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WO2024222894A1 - Composés de benzofurane et leur utilisation en tant qu'inhibiteurs de pi3k alpha - Google Patents

Composés de benzofurane et leur utilisation en tant qu'inhibiteurs de pi3k alpha Download PDF

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Publication number
WO2024222894A1
WO2024222894A1 PCT/CN2024/090120 CN2024090120W WO2024222894A1 WO 2024222894 A1 WO2024222894 A1 WO 2024222894A1 CN 2024090120 W CN2024090120 W CN 2024090120W WO 2024222894 A1 WO2024222894 A1 WO 2024222894A1
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compound
alkyl
ring
alkoxy
cancer
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PCT/CN2024/090120
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English (en)
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Ming Li
Ruipeng ZHANG
Chun-Yen Chen
Xiang-Ju Justin Gu
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Laekna Pharmaceutical Ningbo Co., Ltd.
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Publication of WO2024222894A1 publication Critical patent/WO2024222894A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • 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
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
    • C07D493/10—Spiro-condensed systems

Definitions

  • PI3K alpha (PI3K ⁇ ) inhibitors certain multicyclic compounds as PI3K alpha (PI3K ⁇ ) inhibitors, pharmaceutical compositions comprising the compounds, and method of use of the compounds or pharmaceutical compositions in the treatment of diseases or disorders.
  • Lipid phosphoinositides in cell membranes are master regulators of membrane signaling events for membrane trafficking, metabolism, growth, signaling and autophagy, with alterations in phosphoinositide metabolism being causative for many human diseases (Dickson, E.J., Hille, B., Biochem. J. 2019, 476 (1) , 1–23) .
  • Phosphoinositides are generated from phosphatidylinositol (PI) by the action of lipid phosphoinositide kinases (19 unique genes in mammals) and are degraded by the action of phosphoinositide phosphatases (Schink, K.O. et al., Annu. Rev. Cell Dev. Biol. 2016, 32, 143–171) .
  • PI3Ks Class I phosphoinositide 3-kinases
  • RTKs tyrosine kinases
  • GPCRs G protein-coupled receptors
  • GTPases such as RAS, RAC, and CDC42, regulating a range of cellular activities, including metabolism, proliferation, and migration (Vanhaesebroeck, B. et al., Nat Rev Drug Discov 2021, 20, 741–769) .
  • Class I PI3Ks comprise heterodimers formed by p110 catalytic subunits ( ⁇ , ⁇ , ⁇ or ⁇ ) and p85 regulatory subunits, among which PI3K ⁇ and PI3K ⁇ have a wide tissue distribution, while PI3K ⁇ and PI3K ⁇ are more abundant in leukocytes.
  • a key function of PI3K ⁇ is to convert growth factor stimulation into activation of anabolic processes and concomitant inhibition of catabolic processes (Hammond, G. R. V. &Burke, J.E., Curr. Opin. Cell Biol. 2020, 63, 57–67) .
  • AKT and mTOR Two key effectors of PI3K ⁇ involved in this response are AKT and mTOR, these are serine/threonine kinases with a myriad of substrates and pleiotropic functions. Combined with AKT/mTOR, PI3K ⁇ pathway endows the widespread transcriptional changes for energy generation and biosynthetic activity, key requisites for cell proliferation and survival (Lee, J.V. et al., Cell Metab. 2014, 20, 306–319) .
  • the human p110 ⁇ protein is encoded by the PIK3CA gene.
  • PIK3CA is a 34 kb gene located on chromosome 3q26.3 that consists of 20 exons coding for 1068 amino acids yielding a 124 kDa size protein.
  • PIK3CA is one of the most frequently mutated kinase gene in solid tumors. Oncogenic mutations are present across PIK3CA, apart from the RAS-binding domain, also highly enriched for hotspot mutations in the helical (E542K, E545K) and kinase (H1047R) domains, having the strongest biological impact in experimental cell model systems compared with other PIK3CA mutations (Zhang, Y.
  • PIK3CA mutation has multiple impacts, including the reduction of growth factor dependence, emergence of stem cell-like properties, the toleration of chromosomal instability, potentially driving tumor evolution (Vanhaesebroeck, B. et al., Biomolecules 9, 331) .
  • Transcriptional profiling of a PIK3CA-mutated derivative of the MCF10A breast cell line indicated the expression of PI3K-driven, nuclear factor- ⁇ B (NF- ⁇ B) -dependent target genes enriched in cytokines, chemokines or secreted proteins (Hutti, J. E. et al., Cancer Res. 2012, 72, 3260–3269) .
  • PIK3CA mutation in cancer cells also create an immunosuppressive stromal environment by induction of high glycolysis in cancer cells, leading to a high demand for glucose and subsequent depletion of metabolic fuels in the stroma, thus contributing to immune suppression (Hao, Y. et al., Nat. Commun. 2016, 7, 11971; Biswas, S. K., Immunity 2015, 43, 435–449) .
  • PI3K ⁇ inhibitors Because of the PI3K ⁇ pathway’s role in oncogenesis, a variety of PI3K ⁇ inhibitors have been developed to attempt to improve cancer control. Isoform-selective PI3K ⁇ inhibitors have a good potency for the ATP pocket and became a main rationale for the use in oncology to target cancer cell-intrinsic PI3K pathway (Tarantelli, C. et al., Clin. Cancer Res. 2018, 24, 120–129) . Main challenge in the therapeutic exploitation of PI3K ⁇ inhibitors is toxicity and pathway reactivation. Feedback can counteract PI3K ⁇ inhibition by both cell-intrinsic and systematic mechanisms (Burke, J.E. et al.
  • PI3K ⁇ dominant mutations may improve the therapeutic window, enabling sufficient target inhibition in tumor as well as avoiding the dose-limiting toxicity.
  • multicyclic compounds as PI3K ⁇ inhibitors.
  • X 1 , X 2 , R a3 , R a4 , R a5 , R a6 , Ring A, Ring B, L, R and R 1 are as defined herein or elsewhere.
  • compositions comprising a compound provided herein and a pharmaceutically acceptable excipient.
  • the terms “comprising” and “including” can be used interchangeably.
  • the terms “comprising” and “including” are to be interpreted as specifying the presence of the stated features or components as referred to, but does not preclude the presence or addition of one or more features, or components, or groups thereof. Additionally, the terms “comprising” and “including” are intended to include examples encompassed by the term “consisting of” . Consequently, the term “consisting of” can be used in place of the terms “comprising” and “including” to provide for more specific embodiments.
  • the term “or” is to be interpreted as an inclusive “or” meaning any one or any combination. Therefore, “A, B or C” means any of the following: “A; B; C; A and B; A and C; B and C; A, B and C” . An exception to this definition will occur only when a combination of elements, functions, steps or acts are in some way inherently mutually exclusive.
  • phrase “and/or” as used in a phrase such as “A and/or B” herein is intended to include both A and B; A or B; A (alone) ; and B (alone) .
  • phrase “and/or” as used in a phrase such as “A, B, and/or C” is intended to encompass each of the following embodiments: A, B, and C; A, B, or C; A or C; A or B; B or C; A and C; A and B; B and C; A (alone) ; B (alone) ; and C (alone) .
  • alkyl refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, which is saturated.
  • the alkyl group has, for example, from one to twenty-four carbon atoms (C 1 -C 24 alkyl) , four to twenty carbon atoms (C 4 -C 20 alkyl) , six to sixteen carbon atoms (C 6 -C 16 alkyl) , six to nine carbon atoms (C 6 -C 9 alkyl) , one to fifteen carbon atoms (C 1 -C 15 alkyl) , one to twelve carbon atoms (C 1 -C 12 alkyl) , one to eight carbon atoms (C 1 -C 8 alkyl) or one to six carbon atoms (C 1 -C 6 alkyl) and which is attached to the rest of the molecule by a single bond.
  • alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, 1-methylethyl (isopropyl) , n-butyl, n-pentyl, 1, 1-dimethylethyl (t-butyl) , 3-methylhexyl, 2-methylhexyl, and the like. Unless otherwise specified, an alkyl group is optionally substituted.
  • alkenyl refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, which contains one or more carbon-carbon double bonds.
  • alkenyl also embraces radicals having “cis” and “trans” configurations, or alternatively, “E” and “Z” configurations, as appreciated by those of ordinary skill in the art.
  • the alkenyl group has, for example, from two to twenty-four carbon atoms (C 2 -C 24 alkenyl) , four to twenty carbon atoms (C 4 -C 20 alkenyl) , six to sixteen carbon atoms (C 6 -C 16 alkenyl) , six to nine carbon atoms (C 6 -C 9 alkenyl) , two to fifteen carbon atoms (C 2 -C 15 alkenyl) , two to twelve carbon atoms (C 2 -C 12 alkenyl) , two to eight carbon atoms (C 2 -C 8 alkenyl) or two to six carbon atoms (C 2 -C 6 alkenyl) and which is attached to the rest of the molecule by a single bond.
  • alkenyl groups include, but are not limited to, ethenyl, prop-1-enyl, but-1-enyl, pent-1-enyl, penta-1, 4-dienyl, and the like. Unless otherwise specified, an alkenyl group is optionally substituted.
  • alkynyl refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, which contains one or more carbon-carbon triple bonds.
  • the alkynyl group has, for example, from two to twenty-four carbon atoms (C 2 -C 24 alkynyl) , four to twenty carbon atoms (C 4 -C 20 alkynyl) , six to sixteen carbon atoms (C 6 -C 16 alkynyl) , six to nine carbon atoms (C 6 -C 9 alkynyl) , two to fifteen carbon atoms (C 2 -C 15 alkynyl) , two to twelve carbon atoms (C 2 -C 12 alkynyl) , two to eight carbon atoms (C 2 -C 8 alkynyl) or two to six carbon atoms (C 2 -C 6 alkynyl) and which is attached to the
  • alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, pentynyl, and the like. Unless otherwise specified, an alkynyl group is optionally substituted.
  • cycloalkyl refers to a non-aromatic monocyclic or polycyclic hydrocarbon radical consisting solely of carbon and hydrogen atoms, and which is saturated. Cycloalkyl group may include fused, bridged, or spiro ring systems. In one embodiment, the cycloalkyl has, for example, from 3 to 15 ring carbon atoms (C 3 -C 15 cycloalkyl) , from 3 to 10 ring carbon atoms (C 3 -C 10 cycloalkyl) , or from 3 to 8 ring carbon atoms (C 3 -C 8 cycloalkyl) .
  • the cycloalkyl is attached to the rest of the molecule by a single bond.
  • monocyclic cycloalkyl radicals include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
  • polycyclic cycloalkyl radicals include, but are not limited to, adamantyl, norbornyl, decalinyl, 7, 7-dimethyl-bicyclo [2.2.1] heptanyl, and the like. Unless otherwise specified, a cycloalkyl group is optionally substituted.
  • cycloalkenyl refers to a non-aromatic monocyclic or polycyclic hydrocarbon radical consisting solely of carbon and hydrogen atoms, and which includes one or more carbon-carbon double bonds. Cycloalkenyl may include fused, bridged, or spiro ring systems. In one embodiment, the cycloalkenyl has, for example, from 3 to 15 ring carbon atoms (C 3 -C 15 cycloalkenyl) , from 3 to 10 ring carbon atoms (C 3 -C 10 cycloalkenyl) , or from 3 to 8 ring carbon atoms (C 3 -C 8 cycloalkenyl) .
  • cycloalkenyl is attached to the rest of the molecule by a single bond.
  • monocyclic cycloalkenyl radicals include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, and the like.
  • a cycloalkenyl group is optionally substituted.
  • cycloalkynyl refers to a non-aromatic monocyclic or polycyclic hydrocarbon radical consisting solely of carbon and hydrogen atoms, and which includes one or more carbon-carbon triple bonds.
  • heteroalkyl refers to an alkyl radical that has one or more skeletal chain atoms selected from an atom other than carbon, e.g., oxygen, nitrogen, sulfur, and phosphorus, or combinations thereof.
  • a numerical range can be given to refer to the chain length in total.
  • a -CH 2 OCH 2 CH 3 radical is referred to as a “C 4 ” heteroalkyl.
  • Connection to the parent molecular structure can be through either a heteroatom or a carbon in the heteroalkyl chain.
  • One or more heteroatom (s) in the heteroalkyl radical can be optionally oxidized.
  • One or more nitrogen atoms, if present, can also be optionally quaternized.
  • a heteroalkyl group is optionally substituted.
  • aryl refers to a monocyclic aromatic group and/or multicyclic aromatic group that contain at least one aromatic hydrocarbon ring.
  • the aryl has from 6 to 18 ring carbon atoms (C 6 -C 18 aryl) , from 6 to 14 ring carbon atoms (C 6 -C 14 aryl) , or from 6 to 10 ring carbon atoms (C 6 -C 10 aryl) .
  • aryl groups include, but are not limited to, phenyl, naphthyl, fluorenyl, azulenyl, anthryl, phenanthryl, pyrenyl, biphenyl, and terphenyl.
  • aryl also refers to bicyclic, tricyclic, or other multicyclic hydrocarbon rings, where at least one of the rings is aromatic and the others of which may be saturated, partially unsaturated, or aromatic, for example, dihydronaphthyl, indenyl, indanyl, or tetrahydronaphthyl (tetralinyl) . Unless otherwise specified, an aryl group is optionally substituted.
  • heteroaryl refers to a monocyclic aromatic group and/or multicyclic aromatic group that contains at least one aromatic ring, wherein at least one aromatic ring contains one or more (e.g., one, one or two, one to three, or one to four) heteroatoms independently selected from O, S, and N.
  • the heteroaryl may be attached to the main structure at any heteroatom or carbon atom. In certain embodiments, the heteroaryl has from 5 to 20, from 5 to 15, or from 5 to 10 ring atoms.
  • heteroaryl also refers to bicyclic, tricyclic, or other multicyclic rings, where at least one of the rings is aromatic and the others of which may be saturated, partially unsaturated, or aromatic, wherein at least one aromatic ring contains one or more heteroatoms independently selected from O, S, and N.
  • Examples of monocyclic heteroaryl groups include, but are not limited to, pyrrolyl, pyrazolyl, pyrazolinyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, isothiazolyl, furanyl, thienyl, oxadiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, and triazinyl.
  • bicyclic heteroaryl groups include, but are not limited to, indolyl, benzothiazolyl, benzoxazolyl, benzothienyl, quinolinyl, tetrahydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzopyranyl, indolizinyl, benzofuranyl, isobenzofuranyl, chromonyl, coumarinyl, cinnolinyl, quinoxalinyl, indazolyl, purinyl, pyrrolopyridinyl, furopyridinyl, thienopyridinyl, dihydroisoindolyl, and tetrahydroquinolinyl.
  • tricyclic heteroaryl groups include, but are not limited to, carbazolyl, benzindolyl, phenanthrollinyl, acridinyl, phenanthridinyl, and xanthenyl. Unless otherwise specified, a heteroaryl group is optionally substituted.
  • heterocyclyl refers to a monocyclic and/or multicyclic non-aromatic group that contains one or more (e.g., one, one or two, one to three, or one to four) heteroatoms independently selected from nitrogen, oxygen, phosphorous, and sulfur.
  • the heterocyclyl may be attached to the main structure at any heteroatom or carbon atom.
  • a heterocyclyl group can be a monocyclic, bicyclic, tricyclic, tetracyclic, or other multicyclic ring system, wherein the multicyclic ring systems can be a fused, bridged or spiro ring system.
  • Heterocyclyl multicyclic ring systems can include one or more heteroatoms in one or more rings.
  • a heterocyclyl group can be saturated or partially unsaturated.
  • Saturated heterocyclyl groups can be termed “heterocycloalkyl” .
  • Partially unsaturated heterocyclyl groups can be termed “heterocycloalkenyl” if the heterocyclyl contains at least one double bond, or “heterocycloalkynyl” if the heterocyclyl contains at least one triple bond.
  • the heterocyclyl has, for example, 3 to 18 ring atoms (3-to 18-membered heterocyclyl) , 4 to 18 ring atoms (4-to 18-membered heterocyclyl) , 3 to 12 ring atoms (3-to 12-membered heterocyclyl) , 5 to 18 ring atoms (5-to 18-membered heterocyclyl) , 4 to 8 ring atoms (4-to 8-membered heterocyclyl) , or 5 to 8 ring atoms (5-to 8-membered heterocyclyl) .
  • heterocyclyl groups include, but are not limited to, imidazolidinyl, oxazolidinyl, thiazolidinyl, pyrazolidinyl, isoxazolidinyl, isothiazolidinyl, morpholinyl, pyrrolidinyl, tetrahydrofuryl, and piperidinyl. Unless otherwise specified, a heterocyclyl group is optionally substituted.
  • a numerical range such as “3 to 18” refers to each integer in the given range; e.g., a heterocyclyl with “3 to 18 ring atoms” means that the heterocyclyl group can consist of 3 ring atoms, 4 ring atoms, 5 ring atoms, 6 ring atoms, 7 ring atoms, 8 ring atoms, 9 ring atoms, 10 ring atoms, etc., up to and including 18 ring atoms.
  • a C 1 -C 6 alkyl means that the alkyl group can consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, and 6 carbon atoms.
  • a “cycloalkylalkyl” group is a radical of the formula: -alkyl-cycloalkyl, wherein alkyl and cycloalkyl are defined above. Substituted cycloalkylalkyl groups may be substituted at the alkyl, the cycloalkyl, or both the alkyl and the cycloalkyl portions of the group.
  • Representative cycloalkylalkyl groups include but are not limited to cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cyclopropylethyl, cyclobutylethyl, cyclopentylethyl, cyclohexylethyl, cyclopentylpropyl, cyclohexylpropyl and the like.
  • an “aralkyl” group is a radical of the formula: -alkyl-aryl, wherein alkyl and aryl are defined above. Substituted aralkyl groups may be substituted at the alkyl, the aryl, or both the alkyl and the aryl portions of the group.
  • Representative aralkyl groups include but are not limited to benzyl and phenethyl groups and aralkyl groups wherein the aryl group is fused to a cycloalkyl group such as indan-4-yl ethyl.
  • cycloalkylalkyl As used herein and unless otherwise specified, other similar composite terms mirror the above description for “cycloalkylalkyl” and “aralkyl” .
  • a “heterocyclylalkyl” group is a radical of the formula: -alkyl-heterocyclyl, wherein alkyl and heterocyclyl are defined above.
  • a “heteroarylalkyl” group is a radical of the formula: -alkyl-heteroaryl, wherein alkyl and heteroaryl are defined above.
  • a “heterocycloalkylalkyl” group is a radical of the formula: -alkyl-heterocycloalkyl, wherein alkyl and heterocycloalkyl are defined above.
  • halogen refers to fluorine, chlorine, bromine, and/or iodine.
  • haloalkyl, ” “haloalkenyl, ” “haloalkynyl, ” and “haloalkoxy” refer to alkyl, alkenyl, alkynyl, and alkoxy structures that are substituted with one or more halo groups or with combinations thereof.
  • alkoxy refers to -O- (alkyl) , wherein alkyl is defined above.
  • aryloxy refers to -O- (aryl) , wherein aryl is defined above.
  • alkyl sulfonyl refers to —SO 2 -alkyl, wherein alkyl is defined above.
  • arylalkyloxy refers to -O- (alkyl) - (aryl) , wherein alkyl and aryl are defined above.
  • cycloalkyloxy refers to -O- (cycloalkyl) , wherein cycloalkyl is defined above.
  • cycloalkylalkyloxy refers to -O- (alkyl) - (cycloalkyl) , wherein cycloalkyl and alkyl are defined above.
  • acyl refers to –C (O) -R a , wherein R a can be, but is not limited to, hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, aryl, cycloalkyl, heteroaryl, heterocyclyl, each of which is defined above. In certain embodiments, R a may be unsubstituted or substituted with one or more substituents.
  • acyloxy refers to –O-C (O) -R a , wherein R a can be, but is not limited to, hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, aryl, cycloalkyl, heteroaryl, heterocyclyl, each of which is defined above. In certain embodiments, R a may be unsubstituted or substituted with one or more substituents.
  • amino refers to –N (R # ) (R # ) , wherein each R # independently can be, but is not limited to, hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, aryl, cycloalkyl, heteroaryl, heterocyclyl, each of which is defined above.
  • R # independently can be, but is not limited to, hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, aryl, cycloalkyl, heteroaryl, heterocyclyl, each of which is defined above.
  • R # When a -N (R # ) (R # ) group has two R # other than hydrogen, they can be combined with the nitrogen atom to form a ring.
  • the ring is a 3-, 4-, 5-, 6-, 7-, or 8-membered ring.
  • one or more ring atoms are heteroatoms independently selected from O, S, or N.
  • amino also includes N-oxide (–N + (R # ) (R # ) O - ) .
  • each R # or the ring formed by -N (R # ) (R # ) independently may be unsubstituted or substituted with one or more substituents.
  • amide or “amido” refers to –C (O) N (R # ) 2 or –NR # C (O) R # , wherein each R # independently can be, but is not limited to, hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, aryl, cycloalkyl, heteroaryl, heterocyclyl, each of which is defined above.
  • R # independently can be, but is not limited to, hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, aryl, cycloalkyl, heteroaryl, heterocyclyl, each of which is defined above.
  • R # independently can be, but is not limited to, hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, aryl, cycloalkyl, heteroaryl, heterocyclyl, each of which is defined above.
  • R # independently can be, but is not limited to, hydrogen, alkyl, heteroalkyl, alken
  • one or more ring atoms are heteroatoms independently selected from O, S, or N.
  • each R # or the ring formed by -N (R # ) (R # ) independently may be unsubstituted or substituted with one or more substituents.
  • aminoalkyl refers to - (alkyl) - (amino) , wherein alkyl and amino are defined above.
  • aminoalkoxy refers to -O- (alkyl) - (amino) , wherein alkyl and amino are defined above.
  • alkylamino refers to -NH (alkyl) or -N (alkyl) (alkyl) , wherein alkyl is defined above.
  • alkylamino groups include, but are not limited to, -NHCH 3 , -NHCH 2 CH 3 , -NH (CH 2 ) 2 CH 3 , -NH (CH 2 ) 3 CH 3 , -NH (CH 2 ) 4 CH 3 , -NH (CH 2 ) 5 CH 3 , -N (CH 3 ) 2 , -N (CH 2 CH 3 ) 2 , -N ( (CH 2 ) 2 CH 3 ) 2 , -N (CH 3 ) (CH 2 CH 3 ) , and the like.
  • arylamino refers to -NH (aryl) or -N (aryl) (aryl) , wherein aryl is defined above.
  • similar composite terms such as “arylalkylamino” and “cycloalkylamino” mirrors the descriptions above for “alkylamino” and “arylamino” .
  • sulfanyl As used herein, and unless otherwise specified, the term “sulfanyl” , “sulfide” , or “thio” refers to -S-R a , wherein R a can be, but is not limited to, alkyl, heteroalkyl, alkenyl, alkynyl, aryl, cycloalkyl, heteroaryl, heterocyclyl, each of which is defined above. In certain embodiments, R a may be unsubstituted or substituted with one or more substituents.
  • sulfoxide refers to –S (O) -R a , wherein R a can be, but is not limited to, alkyl, heteroalkyl, alkenyl, alkynyl, aryl, cycloalkyl, heteroaryl, heterocyclyl, each of which is defined above. In certain embodiments, R a may be unsubstituted or substituted with one or more substituents.
  • sulfonyl or “sulfone” refers to –S (O) 2 -R a , wherein R a can be, but is not limited to, alkyl, heteroalkyl, alkenyl, alkynyl, aryl, cycloalkyl, heteroaryl, heterocyclyl, each of which is defined above. In certain embodiments, R a may be unsubstituted or substituted with one or more substituents.
  • R # independently can be, but is not limited to, hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, aryl, cycloalkyl, heteroaryl, heterocyclyl, each of which is defined above.
  • R # independently can be, but is not limited to, hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, aryl, cycloalkyl, heteroaryl, heterocyclyl, each of which is defined above.
  • the ring is a 3-, 4-, 5-, 6-, 7-, or 8-membered ring.
  • one or more ring atoms are heteroatoms independently selected from O, S, or N.
  • each R # or the ring formed by -N (R # ) (R # ) independently may be unsubstituted or substituted with one or more substituents.
  • optionally substituted means that the subsequently described event of circumstances may or may not occur, and that the description includes instances where said event or circumstance occurs and instances in which it does not.
  • optionally substituted alkyl means that the alkyl radical may or may not be substituted and that the description includes both substituted alkyl radicals and alkyl radicals having no substitution.
  • substituents include, but are not limited to, those found in the exemplary compounds and embodiments provided herein, as well as halogen (chloro, iodo, bromo, or fluoro) ; alkyl; alkenyl; alkynyl; hydroxyl; alkoxy; alkoxyalkyl; amino; alkylamino; carboxy; nitro; cyano; thiol; thioether; imine; imide; amidine; guanidine; enamine; aminocarbonyl; acylamino; phosphonate; phosphine; thiocarbonyl; sulfinyl; sulfone; sulfonamide; ketone; aldehyde; ester; urea; urethane; oxime; hydroxyl amine; alkoxyamine
  • the term “isomer” refers to different compounds that have the same molecular formula.
  • “Stereoisomers” are isomers that differ only in the way the atoms are arranged in space.
  • “Atropisomers” are stereoisomers from hindered rotation about single bonds.
  • “Enantiomers” are a pair of stereoisomers that are non-superimposable mirror images of each other. A mixture of a pair of enantiomers in any proportion can be known as a “racemic” mixture.
  • “Diastereoisomers” are stereoisomers that have at least two asymmetric atoms, but which are not mirror-images of each other.
  • the absolute stereochemistry can be specified according to the Cahn-Ingold-Prelog R-Ssystem.
  • the stereochemistry at each chiral carbon can be specified by either R or S.
  • Resolved compounds whose absolute configuration is unknown can be designated (+) or (-) depending on the direction (dextro-or levorotatory) which they rotate plane polarized light at the wavelength of the sodium D line.
  • the sign of optical rotation, (+) and (-) is not related to the absolute configuration of the molecule, R and S.
  • Certain compounds described herein contain one or more asymmetric centers and can thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that can be defined, in terms of absolute stereochemistry at each asymmetric atom, as (R) -or (S) -.
  • the present chemical entities, pharmaceutical compositions and methods are meant to include all such possible isomers, including racemic mixtures, optically substantially pure forms and intermediate mixtures.
  • Optically active (R) -and (S) -isomers can be prepared, for example, using chiral synthons or chiral reagents, or resolved using conventional techniques.
  • enantiomeric purity or “enantiomer purity” refers to a qualitative or quantitative measure of a purified enantiomer.
  • the enantiomeric purity of compounds described herein may be described in terms of enantiomeric excess (ee) , which indicates the degree to which a sample contains one enantiomer in greater amounts than the other.
  • ee enantiomeric excess
  • a racemic mixture has an ee of 0%, while a single completely pure enantiomer has an ee of 100%.
  • Examples of the enantiomeric purity include an ee of at least about 10%, at least about 12%, at least about 14%, at least about 16%, at least about 18%, at least about 20%, at least about 22%, at least about 24%, at least about 26%, at least about 28%, at least about 30%, at least about 32%, at least about 34%, at least about 36%, at least about 38%, at least about 40%, at least about 42%, at least about 44%, at least about 46%, at least about 48%, at least about 50%, at least about 52%, at least about 54%, at least about 56%, at least about 58%, at least about 60%, at least about 62%, at least about 64%, at least about 66%, at least about 68%, at least about 70%, at least about 72%, at least about 74%, at least about 76%, at least about 78%, at least about 80%, at least about 81%, at least about 82%, at least about 83%, at least about 84%, at least about 85%,
  • substantially purified enantiomer refers to a compound wherein one enantiomer has been enriched over the other.
  • the other enantiomer represents less than about 20%, less than about 10%, less than about 5%, or less than about 2%of the enantiomer.
  • a substantially purified enantiomer has an enantiomeric excess of S enantiomer of at least about 80%, at least about 81%, at least about 82%, at least about 83%, at least about 84%, at least about 85%, at least about 86%, at least about 87%, at least about 88%, at least about 89%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, at least about 99.5%or at least about 99.9%.
  • a substantially purified enantiomer has an enantiomeric excess of R enantiomer of at least about 80%, at least about 81%, at least about 82%, at least about 83%, at least about 84%, at least about 85%, at least about 86%, at least about 87%, at least about 88%, at least about 89%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, at least about 99.5%or at least about 99.9%.
  • Steps can also include E and Z isomers, or a mixture thereof, and cis and trans isomers or a mixture thereof.
  • a compound described herein is isolated as either the E or Z isomer.
  • a compound described herein is a mixture of the E and Z isomers.
  • tautomer or “tautomeric form” refers to isomeric forms of a compound that are in equilibrium with each other.
  • a tautomer is formed by the migration of a proton from one atom of a molecule to another atom of the same molecule (known as proton tautomers, such as keto-enol tautomerization or imine-enamine tautomerization) .
  • proton tautomers such as keto-enol tautomerization or imine-enamine tautomerization
  • concentrations of the isomeric forms will depend on the environment the compound is found in and may be different depending upon, for example, whether the compound is a solid or is in an organic or aqueous solution.
  • pyrazoles may exhibit the following isomeric forms, which are referred to as tautomers of each other:
  • the term “pharmaceutically acceptable salt” includes both acid and base addition salts.
  • Examples of pharmaceutically acceptable acid addition salts include, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, and organic acids such as, but not limited to, acetic acid, 2, 2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, camphoric acid, camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane-1, 2-disulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, gluconic acid, glu
  • Examples of pharmaceutically acceptable base addition salt include, but are not limited to, salts prepared from addition of an inorganic base or an organic base to a free acid compound.
  • Salts derived from inorganic bases include, but are not limited to, the sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like.
  • the inorganic salts are the ammonium, sodium, potassium, calcium, and magnesium salts.
  • Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, diethanolamine, ethanolamine, deanol, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, benethamine, benzathine, ethylenediamine, glucosamine, methylglucamine, theobromine, triethanolamine, tromethamine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins and the like.
  • the organic bases are isopropyl
  • the term “subject” refers to an animal, including, but not limited to, a primate (e.g., human) , cow, sheep, goat, horse, dog, cat, rabbit, rat, or mouse.
  • a primate e.g., human
  • the terms “subject” and “patient” are used interchangeably herein in reference, for example, to a mammalian subject, such as a human subject.
  • the subject is a mammal.
  • the subject is a human.
  • the terms “treat, ” “treating, ” and “treatment” refer to the eradication or amelioration of a disease or disorder, or of one or more symptoms associated with the disease or disorder. In general, treatment occurs after the onset of the disease or disorder. In certain embodiments, the terms refer to minimizing the spread or worsening of the disease or disorder resulting from the administration of one or more prophylactic or therapeutic agents to a subject with such a disease or disorder.
  • prevention refers to the prevention of the onset, recurrence or spread of a disease or disorder, or of one or more symptoms thereof. In general, prevention occurs prior to the onset of the disease or disorder.
  • the terms “manage, ” “managing, ” and “management” refer to preventing or slowing the progression, spread or worsening of a disease or disorder, or of one or more symptoms thereof. Sometimes, the beneficial effects that a subject derives from a prophylactic or therapeutic agent do not result in a cure of the disease or disorder.
  • the term “therapeutically effective amount” are meant to include the amount of a compound that, when administered, is sufficient to prevent development of, or alleviate to some extent, one or more of the symptoms of the disorder, disease, or condition being treated.
  • therapeutically effective amount also refers to the amount of a compound that is sufficient to elicit the biological or medical response of a cell, tissue, system, animal, or human, which is being sought by a researcher, veterinarian, medical doctor, or clinician.
  • IC 50 refers an amount, concentration, or dosage of a compound that is required for 50%inhibition of a maximal response in an assay that measures such response.
  • PI3K ⁇ -associated disease or disorder refers to diseases or disorders associated with or having a dysregulation of a PIK3CA gene, a PI3K ⁇ 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 PI3K ⁇ protein, or the expression or activity or level of any of the same described herein) .
  • Non-limiting examples of a PI3K ⁇ -associated disease or disorder include, for example, PIK3CA-related overgrowth syndromes (PROS) , brain disorders (e.g., as macrocephaly-capillary malformation (MCAP) and hemimegalencephaly) , congenital lipomatous (e.g., overgrowth of vascular malformations) , epidermal nevi and skeletal/spinal anomalies (e.g., CLOVES syndrome) and fibroadipose hyperplasia (FH) , or cancer (e.g., PI3K ⁇ -associated cancer) .
  • PROS PIK3CA-related overgrowth syndromes
  • brain disorders e.g., as macrocephaly-capillary malformation (MCAP) and hemimegalencephaly
  • congenital lipomatous e.g., overgrowth of vascular malformations
  • epidermal nevi and skeletal/spinal anomalies e.g., CLOVE
  • PI3K ⁇ -associated cancer refers to cancers associated with or having a dysregulation of a PIK3CA gene, a PI3K ⁇ protein, or expression or activity, or level of any of the same.
  • the term “dysregulation of a PIK3CA gene, a PI3K ⁇ 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 PI3K ⁇ that includes a deletion of at least one amino acid as compared to a wild type PI3K ⁇ , a mutation in a PIK3CA gene that results in the expression of PI3K ⁇ with one or more point mutations as compared to a wild type PI3K ⁇ , a mutation in a PIK3CA gene that results in the expression of PI3K ⁇ with at least one inserted amino acid as compared to a wild type PI3K ⁇ , a gene duplication that results in an increased level of PI3K ⁇ in a cell, or a mutation in a regulatory sequence (e.g., a promoter and/or enhancer) that results in an increased level
  • a regulatory sequence e.g
  • a dysregulation of a PIK3CA gene, a PI3K ⁇ protein, or expression or activity, or level of any of the same is a mutation in PIK3CA gene that encodes a PI3K ⁇ 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 PI3K ⁇ point mutations/substitutions/insertions/deletions are described in Table 2.
  • activating mutation in reference to PI3K ⁇ describes a mutation in a PIK3CA gene that results in the expression of PI3K ⁇ that has an increased kinase activity, e.g., as compared to a wild type PI3K ⁇ , e.g., when assayed under identical conditions.
  • an activating mutation is a mutation in a PIK3CA gene that results in the expression of a PI3K ⁇ that has one or more (e.g., two, three, four, five, six, seven, eight, nine, or ten) amino acid substitutions (e.g., any combination of any of the amino acid substitutions described herein) that has increased kinase activity, e.g., as compared to a wild type a PI3K ⁇ , e.g., when assayed under identical conditions.
  • one or more e.g., two, three, four, five, six, seven, eight, nine, or ten amino acid substitutions (e.g., any combination of any of the amino acid substitutions described herein) that has increased kinase activity, e.g., as compared to a wild type a PI3K ⁇ , e.g., when assayed under identical conditions.
  • an activating mutation is a mutation in a PIK3CA that results in the expression of a PI3K ⁇ that has one or more (e.g., two, three, four, five, six, seven, eight, nine, or ten) amino acids deleted, e.g., as compared to a wild type PI3K ⁇ , e.g., when assayed under identical conditions.
  • an activating mutation is a mutation in a PIK3CA gene that results in the expression of a PI3K ⁇ that has at least one (e.g., at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 12, at least 14, at least 16, at least 18, or at least 20) amino acid inserted as compared to a wild type PI3K ⁇ , e.g., the exemplary wild type PI3K ⁇ described herein, e.g., when assayed under identical conditions.
  • at least one e.g., at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 12, at least 14, at least 16, at least 18, or at least 20 amino acid inserted as compared to a wild type PI3K ⁇ , e.g., the exemplary wild type PI3K ⁇ described herein, e.g., when assayed under identical conditions.
  • wild type refers to a nucleic acid (e.g., a PIK3CA gene or a PI3K ⁇ mRNA) or protein (e.g., a PI3K ⁇ ) sequence that is typically found in a subject that does not have a disease or disorder related to the reference nucleic acid or protein.
  • a nucleic acid e.g., a PIK3CA gene or a PI3K ⁇ mRNA
  • protein e.g., a PI3K ⁇ sequence that is typically found in a subject that does not have a disease or disorder related to the reference nucleic acid or protein.
  • wild type PI3K ⁇ or “wild-type PI3K ⁇ ” describes a normal PI3K ⁇ nucleic acid (e.g., PIK3CA or PI3K ⁇ mRNA) or protein that is found in a subject that does not have a PI3K ⁇ -associated disease, e.g., a PI3K ⁇ -associated cancer (and optionally also does not have an increased risk of developing a PI3K ⁇ -associated disease and/or is not suspected of having a PI3K ⁇ -associated disease) , or is found in a cell or tissue from a subject that does not have a PI3K ⁇ -associated disease, e.g., a PI3K ⁇ -associated cancer (and optionally also does not have an increased risk of developing a PI3K ⁇ -associated disease and/or is not suspected of having a PI3K ⁇ -associated disease) .
  • a PI3K ⁇ -associated disease e.g., a PI3K ⁇ -associated cancer
  • the term “pharmaceutically acceptable carrier, ” “pharmaceutically acceptable excipient, ” “physiologically acceptable carrier, ” or “physiologically acceptable excipient” refers to a pharmaceutically-acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material.
  • each component is “pharmaceutically acceptable” in the sense of being compatible with the other ingredients of a pharmaceutical formulation, and suitable for use in contact with the tissue or organ of humans and animals without excessive toxicity, irritation, allergic response, immunogenicity, or other problems or complications, commensurate with a reasonable benefit/risk ratio.
  • structures depicted herein are also meant to include compounds which differ only in the presence of one or more isotopically enriched atoms.
  • isotopes that can be incorporated into compounds provided herein include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as, e.g., 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 17 O, 31 P, 32 P, 35 S, 18 F, and 36 Cl, respectively.
  • provided herein are compounds having the present structures except for the replacement or enrichment of a hydrogen by deuterium or tritium at one or more atoms in the molecule, or the replacement or enrichment of a carbon by 13 C or 14 C at one or more atoms in the molecule.
  • isotopically labeled compounds having one or more hydrogen atoms replaced by or enriched by deuterium.
  • isotopically labeled compounds having one or more hydrogen atoms replaced by or enriched by tritium In one embodiment, provided herein are isotopically labeled compounds having one or more carbon atoms replaced or enriched by 13 C. In one embodiment, provided herein are isotopically labeled compounds having one or more carbon atoms replaced or enriched by 14 C.
  • the term “about” or “approximately” means an acceptable error for a particular value as determined by one of ordinary skill in the art, which depends in part on how the value is measured or determined. In certain embodiments, the term “about” or “approximately” means within 1, 2, 3, or 4 standard deviations. In certain embodiments, the term “about” or “approximately” means within 50%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, or 0.05%of a given value or range.
  • multicyclic compounds as PI3K ⁇ inhibitors.
  • multicyclic compounds comprising a benzofuran core and a urea moiety as PI3K ⁇ inhibitors.
  • X 1 is CR a1 or N
  • X 2 is NR a2 , O, or S;
  • R a1 is hydrogen, C 1 -C 6 alkyl, or C 1 -C 6 alkoxy, and wherein the alkyl and alkoxy are optionally substituted;
  • R a2 is hydrogen or C 1 -C 6 alkyl, and wherein the alkyl is optionally substituted;
  • R a3 , R a4 , R a5 , and R a6 are each independently hydrogen, halogen, nitro, cyano, hydroxyl, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, 5 to 10-membered heteroaryl, or 3 to 8-membered heterocyclyl, and wherein the alkyl, alkoxy, cycloalkyl, aryl, heteroaryl, and heterocyclyl are optionally substituted;
  • R is C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 8 cycloalkyl, or 3 to 8-membered heterocyclyl, and wherein the alkyl, alkoxy, cycloalkyl, and heterocyclyl are optionally substituted;
  • Ring A is C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, 5 to 10-membered heteroaryl, or 3 to 8-membered heterocyclyl, and wherein the cycloalkyl, aryl, heteroaryl, and heterocyclyl are optionally substituted;
  • Ring B is C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, 5 to 12-membered heteroaryl, or 3 to 8-membered heterocyclyl, and wherein the cycloalkyl, aryl, heteroaryl, and heterocyclyl are optionally substituted;
  • L is C 1 -C 6 alkylene or C 3 -C 8 cycloalkylene, and wherein the alkylene, and cycloalkylene are optionally substituted;
  • R b is hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, 5 to 12-membered heteroaryl, or 3 to 8-membered heterocyclyl, and wherein the alkyl, alkenyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl are optionally substituted; and
  • R c is C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, 5 to 12-membered heteroaryl, or 3 to 8-membered heterocyclyl, and wherein the alkyl, alkenyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl are optionally substituted.
  • R 1 is optionally substituted 3 to 12-membered heterocyclyl.
  • X 1 is N.
  • X 1 is CR a1 . In one embodiment, X 1 is CH. In one embodiment, X 1 is C- (C 1 -C 6 alkyl) . In one embodiment, X 1 is C-CH 3 . In one embodiment, X 1 is C-C 2 H 5 . In one embodiment, X 1 is C- (C 3 alkyl) . In one embodiment, X 1 is C- (C 4 alkyl) . In one embodiment, X 1 is C- (C 5 alkyl) . In one embodiment, X 1 is C- (C 6 alkyl) .
  • X 1 is C- (C 1 -C 6 alkoxy) . In one embodiment, X 1 is C-methoxy. In one embodiment, X 1 is C-ethoxy. In one embodiment, X 1 is C- (C 3 alkoxy) . In one embodiment, X 1 is C- (C 4 alkoxy) . In one embodiment, X 1 is C- (C 5 alkoxy) . In one embodiment, X 1 is C- (C 6 alkoxy) .
  • R a1 is H. In one embodiment, R a1 is C 1 -C 6 alkyl. In one embodiment, R a1 is C 1 -C 3 alkyl. In one embodiment, R a1 is methyl. In one embodiment, R a1 is ethyl. In one embodiment, R a1 is C 3 alkyl. In one embodiment, R a1 is C 4 alkyl. In one embodiment, R a1 is C 5 alkyl. In one embodiment, R a1 is C 6 alkyl. In one embodiment, the alkyl is unsubstituted. In one embodiment, the alkyl is substituted. In one embodiment, the alkyl is substituted with one or more halogen, hydroxyl, or C 1 -C 6 alkoxy.
  • R a1 is C 1 -C 6 alkoxy. In one embodiment, R a1 is C 1 -C 3 alkoxy. In one embodiment, R a1 is methoxy. In one embodiment, R a1 is ethoxy. In one embodiment, R a1 is C 3 alkoxy. In one embodiment, R a1 is C 4 alkoxy. In one embodiment, R a1 is C 5 alkoxy. In one embodiment, R a1 is C 6 alkoxy. In one embodiment, the alkoxy is unsubstituted. In one embodiment, the alkoxy is substituted. In one embodiment, the alkoxy is substituted with one or more halogen, hydroxyl, or C 1 -C 6 alkyl.
  • X 2 is O. In one embodiment, X 2 is S.
  • X 2 is NR a2 . In one embodiment, X 2 is N- (C 1 -C 6 alkyl) . In one embodiment, X 2 is NH. In one embodiment, X 2 is N-CH 3 . In one embodiment, X 2 is N-C 2 H 5 . In one embodiment, X 2 is N- (n-propyl) or N- (iso-propyl) . In one embodiment, X 2 is N- (n-butyl) , N- (iso-butyl) , or N- (tert-butyl) . In one embodiment, X 2 is N- (C 5 alkyl) . In one embodiment, X 1 is N- (C 6 alkyl) .
  • R a2 is H. In one embodiment, R a2 is C 1 -C 6 alkyl. In one embodiment, R a2 is C 1 -C 3 alkyl. In one embodiment, R a2 is methyl. In one embodiment, R a2 is ethyl. In one embodiment, R a2 is C 3 alkyl. In one embodiment, R a2 is C 4 alkyl. In one embodiment, R a2 is C 5 alkyl. In one embodiment, R a2 is C 6 alkyl. In one embodiment, the alkyl is unsubstituted. In one embodiment, the alkyl is substituted. In one embodiment, the alkyl is substituted with one or more halogen, hydroxyl, or C 1 -C 6 alkoxy.
  • R a3 is hydrogen. In one embodiment, R a3 is halogen (F, Cl, Br, or I) . In one embodiment, R a3 is fluorine. In one embodiment, R a3 is nitro. In one embodiment, R a3 is cyano. In one embodiment, R a3 is C 1 -C 6 alkyl. In one embodiment, R a3 is C 1 -C 3 alkyl. In one embodiment, R a3 is methyl. In one embodiment, R a3 is ethyl. In one embodiment, R a3 is C 3 alkyl. In one embodiment, R a3 is C 4 alkyl. In one embodiment, R a3 is C 5 alkyl. In one embodiment, R a3 is C 6 alkyl.
  • R a3 is C 1 -C 6 alkoxy. In one embodiment, R a3 is C 1 -C 3 alkoxy. In one embodiment, R a3 is methoxy. In one embodiment, R a3 is ethoxy. In one embodiment, R a3 is C 3 alkoxy. In one embodiment, R a3 is C 4 alkoxy. In one embodiment, R a3 is C 5 alkoxy. In one embodiment, R a3 is C 6 alkoxy.
  • R a3 is C 3 -C 8 cycloalkyl. In one embodiment, R a3 is C 3 -C 6 cycloalkyl. In one embodiment, R a3 is cyclopropyl. In one embodiment, R a3 is cyclobutyl. In one embodiment, R a3 is cyclopentyl. In one embodiment, R a3 is cyclohexyl.
  • R a3 is C 6 -C 10 aryl. In one embodiment, R a3 is C 6 -C 8 aryl. In one embodiment, R a3 is phenyl. In one embodiment, R a3 is naphthyl.
  • R a3 is 5 to 10-membered heteroaryl. In one embodiment, R a3 is 5 to 8-membered heteroaryl. In one embodiment, R a3 is 5-membered heteroaryl. In one embodiment, R a3 is 6-membered heteroaryl. In one embodiment, R a3 is a 5 or 6-membered heteroaryl containing one or more nitrogen, oxygen, or sulfur ring atoms.
  • R a3 is 3 to 8-membered heterocyclyl. In one embodiment, R a3 is 3 to 6-membered heterocyclyl. In one embodiment, R a3 is a 3-membered heterocyclyl. In one embodiment, R a3 is a 4-membered heterocyclyl. In one embodiment, R a3 is a 5-membered heterocyclyl. In one embodiment, R a3 is a 6-membered heterocyclyl. In one embodiment, R a3 is a 3-to 6-membered heterocyclyl containing one or more nitrogen, oxygen, or sulfur ring atoms.
  • R a3 is unsubstituted. In one embodiment, R a3 is substituted. In one embodiment, R a3 is substituted with one or more halogen, hydroxyl, or C 1 -C 6 alkyl.
  • R a4 is hydrogen. In one embodiment, R a4 is halogen (F, Cl, Br, or I) . In one embodiment, R a4 is nitro. In one embodiment, R a4 is cyano. In one embodiment, R a4 is C 1 -C 6 alkyl. In one embodiment, R a4 is C 1 -C 3 alkyl. In one embodiment, R a4 is methyl. In one embodiment, R a4 is ethyl. In one embodiment, R a4 is C 3 alkyl. In one embodiment, R a4 is C 4 alkyl. In one embodiment, R a4 is C 5 alkyl. In one embodiment, R a4 is C 6 alkyl.
  • R a4 is C 1 -C 6 alkoxy. In one embodiment, R a4 is C 1 -C 3 alkoxy. In one embodiment, R a4 is methoxy. In one embodiment, R a4 is ethoxy. In one embodiment, R a4 is C 3 alkoxy. In one embodiment, R a4 is C 4 alkoxy. In one embodiment, R a4 is C 5 alkoxy. In one embodiment, R a4 is C 6 alkoxy.
  • R a4 is C 3 -C 8 cycloalkyl. In one embodiment, R a4 is C 3 -C 6 cycloalkyl. In one embodiment, R a4 is cyclopropyl. In one embodiment, R a4 is cyclobutyl. In one embodiment, R a4 is cyclopentyl. In one embodiment, R a4 is cyclohexyl.
  • R a4 is C 6 -C 10 aryl. In one embodiment, R a4 is C 6 -C 8 aryl. In one embodiment, R a4 is phenyl. In one embodiment, R a4 is naphthyl.
  • R a4 is 5 to 10-membered heteroaryl. In one embodiment, R a4 is 5 to 8-membered heteroaryl. In one embodiment, R a4 is 5-membered heteroaryl. In one embodiment, R a4 is 6-membered heteroaryl. In one embodiment, R a4 is a 5 or 6-membered heteroaryl containing one or more nitrogen, oxygen, or sulfur ring atoms.
  • R a4 is 3 to 8-membered heterocyclyl. In one embodiment, R a4 is 3 to 6-membered heterocyclyl. In one embodiment, R a4 is a 3-membered heterocyclyl. In one embodiment, R a4 is a 4-membered heterocyclyl. In one embodiment, R a4 is a 5-membered heterocyclyl. In one embodiment, R a4 is a 6-membered heterocyclyl. In one embodiment, R a4 is a 3-to 6-membered heterocyclyl containing one or more nitrogen, oxygen, or sulfur ring atoms.
  • R a4 is unsubstituted. In one embodiment, R a4 is substituted. In one embodiment, R a4 is substituted with one or more halogen, hydroxyl, or C 1 -C 6 alkyl.
  • R a5 is hydrogen. In one embodiment, R a5 is halogen (F, Cl, Br, or I) . In one embodiment, R a5 is fluorine. In one embodiment, R a5 is nitro. In one embodiment, R a5 is cyano. In one embodiment, R a5 is C 1 -C 6 alkyl. In one embodiment, R a5 is C 1 -C 3 alkyl. In one embodiment, R a5 is methyl. In one embodiment, R a5 is ethyl. In one embodiment, R a5 is C 3 alkyl. In one embodiment, R a5 is C 4 alkyl. In one embodiment, R a5 is C 5 alkyl. In one embodiment, R a5 is C 6 alkyl.
  • R a5 is C 1 -C 6 alkoxy. In one embodiment, R a5 is C 1 -C 3 alkoxy. In one embodiment, R a5 is methoxy. In one embodiment, R a5 is ethoxy. In one embodiment, R a5 is C 3 alkoxy. In one embodiment, R a5 is C 4 alkoxy. In one embodiment, R a5 is C 5 alkoxy. In one embodiment, R a5 is C 6 alkoxy.
  • R a5 is C 3 -C 8 cycloalkyl. In one embodiment, R a5 is C 3 -C 6 cycloalkyl. In one embodiment, R a5 is cyclopropyl. In one embodiment, R a5 is cyclobutyl. In one embodiment, R a5 is cyclopentyl. In one embodiment, R a5 is cyclohexyl.
  • R a5 is C 6 -C 10 aryl. In one embodiment, R a5 is C 6 -C 8 aryl. In one embodiment, R a5 is phenyl. In one embodiment, R a5 is naphthyl.
  • R a5 is 5 to 10-membered heteroaryl. In one embodiment, R a5 is 5 to 8-membered heteroaryl. In one embodiment, R a5 is 5-membered heteroaryl. In one embodiment, R a5 is 6-membered heteroaryl. In one embodiment, R a5 is a 5 or 6-membered heteroaryl containing one or more nitrogen, oxygen, or sulfur ring atoms.
  • R a5 is 3 to 8-membered heterocyclyl. In one embodiment, R a5 is 3 to 6-membered heterocyclyl. In one embodiment, R a5 is a 3-membered heterocyclyl. In one embodiment, R a5 is a 4-membered heterocyclyl. In one embodiment, R a5 is a 5-membered heterocyclyl. In one embodiment, R a5 is a 6-membered heterocyclyl. In one embodiment, R a5 is a 3-to 6-membered heterocyclyl containing one or more nitrogen, oxygen, or sulfur ring atoms.
  • R a5 is unsubstituted. In one embodiment, R a5 is substituted. In one embodiment, R a5 is substituted with one or more halogen, hydroxyl, or C 1 -C 6 alkyl.
  • R a6 is hydrogen. In one embodiment, R a6 is halogen (F, Cl, Br, or I) . In one embodiment, R a6 is nitro. In one embodiment, R a6 is cyano. In one embodiment, R a6 is C 1 -C 6 alkyl. In one embodiment, R a6 is C 1 -C 3 alkyl. In one embodiment, R a6 is methyl. In one embodiment, R a6 is ethyl. In one embodiment, R a6 is C 3 alkyl. In one embodiment, R a6 is C 4 alkyl. In one embodiment, R a6 is C 5 alkyl. In one embodiment, R a6 is C 6 alkyl.
  • R a6 is C 1 -C 6 alkoxy. In one embodiment, R a6 is C 1 -C 3 alkoxy. In one embodiment, R a6 is methoxy. In one embodiment, R a6 is ethoxy. In one embodiment, R a6 is C 3 alkoxy. In one embodiment, R a6 is C 4 alkoxy. In one embodiment, R a6 is C 5 alkoxy. In one embodiment, R a6 is C 6 alkoxy.
  • R a6 is C 3 -C 8 cycloalkyl. In one embodiment, R a6 is C 3 -C 6 cycloalkyl. In one embodiment, R a6 is cyclopropyl. In one embodiment, R a6 is cyclobutyl. In one embodiment, R a6 is cyclopentyl. In one embodiment, R a6 is cyclohexyl.
  • R a6 is C 6 -C 10 aryl. In one embodiment, R a6 is C 6 -C 8 aryl. In one embodiment, R a6 is phenyl. In one embodiment, R a6 is naphthyl.
  • R a6 is 5 to 10-membered heteroaryl. In one embodiment, R a6 is 5 to 8-membered heteroaryl. In one embodiment, R a6 is 5-membered heteroaryl. In one embodiment, R a6 is 6-membered heteroaryl. In one embodiment, R a6 is a 5 or 6-membered heteroaryl containing one or more nitrogen, oxygen, or sulfur ring atoms.
  • R a6 is 3 to 8-membered heterocyclyl. In one embodiment, R a6 is 3 to 6-membered heterocyclyl. In one embodiment, R a6 is a 3-membered heterocyclyl. In one embodiment, R a6 is a 4-membered heterocyclyl. In one embodiment, R a6 is a 5-membered heterocyclyl. In one embodiment, R a6 is a 6-membered heterocyclyl. In one embodiment, R a6 is a 3-to 6-membered heterocyclyl containing one or more nitrogen, oxygen, or sulfur ring atoms.
  • R a6 is unsubstituted. In one embodiment, R a6 is substituted. In one embodiment, R a6 is substituted with one or more halogen, hydroxyl, or C 1 -C 6 alkyl.
  • the displayed R a3 , R a4 , R a5 , and R a6 are not hydrogen.
  • R a4 and R a6 are both hydrogen. In one embodiment, R a3 and R a5 are both halogen. In one embodiment, R a3 and R a5 are both fluorine. In one embodiment, R a3 is hydrogen and R a5 is fluorine. In one embodiment, R a4 and R a6 are both hydrogen, and R a3 and R a5 are both halogen. In one embodiment, R a3 , R a4 , and R a6 are all hydrogen, and R a5 is halogen. In one embodiment, R a3 , R a4 , and R a6 are all hydrogen, and R a5 is fluorine.
  • R a3 , R a4 , and R a6 are all hydrogen, and R a5 is C 1 -C 6 alkoxy. In one embodiment, R a3 , R a4 , and R a6 are all hydrogen, and R a5 is methoxy.
  • the compound is a compound of Formula (II) :
  • both R a3 and R a5 are not hydrogen.
  • R a3 is hydrogen, and R a5 is not hydrogen.
  • R a3 is hydrogen, and R a5 is halogen.
  • R a3 is hydrogen, and R a5 is C 1 -C 6 alkoxy.
  • Ring A is C 3 -C 8 cycloalkyl. In one embodiment, Ring A is C 3 -C 6 cycloalkyl. In one embodiment, Ring A is cyclopropyl. In one embodiment, Ring A is cyclobutyl. In one embodiment, Ring A is cyclopentyl. In one embodiment, Ring A is cyclohexyl. In one embodiment, the cycloalkyl is unsubstituted. In one embodiment, the cycloalkyl is substituted.
  • Ring A is C 6 -C 10 aryl. In one embodiment, Ring A is C 6 -C 8 aryl. In one embodiment, Ring A is phenyl. In one embodiment, the phenyl is unsubstituted. In one embodiment, the phenyl is substituted.
  • Ring A is 5 to 10-membered heteroaryl. In one embodiment, Ring A is 5 to 8-membered heteroaryl. In one embodiment, Ring A is 5-membered heteroaryl. In one embodiment, Ring A is 6-membered heteroaryl. In one embodiment, Ring A is a 5 or 6-membered heteroaryl containing one or more nitrogen, oxygen, or sulfur ring atoms. In one embodiment, Ring A is a 5-or 6-membered nitrogen-containing heteroaryl. In one embodiment, Ring A is 5 or 6-membered nitrogen-containing heteroaryl, and nitrogen is the only type of heteroatom contained in the heteroaryl. In one embodiment, the heteroaryl is unsubstituted. In one embodiment, the heteroaryl is substituted.
  • Ring A is 3 to 8-membered heterocyclyl. In one embodiment, Ring A is 3 to 6-membered heterocyclyl. In one embodiment, Ring A is 3-membered heterocyclyl. In one embodiment, Ring A is 4-membered heterocyclyl. In one embodiment, Ring A is 5-membered heterocyclyl. In one embodiment, Ring A is 6-membered heterocyclyl. In one embodiment, Ring A is 4-to 6-membered heterocyclyl containing one or more nitrogen, oxygen, or sulfur ring atoms. In one embodiment, Ring A is 4-to 6-membered nitrogen-containing heterocyclyl. In one embodiment, Ring A is 4-to 6-membered oxygen-containing heterocyclyl.
  • Ring A is 4-to 6-membered nitrogen-containing heterocyclyl, and nitrogen is the only type of heteroatom contained in the heteroaryl.
  • Ring A is 4-to 6-membered oxygen-containing heterocyclyl, and oxygen is the only type of heteroatom contained in the heteroaryl.
  • the heterocyclyl is unsubstituted. In one embodiment, the heterocyclyl is substituted.
  • Ring A is imidazolyl. In one embodiment, Ring A is pyridyl. In one embodiment, Ring A is pyrazolyl. In one embodiment, Ring A is pyridazinyl. In one embodiment, Ring A is pyrimidinyl. In one embodiment, Ring A is triazinyl. In one embodiment, Ring A is pyrazinyl. In one embodiment, Ring A is triazolyl. In one embodiment, Ring A is oxazolyl. In one embodiment, Ring A is thiazolyl. In one embodiment, Ring A is pyrrolidinyl. In one embodiment, Ring A is piperidinyl. In one embodiment, Ring A is morpholinyl. In one embodiment, Ring A is oxazolyl.
  • Ring A is wherein the attachment to the left is to the urea moiety, and the attachment to the right is to Ring B. In one embodiment, Ring A is wherein the attachment to the left is to the urea moiety, and the attachment to the right is to Ring B.
  • Ring A is unsubstituted. In one embodiment, Ring A is substituted. In one embodiment, Ring A is substituted. In one embodiment, Ring A is substituted with one or more halogen, nitro, cyano, hydroxyl, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl. In one embodiment, Ring A is substituted with one or more halogen, hydroxyl, nitro, cyano, C 1 -C 6 alkyl, or C 1 -C 6 alkoxy.
  • Ring B is C 3 -C 8 cycloalkyl. In one embodiment, Ring B is C 3 -C 6 cycloalkyl. In one embodiment, Ring B is cyclopropyl. In one embodiment, Ring B is cyclobutyl. In one embodiment, Ring B is cyclopentyl. In one embodiment, Ring B is cyclohexyl. In one embodiment, the cycloalkyl is unsubstituted. In one embodiment, the cycloalkyl is substituted.
  • Ring B is C 6 -C 10 aryl. In one embodiment, Ring B is C 6 -C 8 aryl. In one embodiment, Ring B is phenyl. In one embodiment, the phenyl is unsubstituted. In one embodiment, the phenyl is substituted.
  • Ring B is 5 to 10-membered heteroaryl. In one embodiment, Ring B is 5 to 8-membered heteroaryl. In one embodiment, Ring B is 5-membered heteroaryl. In one embodiment, Ring B is 6-membered heteroaryl. In one embodiment, Ring B is a 5 or 6-membered heteroaryl containing one or more nitrogen, oxygen, or sulfur ring atoms. In one embodiment, Ring B is a 5-or 6-membered nitrogen-containing heteroaryl. In one embodiment, Ring B is 5 or 6-membered nitrogen-containing heteroaryl, and nitrogen is the only type of heteroatom contained in the heteroaryl. In one embodiment, the heteroaryl is unsubstituted. In one embodiment, the heteroaryl is substituted.
  • Ring B is 3 to 8-membered heterocyclyl. In one embodiment, Ring B is 4 to 6-membered heterocyclyl. In one embodiment, Ring B is 3-membered heterocyclyl. In one embodiment, Ring B is 4-membered heterocyclyl. In one embodiment, Ring B is 5-membered heterocyclyl. In one embodiment, Ring B is 6-membered heterocyclyl. In one embodiment, Ring B is 3-to 8-membered heterocyclyl containing one or more nitrogen, oxygen, or sulfur ring atoms. In one embodiment, Ring B is a nitrogen-containing 3 to 8-membered heterocyclyl. In one embodiment, Ring B is 4 to 6-membered nitrogen-containing heterocyclyl.
  • Ring B is 4 to 6-membered oxygen-containing heterocyclyl. In one embodiment, Ring B is 4 to 6-membered nitrogen-containing heterocyclyl, and nitrogen is the only type of heteroatom contained in the heteroaryl. In one embodiment, Ring B is 4 to 6-membered oxygen-containing heterocyclyl, and oxygen is the only type of heteroatom contained in the heteroaryl. In one embodiment, the heterocyclyl is unsubstituted. In one embodiment, the heterocyclyl is substituted.
  • Ring B is azetidinyl. In one embodiment, Ring B is pyrrolidinyl. In one embodiment, Ring B is piperidinyl. In one embodiment, Ring B is piperazinyl. In one embodiment, Ring B is morpholinyl. In one embodiment, Ring B is thiazolyl. In one embodiment, Ring B is oxazolyl. In one embodiment, Ring B is imidazolyl.
  • Ring B is In one embodiment, Ring B is In one embodiment, Ring B is In these embodiments, the attachment to the left is to the Ring A, and the attachment to the right is to L.
  • Ring B is unsubstituted. In one embodiment, Ring B is substituted. In one embodiment, Ring B is substituted. In one embodiment, Ring B is substituted with one or more halogen, nitro, cyano, hydroxyl, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl. In one embodiment, Ring B is substituted with one or more halogen, hydroxyl, nitro, cyano, C 1 -C 6 alkyl, or C 1 -C 6 alkoxy.
  • Ring A is 5 to 6-membered heteroaryl, and Ring B is 4 to 6-membered heterocyclyl. In one embodiment, Ring A is 5 to 6-membered nitrogen-containing heteroaryl, and Ring B is 4 to 6-membered nitrogen-containing heterocyclyl. In one embodiment, Ring A is 6-membered nitrogen-containing heteroaryl, and Ring B is 4-membered nitrogen-containing heterocyclyl. In one embodiment, Ring A is phenyl, and Ring B is 4 to 6-membered heterocyclyl. In one embodiment, Ring A is phenyl, and Ring B is 4 to 6-membered nitrogen containing heterocyclyl. In one embodiment, Ring A is phenyl, and Ring B is azetidinyl. In one embodiment, Ring A is pyrimidinyl, and Ring B is azetidinyl.
  • the compound is a compound of Formula (III-A) , or (III-B) :
  • Ring B is a nitrogen containing 3 to 8-membered heterocyclyl
  • X 3 is CR a7 or N
  • X 4 is CR a8 or N
  • X 5 is CR a9 or N
  • X 6 is CR a10 or N
  • R a7 , R a8 , R a9 , and R a10 are each independently hydrogen, halogen, nitro, cyano, hydroxyl, C 1 -C 6 alkyl, or C 1 -C 6 alkoxy, and wherein the alkyl and alkoxy are optionally substituted.
  • X 3 is CR a7 . In one embodiment, X 3 is N.
  • R a7 is hydrogen. In one embodiment, R a7 is halogen (F, Cl, Br, or I) . In one embodiment, R a7 is nitro. In one embodiment, R a7 is cyano. In one embodiment, R a7 is C 1 -C 6 alkyl. In one embodiment, R a7 is C 1 -C 3 alkyl. In one embodiment, R a7 is methyl. In one embodiment, R a7 is ethyl. In one embodiment, R a7 is C 3 alkyl. In one embodiment, R a7 is C 4 alkyl. In one embodiment, R a7 is C 5 alkyl. In one embodiment, R a7 is C 6 alkyl.
  • R a7 is C 1 -C 6 alkoxy. In one embodiment, R a7 is C 1 -C 3 alkoxy. In one embodiment, R a7 is methoxy. In one embodiment, R a7 is ethoxy. In one embodiment, R a7 is C 3 alkoxy. In one embodiment, R a7 is C 4 alkoxy. In one embodiment, R a7 is C 5 alkoxy. In one embodiment, R a7 is C 6 alkoxy. In one embodiment, R a7 is unsubstituted. In one embodiment, R a7 is substituted. In one embodiment, R a7 is substituted with one or more halogen, hydroxyl, or C 1 -C 6 alkyl.
  • X 4 is CR a8 . In one embodiment, X 3 is N.
  • R a8 is hydrogen. In one embodiment, R a8 is halogen (F, Cl, Br, or I) . In one embodiment, R a8 is nitro. In one embodiment, R a8 is cyano. In one embodiment, R a8 is C 1 -C 6 alkyl. In one embodiment, R a8 is C 1 -C 3 alkyl. In one embodiment, R a8 is methyl. In one embodiment, R a8 is ethyl. In one embodiment, R a8 is C 3 alkyl. In one embodiment, R a8 is C 4 alkyl. In one embodiment, R a8 is C 5 alkyl. In one embodiment, R a8 is C 6 alkyl.
  • R a8 is C 1 -C 6 alkoxy. In one embodiment, R a8 is C 1 -C 3 alkoxy. In one embodiment, R a8 is methoxy. In one embodiment, R a8 is ethoxy. In one embodiment, R a8 is C 3 alkoxy. In one embodiment, R a8 is C 4 alkoxy. In one embodiment, R a8 is C 5 alkoxy. In one embodiment, R a8 is C 6 alkoxy. In one embodiment, R a8 is unsubstituted. In one embodiment, R a8 is substituted. In one embodiment, R a8 is substituted with one or more halogen, hydroxyl, or C 1 -C 6 alkyl.
  • X 5 is CR a9 . In one embodiment, X 3 is N.
  • R a9 is hydrogen. In one embodiment, R a9 is halogen (F, Cl, Br, or I) . In one embodiment, R a9 is nitro. In one embodiment, R a9 is cyano. In one embodiment, R a9 is C 1 -C 6 alkyl. In one embodiment, R a9 is C 1 -C 3 alkyl. In one embodiment, R a9 is methyl. In one embodiment, R a9 is ethyl. In one embodiment, R a9 is C 3 alkyl. In one embodiment, R a9 is C 4 alkyl. In one embodiment, R a9 is C 5 alkyl. In one embodiment, R a9 is C 6 alkyl.
  • R a9 is C 1 -C 6 alkoxy. In one embodiment, R a9 is C 1 -C 3 alkoxy. In one embodiment, R a9 is methoxy. In one embodiment, R a9 is ethoxy. In one embodiment, R a9 is C 3 alkoxy. In one embodiment, R a9 is C 4 alkoxy. In one embodiment, R a9 is C 5 alkoxy. In one embodiment, R a9 is C 6 alkoxy. In one embodiment, R a9 is unsubstituted. In one embodiment, R a9 is substituted. In one embodiment, R a9 is substituted with one or more halogen, hydroxyl, or C 1 -C 6 alkyl.
  • X 6 is CR a10 . In one embodiment, X 3 is N.
  • R a10 is hydrogen. In one embodiment, R a10 is halogen (F, Cl, Br, or I) . In one embodiment, R a10 is nitro. In one embodiment, R a10 is cyano. In one embodiment, R a10 is C 1 -C 6 alkyl. In one embodiment, R a10 is C 1 -C 3 alkyl. In one embodiment, R a10 is methyl. In one embodiment, R a10 is ethyl. In one embodiment, R a10 is C 3 alkyl. In one embodiment, R a10 is C 4 alkyl. In one embodiment, R a10 is C 5 alkyl. In one embodiment, R a10 is C 6 alkyl.
  • R a10 is C 1 -C 6 alkoxy. In one embodiment, R a10 is C 1 -C 3 alkoxy. In one embodiment, R a10 is methoxy. In one embodiment, R a10 is ethoxy. In one embodiment, R a10 is C 3 alkoxy. In one embodiment, R a10 is C 4 alkoxy. In one embodiment, R a10 is C 5 alkoxy. In one embodiment, R a10 is C 6 alkoxy. In one embodiment, R a10 is unsubstituted. In one embodiment, R a10 is substituted. In one embodiment, R a10 is substituted with one or more halogen, hydroxyl, or C 1 -C 6 alkyl.
  • X 3 is CR a7
  • X 6 is CR a10 .
  • X 3 and X 6 are both CH.
  • X 4 and X 5 are both nitrogen.
  • X 3 is CR a7
  • X 4 is nitrogen
  • X 6 is CR a10 .
  • X 3 is CR a7
  • X 5 is nitrogen
  • X 6 is CR a10 .
  • the compound is a compound of Formula (IV-A) , (IV-B) , (IV-C) , or (IV-D) :
  • R a11 is hydrogen, hydroxyl, halogen, nitro, cyano, C 1 -C 6 alkyl, or C 1 -C 6 alkoxy, and wherein the alkyl, and alkoxy are optionally substituted;
  • each instance of R a12 is independently hydrogen, halogen, nitro, cyano, hydroxyl, C 1 -C 6 alkyl, or C 1 -C 6 alkoxy, and wherein the alkyl, and alkoxy are optionally substituted.
  • each instance of R a12 is independently hydrogen, or C 1 -C 6 alkyl. In one embodiment, all of the R a12 are hydrogen. In one embodiment, one of the R a12 is C 1 -C 6 alkyl, and the rest of R a12 are hydrogen. In one embodiment, one of the R a12 is methyl, and the rest of R a12 are hydrogen. In one embodiment, two of the R a12 are C 1 -C 6 alkyl, and the rest of R a12 are hydrogen. In one embodiment, when a carbon connected to a R a12 is a chiral center, it has S-configuration. In one embodiment, when a carbon connected to a R a12 is a chiral center, it has R-configuration.
  • L is C 1 -C 6 alkylene. In one embodiment, L is C 1 -C 3 alkylene. In one embodiment, L is -CH 2 -. In one embodiment, L is -CH 2 CH 2 -. In one embodiment, L is -CH (CH 3 ) -. In one embodiment, L is C 3 alkylene, such as -C (CH 3 ) 2 -, -CH (CH 3 ) CH 2 -, or -CH 2 CH 2 CH 2 -. In one embodiment, L is C 4 alkylene. In one embodiment, L is C 5 alkylene. In one embodiment, L is C 6 alkylene. In one embodiment, the alkylene is unsubstituted. In one embodiment, the alkylene is substituted. In one embodiment, the alkylene is substituted with one or more hydroxyl, halogen, or C 1 -C 6 alkoxy.
  • L is C 3 -C 8 cycloalkylene. In one embodiment, L is C 3 -C 6 cycloalkylene. In one embodiment, L is C 3 cycloalkylene. In one embodiment, L is C 4 cycloalkylene. In one embodiment, L is C 5 cycloalkylene. In one embodiment, L is C 6 cycloalkylene. In one embodiment, L is C 7 cycloalkylene. In one embodiment, L is C 8 cycloalkylene. In one embodiment, the cycloalkylene is substituted. In one embodiment, the cycloalkylene is substituted with one or more hydroxyl, halogen, C 1 -C 6 alkyl, or C 1 -C 6 alkoxy.
  • R 1 is -SO 2 R c . In one embodiment, R 1 is -SO 2 CH 3 .
  • R 1 is -OR c . In one embodiment, R 1 is -OCH 3 . In one embodiment, R 1 is -OC 2 H 5 .
  • R 1 is -NR b R c . In one embodiment, R 1 is -NHR c . In one embodiment, R 1 is -NH (C 1-6 alkyl) . In one embodiment, R 1 is -N (C 1-6 alkyl) 2 . In one embodiment, R 1 is -NH (CH 3 ) . In one embodiment, R 1 is -N (CH 3 ) 2 .
  • R 1 is an optionally substituted 3 to 12-membered heterocyclyl. In one embodiment, R 1 is an optionally substituted 3 to 10-membered heterocyclyl. In one embodiment, R 1 is an optionally substituted 3 to 8-membered heterocyclyl. In one embodiment, R 1 is an optionally substituted 3 to 6-membered heterocyclyl. In one embodiment, R 1 is an optionally substituted 3 to 6-membered monocyclic heterocyclyl. In one embodiment, R 1 is an optionally substituted 3 to 6-membered nitrogen-containing monocyclic heterocyclyl. In one embodiment, R 1 is an optionally substituted 6 to 12-membered bicyclic heterocyclyl.
  • R 1 is an optionally substituted 6 to 12-membered nitrogen-containing bicyclic heterocyclyl. In one embodiment, R 1 is an optionally substituted 6 to 12-membered spiro heterocyclyl. In one embodiment, R 1 is an optionally substituted 6 to 12-membered fused heterocyclyl. In one embodiment, R 1 is an optionally substituted 6 to 12-membered bridged heterocyclyl. In one embodiment, R 1 is optionally substituted with one or more R a13 . In one embodiment, the heterocyclyl R 1 is Ring C as described herein and elsewhere.
  • the compound is a compound of Formula (V-A) , (V-B) , (V-C) , or (V-D) , (V-E) , (V-F) , (V-G) , (V-H) , (V-I) , (V-J) , (V-K) , (V-L) , (V-M) , or (V-N) :
  • n 1, 2, 3, 4, 5, or 6;
  • Ring C is a 3 to 12-membered heterocyclyl optionally substituted with one or more R a13 ;
  • Ring C is a 3 to 6-membered monocyclic heterocyclyl. In one embodiment, Ring C is a 3 to 6-membered nitrogen-containing monocyclic heterocyclyl. In one embodiment, Ring C is a 5 or 6-membered monocyclic heterocyclyl. In one embodiment, Ring C is a 5 or 6-membered nitrogen-containing heterocyclyl.
  • Ring C is a 6 to 12-membered spiro heterocyclyl. In one embodiment, Ring C is a 6 to 12-membered nitrogen-containing spiro heterocyclyl. In one embodiment, Ring C is a 6 to 12-membered fused heterocyclyl. In one embodiment, Ring C is a 6 to 12-membered nitrogen-containing fused heterocyclyl. In one embodiment, Ring C is a 6 to 12-membered bridged heterocyclyl. In one embodiment, Ring C is a 6 to 12-membered nitrogen-containing bridged heterocyclyl.
  • Ring C is azetidinyl. In one embodiment, Ring C is pyrrolidinyl. In one embodiment, Ring C is piperidinyl. In one embodiment, Ring B is piperazinyl. In one embodiment, Ring C is morpholinyl. In one embodiment, Ring C is thiazolyl. In one embodiment, Ring C is oxazolyl. In one embodiment, Ring C is imidazolyl.
  • Ring C is: wherein the point of attachment is to L, and each of which is optionally substituted.
  • Ring C is unsubstituted. In one embodiment, Ring C is substituted with one or more R a13 . In one embodiment, Ring C is substituted with one R a13 . In one embodiment, Ring C is substituted with two R a13 . In one embodiment, Ring C is substituted with three R a13 .
  • R a13 is C 1 -C 6 alkyl. In one embodiment, R a13 is C 1 -C 3 alkyl. In one embodiment, R a13 is methyl. In one embodiment, R a13 is ethyl. In one embodiment, R a13 is C 3 alkyl. In one embodiment, R a13 is C 4 alkyl. In one embodiment, R a13 is C 5 alkyl. In one embodiment, R a13 is C 6 alkyl. In one embodiment, the alkyl (in R a13 ) is unsubstituted. In one embodiment, the alkyl is substituted. In one embodiment, the alkyl is substituted with one or more halogen, hydroxyl, or oxo.
  • R a13 is C 1 -C 6 alkoxy. In one embodiment, R a13 is C 1 -C 3 alkoxy. In one embodiment, R a13 is methoxy. In one embodiment, R a13 is ethoxy. In one embodiment, R a13 is C 3 alkoxy. In one embodiment, R a13 is C 4 alkoxy. In one embodiment, R a13 is C 5 alkoxy. In one embodiment, R a13 is C 6 alkoxy. In one embodiment, the alkoxy is unsubstituted. In one embodiment, the alkoxy (in R a13 ) is substituted. In one embodiment, the alkoxy is substituted with one or more halogen, hydroxyl, or oxo.
  • R a13 is -NH (C 2 H 5 ) . In one embodiment, R a13 is -N (CH 3 ) 2 . In one embodiment, R a13 is -N (CH 3 ) (C 2 H 5 ) . In one embodiment, the alkyl (in R a13 ) is unsubstituted. In one embodiment, the alkyl is substituted. In one embodiment, the alkyl is substituted with one or more halogen, hydroxyl, or oxo.
  • Ring C is:
  • n is 1. In one embodiment, n is 2. In one embodiment, n is 3. In one embodiment, n is 4. In one embodiment, n is 5. In one embodiment, n is 6.
  • R a11 is hydrogen. In one embodiment, R a11 is hydroxyl. In one embodiment, R a11 is halogen. In one embodiment, R a11 is fluorine. In one embodiment, R a11 is nitro. In one embodiment, R a11 is cyano.
  • R a11 is C 1 -C 6 alkyl. In one embodiment, R a11 is C 1 -C 3 alkyl. In one embodiment, R a11 is methyl. In one embodiment, R a11 is ethyl. In one embodiment, R a11 is C 3 alkyl. In one embodiment, R a11 is C 4 alkyl. In one embodiment, R a11 is C 5 alkyl. In one embodiment, R a11 is C 6 alkyl. In one embodiment, the alkyl (in R a11 ) is unsubstituted. In one embodiment, the alkyl is substituted. In one embodiment, the alkyl is substituted with one or more halogen, hydroxyl, or C 1 -C 6 alkoxy.
  • R a11 is C 1 -C 6 alkoxy. In one embodiment, R a11 is C 1 -C 3 alkoxy. In one embodiment, R a11 is methoxy. In one embodiment, R a11 is ethoxy. In one embodiment, R a11 is C 3 alkoxy. In one embodiment, R a11 is C 4 alkoxy. In one embodiment, R a11 is C 5 alkoxy. In one embodiment, R a11 is C 6 alkoxy. In one embodiment, the alkoxy is unsubstituted. In one embodiment, the alkoxy (in R a11 ) is substituted. In one embodiment, the alkoxy is substituted with one or more halogen, hydroxyl, C 1 -C 6 alkoxy, or C 1 -C 6 alkyl.
  • the carbon connected to R a11 when the carbon connected to R a11 is a chiral center, it has R-configuration. In one embodiment, when the carbon connected to R a11 is a chiral center, it has S-configuration.
  • R b is hydrogen. In one embodiment, R b is C 1 -C 6 alkyl. In one embodiment, R b is C 1 -C 3 alkyl. In one embodiment, R b is methyl. In one embodiment, R b is hydroxymethyl. In one embodiment, R b is ethyl. In one embodiment, R b is 2-hydroxyethyl. In one embodiment, R b is 2-dimethylaminoethyl. In one embodiment, R b is 2- methoxyethyl. In one embodiment, R b is C 3 alkyl. In one embodiment, R b is C 4 alkyl. In one embodiment, R b is C 5 alkyl. In one embodiment, R b is C 6 alkyl.
  • R b is C 1 -C 6 alkyl terminally substituted with hydroxy, C 1 -C 6 alkoxy, -NH 2 , -NH (C 1 -C 6 alkyl) , or -N (C 1 -C 6 alkyl) 2 .
  • R b is C 2 -C 6 alkyl terminally substituted with hydroxy, C 1 -C 6 alkoxy, -NH 2 , -NH (C 1 -C 6 alkyl) , or -N (C 1 -C 6 alkyl) 2 .
  • R b is ethyl terminally substituted with hydroxy, C 1 -C 6 alkoxy, -NH 2 , -NH (C 1 -C 6 alkyl) , or -N (C 1 -C 6 alkyl) 2 .
  • R b is - (C 1 -C 6 alkylene) -OH.
  • R b is - (C 1 -C 6 alkylene) - (C 1 -C 6 alkoxy) .
  • R b is - (C 1 -C 6 alkylene) -OCH 3 .
  • R b is - (C 1 -C 6 alkylene) -NH 2 .
  • R b is - (C 1 -C 6 alkylene) -NH(C 1 -C 6 alkyl) . In one embodiment, R b is - (C 1 -C 6 alkylene) -NHCH 3 . In one embodiment, R b is - (C 1 -C 6 alkylene) -N (C 1 -C 6 alkyl) 2 . In one embodiment, R b is - (C 1 -C 6 alkylene) -N (CH 3 ) 2 . In one embodiment, R b is - (C 2 -C 6 alkylene) -OH.
  • R b is - (C 2 -C 6 alkylene) - (C 1 -C 6 alkoxy) . In one embodiment, R b is - (C 2 -C 6 alkylene) -OCH 3 . In one embodiment, R b is - (C 2 -C 6 alkylene) -NH 2 . In one embodiment, R b is - (C 2 -C 6 alkylene) -NH (C 1 -C 6 alkyl) . In one embodiment, R b is - (C 2 -C 6 alkylene) -NHCH 3 .
  • R b is - (C 2 -C 6 alkylene) -N (C 1 -C 6 alkyl) 2 . In one embodiment, R b is - (C 2 -C 6 alkylene) -N (CH 3 ) 2 . In one embodiment, the alkyl (in R b ) is unsubstituted. In one embodiment, the alkyl is substituted. In one embodiment, the alkyl is substituted with one or more halogen, hydroxyl, or C 1 -C 6 alkoxy. In one embodiment, the alkylene (in R b ) is unsubstituted. In one embodiment, the alkylene is substituted with one or more halogen. In one embodiment, the alkylene is - (CH 2 ) 2-6 -. In one embodiment, the alkylene is -CH 2 CH 2 -.
  • R b is C 2 -C 6 alkenyl. In one embodiment, R b is ethenyl (other name: vinyl) . In one embodiment, R b is C 3 alkenyl. In one embodiment, R b is prop-1-enyl. In one embodiment, R b is allyl. In one embodiment, R b is C 4 alkenyl. In one embodiment, R b is but-1-enyl. In one embodiment, R b is C 5 alkenyl. In one embodiment, R b is pent-1-enyl. In one embodiment, R b is penta-1, 4-dienyl. In one embodiment, R b is C 6 alkenyl.
  • the alkenyl is unsubstituted. In one embodiment, the alkenyl is substituted. In one embodiment, the alkenyl is substituted with one or more halogen, hydroxyl, or C 1 -C 6 alkoxy.
  • R b is C 3 -C 8 cycloalkyl. In one embodiment, R b is C 3 -C 6 cycloalkyl. In one embodiment, R b is cyclopropyl. In one embodiment, R b is cyclobutyl. In one embodiment, R b is cyclopentyl. In one embodiment, R b is cyclohexyl. In one embodiment, the cycloalkyl is unsubstituted. In one embodiment, the cycloalkyl is substituted. In one embodiment, the cycloalkyl is substituted with one or more halogen, hydroxyl, C 1 -C 6 alkyl, or C 1 -C 6 alkoxy.
  • R b is C 6 -C 10 aryl. In one embodiment, R b is C 6 -C 8 aryl. In one embodiment, R b is phenyl. In one embodiment, the phenyl is unsubstituted. In one embodiment, the phenyl is substituted. In one embodiment, the phenyl is substituted with one or more halogen, nitro, cyano, hydroxyl, C 1 -C 6 alkyl, or C 1 -C 6 alkoxy.
  • R b is 5 to 10-membered heteroaryl. In one embodiment, R b is 5 to 8-membered heteroaryl. In one embodiment, R b is 5-membered heteroaryl. In one embodiment, R b is 6-membered heteroaryl. In one embodiment, R b is a 5 or 6-membered heteroaryl containing one or more nitrogen, oxygen, or sulfur ring atoms. In one embodiment, R b is a 5 or 6-membered nitrogen-containing heteroaryl. In one embodiment, the heteroaryl is unsubstituted. In one embodiment, the heteroaryl is substituted. In one embodiment, the heteroaryl is substituted. In one embodiment, the heteroaryl is substituted with one or more halogen, nitro, cyano, hydroxyl, C 1 -C 6 alkyl, or C 1 -C 6 alkoxy.
  • R b is 3 to 8-membered heterocyclyl. In one embodiment, R b is 3 to 6-membered heterocyclyl. In one embodiment, R b is a 3-membered heterocyclyl. In one embodiment, R b is a 4-membered heterocyclyl. In one embodiment, R b is a 5-membered heterocyclyl. In one embodiment, R b is a 6-membered heterocyclyl. In one embodiment, R b is a 3-to 6-membered heterocyclyl containing one or more nitrogen, oxygen, or sulfur ring atoms. In one embodiment, R b is a 3-to 6-membered oxygen-containing heterocyclyl.
  • R b is a 3-to 6-membered nitrogen-containing heterocyclyl.
  • the heterocyclyl is unsubstituted.
  • the heterocyclyl is substituted.
  • the heterocyclyl is substituted with one or more halogen, nitro, cyano, hydroxyl, C 1 -C 6 alkyl, or C 1 -C 6 alkoxy.
  • R b is oxiran-2-yl. In one embodiment, R b is oxetan-2-yl. In one embodiment, R b is oxetan-3-yl. In one embodiment, R b is tetrahydrofuran-2-yl. In one embodiment, R b is tetrahydrofuran-3-yl. In one embodiment, R b is tetrahydro-2H-pyran-4-yl. In one embodiment, R b is tetrahydro-2H-pyran-3-yl. In one embodiment, R b is tetrahydro-2H-pyran-2-yl.
  • R b is azetidinyl (e.g., 1-azetidinyl, or 3-azetidinyl) .
  • R b is pyrrolidinyl (e.g., pyrrolidin-1-yl) .
  • R b is piperidinyl (e.g., piperidin-1-yl) .
  • R b is piperazinyl (e.g., piperazin-1-yl, or 4- (C 1 -C 6 alkyl) piperazin-1-yl) .
  • R b is morpholinyl (e.g., 4-morpholinyl) .
  • R b is thiazolyl (e.g., thiazol-2-yl) . In one embodiment, R b is oxazolyl (e.g., oxazol-2-yl) . In one embodiment, R b is imidazolyl (e.g., 1H-imidazol-2-yl) . In one embodiment, R b is pyridyl (e.g., pyridine-2-yl, pyridine-3-yl, or pyridine-4-yl) .
  • R c is C 1 -C 6 alkyl. In one embodiment, R c is C 1 -C 3 alkyl. In one embodiment, R c is methyl. In one embodiment, R c is hydroxymethyl. In one embodiment, R c is ethyl. In one embodiment, R c is 2-hydroxyethyl. In one embodiment, R c is 2-dimethylaminoethyl. In one embodiment, R c is 2-methoxyethyl. In one embodiment, R c is C 3 alkyl. In one embodiment, R c is C 4 alkyl. In one embodiment, R c is C 5 alkyl. In one embodiment, R c is C 6 alkyl.
  • R c is C 1 -C 6 alkyl terminally substituted with hydroxy, C 1 -C 6 alkoxy, -NH 2 , -NH (C 1 -C 6 alkyl) , or -N (C 1 -C 6 alkyl) 2 .
  • R c is C 2 -C 6 alkyl terminally substituted with hydroxy, C 1 -C 6 alkoxy, -NH 2 , -NH (C 1 -C 6 alkyl) , or -N (C 1 -C 6 alkyl) 2 .
  • R c is ethyl terminally substituted with hydroxy, C 1 -C 6 alkoxy, -NH 2 , -NH (C 1 -C 6 alkyl) , or -N (C 1 -C 6 alkyl) 2 .
  • R c is - (C 1 -C 6 alkylene) -OH.
  • R c is - (C 1 -C 6 alkylene) - (C 1 -C 6 alkoxy) .
  • R c is - (C 1 -C 6 alkylene) -OCH 3 .
  • R c is - (C 1 -C 6 alkylene) -NH 2 .
  • R c is - (C 1 -C 6 alkylene) -NH (C 1 -C 6 alkyl) . In one embodiment, R c is - (C 1 -C 6 alkylene) -NHCH 3 . In one embodiment, R c is - (C 1 -C 6 alkylene) -N (C 1 -C 6 alkyl) 2 . In one embodiment, R c is - (C 1 -C 6 alkylene) -N (CH 3 ) 2 . In one embodiment, the alkyl (in R c ) is unsubstituted. In one embodiment, the alkyl is substituted.
  • the alkyl is substituted with one or more halogen, hydroxyl, or C 1 -C 6 alkoxy.
  • the alkylene (in R c ) is unsubstituted.
  • the alkylene is substituted with one or more halogen.
  • the alkylene is - (CH 2 ) 2-6 -.
  • the alkylene is -CH 2 CH 2 -.
  • R c is C 2 -C 6 alkenyl. In one embodiment, R c is ethenyl (other name: vinyl) . In one embodiment, R c is C 3 alkenyl. In one embodiment, R c is prop-1-enyl. In one embodiment, R c is allyl. In one embodiment, R c is C 4 alkenyl. In one embodiment, R c is but-1-enyl. In one embodiment, R c is C 5 alkenyl. In one embodiment, R c is pent-1-enyl. In one embodiment, R c is penta-1, 4-dienyl. In one embodiment, R c is C 6 alkenyl.
  • the alkenyl is unsubstituted. In one embodiment, the alkenyl is substituted. In one embodiment, the alkenyl is substituted with one or more halogen, hydroxyl, or C 1 -C 6 alkoxy.
  • R c is C 3 -C 8 cycloalkyl. In one embodiment, R c is C 3 -C 6 cycloalkyl. In one embodiment, R c is cyclopropyl. In one embodiment, R c is cyclobutyl. In one embodiment, R c is cyclopentyl. In one embodiment, R c is cyclohexyl. In one embodiment, the cycloalkyl is unsubstituted. In one embodiment, the cycloalkyl is substituted. In one embodiment, the cycloalkyl is substituted with one or more halogen, hydroxyl, C 1 -C 6 alkyl, or C 1 -C 6 alkoxy.
  • R c is C 6 -C 10 aryl. In one embodiment, R c is C 6 -C 8 aryl. In one embodiment, R c is phenyl. In one embodiment, the phenyl is unsubstituted. In one embodiment, the phenyl is substituted. In one embodiment, the phenyl is substituted with one or more halogen, nitro, cyano, hydroxyl, C 1 -C 6 alkyl, or C 1 -C 6 alkoxy.
  • R c is 5 to 10-membered heteroaryl. In one embodiment, R c is 5 to 8-membered heteroaryl. In one embodiment, R c is 5-membered heteroaryl. In one embodiment, R c is 6-membered heteroaryl. In one embodiment, R c is a 5 or 6-membered heteroaryl containing one or more nitrogen, oxygen, or sulfur ring atoms. In one embodiment, R c is a 5 or 6-membered nitrogen-containing heteroaryl. In one embodiment, the heteroaryl is unsubstituted. In one embodiment, the heteroaryl is substituted. In one embodiment, the heteroaryl is substituted. In one embodiment, the heteroaryl is substituted with one or more halogen, nitro, cyano, hydroxyl, C 1 -C 6 alkyl, or C 1 -C 6 alkoxy.
  • R c is 3 to 8-membered heterocyclyl. In one embodiment, R c is 3 to 6-membered heterocyclyl. In one embodiment, R c is a 3-membered heterocyclyl. In one embodiment, R c is a 4-membered heterocyclyl. In one embodiment, R c is a 5-membered heterocyclyl. In one embodiment, R c is a 6-membered heterocyclyl. In one embodiment, R c is a 3-to 6-membered heterocyclyl containing one or more nitrogen, oxygen, or sulfur ring atoms. In one embodiment, R c is a 3-to 6-membered oxygen-containing heterocyclyl.
  • R c is a 3-to 6-membered nitrogen-containing heterocyclyl.
  • the heterocyclyl is unsubstituted.
  • the heterocyclyl is substituted.
  • the heterocyclyl is substituted with one or more halogen, nitro, cyano, hydroxyl, C 1 -C 6 alkyl, or C 1 -C 6 alkoxy.
  • R c is oxiran-2-yl. In one embodiment, R c is oxetan-2-yl. In one embodiment, R c is oxetan-3-yl. In one embodiment, R c is tetrahydrofuran-2-yl. In one embodiment, R c is tetrahydrofuran-3-yl. In one embodiment, R c is tetrahydro-2H-pyran-4-yl. In one embodiment, R c is tetrahydro-2H-pyran-3-yl. In one embodiment, R c is tetrahydro-2H-pyran-2-yl.
  • R c is azetidinyl (e.g., 1-azetidinyl, or 3-azetidinyl) .
  • R c is pyrrolidinyl (e.g., pyrrolidin-1-yl) .
  • R c is piperidinyl (e.g., piperidin-1-yl) .
  • R c is piperazinyl (e.g., piperazin-1-yl, or 4- (C 1 -C 6 alkyl) piperazin-1-yl) .
  • R c is morpholinyl (e.g., 4-morpholinyl) .
  • R c is thiazolyl (e.g., thiazol-2-yl) . In one embodiment, R c is oxazolyl (e.g., oxazol-2-yl) . In one embodiment, R c is is imidazolyl (e.g., 1H-imidazol-2-yl) . In one embodiment, R c is pyridyl (e.g., pyridine-2-yl, pyridine-3-yl, or pyridine-4-yl) .
  • R is C 1 -C 6 alkyl. In one embodiment, R is C 1 -C 6 alkyl substituted with one or more halogens. In one embodiment, R is C 1 -C 3 alkyl. In one embodiment, R is methyl. In one embodiment, R is fluoromethyl. In one embodiment, R is difluoromethyl. In one embodiment, R is trifluoromethyl. In one embodiment, R is ethyl. In one embodiment, R is C 3 alkyl. In one embodiment, R is is isopropyl. In one embodiment, R is C 4 alkyl. In one embodiment, R is C 5 alkyl. In one embodiment, R is C 6 alkyl.
  • the alkyl (in R) is unsubstituted. In one embodiment, the alkyl is substituted. In one embodiment, the alkyl is substituted with one or more hydroxyl. In one embodiment, the alkyl is substituted with one or more C 1 -C 6 alkoxy.
  • R is C 1 -C 6 alkoxy. In one embodiment, R is C 1 -C 3 alkoxy. In one embodiment, R is methoxy. In one embodiment, R is ethoxy. In one embodiment, R is C 3 alkoxy. In one embodiment, R is C 4 alkoxy. In one embodiment, R is C 5 alkoxy. In one embodiment, R is C 6 alkoxy. In one embodiment, the alkoxy (in R) is unsubstituted. In one embodiment, the alkoxy is substituted. In one embodiment, the alkoxy is substituted with one or more halogen, hydroxyl, or C 1 -C 6 alkyl.
  • R is C 3 -C 8 cycloalkyl. In one embodiment, R is C 3 -C 6 cycloalkyl. In one embodiment, R is cyclopropyl. In one embodiment, R is cyclobutyl. In one embodiment, R is cyclopentyl. In one embodiment, R is cyclohexyl. In one embodiment, the cycloalkyl is unsubstituted. In one embodiment, the cycloalkyl (in R) is substituted. In one embodiment, the cycloalkyl is substituted with one or more halogen, hydroxyl, C 1 -C 6 alkyl, or C 1 -C 6 alkoxy.
  • R is 3 to 8-membered heterocyclyl. In one embodiment, R is 3 to 6-membered heterocyclyl. In one embodiment, R is a 3-membered heterocyclyl. In one embodiment, R is a 4-membered heterocyclyl. In one embodiment, R is a 5-membered heterocyclyl. In one embodiment, R is a 6-membered heterocyclyl. In one embodiment, R is a 3-to 6-membered heterocyclyl containing one or more nitrogen, oxygen, or sulfur ring atoms. In one embodiment, R is a 3-to 6-membered oxygen-containing heterocyclyl. In one embodiment, R is a 4-membered oxygen-containing heterocyclyl.
  • R is a 5-membered oxygen-containing heterocyclyl. In one embodiment, R is a 6-membered oxygen-containing heterocyclyl. In one embodiment, R is a 3-to 6-membered nitrogen-containing heterocyclyl. In one embodiment, the heterocyclyl (in R) is unsubstituted. In one embodiment, the heterocyclyl is substituted. In one embodiment, the heterocyclyl is substituted with one or more halogen, nitro, cyano, hydroxyl, C 1 -C 6 alkyl, or C 1 -C 6 alkoxy.
  • R is oxiran-2-yl. In one embodiment, R is oxetan-2-yl. In one embodiment, R is oxetan-3-yl. In one embodiment, R is tetrahydrofuran-2-yl. In one embodiment, R is tetrahydrofuran-3-yl. In one embodiment, R is tetrahydro-2H-pyran-4-yl. In one embodiment, R is tetrahydro-2H-pyran-3-yl. In one embodiment, R is tetrahydro-2H-pyran-2-yl.
  • R is azetidinyl (e.g., 1-azetidinyl, or 3-azetidinyl) .
  • R is pyrrolidinyl (e.g., pyrrolidin-1-yl) .
  • R is piperidinyl (e.g., piperidin-1-yl) .
  • R is piperazinyl (e.g., piperazin-1-yl, or 4- (C 1 -C 6 alkyl) piperazin-1-yl) .
  • R is morpholinyl (e.g., 4-morpholinyl) .
  • the carbon connected to R has S-configuration. In one embodiment, the carbon connected to R has R-configuration.
  • the compounds provided herein are single enantiomers. In one embodiment, the compounds provided herein are single diastereoisomers. In one embodiment, the compounds provided herein are mixtures of enantiomers. In one embodiment, the compounds provided herein are mixtures of diastereoisomers. In one embodiment, the compounds provided herein are racemic compounds.
  • the compounds provided herein have an enantiomeric excess (ee) of at least about 50%. In one embodiment, the compounds provided herein have an enantiomeric excess of at least about 80%. In one embodiment, the compounds provided herein have an enantiomeric excess of at least about 90%. In one embodiment, the compounds provided herein have an enantiomeric excess of at least about 95%. In one embodiment, the compounds provided herein have an enantiomeric excess of at least about 97%. In one embodiment, the compounds provided herein have an enantiomeric excess of at least about 99%. In one embodiment, the compounds provided herein have an enantiomeric excess of at least about 99.5%. In one embodiment, the compounds provided herein have an enantiomeric excess of at least about 99.9%.
  • the compounds provided herein have a diastereomeric excess (de) of at least about 50%. In one embodiment, the compounds provided herein have a diastereomeric excess of at least about 80%. In one embodiment, the compounds provided herein have a diastereomeric excess of at least about 90%. In one embodiment, the compounds provided herein have a diastereomeric excess of at least about 95%. In one embodiment, the compounds provided herein have a diastereomeric excess of at least about 97%. In one embodiment, the compounds provided herein have a diastereomeric excess of at least about 99%. In one embodiment, the compounds provided herein have a diastereomeric excess of at least about 99.5%. In one embodiment, the compounds provided herein have a diastereomeric excess of at least about 99.9%.
  • the compound is a compound in Table 1, or a pharmaceutically acceptable salt thereof.
  • the compounds provided herein are PI3K ⁇ inhibitors that reduce the level of PI3K ⁇ protein and/or inhibit or reduce at least one biological activity (e.g., enzymatic activity) of PI3K ⁇ protein.
  • the expression level of the PI3K ⁇ protein is reduced by 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%or 99%.
  • the biological activity of the PI3K ⁇ protein is reduced by 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%or 99%.
  • test compounds to act as inhibitors of PI3K ⁇ may be demonstrated by assays known in the art.
  • the activity of the compounds and compositions provided herein as PI3K ⁇ 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 PI3K ⁇ inhibitor as provided herein can be determined by EC 50 value.
  • a compound with a lower EC 50 value, as determined under substantially similar conditions, is a more potent inhibitor relative to a compound with a higher EC 50 value.
  • the substantially similar conditions comprise determining a PI3K ⁇ -dependent phosphorylation level, in vitro or in vivo (e.g., in tumor cells, A594 cells, U2OS cells, A431 cells, Ba/F3 cells, or 3T3 cells expressing a wild type PI3K ⁇ , a mutant PI3K ⁇ , or a fragment of any thereof) .
  • Potency of a PI3K ⁇ inhibitor as provided herein can also be determined by IC 50 value.
  • the substantially similar conditions comprise determining a PI3K ⁇ -dependent phosphorylation level, in vitro or in vivo (e.g., in tumor cells, SKOV3, T47D, CAL33, BT20, HSC2, OAW42, NCI, HCC1954, NCIH1048, Detroit562, A594 cells, U2OS cells, A431 cells, A594 cells, U2OS cells, Ba/F3 cells, or 3T3 cells expressing a wild type PI3K ⁇ , a mutant PI3K ⁇ , or a fragment of any thereof) .
  • a PI3K ⁇ -dependent phosphorylation level in vitro or in vivo (e.g., in tumor cells, SKOV3, T47D, CAL33, BT20, HSC2, OAW42, NCI, HCC1954, NCIH1048, Detroit562, A594 cells, U2OS cells, A431 cells, A594 cells, U2OS cells, Ba/F3 cells, or 3T3 cells
  • the compounds provided herein bind to a PI3K ⁇ protein with an affinity in the range of about 1 pM to about 100 ⁇ M, about 1 pM to about 1 ⁇ M, about 1 pM to about 500 nM, or about 1 pM to about 100 nM.
  • the compounds provided herein bind to a PI3K ⁇ protein with an affinity of about 100 nM to about 1 ⁇ M, about 100 nM to about 900 nM, about 100 nM to about 800 nM, about 100 nM to about 700 nM, about 100 nM to about 600 nM, about 100 nM to about 500 nM, about 100 nM to about 400 nM, about 100 nM to about 300 nM, about 100 nM to about 200 nM, about 200 nM to about 1 ⁇ M, about 300 nM to about 1 ⁇ M, about 400 nM to about 1 ⁇ M, about 500 nM to about 1 ⁇ M, about 600 nM to about 1 ⁇ M, about 700 nM to about 1 ⁇ M, about 800 nM to about 1 ⁇ M, about 900 nM to about 1 ⁇ M, about 100 nM, about 200 nM, about 300 nM, about 400 nM, about
  • the compounds provided herein bind to a PI3K ⁇ protein with an affinity of about 1 nM to about 100 nM, about 1 nM to about 90 nM, about 1 nM to about 80 nM, about 1 nM to about 70 nM, about 1 nM to about 60 nM, about 1 nM to about 50 nM, about 1 nM to about 40 nM, about 1 nM to about 30 nM, about 1 nM to about 20 nM, about 1 nM to about 10 nM, about 10 nM to about 100 nM, about 20 nM to about 100 nM, about 30 nM to about 100 nM, about 40 nM to about 100 nM, about 50 nM to about 100 nM, about 60 nM to about 100 nM, about 70 nM to about 100 nM, about 80 nM to about 100 nM, about 90 nM to about 100 nM, about 1 nM,
  • the compounds provided herein bind to a PI3K ⁇ protein with an affinity of less than about 1 ⁇ M, less than about 500 nM, less than about 100 nM, less than about 10 nM, or less than about 1 nM. In one embodiment, the compounds provided herein bind to a PI3K ⁇ protein with an affinity of less than 1 nM. In one embodiment, the affinity is characterized by an IC 50 value. In one embodiment, the affinity is characterized by an EC 50 value. In one embodiment, the PI3K ⁇ protein is wild type PI3K ⁇ . In one embodiment, the PI3K ⁇ protein has one or more mutations, e.g., the mutations in Table 2.
  • the compounds provided herein exhibit selective inhibition of PI3K ⁇ . In one embodiment, the compounds provided herein selectively target PI3K ⁇ over another isoform of PI3K (e.g., PI3K ⁇ , PI3K ⁇ , or PI3K ⁇ ) . In one embodiment, the compounds provided herein is capable of binding to the helical or kinase domain of PI3K ⁇ .
  • the helical or kinase domain of PI3K ⁇ is known in the art (e.g. Zhao et al., Proc Natl Acad Sci. 2008, 105: 2652–2657) . In one embodiment, the compounds provided herein bind to an allosteric site in the kinase domain.
  • the compounds provided herein exhibits picomolar, nanomolar, or micromolar potency against a PI3K ⁇ kinase with one or more mutations, with minimal activity against related kinases (e.g., wild type PI3K ⁇ ) .
  • Inhibition of wild type PI3K ⁇ can cause undesirable side effects (e.g., hyperglycemia and skin rashes) that can impact quality of life and compliance, or lead to dose limiting toxicities. See, e.g., Hanker, et al., Cancer Disc. 2019, 9 (4) : 482-491.
  • Mutant-selective inhibitors may reduce the risk of such dose limiting toxicities, including hyperglycemia, observed with inhibitors of wild type PI3K ⁇ .
  • the compounds provided herein exhibits higher inhibition of a mutant PI3K ⁇ than wild type PI3K ⁇ . In one embodiment, the compounds provided herein exhibit at least 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 10-fold, 20-fold, 30-fold, 40-fold, 50-fold, 100-fold, 500-fold, or 1000-fold higher inhibition of a mutant PI3K ⁇ than wild type PI3K ⁇ .
  • a compound provided herein exhibits from about 2-fold to about 10-fold greater inhibition of PI3K ⁇ containing one or more mutations as described herein relative to inhibition of wild type PI3K ⁇ . In one embodiment, a compound provided herein exhibits from about 10-fold to about 100-fold greater inhibition of PI3K ⁇ containing one or more mutations as described herein relative to inhibition of wild type PI3K ⁇ . In one embodiment, a compound provided herein exhibits from about 100-fold to about 1000-fold greater inhibition of PI3K ⁇ containing one or more mutations as described herein relative to inhibition of wild type PI3K ⁇ . In one embodiment, the mutant PI3K ⁇ has one or more mutations, e.g., the mutations in Table 2.
  • the selectivity between wild type PI3K ⁇ and PI3K ⁇ 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 PI3K ⁇ activity, or proliferation assays where cell proliferation is dependent on mutant PI3K ⁇ 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 PI3K ⁇ activity, or proliferation assays where cell proliferation is dependent on mutant PI3K ⁇ kinase activity.
  • provided herein is a method of treating diseases or conditions by inhibiting a PI3K ⁇ protein comprising administering to a subject in need thereof a therapeutically effective amount of a compound provided herein or a pharmaceutical composition provided herein.
  • provided herein is a method of treating a PI3K ⁇ -associated disease or disorder, comprising administering to a subject in need thereof a therapeutically effective amount of a compound provided herein or a pharmaceutical composition provided herein.
  • the disease or disorder is PIK3CA-related overgrowth syndromes (PROS) .
  • the disease or disorder is a proliferative disease (e.g., cancer) .
  • provided herein is a method of treating a cancer, comprising administering to a subject having the cancer a therapeutically effective amount of a compound provided herein or a pharmaceutical composition provided herein.
  • the cancer is a PI3K ⁇ -associated cancer.
  • the PI3K ⁇ -associated cancer has one or more mutations described in Table 2.
  • the cancer is a hematological cancer. In one embodiment, the cancer is a solid tumor. In one embodiment the cancer is breast cancer (including both HER2+ and HER2-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) , glioma, esophageal squamous cell carcinoma,
  • the cancer is head and neck cancer, brain cancer, breast cancer, ovarian cancer, cervical cancer, endometrial cancer, lung cancer, kidney cancer, bladder cancer, prostate cancer, liver cancer, stomach cancer, hematological cancer, thyroid cancer, colon cancer, or gastric cancer
  • the cancer is head and neck cancer (e.g., head and neck squamous cell carcinoma (HNSCC) , or oropharyngeal squamous cell carcinoma) .
  • the cancer is brain cancer (e.g., glioblastoma) .
  • the cancer is breast cancer (e.g., triple negative breast cancer, ER-positive breast cancer, HER2-positive breast cancer, or HER2-negative breast cancer) .
  • the cancer is ovarian cancer.
  • the cancer is cervical cancer.
  • the cancer is lung cancer (e.g., adenocarcinoma lung cancer, and squamous cell lung carcinoma) .
  • the cancer is kidney cancer.
  • the cancer is bladder cancer. In one embodiment, the cancer is liver cancer. In one embodiment, the cancer is sarcoma. In one embodiment, the cancer is a hematological cancer (e.g., leukemia, lymphoma, or myeloma) . In one embodiment, the cancer is thyroid cancer. In one embodiment, the cancer is colon cancer. In one embodiment, the cancer is gastric cancer. In one embodiment, the cancer is colorectal cancer. In one embodiment, the cancer is endometrial cancer. In one embodiment, the cancer is an advanced or metastatic.
  • the cancer is associated with or has a dysregulation of a PIK3CA gene, a PI3K ⁇ protein, or expression or activity, or level of any of the same. In one embodiment, the cancer is associated with or has a dysregulation of a PIK3CA gene. In one embodiment, the cancer is associated with or has one or more mutations in the PIK3CA gene. In one embodiment, the cancer is associated with or has a dysregulation of a PI3K ⁇ protein. In one embodiment, the cancer is associated with or has one or more mutations in a PI3K ⁇ protein. In one embodiment, the mutation in a PI3K ⁇ protein comprises one or more PI3K ⁇ protein substitutions, point mutations, and insertions. Non-limiting examples of PI3K ⁇ protein mutations (e.g. substitutions, insertions, or deletions) are described in Table 2.
  • the dysregulation of a PIK3CA gene, a PI3K ⁇ protein, or expression or activity or level of any of the same includes a splice variation in a PI3K ⁇ mRNA which results in an expressed protein that is an alternatively spliced variant of PI3K ⁇ having at least one residue deleted (as compared to the wild type PI3K ⁇ protein) resulting in a constitutive activity of a PI3K ⁇ protein domain.
  • the dysregulation of a PIK3CA gene, a PI3K ⁇ 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 PI3K ⁇ protein that has one or more amino acid substitutions or insertions or deletions in a PIK3CA gene that results in the production of a PI3K ⁇ protein that has one or more amino acids inserted or removed, as compared to the wild type PI3K ⁇ protein.
  • the resulting mutant PI3K ⁇ protein has increased activity, as compared to a wild type PI3K ⁇ protein or a PI3K ⁇ protein not including the same mutation.
  • the compounds described herein selectively inhibit the resulting mutant PI3K ⁇ protein relative to a wild type PI3K ⁇ protein or a PI3K ⁇ protein not including the same mutation.
  • the PI3K ⁇ protein mutation is E542A, E542G, E542K, E542Q, E542V, E545A, E545D, E545G, E545K, E545Q, M1043I, M1043L, M1043T, M1043V, H1047L, H1047Q, H1047R, H1047Y, or G1049R, or a combinations thereof.
  • the PI3K ⁇ protein mutation is H1047X, where X is any amino acid.
  • the PI3K ⁇ protein mutation is H1047R.
  • the PIK3CA mutation comprises a modification in a codon that encodes an amino acid substitution at a specific position selected from a group consisting of G118, C420, E542, E545, Q546, H1047, and any combination thereof, in the corresponding PI3K ⁇ protein.
  • the PIK3CA mutation results in the translation of a PI3K ⁇ protein having one or more mutations in the adaptor-binding domain (ABD) , C2 domain, helicase domain, or kinase domain.
  • the PI3K ⁇ protein has a mutation in the helicase domain, for example, in Exon 7 (e.g., C420R) , or in Exon 9 (e.g., E542K, E545A, E545D, E545G, E545K, Q546E, or Q546R) .
  • the PI3K ⁇ protein has a mutation in the kinase domain, for example, in Exon 20 (e.g., H1047L, H1047R, or H1047Y) .
  • the PI3K ⁇ protein has mutations in both the helical domain and kinase domain.
  • the PIK3CA mutations and PI3K ⁇ protein mutations are those described in Mangone et al., Clinics. 2012; 67 (11) : 1285-1290; Ligresti et al., Cell Cycle, 2009, 8 (9) : 1352–1358; Zhao et al., Proc Natl Acad Sci. 2008, 105: 2652–2657, the entirely of each of which is incorporated herein by reference.
  • a compound provided herein is used to treat a cancer, wherein the cancer is a PIK3CA mutant cancer.
  • the cancer is colon cancer having one or more mutations selected from the group consisting of C311G, G317T, G323C, del332–334, G353A, G365A, C370A, T1035A, T1258C, G1357C, C1616G, A1625G, A1634G, G1635T, C1636A, A1637C, C1981A, G2702T, T2725C, T3022C, A3073G, C3074A, G3129T, C3139T, and A3140T in the coding exons of PIK3CA.
  • the PIK3CA mutant cancer is glioblastomas having one or more mutations selected from the group consisting of T1132C, G1048C, A2102C, and G3145A in the coding exons of PIK3CA.
  • the PIK3CA mutant cancer is gastric cancer having G2702T, or A3140G mutation in the coding exons of PIK3CA.
  • the PIK3CA mutant cancer is lung cancer having G1633A mutation in the coding exons of PIK3CA.
  • the PIK3CA mutant cancer is breast cancer having one or more mutations selected from the group consisting of C1241T, T1258C, del1352–1366, G1624A, G1633A, C1636G, A3140G, A3140T, G1624A, G1633A, A1634G, C3075T, A3140T, and A3140G in the coding exons of PIK3CA.
  • the PIK3CA mutant cancers are those described in Ligresti et al., Cell Cycle, 2009, 8 (9) : 1352–1358, the entirely of which is incorporated herein by reference.
  • a method of treating a PI3K ⁇ -associated cancer in a subject comprising (a) diagnosing the cancer in the subject as a PI3K ⁇ -associated cancer, and then (b) administering a therapeutically effective amount of a compound provided herein to the subject.
  • the diagnosing of PI3K ⁇ -associated cancer involves liquid biopsy.
  • the diagnosing of PI3K ⁇ -associated cancer involves tumor biopsy.
  • the diagnosing of PI3K ⁇ -associated cancer involves genetic testing (e.g. DNA sequencing) .
  • provided herein is a method of treating a subject having a dysregulation of a PIK3CA gene or PI3K ⁇ protein by administering a compound provided herein to the subject.
  • the subject has been identified or diagnosed as having a cancer with a dysregulation of a PIK3CA gene or a PI3K ⁇ protein.
  • the subject has a tumor that is positive for a dysregulation of a PIK3CA gene or a PI3K ⁇ protein.
  • the subject has a tumor that is positive for a mutation in the coding exons of PIK3CA.
  • the subject has a tumor that is positive for a mutation in the amino acid sequence of PI3K ⁇ .
  • the one or more mutations in a PIK3CA gene can result, e.g., in the translation of an PI3K ⁇ protein having one or more of the following amino acids: 542, 545, 1043, and 1047 and 1049.
  • PI3K ⁇ protein has one or more mutations selected from the groups consisting of E542A, E542G, E542K, E542Q, E542V, E545A, E545D, E545G, E545K, E545Q, M1043I, M1043L, M1043T, M1043V, H1047L, H1047Q, H1047R, H1047Y, and G1049R.
  • the cancer with a dysregulation of a PIK3CA gene, a PI3K ⁇ protein, or expression or activity or level of any of the same is determined using a regulatory agency-approved, e.g., FDA-approved, assay or kit.
  • the assay utilizes next generation sequencing, pyrosequencing, immunohistochemistry, or break apart FISH analysis.
  • the assay is a regulatory agency-approved assay, e.g., FDA-approved kit.
  • the assay is a liquid biopsy.
  • the biological sample to be used in a liquid biopsy includes, e.g., blood, plasma, urine, cerebrospinal fluid, saliva, sputum, broncho-alveolar lavage, bile, lymphatic fluid, cyst fluid, stool, ascites, or a combination thereof.
  • a liquid biopsy is used to detect circulating tumor cells (CTCs) .
  • a liquid biopsy is used to detect cell-free DNA.
  • cell-free DNA detected using a liquid biopsy is circulating tumor DNA (ctDNA) that is derived from tumor cells.
  • analysis of ctDNA e.g., using sensitive detection techniques such as next-generation sequencing (NGS) , traditional PCR, digital PCR, or microarray analysis
  • NGS next-generation sequencing
  • PIK3CA gene
  • PI3K ⁇ protein protein
  • microarray analysis is used to identify dysregulation of a PIK3CA gene, a PI3K ⁇ protein, or the expression or activity or level of any of the same. Additional assays are also known in the art.
  • compounds provided herein are provided for use as a medicament or are provided for use in preparing a medicament, e.g., for the treatment of cancer. In some embodiment, compounds provided herein are provided for use in a method for the treatment of cancer.
  • compounds provided herein are provided for use in a method for the treatment of diseases or conditions by inhibiting PI3K ⁇ protein.
  • compositions comprising a compound provided herein and a pharmaceutically acceptable excipient.
  • the pharmaceutical composition provided herein is administered by various routes to mammals, including rodents and humans.
  • the administration is intranasal, intravenous, intraperitoneal, intramuscular, intraarticular, intralesional, intratracheal, subcutaneous, or intradermal administration.
  • the administration is intravenous administration.
  • the administration is intramuscular administration.
  • the administration is oral administration.
  • a pharmaceutical composition provided herein is orally administered in an orally acceptable dosage form including capsules, tablets, aqueous suspensions or solutions.
  • compounds provided herein are administered to a mammal in the form of a raw chemical without any other components present.
  • compounds provided herein are administered to a mammal as part of a pharmaceutical composition containing the compound combined with a suitable pharmaceutically acceptable carrier (see, for example, Gennaro, Remington: The Science and Practice of Pharmacy with Facts and Comparisons: Drugfacts Plus, 20th ed. (2003) ; Ansel et al., Pharmaceutical Dosage Forms and Drug Delivery Systems, 7th ed., Lippencott Williams and Wilkins (2004) ; Kibbe et al., Handbook of Pharmaceutical Excipients, 3rd ed., Pharmaceutical Press (2000) ) .
  • Non-limiting examples of pharmaceutically suitable carriers include solids and/or liquids such as water, alcohol and glycerol.
  • Pharmaceutically acceptable excipients and diluents include, but are not limited to buffers, preservatives, binders, fillers, disintegrants, lubricants, wetting agents, antioxidants, flavorings, thickeners, coloring agents, emulsifiers, suspending agents and the like.
  • excipients and diluents also include sucrose, lactose, dextrose, sorbitol, mannitol, erythritol, maltitol, starch, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, polyvinyl pyrrolidone, water, methylhydroxy benzoate, propylhydroxy benzoate, talc, magnesium stearate and mineral oil.
  • a pharmaceutical composition provided herein is prepared as liquid suspensions or solutions using a liquid, such as an oil, water, an alcohol, and combinations of these.
  • a pharmaceutical composition provided herein is prepared as a sterile injectable, which may be aqueous or oleaginous suspensions.
  • the suspension is formulated according to techniques known in the art using suitable dispersing or wetting agents (e.g., Polysorbate) .
  • the sterile injectable formulation is a sterile injectable solution or suspension in a diluent or solvent.
  • sterile fixed oils are employed as a solvent or suspending medium. Pharmaceutically acceptable natural oils or fatty acids may also be used in the preparation of injectable formulations.
  • a pharmaceutical composition provided herein is administered in the form of suppositories for rectal administration.
  • a pharmaceutical composition provided herein is administered topically, especially when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, the skin, or the lower intestinal tract.
  • Topical application for the lower intestinal tract is effected in a rectal suppository formulation or in a suitable enema formulation.
  • Topically-transdermal patches may also be used.
  • the pharmaceutical compositions is formulated in a suitable ointment, lotion, or cream containing the active component suspended or dissolved in one or more carriers.
  • a pharmaceutical composition provided herein is administered ophthalmically and formulated as micronized suspensions in isotonic, pH adjusted sterile saline, or, solutions in isotonic, pH adjusted sterile saline, either with or without a preservative such as benzyl alkonium chloride.
  • the pharmaceutical compositions is formulated in an ointment such as petrolatum.
  • a pharmaceutical composition provided herein is administered by nasal aerosol or inhalation.
  • Such compositions are prepared according to techniques known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other conventional solubilizing or dispersing agents.
  • the pharmaceutical compositions to be used for in vivo administration can be sterile. In one embodiment, this is accomplished by filtration through, e.g., sterile filtration membranes.
  • a pharmaceutical composition provided herein is administered to a patient that may experience the beneficial effects of a compound provided herein.
  • the patients are mammals, e.g., humans and companion animals.
  • the patient is a human.
  • kits which comprise a compound provided herein (or a composition comprising a compound provided herein) packaged in a manner that facilitates their use to practice methods provided herein.
  • the kit includes a compound provided herein (or a composition comprising a compound provided herein) packaged in a container, such as a sealed vial, with a label affixed to the container or included in the kit that describes use of the compound or composition to practice the method provided herein.
  • the compound or composition is packaged in a unit dosage form.
  • the kit further includes a device suitable for administering the compound or composition according to the intended route of administration.
  • the kit comprises a compound provided herein, and instructions for administering the compound to a patient having cancer.
  • stereochemical configuration for a chiral center in a compound provided herein is drawn stereo specifically (e.g., with widget and/or dash bonds) , either without additional designation or being designated “R” (or “ (R) ” ) or “S’ (or “ (S) ” ) , it means the mixture (s) was separated and absolute stereochemistry was known, or only one enantiomer was obtained and absolute stereochemistry was known.
  • the stereochemical configuration at indicated centers has been designated as “*R” (first eluted from the column in case the column conditions of the separation are described in the synthesis protocol and when only one stereocenter present or indicated) or “*S” (second eluted from the column in case the column conditions of the separation are described in the synthesis protocol and when only one stereocenter present or indicated) when the absolute stereochemistry is undetermined (even if the bonds are drawn stereo specifically) although the compound itself has been isolated as a single stereoisomer and is enantiomerically pure.
  • the “*R” indication of the resulting compound is derived from its starting material.
  • Intermediate 11 (5 g, 13.31 mmol) was separated by supercritical fluid chromatography (column: DAICEL CHIRALPAK AD (250mm*50mm, 10 um) ; mobile phase: [CO 2 -EtOH (0.1%NH 3 H 2 O) ] ; B%: 30%, isocratic elution mode) .
  • the first fraction was collected as intermediate 11a (2.81 g, 5.43 mmol, 40.81%yield, 81.21%purity) as a yellow solid.
  • the second fraction was collected as intermediate 11b (1.75 g, 4.07 mmol, 30.57%yield, 98.09%purity) as a yellow solid.
  • reaction mixture was quenched by addition of MeOH 30 mL at 0 °C and concentrated under reduced pressure to give a residue.
  • residue was purified by flash column chromatography on silica gel (eluent: A, petroleum ether; B, ethyl acetate, 0%B to 48%B in A) to afford intermediate 20 (2.29 g, 4.72 mmol, 38.57%yield) as a yellow oil.
  • reaction mixture was quenched with the saturated solution of sodium bicarbonate (20 mL) at 0 °C, then H 2 O (50 mL) was added, and the mixture was extracted with ethyl acetate (50 mL x 3) .
  • the combined organic layers were dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure to give intermediate 56 (700 mg, crude) , which was used in the next step without further purification.
  • the reaction mixture was cooled down to 25 °C and 5-bromo-2-iodo-pyrimidine (20.13 g, 70.64 mmol) , Pd (dppf) Cl 2 ⁇ CH 2 Cl 2 (5.77 g, 7.06 mmol) and CuI (1.35 g, 7.06 mmol) were added.
  • the reaction mixture was stirred at 80 °C for 2 hr.
  • the reaction mixture was cooled to room temperature, diluted with ethyl acetate (200 mL) and water (500 mL) and then filtered. The filtrate was extracted with ethyl acetate (3 x 300 mL) .
  • the combined organic layers were washed with aq.
  • intermediate 89 330 mg, 0.58 mmol
  • MeOH MeOH
  • urea hydrogen peroxide 135 mg, 1.44 mmol
  • the reaction mixture was stirred for 4 hr.
  • the reaction was diluted with water (20 mL) .
  • the reaction mixture was extracted with EtOAc (20 mL x 3) and the combined organic layers were washed with brine, dried over anhydrous sodium sulphate.
  • the mixture was filtered, and the filtrate was evaporated under reduced pressure to give intermediate 90 (230 mg, yield: 86.24 %) , which was used for next step and without further purification.
  • intermediate 105 50 mg, 0.34 mmol
  • 2-chloro-5-nitropyrimidine 55 mg, 0.34 mmol
  • EtOH 5 mL
  • DIEA 133 mg, 1.03 mmol
  • the reaction mixture was stirred at 80 °C for 3 hr.
  • the reaction mixture was concentrated under reduced pressure to give a residue, which was purified by column chromatography on silica gel eluted with DCM/MeOH (25/1) to afford intermediate 106 (88 mg, yield: 95.27%) as a yellow solid.
  • intermediate 106 To a solution of intermediate 106 (88 mg, 0.33 mmol) in CH 3 CN (4 mL) was added HCl (1 mL, 1 N) and NCS (175 mg, 1.31 mmol) at 0 °C and stirred at r. t. for 1 hr. The reaction mixture was poured into water (100 mL) and extracted with EtOAc (50 mL x 2) . The combined organic layers were washed with saturated NaHCO 3 and brine. The organic layer was dried over Na 2 SO 4 and filtered. The filtrate was concentrated under reduced pressure to afford intermediate 107 (90 mg, crude) as a light-yellow solid, which was used for the next step without further purification.
  • intermediate 131 500 mg, 2.08 mmol
  • acetone 10 mL
  • K 2 CO 3 863 mg, 6.24 mmol
  • dimethyl sulfate 0.3 mL, 2.70 mmol
  • the reaction mixture was stirred at 60 °C for 6 hr.
  • the reaction mixture was filtered and concentrated in vacuo to give a residue, which was purified by column chromatography on silica gel eluted with PE/EA (5/1) to afford intermediate 132 (450 mg, yield: 85.07%) as a yellow solid.
  • Compound 1 was separated by SFC (column: (s, s) WHELK-O1 (250mm*30mm, 5um) ; mobile phase: [CO 2 -i-PrOH (0.1%NH 3 H 2 O) ] ; B%: 50%, isocratic elution mode) . The pure fractions were collected, and the solvent was evaporated under vacuum. The residue was partitioned between acetonitrile (2 mL) and water (10 mL) . The mixture was lyophilized to dryness to give the desired compound.
  • SFC column: (s, s) WHELK-O1 (250mm*30mm, 5um) ; mobile phase: [CO 2 -i-PrOH (0.1%NH 3 H 2 O) ] ; B%: 50%, isocratic elution mode
  • the first fraction was obtained as Compound 2 (43.31 mg, 84.02 ⁇ mol, 43.31%yield)
  • the second fraction was obtained as Compound 3 (41.26 mg, 78.68 ⁇ mol, 40.56%yield) .
  • Compound 4 was separated by SFC, basic condition; column: (s, s) WHELK-O1 (250mm*30mm, 10um) ; mobile phase: [CO 2 -EtOH (0.1%NH 3 H 2 O) ] ; B%: 35%, isocratic elution mode. The pure fractions were collected, and the solvent was evaporated under vacuum. The residue was partitioned between acetonitrile (2 mL) and water (10 mL) . The mixture was lyophilized to dryness to give the desired compound.
  • the first fraction was collected as Compound 5 (38.94 mg, 71.28 ⁇ mol, 25.35%yield)
  • the second fraction was collected as Compound 6 (42.56 mg, 77.33 ⁇ mol, 27.50%yield) .
  • the first fraction was collected as Compound 60 (52.23 mg, 100.92 ⁇ mol, 42%yield, 99.59%purity) as a white solid and the second fraction was collected as Compound 61 (50.28 mg, 97.30 ⁇ mol, 40%yield, 99.74%purity) as a white solid.
  • HPLC High-Performance Liquid Chromatography
  • MS Mass Spectrometer
  • Mobile phase Ramp from 30%ACN (0.018%TFA) in water (0.037%TFA) to 90%ACN in 2.00 min, Flow rate is set at 1.5 mL/min; then ramp from 90%ACN in water to 100%ACN in 1.70 min. Flow rate is set at 1.5 mL/min; return to 30%ACN in water and hold for 0.30 min. Flow rate is set at 2.0 mL/min.
  • Column temperature at 50°C and detector wavelength from 210 nm to 265 nm. The column is of EVO C18 4.6 x 50 mm, 5 ⁇ m.
  • Mobile phase Ramp from 5%ACN (0.01875%TFA) in water (0.0375%TFA) to 95%ACN in 2.40 min, Flow rate is set at 2.0 mL/min; then hold at 95%ACN for 0.30 minutes. Flow rate is set at 2.0 mL/min; return back to 5%ACN in water and hold for 0.30 min. Flow rate is set at 2.0 mL/min.
  • Mobile phase Ramp from 5%ACN (0.01875%TFA) in water (0.0375%TFA) to 95%ACN in 3.20 min, Flow rate is set at 1.5 mL/min; then hold at 95%ACN for 0.30 minutes. Flow rate is set at 1.5 mL/min; return to 5%ACN in water and hold for 0.30 min. Flow rate is set at 2.0 mL/min.
  • Mobile phase Ramp from 5%ACN in water (0.025%NH 3 ⁇ H 2 O) to 95%ACN in 3.00 min, Flow rate is set at 0.6 mL/min; then hold at 95%ACN for 0.70 minutes Flow rate is set at 0.6 mL/min; return to 5%ACN in water and hold for 0.30 min. Flow rate is set at 1.2 mL/min.
  • Column temperature at 40°C and detector wavelength from 210 nm to 265 nm.
  • the column is XBridge C18 2.1 x 30 mm, 3.5 ⁇ m.
  • Mobile phase Ramp from 5%ACN (0.01875%TFA) in water (0.0375%TFA) to 95%ACN in 4.8 min, Flow rate is set at 0.6 mL/min; then hold at 95%ACN for 0.60 minutes. Flow rate is set at 1.0 mL/min; return to 5%ACN in water and hold for 0.60 min. Flow rate is set at 1.0 mL/min.
  • Column temperature at 50 °C. The column is Kinetex EVO C18 2.1*50mm, 1.7 ⁇ m.
  • Mobile phase Ramp from 5%ACN (0.01875%TFA) in water (0.0375%TFA) to 95%ACN in 3.20 min, Flow rate is set at 1.5 mL/min; then hold at 95%ACN for 0.30 minutes. Flow rate is set at 1.5 mL/min; return to 5%ACN in water and hold for 0.30 min. Flow rate is set at 2.0 mL/min.
  • Column temperature at 50°C. The column is of EVO C18 4.6 x50 mm, 5 ⁇ m.
  • Mobile phase Ramp from 5%ACN (0.01875%TFA) in water (0.0375%TFA) to 95%ACN in 2.40 min, Flow rate is set at 2.0 mL/min; then hold at 95%ACN for 0.30 minutes Flow rate is set at 2.0 mL/min; return to 5%ACN in water and hold for 0.30 min. Flow rate is set at 2.0 mL/min.
  • Column temperature at 50 °C. The column is of EVO C18 4.6 x 50 mm, 5 ⁇ m.
  • Mobile phase Ramp from 5%ACN (0.01875%TFA) in water (0.0375%TFA) to 95%ACN in 3.20 min, Flow rate is set at 1.5 mL/min; then hold at 95%ACN for 0.30 minutes. Flow rate is set at 1.5 mL/min; return to 5%ACN in water and hold for 0.30 min. Flow rate is set at 2.0 mL/min.
  • Column temperature at 50 °C. The column is of EVO C18 4.6 x 50 mm, 5 ⁇ m.
  • Mobile phase Ramp from 5%ACN (0.018%TFA) in water (0.037%TFA) to 95%ACN in 3.0 min, Flow rate is set at 1.0 mL/min; then hold at 95%ACN for 0.60 minutes. Flow rate is set from 1.0 mL/min to 1.5 mL/min; return to 5%ACN in water and hold for 0.40 min. Flow rate is set at 1.5 mL/min.
  • Mobile phase Ramp from 5%ACN in water (0.025%NH 3 ⁇ H 2 O) to 95%ACN in 2.60 min, Flow rate is set at 0.6 mL/min; then hold at 95%ACN for 0.25 minutes. Flow rate is set at 0.8 mL/min; return to 5%ACN in water and hold for 0.15 min. Flow rate is set at 1.2 mL/min.
  • Column temperature at 40°C and detector wavelength from 210 nm to 265 nm. The column is of XBridge C18 2.1 x 30 mm, 3.5 ⁇ m.
  • Mobile phase Ramp from 5%ACN (0.01875%TFA) in water (0.0375%TFA) to 95%ACN in water in 0.60 min, Flow rate is set at 2.0 mL/min; then hold at 95%ACN for 0.18 minutes. Flow rate is set at 2.0 mL/min; return back to 5%ACN in water and hold for 0.02 min. Flow rate is set at 2.0 mL/min.
  • Mobile phase Ramp from 5%ACN in water (0.025%NH 3 ⁇ H 2 O) to 95%ACN in 3.00 min, Flow rate is set at 0.9 mL/min; then hold at 95%ACN for 0.70 minutes. Flow rate is set at 0.9 mL/min; return to 5%ACN in water and hold for 0.30 min. Flow rate is set at 1.2 mL/min.
  • Column temperature at 40°C and detector wavelength from 210 nm to 265 nm. The column is of XBridge C18 3.0 x 50 mm, 5 ⁇ m.
  • NMR experiments were carried out using a Bruker Advance III 400 spectrometer at ambient temperature (298.6 K) , using internal deuterium lock, and equipped with BBO 400 MHz S1 5 mm probe head with z gradients and operating at 400 MHz for the proton and 100 MHz for carbon. Chemical shifts ( ⁇ ) are reported in parts per million (ppm) . J values are expressed in Hz.
  • PI3K ⁇ kinase activity and the determination of inhibitors IC 50 was determined by ADP-Glo TM Kinase Assay (V9102, Promega) .
  • Recombinant, Full length human PI3K ⁇ wild-type or H1047R mutant protein were purchased as 1: 1 complex of N-terminal 6x his-tagged PIK3CA (p110 ⁇ , catalytic subunit) and untagged PIK3R1 (p85 ⁇ , regulatory subunit) from Viva Biotech.
  • L- ⁇ -phosphatidylinositol from Glycine max Soy PI, Cat. L130328 was used for the lipid substrate by dissolving in the ddH 2 O to a final concentration of 1 mM.
  • kinase buffer was prepared in 50 mM HEPES, 10 mM MgCl 2 , 1 mM EGTA, 2 mM DTT, and 0.015%Brij-35.5 nM PI3K ⁇ proteins plus 2 ⁇ M Soy PI were pre-incubated with compounds in plate at RT for 30 min. After the pre-incubation, the reaction was initiated by adding a final concentration of 100 ⁇ M ATP for 2 h.
  • the human breast cancer cells T-47D with PICKCA mutation H1047R were maintained in RPMI 1640 (Gibco, 11875093) supplemented with 10%Fetal Bovine Serum, heat inactivated (Invitrogen, 10091-148) . Cultures were maintained in a humidified incubator at 37°C under 5%CO 2 /95%air. For compound testing, T-47D cells were seeded at a density of 2x10E4 cells per well in 96-well plates in 100 ⁇ L of RPMI 1640 Media with 0.1%FBS, incubated overnight. Compounds dissolved in 10 mM stock solutions in DMSO were serially diluted 1: 5 in DMSO to generate a 10-point dilution series.
  • the supernatant of cells was aspirated from 96-well plate, and 100 ⁇ L dilution series of compounds in RPMI 1640 Media with 0.1%FBS were added to the cell plate to final concentrations ranging from 20 ⁇ M to 0.0000102 ⁇ M in 0.2%DMSO. 0.2%DMSO alone was used to establish the maximum (MAX) signal and Alpelisib was used as a reference compound.
  • the medium was removed, and the cells lysed in 40 ⁇ L of freshly prepared 1 x Lysis Buffer with shaking ( ⁇ 350 rpm) for 20 minutes at room temperature.
  • the Donor Mix (Dilution Buffer + Alpha Streptavidin Donor Beads) was prepared by diluting Donor Beads 50-fold in dilution buffer. 2.5 ⁇ L of the Donor Mix was added to each well and the plate sealed and covered with foil and incubated for 1 hour at room temperature in the dark. The plates were read on a Spark multimode plate reader instrument from Tecan using standard AlphaLisa settings.
  • the human breast cancer cells with PI3KCA mutations T-47D (PI3KCA H1047R/WT) , MDA-MB-453 (PI3KCA H1047R/WT) , were employed to test the activity of compounds on cell proliferation.
  • T-47D, MDA-MB-453 and SK-BR3 cells were maintained in RPMI 1640 (Gibco, 11875093) , DMEM (Gibco, 11965092) or McCoy's 5A (Gibco, 16600082) medium respectively, supplemented with 10%Fetal Bovine Serum, heat inactivated (Invitrogen, 10091-148) . Cultures were maintained in a humidified incubator at 37°C under 5%CO 2 /95%air. To investigate the effect of various compounds on cell growth, T-47D, MDA-MB-453 or SK-BR-3 cells were seeded at a density of 500 cells per well in 384-well plates in 40 ⁇ L of growth medium.
  • the plate was then incubated at 37°C with 5%CO 2 for adhesion.
  • compounds at a 2X top concentration (20 ⁇ M) were prepared in growth medium and 40 ⁇ L of the compound solution was added to each well, then the plate was incubated at 37°C for 5 days.
  • 1/10th volume of (10 ⁇ ) Alamar blue reagent (Thermo, A50100) was added directly to cells in culture medium, and the plate was incubated overnight at 37°C with 5%CO 2 . Fluorescence was measured by plate reader (Perkin Elmer Victor Nivo 5F) using an excitation wavelength of 560 nm and an emission wavelength of 590 nm.
  • T47D anti-proliferation IC 50 (nM) and MB-453 anti-proliferation IC 50 (nM) A denotes ⁇ 100 nM; B denotes 100 nM ⁇ IC 50 ⁇ 500 nM; C denotes 500 nM ⁇ IC 50 ⁇ 1000 nM; D denotes IC 50 ⁇ 1000 nM.

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Abstract

L'invention concerne certains composés multicycliques, tels qu'un composé de formule (I), utilisés comme inhibiteurs de PI3Kα, des compositions pharmaceutiques comprenant les composés, et un procédé d'utilisation des composés ou des compositions pharmaceutiques dans le traitement de maladies ou de troubles.
PCT/CN2024/090120 2023-04-27 2024-04-26 Composés de benzofurane et leur utilisation en tant qu'inhibiteurs de pi3k alpha WO2024222894A1 (fr)

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