(r)-3-(6-chloro-3-((1-(2-cyclopropyl-6-fluoro-3-methyl-4-OXO-4h-chromen-8-YL)ethyl)amino)pyridin-2-YL)-1,2,4-oxadiazol-5(4H)-one as PI3k inhibitor for the treatment of cancer

Abstract

The disclosure relates to the compound (( R)-3-(6-chloro-3-((l-(2- cyclopropyl-6-fluoro-3-methyl-4-oxo-4H-chromen-8-yl)ethyl)amino) pyridin-2-yl)-l,2,4-oxadiazol-5(4H)-one) of the Formula I, or to a pharmaceutically acceptable salt thereof, which is useful in the treatment of diseases or disorders associated with modulation of PI3K (phosphoinositide 3 kinase), such as e.g. cancer.

Description

[0001] (R)-3-(6-CHLORO-3-((1-(2-CYCLOPROPYL-6-FLUORO-3-METHYL-4-OXO-4H-CHROMEN-8-YL)ETHYL)AMINO)PYRIDIN-2-YL) -1,2,4-OXADIAZOL-5(4H)-ONE AS PI3K INHIBITOR FOR THE TREATMENT OF CANCER

[0002] Field

[0003] [1] The present invention is directed to allosteric chromenone inhibitors of phosphoinositide 3- kinase (PI3K) useful in the treatment of diseases, or disorders associated with PI3K modulation. The invention is directed toward compounds, and compositions which inhibit PI3K, 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), PlK3CA-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, optionally in combination with one or more additional cancer therapies.

[0004] Background

[0005] [2] The phosphoinositide 3 -kinases (PI3Ks) signaling pathway is one of the most highly mutated systems in human cancers. PI3K signaling is involved in many other disease states including allergic contact dermatitis, rheumatoid arthritis, osteoarthritis, inflammatory bowel diseases, chronic obstructive pulmonary disorder, psoriasis, multiple sclerosis, asthma, disorders related to diabetic complications, and inflammatory complications of the cardiovascular system such as acute coronary syndrome.

[0006] [3] 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 (Katso et al., Annu Rev Cell Dev Biol. 2001;17:615-75). The class I PI3Ks (pl 10a, pl 10p, pl 105, and pl 10y) 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 / PDKl, 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.

[0007] [4] The PI3K isoforms have been implicated, for example, in a variety of human cancers, and disorders. Mutations in the gene coding for PI3K isoforms, or mutations which lead to upregulation of a PI3K isoform are believed to occur in many human cancers. Mutations in the gene coding for a PI3K isoform are point mutations clustered within several hotspots in helical, and kinase domains. Because of the high rate of PI3K mutations, targeting of this pathway may provide valuable therapeutic opportunities.

[0008] [5] Genetic alterations in genes in PI3K signaling are believed to be involved in a range of cancers such as 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, colorectal cancer, pancreatic cancer, cholangiocarcinoma, B-cell lymphoma, mesothelioma, adrenocortical carcinoma, renal non-clear-cell carcinoma, renal clearcell carcinoma, germ-cell carcinoma, thymic tumor, pheochromocytoma, miscellaneous neuroepithelial tumor, thyroid cancer, leukemia, and encapsulated glioma (Goncalves MD, Hopkins BD, Cantley LC. Phosphatidylinositol 3-Kinase, Growth Disorders, and Cancer. N Engl J Med. 2018 Nov 22;379(21):2052-2062).

[0009] [6] The alpha (a) isoform of PI3K otherwise referred to as PI3KCA, has been implicated, for example, in a variety of human cancers. Angiogenesis has been shown to selectively require PIK3CA in the control of endothelial cell migration. (Graupera et al, Nature 2008; 453; 662-6). Mutations in the gene coding for PI3KCA, or mutations which lead to upregulation of PI3KCA 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 PI3KCA 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 PI3KCA mutations, targeting of this pathway may provide valuable therapeutic opportunities.

[0010] [7] Mutated PI3KCA has been implicated in brain metastases in HR+ / HER2- metastatic breast cancers. Development of brain-penetrant PI3KCA inhibitors may provide improved therapeutic benefit over current PI3KCA inhibitors. (Fitzgerald et al., Association between PIK3CA mutation status and development of brain metastases in HR+ / HER2- metastatic breast cancer. Ann Oncol 30: vl 10, 2019 (suppl 5)).

[0011] [8] Due to the central role of PI3KCA in regulating organismal glucose homeostasis, PI3K inhibition in patients often gives rise to hyperglycemia and / or hyperinsulinemia (Busaidy NL, et al, Management of metabolic effects associated with anticancer agents targeting the PI3K-Akt- mTOR pathway. J Clin Oncol 2012;30:2919-28). High levels of circulating insulin could potentially be mitogenic and / or antiapoptotic for cancer cells, and thus negate the antiproliferative effects of PI3K inhibitors (Blouin M-J, et al, Abstract 4615: the hyperinsulinemia caused by PI3K inhibitors attenuates their antineoplastic efficacy, but can be minimized by co-administration of metformin. Cancer Res 2013;73:4615).

[0012] [9] In the setting of cancer with mutated PI3KCA, one way to overcome the problem of compensatory production of insulin and / or glucose upon systemic PI3KCA inhibition would be to develop inhibitors with enhanced selectivity for mutant PI3KCA over wild-type PI3KCA. This would create an increased window for drug dosing to selectively inhibit the pathologic signaling of mutant PI3KCA in the cancer cells without affecting the wild-type PI3KCA in the host tissues that control systemic metabolism (Okkenhaug K, Graupera M, Vanhaesebroeck B. Targeting PI3K in Cancer: Impact on Tumor Cells, Their Protective Stroma, Angiogenesis, and Immunotherapy. Cancer Discov. 2016 Oct;6( 10): 1090- 1105), thus limiting toxicides, and permitting higher doses, and more complete inhibition of the drug target (Ariella B. Hanker, et al, Challenges for the clinical development of PI3K inhibitors: Strategies to improve their impact in solid tumors. Cancer Discov. 2019 Apr; 9(4): 482-491).

[0013] [ 101 Currently PI3KCA inhibitors are nearly equipotent to wild-type, and mutant PI3KCA. Mutant selective inhibitors have been elusive due to the PI3KCA mutations location far from the active site. As such, inhibitors which target a second, peripheral binding pocket near a known mutation (e.g., H1047R) may provide a route to selective PI3KCA inhibition. Thus, targeting a mutated, peripheral binding pocket of PI3KCA, provides a valuable therapeutic target for drug development.

[0014]

[0011] As such, kinase inhibitors of lipid kinases such as PI3KCA are prime areas for drug development. One goal is to develop PI3KCA inhibitors that exhibit suitable potency for PI3KCA’s. One goal is to develop PI3KCA inhibitors that exhibit suitable potency for PI3KCA that are associated with metastatic disease such as PI3KCA(H1047R), and PI3KCA(E545K). Another goal is to develop PI3KCA inhibitors that exhibit suitable selectivity versus wild-type for mutant PI3KCAs that are associated with metastatic disease including PI3KCA(H1047R), and PI3KCA(E545K). Another goal is to develop PI3KCA inhibitors that exhibit suitable metabolic stability and pharmacokinetics. Another goal is to develop PI3KCA inhibitors that do not cause adverse events (AEs), such as hyperglycemia, hyperinsulinemia, and diarrhea, or exhibit only minimal, mild, or reduced AEs, when the PI3KCA inhibitors are administered at an effective dose for inhibiting the activity of PI3KCA and treating a disease or disorder associated with PI3KCA activity. Another goal is to develop PI3KCA inhibitors that do not exhibit substantial activity against targets other than PI3KCA, including other kinases other than PI3KCA. A desirable P13KCA inhibitor will achieve some or all of these goals.

[0015] Summary

[0016]

[0012] Disclosed herein are compounds that achieve some or all of these goals. In one aspect, the present invention relates to a compound of Formula I: or a pharmaceutically acceptable salt thereof. In one aspect, the present invention relates to a compound named (7?)-3-(6-chloro-3-((l-(2-cyclopropyl-6-fhioro-3-methyl-4-oxo-4H-chromen-8- yl)ethyl)amino)pyridin-2-yl)-l,2,4-oxadiazol-5(4 / f)-one or a pharmaceutically acceptable salt thereof.

[0017]

[0013] In one aspect, the disclosed compounds or a pharmaceutically acceptable salt thereof may have one or more activities as disclosed herein.

[0018]

[0014] In one aspect, the disclosed compounds or a pharmaceutically acceptable salt thereof may modulate the activity of PI3KCA and the disclosed compounds or a pharmaceutically acceptable salt thereof may be characterized as having PIK3CA inhibitory activity. In one aspect, the disclosed compounds or a pharmaceutically acceptable salt thereof may inhibit the activity of wild-type PIK3CA. In one aspect, the disclosed compounds or a pharmaceutically acceptable salt thereof may inhibit the activity of a mutant PIK3CA having one or more amino acid substitutions, deletions, or insertions relative to the amino acid sequence of wild-type PIK3CA. In one aspect, the disclosed compounds or a pharmaceutically acceptable salt thereof may selectively inhibit the activity of a mutant PI3KCA relative to wild-type PI3KCA.

[0015] In one aspect, the disclosed compounds or a pharmaceutically acceptable salt thereof may exhibit suitable metabolic stability. In one aspect, the disclosed compounds or a pharmaceutically acceptable salt thereof may exhibit suitable metabolic stability as measured in one or more in vitro metabolic stability assays as disclosed herein. In one aspect, the disclosed compounds or a pharmaceutically acceptable salt thereof may exhibit metabolic stability as measured in one or more in vivo metabolic stability assays as disclosed herein.

[0019]

[0016] In one aspect, the disclosed compounds or a pharmaceutically acceptable salt thereof may exhibit suitable pharmacokinetics. In one aspect, the disclosed compounds or a pharmaceutically acceptable salt thereof may exhibit suitable pharmacokinetics as measured in one or more in vitro clearance assays as disclosed herein. In one aspect, the disclosed compounds or a pharmaceutically acceptable salt thereof may exhibit suitable pharmacokinetics as measured in one or more in vivo clearance assays as disclosed herein.

[0020]

[0017] In one aspect, the disclosed compounds or a pharmaceutically acceptable salt thereof do not induce expression of a cytochrome P450 enzyme in comparison to a control or vehicle in an in vitro assay, or the disclosed compounds or a pharmaceutically acceptable salt thereof induce expression of a cytochrome P450 enzyme at a relatively low level in comparison to a control or vehicle in an in vitro assay. In one aspect, the disclosed compounds or a pharmaceutically acceptable salt thereof do not inhibit expression of a cytochrome P450 enzyme in comparison to a control or vehicle in an in vitro assay, or the disclosed compounds or a pharmaceutically acceptable salt thereof do not inhibit expression of a cytochrome P450 enzyme at a substantial level in comparison to a control or vehicle in an in vitro assay.

[0021]

[0018] In one aspect, the disclosed compounds or a pharmaceutically acceptable salt thereof do not cause adverse events (AEs) or exhibit only minimal AEs or mild AEs when the compounds are administered at an effective dose for inhibiting the activity of PI3KCA and treating a disease or disorder associated with PI3KCA activity. In one aspect, the disclosed compounds or a pharmaceutically acceptable salt thereof do not cause hyperglycemia, hyperinsulinemia, and diarrhea when the compounds are administered at an effective dose for inhibiting the activity of PI3KCA and treating a disease or disorder associated with PI3KCA activity.

[0022]

[0019] In one aspect, the disclosed compounds or a pharmaceutically acceptable salt thereof do not exhibit substantial inhibitory activity against kinases other than PI3KCA.

[0023]

[0020] In another aspect, the present invention provides a pharmaceutical composition comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent, or carrier.

[0024]

[0021] In another aspect, the present invention provides a method of modulating wild-type or mutant PI3K activity (e.g., in vitro, or in vivo), comprising contacting a cell with a therapeutically effective amount of a compound of Formula 1, or a pharmaceutically acceptable salt thereof.

[0025]

[0022] In another aspect, the present invention provides a method of modulating one or more of PI3KCA(H1047R) activity, and PI3KCA(E545K) activity, (e.g., in vitro, or in vivo), comprising contacting a cell with a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof.

[0026]

[0023] In some aspects, the present invention provides a method of treating, or preventing a disease, or disorder disclosed herein in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof. In some aspects, the compound of Formula I, or a pharmaceutically acceptable salt thereof is administered in a method of treating, or preventing a disease in first-line administration. In some aspects, the compound of Formula I, or a pharmaceutically acceptable salt thereof is administered in a method of treating, or preventing a disease in second-line administration. In some aspects, the compound of Formula I, or a pharmaceutically acceptable salt thereof is administered in a method of treating, or preventing a disease in third-line administration.

[0027]

[0024] In some aspects, the present invention provides a method of treating, or preventing a disease, or disorder disclosed herein in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition of a compound of Formula I, or a pharmaceutically acceptable salt thereof. In some aspects, the pharmaceutical composition of a compound of Formula I, or a pharmaceutically acceptable salt thereof is administered in a method of treating, or preventing a disease in first-line administration. In some aspects, the pharmaceutical composition of a compound of Formula I, or a pharmaceutically acceptable salt thereof is administered in a method of treating, or preventing a disease in second-line administration. In some aspects, the pharmaceutical composition of a compound of Formula I, or a pharmaceutically acceptable salt thereof is administered in a method of treating, or preventing a disease in third-line administration.

[0028]

[0025] In another aspect, the present invention provides a compound of Formula I, or a pharmaceutically acceptable salt thereof for use in therapy. In some aspects, the compound of Formula I, or a pharmaceutically acceptable salt thereof, is used in first-line therapy. In some aspects, the compound of Formula I, or a pharmaceutically acceptable salt thereof, is used in second- line therapy. In some aspects, the compound of Formula I, or a pharmaceutically acceptable salt thereof, is used in third-line therapy.

[0029] [26 J In another aspect, the present invention provides a compound of Formula 1, or a pharmaceutically acceptable salt thereof for use in modulating wild-type or mutant PI3K activity (e.g., in vitro, or in vivo). In another aspect, the present invention provides a compound of Formula I, or a pharmaceutically acceptable salt thereof for use in inhibiting wild-type or mutant PI3K activity (e.g., in vitro, or in vivo).

[0030]

[0027] In another aspect, the present invention provides a compound of Formula I, or a pharmaceutically acceptable salt thereof, for use in selective inhibition of mutant PI3KCA over wild-type PI3KCA. Mutant PI3KCA may comprise one or more mutations relative to wild-type PI3KCA selected from but not limited to H1047R and E545K.

[0031]

[0028] In another aspect, the present invention provides a compound of Formula I, or a pharmaceutically acceptable salt thereof, for use in selective inhibition of PI3KCA (H1047R mutant) over wild-type PI3KCA.

[0032]

[0029] In another aspect, the present invention provides a compound of Formula I, or a pharmaceutically acceptable salt thereof, for use in selective inhibition of PI3KCA (E545K mutant) over wild-type PI3KCA.

[0033]

[0030] In another aspect, the present invention provides a compound of Formula I, or a pharmaceutically acceptable salt thereof, for use in treating, or preventing a disease, or disorder disclosed herein. In some aspects, the compound of Formula I, or a pharmaceutically acceptable salt thereof, is used in treating, or preventing a disease, or disorder in first-line administration. In some aspects, the compound of Formula I, or a pharmaceutically acceptable salt thereof, is used in treating, or preventing a disease, or disorder in second-line administration. In some aspects, the compound of Formula I, or a pharmaceutically acceptable salt thereof, is used in treating, or preventing a disease, or disorder in third-line administration.

[0034]

[0031] In another aspect, the present invention provides a compound of Formula I, or a pharmaceutically acceptable salt thereof, for use in treating a disease, or disorder disclosed herein. In some aspects, the compound of Formula I, or a pharmaceutically acceptable salt thereof, is used for treating a disease, or disorder disclosed herein in first-line treatment. In some aspects, the compound of Formula I, or a pharmaceutically acceptable salt thereof, is used for treating a disease, or disorder disclosed herein in second-line treatment. In some aspects, the compound of Formula I, or a pharmaceutically acceptable salt thereof, is used for treating a disease, or disorder disclosed herein in third-line treatment.

[0035]

[0032] In another aspect, the present invention provides use of a compound of Formula I, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for modulating wild-type or mutant PI3K activity (e.g., in vitro, or in vivo). In another aspect, the present invention provides use of a compound of Formula I, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for inhibiting wild-type or mutant PI3K activity (e.g., in vitro, or in vivo).

[0036]

[0033] In another aspect, the present invention provides use of a compound of Formula I, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating, or preventing a disease, or disorder disclosed herein. In some aspects, the medicament is used for first-line administration. In some aspects, the medicament is used for second-line administration. In some aspects, the medicament is used for third-line administration.

[0037]

[0034] In another aspect, the present invention provides use of a compound of Formula I, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating a disease, or disorder disclosed herein. In some aspects, the medicament is used for first-line treatment. In some aspects, the medicament is used for second-line treatment. In some aspects, the medicament is used for third-line treatment.

[0038]

[0035] In another aspect, the present invention provides a method of preparing a compound of Formula I, or a pharmaceutically acceptable salt thereof.

[0039]

[0036] In another aspect, the present invention provides a method of preparing a compound of Formula I, or a pharmaceutically acceptable salt thereof, comprising one or more steps described herein.

[0040]

[0037] In another aspect, the present invention provides a compound obtainable by, or obtained by, a method for preparing a compound as described herein. In another aspect, the present invention provides a compound of Formula I, or a compound obtained by a method for preparing a compound as described herein.

[0041]

[0038] In another aspect, the present invention provides an intermediate as described herein, being suitable for use in a method for preparing a compound as described herein (e.g., the intermediate is selected from the intermediates described in the Examples). In another aspect, the present invention provides an intermediate as described herein, being suitable for use in a method for preparing a compound of Formula I (e.g., where the intermediate is selected from the intermediates described in the Examples).

[0042]

[0039] Other features, and advantages of the invention will be apparent from the following detailed description, and claims.

[0043] Detailed Description

[0044]

[0040] The present invention provides compounds that modulate the activity of PI3K and 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 by administering to a patient in need thereof a therapeutically effective amount of a compound of the present invention. The disclosed compounds may inhibit the activity of wild-type or mutant PI3K and may be used in the treatment of a variety of PI3K-dependent diseases, and disorders.

[0045]

[0041] In some embodiments, the disease, or disorder is a cancer (e.g., 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). In some embodiments, the disease, or disorder associated with PI3K includes, but is not limited to, CLOVES syndrome, PROS, endometrial cancer, breast cancer, esophageal squamous-cell cancer, cervical squamouscell 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 clearcell carcinoma, germ-cell carcinoma, thymic tumor, pheochromocytoma, miscellaneous neuroepithelial tumor, thyroid cancer, leukemia, and encapsulated glioma.

[0046]

[0042] The details of the invention are set forth in the accompanying description below. Although methods, and materials similar, or equivalent to those described herein can be used in the practice, or testing of the present disclosure, illustrative methods, and materials are now described. Other features, objects, and advantages of the invention will be apparent from the description, and from the claims. In the specification, and the appended claims, the singular forms also include the plural unless the context clearly dictates otherwise. Unless defined otherwise, all technical, and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. All patents, and publications cited in this specification are incorporated herein by reference in their entireties.

[0047] Definitions

[0048] L43 J The articles “a”, and “an” refer to one, or more than one (z.<?., to at least one) of the grammatical object of the article. By way of example, “an element” means one element, or more than one element.

[0049]

[0044] The term “and / or” means either “and”, or “or” unless indicated otherwise.

[0050]

[0045] The term “administer”, “administering”, or “administration” refers to either directly administering a disclosed compound, or pharmaceutically acceptable salt of the disclosed compound, or a composition to a subject.

[0051]

[0046] The term “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”. 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”.

[0052]

[0047] The term “modulating” refers to altering a biological activity of a target, such as PI3KCA, and includes inhibiting the biological activity of a target.

[0053]

[0048] The term “patient”, or “subject” is a mammal, e.g., a human, mouse, rat, guinea pig, dog, cat, horse, cow, pig, or non-human primate, such as a monkey, chimpanzee, baboon, or rhesus. Preferably, the mammal is human.

[0054]

[0049] The term “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. In 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.

[0055]

[0050] The term “treating” with regard to a subject, includes restraining, slowing, stopping, or reversing the progression or severity of an existing symptom or disorder.

[0056] Compounds of the Present Invention

[0057]

[0051] In one aspect, the compounds of the present invention relate to allosteric chromenone inhibitors of phosphoinositide 3-kinase (PI3K) useful in the treatment of diseases, or disorders associated with PI3K modulation. In one aspect, the present invention relates to a compound of Formula I: or a pharmaceutically acceptable salt thereof. In one aspect, the present invention relates to a compound named (J?)-3-(6-chloro-3-((l-(2-cyclopropyl-6-fhioro-3-methyl-4-oxo-4H- chromen-8-yl)ethyl)amino)pyridin-2-yl)-l,2,4-oxadiazol-5(4H)-one or a pharmaceutically acceptable salt thereof.

[0058]

[0052] In a further embodiment of the compound of Formula I, or a pharmaceutically acceptable salt thereof, the compound is an isotopic derivative of any one of the compounds described herein or a pharmaceutically acceptable salt thereof. It is understood that the isotopic derivative can be prepared using any of a variety of art-recognized techniques. For example, the isotopic derivatives can generally be prepared by carrying out the procedures disclosed in the schemes and / or in the examples described herein or a pharmaceutically acceptable salt thereof, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent. In the compounds of this invention any atom not specifically designated as a particular isotope is meant to represent a stable isotope of that atom.

[0059] [53 J In a further embodiment of a compound of Formula 1, or a pharmaceutically acceptable salt thereof, the compound is deuterated at one or more positions. Unless otherwise stated, when an atom is designated specifically as "H" or "hydrogen", the atom is understood to have hydrogen at its natural abundance isotopic composition. Also, unless otherwise stated, when an atom is designated specifically as "D" or "deuterium", the atom is understood to have deuterium at an abundance substantially greater than the natural abundance of deuterium, which is 0.015%.

[0060] Activities of the Disclosed Compounds

[0061]

[0054] The disclosed compounds may have one or more activities as disclosed herein.

[0062]

[0055] In one aspect, the disclosed compounds may inhibit the activity of PI3K- Alpha kinase and may be characterized as having (PIK3CA) inhibitory activity. In one aspect, the disclosed compounds may inhibit the activity of wild-type PIK3CA. In one aspect, the disclosed compounds may inhibit the activity of a mutant PIK3CA having one or more amino acid substitutions, deletions, or insertions relative to the amino acid sequence of wild-type PIK3CA. In one aspect, the disclosed compounds may inhibit the activity of H1047R mutant PIK3CA. In one aspect, the disclosed compounds may inhibit the activity of E545K mutant PIK3CA. In one aspect, the disclosed compounds may inhibit the activity of one or more of H1047R mutant PIK3CA, and E545K mutant PIK3CA. In one aspect, the disclosed compounds may inhibit the activity of a wild-type PI3KCA or mutant PI3KCA as measured in an in vitro cell-based assay such as the assay entitled “PI3K- Alpha kinase (PI3KCA) activity: wild-type PI3KCA, H1047R mutant PI3KCA, E545K mutant PI3KCA in vitro cell based assays and determination of IC50 values for inhibitors” as disclosed herein as an Example. In one aspect, the disclosed compounds may inhibit the activity of a wild-type PI3KCA and / or a mutant PI3KCA as measured in an in vitro cell-based assay and an IC50 may be determined with respect to inhibition.

[0063]

[0056] In one aspect, the disclosed compounds may selectively inhibit the activity of a mutant PI3KCA relative to wild-type PI3KCA, such as H1047R mutant PI3KCA, and E545K mutant PI3KCA, relative to wild-type PI3KCA. In one aspect, the disclosed compounds may have an IC50 for a mutant PI3KCA, such as an in vitro assay as disclosed herein, which is less than about 500 nM, 100 nM, 50 nM, 40 nM, 30 nM, 20 nM, 10 nM, or 5 nM. In one aspect, the disclosed compounds may have an IC50 for a H1047R mutant PI3KCA that is less than about 500 nM, 100 nM, 50 nM, 40 nM, 30 nM, 20 nM, 10 nM, or 5 nM. In one aspect, the disclosed compounds may have an IC50 for an E545K mutant PI3KCA that is less than about 500 nM, 450 nM, 400 nM, 350 nM, 300 nM, 250 nM, 200 nM, 150 nM, 100 nM, or 50 nM. In one aspect, the disclosed compounds may have an IC50 for wild-type PI3KCA which is greater than about 100 nM, 200 nM, 300 nM, 400 nM, 500 nM, 600 nM, 700 nM, 800 nM, 900 nM, 1000 nM, 2000 nM, or 3000 nM. In one aspect, the disclosed compounds may selectively inhibit the activity of a mutant PI3KCA relative to wild-type PI3KCA and the compounds may have an IC50 for a mutant PI3KCA in an assay, such as an in vitro assay as disclosed herein, which is at least 5x, lOx, 20x, 30x, 40x, 50x, 60x, 70x, 80x, 90x, lOOx, 200x, or 500x lower than an IC50 for wild-type P13KCA in the in vitro cell-based assay. In one aspect, the compounds selectively inhibit the activity of a mutant PI3KCA relative to wild-type PI3KCA in an in vitro cell-based assay and the compound has fold selectivity for the mutant PI3KCA of at least 5x, lOx, 20x, 30x, 40x, 50x, 60x, 70x, 80x, 90x, lOOx, 200x, or 500x relative to wild-type PI3KCA.

[0064]

[0057] In one aspect, the disclosed compounds may exhibit metabolic stability. In one aspect, the disclosed compounds may exhibit metabolic stability as measured in one or more in vitro clearance assays or in vivo clearance assays as disclosed herein.

[0065]

[0058] In one aspect, the disclosed compounds may exhibit metabolic stability as measured in an in vitro clearance assay that utilizes liver microsomes such as the assay entitled “Metabolic Stability and Intrinsic Clearance in Liver Microsomes” as disclosed herein as an Example. Suitable liver microsomes for use in an in vitro clearance assay may include, but are not limited to, human liver microsomes, dog liver microsomes, monkey liver microsomes, rat liver microsomes, and mouse liver microsomes. In one aspect, the disclosed compounds may have an intrinsic clearance value in an in vitro liver microsome assay (CLint) which is less than about 1000, 500, 400, 300, 200, 150, 100, 90, 80, 70, 60, 50, 45, 40, 35, 30, 25, 20, 15, 10, 5, 4, 3, 2, or 1 l / min / mg. In one aspect, scaling factors as known in the art may be utilized to calculate a Scaled- up CLhep (mL / min / kg), a Predicted CLint (mL / min / kg), and EH for a given species, including but not limited to human, monkey, dog, rat and mouse.

[0066]

[0059] In one aspect, the disclosed compounds may exhibit metabolic stability as measured in an in vitro clearance assay that utilizes hepatocytes such as the assay entitled “Metabolic Stability and Intrinsic Clearance in Hepatocytes” as disclosed herein as an Example. Suitable hepatocytes for use in an in vitro clearance assay may include, but are not limited to, human hepatocytes, dog hepatocytes, monkey hepatocytes, rat hepatocytes, and mouse hepatocytes. In one aspect, the disclosed compounds may have an intrinsic clearance value in an in vitro hepatocyte stability assay (CLint) which is less than about 200, 150, 100, 90, 80, 70, 60, 50, 45, 40, 35, 30, 25, 20, 15, 10, 5, 4, 3, 2, or 1 pl / min / lxl0^ cells. In one aspect, scaling factors as known in the art may be utilized to calculate a Scaled-up CLint (mL / min / kg), a Predicted Hepatic Predicted Hepatic CLH (mL / min / kg), and Hepatic Extraction Ratio (ER) for a given species, including but not limited to human, monkey, dog, rat and mouse.

[0067]

[0060] In one aspect, the disclosed compounds may exhibit metabolic stability as measured in an in vivo clearance assay. In some aspects, the disclosed compounds may exhibit metabolic stability as measured in an in vivo clearance assay after the compounds are administered orally (PO) as disclosed herein. In some aspects, the disclosed compounds may exhibit metabolic stability as measured in an in vivo clearance assay after the compounds are administered intravenously (IV) as disclosed herein. Metabolic stability may be assessed by administering the compounds to an animal such as a mouse, rat, dog, monkey, or human, and determining the concentration in the animal after administration, for example, determining the concentration in the blood of the animal after administration. The concentration of the compound in the animal after administration versus time may be determined in order to assess metabolic stability of the compound in vivo.

[0068]

[0061] In one aspect, the disclosed compounds do not cause adverse events (AEs) such as hyperglycemia, hyperinsulinemia, and diarrhea when the PI3Ka inhibitors are administered at an effective dose for inhibiting the activity of PI3KCA and treating a disease or disorder associated with PI3KCA activity. In one aspect, the disclosed compounds do not cause adverse events (AEs) such as hyperglycemia, hyperinsulinemia, and diarrhea when the PI3KCA inhibitors are administered at an effective dose for treating cancer and resulting in tumor regression.

[0069] Pharmaceutical Salts

[0070]

[0062] 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. In addition, 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. Handbook of Pharmaceutical Salts: Properties, Selection, and Use, 2n<^ Revised Edition (Wiley-VCH, 2011); S.M. Berge, et al., “Pharmaceutical Salts,” Journal of Pharmaceutical Sciences, Vol. 66, No. 1, January 1977).

[0071]

[0063] Further representative “pharmaceutically acceptable salts” 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, laurate, magnesium, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate, N-methylglucamine ammonium salt, 3-hydroxy-2-naphthoate, oleate, oxalate, palmitate, pamoate, pantothenate, phosphate / diphosphate, picrate, polygalacturonate, propionate, p- toluenesulfonate, salicylate, stearate, subacetate, succinate, sulfate, sulfosalicylate, tannate, tartrate, teoclate, tosylate, triethiodide, and valerate salts.

[0072]

[0064] 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.

[0073] Pharmaceutical Compositions

[0074]

[0065] In some aspects, the present disclosure provides a pharmaceutical composition comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof, as an active ingredient. In some embodiments, the present disclosure provides a pharmaceutical composition comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or excipients.

[0075]

[0066] The compound of Formula I, or a pharmaceutically acceptable salt thereof, 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 compound of Formula 1, or a pharmaceutically acceptable salt thereof, also can 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.

[0076]

[0067] 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.

[0077]

[0068] According to a further aspect of the disclosure there is provided a pharmaceutical composition which comprises a compound of Formula I, or a pharmaceutically acceptable salt, in association with a pharmaceutically acceptable diluent or carrier.

[0078]

[0069] The 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).

[0079]

[0070] The compositions of the disclosure may be obtained by conventional procedures using conventional pharmaceutical excipients, well known in the art. Thus, compositions intended for oral use may contain, for example, one or more coloring, sweetening, flavoring and / or preservative agents.

[0080] Methods of Use

[0081]

[0071] In some aspects, the present disclosure provides a method of modulating PI3K (e.g.,

[0082] PT3KCA) activity (e.g., in vitro or in vivo), comprising contacting a cell with a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof.

[0083]

[0072] In some aspects, the present disclosure provides a method of inhibiting PI3K (e.g., PI3KCA) activity (e.g., in vitro or in vivo), comprising contacting a cell with a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof.

[0084]

[0073] In some aspects, the present disclosure provides a method of treating or preventing a disease or disorder disclosed herein in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof.

[0085]

[0074] In some aspects, the present disclosure provides a method of treating a disease or disorder disclosed herein in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof.

[0086]

[0075] In some aspects, the present disclosure provides a method of treating a disease or disorder disclosed herein in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, in combination with an effective amount of one or more therapeutic agents.

[0087]

[0076] In some aspects, the present disclosure provides a method of treating a disease or disorder disclosed herein in a subject in need thereof, comprising administering to the subject simultaneously, separately, or sequentially, a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, in combination with an effective amount of a CDK4 and 6 inhibitor, or a pharmaceutically acceptable salt thereof.

[0088]

[0077] In some aspects, the present disclosure provides a method of treating a disease or disorder disclosed herein in a subject in need thereof, comprising administering to the subject simultaneously, separately, or sequentially, a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, in combination with an effective amount of a SERD, or a pharmaceutically acceptable salt thereof.

[0089]

[0078] In some aspects, the present disclosure provides a method of treating a disease or disorder disclosed herein in a subject in need thereof, comprising administering to the subject simultaneously, separately, or sequentially, a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, in combination with an effective amount of an aromatase inhibitor, or a pharmaceutically acceptable salt thereof.

[0090]

[0079] In some aspects, the present disclosure provides a method of treating a disease or disorder disclosed herein in a subject in need thereof, comprising administering to the subject simultaneously, separately, or sequentially, a therapeutically effective amount of a compound of Formula 1, or a pharmaceutically acceptable salt thereof, in combination with an effective amount of a taxane, or a pharmaceutically acceptable salt thereof.

[0091]

[0080] In some aspects, the present disclosure provides a method of treating a disease or disorder disclosed herein in a subject in need thereof, comprising administering to the subject simultaneously, separately, or sequentially, a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, in combination with an effective amount of an mTOR inhibitor, or a pharmaceutically acceptable salt thereof.

[0092]

[0081] In some aspects, the present disclosure provides a method of treating a disease or disorder disclosed herein in a subject in need thereof, comprising administering to the subject simultaneously, separately, or sequentially, a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, in combination with an effective amount of a tyrosine kinase inhibitor, or a pharmaceutically acceptable salt thereof.

[0093]

[0082] In some aspects, the present disclosure provides a method of treating a disease or disorder disclosed herein in a subject in need thereof, comprising administering to the subject simultaneously, separately, or sequentially, a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, in combination with an effective amount of a platinum agent, or a pharmaceutically acceptable salt thereof.

[0094]

[0083] In some aspects, the present disclosure provides a method of treating a disease or disorder disclosed herein in a subject in need thereof, comprising administering to the subject simultaneously, separately, or sequentially, a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, in combination with an effective amount of an anthracycline, or a pharmaceutically acceptable salt thereof.

[0095]

[0084] In some aspects, the present disclosure provides a method of treating a disease or disorder disclosed herein in a subject in need thereof, comprising administering to the subject simultaneously, separately, or sequentially, a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, in combination with an effective amount of an immune checkpoint inhibitor, or a pharmaceutically acceptable salt thereof.

[0096]

[0085] In some aspects, the present disclosure provides a method of treating a disease or disorder disclosed herein in a subject in need thereof, comprising administering to the subject simultaneously, separately, or sequentially, a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, in combination with an effective amount of an antiandrogen, or a pharmaceutically acceptable salt thereof.

[0097] [86 J In some aspects, the present disclosure provides a method of treating a disease or disorder disclosed herein in a subject in need thereof, comprising administering to the subject simultaneously, separately, or sequentially, a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, in combination with an effective amount of an anti-HER2 monoclonal antibody.

[0098]

[0087] In some aspects, the present disclosure provides a method of treating a disease or disorder disclosed herein in a subject in need thereof, comprising administering to the subject simultaneously, separately, or sequentially, a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, in combination with an effective amount of an anti-HER2 antibody-drug conjugate.

[0099]

[0088] In some aspects, the present disclosure provides a method of treating a disease or disorder disclosed herein in a subject in need thereof, comprising administering to the subject simultaneously, separately, or sequentially, a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, in combination with an effective amount of a KRAS inhibitor, or a pharmaceutically acceptable salt thereof.

[0100]

[0089] In some aspects, the present disclosure provides a method of treating a disease or disorder disclosed herein in a subject in need thereof, comprising administering to the subject simultaneously, separately, or sequentially, a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, in combination with an effective amount of a MEK inhibitor, or a pharmaceutically acceptable salt thereof.

[0101]

[0090] In some aspects, the present disclosure provides a method of treating a disease or disorder disclosed herein in a subject in need thereof, comprising administering to the subject simultaneously, separately, or sequentially, a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, in combination with an effective amount of an ERK inhibitor, or a pharmaceutically acceptable salt thereof.

[0102]

[0091] In some aspects, the present disclosure provides a method of treating a disease or disorder disclosed herein in a subject in need thereof, comprising administering to the subject simultaneously, separately, or sequentially, a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, in combination with an effective amount of a topoisomerase inhibitor, or a pharmaceutically acceptable salt thereof.

[0103]

[0092] In some aspects, the present disclosure provides a method of treating a disease or disorder disclosed herein in a subject in need thereof, comprising administering to the subject simultaneously, separately, or sequentially, a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, in combination with an effective amount of a SERM, or a pharmaceutically acceptable salt thereof.

[0104]

[0093] In some aspects, the present disclosure provides a method of treating a disease or disorder disclosed herein in a subject in need thereof, comprising administering to the subject simultaneously, separately, or sequentially, a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, in combination with an effective amount of a PARP inhibitor, or a pharmaceutically acceptable salt thereof.

[0105]

[0094] In some embodiments, the disease or disorder is associated with an implicated PI3K activity. In some embodiments, the disease or disorder is a disease or disorder in which PI3K activity is implicated.

[0106]

[0095] In some embodiments, the disease or disorder is a cancer.

[0107]

[0096] In some embodiments, 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 leukemia (CML), colorectal cancer, craniopharyngioma, cutaneous t-cell lymphoma, mycosis fungoides, Sezary syndrome, ductal carcinoma in situ (DCIS), embryonal tumors, medulloblastoma, endometrial cancer, ependymoma, esophageal cancer, esthesioneuroblastoma, Ewing sarcoma, extracranial germ cell tumor, extragonadal germ cell tumor, fallopian tube cancer, gallbladder cancer, gastric cancer, gastrointestinal carcinoid tumor, malignant gastrointestinal stromal tumors (GIST), germ cell tumors, gestational trophoblastic disease, hairy cell leukemia, head and neck cancer, hepatocellular cancer, Langerhans cell histiocytosis, Hodgkin lymphoma, islet cell tumors, pancreatic neuroendocrine tumors, Kaposi sarcoma, kidney cancer, laryngeal cancer, leukemia, liver cancer, lung cancer, lymphoma, male breast cancer, intraocular melanoma, Merkel cell carcinoma, malignant mesothelioma, metastatic cancer, metastatic squamous neck cancer, midline tract carcinoma with nut gene changes, mouth cancer, multiple endocrine neoplasia syndromes, multiple myeloma / plasma cell neoplasms, myelodysplastic syndromes, myelodysplastic neoplasms, myeloproliferative neoplasms, chronic myeloproliferative neoplasm, nasal cavity and paranasal sinus cancer, nasopharyngeal cancer, neuroblastoma, non-Hodgkin lymphoma, nonsmall cell lung cancer, oral cancer, lip and oral cavity cancer, oropharyngeal cancer, malignant fibrous histiocytoma of bone, ovarian cancer, pancreatic cancer, pancreatic neuroendocrine tumors (islet cell tumors), papillomatosis, paraganglioma, paranasal sinus and nasal cavity cancer, parathyroid cancer, penile cancer, pharyngeal cancer, pheochromocytoma, pituitary tumor, plasma cell neoplasm, multiple myeloma, pleuropulmonary blastoma, primary central nervous system (CNS) lymphoma, primary peritoneal cancer, prostate cancer, rectal cancer, recurrent cancer, renal cell (kidney) cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, sarcoma, childhood vascular tumors, skin cancer, small cell lung cancer, small intestine cancer, soft tissue sarcoma, squamous cell carcinoma of the skin, testicular cancer, oropharyngeal cancer, hypopharyngeal cancer, thymoma, thymic carcinoma, thyroid cancer, tracheobronchial tumors, transitional cell cancer of the renal pelvis and ureter, urethral cancer, uterine sarcoma, vaginal cancer, vascular tumors, vulvar cancer, and Wilms tumor.

[0108] [971 In some embodiments, 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, Germ-cell carcinoma, Thymic tumor, Pheochromocytoma, Miscellaneous neuroepithelial tumor, thyroid cancer, leukemia, or encapsulated glioma.

[0109]

[0098] In some embodiments, the cancer is a breast cancer, a prostate cancer, or a brain cancer.

[0110]

[0099] In some embodiments, the cancer is a breast cancer. In some embodiments, the cancer is a prostate cancer. In some embodiments, the cancer is a brain cancer.

[0111]

[0100] In some embodiments, the breast cancer is metastatic breast cancer. In some embodiments, the breast cancer is ductal carcinoma in situ (DCIS). In some embodiments, the breast cancer is invasive ductal carcinoma. In some embodiments, the breast cancer is triple negative breast cancer. In some embodiments, the breast cancer is medullary carcinoma. In some embodiments, the breast cancer is tubular carcinoma. In some embodiments, the breast cancer is mucinous carcinoma. In some embodiments, the breast cancer is Paget disease of the breast or nipple. In some embodiments, the breast cancer is inflammatory breast cancer (1BC). In some embodiments, the breast cancer is hormone receptor-positive (HR+), human epidermal growth factor receptor 2- negative (HER2-) advanced or metastatic breast cancer.

[0112]

[0101] In some embodiments, the prostate cancer is an adenocarcinoma. In some embodiments, the prostate cancer is a small cell carcinoma. In some embodiments, the prostate cancer is a neuroendocrine tumor. In some embodiments, the prostate cancer is a transitional cell carcinoma. In some embodiments, the prostate cancer is a sarcoma.

[0113]

[0102] In some embodiments, the brain cancer is an acoustic neuroma. In some embodiments, 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. In some embodiments, 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.

[0114]

[0103] In some embodiments, the disease or disorder associated with PI3K includes, but is not limited to, CLOVES 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.

[0115]

[0104] In some embodiments, the diseases or disorder associated with PI3K is CLOVES syndrome.

[0116]

[0105] In some embodiments, the disease or disorder associated with PI3K is PROS.

[0117]

[0106] In some embodiments, 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.

[0118]

[0107] In some embodiments, 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. In some embodiments, the disease or disorder associated with PI3K is a breast neoplasm. In some embodiments, the disease or disorder associated with PI3K is a thyroid neoplasm. In some embodiments, the disease or disorder associated with PI3K is an ovarian neoplasm. In some embodiments, the disease or disorder associated with P13K is non-small-cell lung carcinoma. In some embodiments, 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.

[0119]

[0108] 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.

[0120]

[0109] In some embodiments, the disease or disorder associated with PI3K is leukemia, lymphoma, or sarcoma.

[0121]

[0110] In some embodiments, the cancer is endometrial cancer, head and neck cancer, or a sarcoma.

[0122]

[0111] In some embodiments, the cancer is endometrial cancer. In some embodiments, the cancer is head and neck cancer. In some embodiments, the cancer is a sarcoma.

[0123]

[0112] 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.

[0124]

[0113] In some embodiments, the sarcoma is soft tissue sarcoma. In some embodiments 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 sarcoma, myoepithelial carcinoma, malignant phosphaturic mesenchymal tumor, synovial sarcoma, epithelioid sarcoma, alveolar soft part sarcoma, clear cell sarcoma of soft tissue, extraskeletal myxoid chondrosarcoma, extraskeletal Ewing sarcoma, desmoplastic small round cell tumor, extrarenal rhabdoid tumor, perivascular epithelioid cell tumor, intimal sarcoma, undifferentiated spindle cell sarcoma, undifferentiated pleomorphic sarcoma, undifferentiated round cell sarcoma, undifferentiated epithelioid sarcoma, or undifferentiated sarcoma, not otherwise specified.

[0125]

[0114] In some aspects, the present disclosure provides a method of treating or preventing a cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof.

[0126]

[0115] In some aspects, the present disclosure provides a method of treating a cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof.

[0127]

[0116] In some aspects, the present disclosure provides a method of treating or preventing a breast cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof.

[0128]

[0117] In some aspects, the present disclosure provides a method of treating a breast cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof.

[0129]

[0118] In some aspects, the present disclosure provides a method of treating or preventing a prostate cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof.

[0130]

[0119] In some aspects, the present disclosure provides a method of treating a prostate cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof.

[0131]

[0120] In some aspects, the present disclosure provides a compound of Formula I, or a pharmaceutically acceptable salt thereof for use in treating or preventing a breast cancer. In some aspects, the present disclosure provides a pharmaceutical composition comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof for use in treating or preventing a breast cancer.

[0132] L 121 J In some aspects, the present disclosure provides a compound of Formula 1, or a pharmaceutically acceptable salt thereof for use in treating a breast cancer. In some aspects, the present disclosure provides a pharmaceutical composition comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof for use in treating a breast cancer.

[0133]

[0122] In some aspects, the present disclosure provides a compound of Formula I, or a pharmaceutically acceptable salt thereof for use in treating or preventing a prostate cancer. In some aspects, the present disclosure provides a pharmaceutical composition comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof for use in treating or preventing a prostate cancer.

[0134]

[0123] In some aspects, the present disclosure provides a compound of Formula I, or a pharmaceutically acceptable salt thereof for use in treating a prostate cancer. In some aspects, the present disclosure provides a pharmaceutical composition comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof for use in treating a prostate cancer.

[0135]

[0124] In some aspects, the present disclosure provides a compound of Formula I, or a pharmaceutically acceptable salt thereof for use in treating or preventing a brain cancer. In some aspects, the present disclosure provides a pharmaceutical composition comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof for use in treating or preventing a brain cancer.

[0136]

[0125] In some aspects, the present disclosure provides a compound of Formula I, or a pharmaceutically acceptable salt thereof for use in treating a brain cancer. In some aspects, the present disclosure provides a pharmaceutical composition comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof for use in treating a brain cancer.

[0137]

[0126] In some aspects, the present disclosure provides use of a compound of Formula I, or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for modulating PI3K (e.g., PI3KCA) activity (e.g., in vitro or in vivo).

[0138]

[0127] In some aspects, the present disclosure provides use of a compound of Formula I, or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating or preventing a disease or disorder disclosed herein.

[0128] In some aspects, the present disclosure provides use of a compound of Formula I, or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating a disease or disorder disclosed herein.

[0139]

[0129] In some aspects, the present disclosure provides use of a compound of Formula I, or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating or preventing a cancer in a subject in need thereof.

[0140]

[0130] In some aspects, the present disclosure provides use of a compound of Formula I, or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating a cancer in a subject in need thereof.

[0141]

[0131] In some aspects, the present disclosure provides use of a compound of Formula I, or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating or preventing a breast cancer in a subject in need thereof.

[0142]

[0132] In some aspects, the present disclosure provides use of a compound of Formula I, or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating a breast cancer in a subject in need thereof.

[0143]

[0133] In some aspects, the present disclosure provides use of a compound of Formula I, a compound named (l?)-3-(6-chloro-3-((l-(2-cyclopropyl-6-fluoro-3-methyl-4-oxo-4H-chromen-8- yl)ethyl)amino)pyridin-2-yl)-l,2,4-oxadiazol-5(4H)-one, or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating or preventing a prostate cancer in a subject in need thereof.

[0144]

[0134] In some aspects, the present disclosure provides use of a compound of Formula I, or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating a prostate cancer in a subject in need thereof.

[0145]

[0135] In some aspects, the present disclosure provides use of a compound of Formula I, or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating or preventing a brain cancer in a subject in need thereof.

[0146]

[0136] In some aspects, the present disclosure provides use of a compound of Formula I, or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating a brain cancer in a subject in need thereof.

[0147]

[0137] 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 of Formula I, or a pharmaceutically acceptable salt thereof, as defined herein.

[0148]

[0138] In some embodiments, PI3K modulation is inhibition of PI3K.

[0149]

[0139] In some embodiments, the PI3K inhibitor is a PI3KCA inhibitor. In some embodiments, the PI3K inhibitor is one or more of a PI3KCA H1047R mutant inhibitor, and a PI3KCA E545K mutant inhibitor.

[0150]

[0140] 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.

[0151]

[0141] 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 of Formula I, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein.

[0152] Routes of Administration

[0153]

[0142] A compound of Formula I, or a pharmaceutically acceptable salt thereof may be administered to a subject by any convenient route of administration, whether systemically / peripherally or topically. A pharmaceutical composition comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof may be administered to a subject by any convenient route of administration, whether systemically / peripherally or topically (i.e., at the site of desired action).

[0154]

[0143] Routes of administration include, but are not limited to, oral (e.g. by ingestion); buccal; sublingual; 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 intrastemal; by implant of a depot or reservoir, for example, subcutaneously or intramuscularly.

[0155] Further Aspects

[0156]

[0144] The following are further numbered aspects of the invention:

[0145] Aspect 1. A compound of a Formula I or a pharmaceutically acceptable salt thereof:

[0157]

[0146] Aspect 2. A compound named (7?)-3-(6-chloro-3-((l-(2-cyclopropyl-6-fluoro-3-methyl-4- oxo-4H- chromen-8-yl)ethyl)amino)pyridin-2-yl)-l,2,4-oxadiazol-5(4H)-one or a pharmaceutically acceptable salt thereof.

[0158]

[0147] Aspect 3. A compound as disclosed herein or a pharmaceutically acceptable salt thereof, wherein the compound inhibits the activity of a H1047R mutant PIK3CA in an in vitro cellbased assay and has an IC50 for the mutant PI3KCA which is less than about 500 nM, 100 nM, 50 nM, 40 nM, 30 nM,20 nM, 10 nM, or 5 nM, and / or wherein the compound inhibits the activity of a E545K mutant PIK3CA in an in vitro cell-based assay and has an IC50 for the mutant PI3KCA which is less than about 500 nM, 450 nM, 400 nM, 350 nM, 300 nM, 250 nM, 200 nM, 150 nM, 100 nM, or 50 nM.

[0159]

[0148] Aspect 4. A compound as disclosed herein or a pharmaceutically acceptable salt thereof, wherein the compound selectively inhibits the activity of a mutant PI3KCA relative to wild-type PI3KCA in an in vitro cell -based assay and the compound has fold selectivity for the mutant PI3KCA of at least 5x, lOx, 20x, 30x, 40x, 50x, 60x, 70x, 80x, 90x, lOOx, 200x, or 500x relative to wild-type PI3KCA.

[0160]

[0149] Aspect 5. A compound as disclosed herein or a pharmaceutically acceptable salt thereof, wherein the compound has a clearance in an in vitro liver microsome assay which is less than about 1000, 500, 400, 300, 200, 150, 100, 90, 80, 70, 60, 50, 45, 40, 35, 30, 25, 20, 15, 10, 5, 4, 3, 2, or 1 l / min / mg.

[0161]

[0150] Aspect 6. A compound as disclosed herein or a pharmaceutically acceptable salt thereof, wherein the compound has a clearance in an in vitro hepatocyte stability assay which is less than about 200, 150, 100, 90, 80, 70, 60, 50, 45, 40, 35, 30, 25, 20, 15, 10, 5, 4, 3, 2, or 1 pl / min / lxl0^ cells.

[0151] Aspect 7. A compound as disclosed herein or a pharmaceutically acceptable salt thereof, wherein the compound has 1, 2, 3, or 4 of the following properties (a)-(d):

[0162] (a) the compound inhibits the activity of a H1047R mutant PIK3CA in an in vitro cellbased assay and has an 1C50 for the mutant P13KCA which is less than about 500 nM, 100 nM, 50 nM, 40 nM, 30 nM, 20 nM, 10 nM, or 5 nM, and / or wherein the compound inhibits the activity of a E545K mutant PIK3CA in an in vitro cell-based assay and has an IC50 for the mutant PI3KCA which is less than about 500 nM, 450 nM, 400 nM, 350 nM, 300 nM, 250 nM, 200 nM, 150 nM, 100 nM, or 50 nM;

[0163] (b) the compound selectively inhibits the activity of a mutant PI3KCA relative to wildtype PI3KCA in an in vitro cell-based assay and the compound has fold selectivity for the mutant PI3KCA of at least 5x, lOx, 20x, 30x, 40x, 50x, 60x, 70x, 80x, 90x, lOOx, 200x, or 500x relative to wild-type P13KCA;

[0164] (c) the compound has a clearance in an in vitro liver microsome assay which is less than about 1000, 500, 400, 300, 200, 150, 100, 90, 80, 70, 60, 50, 45, 40, 35, 30, 25, 20, 15, 10, 5, 4, 3, 2, or 1 pl / min / mg; and

[0165] (d) the compound has a clearance in an in vitro hepatocyte stability assay which is less than about 200, 150, 100, 90, 80, 70, 60, 50, 45, 40, 35, 30, 25, 20, 15, 10, 5, 4, 3, 2, or 1 l / min / lxlO^ cells.

[0166]

[0152] Aspect 8. A pharmaceutical composition comprising a compound as defined in any one of aspects 1-7, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0167]

[0153] Aspect 9. A method of treating a disease or disorder associated with modulation of phosphoinositide 3-kinase (P13K), comprising administering to a patient in need thereof a therapeutically effective amount of a compound as defined in any one of aspects 1-7, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined in aspect 8.

[0168]

[0154] Aspect 10. The method as defined in aspect 9, wherein the PI3K is PI3KCA.

[0169]

[0155] Aspect 11. The method as defined in aspect 10, wherein the PI3K associated with the disease or disorder has one or more of a H1047R mutation, and an E545K mutation.

[0170]

[0156] Aspect 12. The method as defined in any one of aspects 9-11, wherein the disease or disorder is a cancer.

[0157] Aspect 13. The method as defined in aspect 12, wherein the cancer is endometrial cancer, gastric cancer, leukemia, lymphoma, sarcoma, colorectal cancer, lung cancer, ovarian cancer, skin cancer, head and neck cancer, breast cancer, brain cancer, or prostate cancer.

[0171]

[0158] Aspect 14. The method as defined in aspect 12 or 13, wherein the cancer is breast cancer.

[0172]

[0159] Aspect 15. The method as defined in any one of aspects 12-14, wherein the cancer is hormone receptor- positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced or metastatic breast cancer.

[0173]

[0160] Aspect 16. The method as defined in any one of aspects 10-11, wherein the disorder is CLOVES syndrome, or PROS.

[0174]

[0161] Aspect 17. A method of inhibiting phosphoinositide 3 -kinase (PI3K), comprising administering to a patient in need thereof a therapeutically effective amount of a compound as defined in any one of aspects 1-7, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined in aspect 8.

[0175]

[0162] Aspect 18. A method of treating cancer or a disorder associated with modulation of phosphoinositide 3-kinase (PI3K), the method comprising administering to a patient in need thereof a therapeutically effective amount of a compound as defined in any one of aspects 1-7, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined in aspect 8.

[0176]

[0163] Aspect 19. The method as defined in aspect 18, wherein the cancer is endometrial cancer, gastric cancer, leukemia, lymphoma, sarcoma, colorectal cancer, lung cancer, ovarian cancer, skin cancer, head and neck cancer, breast cancer, brain cancer, or prostate cancer.

[0177]

[0164] Aspect 20. The method as defined in aspect 18 or 19, wherein the cancer is breast cancer.

[0178]

[0165] Aspect 21. The method as defined in any one of aspects 18-20, wherein the cancer is hormone receptor- positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced or metastatic breast cancer.

[0179]

[0166] Aspect 22. The method as defined in aspect 18, wherein the disorder is CLOVES syndrome or PROS.

[0180]

[0167] Aspect 23. The compound as defined in any one of aspects 1-7, or a pharmaceutically acceptable salt thereof, for use in therapy.

[0181]

[0168] Aspect 24. The compound as defined in any one of aspects 1-7, or a pharmaceutically acceptable salt thereof, for use in the treatment of a disease or disorder associated with modulating PI3K.

[0169] Aspect 25. The compound or a pharmaceutically acceptable salt thereof for use as defined in aspect 24, wherein the disease or disorder associated with modulating PI3K is a cancer.

[0182]

[0170] Aspect 26. The compound or a pharmaceutically acceptable salt thereof for use as defined in aspect 24 or 25, wherein the cancer is endometrial cancer, gastric cancer, leukemia, lymphoma, sarcoma, colorectal cancer, lung cancer, ovarian cancer, skin cancer, head and neck cancer, breast cancer, brain cancer, or prostate cancer.

[0183]

[0171] Aspect 27. The compound or a pharmaceutically acceptable salt thereof for use as defined in any one of aspects 24-26, wherein the cancer is breast cancer.

[0184]

[0172] Aspect 28. The compound or a pharmaceutically acceptable salt thereof for use as defined in any one of aspect 24-27, wherein the cancer is hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced or metastatic breast cancer.

[0185]

[0173] Aspect 29. The compound or a pharmaceutically acceptable salt thereof for use as defined in aspect 24, wherein the disorder is CLOVES syndrome or PROS.

[0186]

[0174] Aspect 30. Use of a compound as defined in any one of aspects 1-7, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a disease or disorder associated with modulating PI3K.

[0187]

[0175] Aspect 31. The use as defined in aspect 30, wherein the disease or disorder associated with modulating PI3K is a cancer.

[0188]

[0176] Aspect 32. The use as defined in aspect 30 or 31, wherein the cancer is endometrial cancer, gastric cancer, leukemia, lymphoma, sarcoma, colorectal cancer, lung cancer, ovarian cancer, skin cancer, head and neck cancer, breast cancer, brain cancer, or prostate cancer.

[0189]

[0177] Aspect 33. The use as defined in aspect 31 or 32, wherein the cancer is breast cancer.

[0190]

[0178] Aspect 34. The use as defined in aspect 33, wherein the cancer is hormone receptorpositive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced or metastatic breast cancer.

[0191]

[0179] Aspect 35. The use as defined in aspect 30, wherein the disorder is CLOVES syndrome or PROS.

[0192] EXAMPLES

[0193]

[0180] Exemplary compounds as disclosed herein are synthesized and tested in the following examples. Abbreviations

[0194] AcOH Acetic acid

[0195] A1C13Aluminum trichloride

[0196] CDI 1,1 ’-Carbonyldiimidazole

[0197] CHC13Chloroform

[0198] CO2Carbon dioxide

[0199] CPhos 2-Dicyclohexylphosphino-2',6'-bis(N,N-dimethylamino)biphenyl

[0200] DBU l,8-Diazabicyclo[5.4.0]undec-7-ene

[0201] DCM Dichloromethane

[0202] DIEA N,N-Diisopropylethylamine

[0203] DMF N,N-Dimethylformamide

[0204] EtOAc Ethyl acetate

[0205] EtOH Ethanol h hour(s)

[0206] H ATU 1 - [Bis (dimethy laminojmethy lene] - 1 H- 1 ,2, 3 -triazolo [4 , 5 -b]pyridinium

[0207] 3 -oxide hexafluorophosphate

[0208] H2SO4 Sulfuric acid

[0209] HC1 Hydrogen chloride

[0210] IPA 2-Propanol

[0211] K2CO3Potassium carbonate

[0212] KF Potassium fluoride mCPBA m-Chloroperoxybenzoic acid

[0213] MeOH Methanol

[0214] MTBE Methyl tert-butyl ether min minutes

[0215] MgSO4Magnesium sulfate

[0216] NaCl Sodium chloride

[0217] Na2CO3Sodium carbonate

[0218] NaHCO3Sodium bicarbonate

[0219] NaHMDS Sodium bis(trimethylsilyl)amide

[0220] Na2SO4Sodium sulfate

[0221] NH4CI Ammonium chloride NH4OH Ammonium hydroxide rt Room temperature

[0222] TFA Trifluoroacetic acid

[0223] THF Tetrahydrofuran

[0224] Xantphos 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene

[0225]

[0181] Intermediate 1: 2-Bromo-4-methylphenyl propionate

[0226]

[0182] A mixture of 2-bromo-4-methylphenol (10.0 g, 53.5 mmol) and pyridine (6.34 g, 80.2 mmol) in DCM (100 mL) was treated with propionyl chloride (5.44 g, 58.8 mmol) at 0 °C and stirred at 25 °C for 16 h. The mixture was diluted with water (100 mL), the pH adjusted to 5 with HC1 (2 M), and extracted with DCM (2 x 100 mL). The combined organic extracts were washed with saturated aqueous NaCl (2 x 150 mL), dried over anhydrous Na2SC>4, filtered, and concentrated under reduced pressure to give the title compound as an oil (13 g, crude).1H NMR (400 MHz, DMSO-d6) 5 ppm 1.17 (t, J=7.6 Hz, 3H), 2.30 (s, 3H), 2.62 (q, J=7.6 Hz, 2H), 7.11-7.18 (m, 1H), 7.19-7.26 (m, 1H),

[0227] 7.50-7.55 (m, 1H).

[0228]

[0183] Intermediate 2: 2-Bromo-4-methylphenyl propionate

[0229]

[0184] A mixture of 2-bromo-4-methylphenol (600.0 g, 3.21 mol) and triethylamine (389.8 g, 3.85 mol) in EtOAc (3 L) was treated with propionyl chloride at 15 °C to 20 °C and stirred for 1 h. The reaction was quenched with water (1.2 L) keeping the temperature below 20 °C and then stirred at 10 to 20 °C for 20 min. The layers were separated and the aqueous layer extracted with EtOAc (1.2 L). The combined organic layers were washed with aqueous IM HC1 (600 mL) and water (600 mL). The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure to give the title compound (783.7 g, 100.5%).JH NMR (400 MHz, CDCh) 5 ppm 1.32 (t, J=7.56Hz, 3H), 2.35 (s, 3H), 2.66 (d, J=7.56Hz, 2H), 7.01 (d, J=8.20Hz, 1H), 7.13 (m, 1H), 7.44 (s, 1H).

[0230]

[0185] Intermediate 3: 2-Bromo-4-fluorophenylpropionate

[0231]

[0186] 2-Bromo-4-fluorophenol (3.0 kg, 15.7 mol) and EtOAc (15 L) were added to a 50 L reactor and stirred for 15 min. The solution was slowly treated with triethylamine (1.9 kg, 18.8 mol). The reaction was cooled and propionyl chloride (1.6 kg, 17.3 mol) was added dropwise keeping the temperature between 0 and 10 °C. After addition was completed, the reaction was stirred at rt for 15 h. The reaction was carefully diluted with water (15 L) keeping the temperature of the reaction below 30 °C and then stirred at rt for 30 min. The organic phase was separated, washed with water (10 L), collected, dried over MgSO4, filtered, and concentrated under reduced pressure at 45 °C to give the title compound (3.6 kg, 93%) as a yellow liquid.]H NMR (400 MHz, DMSO-d6) 5 ppm 1.15 (t, 3H), 2.65 (dd, 2H), 7.30 (m, 2H), 7.75 (m, 1H).

[0232]

[0187] Intermediate 4: l-(3-Bromo-2-hydroxy-5-methylphenyl)propan-l-one

[0233]

[0188] A mixture of 2-bromo-4-methylphenyl propionate (12.5 g, 51.4 mmol) and AlCh (24.0 g, 180 mmol) was stirred at 140 °C for 1 h. When cooled to rt, the mixture was quenched dropwise with water (80 mL) and stirred for 30 min. The mixture was extracted with EtOAc (3 x 100 mL). The combined organic extracts were washed with saturated aqueous NaCl (2 x 200 mL), dried over Na2SO4, and filtered. The filtrate was concentrated under reduced pressure and triturated with petroleum ether (20 mL) to give the title compound (9.82 g, 79%). NMR (400 MHz, DMSO-d6) 8 ppm 1.10 (t, J=7.2 Hz, 3H), 2.28 (s, 3H), 3.15 (q, J=7.2 Hz, 2H), 7.66-7.73 (m, 1H), 7.77-7.83 (m, 1H), 12.66 (s, 1H).

[0234]

[0189] Intermediate 5: l-(3-Bromo-2-hydroxy-5-methylphenyl)propan-l-one

[0235]

[0190] A mixture of 2-bromo-4-methylphenyl propionate (2328 g, 9.58 mol) and AlCh (1430 g, 10.73 mol) was heated to 120°C and stirred for 1 h to give a brown gum. The reaction mixture was cooled to 25°C, diluted with water (11.6 L), and stirred for 30 min. Hydrogen chloride (12 M, 1160 mL) was added dropwise and the reaction stirred for another 30 min. The mixture was extracted with EtOAc (11.6 L x 2). The combined organics were washed with water (2328 mL), collected, and concentrated under reduced pressure. The residue was triturated with n-heptane (3492 mL) and filtered to give the product (1700 g, yield: 73.0%) as a yellow solid.

[0236]

[0191] Intermediate 6: l-(3-Bromo-2-hydroxy-5-methylphenyl)propan-l-one

[0237]

[0192] Trifluoromethanesulfonic acid (237 g, 1.58 mol) was cooled to below -5 °C and treated dropwise with 2-bromo-4-methylphenyl propionate (80 g, 329 mmol) over 1 h keeping the temperature between -5 °C and -20 °C. After addition was completed, the cooling bath was removed and the reaction stirred at 55 - 60 °C for 1.5 h. The mixture was cooled to 5 - 10 °C, poured into ice water (5V), stirred for 30 min, and the solid removed by filtration. The cake was rinsed with water (2V), slurried in water (5V) for 30 min, and filtered to give the title compound (72.2 g, 90%) as an off-white solid after drying. ES / MS m / z (79Br / 81Br) 241 / 243 (M-H).

[0238]

[0193] Intermediate 7: l-(3-Bromo-5-fluoro-2-hydroxyphenyl)propan-l-one

[0239]

[0194] 2-Bromo-4-fluorophenyl propionate (3.5 kg, 14.2 mol) in a reactor was heated to 75 ~ 85 °C and treated with A1CL (1.0 kg, 7.4 mol) in batches while the internal temperature increased to 100 ~ 110 °C. The reaction was heated to 100 ~ 120 °C and treated with more A1CL (1.1. kg, 8.2 mol). The reaction was stirred at 110 ~ 130 °C for 18 h. The reaction was cooled to rt and poured into a mixture of MTBE (20 L) and IM aqueous HC1 (20 L) at 0 ~ 10 °C. The reaction was stirred at 0 ~ 15 °C for 1 h. The organic layer was separated and washed with water (2 x 10 L). The organic phase was dried over MgSCL and concentrated under reduced pressure to afford a crude product. The crude material was slurried with n-heptane (7 L) at rt for 6 h and then filtered to give the title compound (2.0 kg, 57%) as a brown solid after drying at 45 NMR (400 MHz, DMSO-d6) 5 ppm 1.15 (t, 3H), 3.20 (m, 2H), 7.95 (m, 2H), 12.50 (s, 1H).

[0195] Intermediate 8: l-(3-Bromo-2-hydroxy-5-methylphenyl)-2-methyl-3-(l-methyl-lH-pyrazol-4- y l)propane- 1 , 3 -dione

[0240]

[0196] A reactor was charged with l-(3-bromo-2-hydroxy-5-methylphenyl)propan- 1-one (1.0 kg, 4.11 mol) and THF (8.0 L) and cooled to -75 °C. When cold, the reaction was treated dropwise with lithium bis(trimethylsilyl)amide (14.4 L, IM in THF, 1439 mol) keeping the internal temperature below -60 °C. After addition was complete, the reaction was stirred at -60 °C for 1 h and then stirred at 0 °C for 2 h. The reaction was cooled to -75 °C and treated dropwise with 1-methyl-lH-pyrazole- 4-carbonyl chloride in THF (6.0 L) keeping the internal temperature below -60 °C. After addition was complete, the reaction was stirred at rt for 15 h. The reaction was cooled to 0 to 10 °C and treated dropwise with AcOH (3.5 L) and water (3.5 L) keeping the temperature below 10 °C. The reaction was concentrated under reduced pressure to 5.0 to 8.0 L of the title compound that was used in the next synthetic step without further workup or purification.

[0241]

[0197] Intermediate 9: 8-Bromo-3,6-dimethyl-2-(l-methyl-lH-pyrazol-4-yl)-4H-chromen-4-one

[0242]

[0198] The solution of l-(3-bromo-2-hydroxy-5-methylphenyl)-2-methyl-3-(l-methyl-lH-pyrazol-4- yl)propane-l, 3-dione from Intermediate 8 was transferred to a reactor and diluted with AcOH (3.5 L) and 12 M aqueous HC1 (0.2 L). The reaction was stirred at 80 °C for 1 h and then at 100 °C for 1 h. After cooling to rt, the reaction was treated with water (5.0 L) and stirred for 30 min. The resulting solid was removed by filtration and washed with water (2.0 L). The filter cake was charged into a reactor and treated with saturated aqueous NaHCCh (5.0 L) and stirred for 30 min. The filter cake was transferred to a reactor and suspended in EtOAc (8.0 L) and stirred for 30 min. The title compound was removed by filtration, washed with EtOAc (2.0 L), and dried at rt giving a gray solid (70% over 2 steps, 95% purity).

[0243]

[0199] Intermediate 10: 8-Bromo-4-hydroxy-3,6-dimethyl-2H-chromene-2-thione

[0244]

[0200] A solution of l-(3-bromo-2-hydroxy-5-methylphenyl)propan- 1-one (495.0 g, 2.04 mol) and carbon disulfide (233.0 g, 3.06 mol) in THF (4.95 L) under nitrogen was cooled to —25 °C and treated dropwise with NaHMDS (3.57 L, 2M in THF) keeping the temperature at - -25 to -20 °C. After addition was complete, the reaction was allowed to warm to 15 - 25 °C over 16 h. The reaction was treated dropwise with 15% aqueous H2SO4 (4.95 L) at - 0 to 10 °C. The layers were separated and the aqueous phase extracted with MTBE (1.49 L). The organic layers were combined and concentrated under reduced pressure. The resulting residue was stirred with n-heptane (1.49 L) for 5 h at rt and the title compound removed by filtration (557.9 g, 96%) as a yellow solid. *H NMR (400 MHz, DMSO-d6) 52.24 (s, 3H), 2.38 (s, 3H), 7.76 (s, 1H), 7.79 (s, 1H).

[0245]

[0201] Intermediate 11: 8-Bromo-6-fhioro-4-hydroxy-3-methyl-2H-chromene-2-thione

[0246]

[0202] Potassium tert-butoxide (3.2 kg, 28.3 mol) and THF (30 L) were added to a 50 L reactor and the mixture stirred for 15 min to give a light yellow solution. Added l-(3-bromo-5-fluoro-2- hydroxyphenyl)propan-l-one (2.0 kg, 8.1 mol) in batches to the reactor keeping the temperature between 0 and 15 °C. Carbon disulfide (740 g, 9.7 mol) was added dropwise keeping the temperature below 30 °C. After addition was completed, the reaction was stirred at 0 to 25 °C for 12 h. The reaction mixture was poured directly into 15% aqueous AcOH (5 L) and stirred at rt for 30 min. The mixture was filtered and the filter cake washed with MTBE (2 L). The filtrate was washed with water (2 x 5 L) and saturated aqueous NaCl (5 L). The organic phase was collected, dried over MgSCh, filtered, and concentrated under reduced pressure to afford the crude product. This material was slurried in heptane (5 L), stirred for 6 h, and filtered to give the title compound (2.8 kg, 120%) as a yellow solid after drying at 45 °C for 12 h. ’H NMR (400 MHz, DMSO-d6) 5 ppm 2.10 (s, 3H), 7.65 (m, 1H), 7.90 (m, 1H).

[0247]

[0203] Intermediate 12: 8-Bromo-2-(ethylthio)-3,6-dimethyl-4H-chromen-4-one

[0248]

[0204] A mixture of 8-bromo-4-hydroxy-3,6-dimethyl-2H-chromene-2-thione (560.0 g, 1.96 mol), K2CO3 (271.4 g, 1.94 mol), and iodoethane (459.5 g, 2.95 mol) in acetone (5.6 L) was stirred at rt for 2 h. The reaction was filtered and the solids washed with THF (1.12 L). The filtrate was concentrated under reduced pressure and the residue purified by silica gel chromatography eluted with EtOAc in n-heptane (1 / 100 to 1 / 2) to give the title compound (545.5 g, 88%) as a brown solid.]H NMR (400 MHz, CDCh) 5 ppm 1.50 (t, 7=7.36Hz, 3H), 2.05 (s, 3H), 2.43 (s, 3H), 3.31 (q, 7=7.36Hz, 2H), 7.64 (s, 1H), 7.93 (s, 1H).

[0249]

[0205] Intermediate 13: 8-Bromo-2-(ethylthio)-6-fluoro-3-methyl-4H-chromen-4-one

[0250]

[0206] Suspended 8-bromo-6-fluoro-4-hydroxy-3-methyl-2H-chromene-2-thione (2.8 kg, 9.7 mol) in acetone (30.0 L) in a 50 L reactor. Treated the suspension with K2CO3 (2.0 kg, 14.5 mol) and slowly added iodoethane (1.8 kg, 11.6 mol) to the mixture at rt. The reaction was stirred at 60 - 65 °C for 2 h. After cooling to rt, the reaction was filtered and the solids washed with MTBE (2.0 L). The filtrate was washed with water (2 x 10 L) and 10% aqueous NaCl (10 L). The organic phase was dried over MgSC and concentrated under reduced pressure. The crude material was slurried with n-heptane (10 L) at rt for 3 h. The title compound was obtained by filtration (1.5 kg, 49%) as a brown solid.!H NMR (400 MHz, DMSO-d6) 5 ppm 1.45 (t, 3H), 1.95(s, 3H), 3.40(m, 2H), 7.90(m, 1H), 8.10(m, 1H)

[0251]

[0207] Intermediate 14: 8-Acetyl-2-(ethylthio)-3,6-dimethyl-4H-chromen-4-one

[0252]

[0208] A mixture of 8-bromo-2-(ethylthio)-3,6-dimethyl-4H-chromen-4-one (344.0 g, 1.1 mol) in 1,4- dioxane (2.75 L) under nitrogen was treated with tributyl(l -ethoxy vinyl)stannane (436.3 g, 1.21 mol) and bis(triphenylphosphine)palladium(II) dichloride (30.8 g, 43.93 mmol). The reaction was stirred at 90 °C for 15 h. After cooling, combined reaction with a 50 g reaction and treated with 2N aqueous HC1 (950 mL) and stirred at rt for 1 h. Added water (2.97 L) and EtOAc (2.97 L) and stirred at rt for 0.5 h. The layers were separated and the organic phase washed with water (1. 19 L). The organic layer was treated with saturated aqueous KF (2.97 L) and stirred at rt for 1 h. The resulting mixture was filtered and the solids washed with EtOAc (1.19 L). The combined filtrates were concentrated and the residue treated with MTBE (395 mL) and n-heptane (1.58 L) and stirred at rt for 1 h. Removed a crude product by filtration which was recrystallized from ACN (600 mL) and MTBE (530 mL) which was heated at 70 °C for 1 h and cooled to rt. The title compound was removed by filtration and dried (252.0 g).!H NMR (400 MHz, CDCh) 8 ppm 1.45 (t, J=7.38Hz, 3H), 2.11 (s, 3H), 2.50 (s, 3H), 2.72 (s, 3H), 3.31 (q, J=7.36Hz, 2H), 7.81 (s, 1H), 8.20 (s, 1H).

[0253]

[0209] Intermediate 15: 8-Acetyl-2-(ethylthio)-6-fluoro-3-methyl-4H-chromen-4-one

[0254]

[0210] A suspension of 8-bromo-2-(ethylthio)-6-fluoro-3-methyl-4H-chromen-4-one (1.32 kg, 4.2 mol) in toluene (6.5 L) was treated dropwise with tributyl(l -ethoxy vinyl) stannane (1.65 kg, 4.6 mol) at rt. The mixture was vacuum degassed and backfilled with nitrogen three times and treated with bis(triphenylphosphine)palladium(II) dichloride (58.4 g, 83.2 mmol). The mixture was vacuum degassed and backfilled with nitrogen three times and stirred at 85 to 95 °C for 36 h. After cooling, added IM aqueous HC1 (2.5 L) and stirred at rt for 36 h. Added EtOAc (6.5 L) and stirred at rt for 30 min. The reaction was filtered and the organic layer collected and washed with aqueous KF (6.5 L). The reaction was filtered and the organic phase washed with water (2 x 6.5 L) and 10% aqueous NaCl (6.5 L). The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure at 45 °C. The crude material was purified by crystallization from heptane: EtOH (2:1; 6.5 L). The title compound was obtained by filtration (430 g, 36%) as a brown solid after drying at 45 °C for 12 h. ’H NMR (400 MHz, DMSO-d6) 6 ppm 1.45 (t, 3H), 1.95(s, 3H), 2.60(s, 3H), 3.45(m, 2H), 7.90(m, 1H), 8.10(m, 1H).

[0255]

[0211] Intermediate 16: 8-Acetyl-3,6-dimethyl-2-(l-methyl-lH-pyrazol-4-yl)-4H-chromen-4-one

[0256]

[0212] A reactor was charged with 8-bromo-3,6-dimethyl-2-(l-methyl-lH-pyrazol-4-yl)-4H- chromen-4-one (1000 g, 3.0 mol), tributy 1(1 -ethoxy vinyl)stannane (1190 g, 3.3 mol), bis(triphenylphosphine)palladium(II) dichloride (63.2 g, 0.09 mol), and 1,4-dioxane (10.0 L). The reaction was stirred at 120 °C under nitrogen for 15 to 19 h. After cooling to rt, the reaction was treated with 2M aqueous HC1 (3.0 L) and stirred for 1 h. The pH of the reaction was adjusted to 8 - 9 with solid NaHCCh (~ 1000 g) and the organic solvent removed under reduced pressure until no obvious distillate was being removed. Added water (2.0 L) and EtOAc (3.0 L) and stirred for 1 h. Removed a solid by filtration and washed with EtOAc (1.0 L). The solid was transferred to a reactor, suspended in water (3.0 L), and stirred for 1 h. The solid was transferred to a reactor and suspended in 2-MeTHF (3.0 L) and stirred for 1 h. The title compound was removed by filtration and dried at 40 °C to give a gray solid (91%).

[0257]

[0213] Intermediate 17: (R,E)-N-(l-(2-(ethylthio)-3,6-dimethyl-4-oxo-4H-chromen-8-yl)ethylidene)- 2-methylpropane-2-sulfinamide

[0258]

[0214] A mixture of 8-acetyl-2-(ethylthio)-3,6-dimethyl-4H-chromen-4-one (180 g, 615.75 mmol) and (R)-2-methylpropane-2-sulfinamide (149.26 g, 1.23 mol) in THF (1500 mL) was treated with titanium(IV) isopropoxide (700.01 g, 2.46 mol, 726.90 mL). The mixture was stirred at 80 °C for 56 h to give a black-brown solution. After cooling to rt, quenched the reaction with saturated aqueous NaCl (2000 mL) and stirred for 30 min and filtered. The filter cake was washed with EtOAc (4000 mL). After separating the organic layer, the aqueous layer was extracted with EtOAc (1000 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was triturated with petroleum ether / EtOAc (1 / 1, 600 mL) to give the title compound as a white solid (186 g, 76%). ES / MS (m / z): 396 (M+H).

[0215] Intermediate 18: (R,E)-N-(l-(3,6-Dimethyl-2-(l-methyl-lH-pyrazol-4-yl)-4-oxo-4H-chromen- 8-yl)ethylidene)-2-methylpropane-2-sulfinamide

[0259]

[0216] A solution of 8-acetyl-3,6-dimethyl-2-(l-methyl-lH-pyrazol-4-yl)-4H-chromen-4-one (400.0 g, 1.35 mol) in toluene (4.0 L) was treated with titanium(IV) ethoxide (461.9 g, 2.02 mol) and (R)-2- methylpropane-2-sulfinamide (245.4 g, 2.03 mol) and stirred at 85 °C for 14 h. After cooling, the reaction was concentrated under reduced pressure. The resulting slurry was treated with MTBE (4.0 L), stirred for 20 min, and the title compound removed by filtration (412.6 g, 77%) as a light yellow solid. *H NMR (400 MHz, Chloroform-d) 5 ppm 1.33 (s, 9H), 2.31 (s, 3H), 2.50 (s, 3H), 2.88 (s, 3H), 4.05 (s, 3H), 7.59 (d, J = 2.3 Hz, 1H), 7.95 (s, 1H), 8.12 (s, 1H), 8.14 (s, 1H).

[0260]

[0217] Intermediate 19: (R,E)-N-(l-(2-(Ethylthio)-6-fluoro-3-methyl-4-oxo-4H-chromen-8- yl)ethylidene)-2-methylpropane-2-sulfinamide

[0261]

[0218] A solution of 8-acetyl-2-(ethylthio)-6-fluoro-3-methyl-4H-chromen-4-one (5.0 g, 17.84 mmol) in THF (80 mL) was treated with (R)-(+)-2-Methylpropane-2-sulphinamide (4.32 g, 35.67 mmol) and titanium(IV) isopropoxide (20.28 g, 71.35 mmol). The reaction vessel was sealed and the reaction stirred at 80 °C overnight. After cooling, the reaction was concentrated under reduced pressure and the residue taken on to the next synthetic step without purification. ES / MS (m / z): 384 (M+H).

[0262]

[0219] Intermediate 20: (R)-N-((R)-l-(2-(Ethylthio)-3,6-dimethyl-4-oxo-4H-chromen-8-yl)ethyl)-2- methylpropane-2-sulfinamide

[0263]

[0220] The toluene solution of (R,E)-N-(l-(2-(ethylthio)-3,6-dimethyl-4-oxo-4H-chromen-8- yl)ethylidene)-2-methylpropane-2-sulfinamide (0.18 mol) was cooled to between -10 °C and 0 °C and treated in portions with sodium borohydride (20.4 g, 0.54 mmol) keeping the internal temperature below 0 °C. After stirring at -10 °C and 0 °C for 1 h, the reaction was quenched with saturated aqueous NH4CI. The resulting white slurry was filtered through diatomaceous earth and the solids washed with THF. The filtrate was washed with brine and the organic layer concentrated onto silica gel under reduced pressure. The material was purified by chromatography to give the product (26 g, 37% over two steps). ES / MS (m / z): 382 (M+H).

[0264]

[0221] Intermediate 21: (R)-N-(l-(3,6-Dimethyl-2-(l-methyl-lH-pyrazol-4-yl)-4-oxo-4H-chromen-8- yl)ethyl)-2-methylpropane-2-sulfinamide

[0265]

[0222] A solution of (R,E)-N-(l-(3,6-dimethyl-2-(l-methyl-lH-pyrazol-4-yl)-4-oxo-4H-chromen-8- yl)ethylidene)-2-methylpropane-2-sulfinamide (400.0 g, 1.00 mol) in MeOH (4.0 L) was treated with sodium borohydride (75.76 g, 2.00 mol) maintaining the temperature below 10 °C. The reaction was stirred at rt for 2 h. The reaction was cooled to -10 °C and quenched by dropwise addition of saturated aqueous NH4CI (~5 V). The resulting mixture was concentrated under reduced pressure to remove volatiles and the residue extracted with DCM (3 x 1.0 L). The organic layers were combined, washed with saturated aqueous NaCl (400 mL), the organic layer collected, dried over MgSO4, and concentrated under reduced pressure to give the title compound (356.2 g, 89%) as a yellow solid.!H NMR (400 MHz, Chloroform-d) 5 ppm 1.25 (s, 9H), 1.68 (d, J = 6.7 Hz, 3H), 2.31 (s, 3H), 2.48 (s, 3H), 3.66 (d, J = 3.1 Hz, 1H), 4.05 (s, 3H), 5.20 (qd, J = 6.5, 3.1 Hz, 1H), 7.52 (d, J = 2.2 Hz, 1 H), 7.98 (dd, J = 2.3, 1.0 Hz, 1H), 8.01 (s, 1H), 8.33 (s, 1H).

[0223] Intermediate 22: (R)-N-((R)-l-(2-(ethylthio)-6-fluoro-3-methyl-4-oxo-4H-chromen-8- yl)ethyl)-2-methylpropane-2-sulfinamide

[0266]

[0224] A solution of crude (R,E)-N-(l-(2-(ethylthio)-6-fluoro-3-methyl-4-oxo-4H-chromen-8- yl)ethylidene)-2-methylpropane-2-sulfinamide (7.0 g, 18.3 mmol) in MeOH (170 mL) was treated with cerium(III) chloride heptahydrate (3.40 g, 9.13 mmol) and cooled to 0 °C. Added sodium borohydride (1.38 g, 36.5 mmol) portionwise and allowed to stir at 0 °C for 1.5 h. The reaction was quenched with saturated aqueous NH4CI and extracted with EtOAc (3 x 100 mL). The combined organic layers were filtered through diatomaceous earth, dried over NazSCL, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluted with 0% to 75% EtOAc in hexanes to give the title compound (4.5 g, 64%) as a pale yellow solid. ES / MS m / z: 386 (M+H).

[0267]

[0225] Intermediate 23: (R)-N-((R)-l-(2-cyclopropyl-6-fluoro-3-methyl-4-oxo-4H-chromen-8- yl)ethyl)-2-methylpropane-2-sulfinamide

[0268]

[0226] Suspended (R)-N-((R)-l-(2-(ethylthio)-6-fluoro-3-methyl-4-oxo-4H-chromen-8-yl)ethyl)-2- methylpropane-2-sulfinamide (30 g, 77.82 mmol), cyclopropylboronic acid (66.85 g, 778.19 mmol), ((2-hydroxy-3-methylbenzoyl)oxy)copper (33.41 g, 155.64 mmol), and tetrakis(triphenyphosphine)palladium(0) (35.97 g, 31.13 mmol) in 1,4-dioxane and stirred at 80 °C for 4 h. Concentrated under reduced pressure and resuspended the residue in EtOAc, filtered through diatomaceous earth, and washed the solids with EtOAc. The filtrate was washed with saturated aqueous NaHCO3 (3 x 300 mL). The organic layer was collected, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluted with 30% to 80% EtOAc in heptane to give the title compound (23 g, 81%) as a yellow solid. ES / MS m / z: 366 (M+H).

[0269]

[0227] Intermediate 24: (R)-8-(l-Aminoethyl)-2-(ethylthio)-3,6-dimethyl-4H-chromen-4-one

[0270]

[0228] A solution of (R)-N-((R)-l-(2-(ethylthio)-3,6-dimethyl-4-oxo-4H-chromen-8-yl)ethyl)-2- methylpropane-2-sulfinamide (20 g, 52.4 mmol) in THF (200 mL) was treated dropwise with 12 M aqueous HC1 (2 eq) and stirred at rt. After 1 h, the reaction was concentrated under reduced pressure, the residue dissolved in water, and extracted with MTBE. The pH of the aqueous phase was adjusted to between 9 and 10 with IM aqueous NaOH and extracted with EtOAc. The organic layer was washed with saturated aqueous NaCl, dried over MgSCL, filtered, and concentrated under reduced pressure to give the product (12.6 g, 87%) as a white solid. ES / MS m / z: 278 (M+H).

[0271]

[0229] Intermediate 25: (R)-8-(l-Aminoethyl)-2-(ethylthio)-6-fluoro-3-methyl-4H-chromen-4-one

[0272]

[0230] A 0 °C solution of (R)-N-((R)-l-(2-(ethylthio)-6-fluoro-3-methyl-4-oxo-4H-chromen-8- yl)ethyl)-2-methylpropane-2-sulfinamide (1.50 g, 3.89 mmol) in DCM (30 mL) was treated with HC1 (3.89 mL, 4M in 1,4-dioxane, 15.56 mmol). After stirring at 0 °C for 5 h, the reaction was diluted with water (100 mL) and extracted with DCM (200 mL). The organic layer was collected and washed with water (3 x 150 mL). All the aqueous layers were combined, pH adjusted to 9 with saturated aqueous sodium carbonate, and extracted with DCM (3 x 500 mL). The organic layers were combined, dried, and concentrated under reduced pressure to give the title compound (1.0 g, 91%) as a white solid. ES / MS m / z: 282 (M+H).

[0273]

[0231] Intermediate 26: (R)-8-(l-Aminoethyl)-3,6-dimethyl-2-(l-methyl-lH-pyrazol-4-yl)-4H- chromen-4-one

[0274]

[0232] A solution of (R)-N-(l-(3,6-dimethyl-2-(l-methyl-lH-pyrazol-4-yl)-4-oxo-4H-chromen-8- yl)ethyl)-2-methylpropane-2-sulfinamide (350.0 g, 0.87 mol) in MeOH at 0 to 10 °C was treated dropwise with HC1 (653.7 mL, 4M in MeOH, 2.61 mol). The reaction was stirred at rt for 2 h. The reaction was concentrated under reduced pressure and the residue slurried with EtOAc (700 mL), stirred for 20 min, and filtered. The cake was dissolved in water (500 mL) and the pH adjusted to 8-9 with saturated aqueous NaHCO3 at 0 to 10 °C to give a thick slurry that was filtered. The solids were washed with DCM until most of the solid had dissolved. The filtrate was concentrated under reduced pressure to give the title compound (145.3 g, 56%) as an off-white solid. 'H NMR (400 MHz, DMSO-d6) 5 ppm 1.36 (d, J = 6.6 Hz, 3H), 2.12 (br, s, 2H), 2.17 (s, 3H), 2.42 (s, 3H), 3.99 (s, 3H), 4.66 (q, J = 6.6 Hz, 1H), 7.69 (d, J = 2.2 Hz, 1H), 7.76 (d, J = 2.3 Hz, 1H), 8.03 (s, 1H), 8.43 (s, 1H).

[0275]

[0233] Intermediate 27: (R)-8-(l-Aminoethyl)-2-cyclopropyl-6-fluoro-3-methyl-4H-chromen-4-one

[0276]

[0234] A solution of (R)-N-((R)-l-(2-cyclopropyL6-fluoro-3-methyl-4-oxo-4H-chromen-8-yl)ethyl)- 2-methylpropane-2-sulfinamide (23.0 g, 62.93 mmol) in DCM (500 mL) was treated dropwise with HC1 (39.33 mL, 4M in 1,4-dioxane, 157.34 mmol) over 15 min at rt. After addition was complete, allowed the reaction to stir at rt for 1 h. The reaction was extracted with water (3 x 500 mL) and the organic layer extracted with water (3 x 150 mL). The aqueous layers were combined, pH adjusted to 9 with saturated aqueous NazCCL, and extracted with DCM (3 x 800 mL). The organic layers were combined, dried, and concentrated under reduced pressure to give the title compound (13 g, 79%) as a white solid. ES / MS m / z: 262 (M+H).

[0277]

[0235] Intermediate 28: (R)-6-Chloro-3-((l-(2-(ethylthio)-3,6-dimethyl-4-oxo-4H-chromen-8- yl)ethyl)amino)picolinonitrile

[0278]

[0236] (R)-8-(l-Aminoethyl)-2-(ethylthio)-3,6-dimethyl-4H-chromen-4-one (30.0 g, 108 mmol), 3- bromo-6-chloropicolinonitrile (23.5 g, 108 mmol), tris(dibenzylideneacetone)dipalladium(0) (9.90 g, 10.8 mmol), Xantphos (12.5 g, 21.6 mmol), and cesium carbonate (52.9 g, 162 mmol) were suspended in toluene (500 mL) and the mixture degassed with argon for 10 min. The reaction was stirred at 105 °C for 45 min. Diluted the thick suspension with 150 mL of toluene and stirred at 107 °C overnight. After cooling, added diatomaceous earth and filtered the reaction through silica gel and washed with EtOAc (-500 mL). The filtrate was concentrated under reduced pressure to give the title compound (48.1 g, 107%) as a dark residue which was taken on to the next synthetic step without purification. ES / MS m / z: 414 (M+H).

[0279]

[0237] Intermediate 29: (R)-6-Chloro-3-((l-(2-(ethylthio)-6-fluoro-3-methyl-4-oxo-4H-chromen-8- y l)ethyl) amino)picolinonitrile

[0280]

[0238] A vessel was charged with (R)-8-(l-aminoethyl)-2-(ethylthio)-6-fluoro-3-methyl-4H-chromen- 4-one (1.0 g, 3.55 mmol), 3-bromo-6-chloropicolinonitrile (0.93 g, 4.27 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.33 g, 0.36 mmol), Xantphos (0.41 g, 0.71 mmol), cesium carbonate (1.74 g, 5.33 mmol), and toluene (15 mL). The mixture was stirred at 110 °C for 16 h. After cooling, the reaction was filtered through a pad of silica gel which was flushed with EtOAc. The filtrate was concentrated under reduced pressure and the residue purified by silica gel chromatography eluted with 10% to 100% EtOAc in heptane to give the title compound (1.20 g, 81%) as a white solid. ES / MS m / z: 418 (M+H).

[0281]

[0239] Intermediate 30: (R,Z)-6-Chloro-3-((l -(2-(ethylthio)-6-fluoro-3-methyl-4-oxo-4H-chromen-8- yl)ethyl)amino)-N'-hydroxypicolinimidamide

[0282]

[0240] A solution of (R)-6-chloro-3-((l-(2-(ethylthio)-6-fluoro-3-methyl-4-oxo-4H-chromen-8- yl)ethyl)amino)picolinonitrile (1.50 g, 3.59 mmol) in EtOH (500 mL) was treated with triethylamine (1.09 g, 10.77 mmol) and hydroxylamine hydrochloride (0.50 g, 7.18 mmol) and stirred at 80 °C for 1 h. The reaction was concentrated under reduced pressure, the residue dissolved in DCM (IL), washed with saturated aqueous NH4CI (2 x 300 mL), and washed with water (200 mL). The organic layer was collected, dried, and concentrated under reduced pressure to give the title compound (1.20 g, 74%) as a white solid. ES / MS m / z: 451 (M+H).

[0283]

[0241] Intermediate 31: (R)-8-(l-Aminoethyl)-2-(5-fhioropyridin-3-yl)-3,6-dimethyl-4H-chromen-4- one

[0284]

[0242] Four tubes were charged with (R)-8-(l-aminoethyl)-2-(ethylthio)-3,6-dimethyl-4H-chromen-4- one (1.25 g, 5.86 mmol), copper(I) thiophene-2-carboxylate (1.29 g, 6.76 mmol), tetrakis(triphenylphosphine)palladium(0) (0.52 g, 0.45 mmol), and EtOH (15 mL). The tubes were degassed with nitrogen for 5 min and stirred at 65 °C for 16 h. The reactions were filtered through diatomaceous earth and the solids washed with DCM, EtOAc, and MeOH. The filtrate was concentrated under reduced pressure and the residue purified by reversed phase chromatography eluted with 10% to 75% ACN in lOmM aqueous ammonium bicarbonate to give the title compound (2.9 g, 44%). ES / MS m / z: 313 (M+H).

[0285]

[0243] Intermediate 32: (R)-6-Chloro-3-((l-(3,6-dimethyl-2-(2-methyl-2H-l,2,3-triazol-4-yl)-4-oxo- 4H-chromen- 8 -y l)ethyl) amino)picolinonitrile

[0286]

[0244] Seven reaction tubes were charged with 2-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)-2H-l,2,3-triazole (1.578 g, 7.55 mmol), (R)-6-chloro-3-((l-(2-(ethylthio)-3,6-dimethyl-4-oxo- 4H-chromen-8-yl)ethyl)amino)picolinonitrile (1.25 g, 3.02 mmol), copper(I) 2-hydroxy-3- methylbenzoate (1.0 g, 4.68 mmol), and EtOH (with 3% water; 15 mL). The tubes were degassed with argon for 10 min and then charged with tetrakis(triphenylphosphine)palladium(0) (1.05 g, 0.91 mmol) and the tubes purged again for 2 min. The tubes were stirred at 50 °C for 7 h. After cooling, the reactions were combined, filtered through diatomaceous earth, and the solids washed with EtOAc / DCM. The filtrate was concentrated under reduced pressure and the residue purified by silica gel chromatography eluted with 0% to 100% EtOAc in EtOH (4:1) in heptane to give the title compound (5.5 g, 60%) as a white solid. ES / MS m / z: 435 (M+H).

[0287]

[0245] Intermediate 33: (R)-6-Chloro-3-((l-(2-cyclopropyl-6-fluoro-3-methyl-4-oxo-4H-chromen-8- y l)ethy 1) amino )picolinonitrile

[0288]

[0246] Charged a flask with (R)-8-(l-aminoethyl)-2-cyclopropyl-6-fluoro-3-methyl-4H-chromen-4- one (13.0 g, 49.75 mmol), 3-bromo-6-chloropicolinonitrile (27.05 g, 124.38 mmol), tris(dibenzylideneacetone)dipalladium(0) (4.56 g, 4.98 mmol), XANTPHOS (5.76 g, 9.95 mmol), cesium carbonate (40.53 g, 124.38 mmol), and toluene (500 mL). The reaction was stirred at 90 °C for 5 h. The reaction was filtered and the solids washed with DCM until all product had been recovered. The filtrate was concentrated under reduced pressure and the residue purified by silica gel chromatography eluted with 10% to 60% EtOAc in heptane to give the title compound (12 g, 61%) as a yellow solid. ES / MS m / z: 398 (M+H).

[0289]

[0247] Intermediate 34: 6-Chloro-3-((l-(2-(ethylthio)-6-fluoro-3-methyl-4-oxo-4H-chromen-8- yl)ethyl)amino)picolinic acid

[0290]

[0248] A solution of 8-(l-bromoethyl)-2-(ethylthio)-6-fluoro-3-methyl-4H-chromen-4-one (100 g, 290 mmol) in DMF (800 mL) was treated with 3-amino-6-chloro-pyridine-2-carboxylic acid (50 g, 290 mmol). The reaction was stirred at 80 to 90 °C for 58 h. The reaction was concentrated under reduced pressure at 60 °C and the residue slurried with MTBE (500 mL) and water (100 mL). After 30 min under sonication, the reaction was filtered and the solids washed with MTBE (2 x 500 mL) to give the title compound (64 g, 51%) as a light yellow solid. ’HNMR (400MHz, CDCE) 5 ppm 1.47-1.51 (m, 3H), 1.64-1.66 (m, 3H), 1.98 (s, 3H) 3.09- 3.36 (m, 2H), 5.15-5.21 (m, 1H), 7.00-7.02 (d, 1H), 7.30-7.35 (m, 1H), 7.49-7.51 (m, 1H), 7.58-7.61 (m, 1H) 8.29-8.31 (m, 1H), 13.15(br, 1H).

[0291]

[0249] Intermediate 35: tert-Butyl 6-chloro-3-((l-(2-(ethylthio)-6-fluoro-3-methyl-4-oxo-4H- chromen-8-yl)ethyl)amino)picolinate

[0292]

[0250] A solution of 6-chloro-3-((l-(2-(ethylthio)-6-fluoro-3-methyl-4-oxo-4H-chromen-8- yl)ethyl)amino)picolinic acid (79 g, 181 mmol) in THF (800 mL) was cooled to 10 °C and treated dropwise with 2-tert-butyl-l,3-diisopropyl-isourea (126.78 g, 633 mmol). The reaction was stirred at 20 °C for 2 h, filtered, and the solids washed with THF (2 x 100 mL). The filtrate was concentrated under reduced pressure and the residue slurried in 200 mL of MTBE under sonication for 30 min giving the title compound (76.3 g, 86%) after filtration, washing with MTBE (100 mL) and drying.]HNMR (400MHz, CDCE) 5 ppm 1.47-1.51 (m, 3H), 1.63-1.74 (m, 12H), 2.12 (s, 3H), 3.21- 3.26 (m, 2H), 5.01-5.07 (m, 1H), 6.59-6.61 (d, 1H), 7.09-7.11 (d, 1H), 7.30-7.33 (m, 1H), 7.75-7.78 (m, 1H), 8.32~8.33(d, 1H).

[0251] Intermediate 36 and Intermediate 37: tert-Butyl 6-chloro-3-((l-(2-(ethylthio)-6-fluoro-3- methyl-4-oxo-4H-chromen-8-yl)ethyl)amino)picolinate, Isomer 1 and Isomer 2

[0293]

[0252] tert-Butyl 6-chloro-3-((l-(2-(ethylthio)-6-fluoro-3-methyl-4-oxo-4H-chromen-8- yl)ethyl)amino)picolinate (76.3 g, 155 mmol) was separated into component isomers using a ChiralPak IC column (250 x 50 mm, 10 m) eluted with 45% i-PrOH (with 0.1% NH4OH) in CO2 to give crude Isomer 1 (38.40 g) and crude Isomer 2 (27 g). Isomer 1 was repurified by preparative HPLC using a Sharpsil-T C 18 column (50 x 250 mm, 8 microns) eluted with 85% to 98% ACN in water (with 0.05% TFA) to give Isomer 1 (28.60 g, 37%) as an off-white solid. ES / MS m / z: 493 (M+H).

[0294]

[0253] Intermediate 38: tert-Butyl (R)-6-chloro-3-((l-(2-(ethylthio)-3,6-dimethyl-4-oxo-4H-chromen- 8-yl)ethyl)amino)picolinate

[0295]

[0254] A vial was charged with (R)-8-(l-aminoethyl)-2-(ethylthio)-3,6-dimethyl-4H-chromen-4-one (1.0 g, 3.61 mmol), tert-butyl 3-bromo-6-chloropicolinate (1.58 g, 5.41 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.25 g, 0.27 mmol), 4,5-bis(diphenylphosphino)-9,9- dimethylxanthene (0.42 g, 0.72 mmol), cesium carbonate (2.93 g, 9.01 mmol), and toluene (12 mL). The suspension was purged with nitrogen for 10 min and the vial sealed. The reaction was stirred at 130 °C overnight. The reaction was cooled to rt, filtered, and the solids washed with DCM. The filtrate was concentrated under reduced pressure and the residue purified by silica gel chromatography eluted with 0% to 100% EtOAc in hexane to give the title compound (0.88 g, 50%) as a pale tan solid. ES / MS m / z: 433 (M+2H-tBu).

[0296]

[0255] Intermediate 39: 6-Chloro-3-((l-(2-(ethylthio)-6-fluoro-3-methyl-4-oxo-4H-chromen-8- yl)ethyl)amino)picolinic acid , Isomer 1

[0297]

[0256] A solution of tert-butyl 6-chloro-3-((l-(2-(ethylthio)-6-fluoro-3-methyl-4-oxo-4H-chromen-8- yl)ethyl)amino)picolinate, Isomer 1 (1.0 g, 2.03 mmol) in DCM (5 mL) was treated with trifluoroacetic acid (5 mL) and stirred at rt for 5 h. The reaction was concentrated under reduced pressure and the residue dissolved in DCM (5 mL) and concentrated under reduced pressure 4 times to give the title compound (0.89 g, 100%) as a yellow solid. ES / MS m / z: 437 (M+H).

[0298]

[0257] Intermediate 40: 6-Chloro-3-((l-(2-(ethylthio)-6-fluoro-3-methyl-4-oxo-4H-chromen-8- yl)ethyl)amino)picolinamide, Isomer 1

[0299]

[0258] A solution of 6-chloro-3-((l-(2-(ethylthio)-6-fluoro-3-methyl-4-oxo-4H-chromen-8- yl)ethyl)amino)picolinic acid , Isomer 1 (0.89 g, 2.03 mmol) and HATU (0.94 g, 2.54 mmol) in DMF (10 mL) was treated with DIEA (3.15 g, 24.3 mmol) and stirred at rt for 10 min. Added ammonia (43.2 mg, 0.4 M in 1,4-dioxane, 2.54 mmol) and ammonium chloride (0.33 g, 6.08 mmol) and stirred at rt for 1 h. Partitioned the reaction between EtOAc and water and extracted the aqueous layer with EtOAc. The organic layers were washed with saturated aqueous ammonium chloride, collected, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluted with 0% to 80% EtOAc in heptane to give the title compound (0.89 g, 95%) as a yellow solid. ES / MS m / z: 436 (M+H).

[0300]

[0259] Intermediate 41: 6-Chloro-3-((l-(2-(ethylthio)-6-fluoro-3-methyl-4-oxo-4H-chromen-8- yl)ethyl)amino)picolinonitrile, Isomer 1

[0301]

[0260] A solution of 6-chloro-3-((l-(2-(ethylthio)-6-fluoro-3-methyl-4-oxo-4H-chromen-8- yl)ethyl)amino)picolinamide, Isomer 1 (0.89 g, 1.94 mmol) in dry DCM (10 mL) at 0 °C was treated with triethylamine (2.94 g, 29.1 mmol) and trifluoroacetic acid anhydride (2.04 g, 9.70 mmol) and stirred at rt for 2 h. The reaction was partitioned between DCM and water. The aqueous layer was extracted with DCM. The organic layers were combined, washed with saturated aqueous NaHCCL, collected, dried over NazSCL, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluted with 0% to 60% EtOAc in heptane to give the title compound (0.96 g, 75% purity, 89%) as a beige solid. ES / MS m / z: 418 (M+H).

[0302]

[0261] Intermediate 42: (R,Z)-6-Chloro-3-((l-(6-fluoro-2-(5-fluoropyridin-3-yl)-3-methyl-4-oxo-4H- chromen-8-yl)ethyl)amino)-N'-hydroxypicolinimidamide

[0303]

[0262] A 20 mL vial was charged with (R,Z)-6-chloro-3-((l-(2-(ethylthio)-6-fluoro-3-methyl-4-oxo- 4H-chromen-8-yl)ethyl)amino)-N'-hydroxypicolinimidamide (0.20 g, 0.44 mmol), (5-fluoropyridin- 3-yl)boronic acid (0.19 g, 1.33 mmol), copper(I) thiophene-2-carboxylate (0.13 g, 0.67 mmol), tetrakis(triphenylphosphine)palladium(0) (0.15 g, 0.13 mmol), and EtOH (7 mL). The reaction was degassed with argon, sealed, and stirred at 65 °C for 3 h. The reaction was filtered, concentrated under reduced pressure, and the residue purified by silica gel chromatography eluted with 0% to 100% EtOAc / EtOH (3:1) in heptane to give the title compound (0.18 g, 50% purity, 42%) as a white solid. ES / MS m / z: 486 (M+H).

[0304]

[0263] Intermediate 43: tert-Butyl 6-chloro-3-(((lR)-l-(2-(ethylsulfinyl)-3,6-dimethyl-4-oxo-4H- chromen-8-yl)ethyl)amino)picolinate

[0305]

[0264] A solution of tert-butyl (R)-6-chloro-3-((l-(2-(ethylthio)-3,6-dimethyl-4-oxo-4H-chromen-8- yl)ethyl)amino)picolinate (1.0 g, 2.05 mmol) in DCM (10 mL) was cooled to 0 °C and treated in portions with mCPBA (0.50 g, 77%, 2.25 mmol). After addition was complete, the reaction was stirred at 0 °C for 1 h. The reaction was diluted with DCM and washed with saturated aqueous NaHCOi. The organic layer was collected and the aqueous layer extracted with DCM. The combined organic layers were dried over MgSCb, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluted with 0% to 100% EtOAc in heptane to give the title compound (1.0 g, 97%) as a pale tan solid. ES / MS m / z: 503 (M-H).

[0306]

[0265] Intermediate 44: tert-Butyl (R)-6-chloro-3-((l-(2-chloro-3,6-dimethyl-4-oxo-4H-chromen-8- y l)ethyl) amino)picolinate

[0307]

[0266]

[0356] A solution of tert-butyl 6-chloro-3-(((lR)-l-(2-(ethylsulfinyl)-3,6-dimethyl-4-oxo-4H- chromen-8-yl)ethyl)amino)picolinate (0.95 g, 1.87 mmol) and benzyl(triethyl) ammonium chloride (0.21 g, 0.94 mmol) in DCM (30 mL) was treated with HC1 (0.78 mL, 37% aqueous, 9.37 mmol). The reaction was stirred at rt for 1 h, treated with additional aqueous HC1 (0.18 mL, 37% aqueous), and allowed to stir for 30 min. The reaction was quenched with saturated aqueous NaHCCL and extracted with DCM. The organic layer was washed with saturated aqueous NaCl, collected, dried over MgSCL, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluted with 0% to 50% EtOAc in heptane to give the title compound (0.42 g, 49%) as a white foam. ES / MS m / z: 407 (MH-tBu).

[0308]

[0267] Intermediate 45: tert-Butyl 6-chloro-3-((l-(6-fluoro-3-methyl-2-(l-methyl-lH-pyrazol-4-yl)-4- oxo-4H-chromen-8-yl)ethyl)amino)picolinate, Isomer 1

[0309]

[0268] A 5 mL microwave vial was charged with tert-butyl 6-chloro-3-((l-(2-(ethylthio)-6-fluoro-3- methyl-4-oxo-4H-chromen-8-yl)ethyl)amino)picolinate, Isomer 1 (1.0 g, 2.0 mmol), (1-methyl-lH- pyrazol-4-yl)boronic acid (0.77 g, 6.1 mmol), ((2-hydroxy-3-methylbenzoyl)oxy)copper (0.65 g, 3.0 mmol), tetrakis(triphenylphosphine)palladium(0) (0.47 g, 0.41 mmol), and EtOH (5 mL). The reaction was degassed and flushed with nitrogen for ~ 2 min and the vial sealed and stirred at 60 °C for 5 h. The reaction was re-charged with (l-methyl-lH-pyrazol-4-yl)boronic acid (0.77 g, 6.1 mmol), ((2-hydroxy-3-methylbenzoyl)oxy)copper (0.65 g, 3.0 mmol), tetrakis(triphenylphosphine)palladium(0) (0.47 g, 0.41 mmol) and the reaction stirred at 60 °C for 4 h. After cooling, the reaction was combined with a 100 mg and 500 mg reactions run in a similar fashion, diluted with 100 mL of EtOAc, and filtered through diatomaceous earth. The filtrate was diluted with water and ~15 mL of saturated aqueous Na2CC>3. The organic layer was collected, washed with saturated aqueous NaCl, dried over Na2SC>4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluted with 0% to 100% EtOAc in heptane to obtain the title compound (0.38 g, 29%, 80% purity).

[0310]

[0269] Intermediate 46: 6-Chloro-3-((l-(6-fluoro-3-methyl-2-(2-methyl-2H- l,2,3-triazol-4-yl)-4-oxo- 4H-chromen-8-yl)ethyl)amino)picolinonitrile, Isomer 1

[0311]

[0270] A vial was charged with 6-chloro-3-((l-(2-(ethylthio)-6-fluoro-3-methyl-4-oxo-4H-chromen- 8-yl)ethyl)amino)picolinonitrile, Isomer 1 (0.25 g, 0.45 mmol), 2-methyl-4-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)-2H-l,2,3-triazole (0.20 g, 0.90 mmol), copper® thiophene-2-carboxylate (0.17 g, 0.90 mmol), tetrakis(triphenylphosphine)palladium(0) (0.16 g, 0.14 mmol), and EtOH (with 1% water; 6 mL). The vial was purged with nitrogen for 5 minutes and stirred at 65 °C for 15 h. After cooling, the reaction was diluted with EtOH, filtered through diatomaceous earth, and the filtrate concentrated under reduced pressure. The residue was purified by silica gel chromatography eluted with 0% to 60% EtOH in EtOAc (3:1 v / v) in heptane to give the title compound (0.28 g, 50% purity, 71%) as a yellow solid. ES / MS m / z: 439 (M+H). 271 J Intermediate 47: tert-Butyl (R)-6-chloro-3-((l-(2-cyclopropyl-3,6-dimethyl-4-oxo-4H- chromen-8-yl)ethyl)amino)picolinate

[0312]

[0272] A dry 20 mL vial was charged with tert-butyl (R)-6-chloro-3-((l-(2-chloro-3,6-dimethyl-4- oxo-4H-chromen-8-yl)ethyl)amino)picolinate (200 mg, 0.43 mmol), palladium(II) acetate (9.69 mg, 43.2 mol), and CPhos (37.7 mg, 86.3 pmol). The vial was evacuated and refilled with nitrogen 3 times and then charged with THF (4 mL) via syringe. The reaction was cooled to 0 °C and treated with cyclopropylzinc(II) iodide (0.61 mL, 0.5 M in THF, 0.30 mmol) via syringe. The reaction was allowed to stir at rt overnight. The reaction was cooled to 0 °C and recharged with palladium(II) acetate (9.69 mg, 43.2 mol), CPhos (37.7 mg, 86.3 nmol), and cyclopropylzinc(II) iodide (0.60 mL, 0.5 M in THF, 0.30 mmol) via syringe. The reaction was allowed to stir at rt for 4 h. The reaction was diluted with EtOAc and washed with saturated aqueous NH4CI. The aqueous layer was extracted twice with EtOAc. The combined organic layers were dried over NaiSO-i, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluted with 0% to 50% EtOAc in n-heptane to give the title compound (137 mg, 68%) as a tan foam. ES / MS m / z: 413 (M-tBu).

[0313]

[0273] Intermediate 48: 6-Chloro-3-((l-(6-fluoro-3-methyl-2-(l-methyl-lH-pyrazol-4-yl)-4-oxo-4H- chromen-8-yl)ethyl)amino)picolinic acid, Isomer 1

[0274] tert-Butyl 6-chloro-3-((l-(6-fluoro-3-methyl-2-(l-methyl-lH-pyrazol-4-yl)-4-oxo-4H- chromen-8-yl)ethyl)amino)picolinate, Isomer 1 (0.38 g, 0.73 mmol) was mixed with TFA (5 mL) and DCM (5 mL) and stirred at rt for 2 h. The reaction was concentrated from DCM three times to give the title compound (390 mg, 85% purity) as a yellow solid after drying under reduced pressure. This product was taken to the next synthetic step without purification.

[0314]

[0275] Intermediate 49: (R)-6-Chloro-3-((l-(2-cyclopropyl-3,6-dimethyl-4-oxo-4H-chromen-8- yl)ethyl)amino)picolinic acid

[0315]

[0276] A solution of tert-butyl (R)-6-chloro-3-((l-(2-cyclopropyl-3,6-dimethyl-4-oxo-4H-chromen-8- yl)ethyl)amino)picolinate (137 mg, 0.29 mmol) in DCM (2 mL) was treated with 50% TFA in DCM (1 mL) and stirred at 50 °C for 1 h. The reaction was concentrated under reduced pressure and the residue purified by reversed phase chromatography eluted with 0% to 100% water (with 0.1% formic acid) in ACN. Fractions containing the product were pooled, washed with saturated aqueous NaCl, and extracted with IPA / CHCL (v:v / l:3). The extract was dried over MgSCL, filtered, and concentrated under reduced pressure to give the title compound (101 mg, 84%) as a colorless gel. ES / MS m / z: 413 (M).

[0316]

[0277] Intermediate 50: 6-Chloro-3-((l-(6-fluoro-3-methyl-2-(l-methyl-lH-pyrazol-4-yl)-4-oxo-4H- chromen-8-yl)ethyl)amino)picolinamide, Isomer 1

[0317]

[0278] A solution of 6-chloro-3-((l-(6-fluoro-3-methyl-2-(l-methyl-lH-pyrazol-4-yl)-4-oxo-4H- chromen-8-yl)ethyl)amino)picolinic acid, Isomer 1 (250 mg, 0.55 mmol) in DMF (5 mL) was treated with HATU (0.26 g, 0.68 mmol) and DIEA (0.85 g, 6.57 mmol) and stirred at rt for 10 min. The reaction was treated with ammonia (1.71 mL, 0.4 M in 1,4-dioxane, 0.68 mmol) and NH4CI (87.8 mg, 1.64 mmol) and stirred at rt for 1 h. The reaction was concentrated under reduced pressure and partitioned between EtOAc and saturated aqueous ammonium carbonate. The organic layer was collected, dried over NazSCU, filtered, and concentrated under reduced pressure. The residue was purified by reversed phase chromatography eluted with 30% to 60% ACN in water (with 10 mM ammonium carbonate) to give the title compound (0.16 g, 59%). ES / MS m / z: 456 (M).

[0318]

[0279] Intermediate 51: (R)-6-Chloro-3-((l-(2-cyclopropyl-3,6-dimethyl-4-oxo-4H-chromen-8- yl)ethyl)amino)picolinamide

[0319]

[0280] A solution of 6-chloro-3-[[(lR)-l-(2-cyclopropyl-3,6-dimethyl-4-oxo-chromen-8- yl)ethyl]amino]pyridine-2-carboxylic acid (66 mg, 0.16 mmol) in DMF (2 mL) was treated with NH4CI (51 mg, 0.96 mmol), HATU (0.12 g, 0.32 mmol), and DIEA (0.12 g, 0.96 mmol) and allowed to stir overnight at rt. The reaction was diluted with EtOAc and washed with 10% aqueous lithium chloride. The organic layer was collected, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluted with 0% to 100% 75% EtOAc in EtOH in heptane to give the title compound (38 mg, 58%) as a white solid. ES / MS m / z: 412 (M).

[0320]

[0281] Intermediate 52: (R)-6-Chloro-3-((l-(2-cyclopropyl-3,6-dimethyl-4-oxo-4H-chromen-8- yl)ethyl)amino)picolinonitrile

[0321]

[0282] A solution of (R)-6-chloro-3-((l-(2-cyclopropyl-3,6-dimethyl-4-oxo-4H-chromen-8- yl)ethyl)amino)picolinamide (31.6 mg, 76.7 pmol) in DCM (1 mL) was cooled to 0 °C and treated with triethylamine (116 mg, 1.15 mmol) and 2,2,2-trifluoroacetic anhydride (80.6 mg, 0.38 mmol). The reaction was allowed to stir at rt for 2 h. The reaction was diluted with EtOAc and washed with saturated aqueous NaHCCh. The organic layer was dried over Na2SC>4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluted with 0% to 100% EtOAc in heptane to give the title compound (69 mg, 50% purity) as a yellow gel. ES / MS m / z: 394 (M+H). 283 J The following compound in Table 1 was made in a similar way as described for (R)-6-chloro- 3-((l-(2-cyclopropyl-3,6-dimethyl-4-oxo-4H-chromen-8-yl)ethyl)amino)picolinonitrile

[0322]

[0284] Table 1

[0323]

[0285] Intermediate 54: (R)-6-Chloro-3-((l-(2-(5-fluoropyridin-3-yl)-3,6-dimethyl-4-oxo-4H- chromen-8-yl)ethyl)amino)picolinonitrile

[0324]

[0286] A vial was charged with (R)-8-(l-aminoethyl)-2-(5-fluoropyridin-3-yl)-3,6-dimethyl-4H- chromen-4-one (0.70 g, 2.24 mmol), 3-bromo-6-chloropicolinonitrile (0.73 g, 3.36 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.21 g, 3.36 mmol), Xantphos (0.26 g, 0.45 mmol), cesium carbonate (1.83 g, 5.60 mmol), and toluene (15 mL). The suspension was purged with nitrogen for 10 min, sealed, and stirred at 130 °C for 2.5 h. After cooling, the reaction was filtered, the solids washed with DCM, and the filtrate concentrated under reduced pressure. The residue was purified by silica gel chromatography eluted with EtOAc in hexanes to give the title compound (1.01 g, 100%) as a yellow foam. ES / MS m / z: 449 (M+H).

[0325]

[0287] Intermediate 55: (R)-6-Chloro-3-((l-(3,6-dimethyl-2-(l-methyl-lH-pyrazol-4-yl)-4-oxo-4H- chromen-8-yl)ethyl)amino)picolinonitrile

[0326]

[0288] A flask was charged with (R)-8-(l-aminoethyl)-3,6-dimethyL2-(l-methyl-lH-pyrazol-4-yl)- 4H-chromen-4-one (6.0 g, 20.18 mmol), 3-bromo-6-chloropicolinonitrile (6.58 g, 30.27 mmol), cesium carbonate (16.44 g, 50.44 mmol), and toluene (15 mL). Bubbled argon through the reaction for 20 min and then added tris(dibenzylideneacetone)dipalladium(0) (1.85 g, 2.02 mmol) and Xantphos (2.34 g, 4.04 mmol), sealed the flask, and stirred at 100 °C for 18 h. Flask was recharged with the reagents and stirred overnight at 100 °C. After cooling, the reaction was quenched with water (50 mL) and filtered through diatomaceous earth. The filtrate was extracted with EtOAc. The organic layer was collected, concentrated under reduced pressure, and the residue purified by silica gel chromatography eluted with 0% to 50% EtOAc in heptane to give the title compound (7.78 g, 89%). ES / MS m / z: 434 (M+H).

[0327]

[0289] Intermediate 56: (R,Z)-6-Chloro-3-((l-(6-fluoro-3-methyl-2-(l-methyl-lH-pyrazol-4-yl)-4- oxo-4H-chromen-8-yl)ethyl)amino)-N'-hydroxypicolinimidamide

[0328]

[0290] A solution of (R)-6-chloro-3-((l-(6-fluoro-3-methyl-2-(l-methyl-lH-pyrazol-4-yl)-4-oxo-4H- chromen-8-yl)ethyl)amino)picolinonitrile (94 mg, 0.21 mmol) in EtOH (2.1 mL) was treated with triethylamine (43 mg, 0.43 mmol) and hydroxylamine hydrochloride (18 mg, 0.26 mmol) and stirred at 80 °C for 1 h. After cooling, the reaction was diluted with water (1 mL) and IM aqueous HC1 (1 M) and extracted with 3: 1 chloroform / isopropanol three times. The organic layers were combined, dried over MgSO4, filtered, and concentrated under reduced pressure to give the title compound (0.11 g, 100%) which was taken on to the next synthetic step without purification. ES / MS m / z: 471 (M+H).

[0291] Intermediate 57: (R,Z)-6-Chloro-3-((l-(2-cyclopropyl-3,6-dimethyl-4-oxo-4H-chromen-8- yl)ethyl)amino)-N'-hydroxypicolinimidamide

[0329]

[0292] A solution of (R)-6-chloro-3-((l-(2-cyclopropyl-3,6-dimethyl-4-oxo-4H-chromen-8- yl)ethyl)amino)picolinonitrile (10.21 g, 25.92 mmol) in EtOH (200 mL) was treated with triethylamine (6.56 g, 64.81 mmol) followed by hydroxylamine hydrochloride (3.0 g, 40 mmol). The reaction was stirred at 70°C for 2 h. After cooling, the reaction was concentrated under reduced pressure and the residue purified by silica gel chromatography eluted with 0% to 30% 25% EtOH in ethyl acetate in heptane to give the title compound (9.41 g, 85%) as a pale tan foam. ES / MS m / z: 427 (M+H).

[0330]

[0293] The following compounds in Table 2 were made in a similar way as described for (R,Z)-6- chloro-3-((l-(2-cyclopropyl-3,6-dimethyl-4-oxo-4H-chromen-8-yl)ethyl)amino)-N'- hydroxypicolinimidamide.

[0331]

[0294] Table 2

[0332]

[0333]

[0295] Intermediate 62: (R,Z)-6-Chloro-3-((l-(2-cyclopropyL6-fluoro-3-methyl-4-oxo-4H-chromen-

[0334] 8-yl)ethyl)amino)-N'-hydroxypicolinimidamide

[0335]

[0296] A solution of (R)-6-chloro-3-((l-(2-cyclopropyl-6-fluoro-3-methyl-4-oxo-4H-chromen-8- yl)ethyl)amino)picolinonitrile (12.5 g, 31.4 mmol) in EtOH (500 mL) was treated with triethylamine (9.54 g, 94.3 mmol) and hydroxylamine hydrochloride (4.37 g, 62.8 mmol). The reaction was stirred at 80 °C for 1 h. The reaction was concentrated under reduced pressure, the residue dissolved in DCM (1 L), and the solution washed with saturated aqueous NH4CI (2 x 300 mL) and water (200 mL). The organic layer was concentrated under reduced pressure to give the title compound (12.1 g, 89%). ES / MS m / z: 431 (M+H).

[0336]

[0297] Example l(6Me): (R)-3-(6-Chloro-3-((l-(2-cyclopropyl-3,6-dimethyl-4-oxo-4H-chromen-8- yl)ethyl)amino)pyridin-2-yl)- 1 ,2,4-oxadiazol-5(4H)-one

[0337]

[0338]

[0298] A solution of (R,Z)-6-chloro-3-((l-(2-cyclopropyl-3,6-dimethyl-4-oxo-4H-chromen-8- yl)ethyl)amino)-N'-hydroxypicolinimidamide (32 mg, 75 pmol) in 1,4-dioxane (2 mL) was treated with DBU (17 mg, 0.11 mmol) and CDI (15 mg, 90 (tmol). The reaction was sealed and stirred at 80 °C for 1 h. The reaction was allowed to cool to rt and concentrated under reduced pressure. The residue was purified hy reversed phase chromatography eluted with 0% to 100% ACN in water (with 0.1% formic acid). Fractions containing the product were pooled, washed with saturated aqueous NaCl, and extracted with 25% (v:v) IPA in CHCh. The organic layer was collected, dried over MgSO4, filtered, and concentrated under reduced pressure to give the title compound (18.8 mg, 55%) as a white solid. ES / MS m / z: 453.

[0339]

[0299] Example 1(6F): (R)-3-(6-Chloro-3-((l-(2-cyclopropyl-6-fluoro-3-methyl-4-oxo-4H-chromen- 8-yl)ethyl)amino)pyridin-2-yl)-l,2,4-oxadiazol-5(4H)-one

[0340]

[0300] A solution of (R,Z)-6-chloro-3-((l-(2-cyclopropyl-6-fluoro-3-methyl-4-oxo-4H-chromen-8- yl)ethyl)amino)-N'-hydroxypicolinimidamide (13.0 g, 30.2 mmol) in 1,4-dioxane (500 mL) was treated with DBU (18.4 g, 121.0 mmol) and CDI (14.7 g, 90.5 mmol) and the reaction stirred at rt for 1 h. The pH of the reaction was adjusted to 3 with IM aqueous HC1 (~75 mL). The reaction was diluted with DCM (1000 mL) and washed with saturated aqueous NH4CI. The organic layer was collected, dried over MgSCL, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluted with 10% to 80% EtOAc in heptane to give the title compound (10.8 g, 78%) as a white solid. ES / MS m / z: 457 (M+H).

[0301] The following compounds in Table 3 were made in a similar way as described for (R)-3-(6- chloro-3-((l-(2-cyclopropyl-3,6-dimethyl-4-oxo-4H-chromen-8-yl)ethyl)amino)pyridin-2-yl)-l,2,4- oxadiazol-5(4H)-one.

[0341]

[0302] Table 3

[0342]

[0303] PI3K- Alpha kinase (PI3KCA) activity: wild-type PI3KCA, H1047R mutant PI3KCA, and E545K mutant PI3KCA, in vitro cell based assays and determination of IC50 values for inhibitors

[0343]

[0304] The MDA-MB-453 (ATCC-HTB-131) cell line (PI3KCA H1047R), MDA-MB-361 (ATCC- HTB-27) cell line (PI3KCA E545K), and SKBR3 (ATCC-HTB-30) cell line (wild type PI3KCA) were obtained from the American Type Culture Collection (Manassas, VA). MDA-MB-453 cells were maintained in Dulbecco’s Modified Eagle Media (DMEM, Gibco 12430) supplemented with 10% Fetal Bovine Serum, heat inactivated (FBS HI, Gibco 10082), IX non-essential amino acids (NEAA, Gibco 11140), 1 mM sodium pyruvate (Gibco 11360) and IX Anti-Anti (Gibco 15240). MDA-MB-361 cells were maintained in Dulbecco’s Modified Eagle Media (DMEM, Gibco 12430) supplemented with 20% Fetal Bovine Serum, heat inactivated (FBS HI, Gibco 10082), IX non- essential amino acids (NEAA, Gibco 11140), 1 mM sodium pyruvate (Gibco 11360) and IX Anti- Anti (Gibco 15240). SKBR3 cells were maintained in McCoy’s 5A (Gibco 16600) supplemented with 10% Fetal Bovine Serum, heat inactivated (FBS HI, Gibco 10082), and IX Anti-Anti (Gibco 15240). Cultures were maintained in a humidified incubator at 37°C under 5% CO2 / 95% air.

[0344]

[0305] For compound testing in 0% FBS, MDA-MB-453 and SKBR3 cells were seeded at a density of 1.5xl04, l.OxlO4, and l.OxlO4cells, respectively, per well in white 384-well plates in 20 pl of Minimum Essential Media (MEM) assay media with IX NEAA, 1 mM sodium pyruvate, and 1 pg / mL human insulin (Sigma 19278) (Assay Medium); while MDA-MB-361 cells were seeded at a density of 1.5xl04per well in white 384-well plates in 20 pl Assay Medium without insulin. After plating, cells were allowed to attach overnight. 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 IX NEAA and 1 mM sodium pyruvate (150 pM starting compound concentration in 1.5% DMSO) was then prepared. Five pl 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 taselisib at a final concentration of 1 p M was used as a reference compound for the minimum (MIN) signal. After 3 hours treatment, the medium was removed, and the cells were lysed in 10 pL of IX 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 u 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 1-2 hours at room temperature in the dark. The plates were read on a Neo2 plate reader instrument from Biotek using standard AlphaLisa settings.

[0345]

[0306] Compounds were tested in duplicate and the average % inhibition at each compound concentration was used to generate two dose response curves. One IC50 was generated using average % inhibition at each compound concentration. 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. The data was analyzed using a 4-parameter nonlinear logistic equation (four-parameter logistic concentration-response curve):

[0346] Y = bottom + [(top - bottom) / l+(X / IC50)slope] where Y = % inhibition, X = concentration of inhibitor, bottom = minimum value of y attained by curve-fit, top = maximum value of y attained by curve-fit and slope = steepness of curve at the IC50. %Inhibition = [(signal at X - median Min) / (median Max - median Min)] x 100

[0347] IC50: concentration of compound that reduces a given response (ligand binding, enzyme response) by 50%.

[0348] Relative IC50: concentration giving half the compound’s maximum response.

[0349]

[0307] Compound selectivity for the H1047R mutant PI3KCA was calculated by dividing the IC50 in SKBR3 (WT PI3KCA) by the IC50 in MDA-MB-453 (H1047R mutant PI3KCA).

[0350]

[0308] Metabolic Stability and Intrinsic Clearance in Liver Microsomes (MICS)

[0309] One objective of this assay is to measure in vitro metabolic stability of a test compound in liver microsomes of one or more different species. The concentration of a control compound in the reaction system is evaluated by LC / MS / MS for calculating intrinsic clearance of a test compound and estimating the stability of the control compound and test compound in liver microsomes of one or more different species.

[0351]

[0310] Microsomes (MICS). Human Liver Microsomes (HLM), Monkey Liver Microsomes (MKLM), Dog Liver Microsomes (DLM), Rat Liver Microsomes (RLM), and Mouse Liver Microsomes (MLM) are obtained at a concentration of 20 mg / mL protein from commercial sources and stored in a -80°C freezer. Prior to use, liver microsomes are removed from the freezer and allowed to thaw in a 37 °C water bath and then stored on wet ice.

[0352]

[0311] Stock Solutions. Test Compound (TC) Stock Solutions are prepared in DMSO at a concentration of 10 mM and stored for later use. Positive Control (PC) Stock Solutions of verapamil.HCL (FW: 491.1 g / mol) in DMSO are prepared at a concentration of 10 mM (4.91 mg / mL), and stored under the condition same as the stock solutions of test compounds.

[0353]

[0312] Phosphate Buffer. Phosphate Buffer (lOOmM, pH 7.4) is prepared by combining a Solution A and a Solution B as follows.

[0354]

[0313] To prepare Solution A, 7.098 g of disodium hydrogen phosphate was combined with 500 mL of pure water and sonicated to dissolve. To prepare the Solution B,

[0355] 3.400 g of potassium dihydrogen phosphate was combined with 250 mL of pure water and sonicated to dissolve. Solution A was placed on a stirrer and Solution B was slowly added into Solution A until the pH reached 7.4.

[0356]

[0314] NADPH Solution. A 10 mM NADPH Solution is prepared by dissolving NADPH (MW: 833.4 g / mol) at 8.334 mg / mL in phosphate buffer (100 mM, pH 7.4).

[0357]

[0315] Microsome Master Solution. A Microsome Master Solution is prepared by adding 6.25 L microsomes (20 mg / mL) to 216.25 pL Phosphate Buffer (100 mM). The final concentration is Phosphate Buffer (100 mM); microsomes (0.5 mg / mL).

[0358]

[0316] Dilution of Stock Solutions. The TC Stock Solutions (10 mM in DMSO) and the PC Stock Solutions (10 mM in DMSO) are diluted by adding 3 pL of the TC Stock Solution or the PC Stock Solution to 297 pL of 50% acetonitrile / 50% water.

[0359]

[0317] Incubation. Two separate experiments were performed as follows, a) With Cofactors (NADPH): 25 pL of 10 mM NADPH was added to the incubations. The final concentrations of microsomes and NADPH were 0.5 mg / mL and 1 mM, respectively, b) Without Cofactors (NADPH): 25 pL of 100 mM Phosphate buffer was added to the incubations. The final concentration of microsomes was 0.5 mg / mL. The mixture was pre-warmed at 37°C for 10 minutes.

[0360]

[0318] The reaction was started with the addition of 2.5 pL of 100 pM PC solution or TC solutions. Verapamil was used as PC in this study. The final concentration of test compound or control compound was 1 pM. The incubation solution was incubated in water batch at 37°C.

[0361]

[0319] Reaction Termination. Aliquots of 30 pL were taken from the reaction solution at 0.5, 5, 15, 30 and 60 minutes and added to plates. The reaction was stopped by the addition of 5 volumes of cold acetonitrile and a solution containing 100 nM alprazolam, 200 nM caffeine and 100 nM tolbutamide.

[0362]

[0320] Sampling. The plates containing the terminated reactions were centrifuged at 4000 rpm for 30 minutes. Supernatant of each compound (40 pL) was transferred into a 96-well analysis plate. Four compound samples are pooled together into one cassette and diluted by adding 160 pL of pure water. All incubations are performed in duplicate.

[0363]

[0321] Analysis and Data Processing. Quantitative LC-MS analysis is performed, and peak areas are determined from extracted ion chromatograms. Percent parent remaining was calculated from peak area of TC or PC. The slope value, k, is determined by linear regression of the natural logarithm of percent parent remaining vs. incubation time curve.

[0364]

[0322] The in vitro half-life (in vitro ti / 2) is determined from the slope value: in vitro ti / 2 = - (0-693 / k)

[0365]

[0323] Conversion of the in vitro 11 / 2 (in min) into the in vitro intrinsic clearance in vitro CLint, in pL / min / mg proteins) is done using the following equation:

[0366] 0,693 voiume of incubation (pl) ( - ) amount of proteins (mg)

[0367]

[0324] Calculations of Scaled-up CLhep (mL / min / kg), predicted CLint (mL / min / kg) and EH may be performed using equations and scaling factors for Human, Monkey, Dog, Rat, and Mouse microsomes as known in the art.

[0325] Metabolic Stability and Intrinsic Clearance in Hepatocytes (HEPS)

[0368]

[0326] One objective of this assay is to measure in vitro metabolic stability of a test compound in hepatocytes of one or more different species and identify compounds having low clearance. The concentration of a control compound in the reaction system is evaluated by LC / MS / MS for calculating intrinsic clearance of a test compound and estimating the stability of the control compound and test compound in hepatocytes of one or more different species.

[0369]

[0327] Hepatocytes (HEPS).

[0370]

[0328] Hepatocytes were purchased from commercial sources and stored at less than -150 °C.

[0371]

[0329] Stock Solutions. Test Compound (TC) Stock Solutions are prepared in DMSO at a concentration of 10 mM and stored for later use. Positive Control (PC) Stock Solutions of verapamil.HCL (FW: 491.1 g / mol) in DMSO are prepared at a concentration of 10 mM (4.91 mg / mL), and stored at the condition same as the stock solutions of test compounds.

[0372]

[0330] Preparation of Hepatocytes.

[0373]

[0331] Incubation medium (William’s E Medium supplemented with GlutaMAX) and hepatocyte thawing medium were warmed in a 37°C water bath for at least 30 minutes prior to use.

[0374]

[0332] Vials of cryopreserved hepatocytes were removed from storage, depressurized, and thawed in a 37°C water bath. The contents were poured into a 50 mL thawing medium conical tube containing the hepatocyte thawing medium that had been pre-warmed to 37°C. Vials were centrifuged at 100 g for 5 minutes at room temperature. The thawing medium was aspirated and the hepatocytes were resuspended with 3-4 mL serum-free incubation medium.

[0375]

[0333] Cell viability and density were counted and the cell density was diluted with serum-free incubation medium to a working cell density of 0.5xl06viable cells / mL.

[0376]

[0334] Dilustion of Stock Solutions. The TC Stock Solutions (10 mM in DMSO) and the PC Stock Solutions (10 mM in DMSO) are diluted to 100 pM by adding 2 pL of the TC Stock Solution or the PC Stock Solution to 198 pL of 50% acetonitrile / 50% water.

[0377]

[0335] Incubation.

[0378]

[0336] The hepatocyte suspension (247.5 pL) was pipetted into each well of a 96-well non-coated plate. The plate was placed in an incubator to allow the hepatocytes to warm for 10 minutes. TC (2.5 pL of the 100 pM TC solution) or PC (2.5 pL of the 100 pM PC solution) were pipetted into respective wells of the 96-well non-coated plate to start the reaction. The plate was returned to the incubator and samples were taken at designated time points.

[0337] Reaction Termination. Well contents were transferred in 25 pL aliquots at time points of 0.5, 30, 60, 90, 120 and 240 minutes to plates. The aliquots were then mixed with 12 volumes (300 pL) of acetonitrile containing the internal standard (100 nM alprazolam, 200 nM caffeine and 100 nM tolbutamide) to terminate the reaction.

[0379]

[0338] Sampling. The plates containing the terminated reactions were centrifuged at 4000 rpm for 40 minutes. Supernatant of each compound (100 pL) was transferred into a 96-well analysis plate. Four compound samples are pooled together into one cassette and diluted by adding 160 pL of pure water. All incubations are performed in duplicate. Aliquots of 100 pL of the supernatant were diluted by 100 pL ultra-pure water, and the mixture was used for LC / MS / MS analysis. All incubations were performed in duplicate.

[0380]

[0339] Analysis and Data Processing. Quantitative LC-MS analysis is performed, and peak areas are determined from extracted ion chromatograms. Percent parent remaining was calculated from peak area of TC or PC. The slope value, k, is determined by linear regression of the natural logarithm of percent parent remaining vs. incubation time curve.

[0381]

[0340] The in vitro half-life (in vitro ti / z) is determined from the slope value: in vitro ti / = - (0.693 / k)

[0382]

[0341] Conversion of the in vitro ti / 2 (in min) into the in vitro intrinsic clearance (in vitro CLint, in pL / min / mg proteins) is done using the following equation:

[0383] 0.693 voiume of incubation (p.1) in vitro CLint ( - ) amount of proteins (mg)

[0384]

[0342] Calculations of Scaled-up CLhep (mL / min / kg), predicted CLint (mL / min / kg) and EH may be performed using equations and scaling factors for Human, Monkey, Dog, Rat, and Mouse microsomes as known in the art.

[0385]

[0343] Comparative Data for Selected Compounds

[0344] The compounds of Examples 1 , 2, 3, and 4 are paired and include a compound having a 6-F substituent and a reference compound having a 6-Me substituent for comparison. The paired compounds were tested in the above-described assays and the results are presented in Table 4.

[0386] L345J Table 4 (6-F vs. 6-Me Comparison)

[0387]

[0346] Regarding potency and selectivity, the compound of Example 1 (6-F) has good potency and selectivity over WT for the PI3KCA H1047R mutation and the PI3KCA E545K mutation.

[0388]

[0347] Regarding in vitro clearance, the compound of Example 1 (6-F) has low clearance in the HEPS assay (15 L / h / kg) and the MICS assay (52 L / h / kg). In comparison, the reference compound of Example 1(6-Me) exhibited increased clearance in the HEPS assay (21 L / h / kg) and the MICS assay (160 L / h / kg). Conversely, for the compound pairs of Examples 2, 3, and 4, the 6-F compounds exhibited increased clearance in the HEPS assay and MICS assay in comparison to their 6-Me counterparts.

[0389]

[0348] The compound of Example 1(6-F) and the reference compound of Example 1(6-Me) were selected for further analysis in vivo in cynomolgus monkeys.

[0390]

[0349] Pharmacokinetic Studies in Cynomolgus Monkeys

[0391]

[0350] Study. Pharmacokinetic studies of the compound of Example 1(6-Me) and the compound of Example 1(6-F) were conducted in male cynomolgus monkeys following single intravenous (IV) infusion (IVinf) or oral (PO) administration. The study design is illustrated in Table 5.

[0351] Table 5. Study Design

[0392]

[0352] Formulation.

[0393]

[0353] Solutions of the compound of Example 1(6-Me) and the compound of Example 1 (6-F) for IV administration were prepared in 70% PEG400 / 30% water. IV formulations were prepared by dissolving the appropriate amount of the compound of Example 1(6-Me) and the compound of Example 1(6-F) in PEG400 equivalent to 70% of the total volume and mixing well. Water equivalent to 30% of the total volume was added and mixed thoroughly. The formulations were heated at 60°C to dissolve, if necessary. Both formulations were clear solutions with no visible particles.

[0394] |354| Solutions of the compound of Example 1(6-Me) and the compound of Example 1(6-F) for oral dosing were prepared in 20% propylene glycol, 10% Cremophor® EL, 70% water, 1 meq NaOH.

[0395] Oral formulations were prepared by dissolving the appropriate amount of the compound of Example 1(6-Me) and the compound of Example 1 (6-F) in propylene glycol equivalent to 20% of the total volume and mixing well, followed by the addition of 1 meq. NaOH and mixing until dissolved. The formulation was heated at 60°C to dissolve, if necessary. Cremophor EL® equivalent to 10% of the total volume was then added and mixed. The formulation was heated again after the addition of Cremophor EL®at 60°C to dissolve, if necessary. Water equivalent to 70% of the total volume was then added and mixed thoroughly to obtain clear to slightly hazy solutions of the compound of Example 1(6-Me) and the compound of Example 1(6-F).

[0396]

[0355] In-life Phase. The compound of Example 1(6-Me) and the compound of Example 1(6-F) were administered via 20-minute IV infusion (IV inf) at 2 mg / kg or via oral gavage at 10 mg / kg to male cynomolgus monkeys weighing between 4 and 5 kg. All animals for IV infusion administration had free access to food and water. Animals for PO administration were fasted overnight prior to dosing and fed approximately 2 hours after dosing.

[0397]

[0356] Blood samples at a volume of 300 pL were collected in potassium (K2) EDTA vacutainers by venipuncture of the peripheral veins (except the dosing vein) at 0.0333, 0.0833, 0.167, 0.33 (immediately after the conclusion of the infusion), 0.5, 1, 2, 4, 8, 12, and 24 hours post-dose (infusion from 0 h to 0.333 h) from the IV dosing groups and at 0.25, 0.5, 1, 2, 4, 8, 12, and 24 hours post-dose from the PO dosing groups. Plasma was separated immediately by centrifugation at approximately 2000 x g for 10 minutes at 2 to 8°C. All samples were maintained on wet ice throughout processing and stored in a freezer at -75 ± 15 °C until analysis.

[0398]

[0357] Urine samples were collected from the IV dosing groups at pre-dose, 0-12, and 12-24 hours and volumes recorded. Cagewash urine samples were collected at 24 hours and combined with the urine samples. Samples were stored in polypropylene tubes in a freezer at -75 ± 15°C until analysis.

[0399]

[0358] Bioanalytical and Pharmacokinetic Phase. Concentrations of the compound of Example 1(6- Me) and the compound of Example 1 (6-F) in plasma and urine samples were quantified using liquid chromatography coupled to tandem mass spectrometry (LC-MS / MS) method. Pharmacokinetic profiles of compounds were determined by standard non-compartmental analysis using Phoenix WinNonlin, version 8.3.

[0400]

[0359] Bioanalysis of plasma and urine samples (LC-MS-MS Assay). Aliquots of 50 pL plasma or urine were prepared by adding 5 pL of blank solution and followed by protein precipitation with 200 pL acetonitrile containing internal standard (dexamethasone). Samples were vortexed for 30 sec. Plasma or urine samples were centrifuged to pellet precipitated protein (3900 rpm for 15 min at

[0401] 4 °C), and the supernatant was diluted 3 times with water. 2 to 6 pL of the diluted supernatant was injected into the LC / MS / MS system for quantitative analysis of the compound of Example 1(6-Me) and the compound of Example 1(6-F). Chromatographic separation of the supernatant was carried out on a Shim-pack Velox Biphenyl 1.8pm (50 x 2.1 mm) column (Shimadzu Corporation) for the compound of Example 1(6-F) or on Agilent Poroshell EC-C18 4pm (50 x 2.1mm) column (Agilent Technologies) for the compound of Example 1(6-Me) using a mobile phase of 5% acetonitrile / 95% water / 0.1% formic acid (Pump A) or 95% acetonitrile / 5% water / 0.1% Formic acid (Pump B) or 100% water / 0.1% formic acid (Pump A) and 100% acetonitrile / 0.1% formic acid (Pump B) at a flow rate of 0.5 to 0.6 ml / min. Detection was performed with an AB API 5500 LC / MS / MS instrument (SCIEX) with electrospray ionization in multiple reaction monitoring mode, using the compounds specific mass transfers. A calibration curve ranging from 0.5 to 2000 pg / L was constructed for the test compounds. Presence of the compound of Example 1(6-Me) and the compound of Example 1(6-F) was validated with spiked samples of monkey plasma or urine. Plasma concentration- time data obtained was used to analyze the pharmacokinetic parameters. Urine concentration data were used to calculate the percentage of the compound of Example 1(6-Me) and the compound of Example 1(6-F) relative to total dose excreted in urine and renal clearance (CLr).

[0402]

[0360] PK Parameter Analysis. Plasma concentration versus time data was analyzed by noncompartmental analysis using Phoenix WinNonlin 8.3 (Pharsight Corporation, Mountain View, CA). Peak plasma concentrations (Cmax), time taken to reach the peak concentrations (Tmax), and half-life (T1 / 2) were calculated. The areas under the plasma concentration-time curve from time zero to the last quantifiable concentration (AUCt) were calculated using linear trapezoidal rule. The areas under the plasma concentration-time curve from time zero to infinity (AUCinf) was calculated as the sum of AUCt and Ct / Xz, where Ctrepresents the last quantifiable concentration and Xz is the apparent terminal elimination rate constant. The total body clearance (CL) and the volume of distribution at steady state (Vss) were calculated after intravenous infusion administration. The oral bioavailability (expressed as a percentage) was estimated by taking the ratio of dose-normalized AUCiast values after oral doses of test compounds to those after intravenous doses of test compounds. The amount of dose extracted in urine (%) and renal clearance (CLr) values were determined from urine concentrations data.

[0403]

[0361] Results. PK profiles for the compound of Example 1(6-Me) and the compound of Example 1 (6-F) are presented in Table 6.

[0404]

[0362] Table 6.

[0405]

[0363] Regarding the IV inf Pharmacokinetics, the compound of Example 1(6-F) exhibited better CL (mL / min / kg), AUCiast (h*nM), AUCinf (h*nM), and AUCiast / D (h*mg / mL) in comparison to the reference compound of Example 1(6-Me). Regarding the PO Pharmacokinetics, the compound of Example 1(6-F) exhibited better AUCiast (h*nM), AUCinf (h*nM), and AUCiast / D (h*mg / mL) in comparison to the reference compound of Example 1(6-Me).

[0406] L364J In summary, the compound of Example 1(6-F) exhibited improved clearance in comparison to the compound of Example 1(6-Me), while maintaining good potency and selectivity over WT for the PI3KCA H1047R mutation and the PI3KCA E545K mutation.

Claims

CLAIMS:

1. A compound of the formula:or a pharmaceutically acceptable salt thereof.

2. A pharmaceutical composition comprising a compound as defined in claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

3. A method of treating a disease or disorder associated with modulation of phosphoinositide 3-kinase (PI3K), comprising administering to a patient in need thereof a therapeutically effective amount of a compound as defined in claim 1 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined in claim 2.

4. The method as defined in claim 3, wherein the PI3K is PI3KCA.

5. The method as defined in claim 4, wherein the PI3K associated with the disease or disorder has a H1047R mutation, an E545K mutation, or both of a H1047R mutation and an E545K mutation.

6. The method as defined in any one of claims 3-5, wherein the disease or disorder is a cancer.

7. The method as defined in claim 6, wherein the cancer is endometrial cancer, gastriccancer, leukemia, lymphoma, sarcoma, colorectal cancer, lung cancer, ovarian cancer, skin cancer, head and neck cancer, breast cancer, brain cancer, or prostate cancer.

8. The method as defined in claim 6 or 7, wherein the cancer is breast cancer.

9. The method as defined in any one of claims 6-8, wherein the cancer is hormone receptorpositive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced or metastatic breast cancer.

10. The method as defined in any one of claims 3-5, wherein the disorder is CLOVES syndrome, or PROS.

11. A method of inhibiting phosphoinositide 3-kinase (PI3K), comprising administering to a patient in need thereof a therapeutically effective amount of a compound as defined in claim 1 , or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined in claim 2.

12. A method of treating cancer or a disorder associated with modulation of phosphoinositide 3-kinase (PI3K), the method comprising administering to a patient in need thereof a therapeutically effective amount of a compound as defined in claim 1 , or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined in claim 2.

13. The method as defined in claim 12, wherein the cancer is endometrial cancer, gastric cancer, leukemia, lymphoma, sarcoma, colorectal cancer, lung cancer, ovarian cancer, skin cancer, head and neck cancer, breast cancer, brain cancer, or prostate cancer.

14. The method as defined in claim 12 or 13, wherein the cancer is breast cancer.

15. The method as defined in any one of claims 12-14, wherein the cancer is hormone receptor- positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced or metastatic breast cancer.

16. The method as defined in claim 12, wherein the disorder is CLOVES syndrome or PROS.

17. The method as defined in any one of claims 3-16, further comprising administering to the patient in need thereof a therapeutic agent selected from a SERD, or a pharmaceutically acceptable salt thereof; an aromatase inhibitor, or a pharmaceutically acceptable salt thereof; a taxane, or a pharmaceutically acceptable salt thereof; an mTOR inhibitor, or a pharmaceutically acceptable salt thereof; a tyrosine kinase inhibitor, or a pharmaceutically acceptable salt thereof; a platinum agent; an anthracycline, or a pharmaceutically acceptable salt thereof; an immune checkpoint inhibitor, or a pharmaceutically acceptable salt thereof; an antiandrogen, or a pharmaceutically acceptable salt thereof; an anti-HER2 monoclonal antibody; an anti-HER2 antibody-drug conjugate; a KRAS inhibitor, or a pharmaceutically acceptable salt thereof; a MEK inhibitor, or a pharmaceutically acceptable salt thereof; an ERK inhibitor, or a pharmaceutically acceptable salt thereof; a topoisomerase inhibitor, or a pharmaceutically acceptable salt thereof; a SERM, or a pharmaceutically acceptable salt thereof; or a PARE inhibitor, or a pharmaceutically acceptable salt thereof; or a combination thereof.

18. The compound as defined in claim 1, or pharmaceutically acceptable salt thereof, for use in therapy.

19. The compound as defined in claim 1, or a pharmaceutically acceptable salt thereof, for use in the treatment of a disease or disorder associated with modulating PI3K.

20. The compound as defined in claim 19, or a pharmaceutically acceptable salt thereof, wherein the disease or disorder associated with modulating PI3K is a cancer.

21. The compound as defined in claim 20, or a pharmaceutically acceptable salt thereof, wherein the cancer is endometrial cancer, gastric cancer, leukemia, lymphoma, sarcoma, colorectal cancer, lung cancer, ovarian cancer, skin cancer, head and neck cancer, breast cancer, brain cancer, or prostate cancer.

22. The compound as defined in claim 20 or 21, or a pharmaceutically acceptable salt thereof, wherein the cancer is breast cancer.

23. The compound as defined in any one of claims 20-22, or a pharmaceutically acceptable salt thereof, wherein the cancer is hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced or metastatic breast cancer.

24. The compound as defined in claim 19, or a pharmaceutically acceptable salt thereof, wherein the disorder is CLOVES syndrome or PROS.

25. Use of a compound as defined in claim 1, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a disease or disorder associated with modulating PI3K.

26. The use as defined in claim 25, wherein the disease or disorder associated with modulating PI3K is a cancer.

27. The use as defined in claim 26, wherein the cancer is endometrial cancer, gastric cancer, leukemia, lymphoma, sarcoma, colorectal cancer, lung cancer, ovarian cancer, skin cancer, head and neck cancer, breast cancer, brain cancer, or prostate cancer.

28. The use as defined in claim 26 or 27, wherein the cancer is breast cancer.

29. The use as defined in claim 28, wherein the cancer is hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced or metastatic breast cancer.

30. The use as defined in claim 25, wherein the disorder is CLOVES syndrome or PROS.

31. The compound as defined in claim 1, or a pharmaceutically acceptable salt thereof, for use in simultaneous, separate, or sequential combination with one or more of a SERD, or a pharmaceutically acceptable salt thereof; an aromatase inhibitor, or a pharmaceutically acceptable salt thereof; a taxane, or a pharmaceutically acceptable salt thereof; an mTOR inhibitor, or a pharmaceutically acceptable salt thereof; a tyrosine kinase inhibitor, or a pharmaceutically acceptable salt thereof; a platinum agent; an anthracycline, or a pharmaceutically acceptable saltthereof; an immune checkpoint inhibitor, or a pharmaceutically acceptable salt thereof; an antiandrogen, or a pharmaceutically acceptable salt thereof; an anti-HER2 monoclonal antibody; an anti-HER2 antibody-drug conjugate; a KRAS inhibitor, or a pharmaceutically acceptable salt thereof; a MEK inhibitor, or a pharmaceutically acceptable salt thereof; an ERK inhibitor, or a pharmaceutically acceptable salt thereof; a topoisomerase inhibitor, or a pharmaceutically acceptable salt thereof; a SERM, or a pharmaceutically acceptable salt thereof; or a PARP inhibitor, or a pharmaceutically acceptable salt thereof; or a combination thereof; in the treatment of a disease or disorder associated with modulating PI3K.

32. The compound or a pharmaceutically acceptable salt thereof for use as defined in claim31, wherein the disease or disorder associated with modulating PI3K is a cancer.

33. The compound or a pharmaceutically acceptable salt thereof for use as defined in claim32, wherein the cancer is endometrial cancer, gastric cancer, leukemia, lymphoma, sarcoma, colorectal cancer, lung cancer, ovarian cancer, skin cancer, head and neck cancer, breast cancer, brain cancer, or prostate cancer.

34. The compound or a pharmaceutically acceptable salt thereof for use as defined in claim 32 or 33, wherein the cancer is breast cancer.

35. The compound or a pharmaceutically acceptable salt thereof for use as defined in any one of claims 32-34, wherein the cancer is hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced or metastatic breast cancer.

36. The compound or a pharmaceutically acceptable salt thereof for use as defined in claim 32, wherein the disorder associated with modulating PI3K is CLOVES syndrome or PROS.

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