a therapeutically effective amount of a compound of any one of Embodiments 1-165, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of Embodiment 166. Embodiment 169. A method of treating a PI3Ka-associated cancer in a subject, comprising administering to a subject identified or diagnosed as having a PI3Ka-associated cancer a therapeutically effective amount of a compound of any one of Embodiments 1-165 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of Embodiment 166. Embodiment 170. A method for inhibiting mutant PI3Ka activity in a mammalian cell, the method comprising contacting the mammalian cell with an effective amount of a compound of any one of Embodiments 1-165, or a pharmaceutically acceptable salt thereof.

Claims

WHAT IS CLAIMED IS:
1. A compound of Formula (I):
Figure imgf000148_0001
or a pharmaceutically acceptable salt thereof, wherein:
R1 is hydrogen, cyano, C3-C6 cycloalkyl, C1-C6 alkyl optionally substituted with phenyl optionally substituted with halogen, C1-C6 thioalkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C1-C6 alkoxy alkyl;
R1 is hydrogen or C1-C6 alkyl; or R1 and R1 , together with the carbon atom to which they are attached form a C3-C10 cycloalkyl;
R2 is C6-C12 aryl optionally substituted with 1-4 independently selected R2A, 5-10 membered heteroaryl optionally substituted with 1-4 independently selected R2A, 4-10 membered heterocyclyl optionally substituted with 1-4 independently selected R2A, C4-C10 cycloalkyl optionally substituted with 1-4 independently selected R2A, C1-C6 alkoxyalkyl optionally substituted with -C(=O)NRARc, C1-C6 aralkyl optionally substituted with 1-4 independently selected R2A, or C1-C6 alkoxy optionally substituted with -C(=O)NRARc; each R2A is independently selected from:
(i) halogen,
(ii) cyano,
(iii) hydroxyl,
(iv) -NRARB,
(v) -C(=O)NRARB,
^Y^NRARB
(vi) O
(vii) -NHC(=O)Rc,
(viii) -C(=O)RD,
(ix) -C(=O)ORE, (x) -SO2RF,
(xi) -NHSO2RF,
(xii) -SO2NRFRG,
(xiii) -NHC(=O)C1-C6 alkyl optionally substituted with NRARB,
(xiv) C1-C6 haloalkyl,
(xv) C1-C6 hydroxyalkyl,
(xvi) 5-10 membered heteroaryl optionally substituted with 1-3 substituents independently selected from C1-C6 alkyl, -C(=O)NRARB, C1-C6 haloalkyl, and -NRARB,
(xvii) 4-10 membered heterocyclyl optionally substituted with 1-3 substituents independently selected from hydroxyl, C1-C6 haloalkyl, -C(=O)C1-C6 alkyl, -SO2(C1-C6 alkyl), -SO2NRFRG, C6-C12 aryl, C1-C6 alkyl optionally substituted with C1-C6 alkoxy, -C(=O)NRARB, or -NHC(=O)C1-C6 alkyl optionally substituted with -NRARB,
(xviii) C1-C6 alkyl optionally substituted with 1-3 substituents independently selected from hydroxyl, oxo, -NRARB, -C(=O)NRARB, C1-C6 alkoxy, C3-C10 cycloalkyl, phenyl, and 4- 10 membered heterocyclyl optionally substituted with hydroxyl, C1-C6 alkyl, aralkyl, heteroaralkyl, -C(=O)NRARB, or -C(=O)C3-C6 cycloalkyl,
(xix) C1-C6 alkoxy optionally substituted with -NRARB or 4-10 membered heterocyclyl optionally substituted with C1-C6 alkyl, hydroxyl, aralkyl, heteroaralkyl, or -C(=O)C3-C6 cycloalkyl,
(xx) C3-C6 cycloalkyl optionally substituted with 4-10 membered heterocyclyl optionally substituted with C1-C6 alkyl;
(xxi) C6-C12 aryl optionally substituted with 1-3 substituents independently selected from hydroxyl, cyano, C1-C6 haloalkyl, -ORE, -C(=O)C1-C6 alkyl, -SO2(C1-C6 alkyl), -SO2NRFRG, 4- 10 membered heterocyclyl, or C1-C6 alkyl optionally substituted with C1-C6 alkoxy, hydroxyl, or -C(=O)NRARD; and
(xxii) 4-10 membered heterocyclyloxy optionally substituted with 1-3 substituents independently selected from hydroxyl, C1-C6 haloalkyl, -C(=O)C1-C6 alkyl, -SO2(C1-C6 alkyl), -SO2NRFRG, C6-C12 aryl, C1-C6 alkyl optionally substituted with C1-C6 alkoxy, -C(=O)NRARB, or -NHC(=O)C1-C6 alkyl optionally substituted with -NRARB; each RA and RB is independently selected from hydrogen, hydroxyl, C 1-C6 alkoxy, C3-C6 cycloalkyl, C2-C6 alkenyl, cyano, 4-10 membered heterocyclyl, and C1-C6 alkyl optionally substituted with hydroxyl or Cl -C6 alkoxy, or RA and RB together with the nitrogen atom to which they are attached form a 4-10 membered heterocyclyl optionally substituted with 1-2 substituents independently selected from halogen, hydroxyl, C1-C6 alkyl, and -C(=O)C1-C6 alkyl; each Rc is independently selected from C3-C6 cycloalkyl, -C(=O)NHRY1, C2-C6 alkenyl, or a C1-C6 alkyl optionally substituted with -NRARB or with 4-10 membered heterocyclyl optionally substituted with C1-C6 alkyl or with C1-C6 hydroxylalkyl; each RD and RE is independently selected from hydrogen, hydroxyl, C1-C6 alkyl, phenyl, 4-10 membered heterocyclyl, -NRARB, C1-C6 alkoxy, and C3-C6 cycloalkyl, wherein the C1-C6 alkyl, 4-10 membered heterocyclyl, and phenyl are optionally substituted with 4-10 membered heterocyclyl, C3-C6 cycloalkyl, or cyano, and the C3-C6 cycloalkyl is optionally substituted with C1-C6 alkyl optionally substituted with hydroxyl or C1-C6 alkoxy; each R3A and R3B is independently selected from hydrogen C1-C6 alkyl, C1-C6 alkoxy, and C1-C6 haloalkyl, or R3A and R3B, together with the carbon and nitrogen atoms, respectively, to which they are attached together form a 4-8 membered heterocyclyl group;
R4 is hydrogen, C1-C6 alkyl, or acrylamido;
R5 is hydrogen, C1-C6 alkyl, halogen, C1-C6 haloalkyl, C3-C6 cycloalkyl, cyano, - NR5AR5B, -NR5AC(=O)R5B, or -C(=O)NR5AR5B;
R5A and R5B are independently selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, and C1-C6 hydroxyalkyl;
R6 is hydrogen, halogen, or C1-C6 alkyl;
X is a bond,
Figure imgf000150_0001
Y is phenyl optionally substituted with 1-3 independently selected R\ naphthyl optionally substituted with 1-3 independently selected RY, or 5-10 membered heteroaryl optionally substituted with 1-3 independently selected RY; each Ry is independently selected from: halogen, cyano, hydroxyl, C1 -C6 haloalkyl, Cl - C6 alkoxy, C1-C6 haloalkoxy, C1-C6 hydroxyalkyl, -NHC(=O)Rc, -C(=O)NHRY1, -CO2RA, -SO2NRFRG, -NHSO2RF, -S(=O)(=NRF)RG, -SO2(C1-C6 alkyl), -C(=O)NRARB, 5-6 membered heteroaryl, heteroaralkyl, and C1-C6 alkyl optionally substituted with -CO2RA or 5-6 membered heteroaryl optionally substituted with RY 1;
RY1 is -SO2(C1-C6 alkyl), hydroxyl, or C1-C6 alkyl optionally substituted with oxo; and each RF and RG is independently selected from hydrogen, phenyl, and C1 -C6 alkyl optionally substituted with oxo or -NRARB.
2. The compound of Claim 1, wherein R2 is C6-C12 aryl optionally substituted with
1-3 independently selected R2A.
3. The compound of Claim 1, wherein R2 is phenyl optionally substituted with 1-3 independently selected R2A.
4. The compound of Claim 1, wherein R2 is 5-10 membered heteroaryl optionally substituted with 1-3 independently selected R2A.
5. The compound of Claim 1, wherein R2 is 4-10 membered heterocyclyl optionally substituted with 1-3 independently selected R2A.
6. The compound of Claim 1, wherein R2 is C4-C10 cycloalkyl optionally substituted with 1-3 independently selected R2A.
7. The compound of any one of Claims 1-6, wherein 1, 2, or 3 of R2A are independently halogen.
8. The compound of any one of Claims 1-7, wherein 1, 2, or 3 of R2A are independently cyano.
9. The compound of any one of Claims 1-8, wherein 1, 2, or 3 of R2A are independently hydroxyl.
10. The compound of any one of Claims 1-9, wherein 1, 2, or 3 of R2A are independently C1-C6 haloalkyl.
11. The compound of any one of Claims 1-10, wherein 1, 2, or 3 of R2A are independently C1-C6 hydroxyalkyl.
12. The compound of any one of Claims 1-11, wherein 1, 2, or 3 of R2A are independently 5-10 membered heteroaryl optionally substituted with 1-3 substituents independently selected from C1-C6 alkyl and -NRARD.
13. The compound of any one of Claims 1-12, wherein 1, 2, or 3 of R2A are independently 4-10 membered heterocyclyl optionally substituted with 1-3 substituents independently selected from hydroxyl, C1-C6 haloalkyl, -C(=O)C1-C6 alkyl, -SCh(Cl-C6 alkyl), -SO2NRFRG, C1-C6 alkyl optionally substituted with C1-C6 alkoxy, -C(=O)NRARB, or -NHC(=O)C1-C6 alkyl optionally substituted with -NRARB.
14. The compound of any one of Claims 1-13, wherein 1, 2, or 3 of R2A are independently C1-C6 alkoxy optionally substituted with -NRARB or 4-10 membered heterocyclyl optionally substituted with C1-C6 alkyl, aralkyl, heteroaralkyl, or -C(=O)C3-C6 cycloalkyl.
15. The compound of any one of Claims 1-14, wherein 1, 2, or 3 of R2A are independently C3-C6 cycloalkyl optionally substituted with 4-10 membered heterocyclyl optionally substituted with C1-C6 alkyl.
16. The compound of any one of Claims 1-15, wherein X is a bond.
17. The compound of any one of Claims 1-16, wherein each of R3A and R3B is hydrogen.
18. The compound of any one of Claims 1-17, wherein Y is phenyl optionally substituted with 1-3 independently selected RY.
19. The compound of any one of Claims 1-17, wherein Y is 5-10 membered heteroaryl optionally substituted with 1-3 independently selected RY.
20. The compound of any one of Claims 1-19, wherein 1, 2, or 3 of R? is independently
-CO2RA
21. The compound of Claim 1, wherein, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is a compound of Formula (I-A2):
Figure imgf000152_0001
or a pharmaceutically acceptable salt thereof.
22. A compound selected from the group consisting of the compounds in Table A, or a pharmaceutically acceptable salt thereof.
23. A pharmaceutical composition comprising a compound of any one of Claims 1-22, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.
24. A method for treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of any one of Claims 1-22, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of Claim 23.
25. A method of treating a PI3Ka-associated cancer in a subject, comprising administering to a subject identified or diagnosed as having a PI3Ka-associated cancer a therapeutically effective amount of a compound of any one of Claims 1-22 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of Claim 23.
PCT/US2024/027254 2023-05-02 2024-05-01 Compounds for treating cancer Pending WO2024229121A1 (en)

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