[go: up one dir, main page]

WO2025212599A1 - Inhibiteurs de pi3kalpha et leurs utilisations - Google Patents

Inhibiteurs de pi3kalpha et leurs utilisations

Info

Publication number
WO2025212599A1
WO2025212599A1 PCT/US2025/022475 US2025022475W WO2025212599A1 WO 2025212599 A1 WO2025212599 A1 WO 2025212599A1 US 2025022475 W US2025022475 W US 2025022475W WO 2025212599 A1 WO2025212599 A1 WO 2025212599A1
Authority
WO
WIPO (PCT)
Prior art keywords
alkyl
heterocyclyl
cycloalkyl
heteroaryl
haloalkyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/US2025/022475
Other languages
English (en)
Inventor
Christopher T. Clark
Zhimin Du
Chao-I HUNG
Zachary A. KASUN
Jennifer A. Loyer-Drew
Shaina V. NGUYEN
Thomas J. PAUL
Rhiannon THOMAS-TRAN
Joshua J. Van Veldhuizen
William J. Watkins
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Gilead Sciences Inc
Original Assignee
Gilead Sciences Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Gilead Sciences Inc filed Critical Gilead Sciences Inc
Publication of WO2025212599A1 publication Critical patent/WO2025212599A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • 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
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C07D491/048—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being five-membered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
    • C07D491/14—Ortho-condensed systems
    • C07D491/147—Ortho-condensed systems the condensed system containing one ring with oxygen as ring hetero atom and two rings with nitrogen as ring hetero atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
    • C07D491/14—Ortho-condensed systems
    • C07D491/153—Ortho-condensed systems the condensed system containing two rings with oxygen as ring hetero atom and one ring with nitrogen as ring hetero atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
    • C07D491/20—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • PI3K ⁇ (Phosphoinositide 3-kinase alpha) is a class IA lipid kinase that catalyzes the phosphorylation of PIP2 to PIP3, initiating downstream AKT/mTOR signaling cascade.
  • PI3K ⁇ is composed of catalytic subunit p110 ⁇ encoded by PIK3CA and regulatory subunit p85 ⁇ encoded by PIK3R1.
  • Mutations in p110 ⁇ lead to hyperactivation of the signaling pathway and promote tumor outgrowth.
  • PI3K ⁇ mutations are prevalent in solid tumors, with a high incidence in HR+/HER2- breast cancer.
  • PI3K ⁇ isoform-selective inhibitor alpelisib
  • alpelisib has been clinically approved for patients with PI3K ⁇ -mutated, HR+/HER2-breast cancer.
  • the clinical benefit of PI3K ⁇ isoform-selective inhibitors is likely reduced by dose-limiting toxicities.
  • a mutant-selective PI3K ⁇ inhibitor that avoids toxicities associated with WT PI3K ⁇ inhibition might achieve sustained target coverage so as to substantially improve efficacy and durability relative to WT PI3K ⁇ inhibitors.
  • the present disclosure provides compounds useful as PI3K ⁇ inhibitors.
  • the disclosure further relates to the use of the compounds for the treatment of diseases and/or conditions through inhibiting PI3K ⁇ by said compounds.
  • the disclosure further relates to the use of the compounds for the treatment of diseases and/or conditions through inhibiting mutant PI3K ⁇ in tumors by said compounds.
  • R 1 is C6-12 aryl, heteroaryl, C3-12 cycloalkyl, heterocyclyl, C1-6 alkyl, or C1-6 haloalkyl; the aryl, heteroaryl, cycloalkyl, heterocyclyl, haloalkyl, or alkyl of R 1 is optionally substituted with one to three Z 1 , which may be the same or different;
  • R 2 is H, C1-6 alkyl, C3-6 cycloalkyl, C3-6 halocycloalkyl, or C1-6 haloalkyl;
  • R 3 is H, CN, C 1-6 alkyl, C 3-6 cycloalkyl, C 3-6 halocycloalkyl, or C 1-6 haloalkyl; or R 2 and R 3 together with the carbon to which they are attached form C 3-6 cycloalkyl;
  • Y is N, CH, or
  • compositions comprising a compound provided herein, or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient or carrier.
  • the pharmaceutical compositions comprise a therapeutically effective amount of a compound provided herein, or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient or carrier.
  • the pharmaceutical compositions provided herein further comprise one or more (e.g., one, two, three, four, one or two, one to three, or one to four) additional therapeutic agents, or pharmaceutically acceptable salts thereof.
  • the pharmaceutical compositions further comprise a therapeutically effective amount of the one or more (e.g., one, two, three, four, one or two, one to three, or one to four) additional therapeutic agents, or pharmaceutically acceptable salts thereof.
  • the present disclosure provides methods of inhibiting PI3K ⁇ in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound provided herein, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition provided herein.
  • DETAILED DESCRIPTION [0013] The present disclosure relates to inhibitors of PI3K ⁇ . The disclosure also relates to compositions and methods relating to PI3K ⁇ inhibitors and the use of such compounds for treatment of diseases and conditions.
  • compositions and methods Attorney Docket No.: 1542-WO-PCT of treating cancer or viral infections that include a PI3K ⁇ inhibitorin combination with one or more additional therapeutic agents.
  • Definitions and General Parameters [0014] The description below is made with the understanding that the present disclosure is to be considered as an exemplification of the claimed subject matter and is not intended to limit the appended claims to the specific embodiments illustrated.
  • the headings used throughout this disclosure are provided for convenience and are not to be construed to limit the claims in any way. Embodiments illustrated under any heading may be combined with embodiments illustrated under any other heading. [0015] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art.
  • a dash at the front or end of a chemical group is a matter of convenience; chemical groups may be depicted with or without one or more dashes without losing their ordinary meaning.
  • a wavy line drawn through a line in a structure indicates a point of attachment of a group. Unless chemically or structurally required, no directionality is indicated or implied by the order in which a chemical group is written or named.
  • a solid line coming out of the center of a ring indicates that the point of attachment for a substituent on the ring can be at any ring atom.
  • R a in the below structure can be attached to any of the five carbon ring atoms or R a can replace the hydrogen attached to the nitrogen ring atom: .
  • C u-v indicates that the following group has from u to v carbon atoms.
  • C1-6 alkyl indicates that the alkyl group has from 1 to 6 carbon atoms.
  • x-y membered rings wherein x and y are numerical ranges, such as “3 to12-membered heterocyclyl”, refers to a ring containing x-y atoms (e.g., 3-12), of which up to 80% may be heteroatoms, such as N, O, S, P, and the remaining atoms are carbon.
  • certain commonly used alternative chemical names may or may not be used.
  • a divalent group such as a divalent “alkyl” group, a divalent “aryl” group, etc.
  • a divalent group such as a divalent “alkyl” group, a divalent “aryl” group, etc.
  • a compound disclosed herein” or “a compound of the present disclosure” or “a compound provided herein” or “a compound described herein” refers to the compounds of Formula (I), (Ia), (Ia-1), (Ia-2), (Ia-3), (Ib), (Ib-1), (Ib-2), (Ib-3), (Ib-4), (Ib-5), (Ib-6), (Ib-7), (Ib-8), (Ib-9), (Ib-10), (Ib-11), (Ib-12), or (Ib-13). Also included are the specific compounds of Examples 1 to 52 provided herein. [0021] Reference to “about” a value or parameter herein includes (and describes) embodiments that are directed to that value or parameter per se.
  • the term “about” includes the indicated amount ⁇ 10%. In other embodiments, the term “about” includes the indicated amount ⁇ 5%. In certain other embodiments, the term “about” includes the indicated amount ⁇ 1%. Also, to the term “about X” includes description of “X”. Also, the singular forms “a” and “the” include plural references unless the context clearly dictates otherwise. Thus, e.g., reference to “the compound” includes a plurality of such compounds and reference to “the assay” includes reference to one or more assays and equivalents thereof known to those skilled in the art. [0022] “Alkyl” refers to an unbranched or branched saturated hydrocarbon chain.
  • alkyl has 1 to 20 carbon atoms (i.e., C1-20 alkyl), 1 to 8 carbon atoms (i.e., C1-8 alkyl), 1 to 6 carbon atoms (i.e., C1-6 alkyl), 1 to 4 carbon atoms (i.e., C1-4 alkyl), or 1 to 3 carbon atoms (i.e., C 1-3 alkyl).
  • alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl, 2-pentyl, isopentyl, neopentyl, n-hexyl, 2-hexyl, 3- hexyl, and 3-methylpentyl.
  • butyl includes n-butyl (i.e., - (CH2)3CH3), sec-butyl (i.e., -CH(CH3)CH2CH3), isobutyl (i.e., -CH2CH(CH3)2) and tert-butyl Attorney Docket No.: 1542-WO-PCT (i.e., -C(CH 3 ) 3 ); and “propyl” includes n-propyl (i.e., -(CH 2 ) 2 CH 3 ) and isopropyl (i.e., - CH(CH3)2).
  • Alkenyl refers to an aliphatic group containing at least one carbon-carbon double bond and having from 2 to 20 carbon atoms (i.e., C 2-20 alkenyl), 2 to 8 carbon atoms (i.e., C 2-8 alkenyl), 2 to 6 carbon atoms (i.e., C2-6 alkenyl), or 2 to 4 carbon atoms (i.e., C2-4 alkenyl).
  • alkenyl groups include ethenyl, propenyl, butadienyl (including 1,2-butadienyl and 1,3-butadienyl).
  • Alkynyl refers to an aliphatic group containing at least one carbon-carbon triple bond and having from 2 to 20 carbon atoms (i.e., C2-20 alkynyl), 2 to 8 carbon atoms (i.e., C2-8 alkynyl), 2 to 6 carbon atoms (i.e., C 2-6 alkynyl), or 2 to 4 carbon atoms (i.e., C 2-4 alkynyl).
  • alkynyl also includes those groups having one triple bond and one double bond.
  • examples of acyl include formyl, acetyl, cylcohexylcarbonyl, cyclohexylmethyl-carbonyl, and benzoyl.
  • Alkoxy refers to an alkyl group having an oxygen atom that connects the alkyl group to the point of attachment: alkyl-O-.
  • alkoxy groups will have any suitable number of carbon atoms, such as C1-6.
  • Alkoxy groups include, for example, methoxy, ethoxy, propoxy, iso-propoxy, butoxy, 2-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, pentoxy, hexoxy, etc.
  • the alkoxy groups can be further substituted with a variety of substituents described within.
  • Alkoxy groups can be substituted or unsubstituted.
  • Alkoxyalkyl refers an alkoxy group linked to an alkyl group which is linked to the remainder of the compound.
  • Alkoxyalkyl have any suitable number of carbon, such as from 2 to 6 (C 2-6 alkoxyalkyl), 2 to 5 (C 2-5 alkoxyalkyl), 2 to 4 (C 2-4 alkoxyalkyl), or 2 to 3 (C 2-3 alkoxyalkyl).
  • the number of carbons refers to the total number of carbons in the alkoxy and the alkyl group.
  • C6 alkoxyalkyl refers to ethoxy (C2 alkoxy) linked to a butyl (C 4 alkyl), and in other embodiments, n-propoxy (C 3 alkoxy) linked to isopropyl (C 3 alkyl).
  • Alkoxy and alkyl are as defined above where the alkyl is divalent, and can include, but is not limited to, methoxymethyl (CH3OCH2-), methoxyethyl (CH3OCH2CH2-) and others.
  • Attorney Docket No.: 1542-WO-PCT [0028] “Amino” refers to the group -NR y R z wherein R y and R z are independently selected from the group consisting of hydrogen, alkyl, haloalkyl, aryl, heteroaryl, cycloalkyl, or heterocyclyl; each of which may be optionally substituted.
  • Aryl refers to a single all carbon aromatic ring or a multicyclic all carbon ring system wherein at least one of the rings is aromatic.
  • an aryl group has 6 to 20 carbon atoms, 6 to 14 carbon atoms, or 6 to 12 carbon atoms.
  • Aryl includes a phenyl radical.
  • Aryl also includes multicyclicring systems (e.g., ring systems comprising 2, 3 or 4 rings) having 9 to 20 carbon atoms, e.g., 9 to 16 carbon atoms, in which at least one ring is aromatic and wherein the other rings may be aromatic or not aromatic (i.e., carbocycle).
  • Such multicyclicring systems are optionally substituted with one or more (e.g., 1, 2 or 3) oxo groups on any carbocycle portion of the multicyclic ring system.
  • the rings of the multicyclic ring system can be connected to each other via fused, spiro and bridged bonds when allowed by valency requirements. It is also to be understood that when reference is made to a certain atom-range membered aryl (e.g., 6-10 membered aryl), the atom range is for the total ring atoms of the aryl.
  • a 6-membered aryl would include phenyl and a 10- membered aryl would include naphthyl and 1,2,3,4-tetrahydronaphthyl.
  • aryl groups include, but are not limited to, phenyl, indenyl, naphthyl, 1,2,3,4- tetrahydronaphthyl, anthracenyl, and the like.
  • Cyano or “carbonitrile” refers to the group -CN.
  • Cycloalkyl refers to a saturated or partially saturated cyclic alkyl group having a single ring or multiple rings including fused, bridged, and spiro ring systems.
  • cycloalkyl includes cycloalkenyl groups (i.e., the cyclic group having at least one double bond).
  • cycloalkyl has from 3 to 20 ring carbon atoms (i.e., C3-20 cycloalkyl), 3 to 12 ring carbon atoms (i.e., C 3-12 cycloalkyl), 3 to 10 ring carbon atoms (i.e., C 3-10 cycloalkyl), 3 to 8 ring carbon atoms (i.e., C3-8 cycloalkyl), or 3 to 6 ring carbon atoms (i.e., C3-6 cycloalkyl).
  • Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
  • “Fused” refers to a ring which is bound to an adjacent ring.
  • the fused ring system is a heterocyclyl.
  • the fused ring system is a oxabicyclohexanyl.
  • the fused ring system Attorney Docket No.: 1542-WO-PCT [0033] “Bridged” refers to a ring fusion wherein non-adjacent atoms on a ring are joined by a divalent substituent, such as alkylenyl group, an alkylenyl group containing one or two heteroatoms, or a single heteroatom. Quinuclidinyl and admantanyl are examples of bridged ring systems.
  • the bridged ring is a bicyclopentyl (e.g., bicyclo[1.1.1]pentyl), bicycloheptyl (e.g., bicyclo[2.2.1]heptyl, bicyclo[3.1.1]heptyl), or bicyclooctyl (e.g., [0034] “Spiro” refers to a ring substituent which is joined by two bonds at the same carbon atom. Examples of spiro groups include 1,1-diethylcyclopentane, dimethyl-dioxolane, and 4- benzyl-4-methylpiperidine, wherein the cyclopentane and piperidine, respectively, are the spiro substituents.
  • bicyclopentyl e.g., bicyclo[1.1.1]pentyl
  • bicycloheptyl e.g., bicyclo[2.2.1]heptyl, bicyclo[3.1.1]heptyl
  • the spiro substituent is a spiropentanyl (spiro[a.b]pentanyl), spirohexanyl, spiroheptanyl, spirooctyl (e.g., spiro[2.5]octyl), spirononanyl (e.g., spiro[3.5]nonanyl), spirodecanyl (e.g., spiro[4.5]decanyl), or spiroundecanyl (e.g., spiro[5.5]undecanyl).
  • spiropentanyl spiro[a.b]pentanyl
  • spirohexanyl e.g., spiro[2.5]octyl
  • spirooctyl e.g., spiro[2.5]octyl
  • spirononanyl e.g., spiro[3.5
  • Halogen or “halo” includes fluoro, chloro, bromo, and iodo.
  • Haloalkyl refers to an alkyl as defined herein, wherein one or more hydrogen atoms of the alkyl are independently replaced by a halo substituent, which may be the same or different.
  • C1-4 haloalkyl is a C1-4 alkyl wherein one or more of the hydrogen atoms of the C 1-4 alkyl have been replaced by a halo substituent.
  • haloalkyl groups include but are not limited to fluoromethyl, fluorochloromethyl, difluoromethyl, difluorochloromethyl, trifluoromethyl, 1,1,1-trifluoroethyl and pentafluoroethyl.
  • Haloalkoxy refers to an alkoxy group where some or all of the hydrogen atoms are substituted with halogen atoms.
  • haloalkoxy groups can have any suitable number of carbon atoms, such as C1-6.
  • the alkoxy groups can be substituted with 1, 2, 3, or more halogens.
  • heteroaryl refers to a single aromatic ring or a multicyclic ring.
  • the term includes single aromatic rings of from about 1 to 6 carbon atoms and about 1-4 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur in the rings.
  • the sulfur and nitrogen atoms may also be present in an oxidized form provided the ring is aromatic.
  • Such rings include but are not limited to pyridyl, pyrimidinyl, oxazolyl or furyl.
  • the term also includes multicyclic ring systems (e.g., ring systems comprising 2 or 3 rings) wherein a heteroaryl group, as defined above, can be fused with one or more heteroaryls (e.g., naphthyridinyl), carbocycles (e.g., 5,6,7,8-tetrahydroquinolyl) or aryls (e.g., indazolyl) to form a multicyclic ring.
  • heteroaryls e.g., naphthyridinyl
  • carbocycles e.g., 5,6,7,8-tetrahydroquinolyl
  • aryls e.g., indazolyl
  • Such multicyclic rings may be optionally substituted with one or more (e.g., 1, 2 or 3) oxo groups on the carbocycle portions of the multicyclic ring. It is to be understood that the point of attachment of a heteroaryl multicyclic ring, as defined above, can be at any position of the ring including a heteroaryl, aryl or a carbocycle portion of the ring.
  • heteroaryls include but are not limited to pyridyl, pyrrolyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrazolyl, thienyl, indolyl, imidazolyl, oxazolyl, thiazolyl, furyl, oxadiazolyl, thiadiazolyl, quinolyl, isoquinolyl, benzothiazolyl, benzoxazolyl, indazolyl, quinoxalyl, quinazolyl, 5,6,7,8- tetrahydroisoquinolinyl benzofuranyl, benzimidazolyl and thianaphthenyl.
  • Heterocyclyl or “heterocyclic ring” or “heterocycle” as used herein refers to a single saturated or partially unsaturated ring or a multicyclic ring.
  • the term includes single saturated or partially unsaturated ring (e.g., 3, 4, 5, 6 or 7-membered ring) from about 1 to 6 carbon atoms and from about 1 to 3 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur in the ring.
  • the ring may be substituted with one or more (e.g., 1, 2 or 3) oxo groups and the sulfur and nitrogen atoms may also be present in their oxidized forms.
  • Such rings include but are not limited to azetidinyl, tetrahydrofuranyl or piperidinyl.
  • the term also includes multicyclic ring systems (e.g., ring systems comprising 2 or 3 rings) wherein a heterocycle group (as defined above) can be connected to two adjacent atoms (fused heterocycle) with one or more heterocycles (e.g., decahydronapthyridinyl ), heteroaryls (e.g., 1,2,3,4- tetrahydronaphthyridinyl), carbocycles (e.g., decahydroquinolyl) or aryls.
  • a heterocycle group as defined above
  • heterocycles e.g., decahydronapthyridinyl
  • heteroaryls e.g., 1,2,3,4- tetrahydronaphthyridinyl
  • carbocycles e.g., decahydroquinolyl or
  • heterocycles include, but are not limited to aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, homopiperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, tetrahydrofuranyl, dihydrooxazolyl, tetrahydropyranyl, tetrahydrothiopyranyl, 1,2,3,4- tetrahydroquinolyl, benzoxazinyl, dihydrooxazolyl, chromanyl, 1,2-dihydropyridinyl, 2,3-dihydrobenzofuranyl, 1,3- benzodioxolyl and 1,4-benzodioxanyl.
  • the above definitions are not intended to include impermissible substitution patterns (e.g., methyl substituted with 5 fluorines or heteroaryl groups having two adjacent oxygen ring atoms). Such impermissible substitution patterns are well known to the skilled artisan.
  • substituted may describe other chemical groups defined herein.
  • substituted aryl includes, but is not limited to, “alkylaryl.” Unless specified otherwise, where a group is described as optionally substituted, any substituents of the group are themselves unsubstituted.
  • the one or more Attorney Docket No.: 1542-WO-PCT substituents may be further substituted with halo, alkyl, haloalkyl, hydroxyl, alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is substituted.
  • the substituents may be further substituted with halo, alkyl, haloalkyl, alkoxy, hydroxyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is unsubstituted.
  • the compounds of the present disclosure can be in the form of a pharmaceutically acceptable salt.
  • pharmaceutically acceptable salts refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids, including inorganic bases or acids and organic bases or acids.
  • the compounds of the present disclosure can be in the form of a pharmaceutically acceptable salt.
  • Such salts Attorney Docket No.: 1542-WO-PCT include sodium salts, potassium salts, calcium salts, magnesium salts or salts with ammonia or organic amines such as, for example, ethylamine, ethanolamine, triethanolamine, amino acids, or other bases known to persons skilled in the art.
  • the compounds of the present disclosure which contain one or more basic groups, i.e., groups which can be protonated, can be present and can be used according to the disclosure in the form of their addition salts with inorganic or organic acids.
  • acids include hydrogen chloride, hydrogen bromide, phosphoric acid, sulfuric acid, nitric acid, methanesulfonic acid, p-toluenesulfonic acid, naphthalenedisulfonic acids, oxalic acid, acetic acid, tartaric acid, lactic acid, salicylic acid, benzoic acid, formic acid, propionic acid, pivalic acid, diethylacetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, malic acid, sulfaminic acid, phenylpropionic acid, gluconic acid, ascorbic acid, isonicotinic acid, citric acid, adipic acid, and other acids known to persons skilled in the art.
  • the disclosure also includes, in addition to the salt forms mentioned, inner salts or betaines (zwitterions).
  • inner salts or betaines can be obtained by customary methods which are known to the person skilled in the art like, for example, by contacting these with an organic or inorganic acid or base in a solvent or dispersant, or by anion exchange or cation exchange with other salts.
  • the present disclosure also includes all salts of the compounds of the present disclosure which, owing to low physiological compatibility, are not directly suitable for use in pharmaceuticals but which can be used, for example, as intermediates for chemical reactions or for the preparation of pharmaceutically acceptable salts.
  • Acids and bases useful for reaction with an underlying compound to form pharmaceutically acceptable salts are known to one of skill in the art.
  • methods of preparing pharmaceutically acceptable salts from an underlying compound are known to one of skill in the art and are disclosed in for example, Berge, at al. Journal of Pharmaceutical Science, Jan.1977 vol.66, No.1, and other sources.
  • compounds disclosed herein may be subject to tautomerism.
  • tautomerism e.g., keto-enol tautomerism
  • the individual forms like, e.g., the keto and enol form, are each within the scope of the disclosure as well as their mixtures in any ratio.
  • stereoisomers like, e.g., enantiomers, cis/trans isomers, diastereomers, conformers, and the like.
  • protecting group refers to a moiety of a compound that masks or alters the properties of a functional group or the properties of the compound as a whole.
  • optical isomers e.g., racemates, or other mixtures thereof (e.g., scalemic mixtures) of the compounds described herein or a pharmaceutically acceptable salt or a mixture thereof.
  • isomers can be separated by methods well known in the art, e.g., by liquid chromatography.
  • the single enantiomer or diastereomer, i.e., optically active form can be obtained by asymmetric synthesis or by resolution. Resolution can be accomplished, for example, by conventional methods such as crystallization in the presence of a resolving agent, or chromatography, using for example, a chiral high-pressure liquid chromatography (HPLC) column.
  • HPLC high-pressure liquid chromatography
  • a “stereoisomer” refers to a compound made up of the same atoms bonded by the same bonds but having different three-dimensional structures, which are not interchangeable.
  • the present invention contemplates various stereoisomers and mixtures thereof and includes “enantiomers,” which refers to two stereoisomers whose molecules are nonsuperimposeable mirror images of one another.
  • “Diastereomers” are stereoisomers that have at least two asymmetric atoms, but which are not mirror-images of each other. Unless otherwise indicated, the description is intended to include individual stereoisomers as well as mixtures.
  • compositions provided herein that include a compound described herein or pharmaceutically acceptable salts, isomer, or a mixture thereof may include racemic mixtures, or mixtures containing an enantiomeric excess of one enantiomer or single diastereomers or diastereomeric mixtures. All such isomeric forms of these compounds are expressly included herein the same as if each and every isomeric form were specifically and individually listed.
  • Any formula or structure given herein is also intended to represent unlabeled forms as well as isotopically labeled forms of the compounds. Isotopically labeled compounds have structures depicted by the formulas given herein except that one or more atoms are replaced by an atom having a selected atomic mass or mass number.
  • isotopes examples include isotopes of hydrogen, carbon, nitrogen, Attorney Docket No.: 1542-WO-PCT oxygen, phosphoros, fluorine and chlorine, such as, but not limited to 2 H (deuterium, D), 3 H (tritium), 11 C, 13 C, 14 C, 15 N, 18 F, 31 P, 32 P, 35 S, 36 Cl and 125 I.
  • Various isotopically labeled compounds of the present disclosure for example those into which radioactive isotopes such as 3 H, 13 C and 14 C are incorporated.
  • Such isotopically labelled compounds may be useful in metabolic studies, reaction kinetic studies, detection or imaging techniques, such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT) including drug or substrate tissue distribution assays or in radioactive treatment of patients.
  • Isotopically labeled compounds of this disclosure and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the schemes or in the examples and preparations described below by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent.
  • Deuterium labelled or substituted therapeutic compounds of the disclosure may have beneficial DMPK (drug metabolism and pharmacokinetics) properties, relating to distribution, metabolism and excretion (ADME). Substitution with heavier isotopes such as deuterium may afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life, reduced dosage requirements and/or an improvement in therapeutic index. An 18 F labeled compound may be useful for PET or SPECT studies. [0063] The concentration of such a heavier isotope, specifically deuterium, may be defined by an isotopic enrichment factor. In the compounds of this disclosure any atom not specifically designated as a particular isotope is meant to represent any stable isotope of that atom.
  • “Pharmaceutical composition” means one or more active ingredients, and one or more inert ingredients that make up the carrier, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients. Accordingly, the pharmaceutical compositions of the present disclosure can encompass any composition made by admixing at least one compound of the present disclosure and a pharmaceutically acceptable carrier.
  • “pharmaceutically acceptable carrier” includes excipients or agents such as solvents, diluents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like that are not deleterious to the disclosed compound or use thereof.
  • excipients or agents such as solvents, diluents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like that are not deleterious to the disclosed compound or use thereof.
  • the use of such carriers and agents to prepare compositions of pharmaceutically active substances is well known in the art (see, e.g., Remington’s Pharmaceutical Sciences, Mace Publishing Co., Philadelphia, PA 17th Ed. (1985); and Modern Pharmaceutics, Marcel Dekker, Inc.3rd Ed. (G.S. Banker & C.T. Rhodes, Eds.).
  • IC50 or “EC50” refers to the inhibitory concentration required to achieve 50% of the maximum desired effect.
  • Treatment or “treating” is an approach for obtaining beneficial or desired results including clinical results.
  • Beneficial or desired clinical results may include one or more of the following: a) inhibiting the disease or condition (e.g., decreasing one or more symptoms resulting from the disease or condition, and/or diminishing the extent of the disease or condition); b) slowing or arresting the development of one or more clinical symptoms associated with the disease or condition (e.g., stabilizing the disease or condition, preventing or delaying the worsening or progression of the disease or condition, and/or preventing or delaying the spread (e.g., metastasis) of the disease or condition); and/or c) relieving the disease, that is, causing the regression of clinical symptoms (e.g., ameliorating the disease state, providing partial or total remission of the disease or condition, enhancing effect of another medication, delaying the progression of the disease,
  • the term “treatment” or “treating” means administering a compound or Attorney Docket No.: 1542-WO-PCT pharmaceutically acceptable salt of Formula (I) for the purpose of: (i) delaying the onset of a disease, that is, causing the clinical symptoms of the disease not to develop or delaying the development thereof; (ii) inhibiting the disease, that is, arresting the development of clinical symptoms; and/or (iii) relieving the disease, that is, causing the regression of clinical symptoms or the severity thereof.
  • “Prevention” or “preventing” means any treatment of a disease or condition that causes the clinical symptoms of the disease or condition not to develop.
  • Compounds may, in some embodiments, be administered to a subject (including a human) who is at risk or has a family history of the disease or condition.
  • Subject refers to an animal, such as a mammal (including a human), that has been or will be the object of treatment, observation or experiment. The methods described herein may be useful in human therapy and/or veterinary applications.
  • the subject is a mammal.
  • the subject is a human.
  • a therapeutically effective amount or “effective amount” of a compound described herein or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, prodrug, or deuterated analog thereof means an amount sufficient to effect treatment when administered to a subject, to provide a therapeutic benefit such as amelioration of symptoms or slowing of disease progression.
  • a therapeutically effective amount may be an amount sufficient to decrease a symptom of a disease or condition responsive to PI3K ⁇ inhibitors.
  • the therapeutically effective amount may vary depending on the subject, and disease or condition being treated, the weight and age of the subject, the severity of the disease or condition, and the manner of administering, which can readily be determined by one or ordinary skill in the art.
  • the present disclosure provides a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein R 1 is C 6-12 aryl, heteroaryl, C 3-12 cycloalkyl, heterocyclyl, C 1-6 alkyl, or C 1-6 haloalkyl; the aryl, heteroaryl, cycloalkyl, heterocyclyl, haloalkyl, or alkyl of R 1 is optionally substituted with one to three Z 1 , which may be the same or different; R 2 is H, C1-6 alkyl, C3-6 cycloalkyl, C3-6 halocycloalkyl, or C1-6 haloalkyl; R 3 is H, CN, C 1-6 alkyl, C 3-6 cycloalkyl, C
  • the compound of Formula (I) is a compound of Formula (II), or a pharmaceutically acceptable salt thereof, wherein R 1 is C 6-12 aryl, C 3-6 cycloalkyl, 4 to 10 membered heterocyclyl, or 5 to 10 membered heteroaryl; the aryl, cycloalkyl, heterocyclyl, or heteroaryl of R 1 is optionally substituted with one to three Z 1 , which may be the same or different; each Z 1 is independently -COOH, halo, oxo, 5 to 10 membered heteroaryl, -C(O)N(R 12b )S(O) 2 (R 12a ), or -S(O) 2 R 12a ; R 2 is H, C 1-6 alkyl, or C 1-6 haloalkyl; R 3 is H, C1-6 alkyl, or C1-6 haloalkyl; Y is N or CH; each R 4 is independently halo; each Q, X
  • the compound of Formula (I) or (II) is a compound of Formula (IIa), or a pharmaceutically acceptable salt thereof.
  • the compound of Formula (I), (II), or (IIa) is a compound of Formula (IIb), or a pharmaceutically acceptable salt thereof.
  • Attorney Docket No.: 1542-WO-PCT [0076]
  • the compound of Formula (I), (II), or (IIa) is a compound of Formula (IIc), or a pharmaceutically acceptable salt thereof.
  • the compound of Formula (I), (II), or (IIa) is a compound of Formula (IId), or a pharmaceutically acceptable salt thereof.
  • the compound of Formula (I), (II), (IIa), or (IId) is a compound of Formula (IIe), or a pharmaceutically acceptable salt thereof.
  • the compound of Formula (I), (II), (IIa), (IId), or (IIe) is a compound of Formula (IIf), Attorney Docket No.: 1542-WO-PCT or a pharmaceutically acceptable salt thereof.
  • the compound of Formula (I), (II), (IIa), (IId), (IIe), or (IIf) is a compound of Formula (IIf-1), or a pharmaceutically acceptable salt thereof.
  • the compound of Formula (I), (II), or (IIa) is a compound wherein R 1 is C6-12 aryl, C3-6 cycloalkyl, 4 to 10 membered heterocyclyl, or 5 to 10 membered heteroaryl; the aryl, cycloalkyl, heterocyclyl, or heteroaryl of R 1 is optionally substituted with one to three Z 1 , which may be the same or different;
  • R 2 is H, C1-6 alkyl, or C1-6 haloalkyl;
  • R 3 is H, CN, C 1-6 alkyl, or C 1-6 haloalkyl;
  • Y is N, CH, or CR 9 ; each R 4 is independently halo, CN, C1-6 alkyl
  • the compound of Formula (I), (II), or (IIa) is a compound wherein R 1 is C 6-12 aryl, or 5 to 10 membered heteroaryl; the aryl or heteroaryl of R 1 is optionally substituted with one to three Z 1 , which may be the same or different; each Z 1 is independently - COOH, halo, 5 to 10 membered heteroaryl, or -S(O)2R 12a ; R 2 is H, C1-6 alkyl, or C1-6 haloalkyl; Attorney Docket No.: 1542-WO-PCT R 3 is H, C 1-6 alkyl, or C 1-6 haloalkyl; Y is N or CH; each R 4 is independently halo; each Q, X, X 1 , or X 2 is independently N, CH, or CR 5 , provided that not more than two of Q, X, X 1 , and X 2 are N; W is O, or NR 8
  • the compound of Formula (I), (II), (IIa), (IIb), (IIc), or (IId) is a compound wherein X is N. In some embodiments, the compound of Formula (I), (II), (IIa), (IIb), (IIc), or (IId) is a compound wherein X is CH. [0084] In some embodiments, the compound of Formula (I), (II), (IIa), (IIb), (IIc), or (IId) is a compound wherein X 1 is CH.
  • the compound of Formula (I), (II), (IIa), (IIb), (IIc), or (IId) is a compound wherein X 1 is CH. [0085] In some embodiments, the compound of Formula (I), (II), (IIa), (IIb), (IIc), (IId), or (IIe) is a compound wherein X 2 is N. In some embodiments, the compound of Formula (I), (II), (IIa), (IIb), (IIc), (IId), or (IIe) is a compound wherein X 2 is CH.
  • the compound of Formula (I), (II), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), or (IIf-1) is a compound wherein W is O.
  • the compound of Formula Attorney Docket No.: 1542-WO-PCT (I), (II), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), or (IIf-1) is a compound wherein W is NR 8 .
  • R 8 is C1-3 alkyl optionally substituted with C3-6 cycloalkyl or phenyl.
  • the compound of Formula (I), (II), (IIa), (IIb), (IIc), (IId), (IIe), or (IIf) is a compound wherein Y is N. In some embodiments, the compound of Formula (I), (II), (IIa), (IIb), (IIc), (IId), (IIe), or (IIf) is a compound wherein Y is CH. [0088] In some embodiments, the compound of Formula (I), (II), (IIa), (IIb), (IIc), (IId), (IIe), or (IIf) is a compound wherein each R 4 is independently C 1-3 alkyl or halo.
  • R 4 is -CH 3 . In some embodiments, R 4 is halo. In some embodiments, R 4 is F. [0089] In some embodiments, the compound of Formula (I), (II), (IIa), (IIb), (IIc), (IId), (IIe), or (IIf) is a compound wherein n is 1. [0090] In some embodiments, the compound of Formula (I), (II), (IIa), (IIb), (IIc), (IId), (IIe), or (IIf) is a compound wherein R 2 is H.
  • the compound of Formula (I), (II), (IIa), (IIb), (IIc), (IId), (IIe), or (IIf) is a compound wherein R 3 is C 1-3 alkyl. In some embodiments, R 3 is -CH 3 .
  • the compound of Formula (I), (II), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), or (IIf-1) is a compound wherein R 1 is phenyl, thiazoyl, or pyridyl; the phenyl, thiazoyl, or pyridyl of R 1 is optionally substituted with one to three Z 1 , which may be the same or different; each Z 1 is independently -COOH, halo, 5 to 6 membered heteroaryl, or -S(O)2R 12a .
  • Z 1 is -C(O)N(R 12b )S(O)2(R 12a ).
  • R 12b is H, and R 12a is C1-3 alkyl.
  • the compound of Formula (I), (II), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), or (IIf-1) is a compound wherein R 1 is phenyl, thiazoyl, or pyridyl; the phenyl, thiazoyl, or pyridyl of R 1 is substituted -COOH; the phenyl or pyridyl of R 1 is optionally additionally substituted with one or two Z 1 , which may be the same or different; each Z 1 is independently halo or -S(O)2R 12a ; and R 12a is C1-3 alkyl.
  • the compound of Formula (I), (II), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), or (IIf-1) is a compound wherein R 1 is phenyl; the phenyl of R 1 is substituted -COOH; the phenyl of R 1 is optionally additionally substituted with one or two Z 1 , which may be the same or different; each Z 1 is independently halo or -S(O)2R 12a ; and R 12a is C1-3 alkyl.
  • the compound of Formula (I), (II), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), or (IIf-1) is a compound wherein each R 5 is independently halo, C1-6 alkyl, C1-6 haloalkyl, C 6-12 aryl, 5 to 10 membered heteroaryl, C 3-6 cycloalkyl, or 4 to 10 membered heterocyclyl; the alkyl, aryl, heteroaryl, cycloalkyl, or heterocyclyl is optionally substituted with one to three Z 5 , which may be the same or different.
  • the compound of Formula (I), (II), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), or (IIf-1) is a compound wherein each R 5 is independently phenyl or 5 to 10 membered Attorney Docket No.: 1542-WO-PCT heteroaryl; wherein the phenyl or heteroaryl of R 5 is optionally substituted with one to three Z 5 , which may be the same or different; each Z 5 is independently C1-6 alkyl, or C1-6 haloalkyl.
  • the compound of Formula (I), (II), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), or (IIf-1) is a compound wherein each R 5 is independently phenyl, pyridyl, morpholinyl, pyrimidinyl, pyrazinyl, pyrazolyl; wherein the phenyl, pyridyl, morpholinyl, pyrimidinyl, pyrazinyl, pyrazolyl of R 5 is optionally substituted with one to three Z 5 , which may be the same or different; each Z 5 is independently C 1-6 alkyl, or C 1-6 haloalkyl.
  • R 5 is phenyl. In some embodiments, R 5 is pyridyl.
  • R 5 is [0100]
  • the compound of Formula (I), (II), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), or (IIf-1) is a compound wherein each R 5 is independently halo, C1-6 haloalkyl, or cyclopropyl; the cyclopropyl is optionally substituted with one to three Z 5 , which may be the same or different.
  • the compound of Formula (I), (II), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), or (IIf-1) is a compound wherein Attorney Docket No.: 1542-WO-PCT [0102]
  • the compound of Formula (I), (II), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), or (IIf-1) is a compound wherein each R 5 is independently C3-6 cycloalkyl; the cycloalkyl is optionally substituted with one to three Z 5 , which may be the same or different.
  • the compound of Formula (I), (II), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), or (IIf-1) is a compound wherein each Z 5 is independently C1-6 alkyl, or C1-6 haloalkyl.
  • the compound of Formula (I), (II), (IIa), (IIb), (IIc), or (IId) is a compound wherein two R 5 are attached to two adjacent carbons, and the two R 5 together with the adjacent carbons to which they are attached form 5 or 10 membered heterocyclyl; wherein the heterocyclyl formed from two R 5 and two adjacent carbons to which they are attached is monocyclic heterocyclyl.
  • the heterocyclyl formed from two R 5 and two adjacent carbons to which they are attached is bicyclic heterocyclyl.
  • the heterocyclyl formed from two R 5 and two adjacent carbons to which they are attached is spiro bicyclic heterocyclyl.
  • compositions comprising at least one compound of the present disclosure, or a prodrug compound thereof, or a pharmaceutically acceptable salt or solvate thereof as active ingredient together with a pharmaceutically acceptable carrier.
  • the pharmaceutical composition of the present disclosure may additionally comprise one or more other compounds as active ingredients like a prodrug compound or other enzyme inhibitors.
  • compositions are suitable for oral, rectal, topical, parenteral (including subcutaneous, intramuscular, and intravenous), ocular (ophthalmic), pulmonary (nasal or buccal inhalation) or nasal administration, although the most suitable route in any given case will depend on the nature and severity of the conditions being treated and on the nature of the active ingredient. They may be conveniently presented in unit dosage form and prepared by any of the methods well-known in the art of pharmacy. [0113] In practical use, the compounds of the present disclosure can be combined as the active ingredient in intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques.
  • tablets and capsules represent the most advantageous oral dosage unit form in which case solid pharmaceutical carriers are employed. If desired, tablets may be coated by standard aqueous or non-aqueous techniques. Such compositions and preparations should contain at least 0.1 percent of active compound. The percentage of active compound in these compositions may, of course, be varied and may conveniently be between about 2 percent to about 60 percent of the weight of the unit. The amount Attorney Docket No.: 1542-WO-PCT of active compound in such therapeutically useful compositions is such that an effective dosage will be obtained.
  • the active compounds can also be administered intranasally as, for example, liquid drops or spray.
  • the PI3K ⁇ -mediated disorder is selected from the group consisting of acute arterial ischemia, alopecia areata, alveolitis, ARDS, asthma, atherosclerosis, atopic dermatitis, autoimmune haematogical disorders (e.g., haemolytic anaemia, aplastic anaemia, pure red cell anaemia and idiopathic thrombocytopenia), autoimmune inflammatory bowel disease (e.g., ulcerative colitis and Crohn's disease), bronchopulmonary aspergillosis, bullous pemphigoid, cardiovascular diseases, chronic active hepatitis, chronic hypersensitivity pneumonitis, conditions characterized by elevated intraocular pressure or secretion of ocular aqueous humor, such as glaucoma; contact dermatitis, COPD, coronary artery disease, deep venous thrombosis, dermatitis herpetiformis, dermatomyositis, endoc
  • the compounds of the present application or the compositions thereof may be administered once, twice, three, or four times daily, using any suitable mode described above. Also, administration or treatment with the compounds may be continued for a number of days; for example, commonly treatment would continue for at least 7 days, 14 days, or 28 days, for one cycle of treatment. Treatment cycles are frequently alternated with resting periods of about 1 to 28 days, commonly about 7 days or about 14 days, between cycles. The treatment cycles, in other embodiments, may also be continuous. [0132] In some embodiments, the methods provided herein comprise administering to the subject an initial daily dose of about 1 to 800 mg of a compound described herein and increasing the dose by increments until clinical efficacy is achieved.
  • an appropriate metal catalyst e.g. XantPhos Pd G3, XPhos Pd G3, RuPhos Pd G3, RockPhos G3
  • base e.g. Na 2 CO 3 , K 2 CO 3 , Cs 2 CO 3
  • Compounds of formula 1.7 can be synthesized by reacting compounds of formula 1.6 with tert-butylsulfinamide and Lewis acid (e.g. TiCl4, Ti(iPrO)4) at elevated temperature, followed by reduction with a suitable reducing reagent (e.g. NaBH 4 , LiBH 4 , DIBAL) in a presence or absence of a Lewis acid (e.g. CeCl 3 -6H 2 O).
  • a suitable reducing reagent e.g. NaBH 4 , LiBH 4 , DIBAL
  • a compound of formula 1.7 can be subsequently deprotected under suitable conditions (e.g. trifluoroacetic acid or hydrochloric acid) to reveal a compound of formula 1.8 that contains a primary amine.
  • Na2CO3, K2CO3, Cs2CO3) in an inert solvent e.g.1,4-dioxane, DMF, toluene
  • the methoxy group of formula 2.2 can be subsequently deprotected with an appropriate Lewis acid (e.g. BBr3, AlCl3, MgCl2, TMSI) to reveal a compound of formula 2.3 that contains a phenol.
  • an appropriate metal catalyst e.g. XantPhos Pd G3, XPhos Pd G3, RuPhos Pd G3, RockPhos G3
  • base e.g. Na2CO3, K2CO3, Cs2CO3
  • an inert solvent e.g.1,4-dioxane, DMF, toluene
  • a suitable reducing reagent e.g. Zn, Mn, TMS silane.
  • Compounds of formula 2.6 can then be synthesized by reacting compounds of formula 2.5 with a suitable alkylating reagent (e.g. R 3 MgCl, R 3 MgBr, R 3 Li).
  • the alcohol group of formula 2.6 can be oxidized using an appropriate oxidant (e.g.
  • the primary amine of formula 3.2 can be subsequently protected with a suitable carbonate group (e.g. Boc, Cbz) using appropriate conditions (e.g. di-tert-butylcarbonate, CbzCl) and base (e.g. Et 3 N, DIPEA) to produce compounds of formula 3.3 (Pg: amine protecting group).
  • a suitable carbonate group e.g. Boc, Cbz
  • appropriate conditions e.g. di-tert-butylcarbonate, CbzCl
  • base e.g. Et 3 N, DIPEA
  • a suitable palladium or nickel catalyst with a suitable reducing reagent (e.g. Zn, Mn, TMS silane).
  • a compound of formula 3.4 can be subsequently deprotected under suitable conditions
  • Attorney Docket No.: 1542-WO-PCT e.g. trifluoroacetic acid or hydrochloric acid for Boc, palladium catalyst with H 2 for Cbz
  • an inert solvent e.g.1,4- dioxane, DMF, toluene
  • Step 5 1-(8-methyl-4-phenylbenzofuro[3,2-b]pyridin-6-yl)ethan-1-ol (INT-A1-5).
  • Step 1 4-chloro-5-fluoro-6-phenylpyrimidine (INT-A2-1).
  • INT-A2-1 4-chloro-5-fluoro-6-phenylpyrimidine
  • phenylboronic acid (0.2.4 mmol)
  • [1,1′- Attorney Docket No.: 1542-WO-PCT bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.24 mmol) in 1,4-dioxane (10.0 mL) was added aqueous sodium carbonate (2.0 M, 5.0 mL) at room temperature.
  • Step 1 1-(2-hydroxy-5-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)phenyl)ethan-1-one (INT-A3-1).
  • Step 1 1-(8-methyl-4-phenylbenzofuro[3,2-c]pyridin-6-yl)ethan-1-one (INT-A4- 1).
  • INT-A4- 1 1-(8-methyl-4-phenylbenzofuro[3,2-c]pyridin-6-yl)ethan-1-one (INT-A4- 1).
  • aqueous sodium carbonate 2.0 M, 1.0 mL
  • Step 1 2-fluoro-5-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)benzaldehyde (INT-A5-1)
  • 3-bromo-2-fluoro-5-methyl- benzaldehyde 9.22 mmol
  • bis(pinacolato)diboron 11.1 mmol
  • potassium acetate 27.6 mmol
  • (1,1'-bis(diphenylphosphino)ferrocene)-dichloropalladium(II) (0.92 mmol).
  • Step 2 3-(4-chloro-3-fluoro-2-pyridyl)-2-fluoro-5-methyl-benzaldehyde (INT-A5- 2)
  • a screw-cap vial was charged with 2-bromo-4-chloro-3-fluoro-pyridine (3.33 mmol), INT- A5-1 (3.66 mmol), and (1,1'-bis(diphenylphosphino)ferrocene)-dichloropalladium(II) (0.33 mmol) followed by 1,2-dimethoxyethane (18.5 mL) and aqueous sodium carbonate (2.0 M, 5.0 mL).
  • Step 3 2-fluoro-3-(3-fluoro-4-phenyl-2-pyridyl)-5-methyl-benzaldehyde (INT-A5- 3)
  • INT-A5-2 (1.49 mmol
  • phenylboronic acid (1.64 mmol)
  • XPhos Pd G3 0.075 mmol
  • 1,2-dimethoxyethane 7.0 mL
  • aqueous sodium carbonate 2.0 M, 2.24 mL
  • Step 4 8-methyl-4-phenyl-benzothiopheno[3,2-b]pyridine-6-carbaldehyde (INT- A5-4) To a solution of INT-A5-3 (1.62 mmol) in N,N-dimethylformamide (16 mL) was added (4-methoxyphenyl)methanethiol (3.39 mmol) and potassium carbonate (559 mg), and it was heated to 100 °C for 16 h. It was cooled to ambient temperature, diluted with ethyl acetate, and washed with water and saturated sodium chloride. It was dried over anhydrous sodium sulfate, filtered, and concentrated.
  • Step 1 3-hydroxy-N-methoxy-N,6-dimethylpicolinamide (INT-A6-1) A vial was charged with 3-hydroxy-6-methylpicolinic acid (19.6 mmol), N,O-dimethylhydroxylamine hydrochloride (29.4 mmol), HATU (29.4 mmol), N,N-diisopropylethylamine (58.8 mmol), and N,N-dimethylformamide (50 mL).
  • Step 2 1-(3-hydroxy-6-methylpyridin-2-yl)ethan-1-one (INT-A6-2) A vial was charged with INT-A6-1 (3.1 mmol) and 2-methyltetrahydrofuran (30 mL).
  • Step 3 1-(4-bromo-3-hydroxy-6-methylpyridin-2-yl)ethan-1-one (INT-A6-3)
  • INT-A6-2 1.1 mmol
  • N,N-dimethylformamide 5 mL
  • N-bromosuccinimide 1.3 mmol
  • the mixture was allowed to stir for 18 h at ambient temperature.
  • the mixture was concentrated and subject to flash column chromatography on silica gel (0% to 100% ethyl acetate in hexanes) to give the title compound.
  • Step 4 3-fluoro-4-phenylpyridine (INT-A6-4) A vial was charged with 4-bromo-3- fluoropyridine (1.7 mmol), phenylboronic acid (2.2 mmol), [1,1′- bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.17 mmol), cesium carbonate (5.1 mmol), 1,4-dioxane (5 mL), and water (1mL). The mixture was stirred at 100 °C for 18 h. The mixture was filtered, concentrated, and subject to flash column chromatography on silica gel (0% to 100% ethyl acetate in hexanes) to give the title compound.
  • Step 5 3-fluoro-4-phenyl-2-(tributylstannyl)pyridine (INT-A6-5)
  • INT-A6-5 3-fluoro-4-phenyl-2-(tributylstannyl)pyridine
  • INT-A6-4 1.6 mmol
  • tetrahydrofuran 5 mL
  • lithium diisopropylamide 2.4 mmol, 1M in THF/hexanes
  • Tributyltin chloride 2.0 mmol
  • the mixture was allowed to warm to ambient temperature over 1 h.
  • Step 6 1-(3-fluoro-3'-hydroxy-6'-methyl-4-phenyl-[2,4'-bipyridin]-2'-yl)ethan-1- one (INT-A6-6)
  • INT-A6-3 (0.26 mmol)
  • INT-A6-5 (0.30 mmol)
  • copper(I) iodide 0.05 mmol
  • cesium fluoride 0.52 mmol
  • tricyclohexylphosphine 0.052 mmol
  • Pd(OAc) 2 0.026 mmol
  • 1,4-dioxane (1 mL).
  • Step 7 1-(8-methyl-4-phenylfuro[3,2-b:5,4-c']dipyridin-6-yl)ethan-1-one (INT- A6-7)
  • INT-A6-6 (0.23 mmol)
  • cesium carbonate (0.91 mmol)
  • N,N-dimethylformamide (1 mL). The mixture was heated to 90 °C for 1 h.
  • Step 2 N-(2-((Z)-benzylidene)-7-bromo-5-methylbenzofuran-3(2H)-ylidene)-4- methylbenzenesulfonamide (INT-A7-2) A vial was charged with INT-A7-1 (1.9 mmol), 4- methylbenzenesulfonamide (2.9 mmol), triethylamine (3.8 mmol), and toluene (20 mL).
  • Titanium tetrachloride (1.9 mmol) was then added, and the mixture was heated to 100 °C for 18 h. The mixture was cooled to ambient temperature, and water (1 mL) was added. The mixture was filtered, concentrated, and subject to flash column chromatography on silica gel (0% to 100% ethyl acetate in hexanes to 50% methanol in ethyl acetate) to give the title compound.
  • Step 3 6-bromo-2-cyclopropyl-8-methyl-4-phenylbenzofuro[3,2-b]pyridine (INT- A7-3)
  • a vial under argon was charged with Cu(MeCN) 4 BF 4 (0.071 mmol), XantPhos (0.071 mmol), and 1,4-dioxane (2 mL).
  • the mixture stirred at ambient temperature for 1 h.
  • INT-A7-2 (0.36 mmol), triethylamine (0.36 mmol), and ethynylcyclopropane (1.1 mmol) were then added, and the mixture was heated to 60 °C for 24 h.
  • Step 1 1-(2-cyclopropyl-8-methyl-4-phenylbenzofuro[3,2-b]pyridin-6-yl)ethan-1- one (INT-A9-1)
  • INT-A7-3 0.093 mmol
  • tributyl(1- ethoxyvinyl)stannane 0.19 mmol
  • copper(I) iodide 0.19 mmol
  • cesium fluoride 0.19 mmol
  • tricyclohexylphosphine 0.28 mmol
  • Pd(OAc) 2 0.14 mmol
  • 1,4-dioxane 1 mL).
  • Step 1 (R,E)-N-(1-(4-chloro-8-methylbenzofuro[3,2-b]pyridin-6-yl)ethylidene)-2- methylpropane-2-sulfinamide (INT-A10-1).
  • INT-A3-3 1.2 mmol
  • R -2- methylpropane-2-sulfinamide
  • Ti(i-PrO)4 3.5 mmol
  • Step 2 (R)-N-((R)-1-(4-chloro-8-methylbenzofuro[3,2-b]pyridin-6-yl)ethyl)-2- methylpropane-2-sulfinamide (INT-A10-2).
  • INT-A10-1 1.3 mmol
  • dichloromethane 2 mL
  • methanol 2 mL
  • CeCl3 • 7H2O 0.6 mmol
  • the mixture was cooled to 0 °C and sodium borohydride (1.9 mmol) was slowly added. The solution was left to stir at 0 °C.
  • Step 3 (R)-1-(4-chloro-8-methylbenzofuro[3,2-b]pyridin-6-yl)ethan-1-amine (INT-A10-3)
  • INT-A10-2 1.0 mmol
  • HCl 4.0 M in 1,4-dioxane, 4.9 mL
  • the solution was left to stir at room temperature. After 2 h, the mixture was concentrated under reduced pressure and carried forward without further purification.
  • Attorney Docket No.: 1542-WO-PCT [0181] The following Examples were made using the general route described in Procedure I- A10 and are shown below in Table A10.
  • Step 1 tert-butyl (R)-(1-(4-chloro-8-methylbenzofuro[3,2-b]pyridin-6- yl)ethyl)carbamate (INT-A11-1).
  • INT-A10-3 1.0 mmol
  • DCM DCM
  • triethylamine 0.8 mL
  • di-tert-butyl dicarbonate 1.5 mmol
  • Step 2 (R)-N-(1-(2-amino-3-bromo-5-methylphenyl)ethylidene)-2-methylpropane- 2-sulfinamide (INT-A12-2)
  • INT-A12-1 381.4
  • R -2-methylpropane-2- sulfinamide
  • titanium(IV) isopropoxide 82.4 mmol
  • the reaction solution was heated to 80 °C and stirred at 80 °C for 16 h. Following this time, the mixture was cooled to room temperature and diluted with brine (500 mL).
  • Step 3 (1R)-1-(2-amino-3-bromo-5-methylphenyl)ethyl)-2-methylpropane- 2-sulfinamide (INT-A12-3)
  • INT-A12-2 274.7 mmol
  • tetrahydrofuran 300 mL
  • diisobutylaluminum hydride 824.0 mmol
  • tetrahydrofuran 300 mL
  • the mixture was stirred for 3 h at -78 °C under nitrogen atmosphere.
  • Step 4 (R)-2-(1-aminoethyl)-6-bromo-4-methylaniline dihydrochloride (INT-A12- 4) A mixture of INT-A12-3 (30.0 mmol) in a solution of HCl (gas) in 1,4-dioxane (100 mL) was stirred for 1 h at room temperature.
  • Step 5 tert-butyl (R)-(1-(2-amino-3-bromo-5-methylphenyl)ethyl)carbamate (INT-A12-5) To a mixture of INT-A12-4 (109.1 mmol) and di-tert-butyl dicarbonate (109.1 mmol) in dichloromethane (150 mL) was added N,N-diisopropylethylamine (327.3 mmol) dropwise at 25 °C under nitrogen atmosphere. The reaction mixture was stirred at 25 °C for 5 h.
  • Step 2 tert-butyl (R)-(1-(2-(benzylamino)-3-(4-fluoropyridin-3-yl)-5- methylphenyl)ethyl)carbamate (INT-A13-2).
  • Step 3 (R)-2-(1-aminoethyl)-N-benzyl-6-(4-fluoropyridin-3-yl)-4-methylaniline (INT-A13-3).
  • INT-A13-3 A solution of INT-A13-2 (0.21 mmol) in dichloromethane (0.5 mL) was added HCl (4.0 M in 1,4-dioxane, 0.53 mL).
  • Step 4 (R)-1-(5-benzyl-8-methyl-5H-pyrido[4,3-b]indol-6-yl)ethan-1-amine (INT- A13-4).
  • INT- A13-3 0.085 mmol
  • cesium carbonate 0.43 mmol
  • N,N- dimethylformamide 0.5 mL
  • Step 1 tert-butyl (R)-(1-(3-bromo-2-((cyclopropylmethyl)amino)-5- methylphenyl)ethyl)carbamate (INT-A14-1).
  • acetic acid 0.16 mL
  • Step 2 tert-butyl (R)-(1-(9-(cyclopropylmethyl)-6-methyl-9H-pyrido[2,3-b]indol- 8-yl)ethyl)carbamate (INT-A14-2).
  • Step 1 tert-butyl (R)-(1-(3-(3-bromopyridin-2-yl)-2-((cyclopropylmethyl)amino)- 5-methylphenyl)ethyl) carbamate (INT-A15-1).
  • Step 2 tert-butyl (R)-(1-(5-(cyclopropylmethyl)-8-methyl-5H-pyrido[3,2-b]indol- 6-yl)ethyl)carbamate (INT-A15-2).
  • INT-A15-1 0.043 mmol
  • cesium carbonate 0.22 mmol
  • XantPhos Pd G3 0.0087 mmol
  • 1,4-dioxane 1.0 mL
  • the resulting mixture was cooled to room temperature, and water (5 mL) and ethyl acetate (5 mL) were added sequentially.
  • Step 3 (R)-1-(5-(cyclopropylmethyl)-8-methyl-5H-pyrido[3,2-b]indol-6-yl)ethan- 1-amine (INT-A15-3).
  • Step 2 1-(8-methyl-4-(pyridin-3-yl)benzofuro[3,2-b]pyridin-6-yl)ethan-1-ol (INT- A16-2) A vial was charged with INT-A16-1 (3.5 mmol) and THF (10 mL).
  • Step 3 6-(1-bromoethyl)-8-methyl-4-(pyridin-3-yl)benzofuro[3,2-b]pyridine (INT- A16-3)
  • INT-A16-2 (0.74 mmol)
  • dichloromethane 5 mL
  • phosphorus tribromide 1.5 mmol, 1M in DCM
  • the mixture was stirred 30 min, after which aqueous potassium carbonate (2.0 M, 5 mL) was added.
  • the mixture was extracted with dichloromethane (3x 10 mL).
  • Step 1 ethyl 1-(3,5-difluoropyridin-4-yl)cyclopentane-1-carboxylate (INT-A17-1)
  • ethyl cyclopentanecarboxylate (11.3 mmol)
  • tetrahydrofuran 50 mL
  • the mixture was cooled to -78 °C, and lithium diisopropylamide (15.0 mmol, 1 M in THF/hexanes) was added.
  • Step 2 4'-fluoro-2'H-spiro[cyclopentane-1,3'-furo[2,3-c]pyridine] (INT-A17-2)
  • INT-A17-1 3. mmol
  • tetrahydrofuran 10 mL
  • isopropanol 0.5 mL
  • lithium borohydride 3.67 mmol
  • the flask was equipped with a reflux condenser, and the mixture was heated to reflux for 18 h. The mixture was allowed to cool to ambient temperature after which water (20 mL) was added. The mixture was extracted with ethyl acetate (3 x 20 mL).
  • Step 3 5'-bromo-4'-fluoro-2'H-spiro[cyclopentane-1,3'-furo[2,3-c]pyridine] (INT- A17-3) A vial was charged with INT-A17-2 (0.84 mmol) and THF (5 mL).
  • Step 4 3-(4'-fluoro-2'H-spiro[cyclopentane-1,3'-furo[2,3-c]pyridin]-5'-yl)-2- methoxy-5-methylbenzaldehyde (INT-A17-4)
  • INT-A17-2 (0.26 mmol)
  • 3-formyl-2-methoxy-5-methylphenyl)boronic acid (0.39 mmol)
  • [1,1′- bis(diphenylphosphino)ferrocene]dichloropalladium(II) 0.026 mmol
  • aqueous potassium carbonate 2.0 M, 0.78 mmol
  • 1,4-dioxane 3 mL.
  • Step 5 3-(4'-fluoro-2'H-spiro[cyclopentane-1,3'-furo[2,3-c]pyridin]-5'-yl)-2- hydroxy-5-methylbenzaldehyde (INT-A17-5)
  • INT-A17-4 (0.15 mmol) and dichloromethane (1 mL), followed by boron tribromide (0.32 mmol, 1M in DCM). The mixture stirred at ambient temperature for 2 h. Water (2 mL) was added. The mixture was extracted with dichloromethane (3 x 2 mL).
  • Step 6 7-methyl-2H-spiro[benzofuro[3,2-b]furo[3,2-d]pyridine-1,1'- cyclopentane]-9-carbaldehyde (INT-A17-6)
  • INT-A17-5 0.15 mmol
  • cesium carbonate 0.90 mmol
  • N,N-dimethylformamide 1 mL
  • Step 7 (S,E)-2-methyl-N-((7-methyl-2H-spiro[benzofuro[3,2-b]furo[3,2- d]pyridine-1,1'-cyclopentan]-9-yl)methylene)propane-2-sulfinamide (INT-A17-7)
  • INT-A17-7 A vial was charged with INT-A17-6 (0.088 mol), (S)-2-methylpropane-2-sulfinamide (0.18 mmol), 2- methyltetrahydrofuran (1 mL), followed by titanium(IV) isopropoxide (0.35 mmol).
  • Step 8 (S)-2-methyl-N-((R)-1-(7-methyl-2H-spiro[benzofuro[3,2-b]furo[3,2- d]pyridine-1,1'-cyclopentan]-9-yl)ethyl)propane-2-sulfinamide (INT-A17-8)
  • INT-A17-7 0.071 mmol
  • tetrahydrofuran 1.0 mL
  • the mixture was cooled to 0 °C, and methylmagnesium iodide (0.14 mmol, 3M in diethyl ether) was added.
  • Step 9 (R)-1-(7-methyl-2H-spiro[benzofuro[3,2-b]furo[3,2-d]pyridine-1,1'- cyclopentan]-9-yl)ethan-1-amine (INT-A17-9) A vial was charged with INT-A17-8 (0.070 mmol), and methanol (0.5 mL).
  • Step 1 (1S)-1-(4-chloro-8-methyl-benzofuro[3,2-c]pyridazin-6-yl)ethanol (INT- A18-1)
  • INT- A18-1 (1S)-1-(4-chloro-8-methyl-benzofuro[3,2-c]pyridazin-6-yl)ethanol (INT- A18-1)
  • RuCl[(S,S)-TsDPEN](mesitylene) 7.81 mmol
  • triethylamine 58.23 g, 575.42 mmol, 2.1 eq
  • formic acid (671.32 mmol) at 0 °C.
  • Step 2 tert-butyl 2-[[(1R)-1-(4-chloro-8-methyl-benzofuro[3,2-c]pyridazin-6- yl)ethyl]-(2,4-dinitrophenyl)sulfonyl-amino]benzoate (INT-A18-2)
  • tetrahydrofuran 3.75 mL
  • triphenylphosphine (2.14 mmol
  • tert- butyl N-tert-butoxycarbonyliminocarbamate (2.14 mmol).
  • Step 3 tert-butyl 2-[[(1R)-1-(4-chloro-8-methyl-benzofuro[3,2-c]pyridazin-6- yl)ethyl]amino]benzoate (INT-A18-3)
  • INT-A18-2 (1.05 mmol) in dichloromethane (6.6 mL)
  • diisopropylethylamine 2.1 mmol
  • 70% aqueous thioglycolic acid (1.36 mmol).
  • Saturated aqueous sodium bicarbonate was added, and the mixture was extracted twice with dichloromethane.
  • Step 1 1-(1,3-dioxoisoindolin-2-yl) 3-methyl bicyclo[1.1.1]pentane-1,3- dicarboxylate (INT-A19-1)
  • a reactor was charged with 3- (methoxycarbonyl)bicyclo[1.1.1]pentane-1-carboxylic acid (1.06 mol), N-hydroxyphthalimide (1.16 mol), N,N-dimethylaminopyridine (0.106 mol), and dichloromethane (1.8 L).
  • N,N'- diisopropylcarbodiimide (1.16 mol) was added dropwise. It was stirred at ambient temperature for 8 hours.
  • Step 2 methyl 3-(3-fluoropyridin-4-yl)bicyclo[1.1.1]pentane-1-carboxylate (INT- A19-2)
  • INT-A19-1 317 mmol
  • 4-bromo-3-fluoropyidine 381 mmol
  • [bipyridine]nickel(II) dichloride 31.7 mmol
  • zinc powder 1.59 mol
  • dimethylacetamide 1 L
  • Step 4 3-(2-bromo-3-fluoropyridin-4-yl)bicyclo[1.1.1]pentane-1-carboxylic acid (INT-A19-4)
  • a reactor was charged with 2,2,6,6-tetramethylpiperidine (6.5 mmol) and tetrahydrofuran (5 mL) and cooled to -60 °C.
  • n-butyllithium 2.5M in hexanes, 6.03 mmol
  • INT-A19-3 (2.41 mmol) was charged in portions to the reactor, and it was stirred at -60 °C for 30 minutes.
  • Step 2 (R)-N-(1-(3-bromo-2-((4-methoxybenzyl)oxy)-5-methylphenyl)ethylidene)-2- methylpropane-2-sulfinamide (INT-A20-2)
  • INT-A20-1 3.3 mol
  • R -2-methylpropane-2-sulfinamide
  • tetraethoxytitanium 2.5 L
  • reaction mixture was cooled to 0 °C, and borane-THF complex (1.0 M in THF 0.15 mmol) was added.
  • the flask was sealed and stirred at ambient temperature overnight.
  • the vigorously stirred reaction mixture was treated with water and the mixture was stirred for 20 min.
  • Ethyl acetate was added followed by saturated sodium carbonate solution.
  • the biphasic mixture was kept stirring until the gas evolution had ceased.
  • the layers were separated, and the aqueous layer was extracted with EtOAc twice. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated. It was purified by flash chromatography on silica (5% to 100% ethyl acetate in hexanes) to yield the product.
  • Step 1 4-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d][1,2,3]triazole (INT-F7-1).
  • N,N- dimethylformamide 5.0 mL
  • sodium hydride 2.1 mmol
  • 2- (chloromethoxy)ethyl)trimethylsilane 2.0 mmol
  • Step 3 (R)-N-(1-(8-methyl-4-phenylbenzofuro[3,2-b]pyridin-6-yl)ethyl)-1H- benzo[d][1,2,3]triazol-4-amine (Ex.66).
  • HCl 4.0 M in 1,4-dioxane, 0.30 mL.
  • the solution was left to stir at room temperature. After 1 h, the mixture was concentrated under reduced pressure and purified by RP-HPLC (30 to 95 % 0.1% TFA in MeCN/0.1% TFA in H2O).
  • Step 2 6-chloro-3-((1-(8-methyl-4-phenylbenzo[4,5]thieno[3,2-b]pyridin-6- yl)ethyl)amino)picolinic acid (Ex.71)
  • INT-F11-1 (0.09 mmol)
  • trifluoroacetic acid 1.0 mL
  • Step 1 2-(((1R)-1-(8-methyl-4-(tetrahydrofuran-3-yl)benzofuro[3,2-b]pyridin-6- yl)ethyl)amino)benzoic acid (Ex.82)
  • 2-carboxyphenylboronic acid (0.235 mmol
  • 1,8- diazabicyclo[5.4.0]undec-7-ene (0.39 mmol
  • copper(II) acetate 0.12 mmol
  • Step 1 methyl 2-[[(1R)-1-[8-methyl-4-(1-methylpyrazol-4-yl)benzofuro[3,2- c]pyridazin-6-yl]ethyl]amino]benzoate (INT-F18-1).
  • a mixture of INT-B1-19 (0.053 mmol), methyl 2-iodobenzoate (0.1 mmol), XantPhos Pd G3 (0.015 mmol), and cesium carbonate (0.32 mmol), in dimethylacetamide (0.25 mL) and 1,4-dioxane (0.40 mL) was degassed by bubbling nitrogen through the mixture for 5 min.
  • Step 2 methyl 2-[[(1R)-1-[8-methyl-4-(1-methylpyrazol-4-yl)benzofuro[3,2- c]pyridazin-6-yl]ethyl]amino]benzoate (Ex.115).
  • Step 1 methyl 6-chloro-3-[[(1R)-1-(8-methyl-4-phenyl-benzofuro[3,2-c]pyridazin-6- yl)ethyl]amino]pyridine-2-carboxylate (INT-F19-1).
  • a mixture of INT-A10-8 (0.20 mmol), methyl 6-chloro-3-fluoro-pyridine-2-carboxylate (0.32 mmol), and N,N-diisopropylethylamine (1.0 mmol) in dimethyl sulfoxide (1.0 mL) was purged with argon and vigorously stirred at 100 °C.
  • Step 2 methyl 6-chloro-3-[[(1R)-1-(8-methyl-4-phenyl-benzofuro[3,2-c]pyridazin-6- yl)ethyl]amino]pyridine-2-carboxylate (INT-F19-2).
  • aqueous lithium hydroxide 1.0 M, 0.25 mL
  • Step 3 6-chloro-3-[[(1R)-1-(8-methyl-4-phenyl-benzofuro[3,2-c]pyridazin-6- yl)ethyl]amino]-N-methylsulfonyl-pyridine-2-carboxamide (Ex. 116).
  • T-47D cell line was obtained from National Cancer Institute. Cells were maintained in RPMI (Gibco 11875-093) supplemented with 10% Fetal Bovine Serum, (FBS, Hyclone SH30071-03), and 1X PenStrep (PS, Gibco 15140-122). SK-BR-3 cell line was obtained from ATCC (ATCC HTB-30). Cells were maintained in McCoy’s 5A (Gibco 16600-082) supplemented with 10% FBS and 1X PS. Cultures were maintained in a humidified incubator at 37°C under 5% CO2/95% air.
  • T-47D cells were seeded at a density of 20,000 cells per well in 40 ⁇ l of RPMI assay media with 10% FBS and 1X PS.
  • SK- BR-3 cells were seeded at a density of 10,000 in 40 ⁇ l of McCoy’s 5A assay media with 10% FBS and 1X PS in white 384-well plates (Greiner 781080). Assay plates were incubated in a humidified incubator at 37°C under 5% CO2/95% air overnight.
  • the assay plates were washed 2x with 70 ⁇ l Dulbecco’s Phosphate-Buffered Saline (DPBS, Gibco 14190-144) with a Biotek washer/dispenser (Biotek EL406) and serum starved with 40 ⁇ l RPMI with 1x PS for T-47D cells and 40 ⁇ l McCoy’s 5A with 1x PS for SK-BR-3 cells overnight.
  • HTRF phospho-AKT (SER473) (Revvity 64AKSPEH) detection reagent (50% 4x lysis buffer, 1.6% blocking reagent, 38% detection buffer, 8.4% water, 1% phosopho-AKT d2 antibody, and 1% phosopho-AKT Eu Cryptate antibody) was prepared during compound treatment. After 2 hours compound treatment, the assay plates were washed with 70 ⁇ L DPBS twice and 10 ⁇ L of the detection reagent was added. The assay plates were sealed and incubated overnight at room temperature.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente divulgation concerne des composés qui inhibent PI3Ka. La divulgation concerne en outre l'utilisation des composés pour la préparation d'un médicament pour le traitement de maladies et/ou d'états par inhibition de PI3Ka. La divulgation concerne en outre l'utilisation des composés pour le traitement d'une maladie ou d'un état associé à PI3Ka mutant. La divulgation concerne en outre l'utilisation des composés pour le traitement de cancers. (Formule (I))
PCT/US2025/022475 2024-04-03 2025-04-01 Inhibiteurs de pi3kalpha et leurs utilisations Pending WO2025212599A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US202463573830P 2024-04-03 2024-04-03
US63/573,830 2024-04-03

Publications (1)

Publication Number Publication Date
WO2025212599A1 true WO2025212599A1 (fr) 2025-10-09

Family

ID=95517104

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2025/022475 Pending WO2025212599A1 (fr) 2024-04-03 2025-04-01 Inhibiteurs de pi3kalpha et leurs utilisations

Country Status (1)

Country Link
WO (1) WO2025212599A1 (fr)

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010138589A1 (fr) * 2009-05-27 2010-12-02 Genentech, Inc. Composés pyrimidines bicycliques inhibiteurs de pi3k sélectifs pour p110 delta, et procédés d'utilisation
US20150031686A1 (en) * 2012-03-08 2015-01-29 Institute Of Medicinal Biotechnology, Chinese Academy Of Medical Sciences Phenyl-oxazolyl derivatives, preparation method thereof, and related application of the phenyl-oxazolyl derivatives as an impdh inhibitor

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010138589A1 (fr) * 2009-05-27 2010-12-02 Genentech, Inc. Composés pyrimidines bicycliques inhibiteurs de pi3k sélectifs pour p110 delta, et procédés d'utilisation
US20150031686A1 (en) * 2012-03-08 2015-01-29 Institute Of Medicinal Biotechnology, Chinese Academy Of Medical Sciences Phenyl-oxazolyl derivatives, preparation method thereof, and related application of the phenyl-oxazolyl derivatives as an impdh inhibitor

Non-Patent Citations (8)

* Cited by examiner, † Cited by third party
Title
"Remington's Pharmaceutical Sciences", 1985, MACE PUBLISHING CO.
BERGE, JOURNAL OF PHARMACEUTICAL SCIENCE, vol. 66, no. 1, January 1977 (1977-01-01)
FIESER ET AL.: "Fiesers'' Reagents for organic Synthesis", 2000, JOHN WILEY & SONS
FOSTER: "Deuterium Isotope Effects in Studies of Drug Metabolism", TRENDS PHARMACOL. SCI., vol. 5, no. 12, 1984, pages 524 - 527, XP025943358, DOI: 10.1016/0165-6147(84)90534-0
GHAZY EHAB ET AL: "Synthesis, structure-activity relationships, cocrystallization and cellular characterization of novel smHDAC8 inhibitors for the treatment of schistosomiasis", EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, vol. 225, December 2021 (2021-12-01), AMSTERDAM, NL, pages 113745, XP093291490, ISSN: 0223-5234, DOI: 10.1016/j.ejmech.2021.113745 *
J. MARCH: "Advanced Organic Chemistry", 1992, JOHN WILEY AND SONS
S. HAUPTMANN: "The Chemistry of Heterocycles; Structures, Reactions, Synthesis and Application", 2003, JOHN WILEY & SONS OR T. EICHER
THEODORA W. GREENE: "Protective Groups in Organic Chemistry", 1991, JOHN WILEY & SONS, INC.

Similar Documents

Publication Publication Date Title
EP3596073B1 (fr) Composés tricycliques et leur utilisation pour la traitement des maladies proliferatifs.
TWI752963B (zh) 用於治療或預防與β-3腎上腺素受體相關病症之β-3腎上腺素受體調節劑
TWI828712B (zh) 作為ｔｒｋ抑制劑的雜環化合物
CN108884066B (zh) 作为蛋白激酶抑制剂的2，3，5-取代的噻吩化合物
CA3103304A1 (fr) Nouveaux composes et compositions pharmaceutiques associees pour le traitement de maladies
EP4392407A1 (fr) Inhibiteurs spiro-indoliniques de la kif18a
CN109745321B (zh) 包含fgfr4抑制剂的药物组合物
CN118076597A (zh) 一种氮杂喹啉酮类衍生物、其制备方法及用途
WO2020108619A1 (fr) Inhibiteur de mnk
TW202430166A (zh) 醯胺或脲類化合物
CN107690434B (zh) 作为tnf活性调节剂的稠合三环咪唑并吡嗪衍生物
WO2019182924A1 (fr) Inhibiteurs de jak
CN112409385A (zh) 氮杂芳基化合物及其应用
CN115636833A (zh) 作为ATM激酶选择性调节剂的取代的咪唑并[4,5-c]噌啉-2-酮化合物及其用途
CA2958543A1 (fr) Derives de dihydropyridazine-3,5-dione utiles comme inhibiteurs de porteur de phosphate dependant au sodium
WO2024249888A2 (fr) Composés et compositions pouvant être utilisés en tant qu'agents de dégradation de cbp/p300 et leurs utilisations
AU2022369094A1 (en) Tricyclic gpr65 modulators
CN114599655B (zh) 咪唑烷酮类化合物及其制备方法与应用
WO2025212599A1 (fr) Inhibiteurs de pi3kalpha et leurs utilisations
CN114599656A (zh) 咪唑烷酮类化合物及其制备方法与应用
TWI894448B (zh) Ctla-4小分子降解劑及其應用
JP7774621B2 (ja) 三複素環誘導体、その医薬組成物及び使用
CN118369323A (zh) 作为shp2抑制剂的杂环化合物、包括该杂环化合物的组合物、及其使用方法
KR20220073680A (ko) 다이아실글리세롤 키나아제 저해제로서 헤테로사이클 화합물 및 이의 용도
JP2019518032A (ja) Ｐｉ３ｋ ｂｅｔａ阻害薬としての二環式ピリジン、ピラジンおよびピリミジン誘導体

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 25721101

Country of ref document: EP

Kind code of ref document: A1