WO2025007074A1 - Composés chimiques - Google Patents

Composés chimiques Download PDF

Info

Publication number
WO2025007074A1
WO2025007074A1 PCT/US2024/036277 US2024036277W WO2025007074A1 WO 2025007074 A1 WO2025007074 A1 WO 2025007074A1 US 2024036277 W US2024036277 W US 2024036277W WO 2025007074 A1 WO2025007074 A1 WO 2025007074A1
Authority
WO
WIPO (PCT)
Prior art keywords
alkyl
alkynyl
alkenyl
compound
group
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.)
Ceased
Application number
PCT/US2024/036277
Other languages
English (en)
Other versions
WO2025007074A9 (fr
Inventor
Stephen John Baker
Matthew Alexander PERRY
Chun Yu Liu
Yasheen Zhou
Marissa Caroline Aubrey
Gregory Lee WARREN
Xianfeng Li
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.)
Reactive Biosciences Inc
Original Assignee
Reactive Biosciences 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 Reactive Biosciences Inc filed Critical Reactive Biosciences Inc
Publication of WO2025007074A1 publication Critical patent/WO2025007074A1/fr
Publication of WO2025007074A9 publication Critical patent/WO2025007074A9/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
    • C07F5/02—Boron compounds
    • C07F5/025—Boronic and borinic acid compounds

Definitions

  • Kinases represent a class of important signaling molecules. Kinases may generally be classified into protein kinases and lipid kinases, and certain kinases exhibit dual specificities.
  • Protein kinases are enzymes that phosphorylate other proteins and/or themselves (i.e., autophosphorylation).
  • Protein kinases can be generally classified into three major groups based upon their substrate utilization: tyrosine kinases which predominantly phosphorylate substrates on tyrosine residues (e.g., erb2, PDGF receptor, EGF receptor, VEGF receptor, src, abl), serine/threonine kinases which predominantly phosphorylate substrates on serine and/or threonine residues (e.g., mTorCl, mTorC2, ATM, ATR, DNA-PK, Akt), and dual-specificity kinases which phosphorylate substrates on tyrosine, serine and/or threonine residues.
  • tyrosine kinases which predominantly phosphorylate substrates on tyrosine residues (e.g., erb2, PDGF receptor, EGF receptor, VEGF receptor, src, abl), serine/threonine kinases which predominantly phosphorylate substrates
  • Lipid kinases are enzymes that catalyze the phosphorylation of lipids within cells. These enzymes, and the resulting phosphorylated lipids and lipid-derived biologically active organic molecules, play a role in many different physiological processes, including cell proliferation, migration, adhesion, and differentiation.
  • a particular group of lipid kinases comprises membrane lipid kinases, i.e., kinases that catalyze the phosphorylation of lipids contained in or associated with cell membranes.
  • phosphinositide(s) kinases such as PB-kinases, PI4-Kinases
  • diacylglycerol kinases examples include sphingosine kinases.
  • PIK3CA phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha
  • PI3K phosphatidylinositol 3-kinase
  • the p110 ⁇ protein is called the catalytic subunit because it performs the action of PI3K, while the other subunit (produced by a different gene) regulates the enzyme's activity.
  • Phosphatidylinositol 3 kinase PI3K
  • An intracellular kinase, PI3K activates multiple intracellular signaling pathways that affect cell growth, proliferation, migration, secretion, differentiation, transcription and translation. Dysregulation of PI3K activity, and aberrant PI3K signaling, lead to a broad range of human diseases, such as cancer, immune disorders, diabetes, and cardiovascular diseases.
  • PI3K signaling pathway is one of the most highly mutated systems in human cancers.
  • PI3K signaling is involved in many other disease states including allergic contact dermatitis, rheumatoid arthritis, osteoarthritis, inflammatory bowel diseases, chronic obstructive pulmonary disorder, psoriasis, multiple sclerosis, asthma, disorders related to diabetic complications, and inflammatory complications of the cardiovascular system such as acute coronary syndrome.
  • PI3K is a member of a unique and conserved family of intracellular lipid kinases that phosphorylate the 3 '-OH group on phosphatidylinositols or phosphoinositides.
  • the class I PI3Ks are typically activated by tyrosine kinases or G-protein coupled receptors, and phosphorylate PIP2 to generate PIP3, which engages downstream effectors such as those in the pathways of Akt/PDKl, mTOR, the Tee family kinases, and the Rho family GTPases.
  • the class II and III play a key role in intracellular trafficking through the synthesis of P1(3)P and P1(3,4)P2.
  • PI3Ks phosphorylate the 3 ⁇ ;-hydroxyl group of phosphatidylinositides (PtdIns). They are divided into three classes based on their structures and substrate specificities.
  • class I PI3Ks are further divided into subclasses IA and IB based on their modes of regulation.
  • Class IA PI3Ks are heterodimers of a p110 catalytic subunit and a p85 regulatory subunit.
  • the genes PIK3CA, PIK3CB, and PIK3CD respectively encode three highly homologous class IA catalytic isoforms: p110 ⁇ , p110 ⁇ , and p110 ⁇ .
  • Class IB PI3Ks are heterodimers of a p110 ⁇ catalytic subunit (encoded by PIK3CG) coupled with regulatory isoforms p101 (PIK3R5) or p87 (p84 or p87 PIKAP , encoded by PIK3R6).
  • PI3K-directed drug discovery consisted largely of non-isoform-selective pan-PI3K inhibitors. More recent studies, however, have demonstrated that different PI3K isoforms play divergent roles in cellular signaling and cancer, suggesting that inhibitors targeting individual isoforms may be able to achieve greater therapeutic efficacy. Isoform-selective inhibitors are now emerging. See, Thorpe et al., PI3K in Cancer: Divergent Roles of Isoforms, Modes of Activation, and Therapeutic Targeting, Nat. Rev.
  • PIK3CA mutation has been established as causative in many cancer types. Mutations in the gene coding for an isoform are point mutations clustered within several hotspots in helical and kinase domains. Missense mutations occur in all domains of p110 ⁇ , but the majority cluster in two hotspots, the most common being E542K and E545K in the helical domain and H1047R in the kinase domain. Cell-based analyses confirmed that these hotspot mutations confer transformation via constitutive activation of p110 ⁇ .
  • the alpha isoform has been implicated, for example, in a variety of human cancers.
  • Angiogenesis has been shown to selectively require the alpha isoform in the control of endothelial cell migration. (Graupera et al, Nature 2008; 453; 662-6). Mutations in the gene coding for PI3Ka or mutations which lead to hyperactivation of PI3Ka are believed to occur in many human cancers such as lung, stomach, endometrial, ovarian, bladder, breast, colon, brain, prostate, and skin cancers.
  • Mutations in the gene coding are point mutations clustered within several hotspots in kinase and helical domains, such as H1047R, E545K and E542K. Many of these mutations have been shown to be oncogenic gain-of-function mutations. Because of the high rate of mutations, targeting of this protein may provide valuable therapeutic opportunities including cancer. While other isoforms are expressed primarily in hematopoietic cells, PI3Ka is expressed constitutively.
  • wild- type PI3K In the setting of cancer with mutated PI3K ⁇ , one way to overcome the problem of compensatory production of insulin and/or glucose upon systemic inhibition caused by inhibition of the patient’s wild- type PI3K would be to develop inhibitors with enhanced selectivity for mutant over wild-type. This would create an increased window for drug dosing to selectively inhibit the pathologic signaling of mutant varients in the cancer cells without affecting the wild-type in the host tissues that control systemic metabolism (Okkenhaug K, Graupera M, Vanhaesebroeck B. Targeting PBK in Cancer: Impact on Tumor Cells, Their Protective Strama, Angiogenesis, and Immunotherapy.
  • inhibitors which target a second, peripheral, binding pocket, with potential differential activity for mutant over wild-type may provide a route to selective PI3K ⁇ inhibition.
  • targeting a, peripheral binding pocket of PI3Ka may in turn provide a valuable therapeutic target for drug development.
  • kinases for example lipid kinases such as PI3Ks, are prime targets for drug development.
  • the present disclosure provides a new class of kinase inhibitors. Summary of the Invention [0019] One embodiment of the present disclosure includes a compound of Formula (I):
  • A is selected from the group consisting of a. C 1-6 alkyl, b. C 2-6 alkenyl, c. C 2-6 alkynyl, and d. 3- to 14- membered mono-ring or fused ring system, which may have one or more degrees of unsaturation, and which may contain one or more heteroatoms selected from O, N, or S, e.
  • R 7 is selected from the group consisting of: CHO, OH, oxo, C 1 -C 6 alkyl(OH), C 2 -C 6 alkenyl(OH), C 2 -C 6 alkynyl(OH), C 1 -C 6 alkyl(NH 2 ), C 2 -C 6 alkenyl(NH 2 ), C 2 -C 6 alkynyl(NH 2 ), C 1 -C 6 alkyl(NH(C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl)), C 2 -C 6 alkenyl(NH(C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl)), C 2 -C 6 alkenyl(NH(C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl)), C 2 -C
  • the Y ring or ring system when Y is incorporated into or includes any ring or ring system: the Y ring or ring system contains a B atom in the Y ring or ring system; the Y ring or ring system is substituted with one or more R Y , which at least one R Y is B(OH) 2 ; the Y ring or ring system is substituted with one or more R Y , which at least one R Y is either (CH 2 ) q -heterocycle or (CH 2 ) q -heteroaryl, where each of said heterocycle or heteroaryl comprises at least one B atom; or the Y ring or ring system is further substituted with one or more R Y , which at least one R Y is (CH 2 ) q -C 3-10 cycloalkyl, (CH 2 ) q -heterocycle, (CH 2 ) q -aryl, or (CH 2 ) q -hetero
  • L 1 is optionally substituted phenylene.
  • L 1 is phenylene substituted with one or more halogen.
  • L 1 is optionally substituted heteroarylene.
  • L 1 is optionally substituted pyridinylene.
  • L 1 is pyridinylene substituted with at least one or more halogen.
  • L 1 is substituted with at least one or more halogen or C 1-6 alkyl.
  • L 1 is optionally substituted pyridinylene, and the pyridinylene is attached as: [0028]
  • R 7 is COOH or C 1 -C 6 alkyl(OH).
  • A is selected from the group consisting of phenyl and 5-6 membered heteroaryl.
  • A is phenyl.
  • A is substituted with one or two R A that may be the same or different.
  • each R A is selected from the group consisting of: C 1-6 alkyl, halogen, and C 1-6 haloalkyl.
  • A is substituted with one or two R A and at least one R A is a halogen.
  • halogen is fluorine or chlorine.
  • R 1a is H; and R 1b independently is selected from the group consisting of H, halogen, CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, and C 1-6 alkoxy.
  • R 1b is C 1-6 alkyl.
  • R 1b is methyl.
  • R 1b is methyl and R 1a is hydrogen.
  • L 2 is O.
  • L 2 is NH.
  • X is O.
  • Y is an N, which combines with R 3a and R 3b to form a 3- to 14-membered mono ring or spiro or fused ring system, which may contain one or more additional heteroatoms selected from the group consisting of N, O, S, and B, and wherein the ring or ring system is optionally substituted with one or more R Y .
  • Y is an N, which combines with R 3a and R 3b to form an isoindolene that is optionally substituted with one or more R Y .
  • Y is an N, which combines with R 3a and R 3b to form a piperidine that is optionally substituted with one or more R Y .
  • Y is an N, which combines with R 3a and R b to form: wherein each R 10 and R 10a is the same or different and is individually selected from an R Y ; each u is 0, 1, 2, 3, 4, 5, or 6; and each L is absent, (CH 2 ), (CH 2 ) 2 , or (CH 2 ) 3 .
  • Y is an N, which combines with R 3a and R 3b to form one of:
  • each of R 2 , R 4 , R 5 , and R 6 independently is H, halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3 -C 6 cycloalkyl, C 2-6 haloalkenyl, C 2-6 haloalkynyl, or C 1-6 haloalkyl.
  • R 2 is H, C 1-6 alkyl, C 2-6 alkenyl, or C 2-6 alkynyl;
  • R 5 is H; and R 6 is H.
  • R 2 is methyl.
  • R 4 is selected from the group consisting of CH 3 .
  • One embodiment of the present disclosure includes a compound of Formula X: or a tautomer, enantiomer, diastereomer, isotopomer, mixture, or salt thereof, wherein Q A is an optionally substituted 8- to 14-membered ring system, which may have one or more degrees of unsaturation, which may contain one or more heteroatoms selected from O, N, or S, and which may be further substituted with one or more R Q ; A is selected from the group consisting of a. C 1-6 alkyl, b. C 2-6 alkenyl, c.
  • C 2-6 alkynyl and d. 3- to 14- membered mono-ring or fused ring system, which may have one or more degrees of unsaturation, and which may contain one or more heteroatoms selected from O, N, or S, e.
  • L 1 is selected from the group consisting of a direct bond, optionally substituted cycloalkylene, optionally substituted heterocyclylene, optionally substituted arylene, and optionally substituted heteroarylene
  • L 2 is selected from the group consisting of consisting of a direct bond, (CR R 2 ) 1-6 , O, C(O), S, and NR R
  • each of R R , R 1a , and R 1b is the same or different and is independently is selected from the group consisting of H, halogen, CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 2-6 haloalkenyl, C 2-6 haloalkynyl, O-C 1-6 alkyl, O-C 2-6 alkenyl, and O-C 2-6 alkynyl; or L 2 -C(R 1a )(R 1b
  • R 3a and R 3b are absent; b. C-R 3c , wherein i. R 3c is absent or is selected from the group consisting of hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 2-6 haloalkenyl, C 2-6 haloalkynyl, aryl, C 3-6 cycloalkyl, and 3 to 6 membered heterocyclyl; ii.
  • each of R 3a and R 3b is the same or different and independently is selected from the group consisting of H, C 1-6 alkyl, C 1-6 alkenyl, C 1-6 alkynyl C 1-6 haloalkyl, C 2-6 haloalkenyl, C 2-6 haloalkynyl, aryl, C 3-6 cycloalkyl, and 3 to 6 membered heterocyclyl; as noted hereinabove, the value for each of alkenyl and alkynyl includes a C1, with the intention that when Y is C, then Y may be bound through a double or triple bond to a C atom; or iii.
  • Y as an C atom, combines with R 3a and R 3b to form a cycloalkyl, aryl, heterocyclic, or heteroaromatic mono ring or spiro or fused ring system, where the heterocyclic and heteroaromatic rings contain one or more heteroatoms selected from the group consisting of N, O, S, and B, and wherein the Y-containing ring or ring system is optionally substituted with one or more R Y ; c. N, wherein i.
  • each of R 3a and R 3b independently is selected from the group consisting of H, C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl, C 1-6 haloalkyl, C 2-6 haloalkenyl, C 2-6 haloalkynyl, aryl, C 3-6 cycloalkyl, and 3 to 6 membered heterocyclyl; or ii.
  • Y as an N atom, combines with R 3a and R 3b to form a 3- to 14-membered mono ring or spiro or fused ring system, which may contain one or more additional heteroatoms selected from the group consisting of N, O, S, and B, and wherein the ring or ring system is optionally substituted with one or more R Y ; d. O, wherein R 3a is absent and R 3b is selected from the group consisting of H, C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl; and e.
  • R 3a is absent and R 3b is selected from the group consisting of H, C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl;
  • R 7 is selected from the group consisting of: H, CHO, OH, oxo, C 1 -C 6 alkyl(OH), C 2 -C 6 alkenyl(OH), C 2 - C 6 alkynyl(OH), C 1 -C 6 alkyl(NH 2 ), C 2 -C 6 alkenyl(NH 2 ), C 2 -C 6 alkynyl(NH 2 ), C 1 -C 6 alkyl(NH(C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl)), C 2 -C 6 alkenyl(NH(C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl)), C 2 -C
  • the compound is of Formula X1: wherein X is C(R x ) 2 , O, NR x , or S; each R x is the same or different and is independently selected from the group consisting of H, C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl; R 2 is selected from the group consisting of H, halogen, CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 2-6 haloalkenyl, C 2-6 haloalkynyl, C 1-6 alkoxy, (CH 2 ) m -R 100 , (CH 2 ) m -OR 100 , (CH 2 ) m -N(R 100 ) 2 , (CH 2 ) m -C(O)R 100 , (CH 2 ) m -C(O)OR 100 , (CH 2 )
  • Y comprises a B atom.
  • Y is incorporated into or includes any ring or ring system: the Y ring or ring system contains a B atom in the Y ring or ring system; the Y ring or ring system is substituted with one or more R Y , which at least one R Y is B(OH) 2 ; the Y ring or ring system is substituted with one or more R Y , which at least one R Y is either (CH 2 ) q -heterocycle or (CH 2 ) q -heteroaryl, where each of said heterocycle or heteroaryl comprises at least one B atom; or the Y ring or ring system is further substituted with one or more R Y , which at least one R Y is (CH 2 ) q -C 3-10 cycloalkyl, (CH 2 ) q -heterocycle, (CH 2 ) q -aryl
  • Y is a ring or ring system wherein: the Y ring or ring system contains a B atom in the Y ring or ring system; the Y ring or ring system is substituted with one or more R Y , which at least one R Y is either (CH 2 ) q -heterocycle or (CH 2 ) q -heteroaryl, where each of said heterocycle or heteroaryl comprises at least one B atom; or Y(R 3a )(R 3b ) is selected from:
  • One embodiment of the present disclosure includes a compound of Formula XX: or a tautomer, enantiomer, diastereomer, isotopomer, mixture, or salt thereof, wherein A is selected from the group consisting of C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, and 3- to 14- membered mono-ring or fused ring system, which may have one or more degrees of unsaturation, and which may contain one or more heteroatoms selected from O, N, or S, each of which A may be further substituted with one or more R A ; R 7 is selected from the group consisting of: CHO, OH, oxo, C 1 -C 6 alkyl(OH), C 2 -C 6 alkenyl(OH), C 2 -C 6 alkynyl(OH), C 1 -C 6 alkyl
  • R 3a and R 3b are absent; b. C-R 3c , wherein i. R 3c is absent or is selected from the group consisting of hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 2-6 haloalkenyl, C 2-6 haloalkynyl, aryl, C 3-6 cycloalkyl, and 3 to 6 membered heterocyclyl; ii.
  • each of R 3a and R 3b is the same or different and independently is selected from the group consisting of H, C 1-6 alkyl, C 1-6 alkenyl, C 1-6 alkynyl C 1-6 haloalkyl, C 2-6 haloalkenyl, C 2-6 haloalkynyl, aryl, C 3-6 cycloalkyl, and 3 to 6 membered heterocyclyl; as noted hereinabove, the value for each of alkenyl and alkynyl includes a C1, with the intention that when Y is C, then Y may be bound through a double or triple bond to a C atom; or iii.
  • Y as an C atom, combines with R 3a and R 3b to form a cycloalkyl, aryl, heterocyclic, or heteroaromatic mono ring or spiro or fused ring system, where the heterocyclic and heteroaromatic rings contain one or more heteroatoms selected from the group consisting of N, O, S, and B, and wherein the Y-containing ring or ring system is optionally substituted with one or more R Y ; c. N, wherein i.
  • each of R 3a and R 3b independently is selected from the group consisting of H, C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl, C 1-6 haloalkyl, C 2-6 haloalkenyl, C 2-6 haloalkynyl, aryl, C 3-6 cycloalkyl, and 3 to 6 membered heterocyclyl; or ii.
  • Y as an N atom, combines with R 3a and R 3b to form a 3- to 14-membered mono ring or spiro or fused ring system, which may contain one or more additional heteroatoms selected from the group consisting of N, O, S, and B, and wherein the ring or ring system is optionally substituted with one or more R Y ; d. O, wherein R 3a is absent and R 3b is selected from the group consisting of H, C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl; and e.
  • R 3a is absent and R 3b is selected from the group consisting of H, C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl; provided that at least one of the following applies: a) the Y ring or ring system contains a B atom in the Y ring or ring system; b) the Y ring or ring system is substituted with one or more R Y , which at least one R Y is B(OH) 2 ; c) the Y ring or ring system is substituted with one or more R Y , which at least one R Y is either (CH 2 ) q -heterocycle or (CH 2 ) q -heteroaryl, where each of said heterocycle or heteroaryl comprises at least one B atom; or d) the Y ring or ring system is further substituted with one or more R Y , which at least one R Y is (CH 2 ) q -C 3-10 cyclo
  • the Y ring or ring system contains a B atom in the ring or ring system.
  • the Y ring or ring system is substituted with a 4-, 5-, or 6-membered ring, which contains a B atom in the ring.
  • L 1 is a direct bond.
  • A is a 5- or 6-membered heteroaryl or phenyl [0062] In one aspect, A is phenyl. [0063] In one aspect, R 7 is COOH. [0064] In one aspect, L 2 is O. [0065] In one aspect, L 2 is NH. [0066] In one aspect, R 1a is H or CH 3 . [0067] In one aspect, R 1b is H or CH 3 . [0068] In one aspect, Q is selected from the group consisting of:
  • each G is, at each occurrence, independently selected from carbon or a heteroatom selected from O, N, or S; each m is, at each occurrence, independently selected from 0, 1, 2, 3, 4, 5, and 6; when m is not 0, each R 100 may be substituted from any depicted ring; and when present, each R 100 is the same or different and independently is selected from the group consisting of halogen, OH, oxo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, (CH 2 ) q -N(H or C 1 - 6alkyl), C 3-10 cycloalkyl, (CH 2 ) q -heterocycle, (CH 2 ) q -aryl, and (CH 2 ) q -heteroaryl, wherein each of the cycloalkyl, heterocycle, aryl, and heteroaryl is optionally substituted with one or more halogen
  • X is C(R x ) 2 , O, NR x , or S; each R x independently is selected from the group consisting of H, C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl; R 2 is selected from the group consisting of H, halogen, CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 2-6 haloalkenyl, C 2-6 haloalkynyl, C 1-6 alkoxy, (CH 2 ) m -R 100 , (CH 2 ) m -OR 100 , (CH 2 ) m -N(R 100 ) 2 , (CH 2 ) m -C(O)R 100 , (CH 2 ) m -C(O)OR 100 , (CH 2 ) m -C(O)N(R 100 ) 2 , (CH 2 ) m
  • X is O.
  • One embodiment of the present disclosure includes a compound of Formula XXX: or a tautomer, enantiomer, diastereomer, isotopomer, mixture, or salt thereof, wherein A is selected from the group consisting of C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, and 3- to 14- membered mono-ring or fused ring system, which may have one or more degrees of unsaturation, and which may contain one or more heteroatoms selected from O, N, or S, each of which A may be further substituted with one or more R A ; Q is a 8- to 14- membered fused ring system, which may have one or more degrees of unsaturation, which may contain one or more heteroatoms selected from O, N, or S, and which may be further substituted with one or more R Q ; L 1 is selected from the group consisting of a direct bond, optionally substituted cycloalkylene
  • L 1 is a direct bond.
  • A is 5- or 6-membered heteroaryl or phenyl.
  • A is phenyl.
  • L 2 is O.
  • L 2 is NH.
  • R 1a is H or CH 3 .
  • R 1b is H or CH 3 .
  • Q is: wherein X is C(R x ) 2 , O, NR x , or S; each R x independently is selected from the group consisting of H, C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl; R 2 is selected from the group consisting of H, halogen, CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 2-6 haloalkenyl, C 2-6 haloalkynyl, C 1-6 alkoxy, (CH 2 ) m -R 100 , (CH 2 ) m -OR 100 , (CH 2 ) m -N(R 100 ) 2 , (CH 2 ) m -C(O)R 100 , (CH 2 ) m -C(O)OR 100 , (CH 2 ) m -C(O)N(R 100
  • X is O.
  • each of R 2 , R 4 , R 5 , and R 6 independently is H, halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3 -C 6 cycloalkyl, C 2-6 haloalkenyl, C 2-6 haloalkynyl, or C 1-6 haloalkyl.
  • R 2 is H, C 1-6 alkyl, C 2-6 alkenyl, or C 2-6 alkynyl; R 5 is H; and R 6 is H.
  • R 2 is methyl.
  • R 4 is methyl.
  • Y is incorporated in or is substituted with a ring or ring system that is selected from: . or a tautomer, enantiomer, diastereomer, isotopomer, mixture, or salt thereof.
  • One embodiment of the present disclosure includes a compound selected from the group consisting of:
  • embodiments of the present invention may include a boron atom incorporated into a ring. Metabolic oxidation or hydrolysis may form alternative products (II) or (III). Species (II) may be in equilibrium with the parent compound (I). The scope of the present disclosure is intended to capture all forms.
  • embodiments of the present invention may include an isotopomer or isotopic isomer, wherein one or more atom of a compound of the present disclosure is replaced with an isotope, such as deuterium for hydrogen or 13 C for carbon.
  • an isotope such as deuterium for hydrogen or 13 C for carbon.
  • the scope of the present disclosure is intended to capture isotopic forms of the compounds.
  • One aspect of the present disclosure includes a depicted dashed bond.
  • the depicted dashed bond is a pi bond.
  • An additional aspect of the present disclosure includes where the depicted dashed bond indicates a pi bond is absent, wherein the octet is filled by hydrogen atoms.
  • a portion, Q may be selected from the noted publications.
  • a portion, Y may be selected from the noted publications.
  • a portion, of the depicted Y(R 3a )(R 3b ) may be selected from the noted publications.
  • a chiral center is in the R configuration, as depicted by: [0028]
  • One aspect of the present disclosure includes wherein the compound is a tautomeric form of a preferred equilibria.
  • One embodiment of the present disclosure includes a pharmaceutical composition comprising a therapeutically effective amount of a compound of the present disclosure and a pharmaceutically acceptable excipient.
  • One embodiment of the present disclosure includes a method of inhibiting cell proliferation comprising contacting a cell with an effective amount of a compound of the present disclosure.
  • One embodiment of the present disclosure includes a method for treating cancer in a patient comprising administering a therapeutically effective amount of a compound of the present disclosure to a patient in need thereof.
  • One embodiment of the present disclosure includes a method of treating a PI3K-mediated disease or disorder in a patient in need of such treatment, the method comprising administering to the patient a therapeutically effective amount of a compound of the present disclosure.
  • One aspect includes a method of treating a disease or disorder mediated by one or more PIK3CA genes comprising modulating one or more of wild type or one or more mutations of the one or more PIK3CA genes.
  • the scope of the present disclosure includes all other isoforms.
  • One aspect includes modulating one mutation.
  • One aspect includes modulating two or more mutations.
  • One aspect includes modulating wild type.
  • One aspect includes wherein the PIK3CA is a PIK3CA mutant. [0038] One aspect includes wherein the PIK3CA mediates a cancer. [0039] One aspect includes wherein the PIK3CA regulates cancer initiation, progression, or metasasis. [0040] One aspect includes wherein wherein the one or more mutations are any p110 mutation. [0041] One aspect includes wherein the one or more mutations are selected from one or more mutations of H1047, E545, E542, N345, E726, C420, Q546, G118, E453, Q546, G1049, M1043, K111, E81, N1044, and E110.
  • One aspect includes wherein the one or more mutations are selected from one or more mutations of H1047, E545, and E542. [0043] One aspect includes wherein modulation is inhibition. [0044] One aspect includes wherein modulation is selective inhibiton for one or more mutations over wild-type. [0045] One aspect includes wherein the mutations are selected from H1047X, E545X, and E542X. [0046] One aspect includes wherein the mutation is H1047X. [0047] One aspect includes wherein the mutation is H1047L [0048] One aspect includes wherein the mutation is H1047R. [0049] One aspect includes wherein a mutation is E545X. [0050] One aspect includes wherein the mutation is E545K.
  • a mutation is E542X.
  • One aspect includes wherein the mutation is E542K.
  • the method further comprises administering a compound of the present disclosure.
  • modulation is selective inhibition over wild-type, providing preferential inhibition at a multiple level of: greater than 1,
  • One aspect includes wherein the mutations are selected from H1047X, E545X, and E542X.
  • One aspect includes wherein a mutation is H1047X.
  • One aspect includes wherein the mutation is H1047L
  • One aspect includes wherein the mutation is H1047R.
  • One aspect includes wherein the mutation is GLU545X.
  • One aspect includes wherein the mutation is E545K. [0061] One aspect includes wherein the mutation is GLU542X. [0062] One aspect includes wherein the mutation is E542K. [0063] One aspect includes wherein the p110 mutated protein subunit comprises at least one amino acid mutation compared to the wild type p110 protein subunit. [0064] One aspect includes wherein the at least one amino acid mutation are selected from one or more mutations of H1047, E545, E542, N345, E726, C420, Q546, G118, E453, Q546, G1049, M1043, K111, E81, N1044, and E110.
  • One aspect includes wherein the one or more mutations are selected from one or more of H1047, E545, and E542. [0066] One aspect includes comprising administering a compound of the present disclosure. [0067] One aspect includes modulating one or more of H1047L and H1047R. [0068] One aspect includes modulating GLU545K. [0069] One aspect includes modulating GLU542K.
  • One aspect includes administering a compound of the present disclosure
  • One embodiment of the present disclosure includes a method of inhibiting a PIK3CA gene target protein (PI3K) comprising modulating two or more mutant variants selected from mutations of H1047, E545, E542, N345, E726, C420, Q546, G118, E453, Q546, G1049, M1043, K111, E81, N1044, and E110.
  • PI3K PIK3CA gene target protein
  • One aspect includes wherein the two or more mutant varients are selected from mutations of H1047, E545, and E542 [0073]
  • One embodiment of the present disclosure includes a method of treating a disease or disorder mediated by PIK3CA, comprising modulating two or more mutant variants selected from mutations of H1047, E545, E542, N345, E726, C420, Q546, G118, E453, Q546, G1049, M1043, K111, E81, N1044, and E110.
  • One aspect includes wherein the two or more mutant varients are selected from mutations of H1047, E545, and E542.
  • One aspect includes administering a compound of the present disclosure.
  • One embodiment of the present disclosure includes a method of modulating a PI3K to treat a disease or disorder by interacting a compound of the present disclosure with at least two mutant variants.
  • the PI3K gene target is PIK3CA.
  • the PI3K mediates a cancer.
  • the PI3K regulates cancer initiation, progression, or metastasis.
  • the mutant variants are selected from mutations of H1047, E545, E542, N345, E726, C420, Q546, G118, E453, Q546, G1049, M1043, K111, E81, N1044, and E110.
  • One aspect includes wherein the mutant variants are selected from mutations of one or more of H1047, E545, and E542. [0082] One aspect includes wherein modulation is inhibition. [0083] One aspect includes wherein modulation is selective inhibiton over wild-type. [0084] One aspect includes wherein the mutation is H1047X. [0085] One aspect includes wherein the mutation is H1047L. [0086] One aspect includes wherein the mutation is H1047R. [0087] One aspect includes wherein the mutation is E545X. [0088] One aspect includes wherein the mutation is E545K. [0089] One aspect includes wherein the mutation is E542. [0090] One aspect includes wherein the mutation is E542K.
  • the present disclosure includes a method of the present disclosure, wherein the disease or disorder is cancer.
  • the disease or disorder is PROS: PIK3CA-Related Overgrowth Spectrum.
  • the disease or disorder is breast cancer, colorectal cancer, uterine cancer, bladder cancer, lung cancer, giloma, head and neck cancer, or other solid tumors.
  • the disease or disorder is breast cancer.
  • the present disclosure includes a method comprising administration of one or more additional therapeutic agent.
  • administration is of two or more additional therapeutic agents.
  • the additional therapeutic agents are selected from selective estrogen receptor degraders, Protac-mediated estrogen receptor inhibitors, complete estrogen receptor antagonists, sarcoplasmic reticulum calcium ATPase inhibitors, CDK2/4/6 inhibitors, CDK4/6 inhibitors, and aromatase inhibitors.
  • the additional therapeutic agents are selected from fulvestrant, vepdegestrant, palazestrant, imlunestrant, elacestrant, giredestrant, camizestrant, palbociclib, ribociclib, abemaciclib, anastronzole, exemestane, and letrozole.
  • each agent is provided in a separate dosage form.
  • one or more agent is provided in a combined dosage form.
  • the present disclosure includes a method to modulate one or more PI3K enzymes to regulate one or more of disease initiation and progression comprising interaction with at least one histidine and modulation of at least one surface accessible amino acid or residue.
  • one or more PI3K is inhibited.
  • the PI3K is PI3K ⁇ .
  • One aspect includes wherein the PI3K ⁇ is a mutated variant thereof.
  • the present disclosure includes a method for treating cancer in a patient in need thereof, comprising: determining that the cancer is associated with a PI3K wild-type or one or more PI3K mutations; and administering to the patient a therapeutically effective amount of a compound of the present disclosure [00106]
  • One aspect includes wherein the PI3K is a mutated variant thereof.
  • the present disclosure includes a compound of the present disclosure, for use in therapy.
  • the present disclosure includes a compound of the present disclosure, for use in the treatment of cancer.
  • the present disclosure includes a compound of the present disclosure, for use in the inhibition of PI3K.
  • the PI3K is PI3K ⁇ .
  • the PI3K ⁇ is wild type.
  • the PI3K ⁇ is a mutated variant thereof.
  • the present disclosure includes a use of a compound of the present disclosure, in the manufacture of a medicament for the treatment of cancer.
  • the present disclosure includes a use of a compound of the present disclosure, in the manufacture of a medicament for the inhibition of activity of PI3K.
  • the present disclosure includes a use of a compound of the present disclosure in the manufacture of a medicament for the treatment of a PI3K-mediated disease or disorder.
  • the PI3K is PI3K ⁇ .
  • the PI3K ⁇ is wild type.
  • the PI3K ⁇ is a mutated variant thereof.
  • One embodiment of the present disclosure includes a process for preparing a compound of the present disclosure.
  • One embodiment of the present disclosure includes a compound obtained by a process of the present disclosure.
  • One or more aspects and embodiments may be incorporated in a different embodiment although not specifically described. That is, all aspects and embodiments may be combined in any way or combination. Brief Description of the Drawings [00122] Figure 1 provides tabulated biological data for compounds of the present disclosure.
  • alkyl refers to monovalent saturated aliphatic hydrocarbon groups having from 1 to 20 carbon atoms, preferably 1-8 carbon atoms, more preferably 1-6 carbon atoms.
  • the hydrocarbon chain may be either straight-chained or branched.
  • alkyl groups include methyl, ethyl, n- propyl, iso-propyl, n-butyl, iso-butyl, and tert-butyl.
  • an “alkenyl” group refers to an alkyl group having one or more double bonds present in the chain
  • an “alkynyl” group refers to an alkyl group having one or more triple bonds present in the chain.
  • halogen refers to a halogen. In some embodiments, the halogen is preferably Br, Cl, or F.
  • haloalkyl refers to monovalent saturated aliphatic hydrocarbon groups having from 1 to 20 carbon atoms, preferably 1-8 carbon atoms, more preferably 1-6 carbon atoms, wherein at least one hydrogen atom is substituted by a halogen, including but not limited to perhalo groups where all hydrogen atoms are replaced with halogen atoms.
  • the haloalkyl chain can be either straight-chained or branched.
  • Illustrative alkyl groups include trifluoromethyl, trifluoroethyl, trifluoropropyl, trifluorobutyl, and pentafluoroethyl.
  • a “haloalkenyl” group refers to a haloalkyl group having one or more double bonds present in the chain
  • a “haloalkynyl” group refers to a haloalkyl group having one or more triple bonds present in the chain.
  • haloalkyloxy refers to O-haloalkyl.
  • alkoxy refers to an O-alkyl group having the specified number of carbon atoms.
  • Alkenoxy and alkynoxy are used similarly to refer to groups with one or more double or triple bonds, respectively. Such groups may be depicted as O-alkyl, O-alkenyl, and O-alkynyl, and should be considered an alternative but equivalent recitations.
  • An “alkylene,” group is an alkyl group, as defined hereinabove, that is positioned between and serves to connect two other chemical groups. Exemplary alkylene groups include, without limitation, methylene, ethylene, propylene, and butylene.
  • an “alkylene” linker group refers to a divalent alkyl group, namely (CH 2 ) x , where x is 1 to 20, preferably 1 to 8, preferably 1 to 6, and more preferably 1 to 3.
  • heteroalkyl refers to an alkyl group, as defined hereinabove, wherein one or more carbon atoms in the chain are replaced by a heteroatom selected from the group consisting of O, S, and N.
  • hydroxyalkyl refers to an alkyl group as herein defined substituted with one or more –OH group.
  • a “hydroxyalkenyl” group refers to a hydroxyalkyl group having one or more double bonds present in the chain
  • a “hydroxyalkynyl” group refers to a hydroxyalkyl group having one or more triple bonds present in the chain
  • a “dihydroxyalkyl” group provides two – OH substituents.
  • aryl refers to a substituted or unsubstituted carbocyclic aromatic ring system, either pendent or fused, such as phenyl, naphthyl, anthracenyl, phenanthryl, tetrahydronaphthyl, or indane.
  • a preferred aryl group is phenyl.
  • An “aralkyl” or “arylalkyl” group comprises an aryl group covalently linked to an alkyl group as defined herein above, either of which may independently be optionally substituted or unsubstituted.
  • An example of an aralkyl group is (C 1 -C 6 )alkyl(C 6 -C 10 )aryl, including, without limitation, benzyl, phenethyl, and naphthylmethyl.
  • An example of a substituted aralkyl is wherein the alkyl group is substituted with hydroxyalkyl.
  • boron is able to form dative bonds with, for example, oxygen or nitrogen under some circumstances. Dative bonds are usually weaker than covalent bonds. In situations where a boron is covalently bonded to at least one oxygen or nitrogen, and is at the same time datively bonded to an oxygen or nitrogen, respectively, the dative bond and covalent bond between the boron and the two identical heteroatoms can interconvert or be in the form of a resonance hybrid. Additionally, the dative bond may be reversible depending on the chemical structure of the parent compound and the biological environement.
  • cycloalkyl refers to a saturated, an unsaturated or a partially saturated hydrocarbon ring, containing from 3 to 15 ring atoms.
  • Illustrative cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, as well as partially saturated versions thereof, such as cyclohexenyl, and cyclohexadienyl.
  • heterocyclyl refers to an unsaturated or partially saturated hydrocarbon ring, containing from 3 to 15 ring atoms, wherein one or more carbon atom is replaced with a heteroatom selected from B, O, N, S, or Si, where each N, S, or Si may be oxidized, and where each N may be quarternized.
  • a heterocyclyl group may be attached to the remainder of the molecule through a heteroatom.
  • Heterocyclyl does not include heteroaryl.
  • Examples include, but are not limited to, aziridine, oxirane, thiirance, azetidine, oxetane, thietane, pyrrolidine, pyrazolidine, imidazolidine, tetrahydrofuran, tetrahydrothiophene, piperidine, piperazine, tetrahydropyran, thiane, morpholine, thiomorpholine, pyrrolizidine, indoline, decahydroquinoline, tetrahydroquinoline, and azaadamantane.
  • heterocyclylalkyl refers to a heterocyclyl group as defined herein covalently linked to an alkyl group as defined hereinabove wherein the radical is on the alkyl group, wherein the alkyl group of the heterocyclylalkyl may be optionally substituted.
  • heteroaryl or “heteroaromatic” refers to aromatic ring groups having 5 to 14 ring atoms selected from carbon and at least one (typically 1-4, more typically 1 or 2) heteroatom (e.g., boron, oxygen, nitrogen, sulfur, or silicon).
  • monocyclic heteroaryl groups include, but are not limited to, furanyl (e.g., 2-furanyl, 3-furanyl), imidazolyl (e.g., N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl), isoxazolyl (e.g., 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl), oxadiazolyl (e.g., 2-oxadiazolyl, 5- oxadiazolyl), oxazolyl (e.g., 2-oxazolyl, 4-oxazolyl, 5-oxazolyl), pyrazolyl (e.g., 3-pyrazolyl, 4- pyrazolyl), pyrrolyl (e.g., 1-
  • Examples of monocyclic six-membered nitrogen- containing heteroaryl groups include pyrimidinyl, pyridinyl and pyridazinyl.
  • Examples of polycyclic aromatic heteroaryl groups include carbazolyl, benzimidazolyl, benzothienyl, benzofuranyl, indolyl, quinolinyl, benzotriazolyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, isoquinolinyl, indolyl, acridinyl, or benzisoxazolyl.
  • arylalkyl refers to those radicals in which an aryl, heteroaryl, or heterocyclyl group is linked through an alkyl group. Examples includes benzyl, phenethyl, pyridylmethyl, and the like.
  • alkyl linking groups in which a carbon atom, for example, a methylene group, has been replaced by, for example, an oxygen atom. Examples include phenoxymethyl, pyrid-2-yloxymethyl, 3-(naphth-1-yloxy)propyl, and the like.
  • benzyl as used herein is a radical in which a phenyl group is attached to a CH 2 group, thus, a CH 2 Ph group. Benzyl groups may be substituted or unsubstituted.
  • substituted benzyl refers to radicals in which the phenyl group or CH 2 contains one or more substituents. In one embodiment, the phenyl group may have 1 to 5 substituents, or in another embodiment 2 to 3 substituents.
  • a “heteroarylalkyl” group comprises a heteroaryl group covalently linked to an alkyl group, wherein the radical is on the alkyl group, either of which is independently optionally substituted or unsubstituted.
  • heteroarylalkyl groups include a heteroaryl group having 5, 6, 9, or 10 ring atoms bonded to a C1-C 6 alkyl group.
  • heteroarylalkyl groups include pyridylmethyl, pyridylethyl, pyrrolylmethyl, pyrrolylethyl, imidazolylmethyl, imidazolylethyl, thiazolylmethyl, thiazolylethyl, benzimidazolylmethyl, benzimidazolylethyl quinazolinylmethyl, quinolinylmethyl, quinolinylethyl, benzofuranylmethyl, isoquinolinylmethyl, cinnolinylmethyl, and benzothiophenylethyl.
  • substitutions refers to a substitution of a hydrogen atom, which would otherwise be present for the substituent.
  • optional substitution is typically with 1, 2, or 3 substituents replacing the normally-present hydrogen.
  • the number of substitutions may be more, occurring wherever hydrogen is present. The substitutions may be the same or different.
  • Illustrative substituents which with multiple substituents can be the same or different, include deuterium, halogen, haloalkyl, R', OR', OH, SH, SR', NO 2 , CN, C(O)R', NH 2 , C(O)OR', OC(O)R', CON(R') 2 , OC(O)N(R') 2 , NH 2 , NHR', N(R') 2 , NHCOR', NHCOH, NHCONH 2 , NHCONHR', NHCON(R') 2 , NRCOR', NRCOH, NHCO 2 H, NHCO 2 R', NHC(S)NH 2 , NHC(S)NHR', NHC(S)N(R') 2 , CO 2 R', CO 2 H, CHO, CONH 2 , CONHR', CON(R') 2 , S(O) 2 H, S(O) 2 R
  • each may be linked through an alkylene linker, (CH 2 ) x , where x is 1, 2, or 3,
  • R’ is the same or different and represents hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, or heteroaryl, or when two R’ are each attached to a nitrogen atom, they may form a saturated or unsaturated heterocyclic ring containing from 4 to 6 ring atoms.
  • a heteroatom may be a boron (B) atom.
  • one strategy to slow the CYP-mediated metabolism of a drug or to reduce the formation of undesirable metabolites includes an attempt to replace one or more hydrogen atoms with deuterium atoms.
  • Deuterium is a safe, stable, non-radioactive isotope of hydrogen. Compared to hydrogen, deuterium forms stronger bonds with carbon. In select cases, the increased bond strength imparted by deuterium can positively impact the ADME properties of a drug, creating the potential for improved drug efficacy, safety, and/or tolerability.
  • the size and shape of deuterium are essentially identical to those of hydrogen, replacement of hydrogen by deuterium would not be expected to affect the biochemical potency and selectivity of the drug as compared to the original chemical entity that contains only hydrogen.
  • deuterium modification has also led experts to question or dismiss deuterium modification as a viable drug design strategy for inhibiting adverse metabolism (see Foster at p.35 and Fisher at p.101).
  • the effects of deuterium modification on a drug's metabolic properties are not predictable even when deuterium atoms are incorporated at known sites of metabolism. Only by actually preparing and testing a deuterated drug can one determine if and how the rate of metabolism will differ from that of its non-deuterated counterpart. See, for example, Fukuto et al. (J. Med. Chem.1991, 34, 2871-76). Many drugs have multiple sites where metabolism is possible.
  • isotopic enrichment factor means the ratio between the isotopic abundance and the natural abundance of a specified isotope.
  • a compound of this invention has an isotopic enrichment factor for each designated deuterium atom of at least 3500 (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation).
  • a compound represented by a particular chemical structure containing one or more deuterium atoms will also contain lesser amounts of isotopologues having hydrogen atoms at one or more of the potential deuterium positions.
  • the relative amount of such isotopologues in a compound of this disclosure will depend upon a number of factors including the isotopic purity of deuterated reagents used to make the compound and the efficiency of incorporation of deuterium in the various synthesis steps used to prepare the compound. As set forth above, the relative amount of such isotopologues will be less than 49.9% of the compound.
  • an effective amount of a compound is an amount that is sufficient to negatively modulate or inhibit the activity of PI3K or a mutant thereof. Such amount may be administered as a single dosage or may be administered according to a regimen, whereby it is effective.
  • a “therapeutically effective amount” of a compound is an amount that is sufficient to ameliorate, or in some manner reduce a symptom or stop or reverse progression of a condition, or negatively modulate or inhibit the activity of PI3K or a mutant thereof. Such amount may be administered as a single dosage or may be administered according to a regimen, whereby it is effective.
  • treatment means any manner in which the symptoms or pathology of a condition, disorder or disease are ameliorated or otherwise beneficially altered. Treatment also encompasses any pharmaceutical use of the compositions herein.
  • amelioration of the symptoms of a particular disorder by administration of a particular pharmaceutical composition refers to any lessening, whether permanent or temporary, lasting or transient that can be attributed to or associated with administration of the composition.
  • the term “about” when used to modify a numerically defined parameter means that the parameter may vary by as much as 10% below or above the stated numerical value for that parameter. For example, a dose of about 5 mg/kg may vary between 4.5 mg/kg and 5.5 mg/kg. “About” when used at the beginning of a listing of parameters is meant to modify each parameter.
  • a salt refers to any salt of a compound disclosed herein which retains its biological properties and which is not toxic or otherwise undesirable for pharmaceutical use.
  • Such salts may be derived from a variety of organic and inorganic counter-ions known in the art.
  • Such salts include acid addition salts formed with organic or inorganic acids such as hydrochloric, hydrobromic, sulfuric, nitric, phosphoric, sulfamic, acetic, trifluoroacetic, trichloroacetic, propionic, hexanoic, cyclopentylpropionic, glycolic, glutaric, pyruvic, lactic, malonic, succinic, sorbic, ascorbic, malic, maleic, fumaric, tartaric, citric, benzoic, 3-(4-hydroxybenzoyl)benzoic, picric, cinnamic, mandelic, phthalic, lauric, methanesulfonic, ethanesulfonic, 1,2-ethane-disulfonic, 2-hydroxyethanesulfonic, benzenesulfonic, 4-chlorobenzenesulfonic, 2-naphthalenesulfonic, 4-toluenesulfonic
  • Salts further include, by way of example only, salts of non-toxic organic or inorganic acids, such as halides, such as, chloride and bromide, sulfate, phosphate, sulfamate, nitrate, acetate, trifluoroacetate, trichloroacetate, propionate, hexanoate, cyclopentylpropionate, glycolate, glutarate, pyruvate, lactate, malonate, succinate, sorbate, ascorbate, malate, maleate, fumarate, tartarate, citrate, benzoate, 3-(4- hydroxybenzoyl)benzoate, picrate, cinnamate, mandelate, phthalate, laurate, methanesulfonate (mesylate), ethanesulfonate, 1,2-ethane-disulfonate, 2-hydroxyethanesulfonate, benzenesulfonate (besy
  • inorganic bases that may be used to form base addition salts include, but are not limited to, metal hydroxides, such as lithium hydroxide, sodium hydroxide, and potassium hydroxide; metal amides, such as lithium amide and sodium amide; metal carbonates, such as lithium carbonate, sodium carbonate, and potassium carbonate; and ammonium bases such as ammonium hydroxide and ammonium carbonate.
  • metal hydroxides such as lithium hydroxide, sodium hydroxide, and potassium hydroxide
  • metal amides such as lithium amide and sodium amide
  • metal carbonates such as lithium carbonate, sodium carbonate, and potassium carbonate
  • ammonium bases such as ammonium hydroxide and ammonium carbonate.
  • organic bases that may be used to form base addition salts include, but are not limited to, metal alkoxides, such as lithium, sodium, and potassium alkoxides including lithium methoxide, sodium methoxide, potassium methoxide, lithium ethoxide, sodium ethoxide, potassium ethoxide, and potassium tert-butoxide; quaternary ammonium hydroxides, such as choline hydroxide; and amines including, but not limited to, aliphatic amines (i.e., alkylamines, alkenylamines, alkynylamines, and alicyclic amines), heterocyclic amines, arylamines, heteroarylamines, basic amino acids, amino sugars, and polyamines.
  • metal alkoxides such as lithium, sodium, and potassium alkoxides including lithium methoxide, sodium methoxide, potassium methoxide, lithium ethoxide, sodium ethoxide, potassium eth
  • salt forms may include lithium, sodium, potassium, and amine salts.
  • the base may be a quaternary ammonium hydroxide, wherein one or more of the alkyl groups of the quaternary ammonium ion are optionally substituted with one or more suitable substituents. Preferably, at least one alkyl group is substituted with one or more hydroxyl groups.
  • quaternary ammonium hydroxides that may be used in accordance with the present disclosure include choline hydroxide, trimethylethylammonium hydroxide, tetramethylammonium hydroxide, and is preferably choline hydroxide.
  • An alkylamine base may be substituted or unsubstituted.
  • Non-limiting examples of unsubstituted alkylamine bases that may be used in accordance with the present disclosure include methylamine, ethylamine, diethylamine, and triethylamine.
  • a substituted alkylamine base may be substituted with one or more hydroxyl groups, and preferably one to three hydroxyl groups.
  • Non-limiting examples of substituted alkylamine bases that may be used in accordance with the present disclosure include 2-(diethylamino)ethanol, ⁇ , ⁇ -dimethylethanolamine (deanol), tromethamine, ethanolamine, and diolamine.
  • Salt counterion refers to positively charged ions that associate with a compound of the invention when the boron is fully negatively or partially negatively charged.
  • salt counterions include H + , H 3 O + , ammonium, lithium, potassium, calcium, magnesium and sodium.
  • the compounds comprising a boron bonded to a carbon and three heteroatoms (such as three oxygens described in this section) can optionally contain a fully negatively charged boron or partially negatively charged boron, due to the nature of the dative bond between the boron and one of the oxygens. Due to the negative charge, a positively charged counterion may associate with this compound, thus forming a salt.
  • Examples of positively charged counterions include H + , H 3 O + , calcium, lithium, sodium, ammonium, potassium, magnesium.
  • the salts of these compounds are implicitly contained in descriptions of these compounds.
  • the present invention also encompasses compounds that are poly- or multi-valent species, including, for example, species such as dimers, trimers, tetramers and higher homologs of the compounds of use in the invention or reactive analogues thereof. [00168] In certain cases, the depicted substituents may contribute to optical isomers and/or stereoisomerism.
  • isomers Compounds having the same molecular formula but differing in the nature or sequence of bonding of their atoms or in the arrangement of their atoms in space are termed “isomers.” Isomers that differ in the arrangement of their atoms in space are termed “stereoisomers.” Stereoisomers that are not mirror images of one another are termed “diastereomers” and those that are non-superimposable mirror images of each other are termed “enantiomers”. When a compound has an asymmetric center, for example when it is bonded to four different groups, a pair of enantiomers is possible.
  • a molecule with at least one stereocenter may be characterized by the absolute configuration of its asymmetric center and is designated (R) or (S) according to the rules of Cahn and Prelog (Cahn et al., 1966, Angew. Chem.78: 413- 447, Angew. Chem., Int. Ed. Engl.5: 385-414 (errata: Angew. Chem., Int. Ed. Engl.5:511); Prelog and Helmchen, 1982, Angew. Chem.94: 614-631, Angew. Chem. Internat. Ed.
  • a chiral compound may exist as either an individual enantiomer or as a mixture thereof.
  • a mixture containing equal proportions of enantiomers is called a “racemic mixture”.
  • the compounds disclosed herein may possess one or more asymmetric centers, and such compounds may therefore be produced as a racemic mixture, an enantiomerically enriched mixture, or as an individual enantiomer.
  • the compounds disclosed herein are “stereochemically pure”.
  • a stereochemically pure compound has a level of stereochemical purity that would be recognized as “pure” by those of skill in the art. Of course, this level of purity may be less than 100%.
  • “stereochemically pure” designates a compound that is substantially free, i.e. at least about 85% or more, of alternate isomers.
  • the compound is at least about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, about 99.5% or about 99.9% free of other isomers.
  • All isomeric forms especially all regio- and stereoisomeric forms, e.g. all chiral, enantiomeric, diastereomeric, racemic forms, tautomeric and all geometric isomeric forms, as well as atropisomers, (including interconverting atropisomerism) of a compound of the present description are intended within this invention, unless the specific isomer form is specifically indicated.
  • the subject is a human.
  • the subject is a companion animal such as a dog or cat.
  • the subject is an animal such as a sheep, cow, horse, goat, fish, pig, or domestic fowl (e.g., chicken, turkey, duck, or goose).
  • the subject is a primate such as a monkey such as a cynomolgous monkey or a chimpanzee.
  • a pharmaceutically acceptable prodrug of the compound represented by the formulae is also included in the present disclosure.
  • the pharmaceutically acceptable prodrug refers to a compound having a group which may be converted into an amino group, a hydroxyl group, a carboxyl group, or the like, by solvolysis or under a physiological condition.
  • Examples of the groups forming the prodrug include those as described in Prog. Med., 5, 2157-2161 (1985) or “Pharmaceutical Research and Development” (Hirokawa Publishing Company, 1990), vol.7, Drug Design, 163-198.
  • the term prodrug is used throughout the specification to describe any pharmaceutically acceptable form of a compound which, upon administration to a patient, provides the active compound.
  • prodrugs refer to a compound that is metabolized, for example hydrolyzed or oxidized, in the host to form the compound of the present disclosure.
  • Typical examples of prodrugs include compounds that have biologically labile protecting groups on a functional moiety of the active compound.
  • Prodrugs include compounds that may be oxidized, reduced, aminated, deaminated, hydroxylated, dehydroxylated, hydrolyzed, dehydrolyzed, alkylated, dealkylated, acylated, deacylated, phosphorylated, or dephosphorylated to produce the active compound.
  • the present disclosure includes all pharmaceutically acceptable isotopically-labelled compounds of the disclosure wherein one or more atoms are replaced by atoms having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
  • isotopes suitable for inclusion in the compounds of the disclosure include isotopes of hydrogen, such as 2 H and 3 H, carbon, such as 11 C, 13 C and 14 C, chlorine, such as 36 Cl, boron, such as 10 B and 11 B, , fluorine, such as 18 F, iodine, such as 123 I and 125 I, nitrogen, such as 13 N and 15 N, oxygen, such as 15 O, 17 O and 18 O, phosphorus, such as 32 P, and sulfur, such as 35 S.
  • Certain isotopically-labelled compounds of the disclosure such as those incorporating a radioactive isotope, may be useful in drug or substrate tissue distribution studies.
  • the radioactive isotopes tritium, i.e.
  • Isotopically-labeled compounds of the disclosure may generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples using an appropriate isotopically-labeled reagent in place of the non-labeled reagent previously employed.
  • Compositions and Methods of Administration [00175] The compounds of the present disclosure used in the methods disclosed herein may be administered in certain embodiments using pharmaceutical compositions including at least one compound, if appropriate in the salt form, either used alone or in the form of a combination with one or more compatible and pharmaceutically acceptable carriers, such as diluents or adjuvants, or with another agent.
  • compositions which comprise a derivative of a compound of the present disclosure or a salt thereof, and an acceptable excipient, carrier or diluent.
  • the composition may also be in a variety of forms which include, but are not limited to, oral formulations, injectable formulations, and topical, dermal or subdermal formulations.
  • the composition may be in a form suitable for oral use, for example, as dietary supplements, troches, lozenges, chewables, tablets, hard or soft capsules, emulsions, aqueous or oily suspensions, aqueous or oily solutions, dispersible powders or granules, syrups, or elixirs.
  • compositions intended for oral use may be prepared according to any method known in the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, bittering agents, flavoring agents, coloring agents and preserving agents in order to provide elegant and palatable preparations.
  • Lozenges are solid compositions containing one or more active ingredients intended to dissolve or disintegrate slowly in the oral cavity by passive incubation in the oral cavity, or actively by sucking or chewing. They may be used for systemic effect if the drug is absorbed through the buccal or esophageal lining or is swallowed. In particular, soft lozenges may be chewed or allowed to dissolve slowly in the mouth.
  • Tablets may contain the active ingredient in admixture with non-toxic, pharmaceutically acceptable excipients which are suitable for the manufacture of tablets.
  • excipients may be, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example, starch, gelatin or acacia, and lubricating agents, for example, magnesium stearate, stearic acid or talc.
  • the tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
  • Formulations for oral use may be hard gelatin capsules, wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin. Capsules may also be soft gelatin capsules, wherein the active ingredient is mixed with water or miscible solvents such as propylene glycol, PEGs and ethanol, or an oil medium, for example, peanut oil, liquid paraffin, or olive oil.
  • the compositions may also be in the form of oil-in-water or water-in-oil emulsions.
  • the oily phase may be a vegetable oil, for example, olive oil or arachis oil, or a mineral oil, for example, liquid paraffin or mixtures of these.
  • Suitable emulsifying agents may be naturally-occurring phosphatides, for example, soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example, sorbitan monoleate, and condensation products of the said partial esters with ethylene oxide, for example, polyoxyethylene sorbitan monooleate.
  • the emulsions may also contain sweetening agents, bittering agents, flavoring agents, and preservatives.
  • the composition is in the form of a microemulsion. Microemulsions are well suited as the liquid carrier vehicle.
  • Microemulsions are quaternary systems comprising an aqueous phase, an oily phase, a surfactant and a cosurfactant. They are translucent and isotropic liquids. Microemulsions are composed of stable dispersions of microdroplets of the aqueous phase in the oily phase or conversely of microdroplets of the oily phase in the aqueous phase. The size of these microdroplets is less than 200 nm (1000 to 100,000 nm for emulsions).
  • the interfacial film is composed of an alternation of surface-active (SA) and co-surface-active (Co-SA) molecules which, by lowering the interfacial tension, allows the microemulsion to be formed spontaneously.
  • SA surface-active
  • Co-SA co-surface-active
  • the oily phase may be formed from mineral or vegetable oils, from unsaturated polyglycosylated glycerides or from triglycerides, or alternatively from mixtures of such compounds.
  • the oily phase comprises of triglycerides; in another embodiment of the oily phase, the triglycerides are medium-chain triglycerides, for example, C 8 -C 10 caprylic/capric triglyceride.
  • the oily phase will represent a % v/v range selected from the group consisting of about 2 to about 15%; about 7 to about 10%; and about 8 to about 9% v/v of the microemulsion.
  • the aqueous phase includes, for example, water or glycol derivatives, such as propylene glycol, glycol ethers, polyethylene glycols or glycerol.
  • glycol derivatives such as propylene glycol, glycol ethers, polyethylene glycols or glycerol.
  • the glycol is selected from the group consisting of propylene glycol, diethylene glycol monoethyl ether, dipropylene glycol monoethyl ether and mixtures thereof.
  • the aqueous phase will represent a proportion from about 1 to about 4% v/v in the microemulsion.
  • Surfactants for the microemulsion include diethylene glycol monoethyl ether, dipropylene glycol monomethyl ether, polyglycolyzed C 8 -C 10 glycerides or polyglyceryl-6 dioleate.
  • the cosurfactants include short-chain alcohols, such as ethanol and propanol.
  • Some compounds are common to the three components discussed above, for example, aqueous phase, surfactant and cosurfactant. However, it is well within the skill level of the practitioner to use different compounds for each component of the same formulation.
  • the cosurfactant to surfactant ratio may be from about 1/10 to about 1/2.
  • Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example, atachis oil, olive oil, sesame oil or coconut oil, or in mineral oil such as liquid paraffin.
  • the oily suspensions may contain a thickening agent, for example, beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as sucrose, saccharin or aspartame, bittering agents, and flavoring agents may be added to provide a palatable oral preparation.
  • compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid, or other known preservatives.
  • an anti-oxidant such as ascorbic acid, or other known preservatives.
  • excipients are suspending agents, for example, sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally- occuring phosphatide, for example, lecithin, or condensation products of an alkylene oxide with fatty acids, for example, polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example, heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide, with partial esters derived from fatty acids and hexitol anhydrides, for example, polyethylene sorbitan monooleate.
  • dispersing or wetting agents may be a naturally- occuring phosphatide, for example, lec
  • the aqueous suspensions may also contain one or more preservatives, for example, ethyl, or n-propyl, p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents and/or bittering agents, such as those set forth herein.
  • Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above.
  • the term “dispersion” refers to a disperse system in which one substance, the dispersed phase, is distributed, in discrete units, throughout a second substance (the continuous phase or vehicle).
  • the size of the dispersed phase can vary considerably (e.g. colloidal particles of nanometer dimension, to multiple microns in size).
  • the dispersed phases can be solids, liquids, or gases. In the case of a solid dispersion, the dispersed and continuous phases are both solids.
  • a solid dispersion can include a crystalline drug (dispersed phase) in an amorphous polymer (continuous phase); or alternatively, an amorphous drug (dispersed phase) in an amorphous polymer (continuous phase).
  • a solid dispersion includes the polymer constituting the dispersed phase, and the drug constitute the continuous phase.
  • a solid dispersion includes the drug constituting the dispersed phase, and the polymer constituting the continuous phase.
  • An amorphous solid dispersion refers to an amorphous active pharmaceutical ingredient stabilized by a polymer matrix to provide enhanced characteristics, including stability, to a solid material having no long range order in the position of its molecules.
  • Amorphous solids are generally isotropic, i.e. exhibit similar properties in all directions and do not have definite melting points.
  • Amorphous solid dispersions may be used for poorly soluble pharmaceutical compounds. In an ASD, the solubility of the drug substance is improved by disarranging its crystalline lattice to produce a higher energy state of amorphous form (See, Duarte et al., 2015; Elgindy et al., 2011).
  • Spray drying converts a liquid feed to a dried particulate form.
  • Spray drying generally involves bringing into contact a highly dispersed liquid suspension or solution and a sufficient volume of hot air to promote drying of the liquid droplets.
  • a liquid solution containing a compound of the present disclosure, or a salt thereof and at least one polymer can be sprayed into a current of warm filtered gas that evaporates the solvent and conveys the dried product to a collector.
  • Evaporated solvent and spent gas are removed from the collector and can be sent to a condenser to capture the solvent.
  • commercial spray dryers are manufactured by Buchi Ltd. and Niro (e.g., the PSD line of spray driers manufactured by Niro) (see, US 2004/0105820, US 2003/0144257).
  • compositions comprising compounds of the present disclosure may prepared as spray dry dispersions.
  • Syrups and elixirs may be formulated with sweetening agents, for example, glycerol, propylene glycol, sorbitol or sucrose.
  • compositions may be in the form of a sterile injectable aqueous or oleaginous suspension.
  • This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example, as a solution in 1,3-butane diol.
  • acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
  • Cosolvents such as ethanol, propylene glycol or polyethylene glycols may also be used. Preservatives, such as phenol or benzyl alcohol, may be used.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid find use in the preparation of injectables.
  • Topical, dermal and subdermal formulations may include emulsions, creams, ointments, gels or pastes.
  • Organic solvents that may be used in the disclosure include but are not limited to: acetyltributyl citrate, fatty acid esters such as the dimethyl ester, diisobutyl adipate, acetone, acetonitrile, benzyl alcohol, butyl diglycol, dimethylacetamide, dimethylformamide, dipropylene glycol n-butyl ether, ethanol, isopropanol, methanol, ethylene glycol monoethyl ether, ethylene glycol monomethyl ether, monomethylacetamide, dipropylene glycol monomethyl ether, liquid polyoxyethylene glycols, propylene glycol, 2-pyrrolidone (e.g.
  • compositions of the present disclosure may include plant oils such as, but not limited to soybean oil, groundnut oil, castor oil, corn oil, cotton oil, olive oil, grape seed oil, sunflower oil, etc.; mineral oils such as, but not limited to, petrolatum, paraffin, silicone, etc.; aliphatic or cyclic hydrocarbons or alternatively, for example, medium-chain (such as C 8 -C 12 ) triglycerides.
  • plant oils such as, but not limited to soybean oil, groundnut oil, castor oil, corn oil, cotton oil, olive oil, grape seed oil, sunflower oil, etc.
  • mineral oils such as, but not limited to, petrolatum, paraffin, silicone, etc.
  • Dosage forms may contain from about 0.5 mg to about 5 g of an active agent.
  • the active agent is present in the formulation at a concentration of about 0.05 to 10% weight/volume.
  • a compound of the present disclosure may be employed as such or in the form of their preparations or formulations as combinations.
  • These one or more additional active agents may be administered as part of the same or separate dosage forms, via the same or different routes of administration, and on the same or different administration schedules according to standard pharmaceutical practice known to one skilled in the art.
  • the pharmaceutical preparation comprising the compounds of the present disclosure for delivery to a human or other mammal, is preferably in unit dosage form, in which the preparation is subdivided into unit doses containing an appropriate quantity of the active component.
  • the unit dosage form may be a packaged preparation containing discrete quantities of the preparation, such as packaged tablets, capsules, and powders in vials or ampoules. Also, the unit dosage form may be a capsule, tablet or lozenge itself, or it may be an appropriate number of any of these in packaged form.
  • the quantity of active component in a unit dose preparation may be varied or adjusted from about 0.1 mg to about 2000 mg, according to the particular application and the potency of the active component.
  • the composition may, if desired, also contain other compatible therapeutic agents.
  • the compounds utilized in the method of treatment are administered at an initial dosage of about 0.1 mg/kg to about 2,000 mg/kg per interval, about 0.1 mg/kg to about 1,900 mg/kg per interval, about 0.1 mg/kg to about 1,800 mg/kg per interval, about 0.1 mg/kg to about 1,700 mg/kg per interval, about 0.1 mg/kg to about 1,600 mg/kg per interval, about 0.1 mg/kg to about 1,500 mg/kg per interval, about 0.1 mg/kg to about 1,400 mg/kg per interval, about 0.1 mg/kg to about 1,300 mg/kg per interval, about 0.1 mg/kg to about 1,200 mg/kg per interval, about 0.1 mg/kg to about 1,100 mg/kg per interval, about 0.1 mg/kg to about 1,000 mg/kg per interval, about 0.1 mg/kg to about 500 mg/kg per interval, about 0.1 mg/kg to about 100
  • Preferred intervals may be daily, twice-daily, thrice-daily, weekly, bi-weekly, monthly, quarterly, semi-annually, or annually.
  • the dosages may be varied depending on the requirements of the patient, for example, the size of the human or mammal being treated, the severity of the condition being treated, the route of administration, and the potency of the compound(s) being used. Determination of the proper dosage and route of administration for a particular situation is within the skill of the practitioner. Generally, the treatment will be initiated with smaller dosages, which are less than the optimum dose of the compound, which may be increased in small increments until the optimum effect under the particular circumstances of the condition is reached. For convenience, the total daily dosage may be divided and administered in portions during the day if desired.
  • the compounds of the present dislcosure are useful in manufacture of a medicament for a method of the treating any indication where inhibition of PI3K or a mutant variant thereof would be desirable.
  • One embodiment of the present disclosure provides the compounds of the present disclosure incorporated in a proteolysis targeting chimera (PROTAC), namely a heterobifunctional molecule comprising two active domains and a linker.
  • a PROTAC may include an E3 ubiquitin ligase targeting moiety and a compound of the present disclosure, namely a targeting warhead to bind a target protein meant for degradation.
  • the disclosure provides for methods for inhibiting PI3K, including PI3Ka, or a mutant thereof, activity in a cell, comprising contacting the cell in which inhibition of PI3K, including PI3Ka, or a mutant thereof, activity is desired with an effective amount of a compound of the present disclosure, pharmaceutically acceptable salts thereof, or pharmaceutical compositions containing the compound or pharmaceutically acceptable salt thereof.
  • the contacting is in vitro.
  • the contacting is in vivo.
  • the term “contacting” refers to the bringing together of indicated moieties in an in vitro system or an in vivo system.
  • “contacting” a PI3K, including PI3Ka, or a mutant thereof, with a compound provided herein includes the administration of a compound provided herein to an individual or patient, such as a human, having PI3K, including PI3Ka, or a mutant thereof, as well as, for example, introducing a compound provided herein into a sample containing a cellular or purified preparation containing the PI3K, including PI3Ka, or a mutant thereof.
  • a cell in which inhibition of PI3K, or a mutant thereof, activity is desired is contacted with an effective amount of a compound of the present disclosure to negatively modulate the activity.
  • a therapeutically effective amount of pharmaceutically acceptable salt or pharmaceutical compositions containing the compound of the present disclosure may be used.
  • the methods described herein are designed to inhibit undesired cellular proliferation resulting from enhanced PI3K, or a mutant thereof, activity within the cell.
  • the cells may be contacted in a single dose or multiple doses in accordance with a particular treatment regimen to effect the desired negative modulation of PI3K, or a mutant thereof.
  • the degree of modulation of PI3K, or a mutant thereof may be monitored in vitro using well known methods, including those described below.
  • exemplary compounds in cells may be monitored, for example, by measuring the inhibition of PI3K, or a mutant thereof, to assess the effectiveness of treatment and dosages may be adjusted accordingly by the attending medical practitioner.
  • methods of treating cancer in a patient in need thereof comprising administering to said patient a therapeutically effective amount of a compound of the present disclosure, pharmaceutically acceptable salts thereof or pharmaceutical compositions comprising the compound or pharmaceutically acceptable salts thereof are provided.
  • compositions and methods provided herein may be used for the treatment of a PI3K- associated cancer (or mutant variant thereof) in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of a compound of the present disclosure, pharmaceutically acceptable salts thereof or pharmaceutical compositions comprising the compound or pharmaceutically acceptable salts thereof are provided.
  • the PI3K-associated, or mutant variant thereof is cancer.
  • the compositions and methods provided herein may be used for the treatment of a wide variety of cancers including tumors such as lung, prostate, breast, brain, skin, cervical carcinomas, testicular carcinomas, etc.
  • cancers that may be treated by the compositions and methods of the disclosure include, but are not limited, to tumor types such as astrocytic, breast, cervical, colorectal, endometrial, esophageal, gastric, head and neck, hepatocellular, laryngeal, lung, oral, ovarian, prostate and thyroid carcinomas and sarcomas.
  • tumor types such as astrocytic, breast, cervical, colorectal, endometrial, esophageal, gastric, head and neck, hepatocellular, laryngeal, lung, oral, ovarian, prostate and thyroid carcinomas and sarcomas.
  • these compounds can be used to treat: cardiac: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma and teratoma; lung: bronchogenic carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma; gastrointestinal: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucago
  • the cancer is selected from breast cancer, colorectal cancer, uterine cancer, bladder cancer, lung cancer, giloma, head and neck cancer, and other solid tumors. In some embodiments, the cancer is breast cancer.
  • concentration and route of administration to the patient will vary depending on the cancer to be treated.
  • the compounds, pharmaceutically acceptable salts thereof and pharmaceutical compositions comprising such compounds and salts also may be co-administered with other anti-neoplastic compounds, e.g., chemotherapy, or used in combination with other treatments, such as radiation or surgical intervention, either as an adjuvant prior to surgery or post-operatively.
  • the disease/condition/cancer to be treated/prevented as herein (above and below) defined is selected from the group consisting of pancreatic cancer, colorectal cancer, lung cancer, multiple myeloma, melanoma, uterine cancer, endometrial cancer, thyroid cancer, acute myeloid leukemia, bladder cancer, urothelial cancer, gastric cancer, cervical cancer, head and neck squamous cell carcinoma, diffuse large B cell lymphoma, esophageal cancer, chronic lymphocytic leukemia, hepatocellular cancer, breast cancer, ovarian cancer, prostate cancer, glioblastoma, renal cancer and sarcomas, salivary gland cancers and urinary tract cancers.
  • the compounds of the disclosure may be used on their own or in combination with one or several other pharmacologically active substances such as state-of-the-art or standard-of-care compounds, such as, e.g., cell proliferation inhibitors, anti-angiogenic substances, steroids or immune modulators/checkpoint inhibitors, and the like.
  • pharmacologically active substances which may be administered in combination with the compounds according to the disclosure, include, without being restricted thereto, hormones, hormone analogues and antihormones (e.g.
  • tamoxifen toremifene, raloxifene, fulvestrant, megestrol acetate, flutamide, nilutamide, bicalutamide, aminoglutethimide, cyproterone acetate, finasteride, buserelin acetate, fludrocortisone, fluoxymesterone, medroxyprogesterone, octreotide), aromatase inhibitors (e.g. anastrozole, letrozole, liarozole, vorozole, exemestane, atamestane), LHRH agonists and antagonists (e.g.
  • growth factors such as for example platelet derived growth factor (PDGF), fibroblast growth factor (FGF), vascular endothelial growth factor (VEGF), epidermal growth factor (EGF), insuline-like growth factors (IGF), human epidermal growth factor (HER, e.g.
  • growth factors such as for example platelet derived growth factor (PDGF), fibroblast growth factor (FGF), vascular endothelial growth factor (VEGF), epidermal growth factor (EGF), insuline-like growth factors (IGF), human epidermal growth factor (HER, e.g.
  • PDGF platelet derived growth factor
  • FGF fibroblast growth factor
  • VEGF vascular endothelial growth factor
  • EGF epidermal growth factor
  • IGF insuline-like growth factors
  • HER human epidermal growth factor
  • inhibitors are for example (anti-)growth factor antibodies, (anti) growth factor receptor antibodies and tyrosine kinase inhibitors, such as for example cetuximab, gefitinib, afatinib, nintedanib, imatinib, lapatinib, bosutinib, bevacizumab and trastuzumab); antimetabolites (e.g.
  • antifolates such as methotrexate, raltitrexed, pyrimidine analogues such as 5- fluorouracil (5-FU), ribonucleoside and deoxyribonucleoside analogues, capecitabine and gemcitabine, purine and adenosine analogues such as mercaptopurine, thioguanine, cladribine and pentostatin, cytarabine (ara C), fludarabine); antitumour antibiotics (e.g.
  • anthracyclins such as doxorubicin, doxil (pegylated liposomal doxorubicin hydrochloride, myocet (non-pegylated liposomal doxorubicin), daunorubicin, epirubicin and idarubicin, mitomycin-C, bleomycin, dactinomycin, plicamycin, streptozocin); platinum derivatives (e.g. cisplatin, oxaliplatin, carboplatin); alkylation agents (e.g.
  • epipodophyllotoxins such as for example etoposide and etopophos, teniposide, amsacrin, topotecan, irinotecan, mitoxantrone), serine/threonine kinase inhibitors (e.g.
  • PDK 1 inhibitors Raf inhibitors, A-Raf inhibitors, B-Raf inhibitors, CRaf inhibitors, mTOR inhibitors, mTORC1/2 inhibitors, PI3K inhibitors, PI3Ka inhibitors, dual mTOR/PI3K inhibitors, STK 33 inhibitors, AKT inhibitors, PLK 1 inhibitors, inhibitors of CDKs, Aurora kinase inhibitors), tyrosine kinase inhibitors (e.g. PTK2/FAK inhibitors), protein protein interaction inhibitors (e.g.
  • IAP activator Mcl-1 , MDM2/MDMX
  • MEK inhibitors ERK inhibitors
  • FLT3 inhibitors BRD4 inhibitors
  • IGF-1 R inhibitors IGF-1 R inhibitors
  • TRAILR2 agonists Bcl-xL inhibitors, Bcl-2 inhibitors, Bcl-2/Bcl-xL inhibitors, ErbB receptor inhibitors, BCR-ABL inhibitors, ABL inhibitors, Src inhibitors, SHP2 inhibitors, rapamycin analogs (e.g.
  • immune checkpoint inhibitors e.g. CTLA4, PD1, PD-L1, PD-L2, LAG3, and TIM3 binding molecules/immunoglobulins, such as e.g. ipilimumab, nivolumab, pembrolizumab
  • anti-CD33 antibodies anti-CD37 antibodies, anti- CD20 antibodies
  • t-cell engagers e.g. bi-specific T-cell engagers (BiTEs®) like e.g. CD3 x BCMA, CD3 x CD33, CD3 x CD19), PSMA x CD3
  • tumor vaccines and various chemotherapeutic agents such as amifostin, anagrelid, clodronat, filgrastin, interferon, interferon alpha, leucovorin, procarbazine, levamisole, mesna, mitotane, pamidronate and porfimer.
  • an SHP2 (Src homology-2 domain-containing protein tyrosine phosphatase-2) is a non-receptor protein tyrosine phosphatase that removes tyrosine phosphorylation. Functionally, SHP2 serves as an important hub to connect several intracellular oncogenic signaling pathways, such as Jak/STAT, PI3K/AKT, RAS/Raf/MAPK, and PD- 1/PD-L1 pathways. Mutations and/or overexpression of SHP2 has been associated with genetic developmental diseases and cancers. [00213] In certain embodiments, a compound of the present disclosure may be combined with one or more additional therapeutic agent.
  • a compound of the present invention may be combined with two or more additional therapeutic agents.
  • the additional therapeutic agents are selected from selective estrogen receptor degraders, Protac-mediated estrogen receptor inhibitors, complete estrogen receptor antagonists, sarcoplasmic reticulum calcium ATPase inhibitors, CDK2 inhibitors, CDK2/4/6 inhibitors, CDK4/6 inhibitors, aromatase inhibitors, KRAS inhibitors, RAF, MEK, or ERK inhibitors, AKT inhibitors, mTOR inhibitors, tyrosine kinase inhibitors, DNA Synthesis inhibitors, SHP2 inhibitors, BCL-2 family inhibitors, immune checkpoint inhibitors, and SRC inhibitors.
  • the additional therapeutic agents are selected from palbociclib, abemaciclib, ribociclib, letrozole, fulvestrant, palazestrant, camizestrant, elacestrant, imlunestrant exernestane, anastrozole, LSZ102, cetuximab, trastuzumab, pertuzumab, nab-paclitaxel, tucatinib, vinorelbine, evexomostat, eribulin, capecitabine, gedatolisib, tamoxifen, zotatifin, neratinib, giredestrant, talazoparib, pembroluzimab, metformin, AMG-510, trametinib, dabrafenib, LY 3214996, PF-07104091, everolimus, and capivasertib.
  • each agent is provided in a separate dosage form. In one aspect, one or more agent is provided in a combined dosage form.
  • a compound of the present disclosure, or a salt thereof, or a pharmaceutical composition thereof as defined herein for use in therapy is also provided herein.
  • a compound of the present disclosure, or a pharmaceutically acceptable salt or solvate thereof or a pharmaceutical composition thereof as defined herein for use in the treatment of cancer is also provided herein.
  • the mutant varient thereof may be a PI3K ⁇ mutation of H1047, E545, E542, N345, E726, C420, Q546, G118, E453, Q546, G1049, M1043, K111, E81, N1044, and E110.
  • the mutant varient thereof may be a PI3K ⁇ mutation of H1047, E545, E542, N345, E726, C420, Q546, G118, E453, Q546, G1049, M1043, K111, E81, N1044, E110, R88, I391, R108H, Y1021, R93W, T1025A, R93, V344, R38, P539, E418, and E970 [00218] Also provided herein is a compound of the present disclosure, or a pharmaceutically acceptable salt or solvate thereof or a pharmaceutical composition thereof as defined herein, for use in the treatment of a PI3K-associated, or mutant variant, disease or disorder.
  • a compound of the present disclosure or a pharmaceutically acceptable salt or solvate thereof, as defined herein in the manufacture of a medicament for the treatment of cancer.
  • a compound of the present disclosure, or a pharmaceutically acceptable salt or solvate thereof, as defined herein in the manufacture of a medicament for the treatment of a PI3K-associated disease or disorder.
  • a PI3K mutation e.g., as determined using an approved assay or kit
  • administering to the patient a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.
  • compositions comprising a therapeutically acceptable amount of any of these compounds is also within the scope of the disclosure.
  • the composition may further comprise a pharmaceutically acceptable excipient, diluent, carrier, or mixture thereof.
  • compositions may be administered to a subject in need thereof to treat or control a disease or disorder mediated, in whole or in part, directly or indirectly, by PI3K or a mutant form thereof.
  • the composition may further comprise an additional active agent, as described herein.
  • SYNTHETIC EXAMPLES [00227] Compounds of the present disclosure may be synthesized following the teachings of the schemes and specification. The following examples provide a more detailed description of the process conditions for preparing compounds of the present disclosure. It is to be understood, however, that the invention, as fully described herein and as recited in the claims, is not intended to be limited by the details of the following schemes or modes of preparation.
  • the compounds of the present disclosure may be prepared from commercially available reagents using the synthetic methods and reaction schemes described herein, or using other reagents and conventional methods well known to those skilled in the art, making appropriate modifications as would be appreciated by those of skill in the art.
  • Certain abbreviations may be used in describing the examples of the present disclosure. The abbreviations are believed to be used consistently within commonly accepted use of those skilled in the art.
  • certain compounds of the present disclosure may not only represent a final product having the desired biological effect, but also capable of serving as a synthetic intermediate to yet an alternative final product compound of the present disclosure.
  • Synthetic support for referenced portions of one or more embodiments of the present disclosure is hereby made to the synthetic teaching and examples disclosed of one or more of the following patent publications: WO 2024/026423, WO 2024/008122, WO 2024/000401, WO 2023/239710, WO 2023/230262, WO 2023/207881, WO 2023/205680, WO 2023/192416, WO 2023/159155, WO 2023/081209, WO 2023/078401, WO 2023/060262, WO 2024/026419, WO 2024/026424, and WO 2021/202964.
  • reaction mixture was warmed to 20°C and stirred at 20°C for 10 h.
  • the reaction mixture was quenched by addition aq. Na 2 S2O8 (30 mL) at 0°C, diluted with H 2 O (25 mL) and the aqueous phase was extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (20 mL), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure.
  • the reaction mixture was quenched by addition H 2 O (150 mL) at 0°C, diluted with H 2 O (150 mL) and extracted with DCM (50 mL x 3). The combined organic layers were washed with brine (150 mL), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give a residue.
  • the residue was purified by flash silica gel chromatography (ISCO®; 330 g SepaFlash® Silica Flash Column, Eluent of 0 ⁇ 20% Ethylacetate/Petroleum ether gradient @ 200 mL/min) to give the title compound (23.0 g, 57.02mmol, 77.35% yield) as yellow oil.
  • the reaction mixture was quenched by addition H 2 O (10 mL) at 0°C, diluted with H 2 O (10 mL) and extracted with EtOAc (10 mL x 2). The combined organic layers were washed with brine (20 mL), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give a residue.
  • the residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0 ⁇ 20% Ethyl acetate/Petroleum ethergradient @ 36 mL/min) to give the title compound (0.750 g, 1.97 mmol, 79.35% yield) as yellow oil.
  • the reaction mixture was stirred at 25°C for 1 h.
  • the combined organic layers were washed with brine (20 mL), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give a residue.
  • the residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of 0 ⁇ 10% Ethylacetate/Petroleum ether gradient @ 50 mL/min) to give the title compound (1.70 g, 7.11 mmol, 90.37% yield) as yellow oil.
  • the reaction mixture was stirred at 25 °C for 2 h.
  • the reaction mixture was quenched by addition H 2 O (200 mL) at 0 °C, and then extracted with DCM (200 mL x 3).
  • the combined organic layers were washed with brine (200 mL), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give a residue.
  • the residue was purified by flash silica gel chromatography (ISCO®; 330 g SepaFlash® Silica Flash Column, Eluent of 0 ⁇ 10% Ethyl acetate/Petroleum ethergradient @ 50 mL/min) to give the title compound (32.60 g, 80.82 mmol, 95.33% yield) as yellow oil.
  • reaction mixture was stirred at 80 °C for 12 h.
  • the reaction mixture was filtered and the filtrate was directly concentrated under reduced pressure.
  • the residue was purified by flash silica gel chromatography (ISCO®; 80 g SepaFlash® Silica Flash Column, Eluent of 0 ⁇ 10% Ethyl acetate/Petroleum ether gradient @ 100 mL/min) to give the title compound (2.87 g, crude) as yellow oil, which was used directly for next step without further purification.
  • the crude product (300 mg) was further purified by prep-HPLC (column: Phenomenex C1880 x 40mm x 3um; mobile phase: [water (NH 4 HCO 3 )-ACN]; B%: 10%-40%,8min) to give the title compound (130 mg, 43.33% yield) as a white solid.
  • reaction mixture was stirred at -78' for 1 h, and then ethyl carbonochloridate (11.03 g, 101.60 mmol, 9.67 mL, 1.5 eq) was added dropwise at -78°C, the resulting reaction mixture was stirred at 0°C for 1 h.
  • the reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give a residue.
  • the residue was purified by flash silica gel chromatography (ISCO®; 240 g SepaFlash® Silica Flash Column, Eluent of 0 ⁇ 30% Ethyl acetate/Petroleum ether gradient @ 200 mL/min) to give the title compound (20.0 g, crude) as white oil, which was used directly for next step without further purification.
  • the reaction mixture was stirred at 25 °C for 2 h.
  • the combined organic layers were washed with brine (100 mL), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give a residue.
  • the residue was purified by prep-HPLC (column: Waters Xbridge BEH C 18 100*30mm*10um;mobile phase: [water( NH 4 HCO 3 )-ACN];B%: 30%-60%, 10min) to give the title compound (0.9 g, 3.37 mmol, 66.59% yield) as a white solid.
  • reaction mixture was stirred at 20°C for 12 h.
  • the reaction mixture was poured into ice-H 2 O (100 mL) and the aqueous phase was extracted with DCM (100 mL x 3).
  • the combined organic phase was dried with anhydrous Na 2 SO 4 , filtered and concentrated in vacuum.
  • reaction mixture was stirred at 20°C for 1 h.
  • the combined organic phase was dried with anhydrous Na 2 SO 4 , filtered and concentrated in vacuum.
  • the reaction mixture was stirred at 25°C for 12 h.
  • the reaction mixture was diluted with H 2 O (100 mL) at 0°C and extracted with EtOAc (100 mL x 3).
  • the combined organic layers were washed with brine (100 mL), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give a residue.
  • the residue was purified by prep-HPLC (column: Phenomenex Titank C18 Bulk 250*70mm 10u;mobile phase: [H 2 O(0.2%FA)- ACN];gradient:30%-60% B over 20.0 min) to give the title compound (550 mg, 2.16 mmol, 23.94% yield) as a white solid.
  • Example 3 [00321] General procedure for synthesis of target compounds: [00322] To a solution of 2-(((1R)-1-(2-(ethylsulfinyl)-3,6-dimethyl-4-oxo-4H-chromen-8- yl)ethyl)amino)benzoic acid (1 eq) and amine (3 eq) in i-PrOH (for each 0.1 g of benzoic acid, 1 mL of i- PrOH was used) was added DIEA (25 eq) in one portion at 25°C, then the resulting mixture was heated to 80°C and stirred at 80°C for 12 h.
  • i-PrOH for each 0.1 g of benzoic acid, 1 mL of i- PrOH was used
  • reaction suspension was cooled to 25°C and directly filtered.
  • the filter cake was further purified by Prep-HPLC (column: Waters Xbridge Prep OBD C18 150*40mm*10um;mobile phase: [H 2 O(10mM NH4HCO3)-ACN];gradient:40%-70% B over 8.0 min ) to give 2-(4,4-dimethylpiperidin-1-yl)-8-(1-((R)-4-hydroxy-3,4-dihydroquinolin-1(2H)-yl)ethyl)-3,6- dimethyl-4H-chromen-4-one (11.8 mg, 25.62 ⁇ mol, 1.47% yield) as a white solid and 2-(4,4- dimethylpiperidin-1-yl)-8-(1-((S)-4-hydroxy-3,4-dihydroquinolin-1(2H)-yl)ethyl)-3,6-dimethyl-4H- chromen-4-one (18.5 mg, 40.16
  • reaction mixture was cooled to 25°C, filtered and the filtrate was directly purified by prep-HPLC (column: Waters Xbridge Prep OBD C18150 x 40mm x 10um; mobile phase: [H 2 O(10mM NH4HCO3)- ACN];gradient:35%-65% B over 8.0 min) to give the title compound (73.2 mg, 139 ⁇ mol, 37.0% yield) as a white solid.
  • the reaction mixture was stirred at 80°C for 2 h under N 2 .
  • the reaction mixture was cooled to 25°C, filtered and the filtrate was concentrated under reduced pressure.
  • the residue was purified by prep-HPLC (column: Waters Xbridge Prep OBD C18150 x 40mm x 10um;mobile phase: [H 2 O(10mM NH 4 HCO3)-ACN];gradient:15%-45% B over 8.0 min) to give the title compound (64 mg, 119 ⁇ mol, 23.6% yield) as a white solid.
  • Part 1 a mixture of [4-chloro-3-(2-hydroxyethyl)phenyl]boronic acid and [3-chloro-4-(2-hydroxyethyl)phenyl]boronic acid (1.67 g, 8.33 mmol, 66.40% yield) as colorless oil.
  • Part 2 a mixture of 2-(2-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethan-1-ol and 2- (2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl) ethan-1-ol (0.6 g, 2.12 mmol, 16.92% yield) as light yellow oil.
  • reaction mixture was degassed and purged with N 2 for 3 times, heated to 95°C and stirred at 95 °C for 16 h under N 2 atmosphere.
  • the reaction mixture was cooled to 20°C, filtered and the filtrate was concentrated under reduced pressure.
  • BIOLOGICAL EXAMPLES [00381] The compounds of the present disclosure may be tested in multiple assays.
  • pAKT [00383] Compounds were tested in cancer cell lines with or without PI3K ⁇ mutations including SKBR3 (wt), MCF7 (E545K), and T-47D (H1047R) cancer cell lines purchased from ATCC.
  • pAKT1/2/3 (Ser473) HTRF kits were purchased from Revvity.
  • the assay utilizes a plate-based assay format to detect endogenous AKT rapidly and directly in cells when Ser473 is phosphorylated.
  • Adherent cells are lysed, then subjected to an Eu 3+ -Cryptate (donor) and d2 (acceptor) antibodies. Emission from the donor antibody triggers a Fluorescence Resonance Energy Transfer (FRET) at the acceptor antibody.
  • FRET Fluorescence Resonance Energy Transfer
  • the signal directly corresponds to pAKT at Ser473.
  • Cells were treated with compounds in dose response titration for 6 hours at 37°C with 5% CO 2 in 96-well tissue culture treated plates.
  • Cells were assayed in media containing 10% FBS and penicillin- streptomyocin. After compound treatment, cells were lysed with 20-25 (L of 1X supplemented lysis buffer for 30 minutes. During cellular lysis, antibodies were prepared according to manufacturer’s instructions. Briefly, antibodies were diluted in detection buffer and pre-mixed at a 1:1 volume of pAKT Eu antibody and pAKT d2 antibody. Ten (L of lysate was transferred to a 384-well plate where the lysates were incubated at room temperature with 2 (L of pre-mixed pAKT antibodies overnight. Plates were read on a Cytation 5 plate reader (BioTek) where 620 and 665 nm wavelength emissions were measured.
  • BioTek Cytation 5 plate reader
  • ADP-Glo Compound activity was determined biochemically via the ADP-Glo Kinase Assay purchased from Promega in conjunction with PIP 2 :PS lipid kinase substrate from ThermoFisher Scientific and (p110a/p85a) and (p110a [H1047R]/p85a) enzymes from Viva. The assay was performed according to the manufacturer’s instructions with compounds pre-incubated with 1nM of enzyme and 2.5nM of pY2- peptide derived from PDGFRb for 4 hours.
  • the reaction proceeded by addition of 1mM ATP and either 200mM, 50mM, or 25mM of lipid substrate. Ideal enzyme and substrate concentrations were determined empirically through enzyme titration to represent 5% product formation as recommended by the manufacturer.
  • the kinase reaction was allowed to proceed for one hour prior to measurement of bioluminescent light output on a Cytation 5 plate reader with a 0.5 second integration time. Compounds were tested in seven point dose response and IC50 were determined by normalization to DMSO and no enzyme controls. [00387] Tested compounds are reported as: (A) less than or equal to 500 nM; (B) greater than 500 nM to less than or equal to 1,000 nM; (C) greater than 1,000 nM.
  • Figure 1 provides tabulated biological data for compounds of the present disclosure according to the testing protocols described herein.
  • One embodiment of the present disclosure includes all exemplified compounds.
  • One embodiment of the present disclosure includes all compounds reported A, B, or C, in one or more assay.
  • One embodiment of the present disclosure includes all compounds reported A or B in one or more assay.
  • One embodiment of the present disclosure includes all compounds reported A, in one or more assay.
  • All publications, patents, and patent applications cited in this specification are incorporated herein by reference for the teaching to which such citation is used.
  • Test compounds for the experiments described herein were employed in free or salt form.

Landscapes

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

Abstract

La présente divulgation concerne de nouveaux composés chimiques ou leurs sels, des compositions les contenant, et leurs utilisations médicales. Les composés sont actifs en tant qu'inhibiteurs de PI3K, notamment de mutants de PI3K, et sont utiles dans le traitement de maladies ou troubles médiés par PI3K et ses mutants ou dans la lutte contre ceux-ci.
PCT/US2024/036277 2023-06-30 2024-06-28 Composés chimiques Ceased WO2025007074A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US202363524518P 2023-06-30 2023-06-30
US63/524,518 2023-06-30
US202363512406P 2023-07-07 2023-07-07
US63/512,406 2023-07-07

Publications (2)

Publication Number Publication Date
WO2025007074A1 true WO2025007074A1 (fr) 2025-01-02
WO2025007074A9 WO2025007074A9 (fr) 2025-07-03

Family

ID=93939955

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2024/036277 Ceased WO2025007074A1 (fr) 2023-06-30 2024-06-28 Composés chimiques

Country Status (1)

Country Link
WO (1) WO2025007074A1 (fr)

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2025240847A1 (fr) 2024-05-17 2025-11-20 Revolution Medicines, Inc. Inhibiteurs de ras
WO2025255438A1 (fr) 2024-06-07 2025-12-11 Revolution Medicines, Inc. Procédés de traitement d'une maladie ou d'un trouble lié à la protéine ras
WO2025265060A1 (fr) 2024-06-21 2025-12-26 Revolution Medicines, Inc. Compositions thérapeutiques et procédés de gestion d'effets liés au traitement
WO2026006747A1 (fr) 2024-06-28 2026-01-02 Revolution Medicines, Inc. Inhibiteurs de ras
WO2026015801A1 (fr) 2024-07-12 2026-01-15 Revolution Medicines, Inc. Méthodes de traitement d'une maladie ou d'un trouble liés à ras
WO2026015790A1 (fr) 2024-07-12 2026-01-15 Revolution Medicines, Inc. Méthodes de traitement d'une maladie ou d'un trouble lié à ras
WO2026015796A1 (fr) 2024-07-12 2026-01-15 Revolution Medicines, Inc. Méthodes de traitement d'une maladie ou d'un trouble lié à ras
WO2026015825A1 (fr) 2024-07-12 2026-01-15 Revolution Medicines, Inc. Utilisation d'un inhibiteur de ras pour traiter le cancer du pancréas
WO2026050446A1 (fr) 2024-08-29 2026-03-05 Revolution Medicines, Inc. Inhibiteurs de ras
WO2026072904A2 (fr) 2024-09-26 2026-04-02 Revolution Medicines, Inc. Compositions et méthodes de traitement du cancer du poumon
WO2026090127A1 (fr) 2024-10-22 2026-04-30 Revolution Medicines, Inc. Méthodes de traitement d'une maladie ou d'un trouble liés à une protéine ras
WO2026090245A1 (fr) 2024-10-22 2026-04-30 Revolution Medicines, Inc. Utilisation d'inhibiteurs ras pour traiter un cancer

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7872011B2 (en) * 2002-08-16 2011-01-18 Astrazeneca Ab Inhibition of phosphoinositide 3-kinase β
WO2017090002A2 (fr) * 2015-11-27 2017-06-01 Gvk Biosciences Private Limited Inhibiteurs de pi3 kinases
CN113072551A (zh) * 2020-01-03 2021-07-06 上海翰森生物医药科技有限公司 含氮联苯类衍生物抑制剂、其制备方法和应用
WO2021202964A1 (fr) * 2020-04-03 2021-10-07 Petra Pharma Corporation Inhibiteurs chroménone allostériques de la phosphoinositide 3-kinase (pi3k) pour le traitement de maladies associées à la modulation de pi3k
WO2023288242A1 (fr) * 2021-07-13 2023-01-19 Relay Therapeutics, Inc. INHIBITEURS DE PI3Kα ET LEURS PROCÉDÉS D'UTILISATION

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7872011B2 (en) * 2002-08-16 2011-01-18 Astrazeneca Ab Inhibition of phosphoinositide 3-kinase β
WO2017090002A2 (fr) * 2015-11-27 2017-06-01 Gvk Biosciences Private Limited Inhibiteurs de pi3 kinases
CN113072551A (zh) * 2020-01-03 2021-07-06 上海翰森生物医药科技有限公司 含氮联苯类衍生物抑制剂、其制备方法和应用
WO2021202964A1 (fr) * 2020-04-03 2021-10-07 Petra Pharma Corporation Inhibiteurs chroménone allostériques de la phosphoinositide 3-kinase (pi3k) pour le traitement de maladies associées à la modulation de pi3k
WO2023288242A1 (fr) * 2021-07-13 2023-01-19 Relay Therapeutics, Inc. INHIBITEURS DE PI3Kα ET LEURS PROCÉDÉS D'UTILISATION

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2025240847A1 (fr) 2024-05-17 2025-11-20 Revolution Medicines, Inc. Inhibiteurs de ras
WO2025255438A1 (fr) 2024-06-07 2025-12-11 Revolution Medicines, Inc. Procédés de traitement d'une maladie ou d'un trouble lié à la protéine ras
WO2025265060A1 (fr) 2024-06-21 2025-12-26 Revolution Medicines, Inc. Compositions thérapeutiques et procédés de gestion d'effets liés au traitement
WO2026006747A1 (fr) 2024-06-28 2026-01-02 Revolution Medicines, Inc. Inhibiteurs de ras
WO2026015801A1 (fr) 2024-07-12 2026-01-15 Revolution Medicines, Inc. Méthodes de traitement d'une maladie ou d'un trouble liés à ras
WO2026015790A1 (fr) 2024-07-12 2026-01-15 Revolution Medicines, Inc. Méthodes de traitement d'une maladie ou d'un trouble lié à ras
WO2026015796A1 (fr) 2024-07-12 2026-01-15 Revolution Medicines, Inc. Méthodes de traitement d'une maladie ou d'un trouble lié à ras
WO2026015825A1 (fr) 2024-07-12 2026-01-15 Revolution Medicines, Inc. Utilisation d'un inhibiteur de ras pour traiter le cancer du pancréas
WO2026050446A1 (fr) 2024-08-29 2026-03-05 Revolution Medicines, Inc. Inhibiteurs de ras
WO2026072904A2 (fr) 2024-09-26 2026-04-02 Revolution Medicines, Inc. Compositions et méthodes de traitement du cancer du poumon
WO2026090127A1 (fr) 2024-10-22 2026-04-30 Revolution Medicines, Inc. Méthodes de traitement d'une maladie ou d'un trouble liés à une protéine ras
WO2026090245A1 (fr) 2024-10-22 2026-04-30 Revolution Medicines, Inc. Utilisation d'inhibiteurs ras pour traiter un cancer

Also Published As

Publication number Publication date
WO2025007074A9 (fr) 2025-07-03

Similar Documents

Publication Publication Date Title
WO2025007074A9 (fr) Composés chimiques
US12281097B2 (en) Isoquinolin-3-yl carboxamides and preparation and use thereof
TWI897895B (zh) 雜環ｒｉｐ１抑制性化合物
RU2689777C1 (ru) Конденсированные трициклические производные бензимидазолов в качестве модуляторов активности tnf
EP4680612A1 (fr) Composés chimiques
KR101962495B1 (ko) C-kit 키나제 억제제로서의 화합물 및 조성물
KR20140071383A (ko) C-kit 키나제 억제제로서의 화합물 및 조성물
WO2017189823A2 (fr) Isoquinolin-3-yl carboxamides et préparation et utilisation de ceux-ci
KR20140071382A (ko) c-KIT 키나제 억제제로서의 화합물 및 조성물
WO2019089835A1 (fr) Diazanaphthalèn-3-yl carboxamides, préparation et utilisation de ceux-ci
EP2976338B1 (fr) N-(2-cyano-hétérocyclyl)pyrazolo-pyridones en tant qu'inhibiteurs de la janus kinase
TW202417458A (zh) 調節her2的化合物及方法
JP2019534320A (ja) ７−置換１−アリール−ナフチリジン−３−カルボン酸アミドおよびその使用
JP2009504755A (ja) 治療剤としての縮合三環式ｍＧｌｕＲ１アンタゴニスト
HK40005209B (en) Isoquinolin-3-yl carboxamides and preparation and use thereof
HK40005209A (en) Isoquinolin-3-yl carboxamides and preparation and use thereof

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: 24833112

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE