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EP4611741A1 - Ciblage de poches allostériques et orthostériques de phosphoinositide 3-kinase (pi3k) pour le traitement d'une maladie - Google Patents

Ciblage de poches allostériques et orthostériques de phosphoinositide 3-kinase (pi3k) pour le traitement d'une maladie

Info

Publication number
EP4611741A1
EP4611741A1 EP23817906.3A EP23817906A EP4611741A1 EP 4611741 A1 EP4611741 A1 EP 4611741A1 EP 23817906 A EP23817906 A EP 23817906A EP 4611741 A1 EP4611741 A1 EP 4611741A1
Authority
EP
European Patent Office
Prior art keywords
pi3kα
optionally substituted
alkyl
patient
inhibitor
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
EP23817906.3A
Other languages
German (de)
English (en)
Inventor
Anke Klippel-Giese
Loredana PUCA
Shuang Chen
Rui Wang
Monica RAMSTETTER
Michele Suzanne DOWLESS
Christopher Glenn MAYNE
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.)
Petra Pharma Corp
Original Assignee
Petra Pharma Corp
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 Petra Pharma Corp filed Critical Petra Pharma Corp
Publication of EP4611741A1 publication Critical patent/EP4611741A1/fr
Pending legal-status Critical Current

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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
    • C07D311/26—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3
    • C07D311/28—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 2 only
    • C07D311/30—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 2 only not hydrogenated in the hetero ring, e.g. flavones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A61K31/353—3,4-Dihydrobenzopyrans, e.g. chroman, catechin
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    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/4035—Isoindoles, e.g. phthalimide
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    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A61K31/4155—1,2-Diazoles non condensed and containing further heterocyclic rings
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    • A61K31/4196—1,2,4-Triazoles
    • A—HUMAN NECESSITIES
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    • A61K31/33—Heterocyclic compounds
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    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4433—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with oxygen as a ring hetero atom
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    • A61K31/33—Heterocyclic compounds
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    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/553—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one oxygen as ring hetero atoms, e.g. loxapine, staurosporine
    • 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
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • 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
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    • 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
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems
    • C07D491/107—Spiro-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00

Definitions

  • the Sequence Listing is provided as a file titled “30449SequenceListing.xml” created October 30, 2023 and is 2,777 bytes in size.
  • the Sequence Listing information in the ST.26 XML format is incorporated herein by reference in its entirety.
  • Field [3] The present invention is directed to inhibitors of phosphoinositide 3-kinase (PI3K) and combinations thereof which are useful in the treatment of diseases, or disorders associated with PI3K modulation.
  • PI3K phosphoinositide 3-kinase
  • the present invention also is directed to allosteric chromenone inhibitors of phosphoinositide 3-kinase (PI3K) useful in the treatment of diseases, or disorders associated with PI3K modulation, and the use of allosteric chromenone inhibitors in combination with other allosteric or orthosteric inhibitors of PI3K useful in the treatment of diseases, or disorders associated with PI3K modulation.
  • PI3K phosphoinositide 3-kinase
  • the present invention also is directed toward inhibitors of PI3K and combination thereof, methods of (or uses for) treating a disease, or disorder associated with PI3K (e.g., CLOVES syndrome (congenital lipomatous overgrowth, vascular malformations, epidermal naevi, scoliosis/skeletal and spinal syndrome), PIK3CA-related overgrowth syndrome (PROS), breast cancer, brain cancer, prostate cancer, endometrial cancer, gastric cancer, leukemia, lymphoma, sarcoma, colorectal cancer, lung cancer, ovarian cancer, skin cancer, or head and neck cancer), and using, or methods of using, PI3K inhibitors in combination with one or more additional cancer therapies.
  • CLOVES syndrome congenital lipomatous overgrowth, vascular malformations, epidermal naevi, scoliosis/skeletal and spinal syndrome
  • PROS PIK3CA-related overgrowth syndrome
  • breast cancer brain cancer, prostate cancer, endometrial cancer, gastric cancer
  • PI3Ks phosphoinositide 3-kinases
  • the phosphoinositide 3-kinases (PI3Ks) signaling pathway is one of the most highly mutated systems in human cancers. PI3K signaling also is involved in 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.
  • PI3Ks are members of a unique, and conserved family of intracellular lipid kinases that phosphorylate the 3’-OH group on phosphatidylinositols or phosphoinositides.
  • the PI3K family comprises 15 kinases with distinct substrate specificities, expression patterns, and modes of regulation.
  • the class I PI3Ks (p110 ⁇ , p110 ⁇ , p110 ⁇ , and p110 ⁇ ) are typically activated by tyrosine kinases, or G-protein coupled receptors to generate PIP3, which engages downstream effectors such as those in the pathways of Akt/PDK1, mTOR, the Tec family kinases, and the Rho family GTPases.
  • the class II, and III PI3Ks play a key role in intracellular trafficking through the synthesis of PI(3)P, and PI(3,4)P2.
  • the PI3K isoforms have been implicated, for example, in a variety of human cancers, and disorders.
  • the alpha ( ⁇ ) isoform of PI3K has been implicated, for example, in a variety of human cancers.
  • Angiogenesis has been shown to selectively require the ⁇ isoform of PI3K in the control of endothelial cell migration. Mutations in the gene coding for PI3K ⁇ , or mutations which lead to upregulation of PI3K ⁇ 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 for PI3K ⁇ are point mutations clustered within several hotspots in helical, and kinase domains, such as E542K, E545K, and H1047R. Many of these mutations have been shown to be oncogenic gain-of-function mutations. Because of the high rate of PI3K ⁇ mutations, targeting of this pathway may provide valuable therapeutic opportunities. While other PI3K isoforms such as PI3K ⁇ , or PI3K ⁇ are expressed primarily in hematopoietic cells, PI3K ⁇ , along with PI3K ⁇ , is expressed constitutively.
  • PI3K inhibition in patients often gives rise to adverse events which include hyperglycemia and/or hyperinsulinemia.
  • High levels of circulating insulin could potentially be mitogenic and/or antiapoptotic for cancer cells, and thus negate the antiproliferative effects of PI3K inhibitors.
  • one way to overcome the problem of compensatory production of insulin and/or glucose upon systemic PI3K ⁇ inhibition would be to develop inhibitors with enhanced selectivity for mutant PI3K ⁇ over wild-type PI3K ⁇ .
  • PI3K ⁇ has an ATP-binding pocket which may be targeted in order to modulate PI3K ⁇ activity.
  • PI3K ⁇ must bind ATP in order to catalyze the transfer of a phosphate group from ATP to the 3’-OH group on phosphatidylinositols or phosphoinositides.
  • PI3K inhibitors tested in clinical trials are antagonists that interact within the PI3K ⁇ ATP-binding pocket and compete with ATP as orthosteric inhibitors.
  • the PI3K ⁇ ATP-binding pocket may alternatively be referred to as “the PI3K ⁇ orthosteric binding pocket.”
  • Current PI3K ⁇ inhibitors are nearly equipotent to wild-type and mutant PI3K ⁇ . Mutant selective inhibitors have been elusive due to the fact that the most common PI3K ⁇ mutations (E542K, E545K, and H1047R) are located far from the PI3K ⁇ orthosteric binding pocket.
  • inhibitors which target a second, peripheral binding pocket near a known mutation may provide a route to selective PI3K ⁇ inhibition.
  • the present invention provides a new class of kinase inhibitors that target a non-ATP binding pocket of PI3K ⁇ which is referred to herein as “the PI3K ⁇ allosteric pocket 1” and may interact with amino acid residues of PI3K ⁇ including R1047.
  • the disclosed kinase inhibitors target PI3K ⁇ allosteric pocket 1 and may be utilized in combination therapies, for example, combination therapies in which the disclosed PI3K ⁇ inhibitors are used in combination with PI3K ⁇ inhibitors that target other pockets of PI3K ⁇ , such as the PI3K ⁇ orthosteric pocket.
  • the present invention also provides a characterization of another non-ATP binding pocket of PI3K ⁇ , which is referred to as “the PI3K ⁇ allosteric pocket 2,” and the interaction of inhibitors of PI3K ⁇ with the PI3K ⁇ allosteric pocket 2.
  • the disclosed kinase inhibitors which target PI3K ⁇ allosteric pocket 1 may be used in combination therapies with PI3K ⁇ inhibitors that target the PI3K ⁇ allosteric pocket 2.
  • Summary [12] The disclosure relates to the use of inhibitors of phosphoinositide 3-kinase (PI3K) that target allosteric and orthosteric pockets of PI3K in methods of treating, preventing, or ameliorating a disease, or disorder, (or uses in the treatment, prevention, or amelioration of a disease, or disorder), in which PI3K plays a role.
  • PI3K inhibitors of phosphoinositide 3-kinase
  • the PI3K inhibitors may be utilized in combination and may target an allosteric pocket of phosphatidylinositol 3-kinase alpha (PI3K ⁇ ) referred to herein as “PI3K ⁇ allosteric pocket 1,,” an allosteric pocket of PI3K ⁇ referred to herein as “PI3K ⁇ allosteric pocket 2,” or the PI3K ⁇ orthosteric pocket. (See Fig.1).
  • PI3K ⁇ phosphatidylinositol 3-kinase alpha
  • a PI3K ⁇ inhibitor may target the PI3K ⁇ allosteric pocket 1, the PI3K ⁇ allosteric pocket 2, or the PI3K ⁇ orthosteric pocket of a PI3K ⁇ mutant that is resistant to treatment with another PI3K ⁇ inhibitor, for example a PI3K ⁇ inhibitor that targets a different pocket of PI3K ⁇ .
  • the methods may include administering to a patient in need thereof a therapeutically effective amount of a PI3K inhibitor of the present invention or combinations of PI3K inhibitors of the present invention and other PI3K inhibitors, which may include other allosteric inhibitors of PI3K and orthosteric inhibitors of PI3K.
  • the methods and PI3K inhibitors of the present invention can be used in the treatment of a variety of PI3K-dependent or PI3K-associated diseases, and disorders.
  • the disclosed methods relate to methods for treating a disease or disorder associated with modulation of PI3K ⁇ .
  • the methods may comprise administering to a patient in need thereof: (i) a therapeutically effective amount of a first PI3K ⁇ selective inhibitor, wherein the first PI3K ⁇ selective inhibitor binds to the PI3K ⁇ allosteric pocket 1; and (ii) a therapeutically effective amount of a second PI3K ⁇ selective inhibitor, wherein the second PI3K ⁇ selective inhibitor binds to the PI3K ⁇ orthosteric pocket.
  • the disclosed methods relate to methods for treating a disease or disorder associated with modulation of PI3K ⁇ .
  • the methods may comprise administering to a patient in need thereof: (i) a therapeutically effective amount of a first PI3K ⁇ selective inhibitor, wherein the first PI3K ⁇ selective inhibitor binds to the PI3K ⁇ allosteric pocket 2; and (ii) a therapeutically effective amount of a second PI3K ⁇ selective inhibitor, wherein the second PI3K ⁇ selective inhibitor binds to the PI3K ⁇ orthosteric pocket.
  • the disclosed methods may comprise administering to the patient: (i) a therapeutically effective amount of a first PI3K ⁇ selective inhibitor, wherein the first PI3K ⁇ selective inhibitor binds to PI3K ⁇ allosteric pocket 1; and (ii) a therapeutically effective amount of a second PI3K ⁇ selective inhibitor, wherein the second PI3K ⁇ selective inhibitor binds to PI3K ⁇ allosteric pocket 2.
  • the disclosed methods may comprise administering to the patient: (i) a therapeutically effective amount of a first PI3K ⁇ selective inhibitor, wherein the first PI3K ⁇ selective inhibitor binds to PI3K ⁇ allosteric pocket 1; and (ii) a therapeutically effective amount of a second PI3K ⁇ selective inhibitor which is different from the first PI3K ⁇ selective inhibitor, wherein the second different PI3K ⁇ selective inhibitor binds to the PI3K ⁇ allosteric pocket 1.
  • the first PI3K ⁇ selective inhibitor and the second PI3K ⁇ selective inhibitor competitively bind to PI3K ⁇ allosteric pocket 1.
  • the first PI3K ⁇ selective inhibitor and the second PI3K ⁇ selective inhibitor are administered simultaneously, separately, or sequentially.
  • the second PI3K ⁇ selective inhibitor is administered to the patient if the patient has a disease or disorder that is resistant to treatment with the first PI3K ⁇ selective inhibitor.
  • the second PI3K ⁇ selective inhibitor is administered to the patient after the disease or disorder of the patient has acquired resistance to treatment with the first PI3K ⁇ selective inhibitor.
  • an additive effect or synergistic effect may be observed.
  • the therapeutically effective amount of the first PI3K ⁇ selective inhibitor administered in the disclosed methods may be less than a therapeutically effective amount of the first PI3K ⁇ selective inhibitor that is required in a treatment method where the second PI3K ⁇ selective inhibitor is not administered. In some aspects of the disclosed methods, the therapeutically effective amount of the second PI3K ⁇ selective inhibitor administered in the disclosed methods may be less than a therapeutically effective amount of the second PI3K ⁇ selective inhibitor that is required in a treatment method where the first PI3K ⁇ selective inhibitor is not administered.
  • the therapeutically effective amount of the first PI3K ⁇ selective inhibitor is effective for reducing PI3K ⁇ activity in the patient without inducing adverse events, or while minimizing the risk of adverse events.
  • the therapeutically effective amount of the second PI3K ⁇ selective inhibitor is effective for reducing PI3K ⁇ activity in the patient without inducing adverse events, or while minimizing the risk of adverse events.
  • Adverse events may include, but are not limited to hyperglycemia, hyperinsulinemia, diarrhea, dehydration, skin rash, lymphopenia, increased alanine transaminase, fatigue, anemia, elevated serum lipase, anorexia, stomatitis, vomiting, weight loss, hypocalcemia, hypoglycemic disorder, alopecia, prolonged activated partial thromboplastin time, kidney disease with reduction in glomerular filtration rate (GFR), acute abdominal pain, and abnormal hepatic function tests.
  • GFR glomerular filtration rate
  • the disclosed methods relate to methods for treating a disease or disorder that is associated with modulation of PI3K ⁇ in a patient that has a disease or disorder that is resistant to treatment with a PI3K ⁇ selective inhibitor, which may be a PI3K ⁇ selective allosteric inhibitor or a PI3K ⁇ selective orthosteric inhibitor.
  • the methods may comprise administering to the patient a different PI3K ⁇ selective inhibitor to which the disease or disorder is not resistant, such as a PI3K ⁇ selective allosteric inhibitor or a PI3K ⁇ selective orthosteric inhibitor.
  • the disclosed methods relate to methods for treating a disease or disorder associated with modulation of PI3K ⁇ in a patient that has a disease or disorder that is resistant to treatment with a PI3K ⁇ selective orthosteric inhibitor. In some aspects, the disclosed methods relate to treating a disease or disorder associated with modulation of PI3K ⁇ in a patient that is identified as having a disease or disorder that is resistant to treatment with a PI3K ⁇ selective orthosteric inhibitor or in a patient that is identified as having a disease or disorder which exhibits an incomplete response to treatment with a PI3K ⁇ selective orthosteric inhibitor.
  • the methods may comprise administering to a patient that is identified as having a disease or disorder that is resistant to treatment with a PI3K ⁇ selective orthosteric inhibitor or that is identified as having a disease or disorder that exhibits an incomplete response to treatment with a PI3K ⁇ selective orthosteric inhibitor, a therapeutically effective amount of a PI3K ⁇ selective allosteric inhibitor, wherein the PI3K ⁇ selective allosteric inhibitor binds to the PI3K ⁇ allosteric pocket 1.
  • the methods may comprise administering to a patient that is identified as having a disease or disorder that is resistant to treatment with a PI3K ⁇ selective orthosteric inhibitor or that is identified as having a disease or disorder which exhibits an incomplete response to treatment with a PI3K ⁇ selective orthosteric inhibitor, a therapeutically effective amount of a PI3K ⁇ selective allosteric inhibitor, wherein the PI3K ⁇ selective allosteric inhibitor binds to the PI3K ⁇ allosteric pocket 2.
  • the disclosed methods relate to treating a disease or disorder associated with modulation of PI3K ⁇ that is resistant to treatment with a first PI3K ⁇ selective allosteric inhibitor, wherein the first PI3K ⁇ selective allosteric inhibitor binds to the PI3K ⁇ allosteric pocket 1.
  • the methods may comprise administering to a patient having the resistant disease or disorder a therapeutically effective amount of a second different PI3K ⁇ selective allosteric inhibitor that binds to the PI3K ⁇ allosteric pocket 1.
  • the methods may comprise administering to a patient having the resistant disease or disorder a therapeutically effective amount of a second different PI3K ⁇ selective allosteric inhibitor that binds to the PI3K ⁇ allosteric pocket 2. In some aspects, the methods may comprise administering to a patient having the resistant disease or disorder a therapeutically effective amount of a PI3K ⁇ selective inhibitor that binds to the PI3K ⁇ orthosteric pocket. [24] In some aspects, the disclosed methods relate to treating a disease or disorder associated with modulation of PI3K ⁇ that is resistant to treatment with a first PI3K ⁇ selective allosteric inhibitor, wherein the first PI3K ⁇ selective allosteric inhibitor binds to PI3K ⁇ allosteric pocket 2.
  • the methods may comprise administering to a patient having the resistant disease or disorder a therapeutically effective amount of a second different PI3K ⁇ selective allosteric inhibitor that binds to the PI3K ⁇ allosteric pocket 1. In some aspects, the methods may comprise administering to a patient having the resistant disease or disorder a therapeutically effective amount of a PI3K ⁇ selective inhibitor that binds to the PI3K ⁇ orthosteric pocket.
  • the disclosed methods relate to methods for treating a disease or disorder associated with modulation of PI3K ⁇ in a patient in need thereof, wherein the patient has been treated previously with a therapeutically effective amount of a PI3K ⁇ selective inhibitor, and the disease or disorder of the patient has acquired resistance to treatment with the PI3K ⁇ selective inhibitor.
  • the method may include administered to the patient a different PI3K ⁇ selective inhibitor to which the disease or disorder is not resistant.
  • the disclosed methods relate to methods for treating a disease or disorder associated with modulation of PI3K ⁇ in a patient in need thereof, wherein the patient previously has been treated with a therapeutically effective amount of a PI3K ⁇ selective allosteric inhibitor, wherein the PI3K ⁇ selective allosteric inhibitor binds to the PI3K ⁇ allosteric pocket 1 or the PI3K ⁇ allosteric pocket 2.
  • the disease or disorder of the patient may have acquired resistance to treatment with the PI3K ⁇ selective allosteric inhibitor, and the methods may comprise administering to the patient a therapeutically effective amount of a PI3K ⁇ selective orthosteric inhibitor.
  • the disease or disorder of the patient may have acquired resistance to treatment with the PI3K ⁇ selective allosteric inhibitor that binds to the PI3K ⁇ allosteric pocket 1, and the methods may comprise administering to the patient a therapeutically effective amount of a different PI3K ⁇ selective allosteric inhibitor that binds to the PI3K ⁇ allosteric pocket 2.
  • the disease or disorder of the patient may have acquired resistance to treatment with the PI3K ⁇ selective allosteric inhibitor that binds to the PI3K ⁇ allosteric pocket 2
  • the methods may comprise administering to the patient a therapeutically effective amount of a different PI3K ⁇ selective allosteric inhibitor that binds to the PI3K ⁇ allosteric pocket 1.
  • the disease or disorder of the patient may have acquired resistance to treatment with the PI3K ⁇ selective allosteric inhibitor that binds to the PI3K ⁇ allosteric pocket 1, and the methods may comprise administering to the patient a therapeutically effective amount of a different PI3K ⁇ selective allosteric inhibitor that binds to the PI3K ⁇ allosteric pocket 1.
  • the disclosed methods relate to methods for treating a disease or disorder associated with modulation of PI3K ⁇ in a patient in need thereof, wherein the patient previously has been treated with a therapeutically effective amount of a PI3K ⁇ selective allosteric inhibitor, wherein the PI3K ⁇ selective allosteric inhibitor binds to the PI3K ⁇ allosteric pocket 1 or the PI3K ⁇ allosteric pocket 2.
  • the disease or disorder of the patient may have acquired resistance to treatment with the PI3K ⁇ selective allosteric inhibitor, and the methods may comprise administering to the patient a therapeutically effective amount of a PI3K ⁇ selective orthosteric inhibitor.
  • the disease or disorder of the patient may have acquired resistance to treatment with the PI3K ⁇ selective allosteric inhibitor that binds to the PI3K ⁇ allosteric pocket 1, and the methods may comprise administering to the patient a therapeutically effective amount of a different PI3K ⁇ selective allosteric inhibitor that binds to the PI3K ⁇ allosteric pocket 2.
  • the disease or disorder of the patient may have acquired resistance to treatment with the PI3K ⁇ selective allosteric inhibitor that binds to the PI3K ⁇ allosteric pocket 2
  • the methods may comprise administering to the patient a therapeutically effective amount of a different PI3K ⁇ selective allosteric inhibitor that binds to the PI3K ⁇ allosteric pocket 1.
  • the disease or disorder of the patient may have acquired resistance to treatment with the PI3K ⁇ selective allosteric inhibitor that binds to the PI3K ⁇ allosteric pocket 1, and the methods may comprise administering to the patient a therapeutically effective amount of a different PI3K ⁇ selective allosteric inhibitor that binds to the PI3K ⁇ allosteric pocket 1.
  • the disclosed methods relate to methods for treating a disease or disorder associated with modulation of PI3K ⁇ in a patient in need thereof, wherein the patient has a disease or disorder comprising an M1043 mutation (e.g., M1043I/L optionally in cis with an H1047R mutation) and/or a C901 mutation (e.g., C901F optionally in cis with an H1047R mutation).
  • the methods may comprise administering to the patient having the disease or disorder a therapeutically effective amount of a PI3K ⁇ selective orthosteric inhibitor.
  • the methods may comprise administering to the patient having the disease or disorder comprising an M1043 mutation (e.g., M1043I/L optionally in cis with an H1047R mutation) and/or a C901 mutation (e.g., C901F optionally in cis with an H1047R mutation) a therapeutically effective amount of a PI3K ⁇ allosteric inhibitor, wherein the PI3K ⁇ allosteric inhibitor binds to the PI3K ⁇ allosteric pocket 1.
  • an M1043 mutation e.g., M1043I/L optionally in cis with an H1047R mutation
  • a C901 mutation e.g., C901F optionally in cis with an H1047R mutation
  • the methods may comprise administering to the patient having the disease or disorder comprising an M1043 mutation (e.g., M1043I/L optionally in cis with an H1047R mutation) and/or a C901 mutation (e.g., C901F optionally in cis with an H1047R mutation) a therapeutically effective amount of a PI3K ⁇ selective allosteric inhibitor that binds the PI3K ⁇ allosteric pocket 2.
  • an M1043 mutation e.g., M1043I/L optionally in cis with an H1047R mutation
  • a C901 mutation e.g., C901F optionally in cis with an H1047R mutation
  • the methods related to methods for treating a disease or disorder associated with modulation of PI3K ⁇ in a patient in need thereof such as a patient having a disease or disorder comprising an M1043 mutation (e.g., M1043I/L optionally in cis with an H1047R mutation) and/or a C901 mutation (e.g., C901F optionally in cis with an H1047R mutation).
  • a disease or disorder associated with modulation of PI3K ⁇ in a patient in need thereof such as a patient having a disease or disorder comprising an M1043 mutation (e.g., M1043I/L optionally in cis with an H1047R mutation) and/or a C901 mutation (e.g., C901F optionally in cis with an H1047R mutation).
  • M1043 mutation e.g., M1043I/L optionally in cis with an H1047R mutation
  • a C901 mutation e.g., C90
  • the methods may comprise determining that the patient has a disease or disorder comprising the M1043 mutation (e.g., M1043I/L optionally in cis with the H1047R mutation) and/or the C901 mutation (e.g., C901F optionally in cis with the H1047R mutation), for example, by ordering or performing a genomic analysis.
  • M1043 mutation e.g., M1043I/L optionally in cis with the H1047R mutation
  • C901 mutation e.g., C901F optionally in cis with the H1047R mutation
  • the methods further may comprise administering treatment to the patient, which may include administering one or more PI3K ⁇ selective inhibitors to the patient, which may include allosteric inhibitors (e.g., an allosteric inhibitor that binds to the PI3K ⁇ allosteric pocket 1 and/or an allosteric inhibitor that binds to the PI3K ⁇ allosteric pocket 2), orthosteric inhibitors, or combinations thereof as disclosed herein.
  • administering treatment to the patient may include administering one or more PI3K ⁇ selective inhibitors to the patient, which may include allosteric inhibitors (e.g., an allosteric inhibitor that binds to the PI3K ⁇ allosteric pocket 1 and/or an allosteric inhibitor that binds to the PI3K ⁇ allosteric pocket 2), orthosteric inhibitors, or combinations thereof as disclosed herein.
  • the disclosed methods comprise selecting a patient for treatment with one or more PI3K ⁇ selective inhibitors.
  • the patient is selected based on the patient having disease or disorder comprising a M1043 mutation (e.g., M1043I/L optionally in cis with the H1047R mutation) and/or a C901 mutation (e.g., C901F optionally in cis with the H1047R mutation).
  • a M1043 mutation e.g., M1043I/L optionally in cis with the H1047R mutation
  • C901 mutation e.g., C901F optionally in cis with the H1047R mutation
  • a selected patient may be administered treatment, which may include administering one or more PI3K ⁇ selective inhibitors to the patient, which may include allosteric inhibitors (e.g., allosteric inhibitor that binds to the PI3K ⁇ allosteric pocket 1 or an allosteric inhibitor that binds to the PI3K ⁇ allosteric pocket 2), orthosteric inhibitors, or combinations thereof as disclosed herein.
  • a patient in need thereof may have cancer.
  • the patient in need thereof may have breast cancer.
  • the patient in need thereof may have PIK3CA-mutated, advanced, or metastatic breast cancer.
  • the patient in need thereof may have PIK3CA H1047R-mutant advanced, or metastatic breast cancer that is estrogen receptor-positive (ER+), human epidermal growth factor receptor 2-negative (HER2-).
  • a patient in need thereof may have cancer and may have been previously administered one or more therapeutic agents for treating the cancer, which may include a PI3K ⁇ selective inhibitor.
  • the patient may have a cancer which exhibits de novo resistance or acquired resistance to treatment with a therapeutic agent, which may include a PI3K ⁇ selective inhibitor, and the patient may be administered a different therapeutic agent, which may include a different PI3K ⁇ selective inhibitor.
  • the patient may have not been previously administered a therapeutic agent for treating the cancer, which may include a PI3K ⁇ selective inhibitor.
  • the patient may be characterized as na ⁇ ve to treatment with a PI3K ⁇ selective inhibitor.
  • Fig.1 Schematic illustration of PI3K ⁇ (H1047R) showing Orthosteric pocket, Allosteric pocket 1, and Allosteric pocket 2.
  • Fig.2. Dose response curve for alpelisib in a T47D (M1043I+H1047R) (double, in cis, 6 ⁇ ) cell proliferation assay.
  • Dose response curve for Compound 21 in a T47D (M1043I+H1047R) (double, in cis, 6 ⁇ ) cell proliferation assay.
  • Fig.4 Dose response curve for Compound N1 in a T47D (M1043I+H1047R) (double, in cis, 6 ⁇ ) cell proliferation assay.
  • Fig.5. Dose response curve for Compound N2 in a T47D (M1043I+H1047R) (double, in cis, 6 ⁇ ) cell proliferation assay.
  • Fig.6 Dose response curve for Compound 1 in a T47D (M1043I+H1047R) (double, in cis, 6 ⁇ ) cell proliferation assay.
  • Fig.7 Dose response curve for Compound HP1 in a T47D (M1043I+H1047R) (double, in cis, 6 ⁇ ) cell proliferation assay.
  • Fig.8 Dose response curve for alpelisib in a T47D (M1043I+H1047R) (double, in cis, 6 ⁇ ) cell proliferation assay.
  • Fig.9. Dose response curve for Compound HP1 in a T47D (M1043I+H1047R) (double, in cis, 6 ⁇ ) cell proliferation assay.
  • Dose response curve for Compound 1 in a T47D (M1043I+H1047R) (double, in cis, 6 ⁇ ) cell proliferation assay.
  • Fig.11 Dose response curve for Compound 21 in a T47D (M1043I+H1047R) (double, in cis, 6 ⁇ ) cell proliferation assay.
  • Fig.12. Combination Index plot for Compound 21 and alpelisib in T47D na ⁇ ve cells based on growth inhibition assay (CTG).
  • CCG growth inhibition assay
  • Combination Index plot for Compound 21 and alpelisib in T47D (M1043I+H1047R) (double, in cis, 6 ⁇ ) cells based on growth inhibition assay (CTG).
  • CCG growth inhibition assay
  • Fig.14 Combination Index plot for Compound 21 and Compound HP1 in T47D na ⁇ ve cells based on growth inhibition assay (CTG).
  • Fig.15 Combination Index plot for Compound 21 and Compound HP1 in T47D (M1043I+H1047R) (double, in cis, 6 ⁇ ) cells based on growth inhibition assay (CTG).
  • Fig.16 Combination Index plot for Compound 21 and alpelisib in T47D (M1043I+H1047R) (double, in cis, 6 ⁇ ) cells based on growth inhibition assay (CTG).
  • CCG growth inhibition assay
  • Fig.17 Combination Index plot for Compound 21 and alpelisib in MDA453 (Cpd 21-R) (double, in cis, 6 ⁇ ) cells based on growth inhibition assay (CTG).
  • Fig.18 Combination Index plot for Compound 21 and Compound HP1 in MDA453 na ⁇ ve cells based on growth inhibition assay (CTG).
  • Fig.19 Combination Index plot for Compound 21 and Compound HP1 in MDA453 (Cpd 21- R) cells based on growth inhibition assay (CTG).
  • Fig.20 Combination Index plot for Compound 21 and Compound HP1 in MDA453 (Cpd 21- R) cells based on growth inhibition assay (CTG).
  • Interactions include direct hydrogen bonding between the carboxy acid group of Compound 172 and the side chains of R1047 and Q981; hydrogen bonding between the chromenone exocyclic ketone group of Compound 172, a bridging water molecule, and the side chain of H931; hydrogen bonding between the cyano group of Compound 172 and the side chain of Y1021; core pi-pi stacking between the chromenone core of Compound 172 and the side chain of F954; and pi-pi T-stacking between the 4-cyano-phenyl group of Compound 172 and the side chain of F909.
  • FIG.22 Graphic illustration of the interaction of PIK ⁇ _H1047R and Compound N3 based on an X-ray structure analysis. Interactions include direct hydrogen bonding between the carboxy acid group of Compound N3 and the side chains of R1047 and Q981; core pi-pi stacking between the chromenone core of Compound N3 and the side chain of F954 in addition to pi-pi T-stacking between the phenyl group of Compound N3 and the side chain of F954.
  • Fig.23 Graphic illustration of the interaction of PIK ⁇ _H1047R and Compound N4 based on an X-ray structure analysis.
  • Interactions include direct hydrogen bonding between the carboxy acid group of Compound N4 and the side chains of R1047 and Q981; and hydrogen bonding between the chromenone exocyclic ketone group of Compound N4, a bridging water molecule, and the side chain of H931.
  • Fig.24 Graphic illustration of the interaction of PIK ⁇ _H1047R and Compound N5 based on an X-ray structure analysis.
  • Interactions include direct hydrogen bonding between the carboxy acid group of Compound N5 and the side chains of R1047 and Q981; direct hydrogen bonding between the isoxazole group of Compound N5 and side chain of H931; and core pi-pi stacking between the isoxazole core of Compound N5 and the side chain of F954.
  • Fig.25 Graphic illustration of the interaction of PIK ⁇ _M1043I_H1047R and Compound HP1 based on an X-ray structure analysis.
  • Interactions include direct hydrogen bonding between the nitrogen atom in the isoindolin-1-one core of Compound HP1 and the carbonyl backbone group of D1018; core pi-pi stacking between the core of the 3-trifluoromethyl, 5-fluorophenyl group of Compound HP1 and the side chain of F937 in addition to pi-pi T-stacking between the core of the 3- trifluoromethyl, 5-fluorophenyl group of Compound HP1 and the side chain of F1002.
  • Fig.26 Graphic illustration of the interaction of PIK ⁇ _M1043I_H1047R and Compound HP2 based on an X-ray structure analysis.
  • Interactions include direct hydrogen bonding between the nitrogen atom in the isoindolin-1-one core of Compound HP2 and the carbonyl backbone group of D1018; core pi-pi T-stacking between the core of the 3-trifluoromethyl, 5-fluorophenyl group of Compound HP2 and the side chain of F1002; and a chlorine-carbonyl interaction between the chlorine atom of the 2-chloro, 5-fluorophenyl group of Compound HP2 and the side chain carbonyl of E1012.
  • Fig.27 Graphic illustration of the interaction of PIK ⁇ _H1047R, Compound N6, and Compound HP2 in their respective allosteric pockets based on an X-ray structure analysis.
  • Fig.28 Graphic illustration of the interaction of PIK ⁇ _H1047R, Compound N6, and Compound HP2 in their respective allosteric pockets based on an X-ray structure analysis.
  • Fig.29 Effect of Compound 21 (37.5mg/kg), alpelisib (6.25mg/kg), and fulvestrant(5mg/animal) in a T47D xenograft (H1047+/1, ER+, PR+, HER2-).
  • Fig.30 Effect of Compound 21 (37.5mg/kg), alpelisib (6.25mg/kg), and fulvestrant(5mg/animal) in a T47D xenograft (H1047+/1, ER+, PR+, HER2-).
  • Fig.31 Na ⁇ ve and Compound 21 resistant MDA453 cells (having an M1043I 2 nd site mutation) were treated with Compound 21, alpelisib, or Compound HP1.
  • Fig.31 Na ⁇ ve and Engineered T47D Cells (having 6x M1043I 2 nd site mutations) were treated with Compound 21, alpelisib, or Compound HP1.
  • Fig.32 Parental SUM185PE cells and Compound 21 resistant SUM185PE cells were treated with Compound 21, Compound 1, alpelisib, or Compound HP1
  • Fig.33 MDA453 na ⁇ ve cells were treated with Compound 21 in combination with alpelisib.
  • Fig.34 MDA453 na ⁇ ve cells were treated with Compound 21 in combination with alpelisib.
  • H1047R homozygous SUM185PE cells were treated with Compound 21 in combination with alpelisib.
  • Fig.40 Compound 21 resistant SUM185PE cells treated with a combination of Compound 21 and alpelisib.
  • Fig.41 H1047R homozygous SUM185PE cells were treated with Compound 21 in combination with Compound HP1.
  • Fig.42 H1047R homozygous SUM185PE cells were treated with alpelisib in combination with Compound HP1.
  • Fig.43 T47D cells treated with Compound 21 in combination with alpelisib.
  • Fig.44 T47D cells treated with Compound 21 in combination with Compound HP1.
  • Fig.45 Compound 21 in combination with Compound HP1.
  • Fig.46. T47D na ⁇ ve cells treated with Compound 21 in combination with alpelisib.
  • Fig.48. Parental SUM185PE cells and Cpd-21-R SUM185PE cells treated with Compound 21, alpelisib, Compound HP1, Compound HP4, Compound HP5, or Compound HP6.
  • T47D cells (5 ⁇ H1047R/1 ⁇ WT) or engineered T47D cells having 2 nd site mutations (5 ⁇ H1047R/6 ⁇ C901F or 6 ⁇ H1047R/M1043I) treated with Compound 21, alpelisib, Compound HP1, Compound HP4, Compound HP5, or Compound HP6.
  • Fig.50 T47D cells treated with Compound 21 in combination with Compound HP6.
  • Fig.51 T47D cells treated with Compound 21 in combination with Compound HP6.
  • Fig.52 Combination Index plot for Compound 21 in combination with Compound HP6 in T47D cells.
  • Fig.53 SUM185PE cells treated with Compound 21 in combination with Compound HP6.
  • Fig.54 Combination Index plot for Compound 21 in combination with Compound HP6 in SUM185PE cells.
  • Fig.55 T47D cells treated with Compound 21 in combination with Compound HP5.
  • Fig.56 Combination Index plot for Compound 21 in combination with Compound HP5 in T47D cells.
  • Fig.57 SUM185PE cells treated with Compound 21 in combination with Compound HP5.
  • Fig.58 Combination Index plot for Compound 21 in combination with Compound HP5 in SUM185PE cells.
  • the present invention provides methods of treating, preventing, or ameliorating a disease or disorder, or uses of PI3K inhibitors in the treatment, prevention, or amelioration of a disease or disorder, where the disease or disorder is dependent or associated with PI3K activity.
  • a patient in need thereof is administered a therapeutically effective amount of a PI3K inhibitor or a combination of PI3K inhibitors, which may include allosteric inhibitors and orthosteric inhibitors.
  • the methods and uses disclosed herein may be performed in the treatment of a variety of PI3K-dependent or PI3K-associated diseases, and disorders.
  • the disease, or disorder is a cancer, such as breast cancer, brain cancers, prostate cancer, endometrial cancer, gastric cancer, leukemia, lymphoma, sarcoma, colorectal cancer, lung cancer, ovarian cancer, skin cancer, or head and neck cancer.
  • a cancer such as breast cancer, brain cancers, prostate cancer, endometrial cancer, gastric cancer, leukemia, lymphoma, sarcoma, colorectal cancer, lung cancer, ovarian cancer, skin cancer, or head and neck cancer.
  • the disease, or disorder associated with PI3K includes, but is not limited to, CLOVES syndrome (congenital lipomatous overgrowth, vascular malformations, epidermal naevi, scoliosis/skeletal and spinal syndrome), PIK3CA-related overgrowth syndrome (PROS), endometrial cancer, breast cancer, esophageal squamous-cell cancer, cervical squamous- cell carcinoma, cervical adenocarcinoma, colorectal adenocarcinoma, bladder urothelial carcinoma, glioblastoma, ovarian cancer, non-small-cell lung cancer, esophagogastric cancer, nerve-sheath tumor, head and neck squamous-cell carcinoma, melanoma, esophagogastric adenocarcinoma, soft- tissue sarcoma, prostate cancer, fibrolamellar carcinoma, hepatocellular carcinoma, diffuse glioma, colorec
  • administering may be performed by a caregiver, for example, by a medical professional or other caregiver where the medical professional or other caregiver administers to a patient a disclosed compound, or pharmaceutically acceptable salt of the disclosed compound, or a composition.
  • administering may be performed by a patient, for example, where a patient administers to themselves a disclosed compound, or pharmaceutically acceptable salt of the disclosed compound, or a composition.
  • alkenyl refers to a straight, or branched chain unsaturated hydrocarbon containing 2-12 carbon atoms.
  • the “alkenyl” group contains at least one double bond in the chain. The double bond of an alkenyl group can be unconjugated, or conjugated to another unsaturated group.
  • alkenyl groups include ethenyl, propenyl, n-butenyl, iso-butenyl, pentenyl, or hexenyl.
  • alkoxy refers to a straight, or branched chain saturated hydrocarbon containing 1-12 carbon atoms containing a terminal “O” in the chain, i.e., -O(alkyl). Examples of alkoxy groups include without limitation, methoxy, ethoxy, propoxy, butoxy, t-butoxy, or pentoxy groups.
  • alkyl refers to a straight, or branched chain saturated hydrocarbon containing 1-12 carbon atoms, preferably 1-6 carbon atoms.
  • Examples of a (C 1 -C 6 ) alkyl group include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, neopentyl, and isohexyl.
  • alkynyl refers to a straight, or branched chain unsaturated hydrocarbon containing 2-12 carbon atoms.
  • the “alkynyl” group contains at least one triple bond in the chain.
  • alkynyl groups examples include ethynyl, propargyl, n-butynyl, iso-butynyl, pentynyl, or hexynyl.
  • aromatic means a planar ring having 4n + 2 electrons in a conjugated system.
  • conjugated system means a system of connected p-orbitals with delocalized electrons, and the system may include lone electron pairs.
  • aryl unless otherwise specifically defined refers to cyclic, aromatic hydrocarbon groups that have 1 to 3 aromatic rings, including monocyclic, or bicyclic groups such as phenyl, biphenyl, or naphthyl.
  • the aromatic rings of the aryl group may be joined at a single point (e.g., biphenyl), or fused (e.g., naphthyl).
  • the aryl groups herein defined may have one, or more saturated, or partially unsaturated ring fused with a fully unsaturated aromatic ring.
  • Exemplary ring systems of these aryl groups include, but are not limited to, phenyl, biphenyl, naphthyl, anthracenyl, phenalenyl, phenanthrenyl, indanyl, indenyl, tetrahydronaphthalenyl, and tetrahydrobenzoannulenyl.
  • carrier encompasses carriers, excipients, and diluents, and means a material, composition, or vehicle, such as a liquid, or solid filler, diluent, excipient, solvent, or encapsulating material, involved in carrying, or transporting a pharmaceutical agent from one organ, or portion of the body, to another organ, or portion of the body of a patient.
  • cyano means a substituent having a carbon atom joined to a nitrogen atom by a triple bond, i.e., C ⁇ N.
  • cycloalkyl means mono, or polycyclic saturated carbon rings containing 3-18 carbon atoms, preferably 3-10 carbon atoms.
  • cycloalkyl groups include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptanyl, cyclooctanyl, norbornyl, norborenyl, bicyclo[2.2.2]octanyl, and bicyclo[2.2.2]octenyl.
  • disorder means, and is used interchangeably with, the terms disease, condition, or illness, unless otherwise indicated.
  • haloalkoxy refers to an alkoxy group, as defined herein, which is substituted with one, or more halogen.
  • haloalkoxy groups include, but are not limited to, trifluoromethoxy, difluoromethoxy, pentafluoroethoxy, and trichloromethoxy.
  • haloalkyl refers to an alkyl group, as defined herein, which is substituted with one, or more halogen. Examples of haloalkyl groups include, but are not limited to, trifluoromethyl, difluoromethyl, pentafluoroethyl, and trichloromethyl.
  • halogen or “halo” refers to fluorine, chlorine, bromine, or iodine.
  • heteroaryl unless otherwise specifically defined means a monovalent monocyclic, or a polycyclic aromatic radical of 5 to 24 ring atoms, preferably 5 to 10 ring atoms, containing one, or more ring heteroatoms selected from N, O, S, P, or B, preferably 1, 2, 3, or 4 ring heteroatoms selected from N, O, or S, the remaining ring atoms being C.
  • a polycyclic aromatic radical includes two, or more fused rings, and may further include two, or more spiro-fused rings, e.g., bicyclic, tricyclic, tetracyclic, and the like. Unless otherwise specifically defined, “fused” means two rings sharing two ring atoms.
  • heteroaryl as herein defined also means a bicyclic heteroaromatic group wherein the heteroatom is selected from N, O, S, P, or B, preferably N, O, or S.
  • Heteroaryl as herein defined also means a tricyclic heteroaromatic group containing one, or more ring heteroatoms selected from N, O, S, P, or B, preferably N, O, or S.
  • Heteroaryl as herein defined also means a tetracyclic heteroaromatic group containing one, or more ring heteroatoms selected from N, O, S, P, or B, preferably N, O, or S.
  • heteroaromatic groups include, but are not limited to, furyl, thienyl, pyrrolyl, pyridyl, pyrazolyl, pyrimidinyl, imidazolyl, isoxazolyl, oxazolyl, oxadiazolyl, pyrazinyl, indolyl, thiophen-2-yl, quinolyl, benzopyranyl, isothiazolyl, thiazolyl, thiadiazole, indazole, benzimidazolyl, thieno[3,2-b]thiophene, triazolyl, triazinyl, imidazo[1,2-b]pyrazolyl, furo[2,3-c]pyridinyl, imidazo[1,2-a]pyridinyl, indazolyl, pyrrolo[2,3-c]pyridinyl, pyrrolo[3,2- c]pyridinyl, pyrazolo[3,4
  • the heteroaryl groups defined herein may have one, or more saturated, or partially unsaturated ring fused with one, or more fully unsaturated aromatic ring.
  • a saturated, or partially unsaturated ring may further be fused with a saturated, or partially unsaturated ring described herein.
  • the heteroaryl groups defined herein may have one, or more saturated, or partially unsaturated ring spiro-fused. Any saturated, or partially unsaturated ring described herein is optionally substituted with one, or more oxo.
  • Exemplary ring systems of these heteroaryl groups include, for example, indolinyl, indolinonyl, dihydrobenzothiophenyl, dihydrobenzofuran, chromanyl, thiochromanyl, tetrahydroquinolinyl, dihydrobenzothiazine, 3,4-dihydro-1H-isoquinolinyl, 2,3-dihydrobenzofuranyl, benzofuranonyl, oxindolyl, indolyl, 1,6-dihydro-7H-pyrazolo[3,4-c]pyridin-7-onyl, 7,8-dihydro-6H-pyrido[3,2- b]pyrrolizinyl, 8H-pyrido[3,2-b]pyrrolizinyl, 1,5,6,7-tetrahydrocyclopenta[b]pyrazolo[4,3- e]pyridinyl, 7,8-dihydro-6H
  • heterocyclyl means mono, or polycyclic rings containing 3-24 atoms, preferably 3-10 atoms, which include carbon, and one, or more heteroatoms selected from N, O, S, P, or B, preferably 1, 2, 3, or 4 heteroatoms selected from N, O, and S, and wherein the rings are not aromatic.
  • heterocyclyl rings include, but are not limited to, oxetanyl, azetidinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, oxazolinyl, oxazolidinyl, thiazolinyl, thiazolidinyl, pyranyl, thiopyranyl, tetrahydropyranyl, dioxalinyl, piperidinyl, morpholinyl, thiomorpholinyl, thiomorpholinyl S-oxide, thiomorpholinyl S-dioxide, piperazinyl, azepinyl, oxepinyl, diazepinyl, tropanyl, oxazolidinonyl, and homotropanyl.
  • hydroxyalkyl refers to an alkyl group, as defined herein, which is substituted with a hydroxy group.
  • in cis when referring to two different mutations means that the two different mutations are located on the same chromosome.
  • isomers refers to compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space. 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”.
  • enantiomers When a compound has an asymmetric center, for example, it is bonded to four different groups, a pair of enantiomers is possible.
  • An enantiomer can be characterized by the absolute configuration of its asymmetric center and is described by the R- and S-sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (i.e., as (+) or (-)-isomers respectively).
  • a chiral compound can exist as either individual enantiomers or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a “racemic mixture”.
  • modulate refers to a biological activity of a compound, or substrate that inhibits and/or activates PI3K. Modulation may include inhibition.
  • patient and “subject” may be utilized interchangeably herein and mean a mammal such as a human, mouse, rat, guinea pig, dog, cat, horse, cow, pig, or non-human primate, such as a monkey, chimpanzee, baboon, or rhesus.
  • the mammal is human.
  • therapeutically effective amount when used in connection with a compound refers to the amount or dose of the compound which upon single or multiple dose administration to the patient, provides the desired effect in the patient under diagnosis or treatment.
  • An effective amount can be determined by one skilled in the art by the use of known techniques and by observing results obtained under analogous circumstances.
  • determining the effective amount for a patient a number of factors are considered by the attending diagnostician, including, but not limited to: the species of patient; its size, age, and general health; the specific disease or disorder involved; the degree of or involvement or the severity of the disease or disorder; the response of the individual patient; the particular compound administered; the mode of administration; the bioavailability characteristics of the preparation administered; the dose regimen selected; the use of concomitant medication; and other relevant circumstances.
  • the term “treating” with regard to a patient includes restraining, slowing, stopping, or reversing the progression or severity of an existing symptom or disorder.
  • treating with regard to a patient, may include prescribing for a patient a therapeutic agent to be administered to the patient or a treatment regimen for the patient.
  • treating with regard to a patient, may include ordering a diagnostic test for the patient. Diagnostic tests may include genomic analyses that identify mutations present in PI3K ⁇ , such as mutations in C901 (e.g., C901F), M1043 (e.g., M1043I/L), and/or H1047 (e.g., H1047R) which mutations may be in cis (i.e., on the same allele), as disclosed herein.
  • C901 e.g., C901F
  • M1043 e.g., M1043I/L
  • H1047 e.g., H1047R
  • preventing with regard to a patient, may mean preventing a disease or disorder and/or preventing a symptom of a disease or disorder.
  • a patient in need thereof may include a patient at risk for developing a disease or disorder wherein the disclosed methods may performed in order to prevent the patient from developing the disease or disorder.
  • a patient in need thereof may include a patient in remission wherein the disclosed methods may performed in order to prevent the disease or disorder from recurring in the patient.
  • treating may mean administering a therapeutic agent to a patient and observing a decrease in tumor growth, a reduction in tumor size, and/or an increase in mean survival time for the patient after treatment.
  • PI3K means “Phosphoinositide 3-Kinase.”
  • PI3K ⁇ means the Phosphoinositide 3-Kinase alpha, which is a Class I PI3K that comprises the PI3k, catalytic, alpha polypeptide (p110- ⁇ ) encoded by the gene PIK3CA.
  • the p110- ⁇ polypeptide alternatively may be referred to as “PIK3CA.”
  • the p110- ⁇ polypeptide comprises 1068 amino acids and has the amino acid sequence of SEQ ID NO:1: p110- ⁇ (SEQ ID NO:1) 661 qrighfffwh lksemhnktv sqrfgllles ycracgmylk hlnrqveame klinltdilk 721 qekkdetqkv qmkflveqmr rpdfmdalqg flsplnpahq lgnlrleecr imssakrplw 781 lnwenpdims ellfqnneii fkngddlrqd mltlqiirim eniwqnqgld lrmlpygcls 841 igdcvgliev vrnshtim
  • the catalytic activity of PI3K ⁇ includes phosphatidylinositol-4,5-bisphosphate 3-kinase activity, whereby a phosphate group from adenosine triphosphate (ATP) is transferred to phosphatidylinositol-4,5-bisphosphate (PIP2) to create phosphatidylinositol-3,4,5-trisphosphate (PIP3).
  • PI3K ⁇ catalyzes the addition of a 3-phosphate group from ATP to PIP2 by binding ATP in an ATP-binding pocket within the kinase catalytic domain in the p100 ⁇ subunit of PI3K ⁇ .
  • the PI3K ⁇ inhibitors disclosed herein inhibit the phosphatidylinositol-4,5-bisphosphate 3- kinase activity of PI3K ⁇ .
  • the disclosed inhibitors may inhibit PI3K ⁇ activity by binding at or near the ATP-binding pocket of PI3K ⁇ , which may be referred to as an “the PI3K ⁇ orthosteric pocket.”
  • the disclosed inhibitors may prevent ATP from binding at the ATP-binding pocket as antagonists and/or the disclosed inhibitors may displace ATP from the ATP-binding pocket.
  • the disclosed inhibitors may include orthosteric inhibitors that compete with ATP for binding at the ATP-binding site of PI3K ⁇ .
  • the ATP-binding pocket is located in a cleft between the N-terminal and C-terminal lobes of the kinase catalytic domain of p100 ⁇ .
  • the ATP-binding pocket may comprise one or more amino acid residues selected from R770, M772, P778, W780, I800, K802, D810, Y836, I848, V850, V851, S854, Q859, N920, M922, F930, I932, and D933.
  • Orthosteric inhibitors of PI3K ⁇ may bind to PI3K ⁇ at or near the ATP-binding pocket of PI3K ⁇ and may form interactions with one or more amino acids selected from R770, M772, P778, W780, I800, K802, D810, Y836, I848, V850, V851, S854, Q859, N920, M922, F930, I932, and D933. Interactions may include, but are not limited to hydrogen bonding either directly or via a bridging water molecule, pi-pi T-stacking, and coplanar core pi-pi stacking.
  • Orthosteric inhibitors of PI3K ⁇ are known and may include, but are not limited to, alpelisib, inavolisib, and serabelisib, which are PI3K ⁇ selective inhibitors.
  • the disclosed inhibitors may inhibit PI3K ⁇ by binding at or near a pocket of PI3K ⁇ which is not the ATP-binding pocket of PI3K ⁇ , which may be referred to as an “allosteric pocket.”
  • the disclosed inhibitors may function as allosteric inhibitors of PI3K ⁇ .
  • Allosteric inhibitors of PI3K ⁇ which may be utilized in the disclosed methods are disclosed in WO2021/202964 (Petra), WO2021/222556, WO2022/235574, WO2022/235575, WO2022/251482, WO2022/265993, WO2023/018636, WO2023/039532, WO2023/056407, WO2023/060262, WO2023/288242, WO2023/081209, WO2023/081757, WO2023/081759, WO2023/078401, WO2023/104111, WO2023/109870, WO2023/159155, WO2023/168378, WO2023/173124, and WO2023/192416, and WO2023/288242, the contents of which are incorporated herein by reference in their entireties with respect to the PI3K ⁇ inhibitor compounds and methods of making and using the PI3K ⁇ inhibitor compounds disclosed therein.
  • the allosteric inhibitors disclosed herein may bind to PI3K ⁇ at or near an allosteric pocket of PI3K ⁇ referred to herein as “the PI3K ⁇ allosteric pocket 1.”
  • allosteric inhibitors of PI3K ⁇ may bind the PI3K ⁇ allosteric pocket 1 and may form an interaction with one or more amino acids selected from C901, T908, F909, H931, F954, Q981, Y985, Y1021, and R1047. Interactions may include, but are not limited to hydrogen bonding either directly or via a bridging water molecule, pi-pi T-stacking, and coplanar core pi-pi stacking.
  • Particular interactions may include one or more of the following interactions: direct hydrogen bonding between a carboxy acid group of the inhibitor and the side chains of R1047 and Q981; hydrogen bonding between a carboxy acid group of inhibitor, a bridging water molecule, and the side chain of Y985; hydrogen bonding between the chromenone exocyclic ketone group of the inhibitor, a bridging water molecule, and the side chain of H931; hydrogen bonding between the chromenone exocyclic ketone group of the inhibitor, a bridging water molecule, and the carbonyl backbone group of C901; hydrogen bonding between a cyano group of the inhibitor and the side chain of Y1021; core pi-pi stacking between the chromenone core of the inhibitor and the side chain of F954; pi-pi T-stacking between a phenyl core group of the inhibitor (e.g., a core in a substituent at position C2 of the chromenone core) and the side chain of F909
  • Allosteric inhibitors of PI3K ⁇ that bind to the PI3K ⁇ allosteric pocket 1 are disclosed in WO2021/202964, WO2022/235574, WO2022/235575, WO2022/251482, WO2023/056407, WO2023/060262, and WO2023/078401, the contents of which are incorporated herein by reference in their entireties with respect to the PI3K ⁇ inhibitor compounds and methods of making and using the PI3K ⁇ inhibitor compounds disclosed therein.
  • the allosteric inhibitors disclosed herein may bind to PI3K ⁇ at or near an allosteric pocket of PI3K ⁇ referred to herein as “the PI3K ⁇ allosteric pocket 2.”
  • allosteric inhibitors of PI3K ⁇ may bind the PI3K ⁇ allosteric pocket 2 and may form an interaction with one or more amino acids selected from L911, F937, F1002, E1012, and D1018. Interactions may include, but are not limited to hydrogen bonding either directly or via a bridging water molecule, pi-pi T-stacking, and coplanar core pi-pi stacking.
  • Particular interactions may include one or more of the following interactions: direct hydrogen bonding between the nitrogen atom in an isoindolin-1-one core of the inhibitor and the carbonyl backbone group of D1018; core pi-pi stacking between the core of a 3-trifluoromethyl, 5-fluorophenyl group of the inhibitor and the side chain of F937; pi-pi T-stacking between the core of a 3-trifluoromethyl, 5-fluorophenyl group of the inhibitor and the side chain of F1002; and a chlorine-carbonyl interaction between the chlorine atom of a 2- chloro, 5-fluorophenyl group of the compound and the side chain carbonyl of E1012.
  • Allosteric inhibitors of PI3K ⁇ are disclosed in WO2021/222556, WO2022/265993, WO2023/018636, WO2023/039532, WO2023/288242, WO2023/081757, and WO2023/081759, the contents of which are incorporated herein by reference in their entireties with respect to the PI3K ⁇ inhibitor compounds and methods of making and using the PI3K ⁇ inhibitor compounds disclosed therein.
  • the disclosed methods may utilize a PI3K ⁇ allosteric specific inhibitor disclosed in WO2021/222556, WO2022/265993, WO2023/018636, WO2023/039532, WO2023/288242, WO2023/081757, or WO2023/081759, which optionally may bind to the PI3K ⁇ allosteric pocket 2.
  • the methods may utilize a PI3K ⁇ allosteric specific inhibitor disclosed in WO2021/222556, at Table 1, pages 162-855, and referred to as Compounds I-1 through I-2704 or a pharmaceutically acceptable salt thereof.
  • the methods may utilize a PI3K ⁇ allosteric specific inhibitor selected from:
  • the methods may utilize a PI3K ⁇ allosteric specific inhibitor as disclosed in WO2021/222556, Table 1, selected from:
  • the methods may utilize a PI3K ⁇ allosteric specific inhibitor disclosed in WO2022/265993, at Tables A-D, pages 175-259. In some embodiments, the methods may utilize a PI3K ⁇ allosteric specific inhibitor disclosed in WO2022/265993 selected from: or a pharmaceutically acceptable salt thereof. [135] In some aspects, the PI3K ⁇ inhibitors utilized in the disclosed methods may bind to PI3K ⁇ concurrently.
  • the disclosed combinations of inhibitors may bind to one or more allosteric pockets (e.g., PI3K ⁇ allosteric pocket 1 and/or PI3K ⁇ allosteric pocket 2) and the disclosed combinations of inhibitors may bind to the PI3K ⁇ orthosteric pocket, concurrently.
  • the disclosed combination of inhibitors may bind to a first allosteric pocket (e.g., one of PI3K ⁇ allosteric pocket 1 and PI3K ⁇ allosteric pocket 1) and the disclosed combinations of inhibitors may bind to a second allosteric pocket (e.g., the other of PI3K ⁇ allosteric pocket 1 and PI3K ⁇ allosteric pocket 2), concurrently.
  • the disclosed combinations of inhibitors may bind to a first allosteric pocket (e.g., PI3K ⁇ allosteric pocket 1), the disclosed combinations of inhibitors may bind to a second or allosteric pocket (e.g., PI3K ⁇ allosteric pocket 2), and the disclosed combinations of inhibitors may bind to the PI3K ⁇ orthosteric pocket, concurrently.
  • the PI3K ⁇ inhibitors utilized in the disclosed methods may bind to PI3K ⁇ competitively.
  • the disclosed combinations of inhibitors bind to one or more allosteric pockets (e.g., PI3K ⁇ allosteric pocket 1 and/or PI3K ⁇ allosteric pocket 2) competitively.
  • PI3K ⁇ selective inhibitors which may include PI3K ⁇ selective allosteric inhibitors and PI3K ⁇ selective orthosteric inhibitors, may inhibit activity of PI3K ⁇ , such as phosphorylation activity of PI3K ⁇ . Phosphorylation activity may be assayed by methods including the methods disclosed herein.
  • PI3K ⁇ selective inhibitors disclosed herein have an IC 50 in an in vitro phosphorylation assay which is less than about 100 nM, 50 nM, 10 nM, or 1 nM.
  • PI3K ⁇ selective inhibitors disclosed herein have an EC50 in an in vitro cell phosphorylation assay (e.g., a phosphorylation assay which measures phosphorylation of a substrate of PI3K ⁇ such as p-AKT, p-S6, or FOXM1) which is less than about 100 nM, 50 nM, 10 nM, or 1 nM.
  • PI3K ⁇ selective inhibitors which may include PI3K ⁇ selective allosteric inhibitors and PI3K ⁇ selective orthosteric inhibitors, may inhibit the growth of cancer cells whose growth is dependent on PI3K ⁇ activity.
  • PI3K ⁇ selective inhibitors disclosed herein have an EC50 in a growth inhibition assay which is less than about 100 nM, 50 nM, 10 nM, or 1 nM.
  • the disclosed subject matter relates to methods of using multiple inhibitors of PI3K ⁇ or combinations of inhibitors of PI3K ⁇ for treating diseases and disorders associated with PI3K ⁇ modulation.
  • multiple inhibitors of PI3K ⁇ or “combination of inhibitors of PI3K ⁇ ” as used herein, should be interpreted to mean “two or more different inhibitors of PI3K ⁇ .”
  • the multiple inhibitors of PI3K ⁇ may inhibit PI3K ⁇ by binding at or near the same pocket of PI3K ⁇ (e.g., at or near an allosteric pocket of PI3K ⁇ ), or the multiple inhibitors of PI3K ⁇ may inhibit PI3K ⁇ by binding at or near different pockets of PI3K ⁇ (e.g., where one inhibitor binds at or near an allosteric pocket of PI3K ⁇ and the other inhibitor binds at or near an orthosteric pocket of PI3K ⁇ , or where one inhibitor binds at or near an allosteric pocket of PI3K ⁇ and the other inhibitor binds at or near a different allosteric pocket of PI3K ⁇ ).
  • the disclosed methods may include administered a PI3K ⁇ selective inhibitor.
  • a PI3K ⁇ selective inhibitor may be defined as an inhibitor of PI3K ⁇ which has an inhibitory activity for PI3K ⁇ which is greater than an inhibitory activity for one or more of PI3K ⁇ , PI3K ⁇ , and PI3K ⁇ .
  • a PI3K ⁇ selective inhibitor may have an IC50 value or an EC50 value for PI3K ⁇ in a phosphorylation assay which is lower than an IC50 value or an EC50 value, respectively, for one or more of PI3K ⁇ , PI3K ⁇ , and PI3K ⁇ in the phosphorylation assay.
  • Suitable phosphorylation assays for determining IC50 values for PI3K ⁇ , PI3K ⁇ , PI3K ⁇ , and PI3K ⁇ may include, but are not limited to in vitro biochemical or cell-based phosphorylation assays.
  • a PI3K ⁇ selective inhibitor has an IC 50 value or an EC 50 value for PI3K ⁇ in a phosphorylation assay which is less than about 100 nM, 50 nM, 10 nM, or 1 nM.
  • a PI3K ⁇ selective inhibitor has an IC50 value or an EC50 value for one or more of PI3K ⁇ , PI3K ⁇ , and PI3K ⁇ in a phosphorylation assay which is greater than about 100 nM, 200 nM, 500 nM, or 1000 nM.
  • a PI3K ⁇ selective inhibitor has an IC50 value or an EC50 value for PI3K ⁇ in a phosphorylation assay which is at least 5 ⁇ , 10 ⁇ , 20 ⁇ , 30 ⁇ , 40 ⁇ , 50 ⁇ , 100 ⁇ , 500 ⁇ , or 1000 ⁇ less than an IC50 value or an EC50 value, respectively, for one or more of PI3K ⁇ , PI3K ⁇ , and PI3K ⁇ in the phosphorylation assay.
  • the disclosed PI3K ⁇ selective inhibitors may exhibit selectivity for mutant forms of PI3K ⁇ relative to wild-type forms of PI3K ⁇ .
  • the disclosed PI3K ⁇ selective inhibitors may exhibit selectivity for H1047R mutant PI3K ⁇ relative to wild-type PI3K ⁇ .
  • a PI3K ⁇ selective inhibitor has an IC 50 value or an EC 50 value for H1047R mutant PI3K ⁇ in a phosphorylation assay which is less than an IC50 value or an EC50 value, respectively for wild-type PI3K ⁇ in the phosphorylation assay.
  • a PI3K ⁇ selective inhibitor has an IC50 value or an EC50 value for H1047R mutant PI3K ⁇ in a phosphorylation assay which is less than about 100 nM, 50 nM, 10 nM, or 1 nM.
  • a PI3K ⁇ selective inhibitor has an IC50 value or an EC50 value for wild-type PI3K ⁇ in a phosphorylation assay which is greater than about 100 nM, 200 nM, 500 nM, or 1000 nM. In some aspects, a PI3K ⁇ selective inhibitor has an IC50 value or an EC50 value for H1047R mutant PI3K ⁇ in a phosphorylation assay which is at least 5 ⁇ , 10 ⁇ , 20 ⁇ , 30 ⁇ , 40 ⁇ , 50 ⁇ , 100 ⁇ , 500 ⁇ , or 1000 ⁇ less than an IC50 value or an EC50 value for wild-type PI3K ⁇ in the phosphorylation assay.
  • Suitable phosphorylation assays for determining IC50 values or EC50 values for H1047R mutant PI3K ⁇ relative to wild-type PI3K ⁇ may include, but are not limited to in vitro biochemical or cell-based phosphorylation assays.
  • the methods disclosed herein may recite a “first PI3K ⁇ selective inhibitor” and a “second PI3K ⁇ selective inhibitor.” This should not be interpreted as requiring that the first PI3K ⁇ selective inhibitor is administered prior (e.g., temporally) to the second PI3K ⁇ selective inhibitor in the disclosed methods.
  • the first PI3K ⁇ selective inhibitor and the second PI3K ⁇ selective inhibitor may be administered simultaneously or substantially simultaneously (e.g.
  • the first PI3K ⁇ selective inhibitor and the second PI3K ⁇ selective inhibitor may be administered by the same actor.
  • a caretaker e.g., a patient’s physician or a patient’s non-physician caretaker
  • a patient administers both of the first PI3K ⁇ selective inhibitor and the second PI3K ⁇ selective inhibitor to themself.
  • the first PI3K ⁇ selective inhibitor and the second PI3K ⁇ selective inhibitor may be administered by separate actors.
  • a caretaker administers one of the first PI3K ⁇ selective inhibitor and the second PI3K ⁇ selective inhibitor, and a different caretaker administers the other of the first PI3K ⁇ selective inhibitor and the second PI3K ⁇ selective inhibitor.
  • a caretaker administers one of the first PI3K ⁇ selective inhibitor and the second PI3K ⁇ selective inhibitor to the patient, and a patient administers the other of the first PI3K ⁇ selective inhibitor and the second PI3K ⁇ selective inhibitor to themself.
  • the therapeutically effective amount of the PI3K ⁇ selective inhibitor is effective for reducing PI3K ⁇ activity in the patient without inducing adverse events, or while minimizing the risk of adverse events.
  • Adverse events may include, but are not limited to hyperglycemia, which may be defined as blood glucose greater than about 100, 105, 110, 115, 120, or 125 mg/dL while fasting (e.g., after not eating for at least 8 hours), or blood glucose greater than about 155, 160, 165, 170, 175, or 180 mg/dL one to two hours after eating.
  • hyperglycemia may be defined as blood glucose greater than about 100, 105, 110, 115, 120, or 125 mg/dL while fasting (e.g., after not eating for at least 8 hours), or blood glucose greater than about 155, 160, 165, 170, 175, or 180 mg/dL one to two hours after eating.
  • Adverse events may include but are not limited to hyperinsulinemia, diarrhea, dehydration, skin rash, lymphopenia, Increased alanine transaminase, fatigue, anemia, elevated serum lipase, anorexia, stomatitis, vomiting, weight loss, hypocalcemia, hypoglycemic disorder, alopecia, prolonged activated partial thromboplastin time, kidney disease with reduction in glomerular filtration rate (GFR), acute abdominal pain, and abnormal hepatic function tests.
  • a therapeutically effective amount of a PI3K ⁇ selective inhibitor is administered to the patient in need thereof, and the PI3K ⁇ selective inhibitor functions as an allosteric inhibitor.
  • the therapeutically effective amount of a PI3K ⁇ selective allosteric inhibitor administered to the patient is a 100-1200 mg oral dose (e.g., BID (administered two times daily)).
  • the therapeutically effective amount of the first allosteric inhibitor administered to the patient is 9-75 mg/kg oral dose (e.g., 37.5 mg/kg oral dose BID).
  • the PI3K ⁇ selective allosteric inhibitors disclosed herein, or a pharmaceutically acceptable salts thereof, and the one or more additional therapeutic agents and their respective pharmaceutically acceptable salts are generally effective over a wide dosage range.
  • a PI3K ⁇ selective allosteric inhibitor, or a pharmaceutically salt thereof is administered at a total daily dose of 200 mg to 2400 mg. In an embodiment, a PI3K ⁇ selective allosteric inhibitor, or a pharmaceutically salt thereof, is administered at a total daily dose of 400 mg to 2000 mg.
  • a PI3K ⁇ selective allosteric inhibitor, or a pharmaceutically salt thereof is administered at a total daily dose of 600 mg to 1200 mg. [147] In an embodiment, a PI3K ⁇ selective allosteric inhibitor, or a pharmaceutically salt thereof, is administered at a total daily dose of 200 mg. In an embodiment, a PI3K ⁇ selective allosteric inhibitor, or a pharmaceutically salt thereof, is administered at a total daily dose of 300 mg. In an embodiment, a PI3K ⁇ selective allosteric inhibitor, or a pharmaceutically salt thereof, is administered at a total daily dose of 400 mg.
  • a PI3K ⁇ selective allosteric inhibitor, or a pharmaceutically salt thereof is administered at a total daily dose of 500 mg. In an embodiment, a PI3K ⁇ selective allosteric inhibitor, or a pharmaceutically salt thereof, is administered at a total daily dose of 600 mg. In an embodiment, a PI3K ⁇ selective allosteric inhibitor, or a pharmaceutically salt thereof, is administered at a total daily dose of 700 mg. In an embodiment, a PI3K ⁇ selective allosteric inhibitor, or a pharmaceutically salt thereof, is administered at a total daily dose of 800 mg. In an embodiment, a PI3K ⁇ selective allosteric inhibitor, or a pharmaceutically salt thereof, is administered at a total daily dose of 900 mg.
  • a PI3K ⁇ selective allosteric inhibitor, or a pharmaceutically salt thereof is administered at a total daily dose of 1000 mg. In an embodiment, a PI3K ⁇ selective allosteric inhibitor, or a pharmaceutically salt thereof, is administered at a total daily dose of 1100 mg. In an embodiment, a PI3K ⁇ selective allosteric inhibitor, or a pharmaceutically salt thereof, is administered at a total daily dose of 1200 mg. In an embodiment, a PI3K ⁇ selective allosteric inhibitor, or a pharmaceutically salt thereof, is administered at a total daily dose of 1300 mg.
  • a PI3K ⁇ selective allosteric inhibitor, or a pharmaceutically salt thereof is administered at a total daily dose of 1400 mg. In an embodiment, a PI3K ⁇ selective allosteric inhibitor, or a pharmaceutically salt thereof, is administered at a total daily dose of 1500 mg. In an embodiment, a PI3K ⁇ selective allosteric inhibitor, or a pharmaceutically salt thereof, is administered at a total daily dose of 1600 mg. In an embodiment, a PI3K ⁇ selective allosteric inhibitor, or a pharmaceutically salt thereof, is administered at a total daily dose of 1700 mg. In an embodiment, a PI3K ⁇ selective allosteric inhibitor, or a pharmaceutically salt thereof, is administered at a total daily dose of 1800 mg.
  • a PI3K ⁇ selective allosteric inhibitor, or a pharmaceutically salt thereof is administered at a total daily dose of 1900 mg. In an embodiment, a PI3K ⁇ selective allosteric inhibitor, or a pharmaceutically salt thereof, is administered at a total daily dose of 2000 mg. In an embodiment, a PI3K ⁇ selective allosteric inhibitor, or a pharmaceutically salt thereof, is administered at a total daily dose of 2100 mg. In an embodiment, a PI3K ⁇ selective allosteric inhibitor, or a pharmaceutically salt thereof, is administered at a total daily dose of 2200 mg.
  • a PI3K ⁇ selective allosteric inhibitor, or a pharmaceutically salt thereof is administered at a total daily dose of 2300 mg. In an embodiment, a PI3K ⁇ selective allosteric inhibitor, or a pharmaceutically salt thereof, is administered at a total daily dose of 2400 mg. [148] In an embodiment, a PI3K ⁇ selective allosteric inhibitor, or a pharmaceutically salt thereof, is administered at a total daily dose of 200 mg in a 28-day cycle. In an embodiment, a PI3K ⁇ selective allosteric inhibitor, or a pharmaceutically salt thereof, is administered at a total daily dose of 300 mg in a 28-day cycle.
  • a PI3K ⁇ selective allosteric inhibitor, or a pharmaceutically salt thereof is administered at a total daily dose of 400 mg in a 28-day cycle. In an embodiment, a PI3K ⁇ selective allosteric inhibitor, or a pharmaceutically salt thereof, is administered at a total daily dose of 500 mg in a 28-day cycle. In an embodiment, a PI3K ⁇ selective allosteric inhibitor, or a pharmaceutically salt thereof, is administered at a total daily dose of 600 mg in a 28-day cycle. In an embodiment, a PI3K ⁇ selective allosteric inhibitor, or a pharmaceutically salt thereof, is administered at a total daily dose of 700 mg in a 28-day cycle.
  • a PI3K ⁇ selective allosteric inhibitor, or a pharmaceutically salt thereof is administered at a total daily dose of 800 mg in a 28-day cycle. In an embodiment, a PI3K ⁇ selective allosteric inhibitor, or a pharmaceutically salt thereof, is administered at a total daily dose of 900 mg in a 28-day cycle. In an embodiment, a PI3K ⁇ selective allosteric inhibitor, or a pharmaceutically salt thereof, is administered at a total daily dose of 1000 mg in a 28-day cycle. In an embodiment, a PI3K ⁇ selective allosteric inhibitor, or a pharmaceutically salt thereof, is administered at a total daily dose of 1100 mg in a 28-day cycle.
  • a PI3K ⁇ selective allosteric inhibitor, or a pharmaceutically salt thereof is administered at a total daily dose of 1200 mg in a 28-day cycle. In an embodiment, a PI3K ⁇ selective allosteric inhibitor, or a pharmaceutically salt thereof, is administered at a total daily dose of 1300 mg in a 28-day cycle. In an embodiment, a PI3K ⁇ selective allosteric inhibitor, or a pharmaceutically salt thereof, is administered at a total daily dose of 1400 mg in a 28-day cycle. In an embodiment, a PI3K ⁇ selective allosteric inhibitor, or a pharmaceutically salt thereof, is administered at a total daily dose of 1500 mg in a 28-day cycle.
  • a PI3K ⁇ selective allosteric inhibitor, or a pharmaceutically salt thereof is administered at a total daily dose of 1600 mg in a 28-day cycle. In an embodiment, a PI3K ⁇ selective allosteric inhibitor, or a pharmaceutically salt thereof, is administered at a total daily dose of 1700 mg in a 28-day cycle. In an embodiment, a PI3K ⁇ selective allosteric inhibitor, or a pharmaceutically salt thereof, is administered at a total daily dose of 1800 mg in a 28-day cycle. In an embodiment, a PI3K ⁇ selective allosteric inhibitor, or a pharmaceutically salt thereof, is administered at a total daily dose of 1900 mg in a 28-day cycle.
  • a PI3K ⁇ selective allosteric inhibitor, or a pharmaceutically salt thereof is administered at a total daily dose of 2000 mg in a 28-day cycle. In an embodiment, a PI3K ⁇ selective allosteric inhibitor, or a pharmaceutically salt thereof, is administered at a total daily dose of 2100 mg in a 28-day cycle. In an embodiment, a PI3K ⁇ selective allosteric inhibitor, or a pharmaceutically salt thereof, is administered at a total daily dose of 2200 mg in a 28-day cycle. In an embodiment, a PI3K ⁇ selective allosteric inhibitor, or a pharmaceutically salt thereof, is administered at a total daily dose of 2300 mg in a 28-day cycle.
  • a PI3K ⁇ selective allosteric inhibitor, or a pharmaceutically salt thereof is administered at a total daily dose of 2400 mg in a 28-day cycle.
  • a PI3K ⁇ selective allosteric inhibitor, or a pharmaceutically salt thereof is administered at a dose of 100 mg to 1200 mg twice a day.
  • a PI3K ⁇ selective allosteric inhibitor, or a pharmaceutically salt thereof is administered at a dose of 200 mg to 1000 mg twice a day.
  • a PI3K ⁇ selective allosteric inhibitor, or a pharmaceutically salt thereof is administered at a dose of 300 mg to 600 mg twice a day.
  • a PI3K ⁇ selective allosteric inhibitor, or a pharmaceutically salt thereof is administered at a dose of 100 mg twice a day. In an embodiment, a PI3K ⁇ selective allosteric inhibitor, or a pharmaceutically salt thereof, is administered at a dose of 150 mg twice a day. In an embodiment, a PI3K ⁇ selective allosteric inhibitor, or a pharmaceutically salt thereof, is administered at a dose of 200 mg twice a day. In an embodiment, a PI3K ⁇ selective allosteric inhibitor, or a pharmaceutically salt thereof, is administered at a dose of 250 mg twice a day.
  • a PI3K ⁇ selective allosteric inhibitor, or a pharmaceutically salt thereof is administered at a dose of 300 mg twice a day. In an embodiment, a PI3K ⁇ selective allosteric inhibitor, or a pharmaceutically salt thereof, is administered at a dose of 350 mg twice a day. In an embodiment, a PI3K ⁇ selective allosteric inhibitor, or a pharmaceutically salt thereof, is administered at a dose of 400 mg twice a day. In an embodiment, a PI3K ⁇ selective allosteric inhibitor, or a pharmaceutically salt thereof, is administered at a dose of 450 mg twice a day.
  • a PI3K ⁇ selective allosteric inhibitor, or a pharmaceutically salt thereof is administered at a dose of 500 mg twice a day. In an embodiment, a PI3K ⁇ selective allosteric inhibitor, or a pharmaceutically salt thereof, is administered at a dose of 550 mg twice a day. In an embodiment, a PI3K ⁇ selective allosteric inhibitor, or a pharmaceutically salt thereof, is administered at a dose of 600 mg twice a day. In an embodiment, a PI3K ⁇ selective allosteric inhibitor, or a pharmaceutically salt thereof, is administered at a dose of 650 mg twice a day.
  • a PI3K ⁇ selective allosteric inhibitor, or a pharmaceutically salt thereof is administered at a dose of 700 mg twice a day. In an embodiment, a PI3K ⁇ selective allosteric inhibitor, or a pharmaceutically salt thereof, is administered at a dose of 750 mg twice a day. In an embodiment, a PI3K ⁇ selective allosteric inhibitor, or a pharmaceutically salt thereof, is administered at a dose of 800 mg twice a day. In an embodiment, a PI3K ⁇ selective allosteric inhibitor, or a pharmaceutically salt thereof, is administered at a dose of 850 mg twice a day.
  • a PI3K ⁇ selective allosteric inhibitor, or a pharmaceutically salt thereof is administered at a dose of 900 mg twice a day. In an embodiment, a PI3K ⁇ selective allosteric inhibitor, or a pharmaceutically salt thereof, is administered at a dose of 950 mg twice a day. In an embodiment, a PI3K ⁇ selective allosteric inhibitor, or a pharmaceutically salt thereof, is administered at a dose of 1000 mg twice a day. In an embodiment, a PI3K ⁇ selective allosteric inhibitor, or a pharmaceutically salt thereof, is administered at a dose of 1050 mg twice a day.
  • a PI3K ⁇ selective allosteric inhibitor, or a pharmaceutically salt thereof is administered at a dose of 1100 mg twice a day. In an embodiment, a PI3K ⁇ selective allosteric inhibitor, or a pharmaceutically salt thereof, is administered at a dose of 1150 mg twice a day. In an embodiment, a PI3K ⁇ selective allosteric inhibitor, or a pharmaceutically salt thereof, is administered at a dose of 1200 mg twice a day. [151] In an embodiment, a PI3K ⁇ selective allosteric inhibitor, or a pharmaceutically salt thereof, is administered at a dose of 100 mg to 1200 mg twice a day in a 28-day cycle.
  • a PI3K ⁇ selective allosteric inhibitor, or a pharmaceutically salt thereof is administered at a dose of 200 mg to 1000 mg twice a day in a 28-day cycle. In an embodiment, a PI3K ⁇ selective allosteric inhibitor, or a pharmaceutically salt thereof, is administered at a dose of 100 mg twice a day in a 28- day cycle. In an embodiment, a PI3K ⁇ selective allosteric inhibitor, or a pharmaceutically salt thereof, is administered at a dose of 200 mg twice a day in a 28-day cycle. In an embodiment, a PI3K ⁇ selective allosteric inhibitor, or a pharmaceutically salt thereof, is administered at a dose of 150 mg twice a day in a 28-day cycle.
  • a PI3K ⁇ selective allosteric inhibitor, or a pharmaceutically salt thereof is administered at a dose of 200 mg twice a day in a 28-day cycle. In an embodiment, a PI3K ⁇ selective allosteric inhibitor, or a pharmaceutically salt thereof, is administered at a dose of 250 mg twice a day in a 28-day cycle. In an embodiment, a PI3K ⁇ selective allosteric inhibitor, or a pharmaceutically salt thereof, is administered at a dose of 300 mg twice a day in a 28-day cycle. In an embodiment, a PI3K ⁇ selective allosteric inhibitor, or a pharmaceutically salt thereof, is administered at a dose of 350 mg twice a day in a 28-day cycle.
  • a PI3K ⁇ selective allosteric inhibitor, or a pharmaceutically salt thereof is administered at a dose of 400 mg twice a day in a 28-day cycle. In an embodiment, a PI3K ⁇ selective allosteric inhibitor, or a pharmaceutically salt thereof, is administered at a dose of 450 mg twice a day in a 28-day cycle. In an embodiment, a PI3K ⁇ selective allosteric inhibitor, or a pharmaceutically salt thereof, is administered at a dose of 500 mg twice a day in a 28-day cycle. In an embodiment, a PI3K ⁇ selective allosteric inhibitor, or a pharmaceutically salt thereof, is administered at a dose of 550 mg twice a day in a 28-day cycle.
  • a PI3K ⁇ selective allosteric inhibitor, or a pharmaceutically salt thereof is administered at a dose of 600 mg twice a day in a 28-day cycle. In an embodiment, a PI3K ⁇ selective allosteric inhibitor, or a pharmaceutically salt thereof, is administered at a dose of 650 mg twice a day in a 28-day cycle. In an embodiment, a PI3K ⁇ selective allosteric inhibitor, or a pharmaceutically salt thereof, is administered at a dose of 700 mg twice a day in a 28-day cycle. In an embodiment, a PI3K ⁇ selective allosteric inhibitor, or a pharmaceutically salt thereof, is administered at a dose of 750 mg twice a day in a 28-day cycle.
  • a PI3K ⁇ selective allosteric inhibitor, or a pharmaceutically salt thereof is administered at a dose of 800 mg twice a day in a 28-day cycle. In an embodiment, a PI3K ⁇ selective allosteric inhibitor, or a pharmaceutically salt thereof, is administered at a dose of 850 mg twice a day in a 28-day cycle. In an embodiment, a PI3K ⁇ selective allosteric inhibitor, or a pharmaceutically salt thereof, is administered at a dose of 900 mg twice a day in a 28-day cycle. In an embodiment, a PI3K ⁇ selective allosteric inhibitor, or a pharmaceutically salt thereof, is administered at a dose of 950 mg twice a day in a 28-day cycle.
  • a PI3K ⁇ selective allosteric inhibitor, or a pharmaceutically salt thereof is administered at a dose of 1000 mg twice a day in a 28-day cycle. In an embodiment, a PI3K ⁇ selective allosteric inhibitor, or a pharmaceutically salt thereof, is administered at a dose of 1050 mg twice a day in a 28-day cycle. In an embodiment, a PI3K ⁇ selective allosteric inhibitor, or a pharmaceutically salt thereof, is administered at a dose of 1100 mg twice a day in a 28-day cycle. In an embodiment, a PI3K ⁇ selective allosteric inhibitor, or a pharmaceutically salt thereof, is administered at a dose of 1150 mg twice a day in a 28-day cycle.
  • a PI3K ⁇ selective allosteric inhibitor, or a pharmaceutically salt thereof is administered at a dose of 1200 mg twice a day in a 28-day cycle.
  • a PI3K ⁇ selective allosteric inhibitor, or a pharmaceutically salt thereof is administered at a dose of 200 mg twice a day in a 28-day cycle.
  • a PI3K ⁇ selective allosteric inhibitor, or a pharmaceutically salt thereof is administered at a dose of 400 mg twice a day in a 28-day cycle.
  • a PI3K ⁇ selective allosteric inhibitor, or a pharmaceutically salt thereof is administered at a dose of 600 mg twice a day in a 28-day cycle. In another preferred embodiment, a PI3K ⁇ selective allosteric inhibitor, or a pharmaceutically salt thereof, is administered at a dose of 800 mg twice a day in a 28- day cycle. In another preferred embodiment, a PI3K ⁇ selective allosteric inhibitor, or a pharmaceutically salt thereof, is administered at a dose of 1000 mg twice a day in a 28-day cycle.
  • the therapeutically effective amount of the a PI3K ⁇ selective allosteric inhibitor administered to the patient is a 9, 15, 20, 25, 30, 35, 37.5, 40, 45, 50, 55, 60, 65, 70, or 75 mg/kg oral dose (e.g., QD or BID), or a dose within a range bounded by any of these values.
  • the therapeutically effective amount of the a PI3K ⁇ selective allosteric inhibitor administered to the patient is a 9-75 mg/kg oral dose (e.g., QD or BID 37.5 mg/kg).
  • the therapeutically effective amount of the a PI3K ⁇ selective allosteric inhibitor administered to the patient is less than about 75, 70, 65, 60, 55, 50, 45, 40, 37.5, 30, 35, 30, 25, 30 15, 9, 8, 7, 6, or 5 mg/kg oral dose (e.g., QD or BID).
  • a therapeutically effective amount of a PI3K ⁇ selective inhibitor is administered to the patient in need thereof, and the PI3K ⁇ selective inhibitor functions as an orthosteric inhibitor.
  • the therapeutically effective amount of the PI3K ⁇ selective orthosteric inhibitor administered to the patient is a 300 mg oral dose QD (i.e., administered once a day) or less than about a 300 mg oral dose QD, such as less than about 250, 200, 150, 100, or 50 mg QD.
  • the therapeutically effective amount of the PI3K ⁇ selective orthosteric inhibitor administered to the patient is a 50 mg/kg oral dose QD (i.e., administered once a day) or less than about a 50 mg/kg oral dose QD, such as less than about 30, 12.5, 6.25, or 3.125 mg/kg oral dose QD, for example when the PI3K ⁇ selective orthosteric inhibitor is administered with a PI3K ⁇ selective allosteric inhibitor (e.g., a PI3K ⁇ selective allosteric inhibitor that binds the PI3K ⁇ allosteric pocket 1 or the PI3K ⁇ allosteric pocket 2), simultaneously, separately, or sequentially.
  • a PI3K ⁇ selective allosteric inhibitor e.g., a PI3K ⁇ selective allosteric inhibitor that binds the PI3K ⁇ allosteric pocket 1 or the PI3K ⁇ allosteric pocket 2
  • the disclosed methods may relate to treating a patient having a disease or disorder which is resistant to treatment with a PI3K ⁇ selective inhibitor. Resistance may include “acquired resistance” where a patient has a disease or disorder which has developed resistance to treatment with the PI3K ⁇ selective inhibitor after having been treated previously with the PI3K ⁇ selective inhibitor. Resistance may include “de novo resistance” where a patient has a disease or disorder that is resistant to treatment with the PI3K ⁇ selective inhibitor and the patient was not treated previously with the PI3K ⁇ selective inhibitor. [156] The disclosed methods may relate to a patient having a disease or disorder which has acquired resistance to a PI3K ⁇ selective inhibitor.
  • Acquired resistance may be characterized in vitro by methods that include, but are not limited to: an EC50 shift in growth inhibition, for example as measured by a cell viability assay; changes in phosphorylation inhibition, for example as assayed by Western blot and quantification of phosphorylated bands, or as assayed by determining an IC50 value in a phosphorylation assay; and stability of cell colonies in a selection-free condition.
  • Acquired resistance may be characterized in vivo or clinically by observing recurrence in a patient after the patient was treated with the PI3K ⁇ selective inhibitor and the patient previously exhibited remission.
  • acquired resistance may be characterized clinically by observing recurrence after having previously observed remission in the patient when the patient was treated with the PI3K ⁇ selective inhibitor.
  • acquired resistance may be characterized clinically by observing an increase in growth of cancer after having previously observed a decline in growth of the cancer after treatment with the PI3K ⁇ selective inhibitor.
  • acquired resistance may be characterized clinically by observing recurrence of the cancer in a different part of the patient’s body than where the cancer was first observed prior to treatment with the PI3K ⁇ selective inhibitor.
  • a patient may be administered a therapeutically effective amount of one or more PI3K ⁇ selective inhibitors, which may include a combination of allosteric inhibitors and/or orthosteric inhibitors.
  • the disclosed methods further comprise administering to the patient a therapeutically effective amount of another therapeutic agent.
  • the patient further is administered a therapeutically effective amount of a selective estrogen receptor degrader (SERD).
  • SELDs may include, but are not limited to imlunestrant, fulvestrant, giredestrant, amcenestrant, rintodestrant, elacestrant, camizestrant, LSZ102, Zn-c5, and D-0502.
  • the therapeutically effective amount of the SERD is a dose of 500 mg, which may be administered on days 1, 15, and 29 or a treatment regimen.
  • a patient in need thereof may have cancer.
  • the patient in need thereof may have breast cancer.
  • the patient in need thereof may have PIK3CA-mutated, advanced, or metastatic breast cancer.
  • PIK3CA-mutated cancer may include cancer having one or more mutations selected from, but not limited to E542K, E545K, E453Q/K, E726K, C901F, M1043I/L, and H1047R, optionally wherein the one or more mutations are in cis (i.e., on the same allele).
  • the patient in need thereof may have PIK3CACA H1047R-mutant advanced, or metastatic breast cancer which is estrogen receptor-positive (ER+), human epidermal growth factor receptor 2-negative (HER2-).
  • the patient in need thereof is a postmenopausal female.
  • the patient has type II diabetes mellitus.
  • PI3K Phosphoinositide 3-Kinase
  • the disclosed methods relate to methods for treating a disease or disorder associated with modulation of PI3K ⁇ .
  • the methods may comprise administering to a patient in need thereof: (i) a therapeutically effective amount of a first PI3K ⁇ selective inhibitor, wherein the first PI3K ⁇ selective inhibitor binds to the PI3K ⁇ allosteric pocket 1 and optionally may form an interaction with one or more amino acids selected from C901, T908, F909, H931, F954, Q981, Y985, Y1021, and R1047; and (ii) a therapeutically effective amount of a second PI3K ⁇ selective inhibitor, wherein the second PI3K ⁇ selective inhibitor binds to the PI3K ⁇ orthosteric pocket.
  • the disclosed methods may comprise administering a first PI3K ⁇ selective inhibitor which is a PI3K ⁇ selective allosteric inhibitor and a second PI3K ⁇ selective inhibitor which is a PI3K ⁇ selective orthosteric inhibitor.
  • the first PI3K ⁇ selective inhibitor and the second PI3K ⁇ selective inhibitor may be administered simultaneously, separately, or sequentially.
  • the first PI3K ⁇ selective inhibitor is an allosteric inhibitor of a Formula I: or pharmaceutically acceptable salt thereof, wherein: R is -H or C 1 -C 3 alkyl; R 1 is a group of the formula: R 2 is a group of the formula: R 3 is -H, halogen, -CN, -N(H)(C 1 -C 3 alkyl), -N(C 1 -C 3 alkyl) 2 , -N(H)(CH 2 CH 2 CO 2 H), -C(O)C 1 -C 3 alkyl, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 3 -C 5 cycloalkyl, an optionally substituted heterocycle of 3 to 5 ring atoms containing 1, 2, or 3 ring heteroatoms independently selected from N, O, or S, or an optionally substituted heteroaryl of
  • the second PI3K ⁇ selective inhibitor utilized in the disclosed methods binds to the PI3K ⁇ orthosteric pocket and may function as an orthosteric inhibitor.
  • the orthosteric inhibitor is alpelisib or a pharmaceutically acceptable salt thereof.
  • the orthosteric inhibitor is inavolisib or a pharmaceutically acceptable salt thereof.
  • the orthosteric inhibitor is serabelisib or a pharmaceutically acceptable salt thereof.
  • a therapeutically effective amount of the first PI3K ⁇ selective inhibitor is administered to the patient in need thereof, and the first PI3K ⁇ selective inhibitor functions as an allosteric inhibitor.
  • the therapeutically effective amount of the allosteric inhibitor administered to the patient is a 100-1200 mg oral dose BID (i.e., administered two times daily). In some aspects, the therapeutically effective amount of the allosteric inhibitor administered to the patient is 9-75 mg/kg oral dose BID (e.g., 37.5 mg/kg or less than about 37 mg/kg). [167] In some aspects of the disclosed methods, a therapeutically effective amount of the second PI3K ⁇ selective inhibitor administered to the patient in need thereof, and the PI3K ⁇ selective inhibitor functions as an orthosteric inhibitor.
  • the therapeutically effective amount of the orthosteric inhibitor administered to the patient is a 300 mg oral dose QD (i.e., administered once a day) or less than about a 300 mg oral dose QD.
  • a synergistic effect may be observed after administering a therapeutically effective amount of the allosteric inhibitor and a therapeutically effective amount of the orthosteric inhibitor.
  • the therapeutically effective amount of the allosteric inhibitor administered to the patient may be less than a therapeutically effective amount of the allosteric inhibitor that is required in a treatment method where the orthosteric inhibitor is not administered.
  • the therapeutically effective amount of the orthosteric inhibitor that is administered to the patient may be less than a therapeutically effective amount of the orthosteric inhibitor that is required in a treatment method where the allosteric inhibitor is not administered.
  • the therapeutically effective amount of the allosteric inhibitor is effective for reducing PI3K ⁇ activity in the patient without inducing adverse events, or while minimizing the risk of adverse events.
  • the therapeutically effective amount of the orthosteric inhibitor is effective for reducing PI3K ⁇ activity in the patient without inducing adverse events, or while minimizing the risk of adverse events.
  • the allosteric inhibitor and the orthosteric inhibitor are administered simultaneously, separately, or sequentially. In some aspects of the disclosed methods, the allosteric inhibitor and the orthosteric inhibitor are administered simultaneously or substantially simultaneously. In some aspects of the disclosed methods, the dose of the orthosteric inhibitor which is administered to the patient is less than about 50, 30, 12.5, 6.25, or 3.125 mg/kg oral dose QD, optionally where the orthosteric inhibitor is alpelisib.
  • the first PI3K ⁇ selective inhibitor and the second PI3K ⁇ selective inhibitor may be administered sequentially. In some aspects, the methods comprise administering the second PI3K ⁇ selective inhibitor after the disease or disorder has developed resistance to the first PI3K ⁇ selective inhibitor.
  • the second PI3K ⁇ selective inhibitor is administered initially after the disease or disorder has developed resistance to the first PI3K ⁇ selective inhibitor. In some aspects, the second PI3K ⁇ selective inhibitor is not administered until after the disease or disorder has developed resistance to the first PI3K ⁇ selective inhibitor. In some aspects, resistance is characterized by occurrence of a M1043 mutation (e.g., M1043I or M1043L) and/or a C901 mutation (e.g., C901F).
  • M1043 mutation e.g., M1043I or M1043L
  • C901 mutation e.g., C901F
  • a patient exhibiting resistance may have a disease or disorder comprising the M1043I/L mutation and/or the C901F mutation together with the H1047R mutation (optionally wherein the M1043I/L mutation and the C901F mutation are in cis on the same allele with the H1047R mutation).
  • the disclosed methods relate to methods for treating a disease or disorder associated with modulation of PI3K ⁇ in a patient in need thereof.
  • the methods may comprise administering to the patient: (i) a therapeutically effective amount of a first PI3K ⁇ selective inhibitor, wherein the first PI3K ⁇ selective inhibitor binds to the PI3K ⁇ allosteric pocket 1 and optionally may form an interaction with one or more amino acids selected from C901, T908, F909, H931, F954, Q981, Y985, Y1021, and R1047; and (ii) a therapeutically effective amount of a second PI3K ⁇ selective inhibitor, wherein the second PI3K ⁇ selective inhibitor binds to a different allosteric pocket of PI3K ⁇ , such as the PI3K ⁇ allosteric pocket 2, and the second PI3K ⁇ selective inhibitor optionally may form an interaction with one or more amino acids selected from L911, F937, F1002, E1012, and D1018.
  • the disclosed methods may comprise administering a PI3K ⁇ selective allosteric inhibitor (i.e., a first allosteric inhibitor) and a different PI3K ⁇ selective allosteric inhibitor (i.e., a second allosteric inhibitor), where the first allosteric inhibitor and the second allosteric inhibitor bind to different allosteric pockets (e.g., the PI3K ⁇ allosteric pocket 1 and the PI3K ⁇ allosteric pocket 2, respectively), and the first allosteric inhibitor and the second allosteric inhibitor are administered simultaneously, separately, or sequentially.
  • a PI3K ⁇ selective allosteric inhibitor i.e., a first allosteric inhibitor
  • a different PI3K ⁇ selective allosteric inhibitor i.e., a second allosteric inhibitor
  • the first PI3K ⁇ selective inhibitor may be an allosteric inhibitor of a Formula I: or pharmaceutically acceptable salt thereof, wherein: R is -H or C 1 -C 3 alkyl; R 1 is a group of the formula: R 2 is a group of the formula: R3 is -H, halogen, -CN, -N(H)(C 1 -C 3 alkyl), -N(C 1 -C 3 alkyl) 2 , -N(H)(CH 2 CH 2 CO 2 H), -C(O)C 1 -C 3 alkyl, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 3 -C 5 cycloalkyl, an optionally substituted heterocycle of 3 to 5 ring atoms containing 1, 2, or 3 ring heteroatoms independently selected from N, O, or S, or an optionally substituted heteroaryl of 5 or 6
  • the first PI3K ⁇ selective inhibitor is an allosteric inhibitor of a formula: or a pharmaceutically acceptable salt thereof.
  • the second PI3K ⁇ selective inhibitor is an allosteric inhibitor disclosed in WO2021/222556, WO2022/265993, WO2023/018636, WO2023/039532, WO2023/288242, WO2023/081757, or WO2023/081759, the contents of which are incorporated herein by reference in their entireties with respect to the PI3K ⁇ inhibitor compounds and methods of making and using the PI3K ⁇ inhibitor compounds disclosed therein.
  • the second PI3K ⁇ selective inhibitor is an allosteric inhibitor of a Formula IV: or a pharmaceutically acceptable salt thereof, wherein: E is -C(O)-, -C(R E ) 2 -, -C(R E ) 2 C(R E ) 2 -, -C(S)-, -S(O) 2 -, -OC(O)-, -N(R E )C(O)-, -C(O)N(R E )-, or - C(R E ) 2 C(O)-; Q is CH, C(R Q ), or N; X is CH, C(R X ), or N; Y is CH, C(R Y ), or N; Z is CH, C(R Z ), or N; R 1 is -L 1 -R 1A ; R 2 is -L 2 -R 2A ; each instance of R E is independently H or -L E -
  • the second PI3K ⁇ selective inhibitor is an allosteric inhibitor of a Formula: [183] [184] or a pharmaceutically acceptable salt thereof.
  • the second PI3K ⁇ selective inhibitor is of a formula in which [186] R 1 is [187]
  • the second PI3K ⁇ selective inhibitor is of a formula in which each instance of R 1C is independently halogen, -CN, -O-(C 1-6 aliphatic), or C 1-6 aliphatic; wherein each C 1-6 aliphatic is optionally substituted with one or more halogen atoms.
  • the second PI3K ⁇ selective inhibitor is of a formula in which each instance of R 1C is independently halogen or C 1-3 aliphatic optionally substituted with 1-3 halogen.
  • the second PI3K ⁇ selective inhibitor is of a formula in which R 2 is - N(H)C(O)-R 2A , -N(H)C(O)N(H)-R 2A , -C(O)N(H)-R 2A , -N(H)-R 2A , -S(O) 2 CH 2 -R 2A , -CH 2 S(O) 2 -R 2A , or -C(H)(CH 3 )OH.
  • the second PI3K ⁇ selective inhibitor is of a formula in which R 2A is phenyl optionally substituted at one or more positions C 1-3 aliphatic (e.g., methyl), haloalkyl (e.g., trifluoromethyl or difluoromethyl), or halogen.
  • the second PI3K ⁇ selective inhibitor is of a formula in which each instance of R 2C is independently halogen, -CN, -O-(C 1-6 aliphatic), or C 1-6 aliphatic; wherein each C 1-6 aliphatic is optionally substituted with one or more halogen atoms.
  • the second PI3K ⁇ selective inhibitor is of a formula in which each instance of R 2C is independently halogen or C 1-3 aliphatic optionally substituted with 1-3 halogen.
  • the second PI3K ⁇ selective inhibitor is of a formula in which R YA is a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is substituted by r 6 instances of R YC .
  • the second PI3K ⁇ selective inhibitor is of a formula in which R YA is [195] In some aspects, the second PI3K ⁇ selective inhibitor is of a formula in which each instance of R YC is independently oxo, halogen, -CN, -OH, -O-(C 1-3 aliphatic), or C 1-3 aliphatic, wherein each C1- 3 aliphatic is optionally substituted with one or more halogen atoms. [196] In some aspects of the disclosed methods, the second PI3K ⁇ selective inhibitor has a formula selected from:
  • the second PI3K ⁇ selective inhibitor is disclosed in WO2022/265993 and has a formula selected from: or a pharmaceutically acceptable salt thereof.
  • a therapeutically effective amount of the first PI3K ⁇ selective inhibitor is administered to the patient in need thereof, and the first PI3K ⁇ selective inhibitor functions as an allosteric inhibitor (i.e., the first allosteric inhibitor).
  • the therapeutically effective amount of the first allosteric inhibitor administered to the patient is a 100-1200 mg oral dose BID (i.e., administered two times daily).
  • the therapeutically effective amount of the first allosteric inhibitor administered to the patient is 9-75 mg/kg oral dose BID (e.g., 37.5 mg/kg).
  • a synergistic effect may be observed.
  • the therapeutically effective amount of the first allosteric inhibitor administered to the patient may be less than a therapeutically effective amount of the first allosteric inhibitor that is required in a method where the second allosteric inhibitor is not administered.
  • the therapeutically effective amount of the second allosteric inhibitor that is administered to the patient may be less than a therapeutically effective amount of the second allosteric inhibitor that is required in a method where the first allosteric inhibitor is not administered.
  • the therapeutically effective amount of the first allosteric inhibitor is effective for reducing PI3K ⁇ activity in the patient without inducing adverse events, or while minimizing the risk of adverse events.
  • the therapeutically effective amount of the second allosteric inhibitor is effective for reducing PI3K ⁇ activity in the patient without inducing adverse events, or while minimizing the risk of adverse events.
  • the first allosteric inhibitor and the second allosteric inhibitor may be administered sequentially.
  • the methods comprise administering the second allosteric inhibitor after the disease or disorder has developed resistance to the first allosteric inhibitor.
  • the second allosteric inhibitor is administered initially after the disease or disorder has developed resistance to the first allosteric inhibitor.
  • the second allosteric inhibitor is not administered until after the disease or disorder has developed resistance to the first allosteric inhibitor.
  • resistance is characterized by occurrence of a M1043 mutation (e.g., M1043I or M1043L) and/or a C901 mutation (e.g., C901F).
  • a patient has a disease or disorder comprising a M1043I/L mutation and/or a C901F mutation together with a H1047R mutation (optionally wherein the M1043I/L mutation and the C901F mutation are in cis on the same allele with the H1047R mutation).
  • the disclosed methods may relate to methods for treating a disease or disorder associated with modulation of phosphatidylinositol 3-kinase alpha (PI3K ⁇ ) in a patient in need thereof.
  • PI3K ⁇ phosphatidylinositol 3-kinase alpha
  • the methods may comprise administering to the patient: (i) a therapeutically effective amount of a first PI3K ⁇ selective inhibitor, wherein the first PI3K ⁇ selective inhibitor binds the PI3K ⁇ allosteric pocket 1 and may form an interaction with one or more amino acids selected from C901, T908, F909, H931, F954, Q981, Y985, Y1021, and R1047 and (ii) a therapeutically effective amount of a second PI3K ⁇ selective inhibitor, wherein the second PI3K ⁇ selective inhibitor binds to the PI3K ⁇ allosteric pocket 1 and may form an interaction with one or more amino acids selected from C901, T908, F909, H931, F954, Q981, Y985, Y1021, and R1047.
  • the disclosed methods may comprise administering a PI3K ⁇ selective allosteric inhibitor (e.g., the first allosteric inhibitor) and a different PI3K ⁇ selective allosteric inhibitor (e.g., the second allosteric inhibitor), where the PI3K ⁇ selective allosteric inhibitors bind to the PI3K ⁇ allosteric pocket 1.
  • a PI3K ⁇ selective allosteric inhibitor e.g., the first allosteric inhibitor
  • a different PI3K ⁇ selective allosteric inhibitor e.g., the second allosteric inhibitor
  • the first PI3K ⁇ selective inhibitor is an allosteric inhibitor of a Formula I: or pharmaceutically acceptable salt thereof, wherein: R is -H or C 1 -C 3 alkyl; R 1 is a group of the formula: R 2 is a group of the formula: R3 is -H, halogen, -CN, -N(H)(C 1 -C 3 alkyl), -N(C 1 -C 3 alkyl) 2 , -N(H)(CH 2 CH 2 CO 2 H), -C(O)C 1 -C 3 alkyl, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 3 -C 5 cycloalkyl, an optionally substituted heterocycle of 3 to 5 ring atoms containing 1, 2, or 3 ring heteroatoms independently selected from N, O, or S, or an optionally substituted heteroaryl of 5
  • the second PI3K ⁇ selective inhibitor is an allosteric inhibitor of a Formula I: or pharmaceutically acceptable salt thereof, wherein: R is -H or C 1 -C 3 alkyl; R 1 is a group of the formula:
  • R 2 is a group of the formula: ;
  • R3 is -H, halogen, -CN, -N(H)(C 1 -C 3 alkyl), -N(C 1 -C 3 alkyl) 2 , -N(H)(CH 2 CH 2 CO 2 H), -C(O)C 1 -C 3 alkyl, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 3 -C 5 cycloalkyl, an optionally substituted heterocycle of 3 to 5 ring atoms containing 1, 2, or 3 ring heteroatoms independently selected from N, O, or S, or an optionally substituted heteroaryl of 5 or 6 ring atoms containing 1, 2, or 3 ring heteroatoms independently selected from N, O, or S; wherein the optionally substituted heterocycle or heteroaryl is each optionally substituted with one to three substituents each independently selected from halogen, C 1
  • the first allosteric inhibitor of Formula I and the second allosteric inhibitor of Formula I are different.
  • the first allosteric inhibitor is of a Formula: or a pharmaceutically acceptable salt thereof.
  • the second PI3K ⁇ selective inhibitor is not of a formula:
  • the second PI3K ⁇ selective inhibitor is an allosteric inhibitor of a formula: or a pharmaceutically acceptable salt thereof.
  • the second allosteric inhibitor is of a formula selected from:
  • a therapeutically effective amount of the first PI3K ⁇ selective inhibitor is administered to the patient in need thereof, and the first PI3K ⁇ selective inhibitor functions as an allosteric inhibitor.
  • the therapeutically effective amount of the first allosteric inhibitor administered to the patient is a 100-1200 mg oral dose BID (i.e., administered two times daily).
  • the therapeutically effective amount of the first allosteric inhibitor administered to the patient is 9-75 mg/kg oral dose BID (e.g., 37.5 mg/kg).
  • a first allosteric inhibitor and a second allosteric inhibitor may be administered sequentially.
  • the methods comprise administering the second allosteric inhibitor after the disease or disorder has developed resistance to the first allosteric inhibitor.
  • the second allosteric inhibitor is administered initially after the disease or disorder has developed resistance to the first allosteric inhibitor.
  • the second allosteric inhibitor is not administered until after the disease or disorder has developed resistance to the first allosteric inhibitor.
  • resistance is characterized by occurrence of a M1043 mutation (e.g., M1043I or M1043L) and/or a C901 mutation (e.g., C901F).
  • a patient may have a disease or disorder comprising a M1043I/L mutation and/or a C901F mutation together with a H1047R mutation (optionally wherein the M1043I/L mutation the C901F mutation are in cis on the same allele with the H1047R mutation).
  • I.D(i) Use of Allosteric Inhibitors for Treating Diseases or Disorders that are Resistant to Treatment with Orthosteric Inhibitors
  • the disclosed methods relate to methods for treating a disease or disorder associated with modulation of PI3K ⁇ that is resistant to treatment with a PI3K ⁇ selective orthosteric inhibitor.
  • the methods may comprise administering to a patient having the disease or disorder a therapeutically effective amount of a PI3K ⁇ selective allosteric inhibitor, wherein the PI3K ⁇ selective allosteric inhibitor binds to the PI3K ⁇ allosteric pocket 1 and optionally may form an interaction with one or more amino acids selected from C901, T908, F909, H931, F954, Q981, Y985, Y1021, and R1047.
  • the patient has a disease or disorder which has developed resistance to treatment with the orthosteric inhibitor after the patient previously was treated with the orthosteric inhibitor.
  • the patient has a disease or disorder exhibiting de novo resistance to treatment with the orthosteric inhibitor, where the patient was not treated previously with the orthosteric inhibitor.
  • the disease or disorder is resistant to treatment with alpelisib or a pharmaceutically acceptable salt thereof.
  • the disease or disorder is resistant to treatment with inavolisib or a pharmaceutically acceptable salt thereof.
  • the disease or disorder is resistant to treatment with serabelisib or a pharmaceutically acceptable salt thereof.
  • the allosteric inhibitor is of a Formula I: or pharmaceutically acceptable salt thereof, wherein: R is -H or C 1 -C 3 alkyl; R1 is a group of the formula: R 2 is a group of the formula: ; R3 is -H, halogen, -CN, -N(H)(C 1 -C 3 alkyl), -N(C 1 -C 3 alkyl) 2 , -N(H)(CH 2 CH 2 CO 2 H), -C(O)C 1 -C 3 alkyl, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 3 -C 5 cycloalkyl, an optionally substituted heterocycle of 3 to 5 ring atoms containing 1, 2, or 3 ring heteroatoms independently selected from N, O, or S, or an optionally substituted heteroaryl of 5 or 6 ring atom
  • the allosteric inhibitor is of a formula selected from: or a pharmaceutically acceptable salt thereof.
  • the disclosed methods may include administered a therapeutically effective amount of a PI3K ⁇ selective allosteric inhibitor to a patient having a disease or disorder that is resistant to treatment with an orthosteric inhibitor.
  • the disclosed methods further comprise administering to the patient a therapeutically effective amount of a selective estrogen receptor degrader (SERD).
  • SESD selective estrogen receptor degrader
  • the disclosed methods relate to methods for treating a disease or disorder associated with modulation of PI3K ⁇ that is resistant to treatment with a PI3K ⁇ selective orthosteric inhibitor.
  • the methods may comprise administering to a patient having the disease or disorder a therapeutically effective amount of a PI3K ⁇ selective allosteric inhibitor that binds to the PI3K ⁇ allosteric pocket 2 and optionally may form one or more interactions with one or more amino acids selected from L911, F937, F1002, E1012, and D1018.
  • the patient has developed a disease or disorder that is resistant to treatment with the orthosteric inhibitor after the patient previously was treated with the orthosteric inhibitor. In some aspects of the disclosed methods, the patient has a disease or disorder exhibiting de novo resistance to treatment with the orthosteric inhibitor, where the patient was not treated previously with the orthosteric inhibitor. [225] In some aspects of the disclosed methods, the disease or disorder is resistant to treatment with alpelisib or a pharmaceutically acceptable salt thereof. In some aspects of the disclosed methods, the disease or disorder is resistant to treatment with inavolisib or a pharmaceutically acceptable salt thereof. In some aspects of the disclosed methods, the disease or disorder is resistant to treatment with serabelisib or a pharmaceutically acceptable salt thereof.
  • the PI3K ⁇ selective allosteric inhibitor is an allosteric inhibitor disclosed in WO2021/222556, WO2022/265993, WO2023/018636, WO2023/039532, WO2023/288242, WO2023/081757, or WO2023/081759, the contents of which are incorporated herein by reference in their entireties with respect to the PI3K ⁇ inhibitor compounds and methods of making and using the PI3K ⁇ inhibitor compounds disclosed therein.
  • the allosteric inhibitor is of a Formula IV:
  • E is -C(O)-, -C(R E ) 2 -, -C(R E ) 2 C(R E ) 2 -, -C(S)-, -S(O) 2 -, -OC(O)-, -N(R E )C(O)-, -C(O)N(R E )-, or - C(R E ) 2 C(O)-;
  • Q is CH, C(R Q ), or N;
  • X is CH, C(R X ), or N;
  • Y is CH, C(R Y ), or N;
  • Z is CH, C(R Z ), or N;
  • R 1 is -L 1 -R 1A ;
  • R Q is -L Q -R QA ;
  • R X is -L
  • the allosteric inhibitor is of a Formula: or a pharmaceutically acceptable salt thereof.
  • the allosteric inhibitor is of a Formula in which R 1 is [244]
  • the allosteric inhibitor is of a Formula in which each instance of R 1C is independently halogen, -CN, -O-(C 1-6 aliphatic), orC 1-6 aliphatic; wherein each C 1-6 aliphatic is optionally substituted with one or more halogen atoms.
  • the allosteric inhibitor is of a Formula in which each instance of R 1C is independently halogen or C 1-3 aliphatic optionally substituted with 1-3 halogen.
  • the allosteric inhibitor is of a Formula in which R 2 is -N(H)C(O)-R 2A , - N(H)C(O)N(H)-R 2A , -C(O)N(H)-R 2A , -N(H)-R 2A , -S(O) 2 CH 2 -R 2A , -CH 2 S(O) 2 -R 2A , or - C(H)(CH 3 )OH.
  • the allosteric inhibitor is of a Formula in which R 2A is phenyl optionally substituted at one or more positions C 1-3 aliphatic (e.g., methyl), haloalkyl (e.g., trifluoromethyl or difluoromethyl), or halogen.
  • the allosteric inhibitor is of a Formula in which each instance of R 2C is independently halogen, -CN, -O-(C 1-6 aliphatic), or C 1-6 aliphatic; wherein each C 1-6 aliphatic is optionally substituted with one or more halogen atoms.
  • the allosteric inhibitor is of a Formula in which each instance of R 2C is independently halogen or C 1-3 aliphatic optionally substituted with 1-3 halogen.
  • the second PI3K ⁇ selective inhibitor is of a formula in which R YA is a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is substituted by r 6 instances of R YC .
  • the allosteric inhibitor is of a Formula in which R YA is [251]
  • the second PI3K ⁇ selective inhibitor is of a formula in which each instance of R YC is independently oxo, halogen, -CN, -OH, -O-(C 1-3 aliphatic), or C 1-3 aliphatic, wherein each C1- 3 aliphatic is optionally substituted with one or more halogen atoms.
  • the allosteric inhibitor has a formula selected from: [253]
  • the second PI3K ⁇ selective inhibitor has a formula selected from:
  • the second PI3K ⁇ selective inhibitor is disclosed in WO2022/265993 and has a formula selected from: or a pharmaceutically acceptable salt thereof.
  • the disclosed methods may include administered a therapeutically effective amount of a PI3K ⁇ selective allosteric inhibitor to a patient having a disease or disorder that is resistant to treatment with an orthosteric inhibitor.
  • the disclosed methods further comprise administering to the patient a therapeutically effective amount of a selective estrogen receptor degrader (SERD).
  • SESD selective estrogen receptor degrader
  • the disclosed methods relate to methods for treating a disease or disorder associated with modulation of PI3K ⁇ that is resistant to treatment with a first PI3K ⁇ selective allosteric inhibitor, wherein the first PI3K ⁇ selective allosteric inhibitor binds to the PI3K ⁇ allosteric pocket 1 and optionally may form an interaction with one or more amino acids selected from C901, T908, F909, H931, F954, Q981, Y985, Y1021, and R1047.
  • the methods may comprise administering to a patient having the disease or disorder a therapeutically effective amount of a second different PI3K ⁇ selective allosteric inhibitor that binds to the PI3K ⁇ allosteric pocket 1 and optionally form an interaction with one or more amino acids selected from C901, T908, F909, H931, F954, Q981, Y985, Y1021, and R1047.
  • the patient has a disease or disorder which has developed resistance to treatment with the first allosteric inhibitor after the patient previously was treated with the first allosteric inhibitor.
  • the patient has a disease or disorder exhibiting de novo resistance to treatment with the first allosteric inhibitor, where the patient was not treated previously with the first allosteric inhibitor.
  • the patient is resistant to treatment with a first allosteric inhibitor of a Formula I: or pharmaceutically acceptable salt thereof, wherein: R is -H or C 1 -C 3 alkyl; R 1 is a group of the formula: R 3 is -H, halogen, -CN, -N(H)(C 1 -C 3 alkyl), -N(C 1 -C 3 alkyl) 2 , -N(H)(CH 2 CH 2 CO 2 H), -C(O)C 1 -C 3 alkyl, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 3 -C 5 cycloalkyl, an optionally substituted heterocycle of 3
  • the disease or disorder is resistant to treatment with an allosteric inhibitor of a formula: or a pharmaceutically acceptable salt thereof.
  • the patient that is resistant to treatment with the first allosteric inhibitor is administered a therapeutically effective amount of a second allosteric inhibitor of a Formula I:
  • R is -H or C 1 -C 3 alkyl
  • R1 is a group of the formula:
  • R 2 is a group of the formula:
  • R3 is -H, halogen, -CN, -N(H)(C 1 -C 3 alkyl), -N(C 1 -C 3 alkyl) 2 , -N(H)(CH 2 CH 2 CO 2 H), -C(O)C 1 -C 3 alkyl, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 3 -C 5 cycloalkyl, an optionally substituted heterocycle of 3 to 5 ring atoms containing 1, 2, or 3 ring heteroatoms independently selected from N, O, or S, or an optionally substituted heteroaryl of 5 or 6 ring atoms containing 1, 2, or 3 ring heteroatoms independently selected from N, O, or S; wherein the optionally substituted heterocycle
  • the allosteric inhibitor administered to the patient is of a formula selected from: or a pharmaceutically acceptable salt thereof.
  • the disclosed methods may include administered a therapeutically effective amount of a PI3K ⁇ selective allosteric inhibitor to a patient having a disease or disorder that is resistant to treatment with a different PI3K ⁇ selective allosteric inhibitor.
  • the disclosed methods further comprise administering to the patient a therapeutically effective amount of a selective estrogen receptor degrader (SERD).
  • SESD selective estrogen receptor degrader
  • the disclosed methods relate to methods for treating a disease or disorder associated with modulation of PI3K ⁇ that is resistant to treatment with a first PI3K ⁇ selective allosteric inhibitor, wherein the first PI3K ⁇ selective allosteric inhibitor binds the PI3K ⁇ allosteric pocket 1 and optionally may form an interaction with one or more amino acids selected from C901, T908, F909, H931, F954, Q981, Y985, Y1021, and R1047.
  • the methods may comprise administering to a patient having the disease or disorder a therapeutically effective amount of a second different PI3K ⁇ selective allosteric inhibitor that binds to the PI3K ⁇ allosteric pocket 2 and optionally may form an interaction with one or more amino acids selected from L911, F937, F1002, E1012, and D1018.
  • the patient has a disease or disorder which has developed resistance to treatment with the first allosteric inhibitor after the patient previously was treated with the first allosteric inhibitor.
  • the patient has a disease or disorder exhibiting de novo resistance to treatment with the first allosteric inhibitor, where the patient was not treated previously with the first allosteric inhibitor.
  • the patient is resistant to treatment with a first allosteric inhibitor of a Formula I: or pharmaceutically acceptable salt thereof, wherein: R is -H or C 1 -C 3 alkyl; R1 is a group of the formula:
  • R3 is -H, halogen, -CN, -N(H)(C 1 -C 3 alkyl), -N(C 1 -C 3 alkyl) 2 , -N(H)(CH 2 CH 2 CO 2 H), -C(O)C 1 -C 3 alkyl, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 3 -C 5 cycloalkyl, an optionally substituted heterocycle of 3 to 5 ring atoms containing 1, 2, or 3 ring heteroatoms independently selected from N, O, or S, or an optionally substituted heteroaryl of 5 or 6 ring atoms containing 1, 2, or 3 ring heteroatoms independently selected from N, O, or S; wherein the optionally substituted heterocycle or heteroaryl is each optionally substituted with one to three substituents each independently selected from halogen, C 1 -C 3 alkyl, or C 1 -C
  • the disease or disorder is resistant to treatment with an allosteric inhibitor of a formula: or a pharmaceutically acceptable salt thereof.
  • the patient that is resistant to treatment with the first allosteric inhibitor is administered a therapeutically effective amount of a second allosteric inhibitor as disclosed in WO2021/222556, WO2022/265993, WO2023/018636, WO2023/039532, WO2023/288242, WO2023/081757, or WO2023/081759, the contents of which are incorporated herein by reference in their entireties with respect to the PI3K ⁇ inhibitor compounds and methods of making and using the PI3K ⁇ inhibitor compounds disclosed therein.
  • the second allosteric inhibitor is of a Formula IV: or a pharmaceutically acceptable salt thereof, wherein: E is -C(O)-, -C(R E ) 2 -, -C(R E ) 2 C(R E ) 2 -, -C(S)-, -S(O) 2 -, -OC(O)-, -N(R E )C(O)-, -C(O)N(R E )-, or - C(R E ) 2 C(O)-; Q is CH, C(R Q ), or N; X is CH, C(R X ), or N; Y is CH, C(R Y ), or N; Z is CH, C(R Z ), or N; R 1 is -L 1 -R 1A ; R 2 is -L 2 -R 2A ; each instance of R E is independently H or -L E -R EA ; R Q is -L
  • the allosteric inhibitor is of a Formula: or a pharmaceutically acceptable salt thereof.
  • the allosteric inhibitor is of a formula in which R 1 is [288] In some aspects, the allosteric inhibitor is of a formula in which each instance of R 1C is independently halogen, -CN, -O-(C 1-6 aliphatic), or C 1-6 aliphatic; wherein each C 1-6 aliphatic is optionally substituted with one or more halogen atoms.
  • the allosteric inhibitor is of a formula in which each instance of R 1C is independently halogen or C 1-3 aliphatic optionally substituted with 1-3 halogen.
  • the allosteric inhibitor is of a formula in which R 2 is -N(H)C(O)-R 2A , - N(H)C(O)N(H)-R 2A , -C(O)N(H)-R 2A , -N(H)-R 2A , -S(O) 2 CH 2 -R 2A , -CH 2 S(O) 2 -R 2A , or - C(H)(CH 3 )OH.
  • the allosteric inhibitor is of a formula in which R 2A is phenyl optionally substituted at one or more positions C 1-3 aliphatic (e.g., methyl), haloalkyl (e.g., trifluoromethyl or difluoromethyl), or halogen.
  • the allosteric inhibitor is of a formula in which each instance of R 2C is independently halogen, -CN, -O-(C 1-6 aliphatic), or C 1-6 aliphatic; wherein each C 1-6 aliphatic is optionally substituted with one or more halogen atoms.
  • the allosteric inhibitor is of a formula in which each instance of R 2C is independently halogen or C 1-3 aliphatic optionally substituted with 1-3 halogen.
  • the second PI3K ⁇ selective inhibitor is of a formula in which R YA is a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is substituted by r 6 instances of R YC .
  • the allosteric inhibitor is of a formula in which R YA is [296]
  • the second PI3K ⁇ selective inhibitor is of a formula in which each instance of R YC is independently oxo, halogen, -CN, -OH, -O-(C 1-3 aliphatic), or C 1-3 aliphatic, wherein each C1- 3 aliphatic is optionally substituted with one or more halogen atoms.
  • the allosteric inhibitor administered to the patient has a formula selected from:
  • the second PI3K ⁇ selective inhibitor is disclosed in WO2022/265993 and has a formula selected from: or a pharmaceutically acceptable salt thereof.
  • the disclosed methods may include administered a therapeutically effective amount of a PI3K ⁇ selective allosteric inhibitor to a patient having a disease or disorder that is resistant to treatment with another PI3K ⁇ selective allosteric inhibitor.
  • the disclosed methods further comprise administering to the patient a therapeutically effective amount of a selective estrogen receptor degrader (SERD).
  • SESD selective estrogen receptor degrader
  • the disclosed methods relate to treating a disease or disorder associated with modulation of PI3K ⁇ in a patient in need thereof, wherein the patient has cancer comprising a M1043 mutation (e.g., M1043I/L optionally in cis with an H1047R mutation) and/or a C901 mutation (e.g., C901F optionally in cis with an H1047R mutation), optionally after the patient was treated previously with a therapeutically effective amount a PI3K ⁇ selective allosteric inhibitor.
  • a M1043 mutation e.g., M1043I/L optionally in cis with an H1047R mutation
  • C901 mutation e.g., C901F optionally in cis with an H1047R mutation
  • the PI3K ⁇ selective allosteric inhibitor may bind to the PI3K ⁇ allosteric pocket 1 and optionally may form an interaction with one or more amino acids selected from C901, T908, F909, H931, F954, Q981, Y985, Y1021, and R1047.
  • the patient may have a cancer exhibiting acquired resistance to treatment with the PI3K ⁇ selective allosteric inhibitor or the patient may have a cancer exhibiting de novo resistance to treatment with the PI3K ⁇ selective allosteric inhibitor; and in the disclosed methods, the patient may be administered a therapeutically effective amount of a PI3K ⁇ selective orthosteric inhibitor.
  • the patient was previously treated with a PI3K ⁇ selective allosteric inhibitor of a Formula I: or pharmaceutically acceptable salt thereof, wherein: R is -H or C 1 -C 3 alkyl; R1 is a group of the formula:
  • R3 is -H, halogen, -CN, -N(H)(C 1 -C 3 alkyl), -N(C 1 -C 3 alkyl) 2 , -N(H)(CH 2 CH 2 CO 2 H), -C(O)C 1 -C 3 alkyl, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 3 -C 5 cycloalkyl, an optionally substituted heterocycle of 3 to 5 ring atoms containing 1, 2, or 3 ring heteroatoms independently selected from N, O, or S, or an optionally substituted heteroaryl of 5 or 6 ring atoms containing 1, 2, or 3 ring heteroatoms independently selected from N, O, or S; wherein the optionally substituted heterocycle or heteroaryl is each optionally substituted with one to three substituents each independently selected from halogen, C 1 -C 3 alkyl, or C 1 -C
  • the patient was treated previously with a therapeutically effective amount of a PI3K ⁇ selective allosteric inhibitor of a formula: or a pharmaceutically acceptable salt thereof.
  • the therapeutically effective amount of the PI3K ⁇ selective allosteric inhibitor that was administered to the patient was a 100-1200 mg oral dose administered two times daily.
  • the therapeutically effective amount of the first PI3K ⁇ selective inhibitor that was administered to the patient was a 9-75 mg/kg oral dose administered two times daily (e.g., 37.5 mg/kg oral dose administered two times daily).
  • the patient may have acquired resistance to treatment with the PI3K ⁇ selective allosteric inhibitor which was administered at the indicated dose.
  • a therapeutically effective amount of the PI3K ⁇ selective orthosteric inhibitor is administered to the patient in need thereof.
  • the therapeutically effective amount of the PI3K ⁇ selective orthosteric inhibitor administered to the patient is a 300 mg oral dose QD (i.e., administered once a day) or less than about a 300 mg oral dose QD, such as less than about 250, 200, 150, 100, or 50 mg oral dose QD.
  • the disclosed methods comprise administering a patient a therapeutically effective amount of a PI3K ⁇ selective orthosteric inhibitor and the disclosed methods further comprise administering to the patient a therapeutically effective amount of a selective estrogen receptor degrader (SERD).
  • SESD selective estrogen receptor degrader
  • the administered PI3K ⁇ selective orthosteric inhibitor is selected from alpelisib, inavolisib, serabelisib, or pharmaceutically acceptable salts thereof.
  • the disclosed methods relate to method for treating a disease or disorder associated with modulation of PI3K ⁇ in a patient in need thereof, wherein the patient has a cancer comprising an M1043 mutation (e.g., M1043I/L optionally in cis) with an H1047R mutation and/or a C901 mutation (e.g., C901F optionally in cis) with an H1047R mutation.
  • M1043 mutation e.g., M1043I/L optionally in cis
  • C901 mutation e.g., C901F optionally in cis
  • the methods comprise administering to the patient a therapeutically effective amount of a PI3K ⁇ selective allosteric inhibitor that binds to the PI3K ⁇ allosteric pocket 2 and optionally may form an interaction with one or more amino acids selected from L911, F937, F1002, E1012, and D1018.
  • a PI3K ⁇ selective allosteric inhibitor that is administered to the patient is of a Formula IV:
  • E is -C(O)-, -C(R E ) 2 -, -C(R E ) 2 C(R E ) 2 -, -C(S)-, -S(O) 2 -, -OC(O)-, -N(R E )C(O)-, -C(O)N(R E )-, or - C(R E ) 2 C(O)-;
  • Q is CH, C(R Q ), or N;
  • X is CH, C(R X ), or N;
  • Y is CH, C(R Y ), or N;
  • Z is CH, C(R Z ), or N;
  • R 1 is -L 1 -R 1A ;
  • R Q is -L Q -R QA ;
  • R X is -L
  • the allosteric inhibitor is of a Formula: or a pharmaceutically acceptable salt thereof.
  • the allosteric inhibitor is of a formula in which R 1 is [313] In some aspects, the allosteric inhibitor is of a formula in which each instance of R 1C is independently halogen, -CN, -O-(C 1-6 aliphatic), or C 1-6 aliphatic; wherein each C 1-6 aliphatic is optionally substituted with one or more halogen atoms.
  • the allosteric inhibitor is of a formula in which each instance of R 1C is independently halogen or C 1-3 aliphatic optionally substituted with 1-3 halogen.
  • the allosteric inhibitor is of a formula in which R 2 is -N(H)C(O)-R 2A , - N(H)C(O)N(H)-R 2A , -C(O)N(H)-R 2A , -N(H)-R 2A , -S(O) 2 CH 2 -R 2A , -CH 2 S(O) 2 -R 2A , or - C(H)(CH 3 )OH.
  • the allosteric inhibitor is of a formula in which R 2A is phenyl optionally substituted at one or more positions C 1-3 aliphatic (e.g., methyl), haloalkyl (e.g., trifluoromethyl or difluoromethyl), or halogen.
  • the allosteric inhibitor is of a formula in which each instance of R 2C is independently halogen, -CN, -O-(C 1-6 aliphatic), or C 1-6 aliphatic; wherein each C 1-6 aliphatic is optionally substituted with one or more halogen atoms.
  • the allosteric inhibitor is of a formula in which each instance of R 2C is independently halogen or C 1-3 aliphatic optionally substituted with 1-3 halogen.
  • the second PI3K ⁇ selective inhibitor is of a formula in which R YA is a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is substituted by r 6 instances of R YC .
  • the allosteric inhibitor is of a formula in which R YA is [321]
  • the second PI3K ⁇ selective inhibitor is of a formula in which each instance of R YC is independently oxo, halogen, -CN, -OH, -O-(C 1-3 aliphatic), or C 1-3 aliphatic, wherein each C1- 3 aliphatic is optionally substituted with one or more halogen atoms.
  • the PI3K ⁇ selective allosteric inhibitor that is administered to the patient is of a formula selected from:
  • the second PI3K ⁇ selective inhibitor is disclosed in WO2022/265993 and has a formula selected from: or a pharmaceutically acceptable salt thereof.
  • the patient has a cancer which has acquired the M1043 mutation (e.g., M1043I/L optionally in cis with the H1047R mutation) and/or the C901 mutation (e.g, C901F optionally in cis with the H1047R mutation), after the patient was treated previously with a therapeutically effective amount of a first PI3K ⁇ selective allosteric inhibitor that binds to the PI3K ⁇ pocket 1 and may form an interaction with one or more amino acids selected from C901, T908, F909, H931, F954, Q981, Y985, Y1021, and R1047.
  • M1043 mutation e.g., M1043I/L optionally in cis with the H1047R mutation
  • the C901 mutation e.g, C901F optionally in cis with the H1047R
  • the patient has a cancer comprising the M1043 mutation (e.g., M1043I/L optionally in cis with the H1047 R mutation) and/or the C901 mutation (e.g, C901F optionally in cis with the H1047R mutation) without the patient having been treated previously with a therapeutically effective amount of a first PI3K ⁇ selective allosteric inhibitor that binds to the PI3K ⁇ pocket 1 and may form an interaction with one or more amino acids selected from C901, T908, F909, H931, F954, Q981, Y985, Y1021, and R1047.
  • M1043 mutation e.g., M1043I/L optionally in cis with the H1047 R mutation
  • the C901 mutation e.g, C901F optionally in cis with the H1047R mutation
  • the patient has a cancer which has acquired the M1043I/L mutation (optionally in cis with the H1047R mutation) after the patient was treated previously with a therapeutically effective amount of a first PI3K ⁇ selective allosteric inhibitor of a Formula I or pharmaceutically acceptable salt thereof, wherein: R is -H or C 1 -C 3 alkyl; R 1 is a group of the formula:
  • R 2 is a group of the formula: R 3 is -H, halogen, -CN, -N(H)(C 1 -C 3 alkyl), -N(C 1 -C 3 alkyl) 2 , -N(H)(CH 2 CH 2 CO 2 H), -C(O)C 1 -C 3 alkyl, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 3 -C 5 cycloalkyl, an optionally substituted heterocycle of 3 to 5 ring atoms containing 1, 2, or 3 ring heteroatoms independently selected from N, O, or S, or an optionally substituted heteroaryl of 5 or 6 ring atoms containing 1, 2, or 3 ring heteroatoms independently selected from N, O, or S; wherein the optionally substituted heterocycle or heteroaryl is each optionally substituted with one to three substituents each independently selected from halogen, C 1 -C 3
  • the therapeutically effective amount of the PI3K ⁇ selective allosteric inhibitor of Formula I that was administered to the patient was a 100-1200 mg oral dose administered two times daily. In some aspects of the disclosed methods, the therapeutically effective amount of the PI3K ⁇ selective allosteric inhibitor of Formula I that was administered to the patient was a 9-75 mg/kg oral dose administered two times daily (e.g., 37.5 mg/kg oral dose administered two times daily). In the disclosed methods, the patient may have a cancer which acquired resistance after the patient was administered the PI3K ⁇ selective allosteric inhibitor at the indicated dose.
  • the patient was treated previously with a therapeutically effective amount of a PI3K ⁇ selective inhibitor of a formula: or a pharmaceutically acceptable salt thereof.
  • the patient may have a cancer comprising an M1043 mutation (e.g., M1043I/L optionally in cis with an H1047R mutation) and/or a C901 mutation (e.g, C901F optionally in cis with an H1047R mutation), and the patient further may have a cancer comprising one or more mutations selected from E542K, E545K, E453Q/K, and E726K.
  • the patient in need thereof may have advanced, or metastatic breast cancer that is estrogen receptor- positive (ER+), human epidermal growth factor receptor 2-negative (HER 2 -).
  • the disclosed methods comprise administering to the patient a therapeutically effective amount of a PI3K ⁇ selective allosteric inhibitor and the disclosed methods further comprise administering to the patient a therapeutically effective amount of a selective estrogen receptor degrader (SERD).
  • SESD selective estrogen receptor degrader
  • the disclosed methods relate to methods for treating a disease or disorder associated with modulation of PI3K ⁇ in a patient in need thereof, wherein the patient has a cancer comprising an M1043 mutation (e.g., M1043I/L optionally in cis with an H1047R mutation) and/or a C901 mutation (e.g., C901F optionally in cis with an H1047R mutation).
  • M1043 mutation e.g., M1043I/L optionally in cis with an H1047R mutation
  • C901 mutation e.g., C901F optionally in cis with an H1047R mutation
  • the methods comprise administering to the patient a therapeutically effective amount of a PI3K ⁇ selective inhibitor that binds to the PI3K ⁇ pocket 1 and may form an interaction with one or more amino acids selected from C901, T908, F909, H931, F954, Q981, Y985, Y1021, and R1047.
  • the PI3K ⁇ selective allosteric inhibitor that is administered to the patient is of a Formula I: or pharmaceutically acceptable salt thereof, wherein: R is -H or C 1 -C 3 alkyl; R 1 is a group of the formula:
  • R3 is -H, halogen, -CN, -N(H)(C 1 -C 3 alkyl), -N(C 1 -C 3 alkyl) 2 , -N(H)(CH 2 CH 2 CO 2 H), -C(O)C 1 -C 3 alkyl, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 3 -C 5 cycloalkyl, an optionally substituted heterocycle of 3 to 5 ring atoms containing 1, 2, or 3 ring heteroatoms independently selected from N, O, or S, or an optionally substituted heteroaryl of 5 or 6 ring atoms containing 1, 2, or 3 ring heteroatoms independently selected from N, O, or S; wherein the optionally substituted heterocycle or heteroaryl is each optionally substituted with one to three substituents each independently selected from halogen, C 1 -C 3 alkyl, or C 1 -C
  • the PI3K ⁇ selective allosteric inhibitor that is administered to the patient is not of a formula: or a pharmaceutically acceptable salt thereof.
  • the PI3K ⁇ selective allosteric inhibitor of Formula I that is administered to the patient is of a formula:
  • the PI3K ⁇ selective allosteric inhibitor of Formula I that is administered to the patient is selected from: or a pharmaceutically acceptable salt thereof.
  • the patient may have a cancer comprising a mutation M1043I/L (optionally in cis with an H1047R mutation) and/or a C901 mutation (e.g, C901F optionally in cis with an H1047R mutation), and the patient further may have a cancer comprising one or more mutations selected from E542K, E545K, E453Q/K, and E726K.
  • the patient in need thereof may have advanced, or metastatic breast cancer which is estrogen receptor-positive (ER+), human epidermal growth factor receptor 2-negative (HER 2 -).
  • the disclosed methods comprise administering to the patient a therapeutically effective amount of a PI3K ⁇ selective allosteric inhibitor and the disclosed methods further comprise administering to the patient a therapeutically effective amount of a selective estrogen receptor degrader (SERD).
  • SESD selective estrogen receptor degrader
  • the methods related to methods for treating a disease or disorder associated with modulation of PI3K ⁇ in a patient in need thereof such as a patient having a cancer comprising an M1043 mutation (e.g., M1043I/L optionally in cis with an H1047R mutation) and/or a C901 mutation (e.g., C901F optionally in cis with an H1047R mutation).
  • a disease or disorder associated with modulation of PI3K ⁇ in a patient in need thereof such as a patient having a cancer comprising an M1043 mutation (e.g., M1043I/L optionally in cis with an H1047R mutation) and/or a C901 mutation (e.g., C901F optionally in cis with an H1047R mutation).
  • the methods may comprise determining that the patient has a cancer comprising the M1043 mutation (e.g., M1043I/L optionally in cis with the H1047R mutation) and/or the C901 mutation (e.g., C901F optionally in cis with the H1047R mutation), for example, by ordering or performing a genomic analysis that identifies mutations in the patient’s cancer (e.g., M1043I/L and/or C901F and/or H1047R, optionally in cis).
  • M1043 mutation e.g., M1043I/L optionally in cis with the H1047R mutation
  • the C901 mutation e.g., C901F optionally in cis with the H1047R mutation
  • Suitable genomic analysis may include one or more steps such as: ordering a genomic analysis that identifies the M1043 mutation, the C901 mutation, and/or the H1047R mutation (optionally in cis); performing PCR amplification of the allele comprising the M1043 mutation, the C901 mutation, and/or the H1047R mutation (optionally in cis); sequencing of the allele comprising the M1043 mutation, the C901 mutation, and/or the H1047R mutation (optionally in cis); probing of the allele comprising the M1043 mutation, the C901 mutation, and/or the H1047R mutation (optionally in cis); identifying or detecting the allele comprising the M1043 mutation, the C901 mutation, and/or the H1047R mutation (optionally in cis); and determining that a patient has a cancer comprising the M1043 mutation, the C901 mutation, and/or the H1047R mutation (optionally in cis).
  • the methods further may comprise administering treatment to the patient, which may include administering to the patient one or more PI3K ⁇ selective inhibitors to the patient.
  • the methods may comprise administering to the patient a therapeutically effective amount of a PI3K ⁇ selective inhibitor.
  • the PI3K ⁇ selective inhibitor is not of a formula: or a pharmaceutically acceptable salt thereof.
  • the methods may comprise administering to the patient a therapeutically effective amount of a PI3K ⁇ selective orthosteric inhibitor.
  • the PI3K ⁇ selective orthosteric inhibitor is selected from alpelisib, inavolisib, serabelisib, or pharmaceutically acceptable salts thereof.
  • the methods may comprise administering to the patient a therapeutically effective amount of a PI3K ⁇ selective inhibitor, wherein the PI3K ⁇ selective inhibitor binds to the PI3K ⁇ allosteric pocket 2 and may form an interaction with one or more amino acids selected from L911, F937, F1002, E1012, and D1018.
  • the PI3K ⁇ selective allosteric inhibitor is a compound disclosed in WO2021/222556 (e.g., any of Compounds I- 1 through I-2704 in Table 1, pages 162-855). In some aspects, the PI3K ⁇ selective allosteric inhibitor is a compound disclosed in WO2022/265993, Tables A-D, pages 175-259).
  • the PI3K ⁇ selective allosteric inhibitor that is administered to the patient is of a Formula IV: IV or a pharmaceutically acceptable salt thereof, wherein: E is -C(O)-, -C(R E ) 2 -, -C(R E ) 2 C(R E ) 2 -, -C(S)-, -S(O) 2 -, -OC(O)-, -N(R E )C(O)-, -C(O)N(R E )-, or - C(R E ) 2 C(O)-; Q is CH, C(R Q ), or N; X is CH, C(R X ), or N; Y is CH, C(R Y ), or N; Z is CH, C(R Z ), or N; R 1 is -L 1 -R 1A ; R 2 is -L 2 -R 2A ; each instance of R E is independently H or
  • the allosteric inhibitor is of a Formula: or a pharmaceutically acceptable salt thereof.
  • the allosteric inhibitor is of a formula in which R 1 is [347]
  • the allosteric inhibitor is of a formula in which each instance of R 1C is independently halogen, -CN, -O-(C 1-6 aliphatic), or C 1-6 aliphatic; wherein each C 1-6 aliphatic is optionally substituted with one or more halogen atoms.
  • the allosteric inhibitor is of a formula in which each instance of R 1C is independently halogen or C 1-3 aliphatic optionally substituted with 1-3 halogen.
  • the allosteric inhibitor is of a formula in which R 2 is -N(H)C(O)-R 2A , - N(H)C(O)N(H)-R 2A , -C(O)N(H)-R 2A , -N(H)-R 2A , -S(O) 2 CH 2 -R 2A , -CH 2 S(O) 2 -R 2A , or - C(H)(CH 3 )OH.
  • the allosteric inhibitor is of a formula in which R 2A is phenyl optionally substituted at one or more positions C 1-3 aliphatic (e.g., methyl), haloalkyl (e.g., trifluoromethyl or difluoromethyl), or halogen.
  • the allosteric inhibitor is of a formula in which each instance of R 2C is independently halogen, -CN, -O-(C 1-6 aliphatic), or C 1-6 aliphatic; wherein each C 1-6 aliphatic is optionally substituted with one or more halogen atoms.
  • the allosteric inhibitor is of a formula in which each instance of R 2C is independently halogen or C 1-3 aliphatic optionally substituted with 1-3 halogen.
  • the second PI3K ⁇ selective inhibitor is of a formula in which R YA is a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is substituted by r 6 instances of R YC .
  • the allosteric inhibitor is of a formula in which R YA is [355]
  • the second PI3K ⁇ selective inhibitor is of a formula in which each instance of R YC is independently oxo, halogen, -CN, -OH, -O-(C 1-3 aliphatic), or C 1-3 aliphatic, wherein each C1- 3 aliphatic is optionally substituted with one or more halogen atoms.
  • the PI3K ⁇ selective allosteric inhibitor that is administered to the patient is of a formula selected from:
  • the second PI3K ⁇ selective inhibitor is disclosed in WO2022/265993 and has a formula selected from: or a pharmaceutically acceptable salt thereof.
  • the methods may comprise administering to the patient a therapeutically effective amount of a PI3K ⁇ selective inhibitor that binds to the PI3K ⁇ allosteric pocket 1 and may form an interaction with one or more amino acids selected from C901, T908, F909, H931, F954, Q981, Y985, Y1021, and R1047.
  • the PI3K ⁇ selective allosteric inhibitor that is administered to the patient is of a Formula I: or pharmaceutically acceptable salt thereof, wherein: R is -H or C 1 -C 3 alkyl; R1 is a group of the formula: R 2 is a group of the formula:
  • R3 is -H, halogen, -CN, -N(H)(C 1 -C 3 alkyl), -N(C 1 -C 3 alkyl) 2 , -N(H)(CH 2 CH 2 CO 2 H), -C(O)C 1 -C 3 alkyl, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 3 -C 5 cycloalkyl, an optionally substituted heterocycle of 3 to 5 ring atoms containing 1, 2, or 3 ring heteroatoms independently selected from N, O, or S, or an optionally substituted heteroaryl of 5 or 6 ring atoms containing 1, 2, or 3 ring heteroatoms independently selected from N, O, or S; wherein the optionally substituted heterocycle or heteroaryl is each optionally substituted with one to three substituents each independently selected from halogen, C 1 -C 3 alkyl, or C 1 -C
  • the PI3K ⁇ selective allosteric inhibitor of Formula I is of a formula: or a pharmaceutically acceptable salt thereof.
  • the PI3K ⁇ selective allosteric inhibitor of Formula I that is administered to the patient is selected from: or a pharmaceutically acceptable salt thereof.
  • the patient may have a cancer comprising an M1043 mutation (e.g, M1043I/L optionally in cis with an H1047R mutation) and/or a C901 mutation (e.g., C901F optionally in cis with an H1047R mutation), and the patient further may have a cancer comprising one or more mutations selected from E542K, E545K, E453Q/K, and E726K.
  • the patient in need thereof may have advanced, or metastatic breast cancer that is estrogen receptor-positive (ER+), human epidermal growth factor receptor 2-negative (HER 2 -).
  • the disclosed subject matter relates to a first PI3K ⁇ specific inhibitor for use in the treatment of a disease or disorder associated with modulation of phosphatidylinositol 3-kinase alpha (PI3K ⁇ ), in simultaneous, separate or sequential combination with a second PI3K ⁇ specific inhibitor.
  • PI3K ⁇ phosphatidylinositol 3-kinase alpha
  • the disclosed compounds for use in treatment may be further illustrated by the following embodiments.
  • Embodiment 1 A PI3K ⁇ specific inhibitor compound of Formula: or a pharmaceutically acceptable salt thereof, wherein: R is -H or C 1 -C 3 alkyl; R 1 is a group of the formula:
  • R3 is -H, halogen, -CN, -N(H)(C 1 -C 3 alkyl), -N(C 1 -C 3 alkyl) 2 , -N(H)(CH 2 CH 2 CO 2 H), -C(O)C 1 -C 3 alkyl, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 3 -C 5 cycloalkyl, an optionally substituted heterocycle of 3 to 5 ring atoms containing 1, 2, or 3 ring heteroatoms independently selected from N, O, or S, or an optionally substituted heteroaryl of 5 or 6 ring atoms containing 1, 2, or 3 ring heteroatoms independently selected from N, O, or S; wherein the optionally substituted heterocycle or heteroaryl is each optionally substituted with one to three substituents each independently selected from halogen, C 1 -C 3 alkyl, or C 1 -C
  • Embodiment 2 A compound for use according to embodiment 1, wherein the second PI3K ⁇ specific inhibitor is alpelisib or a pharmaceutically acceptable salt thereof.
  • Embodiment 3. A compound for use according to embodiment 1, wherein the second PI3K ⁇ specific inhibitor is inavolisib or a pharmaceutically acceptable salt thereof.
  • Embodiment 4. A compound for use according to any of embodiments 1-3, wherein the dose of the second PI3K ⁇ specific inhibitor is less than about a 300 mg oral dose administered every day.
  • Embodiment 5. A compound for use according to any of embodiments 1-4, wherein the first PI3K ⁇ specific inhibitor and the second PI3K ⁇ specific inhibitor are administered simultaneously.
  • Embodiment 7 A PI3K ⁇ specific inhibitor compound of Formula I: or a pharmaceutically acceptable salt thereof, wherein R, R1, R 2 , R3, R4, R5, R6, R7, and R8, are as defined in embodiment 1; for use in the treatment of a disease or disorder associated with modulation of phosphatidylinositol 3-kinase alpha (PI3K ⁇ ), in simultaneous, separate or sequential combination with a second PI3K ⁇ specific inhibitor which binds to PI3K ⁇ allosteric pocket 2.
  • PI3K ⁇ phosphatidylinositol 3-kinase alpha
  • Embodiment 8 The compound for use according to embodiment 7, wherein the second PI3K ⁇ specific inhibitor forms one or more interactions with one or more amino acids selected from L911, F937, F1002, E1012, and D1018. [373] Embodiment 9.
  • the second PI3K ⁇ specific inhibitor is of a formula: or a pharmaceutically acceptable salt thereof, wherein: E is -C(O)-, -C(R E ) 2 -, -C(R E ) 2 C(R E ) 2 -, -C(S)-, -S(O) 2 -, -OC(O)-, -N(R E )C(O)-, -C(O)N(R E )-, or - C(R E ) 2 C(O)-; Q is CH, C(R Q ), or N; X is CH, C(R X ), or N; Y is CH, C(R Y ), or N; Z is CH, C(R Z ), or N; R 1 is -L 1 -R 1A ; R 2 is -L 2 -R 2A ; each instance of R E is independently H or -L E -R EA ; R
  • Embodiment 10 The compound for use according to any of embodiments 7-9, wherein the second PI3K ⁇ selective inhibitor is of a formula: or a pharmaceutically acceptable salt thereof.
  • Embodiment 11 The compound for use according to any of embodiments 7-10, wherein the second PI3K ⁇ selective inhibitor is of a formula: or a pharmaceutically acceptable salt thereof.
  • Embodiment 12 The compound for use according to any of embodiments 7-11, wherein the second PI3K ⁇ selective inhibitor is of a formula in which R 1 is [377] Embodiment 13.
  • the second PI3K ⁇ selective inhibitor is of a formula in which R 2A is phenyl optionally substituted at one or more positions C 1-3 aliphatic (e.g., methyl), haloalkyl (e.g., trifluoromethyl or difluoromethyl), or halogen.
  • R 2A is phenyl optionally substituted at one or more positions C 1-3 aliphatic (e.g., methyl), haloalkyl (e.g., trifluoromethyl or difluoromethyl), or halogen.
  • the second PI3K ⁇ selective inhibitor is of a formula in which each instance of R 2C is independently halogen, -CN, -O-(C 1-6 aliphatic), or C 1-6 aliphatic; wherein each C 1-6 aliphatic is optionally substituted with one or more halogen atoms.
  • Embodiment 19 The compound for use according to any of embodiments 7-18, wherein the second PI3K ⁇ selective inhibitor is of a formula in which each instance of R YC is independently oxo, halogen, -CN, -OH, -O-(C 1-3 aliphatic), or C 1-3 aliphatic, wherein each C1- 3 aliphatic is optionally substituted with one or more halogen atoms.
  • Embodiment 20 The compound for use according to embodiment 19, wherein the second PI3K ⁇ selective inhibitor has a formula selected from: [385] or pharmaceutically acceptable salts thereof, or the second PI3K ⁇ selective inhibitor has a formula selected from: or pharmaceutically acceptable salts thereof.
  • Embodiment 21 A PI3K ⁇ specific inhibitor compound of Formula I: or pharmaceutically acceptable salt thereof, wherein R, R1, R 2 , R3, R4, R5, R6, R7, and R8, are as defined in claim 1; for use in the treatment of a disease or disorder associated with modulation of phosphatidylinositol 3-kinase alpha (PI3K ⁇ ) in simultaneous, separate or sequential combination with a second PI3K ⁇ specific inhibitor of Formula I or pharmaceutically acceptable salt thereof, wherein the first PI3K ⁇ specific inhibitor and the second PI3K ⁇ specific inhibitor are different compounds.
  • Embodiment 22 A compound for use according to embodiment 21, wherein the second PI3K ⁇ specific inhibitor is not of a formula:
  • Embodiment 23 A compound for use according to embodiment 21 or 22, wherein the second PI3K ⁇ specific inhibitor is of a formula: or a pharmaceutically acceptable salt thereof.
  • Embodiment 24 A compound for use according to any of embodiments 21-23, wherein the second PI3K ⁇ specific inhibitor is of a formula selected from:
  • Embodiment 25 A compound for use according to any of embodiments 1-24, wherein the therapeutically effective amount of the first PI3K ⁇ specific inhibitor is effective for reducing PI3K ⁇ activity in the patient without inducing hyperglycemia in the patient.
  • Embodiment 26 A compound for use according to any of embodiments 1-25, wherein the therapeutically effective amount of the second PI3K ⁇ specific inhibitor is effective for reducing PI3K ⁇ activity in the patient without inducing hyperglycemia in the patient.
  • Embodiment 27 Embodiment 27.
  • PI3K ⁇ phosphatidylinositol 3-kinase alpha
  • a PI3K ⁇ specific inhibitor which binds to an allosteric pocket of PI3K ⁇ and optionally forms one or more interactions with one or more amino acids selected from L911, F937, F1002, E1012, and D1018 for use in the treatment of a disease or disorder associated with modulation of phosphatidylinositol 3-kinase alpha (PI3K ⁇ ), of a patient that is resistant to treatment with alpelisib or inavolisib.
  • PI3K ⁇ phosphatidylinositol 3-kinase alpha
  • Embodiment 30 A PI3K ⁇ specific inhibitor which is a PI3K ⁇ specific orthosteric inhibitor for use in the treatment of a disease or disorder associated with modulation of phosphatidylinositol 3-kinase alpha (PI3K ⁇ ), wherein the patient has been treated previously with compound of Formula I
  • PI3K ⁇ phosphatidylinositol 3-kinase alpha
  • PI3K ⁇ phosphatidylinositol 3-kinase alpha
  • Embodiment 34 A PI3K ⁇ specific inhibitor selected from alpelisib and inavolisib, for use in the treatment of a disease or disorder associated with modulation of phosphatidylinositol 3- kinase alpha (PI3K ⁇ ) in a patient in need thereof, comprising assaying a sample from a patient, determining if a patient has a cancer comprising an M1043I/L in cis with an H1047R mutation and/or a C901F mutation in cis with an H1047 mutation, and administering a therapeutically effective amount of alpelisib, inavolisib, or a pharmaceutically acceptable salt thereof to the patient if an M1043I/L in cis with an H1047R mutation and/or a C901F mutation in cis with an H1047 mutation is present.
  • PI3K ⁇ specific inhibitor selected from alpelisib and inavolisib for use in the treatment of a disease or disorder associated
  • Embodiment 35 A PI3K ⁇ specific inhibitor that binds to PI3K ⁇ allosteric pocket 2 and optionally forms one or more interactions with one or more amino acids selected from L911, F937, F1002, E1012, and D1018, for use in the treatment of a disease or disorder associated with modulation of phosphatidylinositol 3-kinase alpha (PI3K ⁇ ) in a patient in need thereof, comprising assaying a blood sample from a patient, determining if a patient has a cancer comprising an M1043I/L in cis with an H1047R mutation and/or a C901F mutation in cis with an H1047 mutation, and administering a therapeutically effective amount of the PI3K ⁇ specific inhibitor or pharmaceutically acceptable salt thereof to the patient if an M1043I/L in cis with an H1047R mutation and/or a C901F mutation in cis with an H1047 mutation is present.
  • Embodiment 36 A compound for use according to any one of embodiments 1-27, 30, 32, and 33, wherein the compound of Formula I is of the formula: or a pharmaceutically acceptable salt thereof.
  • Embodiment 37 A compound for use according to any one of embodiments 1-27, 30, 32, and 33, wherein the therapeutically effective amount of the compound of Formula I administered to the patient is a 100-1200 mg oral dose administered two times daily.
  • Embodiment 38 A compound for use according to any one of embodiments 1-27, 30, 32, and 33, wherein the therapeutically effective amount of the first PI3K ⁇ specific inhibitor administered to the patient is a 9-75 mg/kg oral dose administered two times daily.
  • Embodiment 39 Embodiment 39.
  • Embodiment 40 A compound for use according to any of embodiments 1-38, wherein the disease or disorder is cancer.
  • Embodiment 40 A compound for use according to any of embodiments 1-39, wherein the disease or disorder is breast cancer.
  • Embodiment 41 A compound for use according to any of embodiments 1-40, wherein the disease or disorder is PIK3CA-mutated, advanced, or metastatic breast cancer.
  • Embodiment 42 A compound for use according to any of embodiments 1-41, wherein the disease or disorder is PIK3CACA H1047R-mutant advanced, or metastatic breast cancer.
  • Embodiment 43 Embodiment 43.
  • Embodiment 44 A compound for use according to any of embodiments 1-43, wherein the patient is a postmenopausal female.
  • Embodiment 45 A compound for use according to any of embodiments 1-44, wherein the patient has type II diabetes mellitus.
  • Embodiment 46 A compound for use according to any of embodiments 1-45, further comprising administering to the patient a therapeutically effective amount of a selective estrogen receptor degrader (SERD).
  • SESD selective estrogen receptor degrader
  • Embodiment 48 A compound for use according to embodiment 46 or 47, wherein the therapeutically effective amount of the SERD is a 500 mg dose administered on days 1, 15, and 29.
  • Embodiment 49 A compound for use according to any one of embodiments 1-48, wherein the second PI3K ⁇ specific inhibitor is administered after the disease or disorder has developed resistance to the first PI3K ⁇ specific inhibitor.
  • Illustrative Compounds [416] The following are illustrative compounds that may be used in some aspects of the disclosed subject matter. [417] In one aspect, the present invention provides compounds of Formula (I), or pharmaceutically acceptable salts thereof:
  • R is -H or C 1 -C 3 alkyl
  • R1 is a group of the formula:
  • R 2 is a group of the formula:
  • R3 is -H, halogen, -CN, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 5 cycloalkyl, a heterocycle of 3 to 5 ring atoms containing 1, 2, or 3 ring heteroatoms independently selected from N, O, or S, or a heteroaryl of 5 ring atoms containing 1, 2, or 3 ring heteroatoms independently selected from N, O, or S; each of R 4 , R 5 and R 6 is independently -H, halogen, C 1 -C 6 alkyl or C 1 -C 6 haloalkyl;
  • R 7 is -CN, C 1 -C 6 alkyl or C 1 -C 6 haloalkyl;
  • R8 is -
  • R 2 is a group of the formula: wherein each R10 is independently -H, -CN, halogen, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, -SO 2 R 11 , -CONR 11 R 11 , -NR 11 R 11 , -NR 11 -CO 2 R 11 , an optionally substituted C 1 -C 6 alkyl, an optionally substituted C 2 -C 6 alkenyl, an optionally substituted C 2 -C 6 alkynyl, an optionally substituted C 3 -C 5 cycloalkyl, an optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine or morpholine, an optionally substituted phenyl, an optionally substituted 1,3-benzodioxole, an optionally substituted
  • R 2 is a group of the formula: wherein each R10 is independently -H, -CN, halogen, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, -SO 2 R 11 , -CONR 11 R 11 , -NR 11 R 11 , -NR 11 -CO 2 R 11 , an optionally substituted C 1 -C 6 alkyl, an optionally substituted C 3 -C 5 cycloalkyl, an optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine or morpholine, an optionally substituted phenyl, or an optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole, or thiazole; wherein the optionally substituted C 1
  • R 2 is a group of the formula: independently -H, -CN, halogen, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, -SO 2 R 11 , -CONR 11 R 11 , -NR 11 R 11 , -NR 11 -CO 2 R 11 , an optionally substituted C 1 -C 6 alkyl, an optionally substituted C 3 -C 5 cycloalkyl, an optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine or morpholine, an optionally substituted phenyl, or an optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole, or thiazole; wherein the optionally substituted C 1 -C 6
  • R 2 is a group of the formula: .
  • each R 10 is independently -H, -CN, halogen, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, -SO 2 R 11 , -CONR 11 R 11 , -NR 11 R 11 , -NR 11 -CO 2 R 11 , an optionally substituted C 1 -C 6 alkyl, an optionally substituted C 3 -C 5 cycloalkyl, an optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine or morpholine, an optionally substituted phenyl, or an optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole, or thiazole; wherein the
  • each R 10 is independently -H, -CN, halogen, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, -SO 2 R 11 , -CONR 11 R 11 , an optionally substituted C 1 -C 6 alkyl, an optionally substituted C 3 -C 5 cycloalkyl, an optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine or morpholine, or an optionally substituted heteroaryl selected from selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole, or thiazole; wherein the optionally substituted C 1 -C 6 alkyl is optionally substituted with a -CN, -OH, or C 1 -C 3 alkoxy; and the optionally substituted C 3 -C 5 cycloalky
  • each R 10 is independently -H, -CN, halogen, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, -SO 2 R 11 , -C(O)OC 1 -C 3 alkyl, -CONR 11 R 11 , a C 1 -C 6 alkyl optionally substituted with -CN or -CONR 11 R 11 (preferably each R 11 is C 1 -C 3 alkyl), a C3 cycloalkyl optionally substituted with C 1 -C 3 alkyl or -CN, an optionally substituted heterocycle selected from pyrrolidine, an optionally substituted phenyl (preferably an optionally substituted phenyl substituted by a -CN), or an optionally substituted heteroaryl selected from pyrazole or oxazole.
  • each R 10 is independently -H, -CN, halogen, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, -SO 2 R 11 , -CONR 11 R 11 , a C 1 -C 6 alkyl optionally substituted with -CN, a C3 cycloalkyl optionally substituted with C 1 -C 3 alkyl or -CN, an optionally substituted heterocycle selected from pyrrolidine, or an optionally substituted heteroaryl selected from pyrazole or oxazole.
  • each R10 is independently -H, -CN, halogen, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, -SO 2 R 11 , -CONR 11 R 11 , a C 1 -C 6 alkyl optionally substituted with -CN, a C3 cycloalkyl optionally substituted with C 1 -C 3 alkyl or -CN, an optionally substitute
  • each R 10 is independently [431] In yet a further compound of Formula (I), or (II), or pharmaceutically acceptable salts thereof, R 2 is a group of the formula:
  • R 2 is a group of the formula:
  • R 3 is -H, halogen, -CN, -N(H)(CH 2 CH 2 CO 2 H), -C(O)C 1 -C 3 alkyl, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, oxetane, isoxazole, or pyridine (preferably 3-pyridine).
  • R 3 is -H, halogen, -CN, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 5 cycloalkyl, a heterocycle of 3 to 5 ring atoms containing 1, 2, or 3 ring heteroatoms independently selected from N, O, or S, or a heteroaryl of 5 ring atoms containing 1, 2, or 3 ring heteroatoms independently selected from N, O, or S.
  • R 3 is -H, halogen, -CN, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, oxetane, or isoxazole.
  • R3 is -H, -CN, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.
  • R 3 is -H, -CN, C 1 -C 3 alkyl or C 1 -C 3 haloalkyl (preferably R3 is -H, -CN, or C 1 -C 3 alkyl); most preferably R3 is -H, or methyl.
  • R 4 is H or halogen, preferably R 4 is H.
  • R 5 is -H, halogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; preferably R 5 is -H, halogen, C 1 -C 3 alkyl or C 1 -C 3 haloalkyl; more preferably R 5 is -H, halogen, methyl, or trifluoromethyl.
  • R6 is -H, or halogen.
  • R3 is -H, -CN, C 1 -C 3 alkyl, or C 1 -C 3 haloalkyl (preferably R3 is -H, -CN, or C 1 -C 3 alkyl), and R 2 is a group of the formula: wherein each R 10 is independently -H, -CN, halogen, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, -SO 2 R 11 , -CONR 11 R 11 , -NR 11 R 11 , -NR 11 -CO 2 R 11 , an optionally substituted C 1 -C 6 alkyl, an optionally substituted C 3 -C 5 cycloalkyl, an optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine or morpholine, an optionally
  • R 3 is -H, -CN, C 1 -C 3 alkyl, or C 1 -C 3 haloalkyl (preferably R 3 is -H, -CN, or C 1 -C 3 alkyl), and R 2 is a group of the formula:
  • each R 10 is independently -H, -CN, halogen, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, -SO 2 R 11 , -CONR 11 R 11 , -NR 11 R 11 , -NR 11 -CO 2 R 11 , an optionally substituted C 1 -C 6 alkyl, an optionally substituted C 3 -C 5 cycloalkyl, an optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine or morpholine, an
  • R3 is -H, methyl or trifluoromethyl (preferably R3 is -H, or methyl), and R 2 is a group of the formula: .
  • each R 10 is independently -H, -CN, halogen, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, -SO 2 R 11 , -CONR 11 R 11 , -NR 11 R 11 , -NR 11 -CO 2 R 11 , an optionally substituted C 1 -C 6 alkyl, an optionally substituted C 3 -C 5 cycloalkyl, an optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine or morpholine, an optionally substituted phenyl, or an optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole, or thiazole; wherein the optionally substituted C 1 -C 6 alkyl is optionally substituted with a -CN, -OH, or C 1 -C 3 alkoxy;
  • R 4 is -H or halogen (preferably R 4 is -H), and R 2 is a group of the formula: wherein each R10 is independently -H, -CN, halogen, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, -SO 2 R 11 , -CONR 11 R 11 , -NR 11 R 11 , -NR 11 -CO 2 R 11 , an optionally substituted C 1 -C 6 alkyl, an optionally substituted C 3 -C 5 cycloalkyl, an optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine or morpholine, an optionally substituted phenyl, or an optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, o
  • R4 is -H or halogen (preferably R4 is -H), and R 2 is a group of the formula: .
  • each R10 is independently -H, -CN, halogen, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, -SO 2 R 11 , -CONR 11 R 11 , -NR 11 R 11 , -NR 11 -CO 2 R 11 , an optionally substituted C 1 -C 6 alkyl, an optionally substituted C 3 -C 5 cycloalkyl, an optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine or morpholine, an optionally substituted phenyl, or an optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole,
  • R4 is -H or halogen (preferably R4 is -H), and R 2 is a group of the formula: .
  • each R10 is independently -H, -CN, halogen, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, -SO 2 R 11 , -CONR 11 R 11 , -NR 11 R 11 , -NR 11 -CO 2 R 11 , an optionally substituted C 1 -C 6 alkyl, an optionally substituted C 3 -C 5 cycloalkyl, an optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine or morpholine, an optionally substituted phenyl, or an optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole,
  • R 5 is -H, halogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl
  • R 2 is a group of the formula: wherein each R 10 is independently -H, -CN, halogen, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, -SO 2 R 11 , -CONR 11 R 11 , -NR 11 R 11 , -NR 11 -CO 2 R 11 , an optionally substituted C 1 -C 6 alkyl, an optionally substituted C 3 -C 5 cycloalkyl, an optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine or morpholine, an optionally substituted phenyl, or an optionally substituted heteroaryl selected from pyrazole,
  • R5 is -H, halogen, C 1 -C 3 alkyl or C 1 -C 3 haloalkyl
  • R 2 is a group of the formula:
  • each R10 is independently -H, -CN, halogen, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, -SO 2 R 11 , -CONR 11 R 11 , -NR 11 R 11 , -NR 11 -CO 2 R 11 , an optionally substituted C 1 -C 6 alkyl, an optionally substituted C 3 -C 5 cycloalkyl, an optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine or morpholine, an optionally substituted phenyl, or an optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole, or thiazole; wherein the optionally substituted C 1 -C 6 alkyl is optionally substituted with a -CN, -OH, or C 1 -C 3 alkoxy;
  • R 5 is -H, halogen, methyl, or trifluoromethyl
  • R 2 is a group of the formula: .
  • each R 10 is independently -H, -CN, halogen, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, -SO 2 R 11 , -CONR 11 R 11 , -NR 11 R 11 , -NR 11 -CO 2 R 11 , an optionally substituted C 1 -C 6 alkyl, an optionally substituted C 3 -C 5 cycloalkyl, an optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine or morpholine, an optionally substituted phenyl, or an optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazo
  • R 6 is -H, or halogen
  • R 2 is a group of the formula: wherein each R10 is independently -H, -CN, halogen, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, -SO 2 R 11 , -CONR 11 R 11 , -NR 11 R 11 , -NR 11 -CO 2 R 11 , an optionally substituted C 1 -C 6 alkyl, an optionally substituted C 3 -C 5 cycloalkyl, an optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine or morpholine, an optionally substituted phenyl, or an optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole,
  • R6 is -H, or halogen
  • R 2 is a group of the formula: .
  • each R10 is independently -H, -CN, halogen, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, -SO 2 R 11 , -CONR 11 R 11 , -NR 11 R 11 , -NR 11 -CO 2 R 11 , an optionally substituted C 1 -C 6 alkyl, an optionally substituted C 3 -C 5 cycloalkyl, an optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine or morpholine, an optionally substituted phenyl, or an optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, o
  • R 6 is -H, or halogen
  • R 2 is a group of the formula: .
  • each R 10 is independently -H, -CN, halogen, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, -SO 2 R 11 , -CONR 11 R 11 , -NR 11 R 11 , -NR 11 -CO 2 R 11 , an optionally substituted C 1 -C 6 alkyl, an optionally substituted C 3 -C 5 cycloalkyl, an optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine or morpholine, an optionally substituted phenyl, or an optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, o
  • R3 is -H, -CN, C 1 -C 3 alkyl or C 1 -C 3 haloalkyl, and R4 is H or halogen; more preferably R3 is -H, -CN, or C 1 -C 3 alkyl, and R4 is H; most preferably R3 is -H, or methyl, and R4 is H.
  • R 3 is -H, -CN, C 1 -C 3 alkyl or C 1 -C 3 haloalkyl, (preferably R 3 is -H, -CN, or C 1 -C 3 alkyl), and R 5 is -H, halogen, C 1 -C 3 alkyl or C 1 -C 3 haloalkyl; more preferably R3 is -H, or methyl, and R5 is -H, halogen, methyl, or trifluoromethyl.
  • R 3 is -H, -CN, C 1 -C 3 alkyl or C 1 -C 3 haloalkyl, (preferably R 3 is -H, -CN, or C 1 -C 3 alkyl), and R 6 is -H, or halogen; more preferably R3 is -H, or methyl, and R6 is -H, or halogen.
  • R 4 is -H or halogen (preferably R 4 is -H), and R 5 is -H, halogen, C 1 -C 3 alkyl or C 1 -C 3 haloalkyl; preferably R5 is -H, halogen, methyl, or trifluoromethyl.
  • R 4 is -H or halogen (preferably R 4 is -H) and R 6 is -H, or halogen.
  • R5 is -H, halogen, C 1 -C 3 alkyl or C 1 -C 3 haloalkyl
  • R6 is -H, or halogen; preferably R5 is -H, halogen, methyl, or trifluoromethyl, and R 6 is H.
  • R3 is -H, -CN, C 1 -C 3 alkyl or C 1 -C 3 haloalkyl, (preferably R3 is -H, -CN, or C 1 -C 3 alkyl), R4 is -H or halogen (preferably R 4 is -H), and R 2 is a group of the formula: ; ; ; or ; preferably R 3 is -H, or methyl, R 4 is -H, and R 2 is a group of the formula: ; ; or .
  • each R 10 is independently -H, -CN, halogen, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, -SO 2 R 11 , -CONR 11 R 11 , -NR 11 R 11 , -NR 11 -CO 2 R 11 , an optionally substituted C 1 -C 6 alkyl, an optionally substituted C 3 -C 5 cycloalkyl, an optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine or morpholine, an optionally substituted phenyl, or an optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole, or thiazole; wherein the optionally substituted C 1 -C 6 alkyl is optionally substituted with a -CN, -OH, or C 1 -C 3 alkoxy;
  • R3 is -H, -CN, C 1 -C 3 alkyl or C 1 -C 3 haloalkyl, (preferably R3 is -H, -CN, or C 1 -C 3 alkyl), R5 is -H, halogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl, and R 2 is a group of the formula: more preferably R3 is -H, or methyl, R 5 is -H, halogen, methyl, or trifluoromethyl, and R 2 is a group of the formula: .
  • each R 10 is independently -H, -CN, halogen, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, -SO 2 R 11 , -CONR 11 R 11 , -NR 11 R 11 , -NR 11 -CO 2 R 11 , an optionally substituted C 1 -C 6 alkyl, an optionally substituted C 3 -C 5 cycloalkyl, an optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine or morpholine, an optionally substituted phenyl, or an optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole, or thiazole; wherein the optionally substituted C 1 -C 6 alkyl is optionally substituted with a -CN, -OH, or C 1 -C 3 alkoxy;
  • R3 is -H, -CN, C 1 -C 3 alkyl or C 1 -C 3 haloalkyl, (preferably R3 is -H, -CN, or C 1 -C 3 alkyl), R6 is -H, or halogen, and R 2 is a group of the formula:
  • each R 10 is independently -H, -CN, halogen, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, -SO 2 R 11 , -CONR 11 R 11 , -NR 11 R 11 , -NR 11 -CO 2 R 11 , an optionally substituted C 1 -C 6 alkyl, an optionally substituted C 3 -C 5 cycloalkyl, an optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine or morpholine, an optionally substituted phenyl, or an optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole, or thiazole; wherein the optionally substituted
  • R 4 is -H or halogen (preferably R 4 is -H), R 5 is -H, halogen, C 1 -C 3 alkyl or C 1 -C 3 haloalkyl, and R 2 is a group of the formula: ; more preferably R5 is -H, halogen, methyl, or trifluoromethyl, and R 2 is a group of the formula:
  • each R10 is independently -H, -CN, halogen, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, -SO 2 R 11 , -CONR 11 R 11 , -NR 11 R 11 , -NR 11 -CO 2 R 11 , an optionally substituted C 1 -C 6 alkyl, an optionally substituted C 3 -C 5 cycloalkyl, an optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine or morpholine, an optionally substituted phenyl, or an optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole, or thiazole; wherein the optionally substituted C 1 -C 6 alkyl is optionally substituted with a -CN, -OH, or C 1 -C 3 alkoxy;
  • R4 is -H or halogen (preferably R 4 is -H), R 6 is -H, or halogen, and R 2 is a group of the formula: ; more preferably R 4 and R 6 are each -H, and R 2 is a group of the formula: .
  • each R 10 is independently -H, -CN, halogen, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, -SO 2 R 11 , -CONR 11 R 11 , -NR 11 R 11 , -NR 11 -CO 2 R 11 , an optionally substituted C 1 -C 6 alkyl, an optionally substituted C 3 -C 5 cycloalkyl, an optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine or morpholine, an optionally substituted phenyl, or an optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole, or thiazole; wherein the optionally substituted C 1 -C 6 alkyl is optionally substituted with a -CN, -OH, or C 1 -C 3 alkoxy;
  • R5 is -H, halogen, C 1 -C 3 alkyl or C 1 -C 3 haloalkyl
  • R6 is -H, or halogen
  • R 2 is a group of the formula: ; preferably R 5 is -H, halogen, methyl, or trifluoromethyl, R6 is -H, and R 2 is a group of the formula: .
  • each R10 is independently -H, -CN, halogen, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, -SO 2 R 11 , -CONR 11 R 11 , -NR 11 R 11 , -NR 11 -CO 2 R 11 , an optionally substituted C 1 -C 6 alkyl, an optionally substituted C 3 -C 5 cycloalkyl, an optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine or morpholine, an optionally substituted phenyl, or an optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole, or thiazole; wherein the optionally substituted C 1 -C 6 alkyl is optionally substituted with a -CN, -OH, or C 1 -C 3 alkoxy;
  • R3 is -H, -CN, C 1 -C 3 alkyl, or C 1 -C 3 haloalkyl (preferably R3 is -H, -CN, or C 1 -C 3 alkyl), R4 is -H or halogen (preferably R 4 is -H), and R 5 is -H, halogen, C 1 -C 3 alkyl or C 1 -C 3 haloalkyl; more preferably R 3 is -H, or methyl, R 4 is -H, and R 5 is -H, halogen, methyl, or trifluoromethyl.
  • R 3 is -H, -CN, C 1 -C 3 alkyl, or C 1 -C 3 haloalkyl (preferably R 3 is -H, -CN, or C 1 -C 3 alkyl), R 4 is -H or halogen (preferably R 4 is -H), and R 6 is -H, or halogen; more preferably R 3 is -H, or methyl, and R 4 and R6 are each H.
  • R 3 is -H, -CN, C 1 -C 3 alkyl, or C 1 -C 3 haloalkyl (preferably R 3 is -H, -CN, or C 1 -C 3 alkyl), R 5 is -H, halogen, C 1 -C 3 alkyl or C 1 -C 3 haloalkyl, R6 is -H, or halogen; more preferably R3 is -H, or methyl, R5 is -H, halogen, methyl, or trifluoromethyl, and R6 is H.
  • R 5 is -H, halogen, C 1 -C 3 alkyl or C 1 -C 3 haloalkyl
  • R 4 is -H or halogen (preferably R 4 is -H)
  • R 6 is -H, or halogen; more preferably R5 is -H, halogen, methyl, or trifluoromethyl
  • R4 and R6 are each H.
  • R3 is -H, -CN, C 1 -C 3 alkyl, or C 1 -C 3 haloalkyl (preferably R3 is -H, -CN, or C 1 -C 3 alkyl)
  • R4 is -H or halogen (preferably R4 is -H)
  • R5 is -H, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 alkoxy
  • R 2 is a group of the formula: ; more preferably R 3 is -H, or methyl
  • R4 is -H
  • R5 is -H, halogen, methyl, or trifluoromethyl
  • R 2 is a group of the formula: .
  • each R10 is independently -H, -CN, halogen, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, -SO 2 R 11 , -CONR 11 R 11 , -NR 11 R 11 , -NR 11 -CO 2 R 11 , an optionally substituted C 1 -C 6 alkyl, an optionally substituted C 3 -C 5 cycloalkyl, an optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine or morpholine, an optionally substituted phenyl, or an optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole, or thiazole; wherein the optionally substituted C 1 -C 6 alkyl is optionally substituted with a -CN, -OH, or C 1 -C 3 alkoxy;
  • R3 is -H, -CN, C 1 -C 3 alkyl, or C 1 -C 3 haloalkyl (preferably R3 is -H, -CN, or C 1 -C 3 alkyl), R4 is -H or halogen (preferably R 4 is -H), R 6 is -H, or halogen, and R 2 is a group of the formula: ; more preferably R 3 is -H, or methyl, R 4 and R 6 are each -H, and R 2 is a group of the formula: .
  • each R 10 is independently -H, -CN, halogen, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, -SO 2 R 11 , -CONR 11 R 11 , -NR 11 R 11 , -NR 11 -CO 2 R 11 , an optionally substituted C 1 -C 6 alkyl, an optionally substituted C 3 -C 5 cycloalkyl, an optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine or morpholine, an optionally substituted phenyl, or an optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole, or thiazole; wherein the optionally substituted C 1 -C 6 alkyl is optionally substituted with a -CN, -OH, or C 1 -C 3 alkoxy;
  • R3 is -H, -CN, C 1 -C 3 alkyl, or C 1 -C 3 haloalkyl (preferably R3 is -H, -CN, or C 1 -C 3 alkyl), R5 is -H, halogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl, R 6 is -H, or halogen, and R 2 is a group of the formula: ; more preferably R 3 is -H, or methyl, R 5 is -H, halogen, methyl, or trifluoromethyl, R 6 is -H, and R 2 is a group of the formula:
  • each R 10 is independently -H, -CN, halogen, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy
  • R5 is -H, halogen, C 1 -C 3 alkyl or C 1 -C 3 haloalkyl
  • R4 is -H or halogen (preferably R4 is -H)
  • R6 is -H, or halogen
  • R 2 is a group of the formula:
  • each R 10 is independently -H, -CN, halogen, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, -SO 2 R 11 , -CONR 11 R 11 , -NR 11 R 11 , -NR 11 -CO 2 R 11 , an optionally substituted C 1 -C 6 alkyl, an optionally substituted C 3 -C 5 cycloalkyl, an optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine or morpholine, an optionally substituted phenyl, or an optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole,
  • R 3 is -H, -CN, C 1 -C 3 alkyl, or C 1 -C 3 haloalkyl (preferably R 3 is -H, -CN, or C 1 -C 3 alkyl), R 4 is -H or halogen (preferably R4 is -H), R6 is -H, or halogen, and R5 is -H, halogen, C 1 -C 3 alkyl or C 1 -C 3 haloalkyl; more preferably R 3 is -H, or methyl, R 4 and R 6 are each -H, and R 5 is -H, halogen, methyl, or trifluoromethyl.
  • R3 is -H, -CN, C 1 -C 3 alkyl, or C 1 -C 3 haloalkyl (preferably R3 is -H, -CN, or C 1 -C 3 alkyl)
  • R4 is -H or halogen (preferably R 4 is -H)
  • R 6 is -H, or halogen
  • R 5 is -H, halogen, C 1 -C 3 alkyl or C 1 -C 3 haloalkyl
  • R 2 is a group of the formula:
  • each R 10 is independently -H, -CN, halogen, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, -SO 2 R 11 , -CONR 11 R 11 , -NR 11 R 11 , -NR 11 -CO 2 R 11 , an optionally substituted C 1 -C 6 alkyl, an optionally substituted C 3 -C 5 cycloalkyl, an optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine or morpholine, an optionally substituted phenyl, or an optionally substituted heteroaryl selected from pyrazole, isoxazole
  • R is -H.
  • R 7 is -CN, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; preferably R 7 is -CN, C 1 -C 3 alkyl or C 1 -C 3 haloalkyl; more preferably R7 is -CN, methyl or trifluoromethyl.
  • R 8 is -H.
  • R7 is -CN, C 1 -C 3 alkyl or C 1 -C 3 haloalkyl, and R is -H.
  • R 7 is C 1 -C 3 alkyl (preferably methyl), and R is -H.
  • R8 and R are each -H.
  • R 7 is -CN, C 1 -C 3 alkyl or C 1 -C 3 haloalkyl, and R 8 is H.
  • R7 is C 1 -C 3 alkyl (preferably methyl), and R8 is H.
  • R 7 is -CN, C 1 -C 3 alkyl or C 1 -C 3 haloalkyl, and R 8 and R are each -H.
  • R7 is C 1 -C 3 alkyl (preferably methyl), and R8 and R are each -H.
  • R 7 is -CN, C 1 -C 3 alkyl or C 1 -C 3 haloalkyl, R 8 is -H, R is -H, and R 2 is a group of the formula: [479]
  • R 7 is C 1 -C 3 alkyl (preferably methyl)
  • R 8 is -H
  • R is -H
  • R 2 is a group of the formula:
  • each R 10 is independently -H, -CN, halogen, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, -SO 2 R 11 , -CONR 11 R 11 , -NR 11 R 11 , -NR 11 -CO 2 R 11 , an optionally substituted C 1 -C 6 alkyl, an optionally substituted C 3 -C 5 cycloalkyl, an optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine or morpholine, an optionally substituted phenyl, or an optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole, or thiazole; wherein the optionally substituted C 1 -C 6 alkyl is optionally substituted with a -CN, -OH, or C 1 -C 3 alkoxy;
  • R 3 is -H, -CN, C 1 -C 3 alkyl, or C 1 -C 3 haloalkyl (preferably R 3 is -H, -CN, or C 1 -C 3 alkyl), R 7 is -CN, C 1 -C 3 alkyl or C 1 -C 3 haloalkyl, and R8 and R are each -H.
  • R3 is -H, or methyl
  • R7 is C 1 -C 3 alkyl (preferably methyl)
  • R 8 and R are each -H.
  • R7 is -CN, C 1 -C 3 alkyl or C 1 -C 3 haloalkyl, and R4, R8 and R are each -H.
  • R 7 is C 1 -C 3 alkyl (preferably methyl), and R 4 , R 8 and R are each -H.
  • R 5 is -H, halogen, C 1 -C 3 alkyl or C 1 -C 3 haloalkyl
  • R 7 is -CN, methyl or trifluoromethyl
  • R 8 and R are each -H.
  • R5 is -H, halogen, methyl, or trifluoromethyl
  • R7 is methyl
  • R8 and R are each -H.
  • R 3 is -H, -CN, C 1 -C 3 alkyl, or C 1 -C 3 haloalkyl (preferably R 3 is -H, -CN, or C 1 -C 3 alkyl), R 4 is -H or halogen (preferably R4 is -H), R6 is -H, or halogen, R5 is -H, halogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl, R7 is -CN, methyl or trifluoromethyl, R8 is -H, R is -H, and R 2 is a group of the formula: more preferably R3 is -H, or methyl, R 4 is -H, R 6 is -H, or halogen, R 5 is -H, halogen, methyl, or trifluoromethyl, R 7 is methyl, R 8 is
  • each R10 is independently -H, -CN, halogen, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, -SO 2 R 11 , -CONR 11 R 11 , -NR 11 R 11 , -NR 11 -CO 2 R 11 , an optionally substituted C 1 -C 6 alkyl, an optionally substituted C 3 -C 5 cycloalkyl, an optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine or morpholine, an optionally substituted phenyl, or an optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole, or thiazole; wherein the optionally substituted C 1 -C 6 alkyl is optionally substituted with a -CN, -OH, or C 1 -C 3 alk
  • R 1 is a group of the formula: wherein each R 9 is independently -H, halogen, -CN, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, C 1 -C 3 alkoxy, or C 3 -C 5 cycloalkyl; preferably each R 9 is independently -H, halogen, -CN, methyl, trifluoromethyl, methoxy, or cyclopropyl.
  • R1 is a group of the formula: or ; wherein each R9 is independently -H, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 3 -C 5 cycloalkyl; preferably each R 9 is independently -H, halogen, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, C 1 -C 3 alkoxy, or C 3 -C 5 cycloalkyl; more preferably each R 9 is independently -H, halogen, methyl, trifluoromethyl, methoxy, or cyclopropyl.
  • R 1 is a group of the formula: wherein each R9 is independently -H, halogen, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, or C3- C5 cycloalkyl; preferably each R 9 is independently -H, halogen, methyl, trifluoromethyl, or cyclopropyl.
  • R 1 is a group of the formula: wherein each R9 is independently -H, halogen, C 1 -C 3 alkyl or C 1 -C 3 haloalkyl; preferably each R9 is independently -H, halogen, methyl or trifluoromethyl.
  • R 1 is a group of the formula: [489] In yet a further compound of Formula (I), or (II), or pharmaceutically acceptable salts thereof, R1 is a group of the formula:
  • R9 is independently -H, halogen, C 1 -C 3 alkyl or C 1 -C 3 haloalkyl; preferably each R9 is independently -H, halogen, methyl or trifluoromethyl.
  • R1 is a group of the formula: ; wherein each R 9 is independently -H, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 3 -C 5 cycloalkyl.
  • each R9 is independently -H, halogen, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, or C 3 -C 5 cycloalkyl. More preferably each R 9 is independently -H, halogen, methyl, trifluoromethyl, or cyclopropyl.
  • R1 is a group of the formula: wherein each R 9 is independently -H, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 3 -C 5 cycloalkyl.
  • each R9 is independently -H, halogen, C 1 -C 3 alkyl or C 1 -C 3 haloalkyl. More preferably each R9 is independently -H, halogen, methyl or trifluoromethyl.
  • R1 is a group of the formula ; wherein each R9 is independently -H, halogen, -CN, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 3 -C 5 cycloalkyl; preferably each R 9 is independently -H, halogen, -CN, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, C 1 -C 3 alkoxy, or C 3 -C 5 cycloalkyl; more preferably each R9 is independently -H, halogen, -CN, methyl, trifluoromethyl, methoxy, or cyclopropyl. [493] In yet a further compound of Formula (I), or (II), or pharmaceutically acceptable salts thereof, R1 is a group of the formula
  • each R9 is independently -H, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 3 -C 5 cycloalkyl; preferably each R 9 is independently -H, halogen, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, C 1 -C 3 alkoxy, or C 3 -C 5 cycloalkyl; more preferably each R 9 is independently -H, halogen, methyl, trifluoromethyl, methoxy, or cyclopropyl.
  • R 1 is a group of the formula: wherein each R 9 is independently -H, halogen, -CN, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl or C 1 -C 3 alkoxy. Preferably each R 9 is independently -H, halogen, C 1 -C 3 alkyl or C 1 -C 3 haloalkyl. More preferably each R9 is independently -H, halogen, methyl or trifluoromethyl. [495] In yet a further compound of Formula (I), or (II), or pharmaceutically acceptable salts thereof, R 1 is a group of the formula:
  • R9 is -H, halogen, -CN, C 1 -C 3 haloalkyl, or C 1 -C 3 alkoxy.
  • R9 is -H, halogen, or C 1 -C 3 haloalkyl. More preferably R9 is -H, or trifluoromethyl.
  • R 1 is a group of the formula: wherein R 9 is -H, halogen, -CN, C 1 -C 3 haloalkyl, or C 1 -C 3 alkoxy.
  • R9 is -H, halogen, or C 1 -C 3 haloalkyl. More preferably R9 is -H, or halogen. Even more preferably, R9 is -H, or fluoro.
  • R 1 is a group of the formula: ; wherein R 9 is -H, halogen, -CN, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, C 1 -C 3 alkoxy, or C 3 -C 5 cycloalkyl.
  • R 9 is -H, halogen, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, or C 3 -C 5 cycloalkyl. More preferably R9 is independently -H, halogen, methyl, trifluoromethyl, or cyclopropyl.
  • R1 is a group of the formula:
  • R9 is -H, halogen, or C 1 -C 3 haloalkyl.
  • R9 is independently halogen or trifluoromethyl. More preferably R9 is chloro or trifluoromethyl.
  • R 1 is a group of the formula: wherein R9 is -H, halogen, -CN, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl or C 1 -C 6 alkoxy.
  • R9 is -H, halogen, C 1 -C 6 alkyl or C 1 -C 6 haloalkyl.
  • R9 is -H, halogen, C 1 -C 3 alkyl or C 1 -C 3 haloalkyl.
  • R1 is a group of the formula: wherein R9 is -H, halogen, -CN, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, C 1 -C 3 alkoxy, or C 3 -C 5 cycloalkyl.
  • R 9 is -H, halogen, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, or C 3 -C 5 cycloalkyl.
  • R 9 is -H, halogen, methyl, trifluoromethyl, or cyclopropyl.
  • R 1 is a group of the formula:
  • R3 is -H, -CN, C 1 -C 3 alkyl, or C 1 -C 3 haloalkyl
  • R4 is -H, or halogen
  • R6 is -H, or halogen
  • R5 is -H, halogen, C 1 -C 3 alkyl or C 1 -C 3 haloalkyl
  • R1 is a group of the formula: ; wherein each R9 is independently -H, halogen, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, or C 3 -C 5 cycloalkyl.
  • each R 9 is independently -H, halogen, methyl, trifluoromethyl, or cyclopropyl.
  • R 3 is -H, methyl, or trifluoromethyl
  • R 4 is -H, or halogen
  • R 6 is -H, or halogen
  • R 5 is -H, halogen, methyl, or trifluoromethyl
  • each R9 is independently -H, halogen, methyl, trifluoromethyl, or cyclopropyl.
  • R 3 is -H, -CN, or C 1 -C 3 alkyl
  • R 4 is -H
  • R 6 is -H
  • R 5 is -H
  • halogen C 1 -C 3 alkyl or C 1 -C 3 haloalkyl
  • R1 is a group of the formula: wherein each R 9 is independently -H, halogen, C 1 -C 3 alkyl or C 1 -C 3 haloalkyl.
  • R 3 is -H, or methyl
  • R 4 is -H
  • R 6 is -H
  • R 5 is -H, halogen, methyl, or trifluoromethyl
  • each R9 is independently -H, halogen, methyl, or trifluoromethyl.
  • R7 is -CN, methyl or trifluoromethyl
  • R8 and R are each -H
  • R1 is a group of the formula: wherein each R 9 is independently -H, halogen, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, or C 3 -C 5 cycloalkyl; more preferably R7 is methyl, R8 and R are each -H, and each R9 is independently -H, halogen, methyl, trifluoromethyl, or cyclopropyl.
  • R7 is -CN, methyl or trifluoromethyl
  • R8 and R are each -H
  • R1 is a group of the formula: wherein each R 9 is independently -H, halogen, C 1 -C 3 alkyl or C 1 -C 3 haloalkyl; more preferably R7 is methyl, R8 and R are each -H, and each R9 is independently -H, halogen, methyl, or trifluoromethyl.
  • R 3 is -H, -CN, C 1 -C 3 alkyl, or C 1 -C 3 haloalkyl
  • R 4 is -H, or halogen
  • R 8 and R are each -H
  • R 5 is -H, halogen, C 1 -C 3 alkyl or C 1 -C 3 haloalkyl
  • R6 is -H, or halogen
  • R7 is -CN, methyl or trifluoromethyl
  • R 1 is a group of the formula:
  • each R 9 is independently -H, halogen, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, or C 3 -C 5 cycloalkyl; more preferably R3 is -H, methyl, or trifluoromethyl, R4 is -H, or halogen, R6 is -H, or halogen, R8 and R are each -H, R 5 is -H, halogen, methyl, or trifluoromethyl, R 7 is methyl, and each R 9 is independently -H, halogen, methyl, trifluoromethyl, or cyclopropyl.
  • R 3 is -H, -CN, or C 1 -C 3 alkyl
  • R 4 , R 8 and R are each -H
  • R 5 is -H, halogen, C 1 -C 3 alkyl or C 1 -C 3 haloalkyl
  • R 6 is -H, or halogen
  • R 7 is -CN, methyl or trifluoromethyl
  • R 1 is a group of the formula: wherein each R 9 is independently -H, halogen, C 1 -C 3 alkyl or C 1 -C 3 haloalkyl; more preferably R3 is -H, or methyl, R4, R6, R8 and R are each -H, R5 is -H, halogen, methyl, or trifluoromethyl, R7 is methyl, and each R9 is independently -H, halogen, methyl, or trifluoromethyl.
  • R3 is -H, -CN, C 1 -C 3 alkyl, or C 1 -C 3 haloalkyl
  • R4 is -H, or halogen
  • R8 and R are each -H
  • R5 is -H, halogen, C 1 -C 3 alkyl or C 1 -C 3 haloalkyl
  • R 6 is -H, or halogen
  • R 7 is -CN, methyl or trifluoromethyl
  • R 1 is a group of the formula:
  • each R9 is independently -H, halogen, C 1 -C 3 alkyl or C 1 -C 3 haloalkyl; preferably R3 is -H, methyl, or trifluoromethyl, R4 is -H, or halogen, R6 is -H, or halogen, R 8 and R are each -H, R 5 is -H, halogen, methyl, or trifluoromethyl, R 7 is methyl, and each R 9 is independently -H, halogen, methyl or trifluoromethyl.
  • R 3 is -H, -CN, or C 1 -C 3 alkyl
  • R 4 , R 8 and R are each -H
  • R 5 is -H, halogen, C 1 -C 3 alkyl or C 1 -C 3 haloalkyl
  • R 6 is -H, or halogen
  • R 7 is -CN, methyl or trifluoromethyl
  • R 1 is a group of the formula: wherein R 9 is -H, halogen, or C 1 -C 3 haloalkyl; preferably R 3 is -H, or methyl, R4, R6, R8 and R are each -H, R5 is -H, halogen, methyl, or trifluoromethyl, R7 is methyl, and R 9 is -H, or trifluoromethyl.
  • R3 is -H, -CN, or C 1 -C 3 alkyl
  • R4, R8 and R are each -H
  • R5 is -H, halogen, C 1 -C 3 alkyl or C 1 -C 3 haloalkyl
  • R6 is -H, or halogen
  • R7 is -CN, methyl or trifluoromethyl
  • R1 is a group of the formula: wherein R9 is -H, halogen, or C 1 -C 3 haloalkyl; preferably R3 is -H, or methyl, R 4 , R 6 , R 8 and R are each -H, R 5 is -H, halogen, methyl, or trifluoromethyl, R 7 is methyl, and R 9 is -H, or halogen, more preferably R 9 is -H, or fluoro.
  • R 3 is -H, -CN, C 1 -C 3 alkyl, or C 1 -C 3 haloalkyl
  • R 4 is -H, or halogen
  • R 8 and R are each -H
  • R 5 is -H, halogen, C 1 -C 3 alkyl or C 1 -C 3 haloalkyl
  • R 6 is -H, or halogen
  • R 7 is -CN, methyl or trifluoromethyl
  • R1 is a group of the formula: ; wherein R 9 is -H, halogen, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, or C 3 -C 5 cycloalkyl; preferably R3 is -H, methyl, or trifluoromethyl, R4 is -H, or halogen, R6 is -H, or halogen, R8 and
  • R3 is -H, -CN, or C 1 -C 3 alkyl
  • R4, R8 and R are each -H
  • R5 is -H, halogen, C 1 -C 3 alkyl or C 1 -C 3 haloalkyl
  • R 6 is -H, or halogen
  • R 7 is -CN, methyl or trifluoromethyl
  • R 1 is a group of the formula: wherein R 9 is -H, halogen, or C 1 -C 3 haloalkyl; preferably R 3 is -H, or methyl, R4, R6, R8 and R are each -H, R5 is -H, halogen, methyl, or trifluoromethyl, R7 is methyl, and R9 is independently halogen or trifluoromethyl.
  • R 3 is -H, -CN, or C 1 -C 3 alkyl
  • R 4 , R 8 and R are each -H
  • R 5 is -H, halogen, C 1 -C 3 alkyl or C 1 -C 3 haloalkyl
  • R6 is -H, or halogen
  • R7 is -CN, methyl or trifluoromethyl
  • R1 is a group of the formula: ; wherein R 9 is -H, halogen, C 1 -C 3 alkyl or C 1 -C 3 haloalkyl; preferably R 3 is -H, or methyl, R4, R6, R8 and R are each -H, R5 is -H, halogen, methyl, or trifluoromethyl, R7 is methyl, and R9 is -H, halogen, C 1 -C 3 alkyl or C 1 -
  • R 3 is -H, -CN, C 1 -C 3 alkyl, or C 1 -C 3 haloalkyl
  • R 4 is -H, or halogen
  • R 8 and R are each -H
  • R 5 is -H, halogen, C 1 -C 3 alkyl or C 1 -C 3 haloalkyl
  • R6 is -H, or halogen
  • R7 is -CN, methyl or trifluoromethyl
  • R 1 is a group of the formula: wherein R 9 is -H, halogen, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, or C 3 -C 5 cycloalkyl; preferably R 3 is -H, methyl, or trifluoromethyl, R 4 is -H, or halogen, R 6 is -H, or halogen, R8 and R
  • each R9 is independently -H, halogen, C 1 -C 3 alkyl or C 1 -C 3 haloalkyl
  • R 2 is a group of the formula: wherein each R 10 is independently -H, -CN, halogen, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, -SO 2 R 11 , -CONR 11 R 11 , -NR 11 R 11 , -NR 11 -CO 2 R 11 , an optionally substituted C 1 -C 6 alkyl, an optionally substituted C 3 -C 5 cycloalkyl, an optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine or morpholine, an optionally substituted phenyl, or an optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole, or
  • each R 9 is independently -H, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 3 -C 5 cycloalkyl
  • R 2 is a group of the formula: .
  • each R9 is independently -H, halogen, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, or C 3 -C 5 cycloalkyl.
  • each R9 is independently -H, halogen, methyl, trifluoromethyl, or cyclopropyl.
  • each R10 is independently -H, -CN, halogen, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, -SO 2 R 11 , -CONR 11 R 11 , -NR 11 R 11 , -NR 11 -CO 2 R 11 , an optionally substituted C 1 -C 6 alkyl, an optionally substituted C 3 -C 5 cycloalkyl, an optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine or morpholine, an optionally substituted phenyl, or an optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole, or thiazole; wherein the optionally substituted C 1 -C 6 alkyl is optionally substituted with a -CN, -OH, or C 1 -C 3 alkoxy;
  • each R 9 is independently -H, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 3 -C 5 cycloalkyl, and R 2 is a group of the formula: .
  • each R9 is independently -H, halogen, C 1 -C 3 alkyl or C 1 -C 3 haloalkyl.
  • each R 9 is independently -H, halogen, methyl, or trifluoromethyl.
  • each R10 is independently -H, -CN, halogen, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, -SO 2 R 11 , -CONR 11 R 11 , -NR 11 R 11 , -NR 11 -CO 2 R 11 , an optionally substituted C 1 -C 6 alkyl, an optionally substituted C 3 -C 5 cycloalkyl, an optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine or morpholine, an optionally substituted phenyl, or an optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole, or thiazole; wherein the optionally substituted C 1 -C 6 alkyl is optionally substituted with a -CN, -OH, or C 1 -C 3 alkoxy;
  • each R9 is independently -H, halogen, C 1 -C 3 alkyl or C 1 -C 3 haloalkyl, and R 2 is a group of the formula: .
  • each R9 is independently -H, halogen, methyl or trifluoromethyl.
  • each R 10 is independently -H, -CN, halogen, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, -SO 2 R 11 , -CONR 11 R 11 , -NR 11 R 11 , -NR 11 -CO 2 R 11 , an optionally substituted C 1 -C 6 alkyl, an optionally substituted C 3 -C 5 cycloalkyl, an optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine or morpholine, an optionally substituted phenyl, or an optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole, or thiazole; wherein the optionally substituted C 1 -C 6 alkyl is optionally substituted with a -CN, -OH, or C 1 -C 3 alkoxy;
  • R 1 is a group of the formula: wherein R 9 is -H, halogen, or C 1 -C 3 haloalkyl, and R 2 is a group of the formula:
  • R9 is -H, or trifluoromethyl.
  • each R 10 is independently -H, -CN, halogen, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, -SO 2 R 11 , -CONR 11 R 11 , -NR 11 R 11 , -NR 11 -CO 2 R 11 , an optionally substituted C 1 -C 6 alkyl, an optionally substituted C 3 -C 5 cycloalkyl, an optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine or morpholine, an optionally substituted phenyl, or an optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole, or thiazole; wherein the optionally substituted C 1 -C 6 alkyl is optionally substituted with a
  • R 1 is a group of the formula: ; wherein R9 is -H, halogen, or C 1 -C 3 haloalkyl, and R 2 is a group of the formula: .
  • R9 is -H, or halogen.
  • each R 10 is independently -H, -CN, halogen, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, -SO 2 R 11 , -CONR 11 R 11 , -NR 11 R 11 , -NR 11 -CO 2 R 11 , an optionally substituted C 1 -C 6 alkyl, an optionally substituted C 3 -C 5 cycloalkyl, an optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine or morpholine, an optionally substituted phenyl, or an optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole, or thiazole; wherein the optionally substituted C 1 -C 6 alkyl is optionally substituted with a -CN, -OH, or C 1 -C 3 alkoxy;
  • R1 is a group of the formula: wherein R9 is -H, halogen, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, or C 3 -C 5 cycloalkyl, and R 2 is a group of the formula: ; ; or ; preferably R 9 is -H, halogen, methyl, trifluoromethyl, or cyclopropyl.
  • each R10 is independently -H, -CN, halogen, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, -SO 2 R 11 , -CONR 11 R 11 , -NR 11 R 11 , -NR 11 -CO 2 R 11 , an optionally substituted C 1 -C 6 alkyl, an optionally substituted C 3 -C 5 cycloalkyl, an optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine or morpholine, an optionally substituted phenyl, or an optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole, or thiazole; wherein the optionally substituted C 1 -C 6 alkyl is optionally substituted with a -CN, -OH, or C 1 -C 3 alkoxy;
  • R1 is a group of the formula: wherein R 9 is halogen, or C 1 -C 3 haloalkyl, and R 2 is a group of the formula: ; ; or ; preferably R 9 is halogen or trifluoromethyl. More preferably R 9 is chloro or trifluoromethyl.
  • each R 10 is independently -H, -CN, halogen, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, -SO 2 R 11 , -CONR 11 R 11 , -NR 11 R 11 , -NR 11 -CO 2 R 11 , an optionally substituted C 1 -C 6 alkyl, an optionally substituted C 3 -C 5 cycloalkyl, an optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine or morpholine, an optionally substituted phenyl, or an optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole, or thiazole; wherein the optionally substituted C 1 -C 6 alkyl is optionally substituted with a -CN, -OH, or C 1 -C 3 alkoxy;
  • each R 10 is independently -H, -CN, halogen, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, -SO 2 R 11 , -CONR 11 R 11 , -NR 11 R 11 , -NR 11 -CO 2 R 11 , an optionally substituted C 1 -C 6 alkyl, an optionally substituted C 3 -C 5 cycloalkyl, an optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine or morpholine, an optionally substituted phenyl, or an optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole,
  • R 1 is a group of the formula: ; wherein R 9 is -H, halogen, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, or C 3 -C 5 cycloalkyl, and R 2 is a group of the formula:
  • each R 10 is independently -H, -CN, halogen, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, -SO 2 R 11 , -CONR 11 R 11 , -NR 11 R 11 , -NR 11 -CO 2 R 11 , an optionally substituted C 1 -C 6 alkyl, an optionally substituted C 3 -C 5 cycloalkyl, an optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine or morpholine, an optionally substituted phenyl, or an optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole, or thiazole; wherein the optionally substituted
  • R 2 is a group of the formula: ; ; ; or , R3 is -H, -CN, C 1 -C 3 alkyl, or C 1 -C 3 haloalkyl, R4 is -H, or halogen, R6 is -H, or halogen, R5 is -H, halogen, C 1 -C 3 alkyl or C 1 -C 3 haloalkyl, and R 1 is a group of the formula:
  • each R 9 is independently -H, halogen, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, or C 3 -C 5 cycloalkyl.
  • R3 is -H, methyl, or trifluoromethyl
  • R4 is -H, or halogen
  • R6 is -H, or halogen
  • R5 is -H, halogen, methyl, or trifluoromethyl
  • each R 9 is independently -H, halogen, methyl, trifluoromethyl, or cyclopropyl.
  • each R10 is independently -H, -CN, halogen, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, -SO 2 R 11 , -CONR 11 R 11 , -NR 11 R 11 , -NR 11 -CO 2 R 11 , an optionally substituted C 1 -C 6 alkyl, an optionally substituted C 3 -C 5 cycloalkyl, an optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine or morpholine, an optionally substituted phenyl, or an optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole, or thiazole; wherein the optionally substituted C 1 -C 6 alkyl is optionally substituted with a -CN, -OH, or C 1 -C 3 alkoxy;
  • R 2 is a group of the formula: R3 is -H, -CN, or C 1 -C 3 alkyl, R4 is -H, R6 is -H, or halogen, R5 is -H, halogen, C 1 -C 3 alkyl or C 1 -C 3 haloalkyl, and R1 is a group of the formula:
  • each R 9 is independently -H, halogen, or C 1 -C 3 haloalkyl.
  • R3 is -H, or methyl
  • R4 and R6 are each -H
  • R5 is -H, halogen, methyl, or trifluoromethyl
  • each R9 is independently -H, halogen, methyl, or trifluoromethyl.
  • each R 10 is independently -H, -CN, halogen, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, -SO 2 R 11 , -CONR 11 R 11 , -NR 11 R 11 , -NR 11 -CO 2 R 11 , an optionally substituted C 1 -C 6 alkyl, an optionally substituted C 3 -C 5 cycloalkyl, an optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine or morpholine, an optionally substituted phenyl, or an optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole, or thiazole; wherein the optionally substituted C 1 -C 6 alkyl is optionally substituted with a -CN, -OH, or C 1 -C 3 alkoxy;
  • R 2 is a group of the formula:
  • R 7 is -CN, methyl or trifluoromethyl
  • R8 and R are each -H
  • R1 is a group of the formula:
  • each R 9 is independently -H, halogen, methyl, C 1 -C 3 haloalkyl, or cyclopropyl.
  • each R10 is independently -H, -CN, halogen, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, -SO 2 R 11 , -CONR 11 R 11 , -NR 11 R 11 , -NR 11 -CO 2 R 11 , an optionally substituted C 1 -C 6 alkyl, an optionally substituted C 3 -C 5 cycloalkyl, an optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine or morpholine, an optionally substituted phenyl, or an optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole, or thiazole; wherein the optional
  • R 2 is a group of the formula: , R7 is -CN, methyl or trifluoromethyl, R 8 and R are each -H, and R 1 is a group of the formula:
  • each R 9 is independently -H, halogen, methyl, or C 1 -C 3 haloalkyl.
  • each R10 is independently -H, -CN, halogen, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, -SO 2 R 11 , -CONR 11 R 11 , -NR 11 R 11 , -NR 11 -CO 2 R 11 , an optionally substituted C 1 -C 6 alkyl, an optionally substituted C 3 -C 5 cycloalkyl, an optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine or morpholine, an optionally substituted phenyl, or an optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole, or thiazole; wherein the optionally substituted C 1 -
  • R1 is a group of the formula: wherein each R9 is independently -H, halogen, methyl or trifluoromethyl, R 2 is a group of the formula: , R7 is C 1 -C 3 alkyl (preferably methyl), and R 8 and R are each -H.
  • each R 10 is independently -H, -CN, halogen, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, -SO 2 R 11 , -CONR 11 R 11 , -NR 11 R 11 , -NR 11 -CO 2 R 11 , an optionally substituted C 1 -C 6 alkyl, an optionally substituted C 3 -C 5 cycloalkyl, an optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine or morpholine, an optionally substituted phenyl, or an optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole, or thiazole; wherein the optionally substituted C 1 -C 6 alkyl is optionally substituted with a -CN, -OH, or C 1 -C 3 alkoxy;
  • R 1 is a group of the formula: ; wherein R 9 is -H, halogen, or trifluoromethyl, (preferably R 9 is -H, or trifluoromethyl), R 2 is a group of the formula: , R7 is C 1 -C 3 alkyl (preferably methyl), and R 8 and R are each -H.
  • each R 10 is independently -H, -CN, halogen, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, -SO 2 R 11 , -CONR 11 R 11 , -NR 11 R 11 , -NR 11 -CO 2 R 11 , an optionally substituted C 1 -C 6 alkyl, an optionally substituted C 3 -C 5 cycloalkyl, an optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine or morpholine, an optionally substituted phenyl, or an optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole, or thiazole; wherein the optionally substituted C 1 -C 6 alkyl is optionally substituted with a -CN, -OH, or C 1 -C 3 alkoxy;
  • R1 is a group of the formula: wherein R 9 is -H, halogen, or C 1 -C 3 haloalkyl (preferably R 9 is -H, or halogen), R 2 is a group of the formula: , R 7 is C 1 -C 3 alkyl (preferably methyl), and R 8 and R are each -H.
  • each R 10 is independently -H, -CN, halogen, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, -SO 2 R 11 , -CONR 11 R 11 , -NR 11 R 11 , -NR 11 -CO 2 R 11 , an optionally substituted C 1 -C 6 alkyl, an optionally substituted C 3 -C 5 cycloalkyl, an optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine or morpholine, an optionally substituted phenyl, or an optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole, or thiazole; wherein the optionally substituted C 1 -C 6 alkyl is optionally substituted with a -CN, -OH, or C 1 -C 3 alkoxy;
  • R9 is -H, halogen, methyl, trifluoromethyl, or cyclopropyl
  • R 2 is a group of the formula: ; ; or , R 7 is C 1 -C 3 alkyl (preferably methyl), and R 8 and R are each -H.
  • each R 10 is independently -H, -CN, halogen, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, -SO 2 R 11 , -CONR 11 R 11 , -NR 11 R 11 , -NR 11 -CO 2 R 11 , an optionally substituted C 1 -C 6 alkyl, an optionally substituted C 3 -C 5 cycloalkyl, an optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine or morpholine, an optionally substituted phenyl, or an optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole, or thiazole; wherein the optionally substituted C 1 -C 6 alkyl is optionally substituted with a -CN, -OH, or C 1 -C 3 alkoxy;
  • R1 is a group of the formula: ; wherein R9 is -H, halogen, or trifluoromethyl (preferably R9 is halogen or trifluoromethyl), R 2 is a group of the formula:
  • R7 is C 1 -C 3 alkyl (preferably methyl), and R 8 and R are each -H.
  • each R 10 is independently -H, -CN, halogen, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, -SO 2 R 11 , -CONR 11 R 11 , -NR 11 R 11 , -NR 11 -CO 2 R 11 , an optionally substituted C 1 -C 6 alkyl, an optionally substituted C 3 -C 5 cycloalkyl, an optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine or morpholine, an optionally substituted phenyl, or an optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole, or thiazole; wherein the optionally substituted C
  • R 1 is a group of the formula: ; wherein R 9 is -H, halogen, C 1 -C 3 alkyl or C 1 -C 3 haloalkyl, R 2 is a group of the formula: ; ; or , R7 is C 1 -C 3 alkyl (preferably methyl), and R 8 and R are each -H.
  • each R 10 is independently -H, -CN, halogen, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, -SO 2 R 11 , -CONR 11 R 11 , -NR 11 R 11 , -NR 11 -CO 2 R 11 , an optionally substituted C 1 -C 6 alkyl, an optionally substituted C 3 -C 5 cycloalkyl, an optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine or morpholine, an optionally substituted phenyl, or an optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole, or thiazole; wherein the optionally substituted C 1 -C 6 alkyl is optionally substituted with a -CN, -OH, or C 1 -C 3 alkoxy;
  • R1 is a group of the formula: ; wherein R9 is -H, halogen, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, or C 3 -C 5 cycloalkyl, R 2 is a group of the formula: ; ; or , R 7 is C 1 -C 3 alkyl (preferably methyl), and R 8 and R are each -H.
  • each R 10 is independently -H, -CN, halogen, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, -SO 2 R 11 , -CONR 11 R 11 , -NR 11 R 11 , -NR 11 -CO 2 R 11 , an optionally substituted C 1 -C 6 alkyl, an optionally substituted C 3 -C 5 cycloalkyl, an optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine or morpholine, an optionally substituted phenyl, or an optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole, or thiazole; wherein the optionally substituted C 1 -C 6 alkyl is optionally substituted with a -CN, -OH, or C 1 -C 3 alkoxy;
  • R 2 is a group of the formula: ; ; ; or , R 3 is -H, -CN, C 1 -C 3 alkyl, or C 1 -C 3 haloalkyl, R4 is -H, or halogen, R8 and R are each -H, R5 is -H, halogen, C 1 -C 3 alkyl or C 1 -C 3 haloalkyl, R6 is H, or halogen, R7 is -CN, methyl or trifluoromethyl, and R1 is a group of the formula: ; ; ; or ; wherein each R9 is independently -H, halogen, methyl, C 1 -C 3 haloalkyl, or cyclopropyl.
  • each R 10 is independently -H, -CN, halogen, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, -SO 2 R 11 , -CONR 11 R 11 , -NR 11 R 11 , -NR 11 -CO 2 R 11 , an optionally substituted C 1 -C 6 alkyl, an optionally substituted C 3 -C 5 cycloalkyl, an optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine or morpholine, an optionally substituted phenyl, or an optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole, or thiazole; wherein the optionally substituted C 1 -C 6 alkyl is optionally substituted with a -CN, -OH, or C 1 -C 3 alkoxy;
  • R 2 is a group of the formula: ; ; ; or , R 3 is -H, -CN, or C 1 -C 3 alkyl, R4, R8 and R are each -H, R5 is -H, halogen, C 1 -C 3 alkyl or C 1 -C 3 haloalkyl, R6 is -H or halogen, R 7 is -CN, methyl or trifluoromethyl, and R 1 is a group of the formula: ; ; or ; wherein each R9 is independently -H, halogen, methyl, or C 1 -C 3 haloalkyl.
  • each R10 is independently -H, -CN, halogen, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, -SO 2 R 11 , -CONR 11 R 11 , -NR 11 R 11 , -NR 11 -CO 2 R 11 , an optionally substituted C 1 -C 6 alkyl, an optionally substituted C 3 -C 5 cycloalkyl, an optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine or morpholine, an optionally substituted phenyl, or an optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole, or thiazole; wherein the optionally substituted C 1 -C 6 alkyl is optionally substituted with a -CN, -OH, or C 1 -C 3 alkoxy;
  • each R9 is independently -H, halogen, methyl or trifluoromethyl
  • R 2 is a group of the formula: ; ; or , R3 is -H, methyl, or trifluoromethyl, R4 is -H, or halogen, R 8 and R are each -H, R 5 is -H, halogen, methyl or trifluoromethyl, R 6 is -H, or halogen, and R7 is C 1 -C 3 alkyl (preferably methyl).
  • each R10 is independently -H, -CN, halogen, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, -SO 2 R 11 , -CONR 11 R 11 , -NR 11 R 11 , -NR 11 -CO 2 R 11 , an optionally substituted C 1 -C 6 alkyl, an optionally substituted C 3 -C 5 cycloalkyl, an optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine or morpholine, an optionally substituted phenyl, or an optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole, or thiazole; wherein the optionally substituted C 1 -C 6 alkyl is optionally substituted with a -CN, -OH, or C 1 -C 3 alkoxy;
  • R1 is a group of the formula: ; wherein R9 is -H, halogen, or trifluoromethyl, (preferably R9 is -H, or trifluoromethyl), R 2 is a group of the formula: ; ; or , R 3 is -H, or methyl, R 4 , R 8 and R are each -H, R 5 is -H, halogen, methyl, or trifluoromethyl, R 6 is -H or halogen, and R 7 is C 1 -C 3 alkyl (preferably methyl).
  • each R10 is independently -H, -CN, halogen, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, -SO 2 R 11 , -CONR 11 R 11 , -NR 11 R 11 , -NR 11 -CO 2 R 11 , an optionally substituted C 1 -C 6 alkyl, an optionally substituted C 3 -C 5 cycloalkyl, an optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine or morpholine, an optionally substituted phenyl, or an optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole, or thiazole; wherein the optionally substituted C 1 -C 6 alkyl is optionally substituted with a -CN, -OH, or C 1 -C 3 alkoxy;
  • R1 is a group of the formula: ; wherein R 9 is -H, halogen, or C 1 -C 3 haloalkyl (preferably R 9 is -H, or halogen), R 2 is a group of the formula: ; ; or , R 3 is -H, or methyl, R 4 , R 8 and R are each -H, R5 is -H, halogen, methyl, or trifluoromethyl, R6 is -H or halogen, and R7 is C 1 -C 3 alkyl (preferably methyl).
  • each R10 is independently -H, -CN, halogen, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, -SO 2 R 11 , -CONR 11 R 11 , -NR 11 R 11 , -NR 11 -CO 2 R 11 , an optionally substituted C 1 -C 6 alkyl, an optionally substituted C 3 -C 5 cycloalkyl, an optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine or morpholine, an optionally substituted phenyl, or an optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole, or thiazole; wherein the optionally substituted C 1 -C 6 alkyl is optionally substituted with a -CN, -OH, or C 1 -C 3 alkoxy;
  • R1 is a group of the formula: ; wherein R9 is independently -H, halogen, methyl, trifluoromethyl, or cyclopropyl, R 2 is a group of the formula: ; ; or , R 3 is -H, methyl, or trifluoromethyl, R 4 is -H, or halogen, R 8 and R are each -H, R 5 is -H, halogen, methyl or trifluoromethyl, R 6 is -H, or halogen, and R7 is C 1 -C 3 alkyl (preferably methyl).
  • each R10 is independently -H, -CN, halogen, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, -SO 2 R 11 , -CONR 11 R 11 , -NR 11 R 11 , -NR 11 -CO 2 R 11 , an optionally substituted C 1 -C 6 alkyl, an optionally substituted C 3 -C 5 cycloalkyl, an optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine or morpholine, an optionally substituted phenyl, or an optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole, or thiazole; wherein the optionally substituted C 1 -C 6 alkyl is optionally substituted with a -CN, -OH, or C 1 -C 3 alkoxy;
  • R 1 is a group of the formula: ; wherein R 9 is -H, halogen, or trifluoromethyl, (preferably R 9 is halogen or trifluoromethyl), R 2 is a group of the formula: ; ; or , R3 is -H, or methyl, R4, R8 and R are each -H, R5 is -H, halogen, methyl, or trifluoromethyl, R6 is -H or halogen, and R7 is C 1 -C 3 alkyl (preferably methyl).
  • each R 10 is independently -H, -CN, halogen, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, -SO 2 R 11 , -CONR 11 R 11 , -NR 11 R 11 , -NR 11 -CO 2 R 11 , an optionally substituted C 1 -C 6 alkyl, an optionally substituted C 3 -C 5 cycloalkyl, an optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine or morpholine, an optionally substituted phenyl, or an optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole, or thiazole; wherein the optionally substituted C 1 -C 6 alkyl is optionally substituted with a -CN, -OH, or C 1 -C 3 alkoxy;
  • R9 is -H, halogen, C 1 -C 3 alkyl or C 1 -C 3 haloalkyl
  • R 2 is a group of the formula: ; or , R 3 is -H, or methyl, R 4 , R 8 and R are each -H, R 5 is -H, halogen, methyl, or trifluoromethyl, R 6 is -H or halogen, and R 7 is C 1 -C 3 alkyl (preferably methyl).
  • each R10 is independently -H, -CN, halogen, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, -SO 2 R 11 , -CONR 11 R 11 , -NR 11 R 11 , -NR 11 -CO 2 R 11 , an optionally substituted C 1 -C 6 alkyl, an optionally substituted C 3 -C 5 cycloalkyl, an optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine or morpholine, an optionally substituted phenyl, or an optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole, or thiazole; wherein the optionally substituted C 1 -C 6 alkyl is optionally substituted with a -CN, -OH, or C 1 -C 3 alkoxy;
  • R1 is a group of the formula: ; wherein R9 is -H, halogen, methyl, trifluoromethyl, or cyclopropyl, R 2 is a group of the formula: ; ; or , R 3 is -H, methyl, or trifluoromethyl, R 4 is -H, or halogen, R 8 and R are each -H, R 5 is -H, halogen, methyl or trifluoromethyl, R 6 is -H, or halogen, and R7 is C 1 -C 3 alkyl (preferably methyl).
  • each R10 is independently -H, -CN, halogen, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, -SO 2 R 11 , -CONR 11 R 11 , -NR 11 R 11 , -NR 11 -CO 2 R 11 , an optionally substituted C 1 -C 6 alkyl, an optionally substituted C 3 -C 5 cycloalkyl, an optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine or morpholine, an optionally substituted phenyl, or an optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole, or thiazole; wherein the optionally substituted C 1 -C 6 alkyl is optionally substituted with a -CN, -OH, or C 1 -C 3 alkoxy;
  • compounds of Formula (I) or (II) have Formula (III), or pharmaceutically acceptable salts thereof: ( III) wherein R1, R 2 , R3, R5, R6, and R7 are as defined in the Summary for Formula (I) above.
  • R 2 is a group of the formula:
  • each R10 is independently -H, -CN, halogen, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, -SO 2 R 11 , -CONR 11 R 11 , -NR 11 R 11 , -NR 11 -CO 2 R 11 , an optionally substituted C 1 -C 6 alkyl, an optionally substituted C 3 -C 5 cycloalkyl, an optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine or morpholine, an optionally substituted phenyl, or an optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole, or thiazole; wherein the optionally substituted C 1 -C 6 alkyl is optionally substituted with a -CN, -OH, or C
  • R 2 is a group of the formula: ; ; or .
  • each R 10 is independently -H, -CN, halogen, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, -SO 2 R 11 , -CONR 11 R 11 , -NR 11 R 11 , -NR 11 -CO 2 R 11 , an optionally substituted C 1 -C 6 alkyl, an optionally substituted C 3 -C 5 cycloalkyl, an optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine or morpholine, an optionally substituted phenyl, or an optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole, or thiazole; wherein the
  • R 3 is -H, -CN, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl; preferably R 3 is -H, -CN, or C 1 -C 3 alkyl; most preferably R3 is -H, or methyl.
  • R 5 is -H, halogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; preferably R 5 is -H, halogen, C 1 -C 3 alkyl or C 1 -C 3 haloalkyl; more preferably R5 is -H, halogen, methyl, or trifluoromethyl.
  • R6 is -H or halogen; preferably R 6 is -H.
  • R7 is -CN, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; preferably R7 is -CN, C 1 -C 3 alkyl or C 1 -C 3 haloalkyl; more preferably R 7 is -CN, methyl or trifluoromethyl.
  • R 1 is a group of the formula: ; ; ; ; or ; wherein each R 9 is independently -H, halogen, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, or C3- C5 cycloalkyl; preferably each R9 is independently -H, halogen, methyl, trifluoromethyl, or cyclopropyl.
  • R 1 is a group of the formula:
  • R 9 is independently -H, halogen, C 1 -C 3 alkyl or C 1 -C 3 haloalkyl; preferably each R9 is independently -H, halogen, methyl, or trifluoromethyl.
  • R 1 is a group of the formula: ; ; ; or ; wherein each R 9 is independently -H, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 3 -C 5 cycloalkyl.
  • each R9 is independently -H, halogen, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, or C 3 -C 5 cycloalkyl. More preferably each R 9 is independently -H, halogen, methyl, trifluoromethyl, or cyclopropyl.
  • R 1 is a group of the formula: ; ; or ; wherein each R 9 is independently -H, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 3 -C 5 cycloalkyl.
  • each R9 is independently -H, halogen, C 1 -C 3 alkyl or C 1 -C 3 haloalkyl. More preferably each R9 is independently -H, halogen, methyl, or trifluoromethyl.
  • R 1 is a group of the formula: ; wherein each R9 is independently -H, halogen, C 1 -C 3 alkyl or C 1 -C 3 haloalkyl.
  • each R 9 is independently -H, halogen, methyl or trifluoromethyl.
  • R1 is a group of the formula: ; wherein R9 is -H, halogen, or C 1 -C 3 haloalkyl. Preferably R9 is -H, or trifluoromethyl.
  • R 1 is a group of the formula: ; wherein R9 is -H, halogen, or C 1 -C 3 haloalkyl. Preferably R9 is -H, or halogen. More preferably, R9 is -H, or fluoro.
  • R 1 is a group of the formula:
  • R9 is -H, halogen, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, or C 3 -C 5 cycloalkyl.
  • R 9 is -H, halogen, methyl, trifluoromethyl, or cyclopropyl.
  • R 1 is a group of the formula: ; wherein R9 is -H, halogen, or C 1 -C 3 haloalkyl.
  • R9 is halogen or trifluoromethyl. More preferably R 9 is chloro or trifluoromethyl.
  • R 1 is a group of the formula: ; wherein R9 is -H, halogen, C 1 -C 3 alkyl or C 1 -C 3 haloalkyl. Preferably R9 is -H, methyl, or trifluoromethyl.
  • R 1 is a group of the formula:
  • each R9 is independently H, halogen, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, or C 3 -C 5 cycloalkyl.
  • R 1 is a group of the formula: ; ; ; ; or ; wherein each R 9 is independently -H, halogen, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, or C3- C5 cycloalkyl, and R 2 is a group of the formula:
  • each R 10 is independently -H, -CN, halogen, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, -SO 2 R 11 , -CONR 11 R 11 , -NR 11 R 11 , -NR 11 -CO 2 R 11 , an optionally substituted C 1 -C 6 alkyl, an optionally substituted C 3 -C 5 cycloalkyl, an optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine or morpholine, an optionally substituted phenyl, or an optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole, or thiazole; wherein the optionally substituted C 1 -C 6 alkyl is optionally substituted with a -CN, -OH, or C 1 -C 3 alkoxy; the optionally
  • R 1 is a group of the formula: ; ; ; or ; wherein each R 9 is independently -H, halogen, C 1 -C 3 alkyl or C 1 -C 3 haloalkyl, and R 2 is a group of the formula:
  • each R 10 is independently -H, -CN, halogen, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, -SO 2 R 11 , -CONR 11 R 11 , -NR 11 R 11 , -NR 11 -CO 2 R 11 , an optionally substituted C 1 -C 6 alkyl, an optionally substituted C 3 -C 5 cycloalkyl, an optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine or morpholine, an optionally substituted phenyl, or an optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole, or thiazole; wherein the optionally substituted C 1 -C 6 alkyl is optionally substituted with a -CN, -OH, or C 1 -C 3 alkoxy; the optionally
  • R 1 is a group of the formula: ; ; or ; wherein each R 9 is independently -H, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 3 -C 5 cycloalkyl, and R 2 is a group of the formula:
  • each R9 is independently -H, halogen, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, or C 3 -C 5 cycloalkyl. Most preferably each R 9 is independently -H, halogen, methyl, trifluoromethyl, or cyclopropyl.
  • each R 10 is independently -H, -CN, halogen, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, -SO 2 R 11 , -CONR 11 R 11 , -NR 11 R 11 , -NR 11 -CO 2 R 11 , an optionally substituted C 1 -C 6 alkyl, an optionally substituted C 3 -C 5 cycloalkyl, an optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine or morpholine, an optionally substituted phenyl, or an optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole, or thiazole; wherein the optionally substituted C 1 -C 6 alkyl is optionally substituted with a -CN, -OH, or C 1 -C 3 alkoxy;
  • R 1 is a group of the formula: ; ; or ; wherein each R 9 is independently -H, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 3 -C 5 cycloalkyl, and R 2 is a group of the formula:
  • each R9 is independently -H, halogen, C 1 -C 3 alkyl or C 1 -C 3 haloalkyl. Most preferably each R 9 is independently -H, halogen, methyl, or trifluoromethyl.
  • each R 10 is independently -H, -CN, halogen, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, -SO 2 R 11 , -CONR 11 R 11 , -NR 11 R 11 , -NR 11 -CO 2 R 11 , an optionally substituted C 1 -C 6 alkyl, an optionally substituted C 3 -C 5 cycloalkyl, an optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine or morpholine, an optionally substituted phenyl, or an optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole, or thiazole; wherein the optionally substituted C 1 -C 6 alkyl is optionally substituted with a -CN, -OH, or C 1 -C 3 alkoxy;
  • R 1 is a group of the formula: ; wherein each R 9 is independently -H, halogen, C 1 -C 3 alkyl or C 1 -C 3 haloalkyl, and R 2 is a group of the formula: ; ; or .
  • each R9 is independently -H, halogen, methyl or trifluoromethyl.
  • each R 10 is independently -H, -CN, halogen, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, -SO 2 R 11 , -CONR 11 R 11 , -NR 11 R 11 , -NR 11 -CO 2 R 11 , an optionally substituted C 1 -C 6 alkyl, an optionally substituted C 3 -C 5 cycloalkyl, an optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine or morpholine, an optionally substituted phenyl, or an optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole, or thiazole; wherein the optionally substituted C 1 -C 6 alkyl is optionally substituted with a -CN, -OH, or C 1 -C 3 alkoxy;
  • R1 is a group of the formula: ; wherein R 9 is -H, halogen, or C 1 -C 3 haloalkyl, and R 2 is a group of the formula: ; ; or .
  • R 9 is -H, or trifluoromethyl.
  • each R10 is independently -H, -CN, halogen, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, -SO 2 R 11 , -CONR 11 R 11 , -NR 11 R 11 , -NR 11 -CO 2 R 11 , an optionally substituted C 1 -C 6 alkyl, an optionally substituted C 3 -C 5 cycloalkyl, an optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine or morpholine, an optionally substituted phenyl, or an optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole, or thiazole; wherein the optionally substituted C 1 -C 6 alkyl is optionally substituted with a -CN, -OH, or C 1 -C 3 alkoxy;
  • R1 is a group of the formula: ; wherein R9 is -H, halogen, or C 1 -C 3 haloalkyl, and R 2 is a group of the formula: ; ; or .
  • R9 is -H, or halogen.
  • each R10 is independently -H, -CN, halogen, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, -SO 2 R 11 , -CONR 11 R 11 , -NR 11 R 11 , -NR 11 -CO 2 R 11 , an optionally substituted C 1 -C 6 alkyl, an optionally substituted C 3 -C 5 cycloalkyl, an optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine or morpholine, an optionally substituted phenyl, or an optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole, or thiazole; wherein the optionally substituted C 1 -C 6 alkyl is optionally substituted with a -CN, -OH, or C 1 -C 3 alkoxy;
  • R9 is -H, halogen, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, or C 3 -C 5 cycloalkyl
  • R 2 is a group of the formula: ; ; or ; preferably R 9 is -H, halogen, methyl, trifluoromethyl, or cyclopropyl.
  • each R10 is independently -H, -CN, halogen, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, -SO 2 R 11 , -CONR 11 R 11 , -NR 11 R 11 , -NR 11 -CO 2 R 11 , an optionally substituted C 1 -C 6 alkyl, an optionally substituted C 3 -C 5 cycloalkyl, an optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine or morpholine, an optionally substituted phenyl, or an optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole, or thiazole; wherein the optionally substituted C 1 -C 6 alkyl is optionally substituted with a -CN, -OH, or C 1 -C 3 alkoxy;
  • R9 is halogen, or C 1 -C 3 haloalkyl
  • R 2 is a group of the formula: ; ; or ; preferably R 9 is halogen or trifluoromethyl. More preferably R9 is chloro or trifluoromethyl.
  • each R10 is independently -H, -CN, halogen, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, -SO 2 R 11 , -CONR 11 R 11 , -NR 11 R 11 , -NR 11 -CO 2 R 11 , an optionally substituted C 1 -C 6 alkyl, an optionally substituted C 3 -C 5 cycloalkyl, an optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine or morpholine, an optionally substituted phenyl, or an optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole, or thiazole; wherein the optionally substituted C 1 -C 6 alkyl is optionally substituted with a -CN, -OH, or C 1 -C 3 alkoxy;
  • each R 10 is independently -H, -CN, halogen, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, -SO 2 R 11 , -CONR 11 R 11 , -NR 11 R 11 , -NR 11 -CO 2 R 11 , an optionally substituted C 1 -C 6 alkyl, an optionally substituted C 3 -C 5 cycloalkyl, an optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine or morpholine, an optionally substituted phenyl, or an optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole,
  • R 1 is a group of the formula: ; wherein R 9 is -H, halogen, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, or C 3 -C 5 cycloalkyl, and R 2 is a group of the formula:
  • each R 10 is independently -H, -CN, halogen, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, -SO 2 R 11 , -CONR 11 R 11 , -NR 11 R 11 , -NR 11 -CO 2 R 11 , an optionally substituted C 1 -C 6 alkyl, an optionally substituted C 3 -C 5 cycloalkyl, an optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine or morpholine, an optionally substituted phenyl, or an optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole, or thiazole; wherein the optionally substituted
  • R 3 is -H, -CN, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl (preferably R3 is -H, -CN, or C 1 -C 3 alkyl), R5 is -H, halogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl, R6 is -H or halogen, R7 is -CN, methyl or trifluoromethyl, and R 2 is a group of the formula: ; ; ; or ; more preferably R 3 is -H, or methyl, R5 is -H, halogen, methyl, or trifluoromethyl, R6 is -H, R7 is methyl, and R 2 is a group of the formula:
  • each R10 is independently -H, -CN, halogen, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, -SO 2 R 11 , -CONR 11 R 11 , -NR 11 R 11 , -NR 11 -CO 2 R 11 , an optionally substituted C 1 -C 6 alkyl, an optionally substituted C 3 -C 5 cycloalkyl, an optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine or morpholine, an optionally substituted phenyl, or an optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole, or thiazole; wherein the optionally substituted C 1 -C 6 alkyl is optionally substituted with a -CN, -OH, or C 1
  • R 2 is a group of the formula: ; ; ; or , R 3 is -H, -CN, C 1 -C 3 alkyl, or C 1 -C 3 haloalkyl, R 5 is -H, halogen, C 1 -C 3 alkyl or C 1 -C 3 haloalkyl, R 6 is -H or halogen, and R 1 is a group of the formula: ; ; ; or ; wherein each R 9 is independently -H, halogen, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, or C 3 -C 5 cycloalkyl.
  • R3 is -H, methyl, or trifluoromethyl
  • R 5 is -H, halogen, methyl, or trifluoromethyl
  • R 6 is -H or halogen
  • each R 9 is independently -H, halogen, methyl, trifluoromethyl, or cyclopropyl.
  • each R 10 is independently -H, -CN, halogen, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, -SO 2 R 11 , -CONR 11 R 11 , -NR 11 R 11 , -NR 11 -CO 2 R 11 , an optionally substituted C 1 -C 6 alkyl, an optionally substituted C 3 -C 5 cycloalkyl, an optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine or morpholine, an optionally substituted phenyl, or an optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole, or thiazole; wherein the optionally substituted C 1 -C 6 alkyl is optionally substituted with a -CN, -OH, or C 1 -C 3 alkoxy;
  • R 2 is a group of the formula: ; ; ; or , R3 is -H, -CN, C 1 -C 3 alkyl, or C 1 -C 3 haloalkyl (preferably R 3 is -H, -CN, or C 1 -C 3 alkyl), R 5 is -H, halogen, C 1 -C 3 alkyl or C 1 -C 3 haloalkyl, R 6 is -H or halogen, and R 1 is a group of the formula: ; ; or ; wherein each R9 is independently -H, halogen, C 1 -C 3 alkyl or C 1 -C 3 haloalkyl.
  • R 3 is -H, or methyl
  • R 5 is -H, halogen, methyl, or trifluoromethyl
  • R 6 is -H or halogen
  • each R 9 is independently -H, halogen, methyl, or trifluoromethyl.
  • each R10 is independently -H, -CN, halogen, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, -SO 2 R 11 , -CONR 11 R 11 , -NR 11 R 11 , -NR 11 -CO 2 R 11 , an optionally substituted C 1 -C 6 alkyl, an optionally substituted C 3 -C 5 cycloalkyl, an optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine or morpholine, an optionally substituted phenyl, or an optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole, or thiazole; wherein the optionally substituted C 1 -C 6 alkyl is optionally substituted with a -CN, -OH, or C 1 -C 3 alkoxy;
  • R 2 is a group of the formula: ; ; ; or , R3 is -H, -CN, C 1 -C 3 alkyl, or C 1 -C 3 haloalkyl, R 5 is -H, halogen, C 1 -C 3 alkyl or C 1 -C 3 haloalkyl, R 6 is -H or halogen, R 7 is -CN, methyl or trifluoromethyl, and R 1 is a group of the formula: ; ; ; or ; wherein each R9 is independently -H, halogen, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, or C 3 -C 5 cycloalkyl.
  • each R 10 is independently -H, -CN, halogen, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, -SO 2 R 11 , -CONR 11 R 11 , -NR 11 R 11 , -NR 11 -CO 2 R 11 , an optionally substituted C 1 -C 6 alkyl, an optionally substituted C 3 -C 5 cycloalkyl, an optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine or morpholine, an optionally substituted phenyl, or an optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole, or thiazole; wherein the optionally substituted C 1 -C 6 alkyl is optionally substituted with a -CN, -OH, or C 1 -C 3 alkoxy;
  • R 2 is a group of the formula: ; ; ; or , R3 is -H, -CN, C 1 -C 3 alkyl, or C 1 -C 3 haloalkyl (preferably R3 is -H, -CN, or C 1 -C 3 alkyl), R5 is -H, halogen, C 1 -C 3 alkyl or C 1 -C 3 haloalkyl, R 6 is -H or halogen, R 7 is -CN, methyl or trifluoromethyl, and R 1 is a group of the formula: ; ; or ; wherein each R 9 is independently -H, halogen, C 1 -C 3 alkyl or C 1 -C 3 haloalkyl.
  • each R 10 is independently -H, -CN, halogen, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, -SO 2 R 11 , -CONR 11 R 11 , -NR 11 R 11 , -NR 11 -CO 2 R 11 , an optionally substituted C 1 -C 6 alkyl, an optionally substituted C 3 -C 5 cycloalkyl, an optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine or morpholine, an optionally substituted phenyl, or an optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole, or thiazole; wherein the optionally substituted C 1 -C 6 alkyl is optionally substituted with a -CN, -OH, or C 1 -C 3 alkoxy;
  • R 1 is a group of the formula: ; wherein each R 9 is independently -H, halogen, methyl or trifluoromethyl, R 2 is a group of the formula: ; ; or , R3 is -H, methyl, or trifluoromethyl, R5 is -H, halogen, methyl or trifluoromethyl, R 6 is -H, or halogen, and R 7 is C 1 -C 3 alkyl (preferably methyl).
  • each R 10 is independently -H, -CN, halogen, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, -SO 2 R 11 , -CONR 11 R 11 , -NR 11 R 11 , -NR 11 -CO 2 R 11 , an optionally substituted C 1 -C 6 alkyl, an optionally substituted C 3 -C 5 cycloalkyl, an optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine or morpholine, an optionally substituted phenyl, or an optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole, or thiazole; wherein the optionally substituted C 1 -C 6 alkyl is optionally substituted with a -CN, -OH, or C 1 -C 3 alkoxy;
  • R9 is -H, halogen, or trifluoromethyl, (preferably R9 is -H, or trifluoromethyl)
  • R 2 is a group of the formula: ; ; or , R3 is -H, or methyl, R5 is -H, halogen, methyl, or trifluoromethyl, R 6 is -H or halogen, and R 7 is C 1 -C 3 alkyl (preferably methyl).
  • each R 10 is independently -H, -CN, halogen, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, -SO 2 R 11 , -CONR 11 R 11 , -NR 11 R 11 , -NR 11 -CO 2 R 11 , an optionally substituted C 1 -C 6 alkyl, an optionally substituted C 3 -C 5 cycloalkyl, an optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine or morpholine, an optionally substituted phenyl, or an optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole, or thiazole; wherein the optionally substituted C 1 -C 6 alkyl is optionally substituted with a -CN, -OH, or C 1 -C 3 alkoxy;
  • R 1 is a group of the formula: ; wherein R 9 is -H, halogen, or C 1 -C 3 haloalkyl (preferably R 9 is -H, or halogen), R 2 is a group of the formula:
  • R3 is -H, or methyl
  • R5 is -H, halogen, methyl, or trifluoromethyl
  • R6 is -H or halogen
  • R7 is C 1 -C 3 alkyl (preferably methyl).
  • each R 10 is independently -H, -CN, halogen, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, -SO 2 R 11 , -CONR 11 R 11 , -NR 11 R 11 , -NR 11 -CO 2 R 11 , an optionally substituted C 1 -C 6 alkyl, an optionally substituted C 3 -C 5 cycloalkyl, an optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine or morpholine, an optionally substituted phenyl, or an optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole, or thiazole; wherein the optionally substituted C 1 -C 6 alkyl is optionally substituted with a -CN, -OH, or C 1 -C 3 alkoxy;
  • R1 is a group of the formula: ; wherein R9 is -H, halogen, methyl, trifluoromethyl, or cyclopropyl, R 2 is a group of the formula: ; ; or , R 3 is -H, methyl, or trifluoromethyl, R 5 is -H, halogen, methyl or trifluoromethyl, R6 is -H, or halogen, and R7 is C 1 -C 3 alkyl (preferably methyl).
  • each R10 is independently -H, -CN, halogen, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, -SO 2 R 11 , -CONR 11 R 11 , -NR 11 R 11 , -NR 11 -CO 2 R 11 , an optionally substituted C 1 -C 6 alkyl, an optionally substituted C 3 -C 5 cycloalkyl, an optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine or morpholine, an optionally substituted phenyl, or an optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole, or thiazole; wherein the optionally substituted C 1 -C 6 alkyl is optionally substituted with a -CN, -OH, or C 1 -C 3 alkoxy;
  • R1 is a group of the formula: ; wherein R9 is -H, halogen, or trifluoromethyl, (preferably R9 is halogen or trifluoromethyl), R 2 is a group of the formula: ; ; or , R 3 is -H, or methyl, R 5 is -H, halogen, methyl, or trifluoromethyl, R 6 is -H or halogen, and R 7 is C 1 -C 3 alkyl (preferably methyl).
  • each R10 is independently -H, -CN, halogen, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, -SO 2 R 11 , -CONR 11 R 11 , -NR 11 R 11 , -NR 11 -CO 2 R 11 , an optionally substituted C 1 -C 6 alkyl, an optionally substituted C 3 -C 5 cycloalkyl, an optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine or morpholine, an optionally substituted phenyl, or an optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole, or thiazole; wherein the optionally substituted C 1 -C 6 alkyl is optionally substituted with a -CN, -OH, or C 1 -C 3 alkoxy;
  • R1 is a group of the formula: ; wherein R 9 is -H, halogen, C 1 -C 3 alkyl or C 1 -C 3 haloalkyl, R 2 is a group of the formula: ; ; or , R 3 is -H, or methyl, R 5 is -H, halogen, methyl, or trifluoromethyl, R6 is -H or halogen, and R7 is C 1 -C 3 alkyl (preferably methyl).
  • each R10 is independently -H, -CN, halogen, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, -SO 2 R 11 , -CONR 11 R 11 , -NR 11 R 11 , -NR 11 -CO 2 R 11 , an optionally substituted C 1 -C 6 alkyl, an optionally substituted C 3 -C 5 cycloalkyl, an optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine or morpholine, an optionally substituted phenyl, or an optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole, or thiazole; wherein the optionally substituted C 1 -C 6 alkyl is optionally substituted with a -CN, -OH, or C 1 -C 3 alkoxy;
  • R9 is -H, halogen, methyl, trifluoromethyl, or cyclopropyl
  • R 2 is a group of the formula: ; ; or , R 3 is -H, methyl, or trifluoromethyl
  • R 5 is -H, halogen, methyl or trifluoromethyl
  • R 6 is -H, or halogen
  • R 7 is C 1 -C 3 alkyl (preferably methyl).
  • each R10 is independently -H, -CN, halogen, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, -SO 2 R 11 , -CONR 11 R 11 , -NR 11 R 11 , -NR 11 -CO 2 R 11 , an optionally substituted C 1 -C 6 alkyl, an optionally substituted C 3 -C 5 cycloalkyl, an optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine or morpholine, an optionally substituted phenyl, or an optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole, or thiazole; wherein the optionally substituted C 1 -C 6 alkyl is optionally substituted with a -CN, -OH, or C 1 -C 3 alkoxy;
  • the compound is selected from: ; ; ; ; ;
  • a pharmaceutically acceptable salt of a compound of the present invention is, for example, an acid-addition salt of a compound of the invention, which is sufficiently basic, for example, an acid- addition salt with, for example, an inorganic or organic acid, for example hydrochloric, hydrobromic, sulfuric, phosphoric, trifluoroacetic, formic, citric, methane sulfonate or maleic acid.
  • a pharmaceutically acceptable salt of a compound of the present invention which is sufficiently acidic is an alkali metal salt, for example a sodium or potassium salt, an alkaline earth metal salt, for example a calcium or magnesium salt, an ammonium salt or a salt with an organic base which affords a pharmaceutically acceptable cation, for example a salt with methylamine, dimethylamine, diethylamine, trimethylamine, piperidine, morpholine or tris-(2-hydroxyethyl)amine.
  • Pharmaceutically acceptable salts, and common methodology for preparing them are well known in the art (see, e.g., P.Stahl, et al.
  • compositions include, e.g., water-soluble, and water-insoluble salts, such as the acetate, amsonate (4,4-diaminostilbene-2,2-disulfonate), benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, butyrate, calcium, calcium edetate, camsylate, carbonate, chloride, citrate, clavulanate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexafluorophosphate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laur
  • the compounds of the present invention can be prepared in a number of ways well known to those skilled in the art of organic synthesis.
  • compounds of the present invention can be synthesized using the methods described below, together with synthetic methods known in the art of synthetic organic chemistry, or variations thereon as appreciated by those skilled in the art. Preferred methods include but are not limited to those methods described below.
  • Compounds of the present invention can be synthesized by following the steps outlined in General Schemes 1, 2, 3, and 4 which comprise different sequences of assembling intermediates or compounds. Starting materials are either commercially available or made by known procedures in the reported literature or as illustrated below.
  • Scheme 1 (1) (2) (3) (4) (7) (6) (5) (8) (9) Formula (II) [596] Scheme 1 depicts the preparation of compounds of Formula (II), where R is H and R 7 is methyl.
  • Acylation of substituted phenol (1) may provide ester (2).
  • Ester (2) may undergo rearrangement under Lewis acid (e.g., AlCl 3 ) or Br ⁇ nsted acid (e.g., triflic acid) conditions to the hydroxy aryl ketone (3).
  • Acidic condensation of an aryl aldehyde with hydroxy aryl ketone (3) may provide keto-alkene (4) which may cyclize to the 2-substituted chromen-4-one (5).
  • Exemplary palladium catalysis conditions may include phenyl bromide (5), about 5-10 mol% PdCl2(Ph3) 2 and about 1.2 mol% tributyl(1-ethoxyvinyl)stannane in about 30-35 equivalents dioxane at 95°C for about 16 hours; or phenyl bromide (5), about 1 mol% Pd(OAc) 2 , about 2 mol% 1,3- bis(diphenylphosphino)propane, about 5 equivalents butyl vinyl ether, about 3 equivalents triethylamine, and about 10 volumes of ethylene glycol at about 100°C for about 16 hours.
  • ketimine (7) Condensation of ketone (6) with tert-butanesulfinamide using a Lewis acidic dehydrating agent such as a titanium(IV) alkoxide may afford ketimine (7).
  • Asymmetric reduction of sulfinimine (7) may be affected with a borohydride reagent in the presence of a transition metal catalyst such as cerium (III) chloride to yield chirally enriched sulfinamide (8).
  • Removal of the sulfinyl group under acidic conditions may be used to transform sulfinamide (8) to benzylamine (9) which can be alkylated with an aryl or heteroaryl halide under Finkelstein or Ullmann-type conditions to give compounds of Formula (II) after hydrolysis of ester present on R1.
  • Scheme 2 (3) (10) (11) (14) (13) (12) (15) (16) Formula (II) [598] Scheme 2 depicts additional preparation of compounds of Formula (II), where R is H and R 7 is methyl.
  • Basic deprotonation of ketone (3) in the presence of carbon disulfide gives the bicyclic chromene-2-thione (10).
  • Phenyl bromide (11) can be acylated via palladium catalysis to produce acyl chromen-4-one (12) which can be condensed with tert-butanesulfinamide using a Lewis acidic dehydrating agent such as a titanium(IV) alkoxide to afford ketimine (13).
  • Asymmetric reduction of sulfinimine (13) may be affected with a borohydride reagent in the presence of a transition metal catalyst such as cerium (III) chloride to yield chirally enriched sulfinamide (14).
  • sulfinyl group under acidic conditions may be used to transform sulfinamide (14) to benzylamine (15) which can be alkylated with an aryl or heteroaryl halide under Finkelstein or Ullmann-type conditions to give arylamine (16).
  • Thiolether (16) can be converted to compounds of Formula (II) using transition metal catalysis to couple phenyl boronic acids, boronic esters, or other coupling partners, followed by hydrolysis of ester present on R1.
  • Aryl ketone (12) can be reduced to hydroxy compound (17) with a reagent such as sodium borohydride.
  • a reagent such as sodium borohydride.
  • Use of a halogenating agent such as phosphorus tribromide can be used to convert hydroxy compound (17) to the halo compound (18).
  • Halo compound (18) can be used to alkylate an arylamine or heteroarylamine to give arylamine or heteroarylamine (19).
  • Thiolether (19) can be converted to compounds of Formula (I) using transition metal catalysis to couple phenyl boronic acids, boronic esters, or other coupling partners, followed by hydrolysis of ester present on R1.
  • Scheme 4 (20) (6) (22) (21) Formula (II) (23) [601] Scheme 4 depicts the preparation of compounds of Formula (II) where R is H and R7 is methyl.
  • Ketone (6) can be reduced to hydroxy compound (20) with a chiral catalyst such as the Noyori catalyst.
  • the hydroxyl compound (20) can be converted into a leaving group with methanesulfonic anhydride or methanesulfonyl chloride to give mesylate (21).
  • Mesylate (21) can be used to alkylate an arylamine or heteroarylamine to give compounds of Formula (II) after hydrolysis of the ester present on R1.
  • ketone (6) can be reduced to hydroxy compound (22) with a chiral catalyst such as the Noyori catalyst.
  • the hydroxyl group can be converted to chloride (23) with a chlorinating agent such as 2,4,6-trichloro-1,3,5-triazine.
  • Chloride (23) can then be used to alkylate an arylamine or heteroarylamine to give compounds of Formula (II) after hydrolysis of the ester present on R1.
  • Pharmaceutical Compositions [603]
  • the present disclosure provides a pharmaceutical composition comprising a compound of Formula (I), (II), or (III) as an active ingredient.
  • the present disclosure provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or excipients.
  • composition is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
  • the compounds of Formula (I), (II), or (III) can be formulated for oral administration in forms such as tablets, capsules (each of which includes sustained release or timed release formulations), pills, powders, granules, elixirs, tinctures, suspensions, syrups and emulsions.
  • the compounds of Formula (I), (II), or (III) can also be formulated for intravenous (bolus or in-fusion), intraperitoneal, topical, subcutaneous, intramuscular or transdermal (e.g., patch) administration, all using forms well known to those of ordinary skill in the pharmaceutical arts.
  • the formulation of the present disclosure may be in the form of an aqueous solution comprising an aqueous vehicle.
  • the aqueous vehicle component may comprise water and at least one pharmaceutically acceptable excipient. Suitable acceptable excipients include those selected from the group consisting of a solubility enhancing agent, chelating agent, preservative, tonicity agent, viscosity/suspending agent, buffer, and pH modifying agent, and a mixture thereof.
  • a pharmaceutical composition which comprises a compound any one of the Formulae disclosed herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, in association with a pharmaceutically acceptable diluent or carrier.
  • compositions of the disclosure may be in a form suitable for oral use (for example as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), for topical use (for example as creams, ointments, gels, or aqueous or oily solutions or suspensions), for administration by inhalation (for example as a finely divided powder or a liquid aerosol), for administration by insufflation (for example as a finely divided powder) or for parenteral administration (for example as a sterile aqueous or oily solution for intravenous, subcutaneous, intramuscular, intraperitoneal or intramuscular dosing or as a suppository for rectal dosing).
  • oral use for example as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or
  • compositions of the disclosure may be obtained by conventional procedures using conventional pharmaceutical excipients, well known in the art.
  • compositions intended for oral use may contain, for example, one or more coloring, sweetening, flavoring and/or preservative agents.
  • Methods of Use [610]
  • the present disclosure provides a method of modulating PI3K (e.g., PI3K ⁇ ) activity (e.g., in vitro or in vivo), comprising contacting a cell with a therapeutically effective amount of a compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof.
  • the present disclosure provides a method of treating or preventing a disease or disorder disclosed herein in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.
  • the present disclosure provides a method of treating a disease or disorder disclosed herein in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.
  • the disease or disorder is associated with an implicated PI3K activity.
  • the disease or disorder is a disease or disorder in which PI3K activity is implicated.
  • the disease or disorder is a cancer.
  • the cancer is selected from acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), adrenocortical carcinoma, aids-related cancers, aids-related lymphoma, anal cancer, astrocytoma, basal cell carcinoma, bile duct cancer, bladder cancer, bone cancer, osteosarcoma, malignant fibrous histiocytoma, brain tumors, breast cancer, bronchial tumors, Burkitt lymphoma, carcinoid tumor, cancer of unknown primary, cardiac (heart) tumors, atypical teratoid/rhabdoid tumor, primary CNS lymphoma, cervical cancer, cholangiocarcinoma, chordoma, chronic lymphocytic leukemia (CLL), chronic myelogenous le
  • ALL acute lymphoblastic leukemia
  • AML acute mye
  • the cancer is Endometrial cancer, Breast cancer, Oesophageal squamous-cell cancer, Cervical squamous-cell carcinoma, Cervical adenocarcinoma, Colorectal adenocarcinoma, Bladder Urothelial Carcinoma, Glioblastoma, Ovarian cancer, Non-small-cell Lung cancer, Esophagogastric cancer, Nerve-sheath tumor, Head and neck squamous-cell carcinoma, Melanoma, Esophagogastric adenocarcinoma, Soft-tissue sarcoma, Prostate cancer, Fibrolamellar carcinoma, Hepatocellular carcinoma, Diffuse glioma, Colorectal cancer, Pancreatic cancer, Cholangiocarcinoma, B-cell lymphoma, Mesothelioma, Adrenocortical carcinoma, Renal non-clear- cell carcinoma, Renal clear-cell carcinoma, Ger
  • the cancer is a breast cancer, a prostate cancer, or a brain cancer.
  • the cancer is a breast cancer.
  • the cancer is a prostate cancer.
  • the cancer is a brain cancer.
  • the breast cancer is metastatic breast cancer.
  • the breast cancer is ductal carcinoma in situ (DCIS).
  • the breast cancer is invasive ductal carcinoma.
  • the breast cancer is triple negative breast cancer.
  • the breast cancer is medullary carcinoma.
  • the breast cancer is tubular carcinoma.
  • the breast cancer is mucinous carcinoma.
  • the breast cancer is Paget disease of the breast or nipple.
  • the breast cancer is inflammatory breast cancer (IBC).
  • the breast cancer is hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER 2 -) advanced or metastatic breast cancer.
  • the prostate cancer is an adenocarcinoma.
  • the prostate cancer is a small cell carcinoma.
  • the prostate cancer is a neuroendocrine tumor.
  • the prostate cancer is a transitional cell carcinoma.
  • the prostate cancer is a sarcoma.
  • the brain cancer is an acoustic neuroma.
  • the brain cancer is an astrocytoma. In some embodiments, the brain cancer is a brain metastasis. In some embodiments, the brain cancer is choroid plexus carcinoma. In some embodiments, the brain cancer is craniopharyngioma. In some embodiments, the brain cancer is an embryonal tumor. In some embodiments, the brain cancer is an ependymoma. In some embodiments, the brain cancer is a glioblastoma. In some embodiments, the brain cancer is a glioma. In some embodiments, the brain cancer is a medulloblastoma. In some embodiments, the brain cancer is a meningioma.
  • the brain cancer is an oligodendroglioma. In some embodiments, the brain cancer is a pediatric brain tumor. In some embodiments, the brain cancer is a pineoblastoma. In some embodiments, the brain cancer is a pituitary tumor.
  • the disease or disorder associated with PI3K includes, but is not limited to, CLOVES syndrome (congenial lipomatous overgrowth, vascular malformations, epidermal naevi, scoliosis/skeletal and spinal syndrome), PIK3CA-related overgrowth syndrome (PROS), breast cancer, brain cancer, prostate cancer, endometrial cancer, gastric cancer, leukemia, lymphoma, sarcoma, colorectal cancer, lung cancer, ovarian cancer, skin cancer, or head and neck cancer.
  • CLOVES syndrome congenial lipomatous overgrowth, vascular malformations, epidermal naevi, scoliosis/skeletal and spinal syndrome
  • PROS PIK3CA-related overgrowth syndrome
  • the diseases or disorder associated with PI3K is CLOVES syndrome (congenital lipomatous overgrowth, vascular malformations, epidermal naevi, scoliosis/skeletal and spinal syndrome).
  • CLOVES syndrome congenital lipomatous overgrowth, vascular malformations, epidermal naevi, scoliosis/skeletal and spinal syndrome.
  • the disease or disorder associated with PI3K is PIK3CA-related overgrowth syndrome (PROS).
  • the disease or disorder associated with PI3K is breast cancer, brain cancer, prostate cancer, endometrial cancer, gastric cancer, leukemia, lymphoma, sarcoma, colorectal cancer, lung cancer, ovarian cancer, skin cancer, or head and neck cancer.
  • the disease or disorder associated with PI3K is a breast neoplasm, a thyroid neoplasm, an ovarian neoplasm, non-small-cell lung carcinoma, an endometrial neoplasm, or a pancreatic neoplasm.
  • the disease or disorder associated with PI3K is a breast neoplasm.
  • the disease or disorder associated with PI3K is a thyroid neoplasm.
  • the disease or disorder associated with PI3K is an ovarian neoplasm.
  • the disease or disorder associated with PI3K is non-small-cell lung carcinoma.
  • the disease or disorder associated with PI3K is an endometrial neoplasm. In some embodiments, the disease or disorder associated with PI3K is a pancreatic neoplasm. [627] In some embodiments, the disease or disorder associated with PI3K is breast cancer, brain cancer, prostate cancer, endometrial cancer, gastric cancer, colorectal cancer, lung cancer, ovarian cancer, skin cancer, or head and neck cancer. [628] In some embodiments, the disease or disorder associated with PI3K is leukemia, lymphoma, or sarcoma. [629] In some embodiments, the cancer is endometrial cancer, head and neck cancer, or a sarcoma.
  • the cancer is endometrial cancer. In some embodiments the cancer is head and neck cancer. In some embodiments, the cancer is a sarcoma. [631] In some embodiments, the sarcoma is soft tissue sarcoma, osteosarcoma, chondrosarcoma, Ewing sarcoma, hemangioendothelioma, angiosarcoma, fibrosarcoma, myofibrosarcoma, chordoma, adamantinoma, liposarcoma, leiomyosarcoma, malignant peripheral nerve sheath tumor, rhabdomyosarcoma, synovial sarcoma, or malignant solitary fibrous tumor.
  • the sarcoma is soft tissue sarcoma.
  • the soft tissue sarcoma is liposarcoma, atypical lipomatous tumor, dermatofibrosarcoma protuberans, malignant solitary fibrous tumor, inflammatory myofibroblastic tumor, low-grade myofibroblastic sarcoma, fibrosarcoma, myxofibrosarcoma, low-grade fibromyxoid sarcoma, giant cell tumor of soft tissues, leiomyosarcoma, malignant glomus tumor, rhabdomyosarcoma, hemangioendothelioma, angiosarcoma of soft tissue, extraskeletal osteosarcoma, gastrointestinal stromal tumor, malignant gastrointestinal stromal tumor (GIST), malignant peripheral nerve sheath tumor, malignant Triton tumor, malignant granular cell tumor, malignant ossifying fibromyxoid tumor, stromal
  • the present disclosure provides a method of treating or preventing a cancer in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.
  • the present disclosure provides a method of treating a cancer in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.
  • the present disclosure provides a method of treating or preventing a breast cancer in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.
  • the present disclosure provides a method of treating a breast cancer in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.
  • the present disclosure provides a method of treating or preventing a prostate cancer in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.
  • the present disclosure provides a method of treating a prostate cancer in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.
  • the present disclosure provides a method of treating or preventing a brain cancer in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.
  • the present disclosure provides a method of treating a brain cancer in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.
  • the present disclosure provides a compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof for use in therapy.
  • the present disclosure provides a compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof for use in modulating PI3K (e.g., PI3K ⁇ ) activity (e.g., in vitro or in vivo).
  • the present disclosure provides a compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof for use in treating or preventing a disease or disorder disclosed herein.
  • the present disclosure provides a compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof for use in treating a disease or disorder disclosed herein.
  • the present disclosure provides a compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof for use in treating or preventing a cancer.
  • the present disclosure provides a compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof for use in treating a cancer.
  • the present disclosure provides a compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof for use in treating or preventing a breast cancer.
  • the present disclosure provides a compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof for use in treating a breast cancer.
  • the present disclosure provides a compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof for use in treating or preventing a prostate cancer.
  • the present disclosure provides a compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof for use in treating a prostate cancer.
  • the present disclosure provides a compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof for use in treating or preventing a brain cancer.
  • the present disclosure provides a compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof for use in treating a brain cancer.
  • the present disclosure provides use of a compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for modulating PI3K (e.g., PI3K ⁇ ) activity (e.g., in vitro or in vivo).
  • PI3K e.g., PI3K ⁇
  • the present disclosure provides use of a compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating or preventing a disease or disorder disclosed herein.
  • the present disclosure provides use of a compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating a disease or disorder disclosed herein.
  • the present disclosure provides use of a compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating or preventing a cancer in a patient in need thereof.
  • the present disclosure provides use of a compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating a cancer in a patient in need thereof.
  • the present disclosure provides use of a compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating or preventing a breast cancer in a patient in need thereof.
  • the present disclosure provides use of a compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating a breast cancer in a patient in need thereof.
  • the present disclosure provides use of a compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating or preventing a prostate cancer in a patient in need thereof.
  • the present disclosure provides use of a compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating a prostate cancer in a patient in need thereof.
  • the present disclosure provides use of a compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating or preventing a brain cancer in a patient in need thereof.
  • the present disclosure provides use of a compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating a brain cancer in a patient in need thereof.
  • the present disclosure provides compounds that function as modulators of PI3K activity.
  • the present disclosure therefore provides a method of modulating PI3K activity in vitro or in vivo, said method comprising contacting a cell with a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt thereof, as defined herein.
  • PI3K modulation is inhibition of PI3K.
  • the PI3K inhibitor is a PI3K ⁇ inhibitor.
  • the PI3K inhibitor is a PI3K ⁇ H1047R mutant inhibitor.
  • Effectiveness of compounds of the disclosure can be determined by industry-accepted assays/ disease models according to standard practices of elucidating the same as described in the art and are found in the current general knowledge.
  • the present disclosure also provides a method of treating a disease or disorder in which PI3K activity is implicated in a patient in need of such treatment, said method comprising administering to said patient a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein.
  • the compounds of Formula (I), (II), or (III), or pharmaceutical compositions comprising these compounds may be administered to a patient by any convenient route of administration, whether systemically/ peripherally or topically (i.e., at the site of desired action).
  • Routes of administration include, but are not limited to, oral (e.g.
  • transdermal including, e.g., by a patch, plaster, etc.
  • transmucosal including, e.g., by a patch, plaster, etc.
  • intranasal e.g., by nasal spray
  • ocular e.g., by eye drops
  • pulmonary e.g., by inhalation or insufflation therapy using, e.g., via an aerosol, e.g., through the mouth or nose
  • rectal e.g., by suppository or enema
  • vaginal e.g., by pessary
  • parenteral for example, by injection, including subcutaneous, intradermal, intramuscular, intravenous, intra-arterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcuticular, intraarticular, subarachnoid, and intrasternal; by implant of
  • LC-MS chromatograms and spectra were recorded using an Agilent 1200 or Shimadzu LC-20 AD&MS 2020 instrument using a C-18 column such as a Luna-C182.0x30 mm or Xbridge Shield RPC182.1x50 mm. Injection volumes were 0.7 – 8.0 ⁇ l and the flow rates were typically 0.8 or 1.2 ml/min. Detection methods were diode array (DAD) or evaporative light scattering (ELSD) as well as positive ion electrospray ionization. MS range was 100 - 1000 Da.
  • DAD diode array
  • ELSD evaporative light scattering
  • Solvents were gradients of water and acetonitrile both containing a modifier (typically 0.01 – 0.04 %) such as trifluoroacetic acid or ammonium carbonate.
  • a modifier typically 0.01 – 0.04 % such as trifluoroacetic acid or ammonium carbonate.
  • reaction was cooled in an ice bath and iodine in dry THF (1M, 1.39 mL, 1.39 mmol) was added dropwise via addition funnel. After addition was complete, the reaction was stirred at 0°C for 1 h and rt for 12 h. The reaction was cooled to -40°C and quenched with methanol (10 mL). Added 50 mL of an ammonium chloride/ammonia solution (aqueous 2M solution; 50 mL) and stirred the reaction at rt for 2 h. Extracted three times with 300 mL of dichloromethane. The organics were combined, washed with aqueous sodium carbonate, collected, dried over Na2SO4, filtered, and concentrated.
  • Example 1 6-Chloro-3-[[(1R)-1-(3,6-dimethyl-4-oxo-2-phenyl-chromen-8- yl)ethyl]amino]pyridine-2-carboxylic acid
  • Example 3 2-[1-[2-[3-(1-Cyano-1-methyl-ethyl)phenyl]-6-methyl-4-oxo-chromen-8- yl]ethylamino]benzoic acid 2,2,2-trifluoroacetic acid TFA [766] Combined tert-butyl 2-[1-[2-[3-(1-cyano-1-methyl-ethyl)phenyl]-6-methyl-4-oxo-chromen-8- yl]ethylamino]benzoate (110.0 mg, 210.5 ⁇ mol) and TFA (3.0 g, 2.0 mL, 26 mmol) in DCM (2 mL) and heated at 40°C for 3 hours.
  • Example 4 and Example 5 2-[1-[2-[3-(1-Cyano-1-methyl-ethyl)phenyl]-6-methyl-4-oxo- chromen-8-yl]ethylamino]benzoic acid, Isomer 1 and Isomer 2 [768] Dissolved 2-[1-[2-[3-(1-cyano-1-methyl-ethyl)phenyl]-6-methyl-4-oxo-chromen-8- yl]ethylamino]benzoic acid 2,2,2-trifluoroacetic acid (40 mg) in MeOH (2.25 mL) and DCM (2.25 mL).
  • Example 22 2-[[(1R)-1-(6-Methyl-4-oxo-2-phenyl-chromen-8-yl)ethyl]amino]benzoic acid [770] A solution of [(1S)-1-(6-methyl-4-oxo-2-phenyl-chromen-8-yl)ethyl] methanesulfonate (48.6 g, 107 mmol) in DCM (480 mL) was stirred at room temperature. Anthranilic acid (44.0 g, 321 mmol), followed slowly by 2,6-lutidine (22.9 g, 214 mmol) was added. The reaction was stirred at room temperature for 14 h.
  • PIP2diC8 (Avanti Polar Lipids Inc., cat.no.850185) or Soy PI (Avanti Polar Lipids Inc., cat. No. 840044P) was used as lipid substrate.
  • PIP2diC8 or PI lyophilized powder was dissolved in milliQ water to a concentration of 1mM just before use.10mM stock compounds in DMSO were serially diluted 1:3 to generate a 10-point curve and plated using an acoustic liquid handler system (Echo 550 series instrument, Labcyte). A 10X intermediate compound plate (200uM starting compound concentration and 10% DMSO) was prepared before starting the reaction.
  • a typical reaction mixture (50 uL) comprised 40mM HEPES buffer, pH 7.4, 25 mM MgCl2, 0.01% v/v triton-X-100, 1% v/v DMSO, 20 mM NaCl, 1-5 nM WT or H1047R PI3K protein, 20 uM ATP, and 50 uM PIP2diC8 or Soy PI.1% DMSO buffer alone without test compound was employed as MAX control (full activity in the absence of any inhibitor), and no enzyme control was used to determine the level of background Adenosine 5'-diphosphate (ADP) (MIN control).
  • ADP Adenosine 5'-diphosphate
  • Wild-type (WT) and H1047R mutant protein in kinase buffer with all components except ATP were incubated with or without compound at 27°C for 1h. After the pre-incubation, the reaction was initiated by the addition of 20uL of 50uM ATP (20uM final concentration). The reaction was allowed to proceed until about 10% conversion of ATP (2 uM ADP) at 27oC. After that time, 5 uL of reaction was mixed with 5 uL of ADP-Kinase Glo Reagent (ADP-Glo Kinase assay kit, Promega cat.no. V9102) supplemented with MgCl210mM to stop the reaction and deplete the remaining ATP for 40 min at room temperature.
  • ADP-Kinase Glo Reagent ADP-Glo Kinase assay kit, Promega cat.no. V9102
  • Y bot + [(top-bot)/1+(x/IC50)slope]
  • Y % inhibition
  • X concentration yielding y% inhibition
  • Bottom minimum value of y attained by curve
  • Top maximum value of y attained by curve
  • Slope steepness of curve at IC50.
  • %Inh [(median Max- x/ median Max – median Min)] ⁇ 100
  • IC50 concentration of compound that reduces a given response (ligand binding, enzyme response) by 50%.
  • IC50 relative concentration giving half the compound’s maximum response.
  • IC50 values shown in Table A “A” means IC50 ⁇ 0.5 ⁇ M; “B” means IC50 ranging between 0.5 ⁇ M and 1.0 ⁇ M; “C” means IC50 ranging between 1 ⁇ M and 5 ⁇ M; “D” means IC50 ranging between 5 ⁇ M and 10 ⁇ M; “E” means IC50 > 10 ⁇ M.
  • DMEM Modified Eagle Media
  • FBS HI Fetal Bovine Serum
  • NEAA 1X non-essential amino acids
  • mM sodium pyruvate 1 mM sodium pyruvate
  • MDA-MB-453 cells were seeded at a density of 1.5 ⁇ 10 4 cells per well in white 384-well plates in 20 ⁇ l of Minimum Essential Media (MEM) assay media with 1X NEAA, 1 mM sodium pyruvate, and 1 ⁇ g/mL human insulin (Sigma I9278).
  • MEM Minimum Essential Media
  • Compounds dissolved in 10 mM stock solutions in DMSO were serially diluted 1:3 in DMSO to generate a 10-point dilution series and plated using an acoustic liquid handler system (Echo 550 Series Liquid Handler, Labcyte).
  • a 5X intermediate compound dilution plate in MEM with 1X NEAA and 1 mM sodium pyruvate (150 ⁇ M starting compound concentration in 1.5% DMSO) was then prepared.
  • Five ⁇ l of the intermediate serially diluted compounds were added to the cell plate to final concentrations ranging from 30 mM to 0.0015 mM in 0.3% DMSO.0.3% DMSO alone was used to establish the maximum (MAX) signal and GDC-0032 at a final concentration of 1 ⁇ M was used as a reference compound for the minimum (MIN) signal.
  • MAX maximum
  • GDC-0032 GDC-0032 at a final concentration of 1 ⁇ M was used as a reference compound for the minimum (MIN) signal.
  • the medium was removed, and the cells lysed in 10 ⁇ L of 1X SureFire Lysis buffer with shaking for 10 minutes at room temperature.
  • the Acceptor Mix (Reaction Buffer 1 + Reaction Buffer 2 + Activation Buffer + SureFire Ultra Acceptor Beads) was prepared by diluting Activation buffer 25-fold in combined Reaction Buffer 1 and Reaction Buffer 2.
  • the Acceptor beads were diluted 50-fold in the combined Reaction Buffers. Five ⁇ L of Acceptor Mix was added to each well, the plate was sealed and covered with foil and incubated for 1 hour at room temperature.
  • the Donor Mix (dilution buffer + SureFire Ultra Donor Beads) was prepared by diluting Donor Beads 50-fold in dilution buffer. Five ⁇ L of the Donor Mix was added to each well and the plate sealed and covered with foil and incubated for 1 hour at room temperature in the dark.
  • the plates were read on a Neo2 plate reader instrument from Biotek using standard AlphaLisa settings. Compounds were tested in duplicate and the average % inhibition at each compound concentration was used to generate a single dose response curve. The data were processed using the Genedata- Screener tool. Relative IC50 values were determined using luminescence units by calculating percent inhibition with respect to the in-plate “MIN” (GDC-0032 reference control) and “MAX” (DMSO) controls.
  • Y bottom + [(top - bottom)/1+(X / IC50)slope]
  • Y % inhibition
  • X concentration of inhibitor
  • bottom minimum value of y attained by curve-fit
  • top maximum value of y attained by curve-fit
  • slope steepness of curve at the IC50.
  • %Inhibition [(signal at X – median Min)/ (median Max – median Min)] x 100
  • IC 50 concentration of compound that reduces a given response (ligand binding, enzyme response) by 50%.
  • Relative IC50 concentration giving half the compound’s maximum response.
  • IC50 values shown in Table B “A” means IC50 ⁇ 50 nM; “B” means IC50 ranging between 50 nM and 100 nM; “C” means IC50 ranging between 100 nM and 500 nM; “D” means IC50 > 500 nM.
  • Table B PI3K- ⁇ (PIK3CA) in vitro cell based assay IC50
  • Compounds 1, 21, 36, 93, and 172 correspond to Example 1, 21, 36, 93, and 172 above.
  • Compound N1, Compound N2, Compound N3, Compound N4, Compound N5, and Compound N6 are described in WO2021/202964, the content of which is incorporated herein by reference in its entirety with respect to the PI3K ⁇ inhibitor compounds and methods of making and using the PI3K ⁇ inhibitor compounds disclosed therein.
  • Compound HP0, Compound HP1, Compound HP2, and Compound HP3 are described in WO2021/222556, the content of which is incorporated herein by reference in its entirety with respect to the PI3K ⁇ inhibitor compounds and methods of making and using the PI3K ⁇ inhibitor compounds disclosed therein.
  • in vitro signaling assay for PI3K ⁇ substrates such as p-AKT and p-S6 may be performed as follows. Cells are cultured and seeded into 60mm dishes. Dishes are incubated at 37 °C overnight allowing cells to be attached on the dish bottom and 50-60% cell confluence was achieved at the time of treatment. [783] Stock solutions of test compounds are diluted in DMSO and added into medium to make final working concentrations. Cell dishes are shaken slightly allowing compound to be distributed evenly and cells are incubated with compound at 37°C for 4 hours. Cells are treated with compounds successively in 3 min interval for each dish.
  • Buffers are prepared as follows. [785] Lysis Buffer: 10 ⁇ l Halt protease inhibitor cocktail is added into 1ml cell lysis buffer (1x working buffer). [786] Electrophoresis Running Buffer: 50 ml 20 ⁇ Running Buffer are diluted into 1000 ml with ddH 2 O. [787] 1 ⁇ Transfer Buffer: Add 100 ml 20 ⁇ Transfer Buffer and 400 ml methanol into 1500 ml ddH2O. [788] 1 ⁇ TBST Buffer: 50 ml 20 ⁇ TBST Buffer are diluted into 1000 ml with ddH2O.
  • Blocking Buffer 2.5 g blocker was dissolved into 50 ml 1 ⁇ TBST Buffer and stored at 4°C.
  • Primary Antibody Dilution All primary antibodies tested are diluted in blocking buffer at the ratio of 1:1000.
  • Secondary Antibody Dilution Anti-rabbit IgG, HRP-linked antibody are diluted with blocking buffer at the ratio of 1:2000.
  • Chemiluminescence Reagent Stable peroxide solution and the Luminol/Enhancer solution were mixed at 1:1 ratio to make final working ECL reagent.
  • Cell proteins are extracted as follows. After treatment for indicated time, cells are washed gently by 5 mL ice-cold PBS once.
  • PBS is aspirated completely and 120 ⁇ L ice-cold complete lysis buffer (with Halt protease inhibitor) is added to each dish drop by drop.
  • Cell lysates are collected by scraper and transferred to 1.5 ml pre-cold eppendorf tube. Lysates are vortexed for few seconds and kept on ice for 1 hour and vortexed every 15 min. Cell lysates are spun at 15000 rpm for 15 min at 4°C and clear lysates for each sample are collected and transferred to a new eppendorf tube without touching the pellet, and a small volume of supernatant (around 20 ⁇ l) is left behind. The total amount of protein is quantified by performing a Bradford assay.
  • a western blot is performed as follows. 15 ⁇ g total protein is loaded on 4-12% Bis-Tris Mini gel and followed by gel electrophoresis at the constant voltage of 120V (Novex Xcell Surelock electrophoresis cell EI0001). Proteins are transferred to nitrocellulose membrane (Trans-Blot Turbo mini 0.2 ⁇ m nitrocellulose transfer pack, BioRad 1704158) using BioRad Transblot Turbo transfer system (BioRad 17001918). After transferring, membrane is blocked by blocking buffer for 1h at RT. Blocked membrane is washed 3x 5min with 1xTBST and incubated with primary antibodies in 1x TBST with 5% BSA overnight at 4°C.
  • SUM185PE cells H1047+/+, TNBC
  • Resistant MDA-MB-453 cells Resistant MDA-MB-453 cells.
  • CCG cell titer glow
  • Compound concentrations (alpelisib, Compound 1, Compound 21, Compound N1, and Compound N2) were gradually increased over several months to achieve low, medium, or high levels of resistance in full serum medium, as follows: at 3 months to 2 ⁇ M (low level of resistance); at 4 months to 5 ⁇ M (medium level of resistance); and at 5 months to 10 ⁇ M (high level of resistance).
  • Cells were replenished with fresh selection medium every 3-4 days and were sub- cultured at 1:3 after confluency reached up to 70-80%. Levels of resistance were assessed by: EC50 shift in growth inhibition measured by CTG assays; b. Changes in signaling inhibition assessed by Western blot analysis of phosphorylation; and c. Stability of the colony in selection-free conditions. [801] Cells were considered resistant after achieving a log fold of EC50 increase in the cell proliferation assay. In addition to cell proliferation, resistance was monitored by Western blotting to confirm PI3K pathway modulation. At the end of the selection process cell line authenticity was confirmed by short tandem repeat (STR) analysis. [802] ii). Resistant SUM185PE cells.
  • Cells selected for acquired resistance to Compound 1 were developed using SUM185PE (H1047+/+, TNBC) parental cells. Cells were continuously exposed to increasing concentrations of alpelisib, Compound 1, Compound 21, Compound N1, and Compound N2. Drug exposure was progressively doubled once the cells resumed a stable proliferation rate from EC5030 - 50 nM to 10 ⁇ M in full serum medium. Cells were replenished with fresh selection medium every 3-4 days and were sub-cultured at 1:3 once confluency reached up to 70-80%. Selected cells are cultured in 10 ⁇ M of drug to maintain the resistant phenotype. For experimental characterization, the drug is removed for 48 h. At the end of the selection process cell line authenticity was confirmed by STR analysis.
  • MDA453 cells that are resistant to alpelisib (ALP-R) or Compound 21 (Cpd 21-R) were created as described above.
  • the ALP-R cells and Cpd 21-R cells then were tested for cross- resistance by performing a cell proliferation assay in the presence of PIK3 ⁇ specific inhibitors including alpelisib, Compound 1, Compound 21, Compound 36, Compound 93, and Compound HP1 and calculating an EC50 and fold change for ALP-R cells and Cpd 21-R cells relative to na ⁇ ve MDA453 cells.
  • the results for the cross-resistance experiments are provided in Table D.
  • the cross- resistance cells demonstrated increased levels of resistance relative to na ⁇ ve cells in varying degrees.
  • Cpd 21 or alpelisib was removed from the growth media for Cpd 21-R MDA453 cells and ALP-R MDA453 cells and resistance was assessed on day 3, day 10, and day 22. No substantial change in resistance levels in Cpd 21-R MDA453 cells and ALP-R MDA453 cells was observed 22 days after the Cpd 21 or alpelisib, respectively, was removed from the cells.
  • [814] Whole Genome Exome Sequencing of Resistant Cells to Identify Acquired Mutations in Cells with Acquired Resistance to Compound 21 or Compound 1 [815] The purpose of these experiments was to identify acquired mutations in cell lines that had acquired resistance to Compound 21 or Compound 1.
  • the T47D HM-6X cells then were tested for resistance to alpelisib, inavolisib (i.e., GDC-0077), Compound 1, Compound 21, Compound 36, Compound 93, Compound N1, Compound N2, inavolisib, and Compound HP1 after low passage and high passage.
  • the results for the low passage T47D HM-6X cells are provided in Figs.2-7 and Table F, and the results for the high passage T47D HM-6X cells are provided in Figs.8-11.
  • the results illustrate that the M1043I mutation in cis with the H1047R mutation resulted in enhanced resistance to PI3K ⁇ specific inhibitors relative to na ⁇ ve cells.
  • Table F Table F.
  • MCF-10A cells were transfected with vectors that overexpress H1047R or H1047R + M1043I.
  • the MCF-10A(H1047R) cells and the MCF-10A(H1047R+M1043I) cells thus generated then were tested for resistance to alpelisib, inavolisib, Compound 1, Compound 21, Compound N1, Compound N2, and Compound HP1 in a cell proliferation assay.
  • the results are presented in Table G and demonstrate that the MCF-10A(H1047R+M1043I) cells were more resistant to PI3K ⁇ specific inhibitors than MCF-10A(H1047R) cells. [826] Table G.
  • CCG cell proliferation assay
  • MDA453 cells and MDA453 (Cpd 21-R) cells were grown in the presence of increasing concentrations of a combination of two different pairs of inhibitors: 1) Compound 21 (six increasing concentrations: 0.004, 0.012, 0.037, 0.11, 0.33, and 1 ⁇ M) and alpelisib (four increasing concentrations: 0.0333, 0.099, 0.297, 0.9 ⁇ M); and 2) Compound 21 (six increasing concentrations: 0.004, 0.012, 0.037, 0.11, 0.33, and 1 ⁇ M) and Compound HP1 (four increasing concentrations: 0.0333, 0.099, 0.297, 0.9 ⁇ M).
  • CCG cell proliferation assay
  • PI3K ⁇ allosteric pocket 1 there are two allosteric pockets in PI3K ⁇ , which may be referred to as “PI3K ⁇ allosteric pocket 1” and “PI3K ⁇ allosteric pocket 2.”
  • Compounds that bind PI3K ⁇ allosteric pocket 1 may interact with amino acid residues that include C901, T908, F909, H931, F954, Q981, Y985, Y1021, and R1047.
  • Compounds that bind PI3K ⁇ allosteric pocket 2 may interact with amino acid residues that include L911, F937, F1002, E1012, and D1018.
  • Fig.27 illustrates binding of Compound N6 in PI3K ⁇ allosteric pocket 1 and concurrent binding of Compound HP2 in PI3K ⁇ allosteric pocket 2.
  • Effect of a Combination of Compound 21 with Alpelisib or Inavolisib in a Cell Proliferation Assay in vitro [835] The purpose of this experiment was to examine the effect of a combination of Compound 21 and alpelisib or a combination of Compound 21 and inavolisib in T-47D cells in a cell proliferation assay in vitro.
  • Cells were seeded at an appropriate density in 20 ⁇ L volume of media into a clear bottom 384- well cell culture plate.
  • Table H Seeding density and culture medium details for each cell line are described in Table H. Plates then are incubated at 37 °C and 5% CO 2 and treated with test compound 24 hours post-seeding.
  • Table H Cell proliferation assay cell line information Seeding Commercial Reading time Cell Line Culture Medium density reference (hours) RPMI 1640 media (Gibco A1049101), 10% h.i. FBS, T-47D 1000 ATCC-HTB-133 96 and 1% penicillin- streptomycin [838] Compounds were prepared as 10 mM DMSO stock solutions and used for dose-response studies.
  • Staurosporine 2 ⁇ M was used as a reference compound for the minimum signal and DMSO 0.2% as the maximum signal.
  • Cell plates were incubated at 37 °C and 5% CO 2 . After incubation with compounds for two cell doubling times, plates were removed from the incubator and 65 ⁇ L of ice-cold EtOH 96% were added to each well to have a final EtOH 70%. After 30 minutes, media was removed and 20 ⁇ L of PBS containing RNase (50 ⁇ g/mL) and propidium iodide (1 ⁇ g/mL) were added per well.
  • Ratios Compound 21-Alpelisib/GDC-0077 were 10:10 [840] Effect of in vivo combination of Compound 21, Alpelisib, and Fulvestrant in an ER-positive, PI3Ka H1047R -/+ breast cancer xenograft tumor model implanted in mice [841] The purpose of the following xenograft tumor inhibition assay was to measure reduction in tumor volume and combination effect in response to test Compound 21 administration alone, and in combination with low doses of PI3K alpha orthosteric inhibitor alpelisib with/without the estrogen receptor degrader (SERD) fulvestrant.
  • SESD estrogen receptor degrader
  • T-47D (ATCC #HTB-133) were expanded in culture, harvested and injected 5 ⁇ 10e 6 cells in 1:1 HBSS+MATRIGELTM solution (200 uL) subcutaneously onto the rear right flank of female NOD scid gamma (NSG) mice (The Jackson Laboratory, Inc). Twenty-four hours prior to implantation of cells, estrogen pellets were implanted (0.72 mg/pellet, 17 ⁇ estradiol, 90-day release, Innovative Research) subcutaneously. Tumor growth and body weight were measured twice per week beginning the seventh day after the implantation. When tumor sizes reached 250-300 mm 3 , animals were randomized into groups of 5 animals.
  • Compound 21 was prepared in an appropriate vehicle (1 molar equivalent of 1N NaOH in DI water) and administered by oral gavage for 28 days, BID.
  • the PI3K ⁇ orthosteric inhibitor alpelisib was prepared in an appropriate vehicle (10% 2- Hydroxypropyl- ⁇ -Cyclodextrin in Sterile Water)) and administered by oral gavage for 28 days, QD.
  • the estrogen receptor degrader fulvestrant (formulated by the supplier) was administered Q7D for 28 days. Groups and treatments are defined in Table J. Tumor response was determined by tumor volume measurement performed twice a week during treatment. Body weight measurement were taken as a general measure of toxicity whenever tumor volume was measured.
  • Compound 21 is found to have improved efficacy for reduction in tumor size when combined with low dose alpelisib with or without fulvestrant in the ER-positive human breast cancer xenograft model T47D as provided in Table K and Fig.28 and Fig.29.
  • Statistical analyses of the combination of Compound 21 with low doses of alpelisib or fulvestrant and the triple combination of compound of Compound 21 and low doses alpelisib plus fulvestrant in the ER-positive human breast cancer xenograft model in mice (as defined by the Bliss Independence method) indicate that Compound 21 demonstrates additive and greater than effect in combinations as shown in Table L. Table J.
  • MDA-MB-453 (ATCC #HTB-131) were expanded in culture, harvested and injected 1 ⁇ 10e 7 cells in 1:1 HBSS+MATRIGELTM solution (200 uL) subcutaneously on to the rear right flank of female NOD scid gamma (NSG) mice (The Jackson Laboratory, Inc). Tumor growth and body weight were measured twice per week beginning the seventh day after the implantation. When tumor sizes reached 250-300 mm 3 , animals were randomized into groups of 5 animals. Compound 21 was prepared in an appropriate vehicle (1 molar equivalent of 1N NaOH in DI water) and administer by oral gavage for 24 days, BID.
  • the Pi3Kalpha orthosteric inhibitor alpelisib was prepared in an appropriate vehicle (10% 2-Hydroxypropyl- ⁇ -Cyclodextrin in Sterile Water) and administered by oral gavage for 24 days, QD. Groups and treatments are shown in Table M. Tumor response was determined by tumor volume measurement performed twice a week during treatment. Body weight measurement were taken as a general measure of toxicity whenever tumor volume was measured. C-peptide and insulin and levels were measured at the time of collection and shown in Table N and Table O. [848] Compound 21 is found to have improved efficacy for reduction in tumor size when combined with low doses of alpelisib in the human triple negative MDA-MB-453 breast cancer as provided in Table P.
  • Delta T/C% is calculated when the endpoint tumor volume in a treated group is at or above baseline tumor volume.
  • the formula is 100*(T-T0)/(C-C0), where T and C are mean endpoint tumor volumes in the treated or control group, respectively. T0 and C0 are mean baseline tumor volumes in those groups. Regression% is calculated when the endpoint volume is below baseline.
  • the formula is 100*(T- T0)/T0, where T0 is the mean baseline tumor volume for the treated group. Grand mean of all groups from baseline (randomization) is used to compute % change of T/C.
  • EAR is the Expected additive response tumor volume. Tumor volumes measured after 24 days treatment. Table Q.
  • COMPOUND 21 37.5 mg/kg + Alpelisib 6.25 mg/kg ⁇ 0.001* 0.0108* ⁇ 0.001* -0.067 0.053 0.2098
  • Additive COMPOUND 21 Greater 75 mg/kg + ⁇ Than Alpelisib 12.5 mg/kg ⁇ 0.001* ⁇ 0.001* ⁇ 0.001* -0.174 0.042 0.001*
  • Additive * significant (p ⁇ 0.05)
  • the combination effect is exactly additive, then by definition of Bliss Independent the two-way interaction contrast estimate equals zero. If the contrast estimate is statistically different from zero ( p ⁇ 0.05 ) , then the combination effect is either greater than (synergistic) or less than (antagonistic) additive if the observed combination mean volume is less than or greater than the expected additive response tumor volume ( ⁇ ⁇ ⁇ ⁇ ⁇ ), respectively.
  • the interaction contrast test is statistically significant (p ⁇ 0.05) and the observed combination mean volume is greater than the EAR volume, then the combination effect is declared less than additive (antagonistic) regardless of the pairwise comparison results.
  • the interaction test is not statistically significant (p ⁇ 0.05), but all pairwise comparisons versus the combination group are significant (p ⁇ 0.05), then the combination effect is declared additive, otherwise the combination effect is inconclusive (no effect).
  • the Bliss Effect was estimated with contrast statement of the following form: 2 ⁇ log10 ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ Control ⁇ log10 ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ Single Agent 1 ⁇ log10 ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ Single Agent 2 ⁇ log10 ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ Single Agent 3 + log10 ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ Combination
  • log 10 ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ is the mean tumor volume for treatment ⁇ [861] Assuming that tumor volumes can, in theory or in practice, reach zero (complete regression), this approach is mathematically equivalent to the Bliss Independence method when analyzing tumor volume on the log scale.
  • the combination effect is exactly additive, then by definition of Bliss Independent the contrast estimate equals zero. If the contrast estimate is statistically different from zero ( ⁇ ⁇ 0.05 ) , then the combination effect is either greater than (synergistic) or less than (antagonistic) additive if the observed combination mean volume is less than or greater than the expected additive response tumor volume ( ⁇ ⁇ ⁇ ⁇ ⁇ ), respectively.
  • MDA453 cells that are resistant to Compound 21 were created as described above and determined to have an M1043I second-site mutation.
  • the Cpd 21-R cells then were tested for cross-resistance by performing a cell proliferation assay in the presence of increasing concentrations of PIK3 ⁇ specific inhibitors Compound 21, alpelisib, and Compound HP1.
  • the results are presented in Fig.30.
  • the cross-resistance cells demonstrated increased levels of resistance relative to na ⁇ ve cells in varying degrees.
  • T47D (6 ⁇ M1043I) cells were created as described above.
  • the T47D (6 ⁇ M1043I) cells then were tested for cross-resistance by performing a cell proliferation assay in the presence of increasing concentrations of PIK3 ⁇ specific inhibitors Compound 21, alpelisib, and Compound HP1.
  • the results are presented in Fig.31.
  • the cross-resistance cells demonstrated increased levels of resistance relative to na ⁇ ve cells in varying degrees.
  • the cross-resistance cells demonstrated increased levels of resistance relative to na ⁇ ve cells in varying degrees.
  • MDA453 na ⁇ ve cells were treated with increasing concentrations of alpelisib in combination with increasing concentrations of Compound 21were treated with increasing concentrations of alpelisib in combination with increasing concentrations of Compound 21.
  • An in vitro signaling assay for PI3K ⁇ substrates p-AKT and p-S6 was performed essentially as described above. (See Fig.33). A Combination Index was plotted versus Total Dose. (See Fig. 34).
  • MDA453 na ⁇ ve cells Treatment of MDA453 na ⁇ ve cells with combination of Compound HP1 and Compound 21.
  • MDA453 na ⁇ ve cells were treated with increasing concentrations of Compound HP1 in combination with increasing concentrations of Compound 21.
  • An in vitro signaling assay for PI3K ⁇ substrates p-AKT and p-S6 was performed essentially as described above. (See Fig.35). A Combination Index was plotted versus Total Dose. (See Fig.36).
  • MDA453 na ⁇ ve cells were treated with increasing concentrations of alpelisib in combination with increasing concentrations of Compound HP1.
  • SUM185PE H1047R homozygous cells were treated with increasing concentrations of HP1 in combination with increasing concentrations of Compound 21.
  • An in vitro signaling assay for PI3K ⁇ substrates p-AKT and p-S6 was performed essentially as described above. (See Fig.41).
  • SUM185PE (H1047R homozygous) cells were treated with increasing concentrations of alpelisib in combination with increasing concentrations of Compound HP1.
  • An in vitro signaling assay for PI3K ⁇ substrates p-AKT and p-S6 was performed essentially as described above.
  • T47D cells Treatment of T47D cells with combination of alpelisib and Compound 21. [890] T47D cells were treated with increasing concentrations of alpelisib in combination with increasing concentrations of Compound 21. An in vitro signaling assay for PI3K ⁇ substrates p- AKT and p-S6 was performed essentially as described above. (See Fig.43). [891] Treatment of T47D cells with combination of Compound HP1 and Compound 21. [892] T47D cells were treated with increasing concentrations of HP1 in combination with increasing concentrations of Compound 21. An in vitro signaling assay for PI3K ⁇ substrates p- AKT and p-S6 was performed essentially as described above.
  • T47D cells Treatment of T47D cells with combination of alpelisib and Compound HP1.
  • T47D cells were treated with increasing concentrations of alpelisib in combination with increasing concentrations of Compound HP1.
  • An in vitro signaling assay for PI3K ⁇ substrates p-AKT and p-S6 was performed essentially as described above.
  • a cell proliferation assay also was performed essentially as described above and %Inhibition was plotted versus Dose (log/ ⁇ M).
  • EC50 values were calculated for alpelisib and Compound 21 either in single dose or in combination. (See Fig.46).
  • T47D cells (5 ⁇ H1047R/1 ⁇ WT) or T47D cells that were engineered to have 2 nd site mutations (5 ⁇ H1047R/6 ⁇ C901F) or (6 ⁇ H1047R/M1043I) were treated with increasing concentrations of Compound 21, alpelisib, Compound HP1, Compound HP4, Compound HP5, or Compound HP6.
  • a cell proliferation assay was performed essentially as described above and %Inhibition was plotted versus Dose (log/ ⁇ M). (See Fig.49).
  • EC50 values were calculated for T47D cells, T47D (5 ⁇ H1047R/6 ⁇ C901F) cells, and T47D (6 ⁇ H1047R/M1043I) cells for each compound as indicated in Table S.

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Abstract

L'invention concerne l'utilisation d'inhibiteurs de la phosphoinositide 3-kinase (PI3K) qui ciblent des poches allostériques et orthostériques de PI3K dans des méthodes de traitement, de prévention ou d'amélioration d'une maladie, ou d'un trouble, (ou des utilisations dans le traitement, la prévention ou l'amélioration d'une maladie, ou d'un trouble), dans laquelle PI3K joue un rôle. Les inhibiteurs de PI3K peuvent être utilisés en combinaison et peuvent cibler des poches allostériques ou orthostériques de PI3Kα simultanément, séparément ou séquentiellement. Dans certains aspects des procédés décrits, un inhibiteur de PI3Kα peut cibler une poche allostérique ou orthostérique d'un mutant de PI3Kα qui est résistant au traitement avec un autre inhibiteur de PI3Kα qui cible une poche différente de PI3Kα.
EP23817906.3A 2022-11-02 2023-11-01 Ciblage de poches allostériques et orthostériques de phosphoinositide 3-kinase (pi3k) pour le traitement d'une maladie Pending EP4611741A1 (fr)

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