Allosteric chromenone inhibitors of phosphoinositide 3-kinase (PI3k) for treatment of disease

Abstract

To provide compounds for treating disease such as PIK3CA-mutated cancer, pharmaceutically acceptable salts thereof, production methods thereof, and use thereof optionally in combination with one or more additional therapeutic agents for the treatment of disease.SOLUTION: The disclosure provides compounds of Formula (I) in the figure as allosteric chromenone inhibitors of phosphoinositide 3 kinase (PI3K) or pharmaceutically acceptable salts thereof. The disclosure also relates to methods of producing and using compounds of Formula (I) or pharmaceutically acceptable salts thereof.SELECTED DRAWING: None

Description

[Technical Field]

[0001] (CROSS-REFERENCE TO RELATED APPLICATIONS) CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of priority to U.S. Provisional Application No. 63 / 511,400, filed June 30, 2023, U.S. Provisional Application No. 63 / 496,280, filed April 14, 2022, and U.S. Provisional Application No. 63 / 421,277, filed November 1, 2023, all documents cited herein are incorporated by reference in their entirety.

[0002] FIELD OF THE INVENTION The present invention relates to allosteric chromenone inhibitors of phosphoinositide 3-kinase (PI3K), useful for treating diseases or disorders associated with PI3K regulation. The present invention relates to compounds and compositions that inhibit PI3K, methods of treating (or uses for treating) diseases or disorders associated with PI3K (e.g., CLOVES syndrome (congenital lipomatous overgrowth, vascular malformations, epidermal nevi, scoliosis / skeletal and spinal syndrome), PIK3CA-associated 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 uses of PI3K inhibitors in combination with one or more additional cancer treatments. [Background technology]

[0003] The phosphoinositide 3-kinase (PI3K) signaling pathway is one of the most highly mutated systems in human cancer. PI3K signaling is involved in many other disease states, including allergic contact dermatitis, rheumatoid arthritis, osteoarthritis, inflammatory bowel disease, chronic obstructive pulmonary disorder, psoriasis, multiple sclerosis, asthma, disorders associated with diabetic complications, and cardiovascular inflammatory complications such as acute coronary syndromes.

[0004] PI3Ks are members of a unique, conserved family of intracellular lipid kinases that phosphorylate the 3'-OH group on phosphatidylinositols or phosphoinositides. The PI3K family includes 15 kinases with distinct substrate specificities, expression patterns, and modes of regulation (Katso et al., Annu Rev Cell Dev Biol. 2001;17:615-75). Class I PI3Ks (p110α, p110β, p110δ, and p110γ) are typically activated by tyrosine kinases or G protein-coupled receptors to generate PIP3, which engages downstream effectors such as Akt / PDK1, mTOR, Tec family kinases, and Rho family GTPases. Class II and III PI3Ks play important roles in the synthesis and intracellular transport of PI(3)P and PI(3,4)P2.

[0005] PI3K isoforms, for example, are involved in various human cancers and disorders. Mutations in genes encoding PI3K isoforms or mutations that cause upregulation of PI3K isoforms are thought to occur in many human cancers. Mutations in genes encoding PI3K isoforms are point mutations clustered within several hotspots in the helix and kinase domains. Due to the high rate of PI3K mutations, targeting this pathway may offer beneficial therapeutic opportunities.

[0006] Genetic alterations in genes involved in PI3K signaling have been implicated in a variety of cancers, including endometrial cancer, breast cancer, esophageal squamous cell carcinoma, cervical squamous cell carcinoma, cervical adenocarcinoma, colorectal adenocarcinoma, bladder urothelial carcinoma, glioblastoma, ovarian cancer, non-small cell lung cancer, esophagogastric carcinoma, 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, non-clear cell renal cell carcinoma, clear cell renal cell carcinoma, germ cell carcinoma, thymic tumors, pheochromocytoma, heterogeneous neuroepithelial tumors, thyroid cancer, leukemia, and encapsulated glioma (Goncalves MD, Hopkins BD, Cantley LC. Phosphatidylinositol 3-Kinase, Growth Disorders, and Cancer.N Engl J Med.2018Nov 22;379(21):2052-2062).

[0007] The alpha (α) isoform of PI3K, for example, has been implicated in various human cancers. It has been shown that angiogenesis selectively requires the α isoform of PI3K in the control of endothelial cell migration (Graupera et al., Nature 2008;453;662-6). Mutations in the gene encoding PI3Kα, or mutations leading to upregulation of PI3Kα, are thought to occur in many human cancers, including those of the lung, stomach, endometrium, ovary, bladder, breast, colon, brain, prostate, and skin. Mutations in the gene encoding PI3Kα are point mutations clustered within several hotspots in the helix and kinase domain, such as E542K, E545K, and H1047R. Many of these mutations have been shown to be oncogenic gain-of-function mutations. Due to the high rate of PI3Kα mutations, targeting this pathway may offer valuable therapeutic opportunities. PI3Kα, along with PI3Kβ, are constitutively expressed, whereas other PI3K isoforms such as PI3Kδ or PI3Kγ are expressed primarily in hematopoietic cells.

[0008] Mutated PI3Kα is involved in brain metastasis in HR+ / HER2- metastatic breast cancer. The development of brain-penetrant PI3Kα inhibitors may offer improved therapeutic efficacy over current PI3Kα inhibitors. (Fitzgerald et al., Association between PIK3CA mutation status and development of brain metastases in HR+ / HER2- metastatic breast cancer. Ann. Oncol. 30:v110;2019(suppl5))

[0009] Due to the central role of PI3Kα in regulating glucose homeostasis in the organism, PI3K inhibition in patients often leads 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 are potentially mitogenic and / or antiapoptotic for cancer cells, thus potentially negating the antiproliferative effects of PI3K inhibitors (Blouin MJ, et al., Abstract 4615: the hyperinsulinemia caused by PI3K inhibitors attenuates their antiproliferative efficacy, but can be minimized by co-administration of metformin. Cancer Res 2013;73(4615)).

[0010] In the setting of cancers with mutant PI3Kα, one way to overcome the problem of compensatory production of insulin and / or glucose due to systemic PI3Kα inhibition is to develop inhibitors with enhanced selectivity for mutant PI3Kα over wild-type PI3Kα. This increases the opportunity for drugs that selectively inhibit the pathological signaling of mutant PI3Kα in cancer cells without affecting wild-type PI3Kα in host tissues, which regulates 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 toxicity, allowing for 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).

[0011] Currently, PI3Kα inhibitors have roughly equivalent efficacy to wild-type and mutant PI3Kα. Mutation-selective inhibitors have been elusive because the location of PI3Kα mutations is far from the active site. Therefore, inhibitors targeting the second peripheral binding pocket near known mutations (e.g., H1047R) may provide a means to selectively inhibit PI3Kα. Therefore, targeting the mutated peripheral binding pocket of PI3Kα provides a valuable therapeutic target for drug development.

[0012] Therefore, kinase inhibitors of lipid kinases such as PI3Kα are a major area for drug development. One goal is to develop PI3Kα inhibitors that exhibit appropriate potency against PI3Kα. One goal is to develop PI3Kα inhibitors that exhibit appropriate potency against PI3Kα associated with metastatic disease, such as PI3Kα(H1047R) and PI3Kα(E545K). Another goal is to develop PI3Kα inhibitors that exhibit appropriate selectivity for mutant PI3Kα associated with metastatic disease, including PI3Kα(H1047R) and PI3Kα(E545K), compared to wild-type PI3Kα. Another goal is to develop PI3Kα inhibitors that exhibit metabolic stability. A further goal is to develop a PI3K α inhibitor that does not substantially alter the expression of cytochrome P450 enzymes (e.g., expression of CYP3A4), which may affect the metabolic stability of the PI3K α inhibitor or that of another drug, resulting in a drug-drug interaction (DDI). Another goal is to develop a PI3K α inhibitor that inhibits the activity of PI3K α and does not cause adverse events (AEs), such as hyperglycemia, hyperinsulinemia, and diarrhea, when administered at a dose effective to treat a disease or disorder associated with PI3K α activity. Another goal is to develop a PI3K α inhibitor that does not exhibit substantial activity against targets other than PI3K α, including other kinases other than PI3K α. Summary of the Invention

[0013] In one aspect, the present invention provides a compound of formula (I): [ka] or a pharmaceutically acceptable salt thereof, wherein R1 is an optionally substituted bicyclic ring selected from isobenzofuranone, benzofuranone, isoindolinone, indolinone, quinazolinone, 3,4-dihydro-2H-isoquinolin-1-one, 2H-isoquinolin-1-one, imidaza[1,2-a]pyridine, or benzothiazolone, wherein the optionally substituted bicyclic ring is optionally substituted with 1 to 3 substituents each independently selected from oxo, —CN, halogen, C1-C6 alkyl, C1-C6 haloalkyl, —OH, or C1-C6 alkoxy; or R1 is a group of the formula: [ka] R' is hydrogen, halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 hydroxyalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -OH, -CH(OH)-CH2OH, -CH(OH)C1-C3 haloalkyl, -CO-CH2OH, C3-C6 cycloalkyl, -NO2, -NR 11 R 11 , -N(R 11 )-CO2C1-C3 alkyl, -N(R 11 )-SO2C1-C3 alkyl, -N(R 11 )-SO2R 15 , -SO2C1-C3 alkyl, -SOC1-C3 alkyl, -SO2NR 11 R 11 , -SO2NR 11 R 12 , -SO2N(R 11 )-CO-C1-C3 alkyl, -SO2N(R 11 )-CN, -C(=N-OH)-NH2, -CN, -CONR 11 R 12 , -CON(R 11 )-(CH2) n -R 13 , -CO-SR 12 , -CO-NHSO2R 16 , -COCH=SOR 11 (R 11 ), or —COCHCN, or a group of the formula: [ka] Ring A is pyrrolidine optionally substituted with -CN, or R' is selected from oxetane, azetidine, pyrrolidine, tetrahydrofuran, morpholine, thiomorpholine, piperidine, piperazine, pyrrole, furan, thiophene, pyrazole, imidazole, isoxazole, oxazole, isothiazole, thiazole, triazole, oxadiazole, oxadiazolinone (e.g., 1,2,4-oxadiazolin-5-one), 1,4-oxazepane, thiadiazole, tetrazole, phenyl, pyridine, pyridazine, pyrimidine, pyrazine, oxazepane, or triazine, each of which is selected from oxo, -OH, -NR 11 R 11 , -N(R 11 )-CO-R 11 , -N(R 11 )-CN, -OR 11 , -CN, halogen, morpholino, oxetane, C1-C6 haloalkyl, or C1-C6 alkyl optionally substituted with -OH, aryl, 5-membered heteroaryl, or 6-membered heteroaryl; or R' is a group of the formula: [ka] R2 is a group of the formula: [ka] R2 is a group of the formula: [ka] R2 is an optionally substituted 5-membered heteroaryl selected from pyrrole, furan, thiophene, pyrazole, isoxazole, isothiazole, imidazole, oxazole, thiazole, triazole, tetrazole, oxadiazole, and thiadiazole, and the optionally substituted 5-membered heteroaryl is selected from -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R 11 , -CO2C1-C3 alkyl, -CONR 11 R 11 , -OH, -NR 11 R 11 , -NR 11 CO2R 11 optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C5 cycloalkyl, an optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine or morpholine, optionally substituted phenyl, optionally substituted 1,3-benzodioxole, optionally substituted 2,3-dihydro-1,4-benzodioxine, or pyridine, pyrimidine, pyridazine, pyrazine, pyrazole, isoxazole, isothiazole, imidazole, oxazole or thiazole optionally substituted with 1 to 3 substituents independently selected from the selected optionally substituted heteroaryl, and optionally substituted C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl are each independently selected from -CN, -OH (e.g., optionally containing C1-C6 hydroxyalkyl such as -CH2-CH2-OH, secondary -OH such as -CH2-CH(CH3)-OH, or tertiary -OH such as -CH2-C(CH3)2-OH), halogen, oxetanyl, 2-oxabicyclo[2.1.1]hexane, C1-C3 alkoxy, optionally substituted C3-C5 cycloalkyl, -CONR 11 R 11or -S(O)2CH3, optionally substituted C3-C5 cycloalkyl, phenyl, 1,3-benzodioxole, 2,3-dihydro-1,4-benzodioxine, heterocycle, or heteroaryl is each independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -SO2R 11 , -NR 11 R 11 , —OH, or —CN; or R2 is 1,3-benzodioxole, 2,3-dihydro-1,4-benzodioxine, quinoxaline, quinazoline, indole, indazole, isoindazole, benzimidazole, benzotriazole, benzothiazole, benzoxazole, benzotriazole, benzofuran, benzofurazan, pyridofurazan, quinoline, 1,5-naphthyridine, isoindolin-1-one, indolin-2-one, benzomorpholine, benzo[d]oxazol-2(3H)-one, imidazo[1,2-a]pyridine, 1,3-dihydro-2H- Pyrrolo[2,3-b]pyridin-2-one, [1,3]dioxolo[4,5-b]pyridine, 6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine, 1,2,3,4-tetrahydroisoquinoline, 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine, pyrazolo[4,3-b]pyridine, pyrazolo[3,4-b]pyridine, pyrazolo[3,4-c]pyridine, pyrazolo[1,5-a]pyrimidine, oxazolo[4,5-b]pyridine, oxazolo[5,4-b]pyridine, thiazolo[5,4-b]pyridine, 2,1,3 -benzothiadiazole, imidazo[1,2-a]pyrimidine, or 2,3-dihydro-[1,4]dioxino[2,3-b]pyridine, 6,7-dihydro-5H-cyclopent[b]pyridine, 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole, 3,4-dihydro-2(1H)quinolinone, 2H-1,4-benzoxazin-3(4H)-one, 2-hydroxyquinoline, 3,4-dihydroisoquinolin-1(2H)-one, 1-hydroxyisoquinoline, 1,4-dihydro-3(2H)-isoquinolinone, 3H-imidazo[4,5- b]pyridine, 4,5-dihydro-7H-pyrazolo[1,5-c]1,3]oxazine, 6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine, furo[3,2-c]pyridine, furo[3,2-b]pyridine, 2,3-dihydropyrazolo[5,1-b]oxazole, 5H,6H,8H-imidazo[2,1-c][1,4]oxazine, pyrazolo[1,5-b]pyridazine, imidazo[1,2-b]pyridazine, 2,4-dihydro-1H-benzo[d][1,3]oxazine, 5-oxaspiro[2,3]hexane, imidazo[1,and optionally substituted bicyclic rings or optionally substituted bicyclic heteroaryls of 8 to 10 ring atoms containing 1, 2, 3, 4, or 5 ring heteroatoms independently selected from N, O, or S, wherein the optionally substituted bicyclic ring is optionally substituted with 1 to 3 substituents each independently selected from halogen and C1-C6 alkyl, and the optionally substituted bicyclic ring or optionally substituted bicyclic heteroaryl is selected from -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R, 11 , -CO2C1-C3 alkyl, -CONR 11 R 11 , -NR 11 R 11 , -NR 11 CO2R 11 , -NR 11 C(O)R 11 , —OH, oxetanyl, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C5 cycloalkyl, an optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine or morpholine, optionally substituted phenyl, optionally substituted 1,3-benzodioxole, optionally substituted 2,3-dihydro-1,4-benzodioxine, or pyridine, pyrimidine, pyridazine, pyrazine, pyrazole, isoxazole, iso optionally substituted with 1 to 3 substituents independently selected from thiazole, imidazole, oxazole, or optionally substituted heteroaryl selected from thiazole, and optionally substituted C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl is, respectively, -CN, -OH (e.g., optionally containing C1-C6 hydroxyalkyl such as -CH2-CH2-OH, secondary -OH such as -CH2-CH(CH3)-OH, or tertiary -OH such as -CH2-C(CH3)2-OH), oxetanyl, C1-C3 alkoxy, or -CONR 11 R 11, phenyl, or optionally substituted C3-C5 cycloalkyl, optionally substituted C3-C5 cycloalkyl, phenyl, 1,3-benzodioxole, 2,3-dihydro-1,4-benzodioxine, heterocycle, or heteroaryl is each independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -SO2R 11 , -NR 11 R 11 , —OH, or —CN; or R2 is cyclopropyl, cyclobutyl, cyclopentyl, bicyclo[1.1.1]pentyne, bicyclo[2.2.2]octyne, or cyclohexyl, each of which has 1 to 3 R 10 optionally substituted with a substituent, or R2 is a group of the formula: [ka] R2 is heterocycloalkyl, and optionally, 1 to 3 R 10 an oxetane substituted with a substituent, R3 is -H, halogen, -CN, -C(CN)=CHOH, -N(H)(C1-C3 alkyl), -N(C1-C3 alkyl)2, -N(H)(CH2CH2CO2H), -CO-C1-C3 alkyl, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C3-C5 cycloalkyl, an optionally substituted heterocycle of 3 to 5 ring atoms containing 1, 2, or 3 ring heteroatoms independently selected from N, O, or S, or an optionally substituted heteroaryl of 5 or 6 ring atoms containing 1, 2, or 3 ring heteroatoms independently selected from N, O, or S, wherein the optionally substituted heterocycle or heteroaryl is each optionally substituted with 1 to 3 substituents each independently selected from halogen, C1-C3 alkyl, or C1-C3 haloalkyl; each of R4, R5, and R6 is independently -H, halogen, -CN, C1-C6 alkyl, or C1-C6 haloalkyl; R7 is -CN, C1-C6 alkyl, CH2OH, or C1-C6 haloalkyl; R8 is —H or C1-C6 alkyl; each R9 is independently -H, halogen, -CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C3-C5 cycloalkyl; Each R 10 are independently -H, -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R 11 , -SONR 11 R 11 , -CO2H, -CO2C1-C3 alkyl, -CONR 11 R 12 , -NR 11 R 11 , -NR 11 -CO2R 11 , -NR 11 -C(O)R 11 , —OH, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C5 cycloalkyl, an optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine, or morpholine, optionally substituted phenyl, optionally substituted 1,3-benzodioxole, optionally substituted 2,3-dihydro-1,4-benzodioxine, optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole, thiazole, or pyridine, or a group of the formula: [ka] Optionally substituted C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl can be —CN, —OH (e.g., R 10is a C1-C6 hydroxyalkyl such as -CH2-CH2-OH, and optionally R 10 containing a secondary —OH such as —CH—CH(CH)—OH or a tertiary —OH such as —CH—C(CH)—OH), oxetanyl, C-C alkoxy, optionally C-C cycloalkyl, or —CONR 11 R 11 optionally substituted C3-C5 cycloalkyl, phenyl, 1,3-benzodioxole, 2,3-dihydro-1,4-benzodioxine, heterocycle, or heteroaryl is each independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -SO2R 11 , -NR 11 R 11 , —OH, or —CN; Each R 11 are independently -H, C1-C3 alkyl, C3-C7 cycloalkyl, or C1-C3 haloalkyl; Each R 12 are independently -H, optionally substituted C1-C3 alkyl, C3-C6 cycloalkyl, -SO2C1-C3 alkyl, -SO2C1-C3 haloalkyl, -SO2NR 11 R 11 , -NR 11 R 11 , -OR 11 , —O—CH—CH(OH)—CHOH, —CN, oxetane, tetrahydrofuran, aryl, a 5-membered heteroaryl optionally substituted with methyl, a 6-membered heteroaryl, or a group of the formula: [ka] the optionally substituted C1-C3 alkyl is optionally substituted with -OH, C3-C6 cycloalkyl, oxetane, tetrahydrofuran, aryl, 5-membered heteroaryl, 6-membered heteroaryl, or indole; R 13 But, -NR 11 R11 , -OR 11 , —SO2C1-C3 alkyl, or a ring selected from oxetane, tetrahydrofuran, or oxadiazole, and the ring is —NR 11 R 11 -OR 11 optionally substituted with R 14 is -H, optionally substituted C1-C3 alkyl, -SO2C1-C3 alkyl, aryl, 5-membered heteroaryl, or 6-membered heteroaryl, wherein the optionally substituted C1-C3 alkyl is optionally substituted with aryl, 5-membered heteroaryl, or 6-membered heteroaryl; R 15 is an optionally substituted aryl or an optionally substituted 6-membered heteroaryl, each of which is optionally substituted with 1 to 3 substituents independently selected from halogen, C1-C3 alkyl, or C1-C3 haloalkyl; R 16 is H, C1-C3 alkyl, —NH2, phenyl, or pyridine; n is 0, 1, or 2.

[0014] In one aspect, the present invention provides a compound of formula (I): [ka] or a pharmaceutically acceptable salt thereof, wherein R1 is an optionally substituted bicyclic ring selected from isobenzofuranone, benzofuranone, isoindolinone, indolinone, quinazolinone, 3,4-dihydro-2H-isoquinolin-1-one, 2H-isoquinolin-1-one, or benzothiazolone, wherein the optionally substituted bicyclic ring is optionally substituted with 1 to 3 substituents each independently selected from oxo, —CN, halogen, C1-C6 alkyl, C1-C6 haloalkyl, —OH, or C1-C6 alkoxy; or R1 is a group of the formula: [ka] R' is hydrogen, halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -OH, -CH(OH)-CH2OH, -CO-CH2OH, C3-C6 cycloalkyl, -NO2-N(R 11 )-CO2C1-C3 alkyl, -N(R 11 )-SO2C1-C3 alkyl, -N(R 11 )-SO2R 15 , -SO2C1-C3 alkyl, -SO2NR 11 R 11 , -SO2N(R 11 )-CO-C1-C3 alkyl, -SO2N(R 11 )-CN, -C(=N-OH)-NH2, -CN, -CONR 11 R 12 , -CON(R 11 )-(CH2) n -R 13 , -CO-SR 12 or a group of the formula: [ka] Ring A is pyrrolidine optionally substituted with -CN, or R' is selected from oxetane, pyrrolidine, tetrahydrofuran, morpholine, piperidine, piperazine, pyrrole, furan, thiophene, pyrazole, imidazole, isoxazole, oxazole, isothiazole, thiazole, triazole, oxadiazole, thiadiazole, tetrazole, phenyl, pyridine, pyridazine, pyrimidine, pyrazine, or triazine, each of which is selected from oxo, -OH, -NR 11 R 11 , -N(R 11 )-CO-R 11 , -N(R 11 )-CN, -OR 11, -CN, halogen, C1-C6 haloalkyl, or C1-C6 alkyl optionally substituted with aryl, 5-membered heteroaryl, or 6-membered heteroaryl; or R' is a group of the formula: [ka] R2 is a group of the formula: [ka] R2 is a group of the formula: [ka] R2 is an optionally substituted 5-membered heteroaryl selected from pyrrole, furan, thiophene, pyrazole, isoxazole, isothiazole, imidazole, oxazole, thiazole, triazole, tetrazole, oxadiazole, and thiadiazole, and the optionally substituted 5-membered heteroaryl is selected from -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R 11 , -CO2C1-C3 alkyl, -CONR 11 R 11 , -OH, -NR 11 R 11 , -NR 11 CO2R 11optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C5 cycloalkyl, an optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine or morpholine, optionally substituted phenyl, optionally substituted 1,3-benzodioxole, optionally substituted 2,3-dihydro-1,4-benzodioxine, or pyridine, pyrimidine, pyridazine, pyrazine, pyrazole, isoxazole, isothiazole, imidazole, oxazole or thiazole optionally substituted with 1 to 3 substituents independently selected from the selected optionally substituted heteroaryl, and optionally substituted C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl are each independently selected from -CN, -OH (e.g., optionally containing C1-C6 hydroxyalkyl such as -CH2-CH2-OH, secondary -OH such as -CH2-CH(CH3)-OH, or tertiary -OH such as -CH2-C(CH3)2-OH), halogen, oxetanyl, 2-oxabicyclo[2.1.1]hexane, C1-C3 alkoxy, optionally substituted C3-C5 cycloalkyl, -CONR 11 R 11 or -S(O)2CH3, optionally substituted C3-C5 cycloalkyl, phenyl, 1,3-benzodioxole, 2,3-dihydro-1,4-benzodioxine, heterocycle, or heteroaryl is each independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -SO2R 11 , -NR 11 R 11 , —OH, or —CN; or R2 is 1,3-benzodioxole, 2,3-dihydro-1,4-benzodioxine, quinoxaline, quinazoline, indole, indazole, isoindazole, benzimidazole, benzotriazole, benzothiazole, benzoxazole, benzotriazole, benzofuran, benzofurazan, pyridofurazan, quinoline, 1,5-naphthyridine, isoindolin-1-one, indolin-2-one, benzomorpholine, benzo[d]oxazol-2(3H)-one, imidazo[1,2-a]pyridine, 1,3-dihydro-2H- Pyrrolo[2,3-b]pyridin-2-one, [1,3]dioxolo[4,5-b]pyridine, 6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine, 1,2,3,4-tetrahydroisoquinoline, 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine, pyrazolo[4,3-b]pyridine, pyrazolo[3,4-b]pyridine, pyrazolo[3,4-c]pyridine, pyrazolo[1,5-a]pyrimidine, oxazolo[4,5-b]pyridine, oxazolo[5,4-b]pyridine, thiazolo[5,4-b]pyridine, 2,1,3 -benzothiadiazole, imidazo[1,2-a]pyrimidine, or 2,3-dihydro-[1,4]dioxino[2,3-b]pyridine, 6,7-dihydro-5H-cyclopent[b]pyridine, 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole, 3,4-dihydro-2(1H)quinolinone, 2H-1,4-benzoxazin-3(4H)-one, 2-hydroxyquinoline, 3,4-dihydroisoquinolin-1(2H)-one, 1-hydroxyisoquinoline, 1,4-dihydro-3(2H)-isoquinolinone, 3H-imidazo[4,5- b]pyridine, 4,5-dihydro-7H-pyrazolo[1,5-c]1,3]oxazine, 6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine, furo[3,2-c]pyridine, furo[3,2-b]pyridine, 2,3-dihydropyrazolo[5,1-b]oxazole, 5H,6H,8H-imidazo[2,1-c][1,4]oxazine, pyrazolo[1,5-b]pyridazine, imidazo[1,2-b]pyridazine, 2,4-dihydro-1H-benzo[d][1,3]oxazine, 5-oxaspiro[2,3]hexane, imidazo[1,or an optionally substituted bicyclic heteroaryl of 8 to 10 ring atoms containing 1, 2, 3, 4, or 5 ring heteroatoms independently selected from N, O, or S, wherein the optionally substituted bicyclic ring is optionally substituted with 1 to 3 substituents each independently selected from halogen and C1-C6 alkyl, or the optionally substituted bicyclic ring or optionally substituted bicyclic heteroaryl is selected from -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R, 11 , -CO2C1-C3 alkyl, -CONR 11 R 11 , -NR 11 R 11 , -NR 11 CO2R 11 , -NR 11 C(O)R 11 , —OH, oxetanyl, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C5 cycloalkyl, an optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine or morpholine, optionally substituted phenyl, optionally substituted 1,3-benzodioxole, optionally substituted 2,3-dihydro-1,4-benzodioxine, or pyridine, pyrimidine, pyridazine, pyrazine, pyrazole, isoxazole, iso optionally substituted with 1 to 3 substituents independently selected from thiazole, imidazole, oxazole, or optionally substituted heteroaryl selected from thiazole, and optionally substituted C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl is, respectively, -CN, -OH (e.g., optionally containing C1-C6 hydroxyalkyl such as -CH2-CH2-OH, secondary -OH such as -CH2-CH(CH3)-OH, or tertiary -OH such as -CH2-C(CH3)2-OH), oxetanyl, C1-C3 alkoxy, or -CONR 11 R 11, phenyl, or optionally substituted C3-C5 cycloalkyl, optionally substituted C3-C5 cycloalkyl, phenyl, 1,3-benzodioxole, 2,3-dihydro-1,4-benzodioxine, heterocycle, or heteroaryl is each independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -SO2R 11 , -NR 11 R 11 , —OH, or —CN; or R2 is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, each of which has 1 to 3 R 10 optionally substituted with a substituent, or R2 is a group of the formula: [ka] R3 is -H, halogen, -CN, -N(H)(C1-C3 alkyl), -N(C1-C3 alkyl)2, -N(H)(CH2CH2CO2H), -CO-C1-C3 alkyl, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C3-C5 cycloalkyl, an optionally substituted heterocycle of 3 to 5 ring atoms containing 1, 2, or 3 ring heteroatoms independently selected from N, O, or S, or an optionally substituted heteroaryl of 5 or 6 ring atoms containing 1, 2, or 3 ring heteroatoms independently selected from N, O, or S, wherein the optionally substituted heterocycle or heteroaryl is each optionally substituted with 1 to 3 substituents each independently selected from halogen, C1-C3 alkyl, or C1-C3 haloalkyl; each of R4, R5, and R6 is independently -H, halogen, C1-C6 alkyl, or C1-C6 haloalkyl; R7 is -CN, C1-C6 alkyl, or C1-C6 haloalkyl; R8 is —H or C1-C6 alkyl; each R9 is independently -H, halogen, -CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C3-C5 cycloalkyl; Each R 10 are independently -H, -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R 11 , -SONR 11 R 11 , -CO2H, -CO2C1-C3 alkyl, -CONR 11 R 12 , -NR 11 R 11 , -NR 11 -CO2R 11 , —OH, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C5 cycloalkyl, an optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine, or morpholine, optionally substituted phenyl, optionally substituted 1,3-benzodioxole, optionally substituted 2,3-dihydro-1,4-benzodioxine, optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole, thiazole, or pyridine, or a group of the formula: [ka] Optionally substituted C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl can be —CN, —OH (e.g., R 10 is a C1-C6 hydroxyalkyl such as -CH2-CH2-OH, optionally containing a secondary -OH such as -CH2-CH(CH3)-OH or a tertiary -OH such as -CH2-C(CH3)2-OH), oxetanyl, C1-C3 alkoxy, or -CONR 11 R 11optionally substituted C3-C5 cycloalkyl, phenyl, 1,3-benzodioxole, 2,3-dihydro-1,4-benzodioxine, heterocycle, or heteroaryl is each independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -SO2R 11 , -NR 11 R 11 , —OH, or —CN; Each R 11 are independently —H or C1-C3 alkyl; Each R 12 are independently -H, optionally substituted C1-C3 alkyl, C3-C6 cycloalkyl, -SO2C1-C3 alkyl, -SO2C1-C3 haloalkyl, -SO2NR 11 R 11 , -NR 11 R 11 , -OR 11 , —O—CH—CH(OH)—CHOH, —CN, oxetane, tetrahydrofuran, aryl, a 5-membered heteroaryl optionally substituted with methyl, a 6-membered heteroaryl, or a group of the formula: [ka] the optionally substituted C1-C3 alkyl is optionally substituted with -OH, C3-C6 cycloalkyl, oxetane, tetrahydrofuran, aryl, 5-membered heteroaryl, 6-membered heteroaryl, or indole; R 13 But, -NR 11 R 11 , -OR 11 , —SO2C1-C3 alkyl, or a ring selected from oxetane, tetrahydrofuran, or oxadiazole, and the ring is —NR 11 R 11 -OR 11 optionally substituted with R 14is -H, optionally substituted C1-C3 alkyl, -SO2C1-C3 alkyl, aryl, 5-membered heteroaryl, or 6-membered heteroaryl, wherein the optionally substituted C1-C3 alkyl is optionally substituted with aryl, 5-membered heteroaryl, or 6-membered heteroaryl; R 15 is an optionally substituted aryl or an optionally substituted 6-membered heteroaryl, each of which is optionally substituted with 1 to 3 substituents independently selected from halogen, C1-C3 alkyl, or C1-C3 haloalkyl; n is 0, 1, or 2.

[0015] In one embodiment, the compound of formula (I) is represented by an asterisk ( * ) may contain an asymmetric carbon atom at the position indicated by . [ka]

[0016] In one aspect, R7 is methyl and R8 is hydrogen; * The bond of position is [ka] It can be expressed as:

[0017] In a further embodiment, the compound of formula (I) where R8 is H has the formula (II): [ka] wherein R1, R2, R3, R4, R5, R6, and R7 are as defined in the Summary for formula (I).

[0018] In a further embodiment, the compound of formula (I) or (II) has formula (III), or a pharmaceutically acceptable salt thereof: [ka] wherein R1, R2, R3, R5, R6, and R7 are as defined in the Summary for formula (I) above.

[0019] In a further embodiment, the compound of formula (I), (II) or (III) has formula (IV), or a pharmaceutically acceptable salt thereof: [ka] where R1 and R2 are as defined in the summary for formula (I) above.

[0020] In one aspect, the disclosed compounds include an R' group that is not -COOH.

[0021] In one embodiment, the compounds of the present disclosure include an R2 group bonded to the chromenone core of the compound through a ring carbon atom of R2, also referred to as a "C-linked R2 group." In one embodiment, the compounds of the present disclosure include an R2 group that is an aryl group bonded to the chromenone core through a ring carbon atom of R2. In one embodiment, the compounds of the present disclosure include an R2 group that is a heteroaryl group bonded to the chromenone core through a ring carbon atom of R2. In one embodiment, the compounds of the present disclosure include an R2 group that is a bicyclic heteroaryl group bonded to the chromenone core through a ring carbon atom of R2. In one embodiment, the compounds of the present disclosure include an R2 group that is a cycloalkyl group bonded to the chromenone core of the compound through a ring carbon atom of R2.

[0022] In one aspect, the disclosed compounds can have one or more activities disclosed herein.

[0023] In one aspect, the disclosed compounds can inhibit the activity of PI3K-α kinase and can be characterized as having (PIK3CA) inhibitory activity. In one aspect, the disclosed compounds can inhibit the activity of wild-type PIK3CA. In one aspect, the disclosed compounds can inhibit the activity of mutant PIK3CA having one or more amino acid substitutions, deletions, or insertions compared to the amino acid sequence of wild-type PIK3CA. In one aspect, the disclosed compounds can selectively inhibit the activity of mutant PI3KCA compared to wild-type PI3KCA.

[0024] In one embodiment, the disclosed compounds can exhibit metabolic stability as measured in one or more in vitro clearance assays disclosed herein.

[0025] In one aspect, the disclosed compounds do not induce expression of cytochrome P450 enzymes in an in vitro assay compared to a control or vehicle, or the compounds induce expression of cytochrome P450 enzymes at a relatively low level in an in vitro assay compared to a control or vehicle.

[0026] In one aspect, the disclosed compounds inhibit the activity of PI3K alpha and do not cause adverse events (AEs), such as hyperglycemia, hyperinsulinemia, and diarrhea, when the compounds are administered at doses effective to treat diseases or disorders associated with PI3K alpha activity.

[0027] In one embodiment, the disclosed compounds do not exhibit substantial inhibitory activity against kinases other than PI3K alpha.

[0028] In another aspect, the present invention provides a pharmaceutical composition comprising a compound of Formula (I), (II), (III), or (IV), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent or carrier.

[0029] In another aspect, the present invention provides a method for modulating PI3K (e.g., PI3K α(H1047R) or PI3K α(E545K)) activity (e.g., in vitro or in vivo), comprising contacting a cell with a therapeutically effective amount of a compound of Formula (I), (II), (III), or (IV) or a pharmaceutically acceptable salt thereof.

[0030] In some aspects, the present invention provides methods 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), (II), (III), or (IV), or a pharmaceutically acceptable salt thereof. In some aspects, the compound of Formula (I), (II), (III), or (IV) is for first-line administration. In some aspects, the compound of Formula (I), (II), (III), or (IV) is for second-line administration. In some aspects, the compound of Formula (I), (II), (III), or (IV) is for third-line administration.

[0031] In some aspects, the present invention provides methods 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), (II), (III), or (IV), or a pharmaceutically acceptable salt thereof. In some aspects, the pharmaceutical composition of a compound of Formula (I), (II), (III), or (IV) is for first-line administration. In some aspects, the pharmaceutical composition of a compound of Formula (I), (II), (III), or (IV) is for second-line administration. In some aspects, the pharmaceutical composition of a compound of Formula (I), (II), (III), or (IV) is for third-line administration.

[0032] In some aspects, the present invention provides methods 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), (II), (III), or (IV), or a pharmaceutically acceptable salt thereof. In some aspects, the compound of Formula (I), (II), (III), or (IV) is administered as a first-line therapy. In some aspects, the compound of Formula (I), (II), (III), or (IV) is administered as a second-line therapy. In some aspects, the compound of Formula (I), (II), (III), or (IV) is administered as a third-line therapy.

[0033] In another aspect, the present invention provides a compound of Formula (I), (II), (III), or (IV), or a pharmaceutically acceptable salt thereof, for use in therapy. In some aspects, a compound of Formula (I), (II), (III), or (IV) is used in first-line therapy. In some aspects, a compound of Formula (I), (II), (III), or (IV) is used in second-line therapy. In some aspects, a compound of Formula (I), (II), (III), or (IV) is used in third-line therapy.

[0034] In another aspect, the invention provides a compound of Formula (I), (II), (III), or (IV) or a pharmaceutically acceptable salt thereof for use in modulating PI3K (e.g., PI3K α(H1047R) or PI3K α(E545K)) activity (e.g., in vitro or in vivo).

[0035] In another aspect, the present invention provides a compound of formula (I), (II), (III), or (IV), or a pharmaceutically acceptable salt thereof, for use in the selective inhibition of mutant PI3K α over wild-type PI3K α.

[0036] In another aspect, the present invention provides a compound of formula (I), (II), (III), or (IV), or a pharmaceutically acceptable salt thereof, for use in selectively inhibiting PI3Kα (H1047R mutant) over wild-type PI3Kα.

[0037] In another aspect, the present invention provides a compound of formula (I), (II), (III), or (IV), or a pharmaceutically acceptable salt thereof, for use in selectively inhibiting mutant PI3Kα (E545K mutant) over wild-type PI3Kα.

[0038] In another aspect, the present invention provides a compound of Formula (I), (II), (III), or (IV), 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), (II), (III), or (IV) is for first-line administration. In some aspects, the compound of Formula (I), (II), (III), or (IV) is for second-line administration. In some aspects, the compound of Formula (I), (II), (III), or (IV) is for third-line administration.

[0039] In another aspect, the present invention provides a compound of Formula (I), (II), (III), or (IV), or a pharmaceutically acceptable salt thereof, for use in treating a disease or disorder disclosed herein. In some aspects, the compound of Formula (I), (II), (III), or (IV) is used as a first line treatment. In some aspects, the compound of Formula (I), (II), (III), or (IV) is used as a second line treatment. In some aspects, the compound of Formula (I), (II), (III), or (IV) is used as a third line treatment.

[0040] In another aspect, the invention provides the use of a compound of Formula (I), (II), (III), or (IV) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for modulating PI3K (e.g., PI3Kα(H1047R) or PI3Kα(E545K)) activity (e.g., in vitro or in vivo).

[0041] In another aspect, the present invention provides the use of a compound of Formula (I), (II), (III), or (IV), 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.

[0042] In another aspect, the present invention provides the use of a compound of Formula (I), (II), (III), or (IV), 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 as a first line treatment. In some aspects, the medicament is used as a second line treatment. In some aspects, the medicament is used as a third line treatment.

[0043] In another aspect, the present invention provides a method for preparing a compound of formula (I), (II), (III), or (IV) or a pharmaceutically acceptable salt thereof.

[0044] In another aspect, the present invention provides a process for preparing a compound of Formula (I), (II), (III), or (IV) or a pharmaceutically acceptable salt thereof, comprising one or more steps as described herein.

[0045] In another aspect, the invention provides compounds obtainable by or obtained by the processes for preparing the compounds described herein.

[0046] In another aspect, the present invention provides an intermediate described herein that is suitable for use in a process for preparing a compound described herein (e.g., the intermediate is selected from the intermediates described in the Examples).

[0047] Other features and advantages of the invention will become apparent from the following detailed description and claims. DETAILED DESCRIPTION OF THE INVENTION

[0048] The present invention provides methods for treating, preventing, or ameliorating (or uses in treating, preventing, or ameliorating) diseases or disorders in which PI3K plays a role by administering to a patient in need thereof a therapeutically effective amount of a PI3K inhibitor of the present invention. The methods (or uses) of the present invention can be used to treat a variety of PI3K-dependent diseases and disorders.

[0049] In some embodiments, the disorder is 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 carcinoma, 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, non-clear cell renal cell carcinoma, clear cell renal cell carcinoma, germ cell carcinoma, thymic tumor, pheochromocytoma, heterogeneous neuroepithelial tumor, thyroid cancer, leukemia, or encapsulated glioma.

[0050] Details of the present invention are described 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, exemplary methods and materials are now described. Other features, objects, and advantages of the present invention will be apparent from the description and claims. In this specification and the appended claims, the singular forms include the plural forms unless the context clearly dictates otherwise. Unless otherwise defined, 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 herein are incorporated by reference in their entirety.

[0051] definition The articles "a" and "an" refer to one or to more than one (i.e., 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.

[0052] The term "and / or" means either "and" or "or" unless otherwise indicated.

[0053] The terms "administer," "administering," or "administration" refer to either administering a disclosed compound, or a pharmaceutically acceptable salt of a disclosed compound, or composition directly to a subject.

[0054] The term "alkenyl" refers to a straight- or branched-chain unsaturated hydrocarbon containing 2 to 12 carbon atoms. An "alkenyl" group contains at least one double bond in the chain. The double bond of an alkenyl group can be unconjugated or conjugated to another unsaturated group. Examples of alkenyl groups include ethenyl, propenyl, n-butenyl, iso-butenyl, pentenyl, or hexenyl.

[0055] The term "alkoxy" refers to a straight or branched chain saturated hydrocarbon containing 1 to 12 carbon atoms containing a terminal "O" in the chain, i.e., -O(alkyl). Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, t-butoxy, or pentoxy groups.

[0056] The term "alkyl" refers to a straight or branched chain saturated hydrocarbon containing 1 to 12 carbon atoms, preferably 1 to 6 carbon atoms. Examples of C1-C6 alkyl groups include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, neopentyl, and isohexyl.

[0057] The term "alkynyl" refers to a straight- or branched-chain unsaturated hydrocarbon containing 2 to 12 carbon atoms. An "alkynyl" group contains at least one triple bond in the chain. Examples of alkynyl groups include ethynyl, propargyl, n-butynyl, iso-butynyl, pentynyl, or hexynyl.

[0058] For example, the terms "alkenyl," "alkoxy," "alkyl," "alkynyl," "haloalkyl," "haloalkoxy," and "cycloalkyl" can be further defined by the number of carbons they contain, e.g., the term "C1-C6 alkoxy" is understood to refer to an alkoxy group, as defined above, containing from 1 to 6 carbon atoms.

[0059] The term "hydroxyalkyl" refers to an alkyl group, which may be straight or branched, having one or more hydrogen atoms replaced with a hydroxyl group. For example, "hydroxyalkyl" includes hydroxyethyl, 2-hydroxypropyl, and 1,2-dihydroxybutyl. The hydroxyl group of a hydroxyalkyl is one in which the hydroxyl group is (-CH2) 1-6It may be a primary hydroxyl group covalently bonded to a carbon atom that is bonded to two hydrogen atoms, such as in -OH. The hydroxyl group of a hydroxyalkyl is one in which the hydroxyl group is (-CH2) 1-6 It may also be a secondary hydroxyl group covalently bonded to a carbon atom bonded to a methyl group and a hydrogen atom, as in -CH(CH)-OH. The hydroxyl group of a hydroxyalkyl is (-CH) 1-6 It may also be a tertiary hydroxyl group, in which the hydroxyl group is covalently bonded to a carbon atom bonded to two methyl groups, as in -C(CH3)2-OH. Alkyl groups containing a primary hydroxyl, a secondary hydroxyl, and a tertiary hydroxyl are each [ka] It can be expressed as:

[0060] The term "aromatic" refers to a planar ring with 4n+2 electrons in a conjugated system. As used herein, "conjugated system" refers to a bonding p-orbital system with delocalized electrons, which may include lone pairs.

[0061] The term "aryl," unless otherwise defined, refers to a cyclic aromatic hydrocarbon group having one to three aromatic rings, including monocyclic or bicyclic groups such as phenyl, biphenyl, or naphthyl. When containing two aromatic rings (e.g., bicyclic), the aromatic rings of the aryl group can be joined at a single point (e.g., biphenyl) or fused (e.g., naphthyl). Furthermore, when containing two fused rings, an aryl group as defined herein can have one or more saturated or partially unsaturated rings fused to a fully unsaturated aromatic ring. Exemplary ring systems of these aryl groups include, but are not limited to, phenyl, biphenyl, naphthyl, anthracenyl, phenalenyl, phenanthrenyl, indanyl, indenyl, tetrahydronaphthalenyl, and tetrahydrobenzoannurenyl.

[0062] The term "carrier" encompasses carriers, excipients, and diluents and means a material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material, that is involved in carrying or transporting a pharmaceutical agent from one organ or part of the body to another organ or part of the body of a subject.

[0063] The term "cyano" refers to a substituent having a carbon atom attached to a nitrogen atom by a triple bond, i.e., C≡N.

[0064] The term "cycloalkyl" means a monocyclic or polycyclic saturated carbocyclic ring containing 3 to 18 carbon atoms, preferably 3 to 10 carbon atoms. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptanyl, cyclooctanyl, norbornyl, norborenyl, bicyclo[2.2.2]octanyl, and bicyclo[2.2.2]octenyl.

[0065] The term "disorder" means, and is used interchangeably with, the terms disease, condition, or illness, unless otherwise indicated.

[0066] The term "haloalkoxy" refers to an alkoxy group, as defined herein, that is substituted with one or more halogens. Examples of haloalkoxy groups include, but are not limited to, trifluoromethoxy, difluoromethoxy, pentafluoroethoxy, and trichloromethoxy.

[0067] The term "haloalkyl" refers to an alkyl group, as defined herein, that is substituted with one or more halogens. Examples of haloalkyl groups include, but are not limited to, trifluoromethyl, difluoromethyl, pentafluoroethyl, and trichloromethyl.

[0068] The term "halogen" or "halo" refers to fluorine, chlorine, bromine, or iodine.

[0069] The term "heteroaryl," unless otherwise defined, refers to a monovalent monocyclic or polycyclic aromatic radical of 5 to 24 ring atoms, preferably 5 to 10 ring atoms, containing one or more ring heteroatoms selected from N, O, S, P, or B, preferably 1, 2, 3, or 4 ring heteroatoms selected from N, O, or S, with the remaining ring atoms being C. Polycyclic aromatic radicals contain two or more fused rings and may further contain two or more spiro-fused rings (e.g., bicyclic, tricyclic, tetracyclic, etc.). Unless specifically defined otherwise, "fused" means two rings that share two ring atoms. Unless specifically defined otherwise, "spiro-fused" means two rings that share one ring atom. Heteroaryl, as defined herein, also refers to bicyclic heteroaromatic groups in which the heteroatoms are selected from N, O, S, P, or B, preferably N, O, or S. Heteroaryl, as defined herein, also refers to a tricyclic heteroaromatic group containing one or more ring heteroatoms selected from N, O, S, P, or B, preferably N, O, or S. Heteroaryl, as defined herein, also refers to a tetracyclic heteroaromatic group containing one or more ring heteroatoms selected from N, O, S, P, or B, preferably N, O, or S. Examples of heteroaromatic groups include, but are not limited to, furyl, thienyl, pyrrolyl, pyridyl, pyrazolyl, pyrimidinyl, imidazolyl, isoxazolyl, oxazolyl, oxadiazolyl, pyrazinyl, indolyl, thiophen-2-yl, quinolyl, benzopyranyl, isothiazolyl, thiazolyl, thiadiazole, indazole, benzimidazolyl, thieno[3,2-b]thiophene, triazolyl, triazinyl, imidazo[1,2-b]pyrazolyl, furo[2,3-c]pyridinyl, imidazo[1,2-a]pyridinyl, indazolyl, pyrrolo[2,3-c]pyridinyl, pyrrolo[3,2-c]pyridinyl, pyrazolo[3,4-c]pyridinyl, thieno[3,2-c]pyridinyl, thieno[2,3-c]pyridinyl, thieno[2,3-b]pyridinyl, benzothiazolyl, indolinyl, indolinonyl, dihydrobenzothiophenyl, dihydrobenzofuranyl, benzofuranyl, chromanyl, thiochromanyl, tetrahydroquinolinyl, dihydrobenzothiazinyl, quinolinyl, isoquinolinyl, 1,6-naphthyridinyl, benzo[de]isoquinolinyl, pyrido[4,3-b][1,6]naphthyridinyl, thieno[2,3-b]pyrazinyl, quinazolinyl, tetrazolo[1 ,5-a]pyridinyl, [1,2,4]triazolo[4,3-a]pyridinyl, isoindolyl, pyrrolo[2,3-b]pyridinyl, pyrrolo[3,4-b]pyridinyl, pyrrolo[3,2-b]pyridinyl, imidazo[5,4-b]pyridinyl, pyrrolo[1,2-a]pyrimidinyl, tetrahydropyrrolo[1,2-a]pyrimidinyl, 3,4-dihydro-2H-1-pyrrolo[2,1-b]pyrimidine, dibenzo[b,d]thiophene, pyridin-2-one furo[3,2-c]pyridinyl, furo[2,3-c]pyridinyl, 1H-pyrido[3,4-b][1,4]thiazinyl, benzoxazolyl, benzisoxazolyl, furo[2,3-b]pyridinyl, benzothiophenyl, 1,5-naphthyridinyl, furo[3,2-b]pyridine, [1,2,4]triazolo[1,5-a]pyridinyl, benzo[1,2,3]triazolyl, imidazo[1,2-a]pyrimidinyl, [1,2,4]triazolo [4,3-b]pyridazinyl, benzo[c][1,2,5]thiadiazolyl, benzo[c][1,2,5]oxadiazole, 1,3-dihydro-2H-benzo[d]imidazol-2-one, 3,4-dihydro-2H-pyrazolo[1,5-b][1,2]oxazinyl, 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridinyl, thiazolo[5,4-d]thiazolyl, imidazo[2,1-b][1,3,4]thiadiazolyl, thieno[2,

[0023] 3-b]pyrrolyl, and 3H-indolyl. Furthermore, when containing two or more fused rings, the heteroaryl groups defined herein can have one or more saturated or partially unsaturated rings fused with one or more fully unsaturated aromatic rings. In heteroaryl ring systems containing three or more fused rings, the saturated or partially unsaturated rings can be further fused with a saturated or partially unsaturated ring as described herein. Furthermore, when containing three or more fused rings, the heteroaryl groups defined herein can have one or more spiro-fused saturated or partially unsaturated rings. Any saturated or partially unsaturated ring as described herein is optionally substituted with one or more oxo. Exemplary ring systems of these heteroaryl groups include, for example, indolinyl, indolinonyl, dihydrobenzothiophenyl, dihydrobenzofuran, chromanyl, thiochromanyl, tetrahydroquinolinyl, dihydrobenzothiazine, 3,4-dihydro-1H-isoquinolinyl, 2,3-dihydrobenzofuranyl, benzofuranonyl, oxindolyl, indolyl, 1,6-dihydro-7H-pyrazolo[3,4-c]pyridin-7-onyl, 7,8-dihydro-6H-pyrido[3,2-b]pyrrolidinyl, 8H-pyrido[3,2-b]pyrrolidinyl, 1,5,6,7-tetrahydrocyclopenta[b]pyrazo 4,3-e]pyridinyl, 7,8-dihydro-6H-pyrido[3,2-b]pyrrolidinyl, pyrazolo[1,5-a]pyrimidin-7(4H)-onyl, 3,4-dihydropyrazino[1,2-a]indol-1(2H)-onyl, benzo[c][1,2]oxaborol-1(3H)-olyl, 6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-onyl, and 6a',7'-dihydro-6'H,9'H-spiro[cyclopropane-1,8'-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin]-9'-onyl.

[0070] The term "5-membered heteroaryl," unless otherwise defined, means a monovalent monocyclic aromatic group of 5 ring atoms containing one or more ring heteroatoms selected from N, O, S, P, or B, preferably 1, 2, 3, or 4 ring heteroatoms selected from N, O, or S, with the remaining ring atoms being C. Exemplary 5-membered heteroaryl groups include, but are not limited to, furyl, thiophenyl, pyrrolyl, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, oxadiazolyl, isothiazolyl, thiazolyl, thiadiazole, triazolyl, and tetrazolyl.

[0071] The term "6-membered heteroaryl," unless otherwise defined, means a monovalent monocyclic aromatic group of 6 ring atoms containing one or more ring heteroatoms selected from N, O, S, P, or B, preferably 1, 2, 3, or 4 ring heteroatoms selected from N, O, or S, with the remaining ring atoms being C. Exemplary 6-membered heteroaryl groups include, but are not limited to, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, or triazinyl.

[0072] The terms "heterocyclyl," "heterocycle," or "heterocycloalkyl" mean a monocyclic or polycyclic ring containing 3 to 24 atoms, preferably 3 to 10 atoms, including carbon, and one or more heteroatoms selected from N, O, S, P, or B, preferably 1, 2, 3, or 4 heteroatoms selected from N, O, and S, and wherein the ring is not aromatic. Examples of heterocyclyl rings include, but are not limited to, oxetanyl, azetidinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, oxazolinyl, oxazolidinyl, thiazolinyl, thiazolidinyl, pyranyl, thiopyranyl, tetrahydropyranyl, dioxalinyl, piperidinyl, morpholinyl, thiomorpholinyl, thiomorpholinyl S-oxide, thiomorpholinyl S-dioxide, piperazinyl, azepinyl, oxepinyl, diazepinyl, tropanyl, oxazolidinonyl, and homotropanyl.

[0073] The term "isomer" refers to compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the spatial arrangement of their atoms. Isomers that differ in the spatial arrangement of their atoms are called "stereoisomers." Stereoisomers that are not mirror images of each other are called "diastereomers," and stereoisomers that are non-superimposable mirror images of each other are called "enantiomers." When a compound has an asymmetric center, for example, when a compound is bonded to four different groups, a pair of enantiomers is possible. Enantiomers can be characterized by the absolute configuration of their asymmetric center and described by the R and S ordering rules of Cahn and Prelog, or by the way the molecule rotates the plane of polarized light and is designated as dextrorotatory or levorotatory (i.e., as (+) or (-)-isomers, respectively). Chiral compounds can exist as either individual enantiomers or as mixtures thereof. A mixture containing equal proportions of enantiomers is called a "racemic mixture."

[0074] The terms "modulate," "modulation," or "modulating" refer to the biological activity of a compound or substrate that inhibits and / or activates PI3K.

[0075] The term "patient" or "subject" refers to a mammal, such as a human, mouse, rat, guinea pig, dog, cat, horse, cow, pig, or non-human primate such as a monkey, chimpanzee, baboon, or rhesus monkey. Preferably, the mammal is a human.

[0076] The term "therapeutically effective amount" when used in reference to a compound refers to an amount or dose of a compound that, upon administration to a patient in single or multiple doses, produces the desired effect in a patient being diagnosed or treated. An effective amount can be determined by one skilled in the art by using known techniques and observing results obtained under similar circumstances. In determining the effective amount for a patient, the attending physician will consider several factors, including, but not limited to, the patient's species; its size, age, and general health; the specific disease or disorder involved; the extent or involvement or severity of the disease or disorder; the individual patient's response; the specific compound administered; the mode of administration, the bioavailability characteristics of the administered formulation, the selected dosing regimen; the use of concomitant medications; and other relevant circumstances.

[0077] The term "treating" with respect to a subject includes inhibiting, slowing, arresting, or reversing the progression or severity of an existing condition or disorder.

[0078] Compounds of the Invention In one aspect, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt thereof: [ka] wherein R1, R2, R3, R4, R5, R6, R7, and R8 are as defined in the Summary for formula (I).

[0079] In the compounds of formula (I) or pharmaceutically acceptable salts thereof, R8 is -H.

[0080] In a further embodiment, the compound of formula (I) where R8 is -H has the formula (II): [ka] wherein R1, R2, R3, R4, R5, R6, and R7 are as defined in the Summary for formula (I).

[0081] In still further compounds of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R4 is -H or halogen. Preferably, R4 is -H.

[0082] In a further embodiment, the compound of formula (I) or (II) has formula (III), or a pharmaceutically acceptable salt thereof: [ka] wherein R1, R2, R3, R5, R6, and R7 are as defined in the Summary for formula (I) above.

[0083] In a further embodiment, the compound of Formula (I), (II), or (III) is represented by Formula (IV), or a pharmaceutically acceptable salt thereof: [ka] where R1 and R2 are as defined in the summary for formula (I) above.

[0084] In still further compounds of formula (I), (II), or (III) or pharmaceutically acceptable salts thereof, R3 is -H, halogen, -CN, C1-C6 alkyl, or C1-C6 haloalkyl, oxetane, oxazole, or isoxazole. Preferably, R3 is -H, -CN, C1-C3 alkyl, or C1-C3 haloalkyl. More preferably, R3 is -H, -CN, methyl, or trifluoromethyl. More preferably, R3 is -H or methyl.

[0085] In still further compounds of formula (I), (II), or (III) or a pharmaceutically acceptable salt thereof, R5 is -H, halogen, C1-C3 alkyl, or C1-C3 haloalkyl. Preferably, R5 is -H, halogen, methyl, or trifluoromethyl.

[0086] In still further compounds of Formula (I), (II), or (III) or a pharmaceutically acceptable salt thereof, R6 is -H or halogen.

[0087] In still further compounds of formula (I), (II), or (III) or pharmaceutically acceptable salts thereof, R7 is -CN, C1-C3 alkyl, or C1-C3 haloalkyl. Preferably, R7 is -CN, methyl, or trifluoromethyl. More preferably, R7 is methyl.

[0088] In still further compounds of Formula (I), (II), (III), or (IV) or pharmaceutically acceptable salts thereof, R1 is an optionally substituted bicyclic ring selected from isobenzofuranone, benzofuranone, isoindolinone, indolinone, quinazolinone, or benzothiazolone, wherein the optionally substituted bicyclic ring is optionally substituted with 1 to 3 substituents each independently selected from oxo, —CN, halogen, C1-C6 alkyl, C1-C6 haloalkyl, —OH, or C1-C6 alkoxy; In still further compounds of formula (I), (II), (III), or (IV) or a pharmaceutically acceptable salt thereof, R 1 is a group of the formula: [ka]

[0089] In still further compounds of formula (I), (II), (III), or (IV) or a pharmaceutically acceptable salt thereof, R 1 is a group of the formula: [ka]

[0090] In still further compounds of formula (I), (II), (III), or (IV) or a pharmaceutically acceptable salt thereof, each R9 is independently H, halogen, C1-C3 alkyl, or C3-C5 cycloalkyl, preferably each R9 is independently H, halogen, methyl, or cyclopropyl.

[0091] In still further compounds of Formula (I), (II), (III), or (IV) or a pharmaceutically acceptable salt thereof, each R9 is independently -H, halogen, C1-C3 alkyl, or C1-C3 alkoxy.

[0092] Further compounds of formula (I), (II), (III), or (IV) or pharmaceutically acceptable salts thereof, wherein R' is C1-C3 haloalkyl, C1-C3 alkoxy, -NO2, -N(R 11 )-CO2C1-C3 alkyl, -N(R 11 )-SO2C1-C3 alkyl, -SO2NR 11 R 11 , -SO2N(R 11 )-CO-C1-C3 alkyl, -C(=N-OH)-NH2, -CN, -CONR 11 R 12 , -CON(R 11 )-(CH2) n -R 13 or [ka] Ring A is pyrrolidine optionally substituted with -CN.

[0093] In still further compounds of Formula (I), (II), (III), or (IV) or a pharmaceutically acceptable salt thereof, R is selected from: [ka] wherein R9 is selected from hydrogen and halogen.

[0094] In still further compounds of Formula (I), (II), (III), or (IV) or a pharmaceutically acceptable salt thereof, R 1 is selected from the following: [ka]

[0095] In still further compounds of Formula (I), (II), (III), or (IV), or a pharmaceutically acceptable salt thereof, R is not —COOH.

[0096] Further compounds of formula (I), (II), (III), or (IV) or pharmaceutically acceptable salts thereof, wherein R' is C1-C3 haloalkyl, C1-C3 alkoxy, -NO2, -N(R 11 )-CO2C1-C3 alkyl, -N(R 11 )-SO2C1~C3 alkyl, -SO2NR 11 R 11 , -SO2N(R 11 )-CO-C1-C3 alkyl, -C(=N-OH)-NH2, -CN, -CONR 11 R 12 , -CON(R 11 )-(CH2) n -R 13 or [ka] Ring A is pyrrolidine optionally substituted with -CN.

[0097] In still further compounds of Formula (I), (II), (III), or (IV) or a pharmaceutically acceptable salt thereof, R' is selected from oxetane, pyrrolidine, tetrahydrofuran, pyrrole, furan, thiophene, pyrazole, imidazole, isoxazole, oxazole, isothiazole, thiazole, triazole, oxadiazole, thiadiazole, tetrazole, pyridine, pyridazine, pyrimidine, pyrazine, or triazine, each of which is selected from oxo, -NR 11 R 11 , -OR 11, -CN, C1-C6 haloalkyl, or C1-C6 alkyl optionally substituted with phenyl.

[0098] In still further compounds of Formula (I), (II), (III), or (IV) or a pharmaceutically acceptable salt thereof, R' is pyrrole, furan, thiophene, pyrazole, isoxazole, oxazole, isothiazole, thiazole, imidazole, triazole, oxadiazole, thiadiazole, tetrazole, pyridine, pyridazine, pyrimidine, pyrazine, or triazine, each of which may be selected from the group consisting of oxo, -NR 11 R 11 , -OR 11 or C1-C6 alkyl optionally substituted with aryl.

[0099] In still further compounds of formula (I), (II), (III), or (IV) or a pharmaceutically acceptable salt thereof, R' is hydrogen, halogen, C1-C3 alkyl, or C3-C6 cycloalkyl, preferably R' is hydrogen, halogen, or methyl.

[0100] Further compounds of formula (I), (II), (III), or (IV) or pharmaceutically acceptable salts thereof, wherein R' is hydrogen, halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 hydroxyalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -OH, -CH(OH)-CH2OH, -CH(OH)C1-C3 haloalkyl, -CO-CH2OH, C3-C6 cycloalkyl, -NO2, -NR 11 R 11 , -N(R 11 )-CO2C1-C3 alkyl, -N(R 11 )-SO2C1-C3 alkyl, -N(R 11 )-SO2R 15 , -SO2C1-C3 alkyl, -SOC1-C3 alkyl, -SO2NR 11 R 11 , -SO2N(R11 )-CO-C1-C3 alkyl, -SO2N(R 11 )-CN, -SO2N(R 11 )(R 13 )-C(=N-OH)-NH2, -CN, -CONR 11 R 12 , -CON(R 11 )-(CH2) n -R 13 , -CO-SR 12 , -CO-NHSO2R 16 , -COCH=SOR 11 (R 11 ), or -COCH2CN.

[0101] In still further compounds of Formula (I), (II), (III), or (IV) or a pharmaceutically acceptable salt thereof, R' is not -COOH.

[0102] In still further compounds of formula (I), (II), (III), or (IV) or a pharmaceutically acceptable salt thereof, R' is -SO2NR 11 R 11 , -SO2N(R 11 (R 13 ), -C(O)NR 11 R 12 , -C(O)N(R 11 )-(CH2) n -R 13 , -C(O)-NHSO2R 16 , or oxadiazolinone (e.g., 1,2,4-oxadiazolin-5-one).

[0103] In still further compounds of formula (I), (II), (III), or (IV) or a pharmaceutically acceptable salt thereof, R' is -SO2NR 11 R 11 is.

[0104] In still further compounds of formula (I), (II), (III), or (IV) or a pharmaceutically acceptable salt thereof, R' is -SON(R 11 )(R 13 )

[0105] In still further compounds of formula (I), (II), (III), or (IV) or a pharmaceutically acceptable salt thereof, R' is -C(O)NR 11 R 12 is.

[0106] In still further compounds of formula (I), (II), (III) or (IV) or a pharmaceutically acceptable salt thereof, R' is -C(O)N(R 11 )-(CH2) n -R 13 is.

[0107] In still further compounds of formula (I), (II), (III), or (IV) or a pharmaceutically acceptable salt thereof, R' is -C(O)-NHSO2R 16 is.

[0108] In still further compounds of formula (I), (II), (III), or (IV), or a pharmaceutically acceptable salt thereof, R' is an oxadiazolinone, preferably 1,2,4-oxadiazolin-5-one.

[0109] In still further compounds of formula (I), (II), (III), or (IV) or a pharmaceutically acceptable salt thereof, R' is hydrogen, C1-C3 alkyl, -CONH-SO2C1-C3 alkyl, or a group of the formula: [ka]

[0110] In still further compounds of formula (I), (II), (III), or (IV) or a pharmaceutically acceptable salt thereof, R' is hydrogen, methyl, -CONH-SO2Me, or a group of the formula: [ka]

[0111] In still further compounds of formula (I), (II), (III), or (IV) or a pharmaceutically acceptable salt thereof, R1 is a group of the formula: [ka] wherein each R9 is independently -H, halogen, C1-C3 alkyl, or C3-C5 cycloalkyl; and R' is hydrogen, halogen, C1-C3 alkyl, or C3-C6 cycloalkyl; preferably, each R9 is independently -H, halogen, methyl, or cyclopropyl; and R' is hydrogen, halogen, or C1-C3 alkyl.

[0112] In still further compounds of formula (I), (II), (III), or (IV) or a pharmaceutically acceptable salt thereof, R1 is a group of the formula: [ka] wherein each R9 is independently -H, halogen, C1-C3 alkyl, or C3-C5 cycloalkyl; and R' is hydrogen, halogen, C1-C3 alkyl, or C3-C6 cycloalkyl; preferably, each R9 is independently -H, halogen, methyl, or cyclopropyl; and R' is hydrogen, halogen, or C1-C3 alkyl.

[0113] In still further compounds of formula (I), (II), (III), or (IV) or a pharmaceutically acceptable salt thereof, R 1 is a group of the formula: [ka]

[0114] In still further compounds of Formula (I), (II), (III), or (IV), or pharmaceutically acceptable salts thereof, R2 is attached to the chromenone core of the compound through a ring carbon atom of R2, also referred to as a "C-linked R2 group." In one embodiment, the compounds of the present disclosure include an R2 group that is an aryl group attached to the chromenone core through a ring carbon atom of R2. In one embodiment, the compounds of the present disclosure include an R2 group that is a heteroaryl group attached to the chromenone core through a ring carbon atom of R2. In one embodiment, the compounds of the present disclosure include an R2 group that is a bicyclic heteroaryl group attached to the chromenone core through a ring carbon atom of R2. In one embodiment, the compounds of the present disclosure include an R2 group that is a cycloalkyl group attached to the chromenone core of the compound through a ring carbon atom of R2.

[0115] In still further compounds of formula (I), (II), (III), or (IV) or a pharmaceutically acceptable salt thereof, R2 is a group of the formula: [ka] Each R 10 are independently -CN, halogen, C1-C6 alkyl, C1-C6 haloalkyl, or -CO2C1-C3 alkyl, or R2 is an optionally substituted pyrazole or an optionally substituted indazole, each optionally substituted with 1 to 3 substituents each independently selected from -CN, halogen, C1-C6 alkyl, C1-C6 haloalkyl, or -CO2C1-C3 alkyl. Preferably, R2 is a group of the formula: [ka] Each R 10 is independently -H, -CN, or halogen, or R2 is optionally substituted pyrazole or optionally substituted indazole, each of which is optionally substituted with C1-C3 alkyl.

[0116] In still further compounds of formula (I), (II), (III), or (IV) or a pharmaceutically acceptable salt thereof, R2 is a group of the formula: [ka] Each R 10 are independently -H, -CN, C1-C6 haloalkyl, -NR 11 R 11 , -CH2-NR 11 R 11 , -CO2C1-C3 alkyl, or -CH2-CO2C1-C3 alkyl, or R2 is indazole optionally substituted with 1 to 3 substituents each independently selected from -CN, halogen, C1-C6 alkyl, or C1-C6 haloalkyl.

[0117] In still further compounds of formula (I), (II), (III), or (IV) or a pharmaceutically acceptable salt thereof, R2 is a group of the formula: [ka] In the formula, each R 10 is independently -H, -CN, or C1-C3 haloalkyl; or R2 is an optionally substituted indazole optionally substituted with C1-C3 alkyl.

[0118] In still further compounds of formula (I), (II), (III), or (IV) or a pharmaceutically acceptable salt thereof, R2 is a group of the formula: [ka] In the formula, each R 10 are independently -H, -CN, halogen, C1-C6 alkyl, or C1-C6 haloalkyl.

[0119] In still further compounds of formula (I), (II), (III), or (IV) or a pharmaceutically acceptable salt thereof, R2 is: [ka]

[0120] In still further compounds of formula (I), (II), (III), or (IV) or a pharmaceutically acceptable salt thereof, R2 is a group of the formula: [ka]

[0121] In still further compounds of formula (I), (II), (III), or (IV) or a pharmaceutically acceptable salt thereof, R2 is a group of the formula: [ka]

[0122] In still further compounds of formula (I), (II), (III), or (IV) or a pharmaceutically acceptable salt thereof, R2 is a group of the formula: [ka] R2 is an optionally substituted 5-membered heteroaryl selected from pyrrole, furan, thiophene, pyrazole, isoxazole, isothiazole, imidazole, oxazole, thiazole, triazole, tetrazole, oxadiazole, and thiadiazole, and the optionally substituted 5-membered heteroaryl is selected from -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R 11 , -C(O)OC1-C3 alkyl, -CONR 11 R 11 , -NR 11 R 11、 -NR 11 CO2R 11, —OH, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C5 cycloalkyl, an optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine, or morpholine, optionally substituted phenyl, optionally substituted 1,3-benzodioxole, optionally substituted 2,3-dihydro-1,4-benzodioxine, or pyridine, pyrimidine, pyridazine, pyrazine, pyrazole, isoxazole, isothiazoline, and optionally substituted C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl each substituted with 1 to 3 substituents independently selected from optionally substituted heteroaryl selected from azole, imidazole, oxazole, or thiazole, and each optionally substituted C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl is selected from -CN, -OH (e.g., optionally containing C1-C6 hydroxyalkyl such as -CH2-CH2-OH, secondary -OH such as -CH2-CH(CH3)-OH, or tertiary -OH such as -CH2-C(CH3)2-OH), oxetanyl, C1-C3 alkoxy, or -CONR 11 R 11 optionally substituted C3-C5 cycloalkyl, phenyl, 1,3-benzodioxole, 2,3-dihydro-1,4-benzodioxine, heterocycle, or heteroaryl is each independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -SO2R 11 , -NR 11 R 11 , —OH, or —CN;

[0123] In still further compounds of formula (I), (II), (III), or (IV) or a pharmaceutically acceptable salt thereof, R2 is a group of the formula: [ka] Each R 10are independently -H, -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, -SO2R 11 , optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C5 cycloalkyl, or optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole, or thiazole, wherein the optionally substituted C1-C6 alkyl or C2-C6 alkynyl is optionally substituted with -CN, -OH (e.g., C1-C6 hydroxyalkyl such as -CH2-CH2-OH, optionally including a secondary -OH such as -CH2-CH(CH3)-OH or a tertiary -OH such as -CH2-C(CH3)2-OH), or C1-C3 alkoxy, and the optionally substituted C3-C5 cycloalkyl or heteroaryl is selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -NR 11 R 11 , —OH, or —CN.

[0124] In still other compounds of formula (I), (II), (III), or (IV), or a pharmaceutically acceptable salt thereof, R2 is an optionally substituted 5-membered heteroaryl selected from pyrrole, furan, thiophene, pyrazole, isoxazole, isothiazole, imidazole, oxazole, thiazole, triazole, tetrazole, oxadiazole, and thiadiazole, and the optionally substituted 5-membered heteroaryl is selected from -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R 11 , -CO2C1-C3 alkyl, -CONR 11 R 11 , -OH, -NR 11 R 11 , -NR 11 CO2R 11optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C5 cycloalkyl, an optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine or morpholine, optionally substituted phenyl, optionally substituted 1,3-benzodioxole, optionally substituted 2,3-dihydro-1,4-benzodioxine, or pyridine, pyrimidine, pyridazine, pyrazine, pyrazole, isoxazole, isothiazole, imidazole, oxazole or thiazole optionally substituted with 1 to 3 substituents independently selected from the selected optionally substituted heteroaryl, and optionally substituted C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl are each independently selected from -CN, -OH (e.g., optionally containing C1-C6 hydroxyalkyl such as -CH2-CH2-OH, secondary -OH such as -CH2-CH(CH3)-OH, or tertiary -OH such as -CH2-C(CH3)2-OH), halogen, oxetanyl, 2-oxabicyclo[2.1.1]hexane, C1-C3 alkoxy, optionally substituted C3-C5 cycloalkyl, -CONR 11 R 11 or -S(O)2CH3, optionally substituted C3-C5 cycloalkyl, phenyl, 1,3-benzodioxole, 2,3-dihydro-1,4-benzodioxine, heterocycle, or heteroaryl is each independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -SO2R 11 , -NR 11 R 11 , —OH, or —CN;

[0125] In still further compounds of Formula (I), (II), (III), or (IV) or a pharmaceutically acceptable salt thereof, 1,3-benzodioxole, 2,3-dihydro-1,4-benzodioxine, quinoxaline, quinazoline, indole, indazole, isoindazole, benzimidazole, benzotriazole, benzothiazole, benzoxazole, benzotriazole, benzofuran, benzofurazan, pyridofurazan, quinoline, 1,5-naphthyridine, isoindolin-1-one, indolin-2-one, benzomorpholine, benzo[d] Oxazol-2(3H)-one, imidazo[1,2-a]pyridine, 1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one, [1,3]dioxolo[4,5-b]pyridine, 6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine, 1,2,3,4-tetrahydroisoquinoline, 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine, pyrazolo[4,3-b]pyridine, pyrazolo[3,4-b]pyridine, pyrazolo[3,4-c]pyridine, pyrazolo[1,5-a]pyrimidine, oxazolo[4,5-b]pyridine oxazolo[5,4-b]pyridine, thiazolo[5,4-b]pyridine, 2,1,3-benzothiadiazole, imidazo[1,2-a]pyrimidine, or 2,3-dihydro-[1,4]dioxino[2,3-b]pyridine, 6,7-dihydro-5H-cyclopent[b]pyridine, 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole, 3,4-dihydro-2(1H)quinolinone, 2H-1,4-benzoxazin-3(4H)-one, 2-hydroxyquinoline, 3,4-dihydroisoquinolin-1(2H)-one, 1-hydroxyisoquinolinone quinolinone, 1,4-dihydro-3(2H)-isoquinolinone, 3H-imidazo[4,5-b]pyridine, 4,5-dihydro-7H-pyrazolo[1,5-c]1,3]oxazine, 6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine, furo[3,2-c]pyridine, furo[3,2-b]pyridine, 2,3-dihydropyrazolo[5,1-b]oxazole, 5H,6H,8H-imidazo[2,1-c][1,4]oxazine, pyrazolo[1,5-b]pyridazine, imidazo[1,2-b]pyridazine, 2,4-dihydro-1H-benzo[d][1,3]oxazine, 5-oxaspiro[2,3]hexane, imidazo[1,5-a]pyridine, pyrazolo[1,5-a]pyridine, or an optionally substituted bicyclic heteroaryl of 8 to 10 ring atoms containing 1, 2, 3, 4, or 5 ring heteroatoms independently selected from N, O, or S, wherein the optionally substituted bicyclic ring is optionally substituted with 1 to 3 substituents each independently selected from halogen and C1-C6 alkyl, or the optionally substituted bicyclic ring or optionally substituted bicyclic heteroaryl is selected from -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R, 11 , -CO2C1-C3 alkyl, -CONR 11 R 11 , -NR 11 R 11 , -NR 11 CO2R 11 , -NR 11 C(O)R 11, —OH, oxetanyl, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C5 cycloalkyl, an optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine or morpholine, optionally substituted phenyl, optionally substituted 1,3-benzodioxole, optionally substituted 2,3-dihydro-1,4-benzodioxine, or pyridine, pyrimidine, pyridazine, pyrazine, pyrazole, isoxazole, iso optionally substituted with 1 to 3 substituents independently selected from thiazole, imidazole, oxazole, or optionally substituted heteroaryl selected from thiazole, and optionally substituted C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl is, respectively, -CN, -OH (e.g., optionally containing C1-C6 hydroxyalkyl such as -CH2-CH2-OH, secondary -OH such as -CH2-CH(CH3)-OH, or tertiary -OH such as -CH2-C(CH3)2-OH), oxetanyl, C1-C3 alkoxy, or -CONR 11 R 11 , phenyl, or optionally substituted C3-C5 cycloalkyl, optionally substituted C3-C5 cycloalkyl, phenyl, 1,3-benzodioxole, 2,3-dihydro-1,4-benzodioxine, heterocycle, or heteroaryl is each independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -SO2R 11 , -NR 11 R 11 , —OH, or —CN;

[0126] In still further compounds of Formula (I), (II), (III), or (IV) or a pharmaceutically acceptable salt thereof, R2 is an optionally substituted bicyclic ring selected from 1,3-benzodioxole, 2,3-dihydro-1,4-benzodioxine, isoindolin-1-one, indolin-2-one, benzo[d]oxazol-2(3H)-one, 1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one, or 2,3-dihydro-[1,4]dioxino[2,3-b]pyridine. or an optionally substituted bicyclic heteroaryl of 8 to 10 ring atoms containing 1, 2, 3, 4, or 5 ring heteroatoms independently selected from N, O, or S, wherein the optionally substituted bicyclic ring is optionally substituted with 1 to 3 substituents each independently selected from halogen and C1-C6 alkyl, and the optionally substituted bicyclic heteroaryl is selected from -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R 10 , -CONR 10 R 10 , -NR 10 R 10 , -NR 10 CO2R 10optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C5 cycloalkyl, an optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine, or morpholine, optionally substituted phenyl, optionally substituted 1,3-benzodioxole, optionally substituted 2,3-dihydro-1,4-benzodioxine, or an optionally substituted heteroaryl selected from pyridine, pyrimidine, pyridazine, pyrazine, pyrazole, isoxazole, isothiazole, imidazole, oxazole, or thiazole. C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl optionally substituted with -CN, -OH (e.g., optionally containing C1-C6 hydroxyalkyl such as -CH2-CH2-OH, secondary -OH such as -CH2-CH(CH3)-OH, or tertiary -OH such as -CH2-C(CH3)2-OH), oxetanyl, or C1-C3 alkoxy, optionally substituted C3-C5 cycloalkyl, phenyl, 1,3-benzodioxole, 2,3-dihydro-1,4-benzodioxine, heterocycle, or heteroaryl optionally substituted with halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -SO2R 10 -NR 10 R 10 , —CH 2 —, or a pharmaceutically acceptable salt thereof.

[0127] In still further compounds of formula (I), (II), (III), or (IV) or pharmaceutically acceptable salts thereof, R2 is selected from 1 to 3 R 10 or R2 is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl optionally substituted with a substituent; or R2 is the formula of the group: [ka]

[0128] In still further compounds of formula (I), (II), (III), or (IV) or a pharmaceutically acceptable salt thereof, R2 is [ka] In the formula, each R 10 is independently —H, halogen, C1-C6 alkyl, or C1-C6 haloalkyl.

[0129] In still further compounds of formula (I), (II), (III), or (IV) or a pharmaceutically acceptable salt thereof, R2 is a group of the formula: [ka] In the formula, R 11 is selected from hydrogen, alkyl, cycloalkyl, and haloalkyl.

[0130] In still further compounds of Formula (I), (II), (III), or (IV) or a pharmaceutically acceptable salt thereof, R2 is pyrazole optionally substituted with alkyl or triazole optionally substituted with alkyl.

[0131] In still further compounds of formula (I), the compound is [ka] or a pharmaceutically acceptable salt of any of the foregoing; During the ceremony, * The bond at the position is as shown, or [ka] or [ka] is.

[0132] In a further embodiment of a compound of Formula (I), (II), (III), or (IV) 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 isotopic derivatives can be prepared using any of a variety of art-recognized techniques. For example, isotopic derivatives can generally be prepared by carrying out the procedures disclosed in the schemes and / or examples described herein by substituting an isotopically labeled reagent or a pharmaceutically acceptable salt thereof for a non-isotopically labeled reagent. In the compounds of the present invention, any atom not specifically designated as a particular isotope is meant to represent a stable isotope of that atom.

[0133] In further embodiments of a compound of Formula (I), (II), (III), or (IV) or a pharmaceutically acceptable salt thereof, the compound is deuterated at one or more positions. Unless otherwise specified, when an atom is specifically designated as "H" or "hydrogen," the atom is understood to have hydrogen at its natural abundance isotopic composition. Also, unless otherwise specified, when an atom is specifically designated as "D" or "deuterium," the atom is understood to have deuterium in an abundance substantially greater than the natural abundance of deuterium, which is 0.015%.

[0134] Activity of the Disclosed Compounds The disclosed compounds can have one or more of the activities disclosed herein.

[0135] In one aspect, the disclosed compounds can inhibit the activity of PI3K-α kinase and can be characterized as having (PIK3CA) inhibitory activity. In one aspect, the disclosed compounds can inhibit the activity of wild-type PIK3CA. In one aspect, the disclosed compounds can inhibit the activity of mutant PIK3CA having one or more amino acid substitutions, deletions, or insertions compared to the amino acid sequence of wild-type PIK3CA. In one aspect, the disclosed compounds can inhibit the activity of H1047R mutant PIK3CA. In one aspect, the disclosed compounds can inhibit the activity of E545K mutant PIK3CA. In one aspect, the disclosed compounds can inhibit the activity of H1047R mutant PIK3CA and E545K mutant PIK3CA. In one aspect, the disclosed compounds can inhibit the activity of wild-type or mutant PI3KCA as measured in an in vitro cell-based assay, such as the assay entitled "PI3K-α Kinase (PI3Kα) Activity: Wild-Type PI3Kα, H1047R Mutant PI3Kα, and E545K Mutant PI3Kα In Vitro Cell-Based Assay and Determination of IC50 Values ​​for Inhibitors," disclosed herein as an Example. In one aspect, the disclosed compounds can inhibit the activity of wild-type and / or mutant PI3KCA as measured in an in vitro cell-based assay, and can exhibit an IC50 value for inhibition. 50 can be determined.

[0136] In one embodiment, the disclosed compounds may selectively inhibit the activity of mutant PI3KCA relative to wild-type PI3KCA, such as H1047R mutant PI3KCA or E545K mutant PI3KCA, relative to wild-type PI3KCA. In one embodiment, the disclosed compounds have an IC50 of less than about 500 nM, 100 nM, 50 nM, 40 nM, 30 nM, 20 nM, 10 nM, or 5 nM for mutant PI3KCA, such as in the in vitro assays disclosed herein. 50 In one aspect, the disclosed compounds may have an IC of less than about 500 nM, 100 nM, 50 nM, 40 nM, 30 nM, 20 nM, 10 nM, or 5 nM for H1047R mutant PI3KCA. 50In one aspect, the disclosed compounds may have an IC of less than about 500 nM, 450 nM, 400 nM, 350 nM, 300 nM, 250 nM, 200 nM, 150 nM, 100 nM, or 50 nM for E545K mutant PI3KCA. 50 In one embodiment, the disclosed compounds may have an IC of 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 for wild-type PI3KCA. 50 In one aspect, the disclosed compounds can selectively inhibit the activity of mutant PI3KCA relative to wild-type PI3KCA, and the compounds can have an IC50 of wild-type PI3KCA in an in vitro cell-based assay. 50 IC of the mutant PI3KCA in an assay, such as an in vitro assay disclosed herein, that is at least 5-fold, 10-fold, 20-fold, 30-fold, 40-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, 100-fold, 200-fold, or 500-fold lower than 50 In one aspect, the compound selectively inhibits the activity of mutant PI3KCA relative to wild-type PI3KCA in an in vitro cell-based assay, and the compound has at least 5-fold, 10-fold, 20-fold, 30-fold, 40-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, 100-fold, 200-fold, or 500-fold selectivity for mutant PI3KCA relative to wild-type PI3KCA.

[0137] In one embodiment, the disclosed compounds can exhibit metabolic stability as measured in one or more in vitro clearance assays disclosed herein.

[0138] In one aspect, the disclosed compounds may exhibit metabolic stability as measured in an in vitro clearance assay utilizing liver microsomes, such as the assay entitled "Metabolic Stability and Intrinsic Clearance in Liver Microsomes" disclosed herein as an example. Liver microsomes suitable for use in in vitro clearance assays 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 exhibit metabolic stability as measured in an in vitro liver microsome assay (CL). int In one aspect, the scaled-up CL values ​​can be calculated for a given species, including, but not limited to, human, monkey, dog, rat, and mouse, utilizing scaling factors known in the art. hep (mL / min / kg), predicted CL int (mL / min / kg), and E H can be calculated.

[0139] In one aspect, the disclosed compounds may exhibit metabolic stability as measured in an in vitro clearance assay utilizing hepatocytes, such as the assay entitled "Metabolic Stability and Intrinsic Clearance in Stem Cells" disclosed herein as an example. Hepatocytes suitable for use in in vitro clearance assays 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 exhibit metabolic stability as measured in an in vitro hepatocyte stability assay (CL int ) at about 200, 150, 100, 90, 80, 70, 60, 50, 45, 40, 35, 30, 25, 20, 15, 10, 5, 4, 3, 2, or 1 μl / min / 1×10 6In one aspect, scaling factors, as known in the art, are utilized to calculate the scaled-up CL for a given species, including, but not limited to, human, monkey, dog, rat, and mouse. int (mL / min / kg), predicted liver CL H (mL / min / kg), and hepatic extraction fraction (ER) can be calculated.

[0140] In one aspect, the disclosed compounds do not induce expression of cytochrome P450 enzymes compared to a control or vehicle in an in vitro assay, or the compounds induce expression of cytochrome P450 enzymes at a relatively low level compared to a control or vehicle in an in vitro assay. In one aspect, the disclosed compounds do not induce expression of cytochrome P450 enzymes or induce expression of cytochrome P450 enzymes at a relatively low level compared to a control or vehicle in an in vitro assay, such as the assay entitled "In Vitro Estimation of CYP1A2, CYP2B6, and CYP3A4 Inducibility of Primary Human Hepatocytes" disclosed herein as an example. The fold induction of CYP expression can be determined by measuring CYP mRNA in the test sample relative to the control or vehicle sample and / or by measuring CYP enzyme activity in the test sample relative to the control or vehicle sample. In one aspect, the disclosed compounds do not induce expression of CYP3A4 at a level greater than about 4.0x, 3.8x, 3.6x, 3.4x, 3.2x, 3.0x, 2.8x, 2.6x, 2.4x, 2.2x, 2.0x, 1.8x, 1.6x, 1.4x, 1.2x compared to a control or vehicle in an in vitro assay as disclosed herein when the disclosed compound is administered in the in vitro assay at a concentration of about 1 μl.

[0141] In one aspect, the disclosed compounds do not cause adverse events (AEs), such as hyperglycemia and diarrhea, when the PI3K alpha inhibitors are administered at doses effective to inhibit the activity of PI3K alpha and treat diseases or disorders associated with PI3K alpha activity. In one aspect, the disclosed compounds do not cause adverse events (AEs), such as hyperglycemia and diarrhea, when the PI3K alpha inhibitors are administered at doses effective to treat cancer and cause tumor regression.

[0142] Pharmaceutical salts Pharmaceutically acceptable salts of the compounds of the present invention are, for example, acid addition salts of the compounds of the present invention that are sufficiently basic, such as, for example, acid addition salts with inorganic or organic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, trifluoroacetic acid, formic acid, citric acid, methanesulfonic acid, or maleic acid. Additionally, pharmaceutically acceptable salts of the compounds of the present invention that are sufficiently acidic are alkali metal salts, such as sodium or potassium salts, alkaline earth metal salts, such as calcium or magnesium salts, ammonium salts, or salts with organic bases that provide pharmaceutically acceptable cations, such as salts with methylamine, dimethylamine, diethylamine, trimethylamine, piperidine, morpholine, or tris-(2-hydroxyethyl)amine. Pharmaceutically acceptable salts and general techniques for preparing them are well known in the art (see, for example, Stahl et al., "Handbook of Pharmaceutical Salts: Properties, Selection and Use," 2004). nd See Revised Edition (Wiley-VCH, 2011); S.M. Berge, et al., "Pharmaceutical Salts," Journal of Pharmaceutical Sciences, Vol. 66, No. 1, January 1977.

[0143] Further representative "pharmaceutically acceptable salts" include, for example, water soluble and water insoluble salts, such as 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, gluceptanate, gluconate, glutamate, glycolyl arsaniphosphate, hexafluorophosphate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide ... These include sothionate, lactate, lactobionate, laurate, magnesium, malate, maleate, mandelate, mesylate, methyl bromide, methyl nitrate, methyl sulfate, 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.

[0144] The compounds of the present invention can be prepared by several methods well known to those skilled in the art of organic synthesis. As an example, the compounds of the present invention can be synthesized using the methods described below, together with synthetic methods known in the art of organic synthetic chemistry, or variations thereof that will be understood by those skilled in the art. Preferred methods include, but are not limited to, the methods described below.

[0145] Further Aspects The following are further numbered aspects of the present invention: 1.Formula: [ka] or a pharmaceutically acceptable salt thereof, wherein R1 is an optionally substituted bicyclic ring selected from isobenzofuranone, benzofuranone, isoindolinone, indolinone, quinazolinone, 3,4-dihydro-2H-isoquinolin-1-one, 2H-isoquinolin-1-one, imidaza[1,2-a]pyridine, or benzothiazolone, wherein the optionally substituted bicyclic ring is optionally substituted with 1 to 3 substituents each independently selected from oxo, —CN, halogen, C1-C6 alkyl, C1-C6 haloalkyl, —OH, or C1-C6 alkoxy; or R1 is a group of the formula: [ka] R' is hydrogen, halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 hydroxyalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -OH, -CH(OH)-CH2OH, -CH(OH)C1-C3 haloalkyl, -CO-CH2OH, C3-C6 cycloalkyl, -NO2, -NR 11 R 11 , -N(R 11 )-CO2C1-C3 alkyl, -N(R 11 )-SO2C1-C3 alkyl, -N(R 11 )-SO2R 15 , -SO2C1-C3 alkyl, -SOC1-C3 alkyl, -SO2NR 11 R 11 , -SO2NR 11 R 12 , -SO2N(R 11 )-CO-C1-C3 alkyl, -SO2N(R 11 )-CN, -C(=N-OH)-NH2, -CN, -CONR 11 R 12 , -CON(R 11 )-(CH2) n -R 13 , -CO-SR 12 , -CO-NHSO2R 16, -COCH=SOR 11 (R 11 ), or —COCHCN, or a group of the formula: [ka] Ring A is pyrrolidine optionally substituted with -CN, or R' is selected from oxetane, azetidine, pyrrolidine, tetrahydrofuran, morpholine, thiomorpholine, piperidine, piperazine, pyrrole, furan, thiophene, pyrazole, imidazole, isoxazole, oxazole, isothiazole, thiazole, triazole, oxadiazole, 1,2,4-oxadiazolin-5-one, 1,4-oxazepane, thiadiazole, tetrazole, phenyl, pyridine, pyridazine, pyrimidine, pyrazine, oxazepane, or triazine, each of which is selected from oxo, -OH, -NR 11 R 11 , -N(R 11 )-CO-R 11 , -N(R 11 )-CN, -OR 11 , -CN, halogen, morpholino, oxetane, C1-C6 haloalkyl, or C1-C6 alkyl optionally substituted with -OH, aryl, 5-membered heteroaryl, or 6-membered heteroaryl; or R' is a group of the formula: [ka] R2 is a group of the formula: [ka] R2 is a group of the formula: [ka] R2 is an optionally substituted 5-membered heteroaryl selected from pyrrole, furan, thiophene, pyrazole, isoxazole, isothiazole, imidazole, oxazole, thiazole, triazole, tetrazole, oxadiazole, and thiadiazole, and the optionally substituted 5-membered heteroaryl is selected from -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R 11 , -CO2C1-C3 alkyl, -CONR 11 R 11 , -OH, -NR 11 R 11 , -NR 11 CO2R 11 optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C5 cycloalkyl, an optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine or morpholine, optionally substituted phenyl, optionally substituted 1,3-benzodioxole, optionally substituted 2,3-dihydro-1,4-benzodioxine, or pyridine, pyrimidine, pyridazine, pyrazine, pyrazole, isoxazole, isothiazole, imidazole, oxazole or thiazole optionally substituted with 1 to 3 substituents independently selected from the selected optionally substituted heteroaryl, and optionally substituted C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl are each independently selected from -CN, -OH (e.g., optionally containing C1-C6 hydroxyalkyl such as -CH2-CH2-OH, secondary -OH such as -CH2-CH(CH3)-OH, or tertiary -OH such as -CH2-C(CH3)2-OH), halogen, oxetanyl, 2-oxabicyclo[2.1.1]hexane, C1-C3 alkoxy, optionally substituted C3-C5 cycloalkyl, -CONR 11 R 11or -S(O)2CH3, optionally substituted C3-C5 cycloalkyl, phenyl, 1,3-benzodioxole, 2,3-dihydro-1,4-benzodioxine, heterocycle, or heteroaryl is each independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -SO2R 11 , -NR 11 R 11 , —OH, or —CN; or R2 is 1,3-benzodioxole, 2,3-dihydro-1,4-benzodioxine, quinoxaline, quinazoline, indole, indazole, isoindazole, benzimidazole, benzotriazole, benzothiazole, benzoxazole, benzotriazole, benzofuran, benzofurazan, pyridofurazan, quinoline, 1,5-naphthyridine, isoindolin-1-one, indolin-2-one, benzomorpholine, benzo[d]oxazol-2(3H)-one, imidazo[1,2-a]pyridine, 1,3-dihydro-2H- Pyrrolo[2,3-b]pyridin-2-one, [1,3]dioxolo[4,5-b]pyridine, 6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine, 1,2,3,4-tetrahydroisoquinoline, 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine, pyrazolo[4,3-b]pyridine, pyrazolo[3,4-b]pyridine, pyrazolo[3,4-c]pyridine, pyrazolo[1,5-a]pyrimidine, oxazolo[4,5-b]pyridine, oxazolo[5,4-b]pyridine, thiazolo[5,4-b]pyridine, 2,1,3 -benzothiadiazole, imidazo[1,2-a]pyrimidine, or 2,3-dihydro-[1,4]dioxino[2,3-b]pyridine, 6,7-dihydro-5H-cyclopent[b]pyridine, 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole, 3,4-dihydro-2(1H)quinolinone, 2H-1,4-benzoxazin-3(4H)-one, 2-hydroxyquinoline, 3,4-dihydroisoquinolin-1(2H)-one, 1-hydroxyisoquinoline, 1,4-dihydro-3(2H)-isoquinolinone, 3H-imidazo[4,5- b]pyridine, 4,5-dihydro-7H-pyrazolo[1,5-c]1,3]oxazine, 6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine, furo[3,2-c]pyridine, furo[3,2-b]pyridine, 2,3-dihydropyrazolo[5,1-b]oxazole, 5H,6H,8H-imidazo[2,1-c][1,4]oxazine, pyrazolo[1,5-b]pyridazine, imidazo[1,2-b]pyridazine, 2,4-dihydro-1H-benzo[d][1,3]oxazine, 5-oxaspiro[2,3]hexane, imidazo[1,or an optionally substituted bicyclic heteroaryl of 8 to 10 ring atoms containing 1, 2, 3, 4, or 5 ring heteroatoms independently selected from N, O, or S, wherein the optionally substituted bicyclic ring is optionally substituted with 1 to 3 substituents each independently selected from halogen and C1-C6 alkyl, or the optionally substituted bicyclic ring or optionally substituted bicyclic heteroaryl is selected from -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R, 11 , -CO2C1-C3 alkyl, -CONR 11 R 11 , -NR 11 R 11 , -NR 11 CO2R 11 , -NR 11 C(O)R 11 , —OH, oxetanyl, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C5 cycloalkyl, an optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine or morpholine, optionally substituted phenyl, optionally substituted 1,3-benzodioxole, optionally substituted 2,3-dihydro-1,4-benzodioxine, or pyridine, pyrimidine, pyridazine, pyrazine, pyrazole, isoxazole, iso optionally substituted with 1 to 3 substituents independently selected from thiazole, imidazole, oxazole, or optionally substituted heteroaryl selected from thiazole, and optionally substituted C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl is, respectively, -CN, -OH (e.g., optionally containing C1-C6 hydroxyalkyl such as -CH2-CH2-OH, secondary -OH such as -CH2-CH(CH3)-OH, or tertiary -OH such as -CH2-C(CH3)2-OH), oxetanyl, C1-C3 alkoxy, or -CONR 11 R 11, phenyl, or optionally substituted C3-C5 cycloalkyl, optionally substituted C3-C5 cycloalkyl, phenyl, 1,3-benzodioxole, 2,3-dihydro-1,4-benzodioxine, heterocycle, or heteroaryl is each independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -SO2R 11 , -NR 11 R 11 , —OH, or —CN; or R2 is cyclopropyl, cyclobutyl, cyclopentyl, bicyclo[1.1.1]pentyne, bicyclo[2.2.2]octyne, or cyclohexyl, each of which is selected from 1 to 3 R 10 optionally substituted with a substituent, or R2 is a group of the formula: [ka] R2 is heterocycloalkyl, optionally 1 to 3 R 10 an oxetane substituted with a substituent, R3 is -H, halogen, -CN, -C(CN)=CHOH, -N(H)(C1-C3 alkyl), -N(C1-C3 alkyl)2, -N(H)(CH2CH2CO2H), -CO-C1-C3 alkyl, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C3-C5 cycloalkyl, an optionally substituted heterocycle of 3 to 5 ring atoms containing 1, 2, or 3 ring heteroatoms independently selected from N, O, or S, or an optionally substituted heteroaryl of 5 or 6 ring atoms containing 1, 2, or 3 ring heteroatoms independently selected from N, O, or S, wherein the optionally substituted heterocycle or heteroaryl is each optionally substituted with 1 to 3 substituents each independently selected from halogen, C1-C3 alkyl, or C1-C3 haloalkyl; each of R4, R5, and R6 is independently -H, halogen, -CN, C1-C6 alkyl, or C1-C6 haloalkyl; R7 is -CN, C1-C6 alkyl, CH2OH, or C1-C6 haloalkyl; R8 is —H or C1-C6 alkyl; each R9 is independently -H, halogen, -CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C3-C5 cycloalkyl; Each R 10 are independently -H, -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R 11 , -SONR 11 R 11 , -CO2H, -CO2C1-C3 alkyl, -CONR 11 R 12 , -NR 11 R 11 , -NR 11 -CO2R 11 , —OH, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C5 cycloalkyl, an optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine, or morpholine, optionally substituted phenyl, optionally substituted 1,3-benzodioxole, optionally substituted 2,3-dihydro-1,4-benzodioxine, optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole, thiazole, or pyridine, or a group of the formula: [ka] Optionally substituted C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl can be —CN, —OH (e.g., R 10 is a C1-C6 hydroxyalkyl such as -CH2-CH2-OH, and optionally R10 is a hydroxyl containing a secondary —OH such as —CH—CH(CH)—OH or a tertiary —OH such as —CH—C(CH)—OH), oxetanyl, C-C alkoxy, or —CONR 11 R 11 optionally substituted C3-C5 cycloalkyl, phenyl, 1,3-benzodioxole, 2,3-dihydro-1,4-benzodioxine, heterocycle, or heteroaryl is each independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -SO2R 11 , -NR 11 R 11 , —OH, or —CN; Each R 11 are independently -H, C1-C3 alkyl, C3-C7 cycloalkyl, or C1-C3 haloalkyl; Each R 12 are independently -H, optionally substituted C1-C3 alkyl, C3-C6 cycloalkyl, -SO2C1-C3 alkyl, -SO2C1-C3 haloalkyl, -SO2NR 11 R 11 , -NR 11 R 11 , -OR 11 , —O—CH—CH(OH)—CHOH, —CN, oxetane, tetrahydrofuran, aryl, a 5-membered heteroaryl optionally substituted with methyl, a 6-membered heteroaryl, or a group of the formula: [ka] the optionally substituted C1-C3 alkyl is optionally substituted with -OH, C3-C6 cycloalkyl, oxetane, tetrahydrofuran, aryl, 5-membered heteroaryl, 6-membered heteroaryl, or indole; R 13 But, -NR 11 R 11 , -OR 11, —SO2C1-C3 alkyl, or a ring selected from oxetane, tetrahydrofuran, or oxadiazole, and the ring is —NR 11 R 11 -OR 11 optionally substituted with R 14 is -H, optionally substituted C1-C3 alkyl, -SO2C1-C3 alkyl, aryl, 5-membered heteroaryl, or 6-membered heteroaryl, wherein the optionally substituted C1-C3 alkyl is optionally substituted with aryl, 5-membered heteroaryl, or 6-membered heteroaryl; R 15 is an optionally substituted aryl or an optionally substituted 6-membered heteroaryl, each of which is optionally substituted with 1 to 3 substituents independently selected from halogen, C1-C3 alkyl, or C1-C3 haloalkyl; R 16 is H, C1-C3 alkyl, —NH2, phenyl, or pyridine; n is 0, 1, or 2.

[0146] 2.Formula: [ka] or a pharmaceutically acceptable salt thereof, wherein R1 is an optionally substituted bicyclic ring selected from isobenzofuranone, benzofuranone, isoindolinone, indolinone, quinazolinone, 3,4-dihydro-2H-isoquinolin-1-one, 2H-isoquinolin-1-one, or benzothiazolone, wherein the optionally substituted bicyclic ring is optionally substituted with 1 to 3 substituents each independently selected from oxo, —CN, halogen, C1-C6 alkyl, C1-C6 haloalkyl, —OH, or C1-C6 alkoxy; or R1 is a group of the formula: [ka] R' is hydrogen, halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -OH, -CH(OH)-CH2OH, -CO-CH2OH, C3-C6 cycloalkyl, -NO2-N(R 11 )-CO2C1-C3 alkyl, -N(R 11 )-SO2C1-C3 alkyl, -N(R 11 )-SO2R 15 , -SO2C1-C3 alkyl, -SO2NR 11 R 11 , -SO2N(R 11 )-CO-C1-C3 alkyl, -SO2N(R 11 )-CN, -C(=N-OH)-NH2, -CN, -CONR 11 R 12 , -CON(R 11 )-(CH2) n -R 13 , -CO-SR 12 or a group of the formula: [ka] Ring A is pyrrolidine optionally substituted with -CN, or R' is selected from oxetane, pyrrolidine, tetrahydrofuran, morpholine, piperidine, piperazine, pyrrole, furan, thiophene, pyrazole, imidazole, isoxazole, oxazole, isothiazole, thiazole, triazole, oxadiazole, thiadiazole, tetrazole, phenyl, pyridine, pyridazine, pyrimidine, pyrazine, or triazine, each of which is selected from oxo, -OH, -NR 11 R 11 , -N(R 11 )-CO-R 11 , -N(R 11 )-CN, -OR 11 , -CN, halogen, C1-C6 haloalkyl, or C1-C6 alkyl optionally substituted with aryl, 5-membered heteroaryl, or 6-membered heteroaryl; or R' is a group of the formula: [ka] R2 is a group of the formula: [ka] R2 is a group of the formula: [ka] R2 is an optionally substituted 5-membered heteroaryl selected from pyrrole, furan, thiophene, pyrazole, isoxazole, isothiazole, imidazole, oxazole, thiazole, triazole, tetrazole, oxadiazole, and thiadiazole, and the optionally substituted 5-membered heteroaryl is selected from -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R 11 , -CO2C1-C3 alkyl, -CONR 11 R 11 , -OH, -NR 11 R 11 , -NR 11 CO2R 11 optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C5 cycloalkyl, optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine or morpholine, optionally substituted phenyl, optionally substituted 1,3-benzodioxole, optionally substituted 2,3-dihydro-1,4-benzodioxine, or optionally substituted heteroaryl selected from pyridine, pyrimidine, pyridazine, pyrazine, pyrazole, isoxazole, isothiazole, imidazole, oxazole or thiazole, each of which is optionally substituted with 1 to 3 substituents independently selected from -CN, -OH (e.g., -R 10is a C1-C6 hydroxyalkyl such as -CH2-CH2-OH, and optionally R 10 is a hydroxyl containing a secondary —OH such as —CH—CH(CH)—OH or a tertiary —OH such as —CH—C(CH)—OH), oxetanyl, C1-C3 alkoxy, or CONR 11 R 11 optionally substituted C3-C5 cycloalkyl, phenyl, 1,3-benzodioxole, 2,3-dihydro-1,4-benzodioxine, heterocycle, or heteroaryl is each independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -SO2R 11 , -NR 11 R 11 , —OH, or —CN; or R2 is an optionally substituted bicyclic ring selected from 1,3-benzodioxole, 2,3-dihydro-1,4-benzodioxine, isoindolin-1-one, indolin-2-one, benzo[d]oxazol-2(3H)-one, 1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one, or 2,3-dihydro-[1,4]dioxino[2,3-b]pyridine, or 1, 2, 3, 4, or 5 independently selected from N, O, or S; Optionally substituted bicyclic heteroaryl of 8 to 10 ring atoms containing 5 ring heteroatoms, wherein the optionally substituted bicyclic ring is optionally substituted with 1 to 3 substituents each independently selected from halogen and C1-C6 alkyl, or the optionally substituted bicyclic ring or optionally substituted bicyclic heteroaryl is selected from -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R 11 , -CO2C1-C3 alkyl, -CONR 11 R 11 , -NR 11 R 11 , -NR 11 CO2R 11, —OH, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C5 cycloalkyl, an optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine or morpholine, optionally substituted phenyl, optionally substituted 1,3-benzodioxole, optionally substituted 2,3-dihydro-1,4-benzodioxine, or pyridine, pyrimidine, pyridazine, pyrazine, pyrazole, isoxazole, isothiazol and optionally substituted C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl, each of which is optionally substituted by 1 to 3 substituents independently selected from optionally substituted heteroaryl selected from aryl, imidazole, oxazole, or thiazole, and each of which is optionally substituted by -CN, -OH (e.g., optionally containing a C1-C6 hydroxyalkyl such as -CH2-CH2-OH, a secondary -OH such as -CH2-CH(CH3)-OH, or a tertiary -OH such as -CH2-C(CH3)2-OH), oxetanyl, C1-C3 alkoxy, -CONR 11 R 11 or phenyl, optionally substituted C3-C5 cycloalkyl, phenyl, 1,3-benzodioxole, 2,3-dihydro-1,4-benzodioxine, heterocycle, or heteroaryl is each independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -SO2R 11 , -NR 11 R 11 , —OH, or —CN; or R2 is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, each of which has 1 to 3 R 10 optionally substituted with a substituent, or R2 is a group of the formula: [ka] R3 is -H, halogen, -CN, -N(H)(C1-C3 alkyl), -N(C1-C3 alkyl)2, -N(H)(CH2CH2CO2H), -CO-C1-C3 alkyl, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C3-C5 cycloalkyl, an optionally substituted heterocycle of 3 to 5 ring atoms containing 1, 2, or 3 ring heteroatoms independently selected from N, O, or S, or an optionally substituted heteroaryl of 5 or 6 ring atoms containing 1, 2, or 3 ring heteroatoms independently selected from N, O, or S, wherein the optionally substituted heterocycle or heteroaryl is each optionally substituted with 1 to 3 substituents each independently selected from halogen, C1-C3 alkyl, or C1-C3 haloalkyl; each of R4, R5, and R6 is independently -H, halogen, C1-C6 alkyl, or C1-C6 haloalkyl; R7 is -CN, C1-C6 alkyl, or C1-C6 haloalkyl; R8 is —H or C1-C6 alkyl; each R9 is independently -H, halogen, -CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C3-C5 cycloalkyl; Each R 10 are independently -H, -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R 11 , -SONR 11 R 11 , -CO2H, -CO2C1-C3 alkyl, -CONR 11 R 12 , -NR 11 R 11 , -NR 11 -CO2R 11, —OH, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C5 cycloalkyl, an optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine, or morpholine, optionally substituted phenyl, optionally substituted 1,3-benzodioxole, optionally substituted 2,3-dihydro-1,4-benzodioxine, optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole, thiazole, or pyridine, or a group of the formula: [ka] Optionally substituted C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl can be —CN, —OH (e.g., R 10 is C1-C6 alkyl, and optionally, R 10 containing a secondary -OH or a tertiary -OH), oxetanyl, C1-C3 alkoxy, or -CONR 11 R 11 optionally substituted C3-C5 cycloalkyl, phenyl, 1,3-benzodioxole, 2,3-dihydro-1,4-benzodioxine, heterocycle, or heteroaryl is each independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -SO2R 11 , -NR 11 R 11 , —OH, or —CN; Each R 11 are independently —H or C1-C3 alkyl; Each R 12 is -H, optionally substituted C1-C3 alkyl, C3-C6 cycloalkyl, -SO2C1-C3 alkyl, -SO2C1-C3 haloalkyl, -SO2NR 11 R 11 , -NR 11R 11 , -OR 11 , —O—CH—CH(OH)—CHOH, —CN, oxetane, tetrahydrofuran, aryl, a 5-membered heteroaryl optionally substituted with methyl, a 6-membered heteroaryl, or a group of the formula: [ka] the optionally substituted C1-C3 alkyl is optionally substituted with -OH, C3-C6 cycloalkyl, oxetane, tetrahydrofuran, aryl, 5-membered heteroaryl, 6-membered heteroaryl, or indole; R 14 is -H, optionally substituted C1-C3 alkyl, -SO2C1-C3 alkyl, aryl, 5-membered heteroaryl, or 6-membered heteroaryl, and the optionally substituted C1-C3 alkyl is optionally substituted with aryl, 5-membered heteroaryl, or 6-membered heteroaryl, or a pharmaceutically acceptable salt thereof.

[0147] 3. A compound according to aspect 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R8 is -H.

[0148] 4. A compound according to any one of aspects 1 to 3, having the formula: or a pharmaceutically acceptable salt thereof. [ka]

[0149] 5. A compound according to any one of aspects 1 to 4, or a pharmaceutically acceptable salt thereof, wherein R4 is -H or halogen.

[0150] 6. A compound according to any one of aspects 1 to 5, or a pharmaceutically acceptable salt thereof, wherein R4 is -H.

[0151] 7. A compound according to any one of aspects 1 to 6, having the formula: or a pharmaceutically acceptable salt thereof. [ka]

[0152] 8. A compound according to any one of aspects 1-7, or a pharmaceutically acceptable salt thereof, wherein R3 is -H, -CN, C1-C3 alkyl, or C1-C3 haloalkyl.

[0153] 9. A compound according to any one of aspects 1 to 8, or a pharmaceutically acceptable salt thereof, wherein R3 is -H, -CN, methyl, or trifluoromethyl.

[0154] 10. A compound according to any one of aspects 1 to 9, or a pharmaceutically acceptable salt thereof, wherein R3 is -H or methyl.

[0155] 11. A compound according to any one of aspects 1-10, or a pharmaceutically acceptable salt thereof, wherein R5 is -H, halogen, C1-C3 alkyl, or C1-C3 haloalkyl.

[0156] 12. A compound according to any one of aspects 1 to 11, or a pharmaceutically acceptable salt thereof, wherein R5 is -H, halogen, methyl, or trifluoromethyl.

[0157] 13. A compound according to any one of aspects 1 to 12, or a pharmaceutically acceptable salt thereof, wherein R6 is -H or halogen.

[0158] 14. A compound according to any one of aspects 1-13, or a pharmaceutically acceptable salt thereof, wherein R7 is -CN, C1-C3 alkyl, or C1-C3 haloalkyl.

[0159] 15. A compound according to any one of aspects 1 to 14, or a pharmaceutically acceptable salt thereof, wherein R7 is -CN, methyl, or trifluoromethyl.

[0160] 16. A compound according to any one of aspects 1 to 15, or a pharmaceutically acceptable salt thereof, wherein R7 is methyl.

[0161] 17. A compound according to any one of aspects 1 to 16, having the formula: or a pharmaceutically acceptable salt thereof. [ka]

[0162] 18. A compound according to any one of aspects 1 to 17, or a pharmaceutically acceptable salt thereof, wherein R1 is a group of the following formula: [ka]

[0163] 19. R1 is a group of the formula: [ka] 19. A compound according to any one of aspects 1 to 18, or a pharmaceutically acceptable salt thereof, wherein R9 is selected from -H and halogen.

[0164] 20. The compound according to any one of aspects 1-18, or a pharmaceutically acceptable salt thereof, wherein each R9 is independently -H, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C3-C5 cycloalkyl.

[0165] 21. The compound according to any one of aspects 1-18, or a pharmaceutically acceptable salt thereof, wherein each R9 is independently -H, halogen, C1-C3 alkyl, or C1-C3 haloalkyl.

[0166] 22. A compound according to any one of aspects 1 to 21, or a pharmaceutically acceptable salt thereof, wherein R2 is a group of the following formula: [ka]

[0167] 23. A compound according to any one of aspects 1 to 22, or a pharmaceutically acceptable salt thereof, wherein R2 is a group of the following formula: [ka]

[0168] 24. R2 is a group of the formula: [ka] R2 is an optionally substituted 5-membered heteroaryl selected from pyrrole, furan, thiophene, pyrazole, isoxazole, isothiazole, imidazole, oxazole, thiazole, triazole, tetrazole, oxadiazole, and thiadiazole, and the optionally substituted 5-membered heteroaryl is selected from -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R 11 , -C(O)OC1-C3 alkyl, -CONR 11 R 11 , -NR 11 R 11、 -NR 11 CO2R 11, —OH, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C5 cycloalkyl, an optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine, or morpholine, optionally substituted phenyl, optionally substituted 1,3-benzodioxole, optionally substituted 2,3-dihydro-1,4-benzodioxine, or pyridine, pyrimidine, pyridazine, pyrazine, pyrazole, isoxazole, isothiazole, imidazole, and optionally substituted C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl, each of which is substituted by 1 to 3 substituents independently selected from optionally substituted heteroaryl selected from oxazole or thiazole, and each of which is optionally substituted C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl is independently selected from -CN, -OH (e.g., optionally containing a C1-C6 hydroxyalkyl such as -CH2-CH2-OH, a secondary -OH such as -CH2-CH(CH3)-OH, or a tertiary -OH such as -CH2-C(CH3)2-OH), oxetanyl, C1-C3 alkoxy, optionally substituted C3-C5 cycloalkyl, or -CONR 11 R 11 optionally substituted C3-C5 cycloalkyl, phenyl, 1,3-benzodioxole, 2,3-dihydro-1,4-benzodioxine, heterocycle, or heteroaryl is each independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -SO2R 11 , -NR 11 R 11 , —CH 2 —, or a pharmaceutically acceptable salt thereof.

[0169] 25. A compound according to any one of aspects 1-21, wherein R2 is 1H-indazol-5-yl, 1H-indazol-6-yl, or 1H-pyrazol-4-yl N-substituted with C1-C3 alkyl or C1-C6 hydroxyalkyl.

[0170] 26. R2 is a group of the formula: [ka] Each R 10 are independently -H, -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, -SO2R 11 , optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C5 cycloalkyl, or optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole, or thiazole, wherein the optionally substituted C1-C6 alkyl or C2-C6 alkynyl is selected from -CN, -OH (e.g., R 10 is a C1-C6 hydroxyalkyl such as -CH2-CH2-OH, and optionally R 10 is hydroxyl containing a secondary —OH such as —CH2—CH(CH3)—OH or a tertiary —OH such as —CH2—C(CH3)2—OH), or C1-C3 alkoxy, optionally substituted C3-C5 cycloalkyl or heteroaryl is selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, —NR 11 R 11 , —CH 2 —, or a pharmaceutically acceptable salt thereof.

[0171] 27. R2 is an optionally substituted bicyclic ring selected from 1,3-benzodioxole, 2,3-dihydro-1,4-benzodioxine, isoindolin-1-one, indolin-2-one, benzo[d]oxazol-2(3H)-one, 1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one, or 2,3-dihydro-[1,4]dioxino[2,3-b]pyridine, or 1, 2, 3, 4 or 5 independently selected from N, O or S. Optionally substituted bicyclic heteroaryl of 8 to 10 ring atoms containing 5 ring heteroatoms, wherein the optionally substituted bicyclic ring is optionally substituted with 1 to 3 substituents each independently selected from halogen and C1-C6 alkyl, or the optionally substituted bicyclic ring or optionally substituted bicyclic heteroaryl is selected from -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R 10 , -C(O)OC1-C3 alkyl, -CONR 10 R 10 , -NR 10 R 10 , -NR 10 CO2R 10, —OH, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C5 cycloalkyl, an optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine or morpholine, optionally substituted phenyl, optionally substituted 1,3-benzodioxole, optionally substituted 2,3-dihydro-1,4-benzodioxine, or pyridine, pyrimidine, pyridazine, pyrazine, pyrazole, isoxazole, isothiazole, imidazole , oxazole, or thiazole, and optionally substituted C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl are each substituted by 1 to 3 substituents independently selected from optionally substituted heteroaryl, and each is optionally substituted with -CN, -OH (e.g., optionally containing a C1-C6 hydroxyalkyl such as -CH2-CH2-OH, a secondary -OH such as -CH2-CH(CH3)-OH, or a tertiary -OH such as -CH2-C(CH3)2-OH), oxetanyl, C1-C3 alkoxy, optionally substituted C3-C5 cycloalkyl, -CONR 10 R 10 or optionally substituted C3-C5 cycloalkyl, phenyl, 1,3-benzodioxole, 2,3-dihydro-1,4-benzodioxine, heterocycle, or heteroaryl is each independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -SO2R 10 -NR 10 R 10 , —CH 2 —, or a pharmaceutically acceptable salt thereof.

[0172] 28. R2 is an optionally substituted bicyclic ring selected from 1,3-benzodioxole, 2,3-dihydro-1,4-benzodioxine, isoindolin-1-one, indolin-2-one, benzo[d]oxazol-2(3H)-one, 1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one, or 2,3-dihydro-[1,4]dioxino[2,3-b]pyridine, or 1, 2, 3, 4 or 5 independently selected from N, O or S. is an optionally substituted bicyclic heteroaryl of 8 to 10 ring atoms containing 5 ring heteroatoms, wherein the optionally substituted bicyclic ring is optionally substituted with 1 to 3 substituents each independently selected from halogen and C1-C6 alkyl, or the optionally substituted bicyclic ring or the optionally substituted bicyclic heteroaryl is selected from -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R 10 , -CONR 10 R 10 , -NR 10 R 10 , -NR 10 CO2R 10 , optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C5 cycloalkyl, optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine or morpholine, optionally substituted phenyl, optionally substituted 1,3-benzodioxole, optionally substituted 2,3-dihydro-1,4-benzodioxine, or optionally substituted heteroaryl selected from pyridine, pyrimidine, pyridazine, pyrazine, pyrazole, isoxazole, isothiazole, imidazole, oxazole or thiazole, and the optionally substituted C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl is each selected from -CN, -OH (e.g., R 10 is a C1-C6 hydroxyalkyl such as -CH2-CH2-OH, and optionally R 10is hydroxyl containing a secondary —OH such as —CH2—CH(CH3)—OH or a tertiary —OH such as —CH2—C(CH3)2—OH), oxetanyl, C1-C3 alkoxy, or optionally substituted C3-C5 cycloalkyl, optionally substituted C3-C5, phenyl, 1,3-benzodioxole, 2,3-dihydro-1,4-benzodioxine, heterocycle or heteroaryl is each independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, —S02R 10 -NR 10 R 10 , —CH 2 —, or a pharmaceutically acceptable salt thereof.

[0173] 29. R2 is 1 to 3 R 10 22. The compound of any one of aspects 1 to 21, or a pharmaceutically acceptable salt thereof, wherein R2 is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl optionally substituted by substituents, or R2 is the following group: [ka]

[0174] 30. The compound according to embodiment 1 or embodiment 2, selected from: [ka] [ka] [ka] [ka] [ka] [ka]

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[0175] 31. A pharmaceutical composition comprising a compound according to any one of aspects 1 to 30, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0176] 32. A method for 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 according to any one of aspects 1 to 30, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to aspect 31.

[0177] 33. The method of embodiment 32, wherein the PI3K is PI3K alpha.

[0178] 34. A method according to aspect 32 or aspect 33, wherein the PI3K associated with the disease or disorder has an H1047R mutation, an E575K mutation, or both an H1047R mutation and an E575K mutation.

[0179] 35. The method of any one of aspects 32 to 34, wherein the disease or disorder is cancer.

[0180] 36. The method of aspect 35, 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.

[0181] 37. The method of embodiment 35, wherein the cancer is breast cancer.

[0182] 38. The method of aspect 35, wherein the cancer is hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced or metastatic breast cancer.

[0183] 39. The method of any one of aspects 32-34, wherein the disorder is CLOVES syndrome or PROS.

[0184] 40. A method for inhibiting phosphoinositide 3-kinase (PI3K), comprising administering to a patient in need thereof a therapeutically effective amount of a compound according to any one of aspects 1 to 30, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to aspect 31.

[0185] 41. A method for treating cancer or a disorder, comprising administering to a patient in need thereof a therapeutically effective amount of a compound according to any one of aspects 1 to 30, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to aspect 31.

[0186] 42. The method of aspect 41, 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.

[0187] 43. The method of embodiment 41, wherein the cancer is breast cancer.

[0188] 44. The method of aspect 41, wherein the cancer is hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced or metastatic breast cancer.

[0189] 45. The method of aspect 41, wherein the disorder is CLOVES syndrome or PROS.

[0190] 46. ​​A compound according to any one of aspects 1-30, or a pharmaceutically acceptable salt thereof, for use in therapy.

[0191] 47. A compound according to any one of aspects 1 to 30, or a pharmaceutically acceptable salt thereof, for use in the treatment of a disease or disorder associated with the modulation of PI3K.

[0192] 48. The compound or a pharmaceutically acceptable salt thereof for use according to aspect 47, wherein the disease or disorder associated with modulation of PI3K is cancer.

[0193] 49. The compound or a pharmaceutically acceptable salt thereof for use according to aspect 48, 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.

[0194] 50. The compound or a pharmaceutically acceptable salt thereof for use according to aspect 48, wherein the cancer is breast cancer.

[0195] 51. The compound or a pharmaceutically acceptable salt thereof for use according to aspect 48, wherein the cancer is hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced or metastatic breast cancer.

[0196] 52. The compound or a pharmaceutically acceptable salt thereof for use according to aspect 47, wherein the disorder is CLOVES syndrome or PROS.

[0197] 53. Use of a compound according to any one of aspects 1 to 30, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a disease or disorder associated with the modulation of PI3K.

[0198] 54. The use according to aspect 53, wherein the disease or disorder associated with the regulation of PI3K is cancer.

[0199] 55. The use according to aspect 54, 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.

[0200] 56. The use according to aspect 54, wherein the cancer is breast cancer.

[0201] 57. The use according to aspect 54, wherein the cancer is hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced or metastatic breast cancer.

[0202] 58. The use according to aspect 53, wherein the disorder is CLOVES syndrome or PROS.

[0203] Pharmaceutical Composition In some aspects, the present disclosure provides pharmaceutical compositions comprising a compound of Formula (I), (II), (III), or (IV) as an active ingredient. In some embodiments, the present disclosure provides pharmaceutical compositions comprising a compound of Formula (I), (II), (III), or (IV), or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or excipients.

[0204] As used herein, the term "composition" is intended to encompass a product containing specified ingredients in specified amounts, and also encompasses any product that results directly or indirectly from the combination of specified ingredients in specified amounts.

[0205] The compounds of Formula (I), (II), (III), or (IV) can be formulated for oral administration in forms such as tablets, capsules (each of which includes sustained-release or extended-release formulations), pills, powders, granules, elixirs, tinctures, suspensions, syrups, and emulsions. The compounds of Formula (I), (II), (III), or (IV) can also be formulated for intravenous (bolus or infusion), intraperitoneal, topical, subcutaneous, intramuscular, or transdermal (e.g., patch) administration, all using forms well known to those of ordinary skill in the pharmaceutical arts.

[0206] The formulation of the present disclosure may be in the form of an aqueous solution containing an aqueous vehicle. The aqueous vehicle component may include water and at least one pharmaceutically acceptable excipient. Suitable acceptable excipients include those selected from the group consisting of solubility enhancers, chelating agents, preservatives, tonicity agents, viscosity / suspending agents, buffers, and pH adjusters, and mixtures thereof.

[0207] According to a further aspect of the present disclosure, there is provided a pharmaceutical composition comprising a compound of any one of the formulae disclosed herein, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable diluent or carrier.

[0208] Compositions of the disclosure may be in a form suitable for oral use (e.g., as tablets, troches, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups, or elixirs), topical use (e.g., as creams, ointments, gels, or aqueous or oily solutions or suspensions), administration by inhalation (e.g., as a finely divided powder or liquid aerosol), administration by insufflation (e.g., as a finely divided powder), or parenteral administration (e.g., as a sterile aqueous or oily solution for intravenous, subcutaneous, intramuscular, intraperitoneal, or intramuscular administration, or as a suppository for rectal administration).

[0209] The compositions of the present disclosure can 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 agents, sweeteners, flavoring agents, and / or preservatives.

[0210] How to use In some aspects, the disclosure provides a method of modulating PI3K (e.g., PI3Kα) activity (e.g., in vitro or in vivo), comprising contacting a cell with a therapeutically effective amount of a compound of Formula (I), (II), (III), or (IV) or a pharmaceutically acceptable salt thereof.

[0211] 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), (II), (III), or (IV), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0212] 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), (II), (III), or (IV), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0213] 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), (II), (III), or (IV) or a pharmaceutically acceptable salt thereof.

[0214] 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 a therapeutically effective amount of a compound of Formula (I), (II), (III), or (IV) or a pharmaceutically acceptable salt thereof, to an effective amount of a CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof; 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; 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.

[0215] In some embodiments, the disease or disorder is associated with PI3K activity being involved. In some embodiments, the disease or disorder is a disease or disorder in which PI3K activity is involved.

[0216] In some embodiments, the disease or disorder is cancer.

[0217] In some embodiments, the cancer is acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), adrenocortical carcinoma, AIDS-related cancer, AIDS-related lymphoma, anal cancer, astrocytoma, basal cell carcinoma, cholangiocarcinoma, bladder cancer, bone cancer, osteosarcoma, malignant fibrous histiocytoma, brain tumor, breast cancer, bronchial tumor, Burkitt's lymphoma, carcinoid tumor, cancer of unknown primary, cardiac (heart) tumor, atypical teratoid / rhabdoid tumor, primary CNS lymphoma, cervical cancer, bile duct carcinoma, chordoma, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, mycosis fungoides, Sézary syndrome, non-invasive DCIS (Digestive Cell Invasion Syndrome), embryonal tumor, medulloblastoma, endometrial cancer, ependymoma, esophageal cancer, esthesioneuroblastoma, Ewing's sarcoma, extracranial germ cell tumor, extragonadal germ cell tumor, fallopian tube cancer, gallbladder cancer, gastric cancer, gastrointestinal carcinoid tumor, malignant gastrointestinal stromal tumor (GIST), germ cell tumor, gestational trophoblastic disease, hairy cell leukemia, head and neck cancer, hepatocellular carcinoma, Langerhans cell histiocytosis, Hodgkin's lymphoma, pancreatic islet cell tumor, pancreatic neuroendocrine tumor, Kaposi's 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 cell cervical cancer, midline carcinoma with nut gene alterations, oral cancer cancer, multiple endocrine neoplasia syndrome, multiple myeloma / plasma cell neoplasm, myelodysplastic syndrome, myelodysplastic tumor, myeloproliferative neoplasm, chronic myeloproliferative neoplasm, nasal cavity and paranasal sinus cancer, nasopharyngeal cancer, neuroblastoma, non-Hodgkin's lymphoma, non-small cell lung cancer, oral cancer, lip and oral cavity cancercancer), oropharyngeal cancer, malignant fibrous histiocytoma of bone, ovarian cancer, pancreatic cancer, pancreatic neuroendocrine tumors (islet cell tumors), papillomatosis, paraganglioma, paranasal sinus and nasal 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, kidney cancer 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 tumor, transitional cell carcinoma of the renal pelvis and ureter, urethral cancer, uterine sarcoma, vaginal cancer, vascular tumors, vulvar cancer, and Wilms' tumor.

[0218] In some embodiments, the cancer is endometrial cancer, breast cancer, esophageal squamous cell carcinoma, cervical squamous cell carcinoma, cervical adenocarcinoma, colorectal adenocarcinoma, bladder urothelial carcinoma, glioblastoma, ovarian cancer, non-small cell lung cancer, esophagogastric carcinoma, 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, non-clear cell renal cell carcinoma, clear cell renal cell carcinoma, germ cell carcinoma, thymic tumor, pheochromocytoma, heterogeneous neuroepithelial tumor, thyroid cancer, leukemia, or encapsulated glioma.

[0219] In some embodiments, the cancer is breast cancer, prostate cancer, or brain cancer.

[0220] In some embodiments, the cancer is breast cancer, in some embodiments, the cancer is prostate cancer, in some embodiments, the cancer is brain cancer.

[0221] 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's disease of the breast or nipple. In some embodiments, the breast cancer is inflammatory breast cancer (IBC). In some embodiments, the breast cancer is hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced or metastatic breast cancer.

[0222] 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.

[0223] 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 a choroid plexus carcinoma. In some embodiments, the brain cancer is a craniopharyngioma. In some embodiments, the brain cancer is a germinal 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.

[0224] In some embodiments, the PI3K-related disease or disorder 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.

[0225] In some embodiments, the disease or disorder associated with PI3K is CLOVES syndrome.

[0226] In some embodiments, the disease or disorder associated with PI3K is PROS.

[0227] In some embodiments, the PI3K-related disease or disorder 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.

[0228] In some embodiments, the disease or disorder associated with PI3K is a breast neoplasm, a thyroid neoplasm, an ovarian neoplasm, a non-small cell lung cancer, 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 PI3K is non-small cell lung cancer. 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.

[0229] In some embodiments, the PI3K-associated disease or disorder is breast cancer, brain cancer, prostate cancer, endometrial cancer, gastric cancer, colorectal cancer, lung cancer, ovarian cancer, skin cancer, or head and neck cancer.

[0230] In some embodiments, the disease or disorder associated with PI3K is leukemia, lymphoma, or sarcoma.

[0231] In some embodiments, the cancer is endometrial cancer, head and neck cancer, or sarcoma.

[0232] In some embodiments, the cancer is endometrial cancer. In some embodiments, the cancer is head and neck cancer. In some embodiments, the cancer is sarcoma.

[0233] In some embodiments, the sarcoma is soft tissue sarcoma, osteosarcoma, chondrosarcoma, Ewing's sarcoma, hemangioendothelioma, angiosarcoma, fibrosarcoma, myofibrosarcoma, chordoma, adamantinoma, liposarcoma, leiomyosarcoma, malignant peripheral nerve sheath tumor, rhabdomyosarcoma, synovial sarcoma, or malignant solitary fibrous tumor.

[0234] In some embodiments, the sarcoma is a soft tissue sarcoma. In some embodiments, the soft tissue sarcoma is, unless otherwise specified, 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 tissue, leiomyosarcoma, malignant glomus tumor, rhabdomyosarcoma, hemangioendothelioma, angiosarcoma of soft tissue, extraskeletal osteosarcoma, gastrointestinal stromal tumor, malignant gastrointestinal stromal tumor (GIST), malignant peripheral sarcoma, ... transthecal 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's 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.

[0235] In some aspects, the present disclosure provides a method of treating or preventing cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), (II), (III), or (IV), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the disclosure.

[0236] In some aspects, the present disclosure provides a method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), (II), (III), or (IV), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the disclosure.

[0237] In some aspects, the present disclosure provides a method of treating or preventing breast cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), (II), (III), or (IV), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the disclosure.

[0238] In some aspects, the present disclosure provides a method of treating breast cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), (II), (III), or (IV), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the disclosure.

[0239] In some aspects, the present disclosure provides methods of treating or preventing prostate cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), (II), (III), or (IV), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the disclosure.

[0240] In some aspects, the present disclosure provides a method of treating prostate cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), (II), (III), or (IV), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the disclosure.

[0241] In some aspects, the present disclosure provides a method of treating or preventing brain cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), (II), (III), or (IV), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the disclosure.

[0242] In some aspects, the present disclosure provides a method of treating brain cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), (II), (III), or (IV), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0243] In some aspects, the disclosure provides a compound of Formula (I), (II), (III), or (IV), or a pharmaceutically acceptable salt thereof, for use in therapy.

[0244] In some aspects, the disclosure provides a compound of Formula (I), (II), (III), or (IV), or a pharmaceutically acceptable salt thereof, for use in modulating PI3K (e.g., PI3Kα) activity (e.g., in vitro or in vivo).

[0245] In some aspects, the present disclosure provides a compound of Formula (I), (II), (III), or (IV), or a pharmaceutically acceptable salt thereof, for use in the treatment or prevention of a disease or disorder disclosed herein.

[0246] In some aspects, the present disclosure provides a compound of Formula (I), (II), (III), or (IV), or a pharmaceutically acceptable salt thereof, for use in treating a disease or disorder disclosed herein.

[0247] In some aspects, the disclosure provides a compound of Formula (I), (II), (III), or (IV), or a pharmaceutically acceptable salt thereof, for use in treating or preventing cancer.

[0248] In some aspects, the present disclosure provides a compound of Formula (I), (II), (III), or (IV), or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer.

[0249] In some aspects, the disclosure provides a compound of Formula (I), (II), (III), or (IV), or a pharmaceutically acceptable salt thereof, for use in treating or preventing breast cancer.

[0250] In some aspects, the disclosure provides a compound of Formula (I), (II), (III), or (IV), or a pharmaceutically acceptable salt thereof, for use in the treatment of breast cancer.

[0251] In some aspects, the disclosure provides a compound of Formula (I), (II), (III), or (IV), or a pharmaceutically acceptable salt thereof, for use in treating or preventing prostate cancer.

[0252] In some aspects, the present disclosure provides a compound of Formula (I), (II), (III), or (IV), or a pharmaceutically acceptable salt thereof, for use in the treatment of prostate cancer.

[0253] In some aspects, the disclosure provides a compound of Formula (I), (II), (III), or (IV), or a pharmaceutically acceptable salt thereof, for use in treating or preventing brain cancer.

[0254] In some aspects, the disclosure provides a compound of Formula (I), (II), (III), or (IV), or a pharmaceutically acceptable salt thereof, for use in the treatment of brain cancer.

[0255] In some aspects, the disclosure provides the use of a compound of Formula (I), (II), (III), or (IV) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for modulating PI3K (e.g., PI3Kα) activity (e.g., in vitro or in vivo).

[0256] In some aspects, the disclosure provides the use of a compound of Formula (I), (II), (III), or (IV), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating or preventing a disease or disorder disclosed herein.

[0257] In some aspects, the disclosure provides the use of a compound of Formula (I), (II), (III), or (IV), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating a disease or disorder disclosed herein.

[0258] In some aspects, the disclosure provides the use of a compound of Formula (I), (II), (III), or (IV), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating or preventing cancer in a subject in need thereof.

[0259] In some aspects, the disclosure provides the use of a compound of Formula (I), (II), (III), or (IV), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating cancer in a subject in need thereof.

[0260] In some aspects, the disclosure provides the use of a compound of Formula (I), (II), (III), or (IV), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating or preventing breast cancer in a subject in need thereof.

[0261] In some aspects, the disclosure provides the use of a compound of Formula (I), (II), (III), or (IV), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating breast cancer in a subject in need thereof.

[0262] In some aspects, the disclosure provides the use of a compound of Formula (I), (II), (III), or (IV), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating or preventing prostate cancer in a subject in need thereof.

[0263] In some aspects, the disclosure provides the use of a compound of Formula (I), (II), (III), or (IV), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating prostate cancer in a subject in need thereof.

[0264] In some aspects, the disclosure provides the use of a compound of Formula (I), (II), (III), or (IV), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating or preventing brain cancer in a subject in need thereof.

[0265] In some aspects, the disclosure provides the use of a compound of Formula (I), (II), (III), or (IV), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating brain cancer in a subject in need thereof.

[0266] The present disclosure provides compounds that function as modulators of PI3K activity. Accordingly, the present disclosure provides a method of modulating PI3K activity in vitro or in vivo, comprising contacting a cell with a therapeutically effective amount of a compound as defined herein, or a pharmaceutically acceptable salt thereof.

[0267] In some embodiments, the PI3K modulation is an inhibition of PI3K.

[0268] In some embodiments, the PI3K inhibitor is a PI3K alpha inhibitor. In some embodiments, the PI3K inhibitor is a PI3K alpha H1047R mutation inhibitor. In some embodiments, the PI3K inhibitor is a PI3K alpha E575K mutation inhibitor. In some embodiments, the PI3K inhibitor is both a PI3K alpha H1047R mutation inhibitor and a PI3K alpha E575K mutation inhibitor.

[0269] The efficacy of the compounds of the present disclosure can be determined by industry-recognized assays / disease models according to standard practices described in the art and elucidating the same found in current general knowledge.

[0270] 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, comprising administering to the patient a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein.

[0271] Administration route Compounds of formula (I), (II), (III), or (IV), or pharmaceutical compositions containing these compounds, may be administered to a subject by any convenient route of administration, whether systemic / peripheral or local (i.e., at the desired site of action).

[0272] Routes of administration include, but are not limited to, oral (e.g., by ingestion); buccal; sublingual; transdermal (including, e.g., by patches, plasters, etc.); transmucosal (including, e.g., by patches, plasters, etc.); intranasal (e.g., by nasal spray); ocular (e.g., by eye drops); pulmonary (e.g., via aerosol, e.g., through the mouth or nose, e.g., by inhalation or insufflation therapy); rectal (e.g., by suppository or enema); vaginal (e.g., by pessary); parenteral, e.g., by injection, including subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcuticular, intraarticular, subarachnoid, and intrasternal; and by implantation of a depot or reservoir, e.g., subcutaneously or intramuscularly. [Example]

[0273] Exemplary compounds of Formulas (I), (II), (III), and (IV) have been synthesized and tested in the Examples. It is understood that the compounds of Formulas (I), (II), (III), and (IV) can be converted to the corresponding pharmaceutically acceptable salts of the compounds using routine techniques in the art.

[0274] Nuclear magnetic resonance (NMR) spectra were recorded at 400 MHz or 300 MHz as indicated and at 300.3 K unless otherwise stated. Chemical shifts (δ) are reported in parts per million (ppm). Spectra were recorded using Bruker or Varian instruments with 8, 16, or 32 scans.

[0275] LC-MS chromatograms and spectra were recorded using an Agilent 1200 or Shimadzu LC-20 AD&MS 2020 instrument using a C-18 column such as a Luna-C18 2.0 x 30 mm or an Xbridge Shield RPC18 2.1 x 50 mm. The injection volume was 0.7-8.0 μl, and the flow rate was typically 0.8 or 1.2 ml / min. The detection method was diode array (DAD) or evaporative light scattering (ELSD) with positive ion electrospray ionization. The MS range was 100-1000 Da. The solvent was a gradient of water and acetonitrile, both containing modifiers such as trifluoroacetic acid or ammonium carbonate (typically 0.01-0.04%).

[0276] Abbreviation: ACN Acetonitrile AcOH acetic acid ADP adenosine diphosphate ATP adenosine triphosphate CDCl3 chloroform-d DCM dichloromethane DIAD Diisopropyl azodicarboxylate DMF N,N-dimethylformamide DMSO dimethyl sulfoxide DMSO-d6 hexadeuterodimethyl sulfoxide eq equivalent EtOAc ethyl acetate EtOH ethanol h hour(s) 1 H NMR Proton Nuclear Magnetic Resonance Spectroscopy IPA Isopropanol K2CO3 Potassium Carbonate LC-MS Liquid Chromatography-Mass Spectrometry MeOH Methanol MgSO4 Magnesium Sulfate min Minute(s) MS ES Mass Spectroscopy Electrospray MTBE Methyl tert-butyl ether NH4HCO3 Ammonium Bicarbonate ppm parts per million rt room temperature SFC Supercritical Fluid Chromatography THF tetrahydrofuran

[0277] Intermediate 1: (2-bromo-4-methyl-phenyl)propanoate [ka] A mixture of 2-bromo-4-methyl-phenol (10.0 g, 53.5 mmol) and pyridine (6.34 g, 80.2 mmol) in DCM (100 mL) was treated with propanoyl 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 HCl (2 M), and extracted with DCM (2 × 100 mL). The combined organic extracts were washed with saturated aqueous sodium chloride solution (2 × 150 mL), dried over anhydrous NaSO, filtered, and concentrated to give the product as an oil (13 g, crude). 1 HNMR (400MHz, DMSO-d6) δppm1.17(t,J=7.6Hz,3H),2.30(s,3H),2.62(q,J=7.6Hz,2H),7.11-7.18(m,1H),7.19-7.26(m,1H),7.50-7.55(m,1H).

[0278] Intermediate 1B: (2-Bromo-4-methyl-phenyl)acetate [ka] A mixture of 2-bromo-4-methyl-phenol (300 g, 1.6 mol) and pyridine (152 g, 1.92 mol) in DCM (2.4 L) was treated with acetyl chloride at 0 °C and stirred at 25 °C for 16 h. The mixture was diluted with water (1500 mL), the pH adjusted to 5 with HCl (2 M aqueous solution), and extracted with DCM (3 × 500 mL). The combined organic extracts were washed with saturated aqueous sodium chloride solution (2 × 250 mL), dried over Na SO , filtered, and concentrated to give the product as an oil (400 g, crude). 1 HNMR(400MHz,CDCl3)δppm2.24(s,3H),2.25(s,3H),6.91(d,J=8.4Hz,2H),7.01-7.02(m,2H),7.33(s,1H)

[0279] Intermediate 2: 1-(3-bromo-2-hydroxy-5-methyl-phenyl)propan-1-one [ka] Route 1: A mixture of (2-bromo-4-methyl-phenyl)propanoic acid (12.5 g, 51.4 mmol) and AlCl (24.0 g, 180 mmol) was stirred at 140 °C for 1 h. After cooling to room temperature, the mixture was quenched by dropwise addition of water (80 mL) and stirred for 30 min. The mixture was extracted with EtOAc (3 × 100 mL). The combined organic extracts were washed with saturated aqueous sodium chloride solution (2 × 200 mL), dried over anhydrous NaSO, and filtered. The filtrate was concentrated and triturated with petroleum ether (20 mL) to give the product as a solid (9.82 g, 79%). 1 HNMR (400MHz, DMSO-d6) δppm1.10(t,J=7.2Hz,3H),2.28(s,3H),3.15(q,J=7.2Hz,2H),7.66-7.73(m,1H),7.77-7.83(m,1H),12.66(s,1H).

[0280] Route 2: (2-Bromo-4-methyl-phenyl)propanoate (120 g, 496 mmol) was transferred to a reactor, cooled to -20°C, and treated with trifluoromethanesulfonic acid (216 mL). After the addition was complete, the reaction was stirred at 60°C for 1 hour. The reaction was cooled to room temperature and poured into ice water (600 mL). The product was removed by filtration as a yellow solid (114 g, 95%). MS ES+ m / z 241, 243 [M+H] - . 1 HNMR(400MHz,CDCl3)δppm1.26(t,3H),2.33(s,3H),3.06(q,2H),7.55(m,2H),12.87(s,1H)

[0281] Intermediate 2B: 1-(3-bromo-2-hydroxy-5-methyl-phenyl)ethanone [ka] A mixture of 2-bromo-4-methyl-phenyl acetate (50 g, 218 mmol) and AlCl (102 g, 764 mmol) was degassed, purged with N three times, and stirred at 140 °C for 1 h. After cooling to room temperature, the reaction was diluted with DCM (30 mL) and added dropwise to 150 mL of water at 0 °C. The mixture was filtered, and the aqueous phase was extracted with DCM (2 × 150 mL). The combined organic extracts were washed with saturated aqueous sodium chloride, dried over anhydrous NaSO, filtered, and concentrated. The residue was triturated with petroleum ether (2 × 150 mL) to give the product as a solid (30 g, 52%). 1 H NMR(400MHz,CDCl3)δppm2.30(s,3H),2.68(s,3H),7.73(s,1H),7.33(s,1H),12.64(s,1H)

[0282] Intermediate 3B: 1-(3-bromo-4-chloro-2-hydroxy-5-methyl-phenyl)propan-1-one [ka] A mixture of 1-(4-chloro-2-hydroxy-5-methyl-phenyl)propan-1-one (6.5 g, 33 mmol) and sodium acetate (4.0 g, 49 mmol) in acetic acid (50 mL) was treated with the dropwise addition of bromine (1.7 mL, 33 mmol). The reaction mixture was stirred at room temperature for 12 hours and then diluted with water (100 mL) and EtOAc (200 mL). The organic phase was concentrated under reduced pressure, and the residue was purified by silica gel chromatography eluting with 0% to 100% EtOAc in heptane to give the title compound (7.8 g, 86%). MS ES+ m / z 277, 279 [M+H] + .

[0283] Intermediate 3: (E)-1-(3-bromo-2-hydroxy-5-methyl-phenyl)-2-methyl-3-phenyl-prop-2-en-1-one [ka] A mixture of 1-(3-bromo-2-hydroxy-5-methyl-phenyl)propan-1-one (200 g, 822.72 mmol), benzaldehyde (96.04 g, 904.99 mmol), AcOH (105.23 g, 1.75 mol), and piperidine (172.33 g, 2.02 mol) in EtOH (1600 mL) was stirred at 70 °C for 16 h. The resulting dark solution was poured into water (3 L), filtered, and the solid was dissolved in 6 L of DCM. The organic solution was dried over anhydrous NaSO, filtered, and concentrated to give the product as a dark gum. MS ES+ m / z 331, 333 [M+H] + .

[0284] Intermediate 4B: (E)-1-(3-bromo-4-chloro-2-hydroxy-5-methyl-phenyl)-2-methyl-3-(3-pyridyl)prop-2-en-1-one [ka] A mixture of 1-(3-bromo-4-chloro-2-hydroxy-5-methyl-phenyl)propan-1-one (1.00 g, 3.60 mmol), nicotinaldehyde (0.463 g, 4.32 mmol), and potassium hydroxide (0.809 g, 14.4 mmol) in EtOH (10 mL) was stirred at room temperature for 2 hours. The mixture was diluted with water (100 mL) and extracted with EtOAc (100 mL). The organic layer was dried and concentrated under reduced pressure to give the title compound (1.3 g, 98%). MS ES+ m / z 366, 368 [M+H] + .

[0285] Intermediate 1A: 8-Bromo-4-hydroxy-3,6-dimethyl-chromene-2-thione [ka] Under nitrogen, a solution of 1-(3-bromo-2-hydroxy-5-methyl-phenyl)propan-1-one (495 g, 2.04 mol) and carbon disulfide (233 g, 3.06 mol) in THF (4.95 L) was cooled to approximately -25 °C and treated dropwise with sodium bis(trimethylsilyl)amide (2 M in THF, 3.57 L, 1.79 mol). Upon complete addition, the reaction was allowed to warm to room temperature over 16 h. The reaction was added dropwise to 15% aqueous HSO (4.95 L) at 0-10 °C to maintain the pH of the mixture between 2 and 3. The layers were separated, and the aqueous layer was extracted with MTBE (495 mL). The organic layers were combined and concentrated under reduced pressure, and the residue was suspended in heptane (1.49 L). The suspension was stirred at room temperature for 5 hours and the title compound (557.9 g, 96%) was collected by filtration as a yellow solid. 1 HNMR(400MHz,DMSO-d6)δppm 2.24(s,3H),2.38(s,3H),7.76(s,1H),7.79(s,1H)

[0286] Intermediate 5B: 8-Bromo-4-hydroxy-6-methyl-chromene-2-thione [ka] A solution of 1-(3-bromo-2-hydroxy-5-methyl-phenyl)ethanone (65 g, 284 mmol) in THF (800 mL) was treated with NaHMDS (851 mL, 1 M) at −50° C. over 30 min, warmed to −5° C. to 0° C., and stirred for 1 h. The reaction was cooled to −20° C., treated dropwise with CS (64.8 g, 851 mmol) over 1 h, warmed to 25° C., and stirred for an additional 16 h. The reaction was quenched with HSO (800 mL, 15%) at −50° C. over 1 h, warmed to room temperature, and extracted with EtOAc (2 × 1 L). The combined organic extracts were washed with saturated aqueous sodium chloride (1 L), dried over anhydrous NaSO, filtered, and concentrated. The residue was triturated with EtOAc (0.5 L) to give the product as a solid (210 g crude, 64%, purity approx. 76%).

[0287] Intermediate 2A: 8-Bromo-2-ethylsulfanyl-3,6-dimethyl-chromen-4-one [ka] A mixture of 8-bromo-4-hydroxy-3,6-dimethyl-chromene-2-thione (560 g, 1.96 mol), KCO (271.4 g, 1.96 mol), and ethyl iodide (459.5 g, 2.95 mol) in acetone (5.60 L) was stirred at 20-25 °C for 2 h. The reaction was filtered and the solid was washed with THF (1.12 L). The mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography eluting with 1% to 33% EtOAc in heptane to give the title compound (545.5 g, 88%) as a brown solid. 1 HNMR (400MHz, CDCl3) δppm1.50(t,J=7.36Hz,3H),2.05(s,3H),2.43(s,3H),3.31(q,J=7.36Hz,2H),7.64(s,1H),7.93(s,1H).

[0288] Intermediate 6B: 8-Bromo-2-ethylsulfanyl-6-methyl-chromen-4-one [ka] A mixture of 8-bromo-4-hydroxy-6-methyl-chromene-2-thione (20.0 g, 73.8 mmol), EtI (46 g, 295 mmol), and KCO (12.2 g, 88.5 mmol) in acetone (200 mL) was stirred at 60 °C for 3 h. When the reaction was cooled to room temperature, the mixture was diluted with water (200 mL) and extracted with DCM (2 × 200 mL). The combined organic extracts were concentrated and purified by silica gel chromatography eluting with 20% to 40% EtOAc in petroleum ether to give the product as a gum. 1 HNMR (400MHz, CDCl3) δppm1.51(t,J=7.2Hz,3H),2.45(s,3H),3.22(q,J=7.2Hz,2H),6.32(s,1H),7.70(s,1H),7.93(s,1H).

[0289] Intermediate 4: 8-Bromo-3,6-dimethyl-2-phenyl-chromen-4-one [ka] Route 1: A mixture of (E)-1-(3-bromo-2-hydroxy-5-methyl-phenyl)-2-methyl-3-phenyl-prop-2-en-1-one (284 g, 857.48 mmol) and iodine (21.76 g, 85.75 mmol, 17.27 mL, 0.1 equiv.) in DMSO (1200 mL) was stirred at 140 °C for 2 h to give a dark brown solution. After cooling to room temperature, the reaction was poured into 3 L of water, filtered, and the solid product was dissolved in DCM (4 L), dried over anhydrous NaSO, filtered, and concentrated to give a residue. The residue was triturated with petroleum ether / EtOAc (1:1, 1 L) to give the product as a pale yellow solid (195 g, 69%). MS ES+ m / z 329, 331 [M+H] + .

[0290] Route 2: A solution of 1-(3-bromo-2-hydroxy-5-methyl-phenyl)propan-1-one (50.0 g, 205.7 mmol) in THF (100 mL) was cooled to -80 °C and treated with lithium bis(trimethylsilyl)amide (1 M in THF, 617 mmol). After stirring at -80 °C for 1 h, the mixture was warmed to 0 °C and stirred for 1 h. The mixture was cooled to -80 °C and treated dropwise with benzoyl chloride (37.6 g, 267.4 mmol). After the addition was complete, the reaction was stirred at 25 °C for 16 h. The reaction was cooled to -20 °C and the pH was adjusted to 4 with 50% aqueous acetic acid. The THF was removed under vacuum, and the precipitate was removed by filtration. The solid was dissolved in acetic acid and aqueous HCl (250 mL / 10 mL), and the resulting solution was stirred at 100 °C for 1 h. The mixture was cooled to 20° C. and diluted with water (100 mL). The solid was removed by filtration, washed with water (50 mL), and triturated with 200 mL of EtOAc at room temperature for 30 minutes. The product was collected by filtration as an off-white solid (170.7 g, 83%). MS ES+ m / z 329,331 [M+H] + . 1 HNMR(400MHz,CDCl3)δppm2.24(s,3H),2.48(s,3H),7.55-7.57(m,3H),7.75-7.78(m,3H),8.00(s,1H) The following compounds in Table 1 were made in a similar manner as described for 8-bromo-3,6-dimethyl-2-phenyl-chromen-4-one, Route 2.

[0291] Table 1 [Table 1]

[0292] Intermediate 7B: 8-Bromo-7-chloro-3,6-dimethyl-2-(3-pyridyl)chromen-4-one [ka] A mixture of (E)-1-(3-bromo-4-chloro-2-hydroxy-5-methyl-phenyl)-2-methyl-3-(3-pyridyl)prop-2-en-1-one (1.2 g, 3.3 mmol) and iodine (0.083 g, 0.33 mmol) in DMSO (5 mL) was heated at 90° C. for 3 h. The reaction mixture was loaded onto a C18 column and purified by reverse-phase chromatography eluting with 60% ACN in water (with trifluoroacetic acid additive) to give the title compound (0.950 g, 80%). MS ES+ m / z 364, 366 [M+H] + .

[0293] Intermediate 6: 8-acetyl-3,6-dimethyl-2-phenyl-chromen-4-one [ka] Route 1: A mixture of 8-bromo-3,6-dimethyl-2-phenyl-chromen-4-one (195 g, 592.37 mmol), bis(triphenylphosphine)palladium(II) dichloride (20.79 g, 29.62 mmol), and tributyl(1-ethoxyvinyl)stannane (256.72 g, 710.84 mmol, 239.92 mL) in dioxane (1600 mL) was stirred at 95 °C under N for 16 h to give a dark brown solution. After cooling to room temperature, the reaction was treated with 1 M aqueous HCl (100 mL) and stirred at 20 °C for 30 min. The mixture was quenched with saturated aqueous KF (2000 mL), stirred for 30 min, and filtered. The filter cake was washed with 10% MeOH in DCM (5 × 5000 mL). The combined extracts were dried over anhydrous Na2SO4, filtered, and concentrated to give a residue. The residue was triturated with petroleum ether / EtOAc (5 / 1, 1000 mL) to give the crude product, which was triturated with DCM / MeOH (10 / 1, 500 mL) to give the product as a pale yellow solid (180 g, 96%, 92% purity). MS ES+ m / z 293 [M+H] + .

[0294] Route 2: A mixture of 8-bromo-3,6-dimethyl-2-phenyl-chromen-4-one (50.0 g, 151.9 mmol), palladium acetate (0.34 g, 1.52 mmol), 1,3-bis(diphenylphosphino)propane (1.25 g, 3.04 mmol), trimethylamine (46.17 g, 455.7 mmol), n-butyl vinyl ether (76 g, 759.5 mmol), and ethylene glycol (400 mL) was stirred at 100 °C for 7 h under a nitrogen atmosphere. The reaction mixture was cooled to 30 °C, treated with 3 g of activated carbon, and stirred. The suspension was filtered through Celite, and the pH of the filtrate was adjusted to 3–4 with HCl and stirred at 60 °C for 12 h. The reaction mixture was cooled to 40 °C, and the solid was removed by filtration. The solid was slurried in 250 mL of THF and stirred at 60° C. for 5 hours. The reaction was cooled to 30° C. and the product (40 g, 90%) was removed by filtration and dried at 50° C. to give an off-white solid. MS ES+ m / z 293 [M+H] + . 1HNMR (400mHz, CDCl3) δppm2.21(s,3H),2.52(s,3H),2.73(s,3H),7.55-7.58(m,3H),7.67-7.70(m,2H),7.97(s,1H),8.26-8.27(m,1H).

[0295] The following compounds in Table 2 were made in a similar manner as described for 8-acetyl-3,6-dimethyl-2-phenyl-chromen-4-one, Route 1. Table 2 [Table 2]

[0296] Intermediate 4A: 2-Ethylsulfanyl-8-[(1S)-1-hydroxyethyl]-3,6-dimethyl-chromen-4-one [ka] Formic acid (9.99 g, 217 mmol) and triethylamine (14.6 g, 145 mmol) were dissolved in DCM (500 mL) and cooled to 0 °C. Upon cooling, 8-acetyl-2-ethylsulfanyl-3,6-dimethyl-chromen-4-one (20.0 g, 72.4 mmol) was added and stirred for 1-2 min to obtain a homogeneous solution. RuCl[(R,R)-Tsdpen(mesitylene) (CAS 174813-82-2, 2.50 g, 90%, 3.62 mmol) was added and stirred for 10 min. After that, the cooling bath was removed and the mixture was stirred at room temperature overnight. The mixture was washed with saturated aqueous NaHCO3. The aqueous layer was extracted three times with IPA / CHCl3 (1:3, v:v). The organic layers were combined, dried over MgSO4, filtered, and concentrated under reduced pressure. The crude residue was suspended in DCM (500 mL) and transferred to a large Erlenmeyer flask equipped with a stir bar. The suspension was diluted with DCM / heptane (5:1) to a total volume of 1500 mL. The contents of the flask were stirred at 200 rpm and warmed to 40°C. While warm, DCM was added until most of the solid dissolved (75 mL). The flask was cooled to room temperature and then placed in a freezer (-20°C) overnight. The solid was removed by filtration, completely dissolved in DCM, and the filtrate was concentrated under reduced pressure to give the title compound (7.41 g, 37%) as a white solid. ES-MS m / z 279 (M+H).

[0297] Intermediate 1C: 2-Ethylsulfanyl-8-[(1R)-1-hydroxyethyl]-3,6-dimethyl-chromen-4-one [ka] To a stirred solution of 8-acetyl-2-ethylsulfanyl-3,6-dimethyl-chromen-4-one (12.0 g, 43.4 mmol) in MeOH (150 mL) was added sodium borohydride (2.46 g, 65.1 mmol) at room temperature under nitrogen. The mixture was cooled to 0 °C, quenched with aqueous HCl (1 M; 10 mL), and the pH was adjusted to approximately 7 with aqueous sodium hydroxide. The resulting mixture was diluted with water (100 mL) and extracted with EtOAc (2 × 500 mL). The combined organic layers were washed with saturated aqueous sodium chloride (100 mL), dried over anhydrous sodium sulfate, and filtered. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography eluting with 60% to 70% ACN in 0.1% aqueous formic acid to afford the title compound (10 g, 83%) as a brown solid. MS ES+ m / z 279 [M+H] + .

[0298] The racemic product was purified by Prep-SFC [Opti-Chiral C9-5, 30 x 250 mm; 15% MeOH in CO2; 100 mL / min] to give two enantiomers as white solids. The first eluting enantiomer (4.7 g, 47%) was the title compound. The second eluting enantiomer (4.1 g, 41%) was consistent with intermediate 4A. For both, MS ES+ m / z 279 [M+H] + .

[0299] Intermediate 10B: 2-Ethylsulfanyl-8-((1S)-1-hydroxyethyl)-6-methyl-chromen-4-one [ka] In a manner similar to that used to prepare Intermediate 4A, 8-acetyl-2-ethylsulfanyl-6-methyl-chromen-4-one was used to obtain the title compound (1.24 g, 63%). MS ES+ m / z 265 [M+H] + .

[0300] Intermediate 2C: 3-chloro-2-ethylsulfanyl-8-((1S)-1-hydroxyethyl)-6-methyl-chromen-4-one [ka] 2-Ethylsulfanyl-8-[(1S)-1-hydroxyethyl]-6-methyl-chromen-4-one (0.105 g, 0.397 mmol), N-chlorosuccinimide (0.066 g, 0.497 mmol), and benzoyl peroxide (0.096 g, 0.397 mmol) were combined in acetonitrile (7 mL) and stirred at 25 °C for 2 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 10% to 70% EtOAc in heptane to give the title compound (0.100 g, 84%) as a white solid. MS ES+ m / z 299 [M+H] + .

[0301] Intermediate 8: 8-[(1S)-1-hydroxyethyl]-3,6-dimethyl-2-phenyl-chromen-4-one [ka] A flask equipped with an overhead stirrer and temperature probe was charged with 8-acetyl-3,6-dimethyl-2-phenyl-chromen-4-one (11.0 g, 37.25 mmol) and chloroform (200 mL). The stirred slurry was treated with formic acid (5.14 g, 111.76 mmol) and cooled to approximately 10°C in an ice bath. The cold solution was slowly treated with 1,8-diazabicyclo[5.4.0]undec-7-ene (17.01 g, 111.76 mmol), maintaining the temperature below 25°C. The reaction was removed from the cooling bath and treated with RuCl(p-cymene)[(S,S)-Ts-DPEN] (CAS 192139-90-5, 0.66 g, 1.12 mmol). The reaction was stirred at 45°C for 16 hours. The reaction was transferred to a separatory funnel and washed with 2 M aqueous HCl (2 × 50 mL). The organic layer was concentrated under vacuum to 50–100 mL at 45–50 °C. It was diluted with ACN (150 mL) and concentrated under vacuum to 50 mL at 45–50 °C. Another solvent exchange was performed until the volume of solvent was 50 mL. The material was cooled to room temperature over 1–2 hours, and the slurry was aged for 4 hours. The product (10.10 g, 92%) was collected by filtration, washed with ACN (25 mL), washed with heptane (50 mL), and dried under vacuum at 45 °C.

[0302] Intermediate 9: 8-[(1R)-1-hydroxyethyl]-3,6-dimethyl-2-phenyl-chromen-4-one [ka] A flask equipped with an overhead stirrer, condenser, and temperature probe was charged with 8-acetyl-3,6-dimethyl-2-phenyl-chromen-4-one (10 g, 34.2 mmol) and RuCl(p-cymene) [(R,R)-TsDPEN] (CAS 192139-92-7, 0.65 g, 1.03 mmol). 50 mL of methanol was added and stirring was initiated. The reaction was cooled to 10 °C and slowly treated with 1,8-diazabicyclo[5.4.0]undec-7-ene (15.62 g, 102.62 mmol), maintaining the temperature below 25 °C. After the addition was complete, the reaction was cooled back to 10 °C and treated in portions with formic acid (4.72 g, 102.62 mmol), maintaining the temperature below 15 °C. After the addition, the reaction was stirred at 55 °C for approximately 3 hours. The reaction was cooled to 20°C and treated with 4 M aqueous HCl (50 mL) over 1 h, and the resulting slurry was stirred at room temperature overnight. The product (9.35 g, 95%) was isolated by filtration, washed with water, and dried under vacuum at 45°C.

[0303] The following compounds in Table 3 were made in a similar manner as described for 8-[(1R)-1-hydroxyethyl]-3,6-dimethyl-2-phenyl-chromen-4-one. Table 3 [Table 3]

[0304] Intermediate 11B: 7-chloro-8-(1-hydroxyethyl)-3,6-dimethyl-2-(3-pyridyl)chromen-4-one. [ka] A solution of 8-acetyl-7-chloro-3,6-dimethyl-2-(3-pyridyl)chromen-4-one (0.550 g, 1.68 mmol) in DCM (10 mL) and MeOH (10 mL) at 0 °C was treated with sodium borohydride (0.064 g, 1.68 mmol) and stirred for 2 h. The reaction mixture was diluted with DCM (120 mL) and water (75 mL). The phases were separated and the aqueous layer was extracted with DCM (2x). The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 0% to 100% EtOAc in heptane to give the title compound (0.23 g, 42%). MS ES+ m / z 330 [M+H] + .

[0305] Intermediate 12B: 2-benzylsulfanyl-6-chloro-3-fluoro-pyridine [ka] A 0°C solution of phenylmethanethiol (0.88 mL, 7.57 mmol) and potassium hydroxide (0.411 g, 7.32 mmol) in EtOH (5 mL) was treated with a solution of 2,6-dichloro-3-fluoropyridine (1.00 g, 6.02 mmol) in EtOH (5 mL), followed by additional EtOH (2 mL). The ice bath was removed, and the reaction mixture was stirred for 20 h. The mixture was diluted with EtOAc, 1 M aqueous NaOH, and saturated aqueous sodium chloride. The organic layer was removed. The aqueous layer was extracted with DCM (2x). The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with a gradient of 0% to 50% MTBE in heptane to give the title compound (0.84 g, 51%) as a colorless oil. MS ES+ m / z 254 [M+H] + .

[0306] The following compounds in Table 4 were made in a similar manner as described for 2 benzylsulfanyl-6-chloro-3-fluoro-pyridine. The compounds were purified using a variety of methods that would be apparent to one skilled in the art. Table 4 [Table 4]

[0307] Intermediate 7C: 3-benzyloxy-2-benzylsulfanyl-6-fluoro-pyridine [ka] To a stirred solution of 2-benzylsulfanyl-6-fluoro-pyridin-3-ol (1.00 g, 4.25 mmol) in acetonitrile (5 mL) was added potassium carbonate (1.76 g, 12.8 mmol) portionwise at room temperature, followed by the dropwise addition of (bromomethyl)benzene (0.80 g, 4.68 mmol). The resulting reaction mixture was heated at 60° C. for 4 hours, then cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography eluting with 0% to 100% EtOAc in heptane to give the title compound (1.12 g, 81%). MS ES+ m / z 326 [M+H] + .

[0308] Intermediate 13B: 6-chloro-3-fluoro-pyridine-2-sulfonamide [ka] A 0°C solution of 2-benzylsulfanyl-6-chloro-3-fluoro-pyridine (12.77 g, 80%, 40.3 mmol), aqueous HCl (12 M, 21 mL), and water (35 mL) in DCM (70 mL) was treated dropwise over 20 minutes with aqueous sodium hypochlorite (7.5 wt%, 140 mL, 169 mmol). The reaction mixture was stirred for 20 minutes and then extracted with DCM (3 x 50 mL). The combined organic layers were cooled to 0°C and treated with ammonium hydroxide (29 wt%, 30 mL, 242 mmol). The resulting mixture was stirred for 10 minutes and then concentrated under reduced pressure. The residue was dissolved in a mixture of EtOAc, DCM, and EtOH and then filtered. The filtrate was concentrated under reduced pressure. The residue was suspended in DCM and filtered to give the title compound (5.6 g, 90% purity) as a white solid. MS ES+m / z 211[M+H]+ .

[0309] The following compounds in Table 5 were made in a similar manner as described for 6-chloro-3-fluoro-pyridine-2-sulfonamide. The compounds were purified using a variety of methods that would be apparent to one skilled in the art. Table 5 [Table 5]

[0310] Intermediate 14B: 6-chloro-3-hydroxy-pyridine-2-sulfonamide [ka] A mixture of 6-chloro-3-fluoro-pyridine-2-sulfonamide (4.93 g, 23.4 mmol) and potassium hydroxide (13.1 g, 234 mmol) in water (35 mL) was heated at 110 °C for 2.5 h. The reaction mixture was cooled to room temperature, and the pH was adjusted to approximately 4-5 with aqueous HCl (12 M, approximately 16 mL) and 10% aqueous citric acid (approximately 15 mL). The mixture was filtered. The filtrate was extracted with isopropanol:chloroform (1:3) (5 × 80 mL). The combined organic layers were washed with saturated aqueous sodium chloride, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with 0% to 50% EtOAc in heptane, to give the title compound (1.30 g, 27%). MS ES+ m / z 209 [M+H] + .

[0311] Intermediate 13C: N-tert-butyl-3-hydroxy-6-methoxy-pyridine-2-sulfonamide. [ka] To a stirred solution of cuprous iodide (0.018 g, 0.093 mmol) and 2-methyl-quinolin-8-ol (0.015 g, 0.093 mmol) in DMSO (2 mL) was added dropwise a solution of 3-bromo-N-tert-butyl-6-methoxy-pyridine-2-sulfonamide (0.300 g, 0.928 mmol) and tetrabutylazanium oxidanide (40 wt%; 2.03 mL, 2.78 mmol) in water (3 mL) at room temperature. The reaction mixture was stirred at 130 °C for 2 hours, then cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 0% to 100% EtOAc in heptane to give the title compound (0.145 g, 60%). MS ES+ m / z 261 [M+H] + .

[0312] Intermediate 14C: 3-Fluoro-6-methyl-pyridine-2-sulfonamide [ka] To a stirred solution of N-tert-butyl-3-fluoro-6-methyl-pyridine-2-sulfonamide (1.50 g, 6.09 mmol) in DCM (10 mL) was added dropwise TFA (10 mL) at room temperature under nitrogen. The resulting mixture was stirred at 50° C. overnight, cooled to room temperature, and concentrated under reduced pressure. The material was diluted with DCM (10 mL) and the pH was adjusted to approximately 8 with triethylamine. The residue was purified by silica gel chromatography eluting with 40% EtOAc in petroleum ether to give the product as a white solid (0.57 g, 49%). MS ES+ m / z 191 [M+H] + .

[0313] Intermediate 15C: 3-hydroxy-6-methoxy-pyridine-2-sulfonamide [ka] In a manner similar to that used to prepare Intermediate 14C, N-tert-butyl-3-hydroxy-6-methoxy-pyridine-2-sulfonamide was used to give the title compound (0.098 g, 89%). MS ES+ m / z 205 [M+H] + .

[0314] Intermediate 16C: 2,3-Difluoro-6-hydroxy-benzenesulfonamide [ka] To a solution of 2,3-difluoro-6-methoxy-benzenesulfonamide (0.465 g, 2.08 mmol) in DCM (20 mL) was added tribromoborane (1 M; 10.4 mL, 10.4 mmol) dropwise at 0 °C. The reaction was stirred at 0 °C for 4 h. The reaction was concentrated under reduced pressure, and the residue was dissolved in 2 mL of DMF and purified by reverse-phase chromatography eluting with 5% to 40% ACN in 10 mM aqueous NH4HCO3 containing 5% MeOH to afford the title compound (0.34 g, 77%) as a white solid. MS ES+ m / z 208 [MH] - .

[0315] Intermediate 17C: 6-Fluoro-3-hydroxy-pyridine-2-sulfonamide [ka] A solution of 3-benzyloxy-6-fluoro-pyridine-2-sulfonamide (0.690 g, 2.44 mmol) in EtOH (10 mL) was sparged with argon for 10 minutes, then Pd / C (10 wt%; 0.260 g) was added. The reaction vial was flushed with hydrogen and stirred vigorously under a hydrogen atmosphere (balloon) for 2 hours. The reaction was filtered through diatomaceous earth. The filtrate was concentrated under reduced pressure to give the crude product. MS ES+ m / z 193 [M+H] + .

[0316] Intermediate 18C: 5-Bromo-2-(fluoromethyl)indazole [ka] To a stirred mixture of 5-bromo-2H-indazole (5.00 g, 25.4 mmol) and fluoromethyl 4-methylbenzenesulfonate (5.70 g, 27.9 mmol) in NMP (50 mL) was added cesium carbonate (9.92 g, 30.5 mmol) portionwise at room temperature under nitrogen. The resulting mixture was stirred at 60 °C for 1 h and then cooled to room temperature. The mixture was diluted with water (60 mL) and extracted with EtOAc (3 × 60 mL). The combined organic extracts were washed with saturated aqueous sodium chloride solution (6 × 30 mL), dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with 15–50% EtOAc in petroleum ether to give the title compound (1.10 g, 19%) as a yellow solid. MS ES+ m / z 229 [M+H] + .

[0317] Intermediate 19C: tert-butyl-dimethyl-[2-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indazol-2-yl]ethoxy]silane [ka] 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole (3.00 g, 12.3 mmol) and (2-bromoethoxy)(tert-butyl)dimethylsilane (14.70 g, 61.5 mmol) were combined with diisopropylethylamine (3.18 g, 24.6 mmol) and N,N-dimethylpyridin-4-amine (1.50 g, 12.3 mmol) in DMF (20 mL). The mixture was stirred at 110 °C for 48 h and then concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 10% to 100% EtOAc in heptane to give the title compound (1.10 g, 22%). MS ES+ m / z 403 [M+H] + .

[0318] The following compounds in Table 6 were made in a similar manner as described for tert-butyl-dimethyl-[2-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indazol-2-yl]ethoxy]silane. The compounds were purified using a variety of methods that would be apparent to one skilled in the art. Table 6 [Table 6]

[0319] Intermediates 21C and 22C: 5-chloro-1-methyl-pyrazolo[4,3-b]pyridine and 5-chloro-2-methyl-pyrazolo[4,3-b]pyridine [ka] To a stirred mixture of 5-chloro-1H-pyrazolo[4,3-b]pyridine (3.20 g, 20.8 mmol) and iodomethane (4.44 g, 31.3 mmol) in THF (30 mL) was added sodium hydride (60%; 1.00 g, 25.0 mmol) portionwise under nitrogen at 0° C. The resulting mixture was stirred at room temperature for 1 hour. The reaction was quenched with water (30 mL) and extracted with EtOAc (3×80 mL). The combined organic extracts were washed with saturated aqueous sodium chloride solution (3×30 mL), dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 10% EtOAc in petroleum ether to give 5-chloro-1-methyl-pyrazolo[4,3-b]pyridine (1.84 g, 53%), and further elution with 30% EtOAc in petroleum ether to give 5-chloro-2-methyl-pyrazolo[4,3-b]pyridine (1.34 g, 38%). MS ES+ m / z 168 [M+H] for both. + .

[0320] The following compounds in Table 7 were made in a similar manner as described for 5-chloro-1-methyl-pyrazolo[4,3-b]pyridine and 5-chloro-2-methyl-pyrazolo[4,3-b]pyridine. The compounds were purified using a variety of methods that would be apparent to one skilled in the art. Table 7 [Table 7]

[0321] Intermediate 27C: Trimethyl-(1-methylpyrazolo[3,4-b]pyridin-6-yl)stannane [ka] To a stirred solution of 6-chloro-1-methylpyrazolo[3.4-b]pyridine (1.10 g, 6.56 mmol) and hexamethyldistannane (2.58 g, 7.88 mmol) in 1,4-dioxane (10 mL) was added tetrakis(triphenylphosphine)palladium(0) (0.758 g, 0.656 mmol) portionwise at room temperature under nitrogen. The resulting mixture was stirred at 100° C. for 2 hours. The reaction was cooled to room temperature, quenched with saturated aqueous cesium fluoride (100 mL), and extracted with EtOAc (2×100 mL). The combined organic extracts were washed with saturated aqueous sodium chloride (2×80 mL), dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give the title compound (2.1 g, 99%) as a yellow solid. MS ES+ m / z 298 [M+H] + .

[0322] The following compounds in Table 8 were made in a similar manner as described for trimethyl-(1-methylpyrazolo[3,4-b]pyridin-6-yl)stannane. Alternative reaction conditions included tributyltin chloride and n-butyllithium in THF. Compounds were purified using a variety of methods that would be apparent to one skilled in the art. Table 8 [Table 8]

[0323] Intermediate 35C: 2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)oxazolo[5,4-b]pyridine [ka] 6-Bromo-2-methyl-oxazolo[5,4-b]pyridine (0.200 g, 0.939 mmol), potassium acetate (0.184 g, 1.88 mmol), 1,1'-bis(diphenylphosphino)ferrocenedichloropalladium(II) (0.069 g, 0.094 mmol), and bis(pinacolato)diboron (0.358 g, 1.41 mmol) were mixed in 1,4-dioxane (4 mL). The reaction was purged with nitrogen for 5 minutes, stirred at 80 °C for 14.5 hours, and then cooled to room temperature. The mixture was diluted with ethanol and filtered through diatomaceous earth. The filtrate was concentrated under reduced pressure to give the crude product. MS ES+ m / z 261 [M+H] + .

[0324] The following compounds in Table 9 were prepared in a similar manner as described for 2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)oxazolo[5,4-b]pyridine. Alternative reaction conditions included palladium(II) acetate and tricyclohexylphosphine. Compounds were purified using a variety of methods that would be apparent to one skilled in the art. Table 9 [Table 9-1]

[0325] (Continued from Table 9) [Table 9-2]

[0326] Intermediate 5A: 6-chloro-3-[(1R)-1-(2-ethylsulfinyl-3,6-dimethyl-4-oxo-chromen-8-yl)ethoxy]pyridine-2-carbonitrile [ka] A solution of 2-ethylsulfanyl-8-[(1S)-1-hydroxyethyl]-3,6-dimethyl-chromen-4-one (1.0 g, 3.59 mmol), 6-chloro-3-hydroxy-pyridine-2-carbonitrile (0.83 g, 5.39 mmol), and triphenylphosphine (1.41 g, 5.39 mmol) in THF (12 mL) was treated with DIAD at 0 °C. After stirring at 0 °C for 1 h, the reaction was concentrated under reduced pressure, and the residue was purified by silica gel chromatography eluting with 0% to 100% EtOAc in heptane to give the title compound (2.39 g, 60% purity, 96%) as a white foam. ES-MS m / z 415 (M+H).

[0327] The following compounds in Table 10 were made in a similar manner as described for 6-chloro-3-[(1R)-1-(2-ethylsulfanyl-3,6-dimethyl-4-oxo-chromen-8-yl)ethoxy]pyridine-2-carbonitrile. The compounds were purified using a variety of methods that would be apparent to one skilled in the art. Table 10 [Table 10-1]

[0328] (Continued from Table 10) [Table 10-2]

[0329] Intermediate 20B: 3[(1R)-1-(2-ethylsulfanyl-6-methyl-4-oxo-chromen-8-yl)ethoxy]-6-fluoro-pyridine-2-carboxamide [ka] A mixture of 3-[(1R)-1-(2-ethylsulfanyl-6-methyl-4-oxo-chromen-8-yl)ethoxy]-6-fluoro-pyridine-2-carbonitrile (0.8 g, 2 mmol) and hydrido(dimethylphosphinite-kP)[hydrogen bis(dimethylphosphinite-kP)]platinum(II) (0.09 g, 0.2 mmol) in EtOH (5 mL) and water (5 mL) was stirred at 60 °C for 12 h. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography eluting with 0% to 6% MeOH in DCM to give the title compound (0.075 g, 50%) as a white solid after lyophilization. MS ES+ m / z 401 [MH] -

[0330] Intermediate 60C: 6-chloro-3-[(1R)-1-(2-ethylsulfanyl-6-methyl-4-oxo-chromen-8-yl)ethoxy]pyridine-2-carboxamide [ka] In a manner similar to that used to prepare Intermediate 20B, 6-chloro-3-[(1R)-1-(2-ethylsulfanyl-6-methyl-4-oxo-chromen-8-yl)ethoxy]pyridine-2-carbonitrilechromen-2-one was used to obtain the title compound (0.122 g, 84%). MS ES+ m / z 417 [MH] - .

[0331] Intermediate 21B: 8-[(1R)-1-[(6-chloro-2-morpholino-3-pyridyl)oxy]ethyl]-2-ethylsulfanyl-3,6-dimethyl-chromen-4-one [ka] A mixture of 8-[(1R)-1-[(6-chloro-2-fluoro-3-pyridyl)oxy]ethyl]-2-ethylsulfanyl-3,6-dimethyl-chromen-4-one (0.129 g, 0.316 mmol), DIPEA (0.22 mL, 1.27 mmol), and DMF (2 mL) was treated with morpholine (0.066 mL, 0.759 mmol). The reaction vessel was sealed, and the mixture was stirred at room temperature for 18 hours. The reaction mixture was heated to 60° C. for 1 hour. Additional DIPEA (0.22 mL, 1.27 mmol) and morpholine (0.066 mL, 0.759 mmol) were added. The reaction mixture was heated to 60° C. for 4 hours and then diluted with EtOAc and water. The phases were separated, and the aqueous layer was extracted with EtOAc (3×). The combined organic layers were washed with saturated aqueous sodium chloride and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with a gradient of 0% to 50% EtOAc in heptane to give the title compound (0.075 g, 50%) as a white solid. MS ES+ m / z 475 [M+H] + .

[0332] Intermediate 22B: 2-Ethylsulfanyl-8-[(1R)-1-[2-(2-fluorophenyl)-3-pyridyl]oxy]ethyl]-3,6-dimethyl-chromen-4-one [ka] 8-[(1R)-1-[(2-chloro-3-pyridyl)oxy]ethyl]-2-ethylsulfanyl-3,6-dimethyl-chromen-4-one (0.210 g, 0.539 mmol), (2-fluorophenyl)boronic acid (0.075 g, 0.539 mmol), KCO (0.149 g, 1.08 mmol), and tetrakis(triphenylphosphine)palladium(0) (0.031 g, 0.027 mmol) were combined with 1,4-dioxane (1.08 mL) and water (0.27 mL). The reaction was sparged with argon for 5 minutes and then stirred at 90 °C for 16 hours. The reaction was concentrated under reduced pressure and purified by silica gel chromatography eluting with 0% to 60% EtOAc in heptane to give the title compound (0.24 g, quantitative) as a yellow oil. MS ES+m / z 450[M+H] + .

[0333] Intermediate 23B: 8-[(1S)-1-[tert-butyl(dimethyl)silyl]oxyethyl]-2-ethylsulfanyl-3,6-dimethyl-chromen-4-one [ka] A solution of 2-ethylsulfanyl-8-[(1S-1-hydroxyethyl]-3,6-dimethyl-chromen-4-one (0.500 g, 1.80 mmol) in DCM (10 mL) was treated with tert-butylchlorodimethylsilane (0.406 g, 2.69 mmol), 1,8-diazabicyclo[5.4.0]undec-7-ene (0.54 mL, 3.59 mmol), and 4-dimethylaminopyridine (0.219 g, 1.80 mmol). The reaction mixture was stirred at room temperature for 3 hours and then concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with a gradient of 0% to 50% EtOAc in heptane to give the title compound (0.720 g, 97%) as a colorless oil. MS ES+ m / z 393 [M+H] + .

[0334] Intermediate 24B: 8-[(1S)-1-[tert-butyl(dimethyl)silyl]oxyethyl]-2-ethylsulfinyl-3,6-dimethyl-chromen-4-one [ka] A solution of 8-[(1S)-1-[tert-butyl(dimethyl)silyl]oxyethyl]-2-ethylsulfanyl-3,6-dimethyl-chromen-4-one (0.720 g, 1.83 mmol) in DCM (12 mL) was cooled to 0 °C and treated portionwise with mCPBA (0.452 g, 77%, 2.02 mmol). After the addition was complete, the reaction was stirred at 0 °C for 1 h. The reaction was diluted with EtOAc and washed with saturated aqueous NaHCO 3 . The organic phase was removed and the aqueous layer was extracted with EtOAc (2×). The combined organic layers were dried over Na-2SO 4 , filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with a gradient of 0% to 100% EtOAc in heptane to give the title compound (0.682 g, 91%) as a colorless gel. MS ES+ m / z 409 [M+H] + .

[0335] Intermediate 25B: 8-[(1S)-1-[tert-butyl(dimethyl)silyl]oxyethyl]-2-chloro-3,6-dimethyl-chromen-4-one [ka] A 0°C solution of 8-[(1S)-1-[tert-butyl(dimethyl)silyl]oxyethyl]-2-ethylsulfinyl-3,6-dimethyl-chromen-4-one (0.680 g, 1.66 mmol) and benzyl(triethyl)ammonium chloride (0.190 g, 0.832 mmol) in DCM (30 mL) was treated with aqueous HCl (12 M, 0.417 mL, 4.99 mmol). After 1 h, additional aqueous HCl (12 M, 0.417 mL, 4.99 mmol) was added. After another 1 h, additional aqueous HCl (12 M, 0.417 mL, 4.99 mmol) was added. After 30 min, the reaction mixture was quenched with saturated aqueous NaHCO3. The aqueous layer was extracted with DCM. The organic layer was washed with saturated aqueous sodium chloride, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 0% to 50% EtOAc in heptane to give the title compound (0.87 g, 77%). MS ES+ m / z 367 [M+H] + .

[0336] Intermediate 26B: 8-[(1S)-1-[tert-butyl(dimethyl)silyl]oxyethyl]-2-cyclopropyl-3,6-dimethyl-chromen-4-one [ka] Cyclopropylzinc iodide: An oven-dried flask was charged with lithium chloride (2.52 g, 59.5 mmol) and heated under high vacuum at 170 °C for 20 minutes. After cooling, the vacuum was removed and nitrogen gas was introduced into the flask. Upon cooling, zinc (3.89 g, 59.5 mmol) was added to the flask, which was dried under high vacuum at 170 °C for 20 minutes and then backfilled with nitrogen. Upon cooling to room temperature, THF (20 mL) and 1,2-dibromoethane (0.13 mL, 1.49 mmol) were added via syringe, and the reaction was heated at 60 °C until effervescence occurred. After cooling to room temperature, chlorotrimethylsilane (0.038 mL, 0.30 mmol) and iodine (0.038 g, 0.15 mmol) in THF (1 mL) were added via syringe, and the reaction was heated at 60 °C for 20 minutes and then cooled to room temperature. Iodocyclopropane (5.0 g, 29.8 mmol) was added and the reaction was stirred overnight at 50° C. The reaction was left at room temperature for 1 h, and the solution on top of the solid was carefully transferred via cannula to a dry flask and used without purification, assuming a concentration of approximately 0.5 M.

[0337] A dry vial was charged with 8-[(1S)-1-[tert-butyl(dimethyl)silyl]oxyethyl]-2-chloro-3,6-dimethyl-chromen-4-one (0.167 g, 0.455 mmol), palladium(II) acetate (10.2 mg, 0.046 mmol), and 2-dicyclohexylphosphino-2',6'-bis(N,N-dimethylamino)biphenyl (CPhos, 0.040 g, 0.091 mmol). The vial was evacuated and refilled with nitrogen three times. THF (3 mL) was added via syringe, and the reaction was cooled to 0 °C. Cyclopropylzinc iodide (ca. 0.5 M, 2.28 mL, 1.14 mmol) was added via syringe, the cooling bath was removed, and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with EtOAc and quenched with saturated aqueous NH4Cl. The organic phase was removed and the aqueous layer was re-extracted with EtOAc (2x). The organic layers were combined, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with a gradient of 0% to 50% EtOAc in heptane to give the title compound (0.135 g, 80%) as a brown gel. MS ES+ m / z 373 [M+H] + .

[0338] Intermediate 61C: Ethyl 2-[8-[(1S)-1-[tert-butyl(dimethyl)silyl]oxyethyl]-3,6-dimethyl-4-oxo-chromen-2-yl]cyclopropanecarboxylate [ka] A microwave vial was charged with 8-[(1S)-1-[tert-butyl(dimethyl)silyl]oxyethyl]-2-chloro-3,6-dimethyl-chromen-4-one (0.500 g, 1.36 mmol), bis(1-adamantyl)-butyl-phosphane (0.147 g, 0.409 mmol), (2-(ethoxycarbonyl)cyclopropyl)trifluoroborate, potassium salt (0.5 M; 5.45 mL, 2.73 mmol), cesium carbonate (1.33 g, 4.09 mmol), and palladium diacetate (0.061 g, 0.273 mmol). The vial was sealed and cycled between vacuum and nitrogen three times. Toluene (10 mL) and water (1 mL) were added via syringe. The mixture was heated in a microwave reactor at 110 °C for 1 h and then diluted with EtOAc. The mixture was washed with water, and the aqueous layer was extracted with EtOAc (2 times). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 0% to 100% EtOAc in heptane to give the title compound (0.709 g, 99%) as a brown gel. MS ES+ m / z 445 [M+H] + .

[0339] The following compounds in Table 11 were prepared in a manner similar to that described for ethyl 2-[8-[(1S)-1-[tert-butyl(dimethyl)silyl]oxyethyl]-3,6-dimethyl-4-oxo-chromen-2-yl]cyclopropanecarboxylate. The compounds were purified using a variety of methods that would be apparent to one skilled in the art. Table 11 [Table 11]

[0340] Intermediate 64C: 8-[(1S)-1-[tert-butyl(dimethyl)silyl]oxyethyl]-3,6-dimethyl-2-(oxetan-3-yl)chromen-4-one [ka] To a small vial was added the photocatalyst (Ir[dF(CF3)ppy]2(dtbpy))PF6 (0.0076 g, 0.0068 mmol), 3-bromooxetane (0.140 g, 1.02 mmol), 8-[(1S)-1-[tert-butyl(dimethyl)silyl]oxyethyl]-2-chloro-3,6-dimethyl-chromen-4-one (0.250 g, 0.681 mmol), tris(trimethylsilyl)silane (0.21 mL, 0.681 mmol), and lutidine (0.16 mL, 1.36 mmol). The vial was sealed and placed under nitrogen, and then dimethoxyethane (9 mL) was added. To a second vial was added (4,4'-di-tert-butyl-2,2'-bipyridine)NiCl2 (0.0014 g, 0.0034 mmol) and dimethoxyethane (1 mL). The mixture was degassed, sonicated for 3 minutes, and then added to the first vial via syringe. The vial was cycled between vacuum and nitrogen three times and then placed in a photobox equipped with a fan and a blue LED lamp. The reaction mixture was stirred overnight and then filtered through diatomaceous earth. The filtrate was concentrated under reduced pressure to give the crude product. MS ES+ m / z 389 [M+H] + .

[0341] Intermediate 27B: 2-Cyclopropyl-8-[(1S-1-hydroxyethyl]-3,6-dimethyl-chromen-4-one [ka] A 0°C solution of 8-[(1S)-1-[tert-butyl(dimethyl)silyl]oxyethyl]-2-cyclopropyl-3,6-dimethyl-chromen-4-one (0.135 g, 0.362 mmol) in THF (3 mL) was treated with tetra-n-butylammonium fluoride (1 M in THF, 0.435 mL, 0.435 mmol). The reaction was stirred at 0°C for 2.5 hours and then concentrated under reduced pressure. The residue was purified by reverse-phase chromatography eluting with a gradient of 0 to 100% ACN in HO + 0.1% formic acid. Fractions containing the desired product were combined, washed with saturated aqueous sodium chloride, and extracted with IPA:CHCl (1:3). The combined extracts were dried over MgSO, filtered, and concentrated under reduced pressure to give the crude title compound. MS ES+ m / z 259 [M+H] + .

[0342] The following compounds in Table 12 were made in a similar manner as described for 2-cyclopropyl-8-[(1S)-1-hydroxyethyl]-3,6-dimethyl-2-chromen-4-one. The compounds were purified using a variety of methods that would be apparent to one skilled in the art. Table 12 [Table 12]

[0343] Intermediate 9A: 8-[(1S)-1-hydroxyethyl]-3,6-dimethyl-2-(2-pyrazyl)chromen-4-one [ka] 2-Ethylsulfanyl-8-[(1S)-1-hydroxyethyl]-3,6-dimethyl-chromen-4-one (500 mg, 1.80 mmol), 2-pyridylboronic acid (662 mg, 5.39 mmol), copper(I) thiophene-2-carboxylate (514 mg, 2.69 mmol), and tetrakis(triphenylphosphine)palladium(0) (415 mg, 0.36 mmol) were combined in EtOH (10 mL), degassed with nitrogen for 2 minutes, and stirred for 16 hours at 60° C. The reaction was recharged with 2-pyridylboronic acid (662 mg, 5.39 mmol), copper(I) thiophene-2-carboxylate (514 mg, 2.69 mmol), and tetrakis(triphenylphosphine)palladium(0) (415 mg, 0.36 mmol), purged with nitrogen for 5 minutes, and stirred at 60° C. for 4 hours. The reaction was filtered and the solid was washed with DCM / MeOH. The filtrate was concentrated under reduced pressure, and the residue was purified by reverse-phase chromatography on a C18 column eluting with 0% to 100% ACN in 10 mM aqueous NH4HCO3 containing 5% MeOH to give the title compound (281 mg, 53%) as a tan solid. ES / MS m / z 296.2 (M+H).

[0344] The following compounds in Table 13 were made in a similar manner as described for 8-[(1S)-1-hydroxyethyl]-3,6-dimethyl-2-(2-pyridyl)chromen-4-one. The compounds were purified using a variety of methods that would be apparent to one skilled in the art. Table 13 [Table 13-1]

[0345] (Continued from Table 13) [Table 13-2]

[0346] (Continued from Table 13) [Table 13-3]

[0347] (Continued from Table 13) [Table 13-4]

[0348] (Continued from Table 13) [Table 13-5]

[0349] (Continued from Table 13) [Table 13-6]

[0350] (Continued from Table 13) [Table 13-7]

[0351] (Continued from Table 13) [Table 13-8]

[0352] (Continued from Table 13) [Table 13-9]

[0353] (Continued from Table 13) [Table 13-10]

[0354] Intermediate 99C: 6-chloro-3-[(1R)-1-[2-(2-ethyl-1,3-benzothiazol-6-yl)-3,6-dimethyl-4-oxo-chromen-8-yl]ethoxy]pyridine-2-carbonitrile [ka] To a 0°C mixture of 2-(2-ethyl-1,3-benzothiazol-6-yl)-8-[(1R)-1-hydroxyethyl]-3,6-dimethyl-chromen-4-one (0.160 g, 0.422 mmol) in THF (10 mL) was added sodium hydride (60%; 0.202 g, 8.44 mmol) under nitrogen. The mixture was stirred at 0°C for 40 minutes, and then 6-chloro-3-fluoro-pyridine-2-carbonitrile (0.198 g, 1.27 mmol) was added. The resulting mixture was stirred at room temperature for 1 hour, then cooled to 0°C and quenched with water (50 mL). The resulting mixture was extracted with EtOAc (3 x 50 mL). The organic layer was washed with saturated aqueous sodium chloride (2 x 50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give the crude compound as a brown solid. MS ES+m / z 516[M+H] + .

[0355] Intermediate 100C: 6-chloro-3-[(1R)-1-[2-(2-ethyl-1,3-benzoxazol-6-yl)-3,6-dimethyl-4-oxo-chromen-8-yl]ethoxy]pyridine-2-carbonitrile [ka] In a manner similar to that used to prepare 6-chloro-3-[(1R)-1-[2-(2-ethyl-1,3-benzothiazol-6-yl)-3,6-dimethyl-4-oxo-chromen-8-yl]ethoxy]pyridine-2-carbonitrile, 2-(2-ethyl-1,3-benzoxazol-6-yl)-8-[(1R)-1-hydroxyethyl]-3,6-dimethyl-chromen-4-one was used to obtain the title compound (0.110 g, 27%). MS ES+ m / z 500 [M+H] + .

[0356] Intermediate 57B: 8-[(1S)-1-hydroxyethyl]-6-methyl-2-(1-methylpyrazol-4-yl)chromen-4-one [ka] 8-Acetyl-6-methyl-2-(1-methylpyrazol-4-yl)chromen-4-one was purified using methylpyrazol-4-yl)chromen-4-one to give the title compound (1.24 g, 63%). MS ES+ m / z 285 [M+H] + .

[0357] Intermediate 58B: 3-bromo-8-[(1S)-1-hydroxyethyl]-6-methyl-2-(1-methylpyrazol-4-yl)chromen-4-one [ka] A mixture of 8-[(1S)-1-hydroxyethyl]-6-methyl-2-(1-methylpyrazol-4-yl)chromen-4-one (1.02 g, 3.59 mmol) and N-bromosuccinimide (0.798 g, 4.48 mmol) in ACN (20 mL) was stirred at room temperature for 1.5 hours. The reaction mixture was filtered, and the solid was washed with acetonitrile and water. The solid was evaporated to dryness under reduced pressure to give the title compound (0.870 g, 80%). MS ES+ m / z 363, 365 [M+H] + .

[0358] Intermediate 59B: 8-[(1S)-1-hydroxyethyl]-6-methyl-2-(1-methylpyrazol-4-yl)-4-oxo-chromene-3-carbonitrile [ka] A mixture of 3-bromo-8-[(1S)-1-hydroxyethyl]-6-methyl-2-(1-methylpyrazol-4-yl)chromen-4-one (0.870 g, 80%, 1.92 mmol) and potassium cyanide (0.624 g, 9.58 mmol) in DMF (10 mL) was stirred at 70 °C for 20 h, then cooled and concentrated. The residue was diluted with isopropanol:chloroform (1:3) and water. The aqueous layer was removed. The organic phase was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with a gradient of 1% to 10% MeOH in DCM to give the title compound (0.519 g, 88%). MS ES+ m / z 310 [M+H] + .

[0359] Intermediate 11: 8-[(1S)-1-chloroethyl]-3,6-dimethyl-2-phenyl-chromen-4-one [ka] A flask equipped with an overhead stirrer was charged with 8-[(1R)-1-hydroxyethyl]-3,6-dimethyl-2-phenyl-chromen-4-one (20.0 g, 68.0 mmol) and cyclopentyl methyl ether (200 mL). 2,4,6-Trichloro[1,3,5]triazine (12.5 g, 23.8 mmol) was added, followed by DMF (7.9 mL, 102 mmol), and stirred at room temperature overnight. The reaction was slowly treated with 2 M aqueous NaOH (100 mL) and stirred for 10 minutes. The reaction was transferred to a separatory funnel, and the organic layer was removed. The organic layer was diluted with water (100 mL) and saturated aqueous NaHCO3 (100 mL). After removing the aqueous layer, the organic layer was washed with 5% aqueous LiCl. The organic layer was transferred to a flask, and the solvent was exchanged with IPA by filling the flask with 200 mL of IPA and concentrating to 100 mL three times. The slurry was then warmed to 45°C, stirred at that temperature for 2 hours, and cooled to room temperature. This material was treated with 80 mL of water via syringe pump over 4 hours, and the reaction was aged overnight. The product (18.4 g, 87%) was collected by filtration, washed with 40 mL of 1:1 IPA / water, and dried at 45°C.

[0360] The following compounds in Table 14 were made in a similar manner as described for 8-[(1S)-1-chloroethyl]-3,6-dimethyl-2-phenyl-chromen-4-one. Table 14 [Table 14]

[0361] Intermediate 13: 6-chloro-3-[(1R)-1-(3,6-dimethyl-4-oxo-2-phenyl-chromen-8-yl)ethoxy]pyridine-2-carbonitrile [ka] To a solution of 8-[(1S)-1-hydroxyethyl]-3,6-dimethyl-2-phenyl-chromen-4-one (0.200 g, 0.679 mmol), 6-chloro-3-hydroxy-pyridine-2-carbonitrile (0.196 g, 1.27 mmol), and triphenylphosphine (0.333 g, 1.27 mmol) in THF (6 mL) was added diisopropyl azodicarboxylate (0.257 g, 1.27 mmol) at 0 °C. After 2 h, the reaction was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with a gradient of 0% to 100% EtOAc in hexanes to give the title compound (0.300 g, 90% pure, 92%). MS ES+ m / z 431 [M+H] + .

[0362] The following compounds in Table 15 were made in a similar manner as described for 6-chloro-3-[(1R)-1-(3,6-dimethyl-4-oxo-2-phenyl-chromen-8-yl)ethoxy]pyridine-2-carbonitrile. The compounds were purified using a variety of methods that would be apparent to one skilled in the art. Table 15 [Table 15-1]

[0363] (Continued from Table 15) [Table 15-2]

[0364] (Continued from Table 15) [Table 15-3]

[0365] (Continued from Table 15) [Table 15-4]

[0366] (Continued from Table 15) [Table 15-5]

[0367] (Continued from Table 15) [Table 15-6]

[0368] Intermediate 18: 6-chloro-3-[(1R)-1-(3,6-dimethyl-4-oxo-2-phenyl-chromen-8-yl)ethoxy]-N'-hydroxy-pyridine-2-carboxamidine [ka] To a solution of 6-chloro-3-[(1R)-1-(3,6-dimethyl-4-oxo-2-phenyl-chromen-8-yl)ethoxy]pyridine-2-carbonitrile (0.588 g, 1.36 mmol) in EtOH (6 mL) was added triethylamine (0.38 mL, 2.73 mmol) and hydroxylamine hydrochloride (0.114 g, 1.64 mmol). The reaction was heated at 80 °C overnight and concentrated under reduced pressure. The residue was purified by reverse-phase chromatography eluting with a gradient of 0 to 100% ACN in HO + 0.1% formic acid. Fractions containing the desired product were combined, washed with saturated aqueous sodium chloride, and extracted with IPA:CHCl (1:3). The combined extracts were dried over MgSO, filtered, and concentrated under reduced pressure to give the title compound (0.180 g, 28%). MS ES+m / z 464[M+H] + .

[0369] The following compounds in Table 16 were prepared in a manner similar to that described for 6-chloro-3-[(1R)-1-(3,6-dimethyl-4-oxo-2-phenyl-chromen-8-yl)ethoxy]-N'-hydroxy-pyridine-2-carboxamidine. The compounds were purified using a variety of methods that would be apparent to one skilled in the art.

[0370] Table 16 [Table 16-1]

[0371] (Continued from Table 16) [Table 16-2]

[0372] (Continued from Table 16) [Table 16-3]

[0373] (Continued from Table 16) [Table 16-4]

[0374] (Continued from Table 16) [Table 16-5]

[0375] (Continued from Table 16) [Table 16-6]

[0376] Intermediate 84B: 2-[1-[(2S)-2-[tert-butyl(dimethyl)silyl]oxypropyl]pyrazol-4-yl]-8-[(1R)-1-[(6-chloro-2-fluoro-3-pyridyl)oxy]ethyl]-3,6-dimethyl-chromen-4-one [ka] A solution of 8-[(1R)-1-[(6-chloro-2-fluoro-3-pyridyl)oxy]ethyl]-2-[1-[(2S)-2-hydroxypropyl]pyrazol-4-yl]-3,6-dimethyl-chromen-4-one (0.278 g, 0.589 mmol) in DCM (6 mL) was treated with tert-butylchlorodimethylsilane (0.133 g, 0.884 mmol), 1,8-diazabicyclo[5.4.0]undec-7-ene (0.179 g, 1.18 mmol), and 4-dimethylaminopyridine (0.072 g, 0.589 mmol). The reaction was stirred at room temperature for 1 hour and then treated with tert-butylchlorodimethylsilane (0.133 g, 0.884 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.179 g, 1.18 mmol). The reaction was stirred at room temperature for 1 hour and then diluted with EtOAc and washed with saturated aqueous sodium chloride. The aqueous layer was back-extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give the title compound (0.35 g, 91%) as a tan gel. MS ES+ m / z 586 [M+H]+ .

[0377] Intermediate 40A: 8-[(1R)-1-[(2-benzylsulfanyl-6-chloro-3-pyridyl)oxy]ethyl]-3,6-dimethyl-2-phenyl-chromen-4-one [ka] A suspension of sodium hydride (1.08 g, 60%, 26.90 mmol) in THF (30 mL) at 0 °C was treated with benzyl mercaptan (3.34 g, 26.90 mmol). The bath was removed and the reaction was allowed to stir for 20 minutes. The reaction was cooled to 0 °C and treated with 8-[(1R)-1-[(6-chloro-2-fluoro-3-pyridyl)oxy]ethyl]-3,6-dimethyl-2-phenyl-chromen-4-one (2.28 g, 26.90 mmol) dissolved in THF (3 mL). The reaction was allowed to warm to room temperature and stirred for 2 hours. The reaction was diluted with EtOAc and washed with water. The organic layer was collected, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with a gradient of 0% to 40% EtOAc in heptane to give the title compound (1.35 g, 48%) as a white solid. ES-MS m / z 528 (M+H).

[0378] The following compounds in Table 17 were made in a similar manner as described for 8-[(1R)-1-[(2-benzylsulfanyl-6-chloro-3-pyridyl)oxy]ethyl]-3,6-dimethyl-2-phenyl-chromen-4-one. The compounds were purified using a variety of methods that would be apparent to one skilled in the art.

[0379] Table 17 [Table 17-1]

[0380] (Continued from Table 17) [Table 17-2]

[0381] (Continued from Table 17) [Table 17-3]

[0382] Intermediate 45A: (2,3,4,5,6-pentafluorophenyl) 6-chloro-3-[(1R)-1-(3,6-dimethyl-4-oxo-2-phenyl-chromen-8-yl)ethoxy]pyridine-2-sulfonate [ka] A solution of 8-[(1R)-1-[(2-benzylsulfanyl-6-chloro-3-pyridyl)oxy]ethyl]-3,6-dimethyl-2-phenyl-chromen-4-one (100 mg, 0.19 mmol) in AcOH / water (3:1; 2 mL) was treated with N-chlorosuccinimide (101 mg, 0.76 mmol) at 0 °C. The cooling bath was removed and the reaction was stirred at room temperature for 2 h. The reaction was recooled to 0 °C and treated with pentafluorophenol (349 mg, 1.89 mmol) and DIPEA (245 mg, 1.89 mmol). The cooling bath was removed and the reaction was stirred at room temperature for 2 h. The reaction was diluted with EtOAc and washed with saturated aqueous NaHCO3. The aqueous layer was re-extracted with EtOAc (2x). The organics were collected, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 0% to 100% EtOAc in heptane to give the title compound (85 mg, 69%) as a white solid. ES-MS m / z 652 (M+H).

[0383] The following compounds in Table 18 were made in a similar manner as described for (2,3,4,5,6-pentafluorophenyl) 6-chloro-3-[(1R)-1-(3,6-dimethyl-4-oxo-2-phenyl-chromen-8-yl)ethoxy]pyridine-2-sulfonate. The compounds were purified using a variety of methods that would be apparent to one skilled in the art. Table 18 [Table 18-1]

[0384] (Continued from Table 18) [Table 18-2]

[0385] (Continued from Table 18) [Table 18-3]

[0386] (Continued from Table 18) [Table 18-4]

[0387] (Continued from Table 18) [Table 18-5]

[0388] Intermediate 117C: Ethyl 2-[8-[(1R)-1-[(6-chloro-2-sulfamoyl-3-pyridyl)oxy]ethyl]-3,6-dimethyl-4-oxo-chromen-2-yl]cyclopropanecarboxylate [ka] A solution of ethyl 2-[8-[(1R)-1-[[6-chloro-2-(2,3,4,5,6-pentafluorophenoxy)sulfonyl-3-pyridyl]oxy]ethyl]-3,6-dimethyl-4-oxo-chromen-2-yl]cyclopropanecarboxylate (1.13 g, 1.64 mmol) in THF (16 mL) was treated with aqueous ammonia (28%, 1.13 mL, 8.21 mmol) and then stirred at 60 °C for 30 min. The reaction was concentrated under reduced pressure, and the residue was purified by reverse-phase chromatography eluting with a gradient of 0 to 100% ACN in HO + 0.1% formic acid. Fractions containing the desired product were combined, washed with saturated aqueous sodium chloride, and extracted with IPA:CHCl (1:3). The combined organic layers were dried over MgSO, filtered, and concentrated under reduced pressure. The material was crystallized from DCM / MeOH / hexane to give the title compound (0.220 g, 26%) as a white solid. MS ES+ m / z 521 [M+H] + .

[0389] Example 22: 6-chloro-3-[(1R)-1-(3,6-dimethyl-4-oxo-2-phenyl-chromen-8-yl)ethoxy]pyridine-2-carboxylic acid [ka] To a solution of methyl 6-chloro-3-[(1R)-1-(3,6-dimethyl-4-oxo-2-phenyl-chromen-8-yl)ethoxy]pyridine-2-carboxylate (0.624 g, 50% pure, 0.673 mmol) in THF (9 mL) and water (3 mL) was added lithium hydroxide (0.0644 g, 2.69 mmol). The reaction was heated at 50° C. for 2 hours and diluted with DCM and saturated aqueous ammonium chloride. The layers were separated. The aqueous layer was extracted with IPA:CHCl (1:3). The combined organic extracts were dried over MgSO, filtered, and concentrated under reduced pressure to give the title compound as a colorless oil (0.158 g, 52%). MS ES+ m / z 450 [M+H] + .

[0390] The following compounds in Table 19 were made in a similar manner as described for 6-chloro-3-[(1R)-1-(3,6-dimethyl-4-oxo-2-phenyl-chromen-8-yl)ethoxy]pyridine-2-carboxylic acid. The compounds were purified using a variety of methods that would be apparent to one skilled in the art. Table 19 [Table 19-1]

[0391] (Continued from Table 19) [Table 19-2]

[0392] Intermediate 117B: 6-chloro-3-[(1R)-1-(2-ethylsulfinyl-3,6-dimethyl-4-oxo-chromen-8-yl)ethoxy]pyridine-2-carboxamide [ka] 6-Chloro-3-[(1R)-1-(2-ethylsulfanyl-3,6-dimethyl-4-oxo-chromen-8-yl)ethoxy]pyridine-2-carboxylic acid (0.8 g, 2 mmol) was dissolved in DMF (3 mL) and treated with HATU (0.9 g, 2 mmol) and DIPEA (1 mL, 6 mmol). The reaction was stirred at room temperature for 10 minutes, and then ammonia (0.4 M in 1,4-dioxane, 20 mL, 7 mmol) was added. The reaction was stirred at room temperature for 4 hours. The reaction was concentrated under reduced pressure, and the residue was dissolved in 2 mL of DMF and purified by reverse-phase chromatography eluting with 30% to 55% ACN in 10 mM aqueous NH4HCO3 containing 5% MeOH to afford the title compound (0.3 g, 40%) as a white solid. MS ES+ m / z 431 [M+H] - .

[0393] Intermediate 120C: 6-chloro-3-[(1R)-1-(2-ethylsulfanyl-3,6-dimethyl-4-oxo-chromen-8-yl)ethoxy]-N-methoxy-pyridine-2-carboxamide [ka] A solution of 6-chloro-3-[(1R)-1-(2-ethylsulfanyl-3,6-dimethyl-4-oxo-chromen-8-yl)ethoxy]pyridine-2-carboxylic acid (50%; 2.69 g, 3.10 mmol), diisopropylethylamine (5.40 mL, 31.0 mmol), 0-methylhydroxylammonium chloride (0.647 g, 7.75 mmol), 4-dimethylaminopyridine (0.038 g, 0.310 mmol), and propylphosphonic anhydride (50 wt% in DMF, 4.75 mL, 7.75 mmol) in DMF (7.5 mL) was combined. The reaction mixture was stirred at 25 °C for 40 min, diluted with water (50 mL), and extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with saturated aqueous sodium chloride (twice), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 0% to 75% EtOAc in heptane to give the title compound (1.38 g, 91%) as a white solid. MS ES-m / z 461 [MH] - .

[0394] The following compounds in Table 20 were made in a similar manner as described for 8-[(1S)-1-hydroxyethyl]-3,6-dimethyl-2-(2-pyridyl)chromen-4-one. The compounds were purified using a variety of methods that would be apparent to one skilled in the art. Table 20 [Table 20-1]

[0395] (Continued from Table 20) [Table 20-2]

[0396] Example 1: 8-[(1R)-1-[(6-chloro-2-methyl-3-pyridyl)oxy]ethyl]-3,6-dimethyl-2-phenyl-chromen-4-one [ka] 8-[(1R)-1-Hydroxyethyl]-3,6-dimethyl-2-phenyl-chromen-4-one (0.100 g, 0.340 mmol), 6-chloro-3-iodo-2-methyl-pyridine (0.0861 g, 0.340 mmol), potassium phosphate tripotassium (0.144 g, 0.679 mmol), copper(I) iodide (6.47 mg, 0.034 mmol), and 4-pyrrolidinopyridine (0.0604 g, 0.408 mmol) were combined in toluene (3 mL). The mixture was sparged with nitrogen (direct line) for 3 minutes. The reaction was heated at reflux for 19 hours, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase chromatography eluting with a gradient of 0 to 100% ACN in aqueous NH4HCO3 (10 mM + 5% MeOH). Fractions containing the desired product were combined, concentrated under reduced pressure, and lyophilized to give the title compound (0.018 g, 12%). MS ES+ m / z 420 [M+H] + .

[0397] Example 2: 3-[6-chloro-3-[(1R)-1-(3,6-dimethyl-4-oxo-2-phenyl-chromen-8-yl)ethoxy]-2-pyridyl]-4H-1,2,4-oxadiazol-5-one [ka] To a solution of 6-chloro-3-[(1R)-1-(3,6-dimethyl-4-oxo-2-phenyl-chromen-8-yl)ethoxy]-N'-hydroxy-pyridine-2-carboxamidine (0.180 g, 0.388 mmol) in 1,4-dioxane (4 mL) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (0.117 mL, 0.776 mmol) and 1,1'-carbonyldiimidazole (0.0944 g, 0.582 mmol). The reaction was sealed, heated under microwave conditions (100 °C, 1 h), and concentrated under reduced pressure. The residue was purified by reverse-phase chromatography eluting with a gradient of 0 to 100% ACN in HO + 0.1% formic acid. The fractions containing the desired product were combined, washed with saturated aqueous sodium chloride, and extracted with IPA:CHCl (1:3). The combined extracts were dried over MgSO, filtered, and concentrated under reduced pressure to give the title compound (0.0846 g, 45%). MS ES+ m / z 490 [M+H] + .

[0398] The following compounds in Table 21 were made in a similar manner as described for 3-[6-chloro-3-[(1R)-1-(3,6-dimethyl-4-oxo-2-phenyl-chromen-8-yl)ethoxy]-2-pyridyl]-4H-1,2,4-oxadiazol-5-one. The compounds were purified using a variety of methods that would be apparent to one skilled in the art. Table 21 [Table 21-1]

[0399] (Continued from Table 21) [Table 21-2]

[0400] (Continued from Table 21) [Table 21-3]

[0401] (Continued from Table 21) [Table 21-4]

[0402] (Continued from Table 21) [Table 21-5]

[0403] (Continued from Table 21) [Table 21-6]

[0404] Example 9A: 2-[(1R)-1-[3,6-dimethyl-2-(2-methylindazol-5-yl)-4-oxo-chromen-8-yl]ethoxy]benzamide [ka] 2-[(1R)-1-[3,6-Dimethyl-2-(2-methylindazol-5-yl)-4-oxo-chromen-8-yl]ethoxy]benzonitrile (120 mg, 0.27 mmol) was dissolved in toluene (0.7 mL) and treated with (E)-propionaldehyde oxime (58.5 mg, 0.80 mmol) and tris(triphenylphosphine)rhodium(I) chloride (Wilkinson's catalyst, 2.47 mg, 0.003 mmol). The reaction was stirred at 110 °C. After cooling to room temperature, the reaction was concentrated under reduced pressure, and the residue was purified by reverse-phase chromatography on a C18 column eluting with 10%-45% ACN / 10 mM NH4HCO3 in water (containing 5% MeOH) to give the title compound (60 mg, 46%). ES-MS m / z 466 (M−H).

[0405] The following compounds in Table 22 were made in a similar manner as described for 2-[(1R)-1-(3,6-dimethyl-2-(2-methylindazol-5-yl)-4-oxo-chromen-8-yl]ethoxy]benzamide. The compounds were purified using a variety of methods that would be apparent to one skilled in the art. Table 22 [Table 22-1]

[0406] (Continued from Table 22) [Table 22-2]

[0407] Example 6: 6-chloro-3-[(1R)-1-(3,6-dimethyl-4-oxo-2-phenyl-chromen-8-yl)ethoxy]-N-methylsulfonyl-pyridine-2-carboxamide [ka] 6-Chloro-3-[(1R)-1-(3,6-dimethyl-4-oxo-2-phenyl-chromen-8-yl)ethoxy]pyridine-2-carboxylic acid (0.158 g, 0.351 mmol), 2-chloro-1-methylpyridinium iodide (0.135 g, 0.527 mmol), methanesulfonamide (0.0668 g, 0.702 mmol), and N,N-dimethylpyridin-4-amine (4.29 mg, 0.0351 mmol) were dissolved in DCM (4 mL). After 5 min, triethylamine (0.147 mL, 1.05 mmol) was added. The reaction mixture was stirred overnight at room temperature and concentrated under reduced pressure. The residue was purified by reverse-phase chromatography eluting with a gradient of 0 to 100% ACN in HO + 0.1% formic acid. The fractions containing the desired product were combined, washed with saturated aqueous sodium chloride, and extracted with IPA:CHCl (1:3). The combined extracts were dried over MgSO, filtered, and concentrated under reduced pressure, and the residue was recrystallized from DCM / hexane to give the title compound (0.028 g, 15%). MS ES+ m / z 527 [M+H]+ .

[0408] Example 7: 8-[(1R)-1-[(6-chloro-3-pyridyl)oxy]ethyl]-3,6-dimethyl-2-phenyl-chromen-4-one [ka] To a solution of 8-[(1S)-1-chloroethyl]-3,6-dimethyl-2-phenyl-chromen-4-one (0.100 g, 0.320 mmol) in toluene (5 mL) was added 6-chloropyridin-3-ol (0.0828 g, 0.639 mmol) and triethylamine (0.239 mL, 1.71 mmol). The reaction mixture was stirred at 100° C. After 48 h, the reaction was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with a gradient of 0% to 100% EtOAc in hexane to give the title compound (0.049 g, 38%). MS ES+ m / z 406 [M+H] + .

[0409] The following compounds in Table 23 were made in a similar manner as described for 8-[(1R)-1-[(6-chloro-3-pyridyl)oxy]ethyl]-3,6-dimethyl-2-phenyl-chromen-4-one. The compounds were purified using a variety of methods that would be apparent to one skilled in the art. Table 23 [Table 23] A The material was prepared from 8-[(1S)-1-chloroethyl]-3,6-dimethyl-2-(3-pyridyl)chromen-4-one. There was a loss of chiral purity during the reaction. B [Chiralcel OJ-H, 21×150mm; 10% MeOH in CO2]

[0410] Example 12A: 8-[(1R)-1-[2-(2-fluorophenyl)-3-pyridyl]oxy]ethyl]-3,6-dimethyl-2-phenyl-chromen-4-one [ka] 8-[(1R)-1-[(2-chloro-3-pyridyl)oxy]ethyl]-3,6-dimethyl-2-phenyl-chromen-4-one (135 mg, 0.33 mmol), (2-fluorophenyl)boronic acid (69.8 mg, 0.50 mmol), KCO (91.9 mg, 0.67 mmol), and tetrakis(triphenylphosphine)palladium(0) (19.2 mg, 0.02 mmol) were combined with 1,4-dioxane (2 mL) and water (0.5 mL). The reaction was sparged with argon for 5 minutes and then heated at 100 °C overnight. The reaction was purified by silica gel chromatography eluting with 0% to 100% EtOAc in heptane, followed by repurification by silica gel chromatography eluting with 0% to 50% EtOAc in heptane to give the title compound (67 mg, 43%). ES / MS m / z 466.2 (M+H).

[0411] Example 13A: 6-chloro-3-[(1R)-1-(3,6-dimethyl-4-oxo-2-phenyl-chromen-8-yl)ethoxy]pyridine-2-sulfonate [ka] A solution of (2,3,4,5,6-pentafluorophenyl) 6-chloro-3-[(1R)-1-(3,6-dimethyl-4-oxo-2-phenyl-chromen-8-yl)ethoxy]pyridine-2-sulfonate (36 mg, 0.055 mmol) in THF (1 mL) was treated with aqueous ammonia (28%, 38 μL, 0.28 mmol) and then stirred at 60 °C overnight. The reaction was concentrated under reduced pressure and purified by reverse-phase chromatography on a C18 column eluting with 0% to 100% ACN in 10 mM aqueous NH4HCO3 containing 5% MeOH. Product-containing fractions were pooled, washed with brine, and extracted with IPA / CHCl3 (1:3, v / v). The organics were collected, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was crystallized from DCM / MeOH / hexane to give the title compound (22 mg, 81%) as a white solid. ES-MS m / z 485 (M+H).

[0412] The following compounds in Table 24 were made in a similar manner as described for 6-chloro-3-[(1R)-1-(3,6-dimethyl-4-oxo-2-phenyl-chromen-8-yl)ethoxy]pyridine-2-sulfonamide. A basic reagent such as diisopropylethylamine was sometimes used. Compounds were purified using a variety of methods that would be apparent to one skilled in the art. Table 24 [Table 24-1]

[0413] (Continued from Table 24) [Table 24-2]

[0414] (Continued from Table 24) [Table 24-3]

[0415] (Continued from Table 24) [Table 24-4]

[0416] Example 32A: 6-chloro-3-[(1R)-1-(3,6-dimethyl-4-oxo-2-phenyl-chromen-8-yl)ethoxy]-N-methoxy-pyridine-2-sulfonamide [ka] A solution of 8-[(1R)-1-[(2-benzylsulfanyl-6-chloro-3-pyridyl)oxy]ethyl]-3,6-dimethyl-2-phenyl-chromen-4-one (0.100 g, 0.189 mmol) in AcOH / water (3:1; 2 mL) was treated with N-chlorosuccinimide (0.101 g, 0.757 mmol) at 0 °C. The cooling bath was removed and the reaction was stirred at room temperature for 2 h. The reaction was recooled to 0 °C and treated with O-methylhydroxylamine hydrochloride (0.158 g, 1.89 mmol) and DIPEA (0.33 mL, 1.89 mmol). The cooling bath was removed and the reaction was stirred at room temperature for 30 min. The reaction was diluted with EtOAc and washed with saturated aqueous NaHCO3. The aqueous layer was re-extracted with EtOAc (2x). The organics were collected, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 0% to 100% (3:1 EtOAc:EtOAc:EtOH) heptane and further purified by prep-TLC (25% EtOAc in hexanes, then 50% EtOAc in hexanes). The desired fractions were combined, concentrated, diluted with DCM / hexanes, and filtered to give the title compound (0.052 g, 54%) as a white solid. MS ES+ m / z 515 [M+H] + .

[0417] Example 8C: 6-chloro-3-[(1R)-1-[3,6-dimethyl-4-oxo-2-(1H-pyrazol-5-yl)chromen-8-yl]ethoxy]pyridine-2-sulfonamide [ka] 8-[(1R)-1-[(2-benzylsulfanyl-6-chloro-3-pyridyl)oxy]ethyl]-3,6-dimethyl-2-(1H-pyrazol-5-yl)chromen-4-one and ammonium hydroxide were used in a manner similar to that used in Example 32A to give the title compound (0.002 g, 4%). MS ES+ m / z 475 [M+H] + .

[0418] Example 17A: 6-[(1R)-1-[3,6-dimethyl-2-(2-methylindazol-5-yl)-4-oxo-chromen-8-yl]ethoxy]-2,3-difluoro-benzamide [ka] 6-[(1R)-1-[3,6-Dimethyl-2-(2-methylindazol-5-yl)-4-oxo-chromen-8-yl]ethoxy]-2,3-difluorobenzoic acid (50 mg, 0.1 mmol) was dissolved in DMF (3 mL) and treated with HATU (57 mg, 0.15 mmol) and DIPEA (64 mg, 0.50 mmol). The reaction was stirred at room temperature for 10 minutes, then ammonia (0.4 M in 1,4-dioxane, 1.2 mL, 0.50 mmol) was added. The reaction was stirred at room temperature for 4 hours. The reaction was concentrated under reduced pressure, and the residue was dissolved in 2 mL of DMF and purified by reverse-phase chromatography on a CSH (30 x 150 mm, 5 μm) eluting with 30% to 60% ACN in 10 mM aqueous NH4HCO3 containing 5% MeOH to give the title compound (6.5 mg, 13%). ES-MS m / z 502 (M−H).

[0419] The following compounds in Table 25 were made in a similar manner as described for 6-[(1R)-1-[3,6-dimethyl-2-(2-methylindazol-5-yl)-4-oxo-chromen-8-yl]ethoxy]-2,3-difluoro-benzamide. The compounds were purified using a variety of methods that would be apparent to one skilled in the art. Table 25 [Table 25]

[0420] Example 23A: 3-[(1R)-1-[3,6-dimethyl-2-(2-methylindazol-5-yl)-4-oxo-chromen-8-yl]ethoxy]-N-methoxy-pyridine-2-carboxamide [ka] 3-[(1R)-1-[3,6-Dimethyl-2-(2-methylindazol-5-yl)-4-oxo-chromen-8-yl]ethoxy]pyridine-2-carboxylic acid (0.040 g, 0.085 mmol), diisopropylethylamine (0.074 mL, 0.43 mmol), 0-methylhydroxylammonium chloride (0.018 g, 0.21 mmol), 4-dimethylaminopyridine (0.52 mg, 0.0043 mmol), and propylphosphonic anhydride (50 wt%, 0.14 g, 0.21 mmol) were combined in DMF (1 mL, degassed with argon). The reaction mixture was stirred at 25 °C for 30 minutes and then filtered. The filtrate was concentrated under reduced pressure. The residue was purified by reverse phase chromatography eluting with 10% to 80% ACN in 0.1% aqueous formic acid to give the title compound as a white solid (0.025 mg, 55%). MS ES+ m / z 499 [M+H] + .

[0421] The following compounds in Table 26 were made in a similar manner as described for 3-[(1R)-1-[3,6-dimethyl-2-(2-methylindazol-5-yl)-4-oxo-chromen-8-yl]ethoxy]-N-methoxy-pyridine-2-carboxamide. The compounds were purified using a variety of methods that would be apparent to one skilled in the art. Table 26 [Table 26]

[0422] Example 29A: 4-[8-[(1R)-1-[2-(2-fluorophenyl)-3-pyridyl]oxy]ethyl]-3,6-dimethyl-4-oxo-chromen-2-yl]-1H-pyridin-2-one [ka] 2-Ethylsulfanyl-8-[(1R)-1-[2-(2-fluorophenyl)-3-pyridyl]oxy]ethyl]-3,6-dimethyl-chromen-4-one (0.210 g, 0.467 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyridin-2-one (0.207 g, 0.934 mmol), copper(I) thiophene-2-carboxylate (0.178 g, 0.934 mmol), and tetrakis(triphenylphosphine)palladium(0) (0.108 g, 0.093 mmol) were combined in EtOH (1.2 mL), degassed with argon for 5 minutes, and stirred at 65° C. for 16 hours. The reaction mixture was filtered through diatomaceous earth, and the solid was washed with DCM. The mixture was concentrated under reduced pressure and the residue was purified by reverse phase chromatography (C18 column) eluting with a gradient of 0% to 100% ACN in water to give the title compound (0.041 g, 17%) as a white solid. MS ES+ m / z 483 [M+H] + .

[0423] The following compounds in Table 27 were made in a similar manner as described for 4-[8-[(1R)-1-[2-(2-fluorophenyl)-3-pyridyl]oxy]ethyl]-3,6-dimethyl-4-oxo-chromen-2-yl]-1H-pyridin-2-one. The compounds were purified using a variety of methods that would be apparent to one skilled in the art. Table 27 [Table 27-1]

[0424] (Continued from Table 27) [Table 27-2]

[0425] (Continued from Table 27) [Table 27-3]

[0426] (Continued from Table 27) [Table 27-4]

[0427] (Continued from Table 27) [Table 27-5]

[0428] (Continued from Table 27) [Table 27-6]

[0429] (Continued from Table 27) [Table 27-7]

[0430] (Continued from Table 27) [Table 27-8]

[0431] (Continued from Table 27) [Table 27-9]

[0432] (Continued from Table 27) [Table 27-10]

[0433] (Continued from Table 27) [Table 27-11]

[0434] (Continued from Table 27) [Table 27-12]

[0435] (Continued from Table 27) [Table 27-13]

[0436] (Continued from Table 27) [Table 27-14]

[0437] (Continued from Table 27) [Table 27-15]

[0438] (Continued from Table 27) [Table 27-16]

[0439] (Continued from Table 27) [Table 27-17]

[0440] (Continued from Table 27) [Table 27-18]

[0441] (Continued from Table 27) [Table 27-19]

[0442] (Continued from Table 27) [Table 27-20]

[0443] Example 20B and Example 21B: 6-chloro-3-[1-[7-chloro-3,6-dimethyl-4-oxo-2-(3-pyridyl)chromen-8-yl]ethoxy]pyridine-2-carboxamide, Isomer 1 and Isomer 2 [ka] A mixture of 6-chloro-3-[1-[7-chloro-3,6-dimethyl-4-oxo-2-(3-pyridyl)chromen-8-yl]ethoxy]pyridine-2-carbonitrile (0.070 g, 0.150 mmol) and hydrido(dimethylphosphinite-kP)[hydrogen bis(dimethylphosphinite-kP)]platinum(II) (0.013 g, 0.030 mmol) in EtOH (2 mL) and water (2 mL) was stirred at 50 °C for 12 h. The reaction mixture was concentrated under reduced pressure, and the residue was purified by reverse-phase chromatography on a C18 column eluting with 0% to 100% ACN in water to give the racemic product (0.033 g, 45%) as a white solid. Chiral separation [Prep-Chiral-HPLC; Phenomenex Lux i-Amylose-3, 30 x 150 mm, 20-100% EtOH in heptane, 42.5 mL / min] to give the two title compounds. MS ES+ m / z 484 [M+H] + .

[0444] The following compounds in Table 28 were made in a similar manner as described for 6-chloro-3-[1-[7-chloro-3,6-dimethyl-4-oxo-2-(3-pyridyl)chromen-8-yl]ethoxy]pyridine-2-carboxamide. The compounds were purified using a variety of methods that would be apparent to one skilled in the art. Table 28 [Table 28-1]

[0445] (Continued from Table 28) [Table 28-2]

[0446] (Continued from Table 28) [Table 28-3]

[0447] Example 25B: 6-chloro-3-[(1R)-1-[3-cyano-6-methyl-2-(1-methylpyrazol-4-yl)-4-oxo-chromen-8-yl]ethoxy]pyridine-2-sulfonamide [ka] A 0°C mixture of 8-[(1S)-1-hydroxyethyl]-6-methyl-2-(1-methylpyrazol-4-yl)-4-oxo-chromene-3-carbonitrile (0.573 g, 1.85 mmol), 6-chloro-3-hydroxy-pyridine-2-sulfonamide (1.16 g, 5.56 mmol), and triphenylphosphine (1.70 g, 6.48 mmol) in THF (22 mL) was treated with diisopropyl azodicarboxylate (1.31 g, 6.48 mmol). After 2 h, the reaction was concentrated under reduced pressure. The residue was purified three times by silica gel chromatography eluting with a gradient of 0-6% MeOH in DCM, then twice with 35-70% EtOAc in heptane to give the title compound (0.503 g, 53%). MS ES+ m / z 500 [M+H] + . The following compounds in Table 29 were made in a similar manner as described for 6-chloro-3-[(1R)-1-(3-cyano-6-methyl-2-(1-methylpyrazol-4-yl)-4-oxo-chromen-8-yl)ethoxy]pyridine-2-sulfonamide. The compounds were purified using a variety of methods that would be apparent to one skilled in the art. Table 29 [Table 29-1]

[0448] (Continued from Table 29) [Table 29-2]

[0449] (Continued from Table 29) [Table 29-3]

[0450] (Continued from Table 29) [Table 29-4]

[0451] (Continued from Table 29) [Table 29-5] A Reversed-phase chromatography (C18) eluting with a gradient of 0 to 100% ACN in H2O + 0.1% formic acid

[0452] Example 115C: 6-chloro-3-[(1R)-1-[3,6-dimethyl-4-oxo-2-(1H-pyrazol-4-yl)chromen-8-yl]ethoxy]pyridine-2-sulfonamide [ka] To a 0°C mixture of 8-[(1R)-1-hydroxyethyl]-3,6-dimethyl-2-(1-tetrahydropyran-2-ylpyrazol-4-yl)chromen-4-one (0.150 g, 0.407 mmol) in THF (10 mL) was added sodium hydride (60%; 0.162 g, 4.07 mmol) portionwise under nitrogen. The mixture was stirred at room temperature for 1 hour, and then 6-chloro-3-fluoro-pyridine-2-sulfonamide (0.171 g, 0.814 mmol) was added. The reaction mixture was stirred at 50°C overnight, cooled to 0°C, quenched with ice / water, and diluted with water (120 mL). The resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution (80 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give crude 6-chloro-3-[(1R)-1-[3,6-dimethyl-4-oxo-2-(1-tetrahydropyran-2-ylpyrazol-4-yl)chromen-8-yl]ethoxy]pyridine-2-sulfonamide as a white solid. MS ES+ m / z 559 [M+H] + .

[0453] A solution of 6-chloro-3-[(1R)-1-[3,6-dimethyl-4-oxo-2-(1-tetrahydropyran-2-ylpyrazol-4-yl)chromen-8-yl]ethoxy]pyridine-2-sulfonamide (0.400 g, 0.716 mmol) and TFA (0.8 mL) in MeOH (4 mL) was stirred at room temperature under nitrogen for 1 hour. The resulting mixture was diluted with water (100 mL) and basified with ammonium hydroxide to pH 8. The resulting mixture was extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution (60 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by reverse-phase chromatography on a C18 column eluting with 18% to 43% ACN in 10 mM aqueous NH4HCO3 containing 0.05% ammonium hydroxide to give the title compound (0.044 g, 23%) as a white solid. MS ES+ m / z 475 [M+H] + .

[0454] The following compounds in Table 30 were made in a similar manner as described for 6-chloro-3-[(1R)-1-(3,6-dimethyl-4-oxo-2-(1H-upyrazol-4-yl)chromen-8-yl)ethoxy]pyridine-2-sulfonamide. Depending on the intermediate used, a deprotection step was not always performed. The compounds were purified using a variety of methods that would be apparent to one skilled in the art.

[0455] Table 30 [Table 30-1]

[0456] (Continued from Table 30) [Table 30-2]

[0457] Example 124C: 6-chloro-3-[(1R)-1-[2-[1-[(1-cyanocyclopropyl)methyl]pyrazol-4-yl]-3,6-dimethyl-4-oxo-chromen-8-yl]ethoxy]pyridine-2-sulfonamide [ka] A mixture of 6-chloro-3-[(1R)-1-[3,6-dimethyl-4-oxo-2-(1H-pyrazol-4-yl)chromen-8-yl]ethoxy]pyridine-2-sulfonamide (0.040 g, 0.084 mmol), 1-bromomethyl-cyclopropanecarbonitrile (0.0081 g, 0.0051 mmol), and cesium carbonate (0.069 g, 0.21 mmol) in N,N-dimethylacetamide (2 mL) was stirred at 45 °C for 8 h. The crude reaction mixture was purified by reverse-phase chromatography eluting with a gradient of 10 to 100% ACN in water (with formic acid). Fractions containing the desired product were combined, concentrated under reduced pressure, and lyophilized to afford the title compound (0.004 g, 7%) as a white solid. MSES+ m / z 554 [M+H] + .

[0458] Examples 125C and 126C: 6-chloro-3-[(1R)-1-[2-[2-(hydroxymethyl)cyclopropyl]-3,6-dimethyl-4-oxo-chromen-8-yl]ethoxy]pyridine-2-sulfonamide, Isomers 1 and 2 [ka] To a 0°C solution of 2-[8-[(1R)-1-[(6-chloro-2-sulfamoyl-3-pyridyl)oxy]ethyl]-3,6-dimethyl-4-oxo-chromen-2-yl]cyclopropanecarboxylic acid (0.210 g, 0.426 mmol) in THF (3 mL) was added borane-THF complex (0.9 M, 1.18 mL, 1.07 mmol). The mixture was stirred at 0°C for 1 h, and then borane-THF complex (0.9 M, 0.23 mL, 0.21 mmol) was added. The mixture was warmed to room temperature and stirred for 1 h. The reaction mixture was concentrated under reduced pressure, and the residue was purified by reverse-phase chromatography eluting with a gradient of 0–100% ACN in HO + 0.1% formic acid. Fractions containing the desired product were combined, washed with saturated aqueous sodium chloride, and extracted with IPA:CHCl (1:3). The combined extracts were dried over MgSO4, filtered, and concentrated under reduced pressure to give the title compounds (Isomer 1, 0.008 g, 4%; Isomer 2, 0.011 g, 5%). MS ES+ m / z 479 [M+H] for both. + .

[0459] Example 127C: 6-chloro-3-[(1R)-1-[2-[1-(2-hydroxyethyl)cyclopropyl]-3,6-dimethyl-4-oxo-chromen-8-yl]ethoxy]pyridine-2-sulfonamide [ka] In a manner similar to the preparation of Examples 125C and 126C, 2-[1-[8-[(1R)-1-[(6-chloro-2-sulfamoyl-3-pyridyl)oxy]ethyl]-3,6-dimethyl-4-oxo-chromen-2-yl]cyclopropyl]acetic acid was used to obtain the title compound (0.063 g, 18%). MSES+m / z 493 [M+H] + .

[0460] Example 128C: 6-chloro-3-[(1R)-1-[2-[1-[(1-hydroxycyclopropyl)methyl]pyrazol-4-yl]-3,6-dimethyl-4-oxo-chromen-8-yl]ethoxy]pyridine-2-sulfonamide [ka] To a solution of 6-chloro-3-[(1R)-1-[3,6-dimethyl-4-oxo-2-[1-[(1-tetrahydropyran-2-yloxycyclopropyl)methyl]pyrazol-4-yl]chromen-8-yl]ethoxy]pyridine-2-sulfonamide (0.098 g, 0.16 mmol) in THF (2 mL) was added HCl (10% aqueous solution; 0.70 mL). The reaction mixture was heated at 50 °C for 1 h and concentrated under reduced pressure. The residue was purified by reverse-phase chromatography eluting with a gradient of 0 to 100% ACN in HO + 0.1% formic acid. Fractions containing the desired product were combined, washed with saturated aqueous sodium chloride, and extracted with IPA:CHCl (1:3). The combined extracts were dried over MgSO, filtered, and concentrated under reduced pressure to give the title compound (0.032 g, 38%) as a white solid. MS ES+m / z 545[M+H] + .

[0461] Example 129C: 6-chloro-3-[(1R)-1-[2-[2-(2-hydroxyethyl)indazol-5-yl]-3,6-dimethyl-4-oxo-chromen-8-yl]ethoxy]pyridine-2-carboxamide [ka] To a solution of 3-[(1R)-1-[2-[2-[2-[tert-butyl(dimethyl)silyl]oxyethyl]indazol-5-yl]-3,6-dimethyl-4-oxo-chromen-8-yl]ethoxy]-6-chloro-pyridine-2-carboxamide (60%; 0.228 g, 0.211 mmol) in THF (5 mL) was added dropwise tetra-n-butylammonium fluoride (1 M in THF, 0.350 mL, 0.350 mmol). The reaction was stirred at room temperature for 1 hour and then quenched with ammonium chloride (5 mL). The resulting mixture was extracted with DCM (3 times). The combined organic extracts were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The reaction was concentrated under reduced pressure and purified by reverse-phase chromatography on a C18 column, eluting with 20% to 100% ACN in 10 mM aqueous NH4HCO3 containing 5% MeOH. Fractions containing the desired product were combined, concentrated under reduced pressure, and lyophilized to give the crude product. This material was dissolved in DCM (5 mL) and washed with saturated aqueous ammonium chloride (3x) and water (1x). The organic layer was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness under a stream of nitrogen to give the title compound (0.061 g, 54%) as a white solid. MS ES+ m / z 531 [MH] - .

[0462] The following compounds in Table 31 were made in a similar manner as described for 6-chloro-3-[(1R)-1-[2-[1-[(1-hydroxycyclopropyl)methyl]pyrazol-4-yl]-3,6-dimethyl-4-oxo-chromen-8-yl]ethoxy]pyridine-2-sulfonamide and 6-chloro-3-[(1R)-1-[2-[2-(2-hydroxyethyl)indazol-5-yl]-3,6-dimethyl-4-oxo-chromen-8-yl]ethoxy]pyridine-2-carboxamide. The compounds were purified using a variety of methods that would be apparent to one skilled in the art. Table 31 [Table 31]

[0463] The following compounds in Table 32 can be made according to the preceding examples and / or using common general knowledge in synthetic chemistry. Table 32 [Table 32-1]

[0464] (Continued from Table 32) [Table 32-2]

[0465] The following compounds in Table 33 can be made according to the preceding examples and / or using common general knowledge in synthetic chemistry. Table 33 [Table 33-1]

[0466] (Continued from Table 33) [Table 33-2]

[0467] (Continued from Table 33) [Table 33-3]

[0468] (Continued from Table 33) [Table 33-4]

[0469] (Continued from Table 33) [Table 33-5]

[0470] (Continued from Table 33) [Table 33-6]

[0471] (Continued from Table 33) [Table 33-7]

[0472] (Continued from Table 33) [Table 33-8]

[0473] PI3K-alpha kinase (PI3Kα) activity: wild-type PI3Kα, H1047R mutant PI3Kα, and E545K mutant PI3Kα in vitro cell-based assays and determination of inhibitor IC50 values The MDA-MB-453 (ATCC-HTB-131) cell line (PI3Kα H1047R), MCF-7 (ATCC-HTB-22) cell line (PI3Kα E545K), MDA-MB-361 (ATCC-HTB-27) cell line (PI3Kα E545K), and SKBR3 (ATCC-HTB-30) cell line (wild-type PI3Kα) were obtained from the American Type Culture Collection (Manassas, VA). MDA-MB-453 cells were maintained in Dulbecco's modified Eagle's medium (DMEM, Gibco 12430) supplemented with 10% heat-inactivated fetal bovine serum (FBS HI, Gibco 10082), 1× non-essential amino acids (NEAA, Gibco 11140), 1 mM sodium pyruvate (Gibco 11360-15240), and 1× Anti-Anti. MCF-7 cells were maintained in minimum essential medium (MEM) (Gibco 11095) supplemented with 10% heat-inactivated fetal bovine serum (FBS HI, Gibco 10082), 1× non-essential amino acids (NEAA, Gibco 11140), 1 mM sodium pyruvate (Gibco 11360), 1× Anti-Anti (Gibco 15240), and 10 μg / mL human insulin (Sigma I 9278). MDA-MB-361 cells were maintained in Dulbecco's modified Eagle's medium (DMEM, Gibco 12430) supplemented with 20% heat-inactivated fetal bovine serum (FBS HI, Gibco 10082), 1x non-essential amino acids (NEAA, Gibco 11140), 1 mM sodium pyruvate (Gibco 11360-15240), and 1x Anti-Anti. SKBR3 cells were maintained in McCoy's 5A (Gibco 16600) supplemented with 10% heat-inactivated fetal bovine serum (FBS HI, Gibco 10082), and 1x Anti-Anti (Gibco 15240). Cultures were maintained in a humidified incubator at 37°C under 5% CO2 / 95% air.

[0474] To test compounds in 0% FBS, MDA-MB-453, MCF-7, and SKBR3 cells were plated at 1.5 x 10 cells per well in white 384-well plates in 20 μl of Minimum Essential Medium (MEM) Assay Medium containing 1× NEAA, 1 mM sodium pyruvate, and 1 μg / mL human insulin (Sigma I9278). 4 , 1.0×10 4 , and 1.0 × 10 4 Meanwhile, MDA-MB-361 cells were seeded at a density of 1.5 x 10 cells in 20 µl assay medium without insulin in a white 384-well plate. 4Cells were seeded at a density of 1000 / well. After plating, cells were allowed to attach overnight. Compounds dissolved in a 10 mM stock solution 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 was then prepared in MEM containing 1x NEAA and 1 mM sodium pyruvate (150 μM starting compound concentration in 1.5% DMSO). Five μl of the intermediate serially diluted compound was added to the cell plate to achieve final concentrations ranging from 30 mM to 0.0015 mM in 0.3% DMSO. 0.3% DMSO alone was used to establish the maximum (MAX) signal, and GDC-0032 at a final concentration of 1 μM was used as a reference compound for the minimum (MIN) signal. After 3 hours of treatment, the medium was removed and the cells were lysed in 10 μL of 1X SureFire Lysis Buffer with shaking for 10 minutes at room temperature. The acceptor mix (Reaction Buffer 1 + Reaction Buffer 2 + Activation Buffer + SureFire Ultra Acceptor Beads) was prepared by diluting the activation buffer 25-fold in the combined Reaction Buffer 1 and Reaction Buffer 2. The acceptor beads were diluted 50-fold in the combined Reaction Buffer. Five μL of the acceptor mix was added to each well, the plate was sealed, covered with foil, and incubated at room temperature for 1 hour. The donor mix (Dilution Buffer + SureFire Ultra Donor Beads) was prepared by diluting the donor beads 50-fold in the dilution buffer. Five μL of the donor mix was added to each well, the plate was sealed, covered with foil, and incubated at room temperature in the dark for 1-2 hours. The plate was read on a Biotek Neo2 plate reader using standard AlphaLisa settings.

[0475] Compounds were tested in duplicate and the % inhibition at each compound concentration was used to generate duplicate dose-response curves. The average % inhibition at each compound concentration was used to generate a single IC50. Data were processed using the Genedata-Screener tool. Relative IC 50Values ​​were determined by calculating percent inhibition relative to the "minimum" (GDC-0032 reference control) and "maximum" (DMSO) controls within the plate using luminescence units. Data were analyzed using a four-parameter nonlinear logistic equation (four-parameter logistic concentration-response curve). Y = Bottom + [(Top-Bottom) / 1 + (X / IC 50 )slope] Y = % inhibition, X = inhibitor concentration, bottom = minimum y value obtained by curve fitting, top = maximum y value obtained by curve fitting, Slope = IC 50 The steepness of the curve in % Inhibition = [(signal at X - minimum median) / (maximum median - minimum median)] x 100 I C 50 : The concentration of a compound that reduces a given response (ligand binding, enzyme response) by 50%. Relative IC 50 : The concentration that gives half the maximal response of the compound.

[0476] Compound selectivity was calculated by dividing the IC50 in SKBR3 by the IC50 in cell lines harboring mutant PI3Kα (MDA-MB-453:H1047R; MCF-7 and MDA-MB-361:E545K).

[0477] Efficacy of test compounds in MDA-MB-453 (ATCC-HTB-131) cell line (PI3KαH1047R) Selected compounds of the Examples were tested in the cell-based PI3Kα H1047R mutant assay described above. Examples 1, 2, 10, 9A, 11A-18A, 26A-30A, 32A, 35A, 37A, 39A, 42A, 46A, 48A, 49A, 52A, 57A, 61A, 64A-66A, 68A, 74A, 83A, 103A-105A, 108A, 123A, 146A, 2B-7B, 12B, 17B, 22B, 24B-27B, 29B, 30B, 6C, 8C-1 3C, 17C-19C, 22C-26C, 30C, 31C, 33C, 36C, 38C, 40C, 45C, 53C, 58C, 63C, 65C, 66C, 69C, 71C-77C, 81C, 85C, 88C, 90C, 94C, 95C, 98C-107C, 109C-111C, 114C-126C, 127C-130C, and 132C-136C had IC values ​​of less than 100 nM for the PI3Kα H1047R mutant. 50 The values ​​were shown.

[0478] Selectivity of test compounds in MDA-MB-453 (ATCC-HTB-131) cell line (PI3KαH1047R) versus wild type Selected compounds of the Examples were tested in the cell-based MDA-MB-453 PI3Kα H1047R mutant and wild-type assays described above. Examples 1, 2, 5, 8-10, 4A-6A, 8A, 11A, 13A-17A, 22A, 27A, 32A-36A, 38A, 39A, 42A, 46A, 47A, 49A, 52A, 55A, 56A, 61A, 64A, 74A, 78A, 83A, 102A, 103A, 108A, 115A, 116A, 137A, 146A, 147A, 1B-8B, 17B, 25B, 26B, 28B-30B, 3C, 6C, 9C, 12C, 13C, 15C, 17C , 21C, 22C, 24C, 25C, 27C, 29C-32C, 34C, 35C, 47C, 56C, 68C, 73C, 74C, 81C, 86C-89C, 91C, 92C-97C, 100C, 101C, 104C-107C, 109C, 110C, 111C, 113C-115C, 119C, 120C, and 122C-127C showed approximately 20-fold selectivity for the PI3K-alpha kinase H1047R mutant over the wild type.

[0479] Selected compounds of the Examples were tested in the cell-based PI3Kα H1047R mutant and wild-type assays described above. Examples 8, 10, 14A, 15A, 35A, 38A, 42A, 74A, 83A, 2B, 5B, 7B, 28B, 3C, 9C, 12C, 13C, 15C, 17C, 21C, 22C, 29C, 31C, 35C, 47C, 56C, 68C, 73C, 74C, 86C-89C, 92C-97C, 106C, 109C, 101C, 104C, 107C, 110C, 111C, 113C-115C, 120C, 122C, and 125C-127C showed greater than about 50-fold selectivity for the PI3K-α kinase H1047R mutant over the wild type.

[0480] Efficacy of test compounds in MCF-7 (ATCC-HTB-22) cell line (PI3KαE545K) Selected compounds of the Examples were tested in the cell-based MCF-7PI3Kα E545K mutant assay described above. Examples 1, 2, 10, 9A~14A, 16A, 17A, 19A, 20A, 22A, 23A, 25A, 26A, 28A~33A, 35A~37A, 46A, 52A, 57A~63A, 65A, 66A, 68A, 69A, 71A, 74A, 83A, 10 4A~113A, 116A, 119A, 120A~123A, 126A, 128A, 140A, 141A, 146A, 149A, 2B~4B, 6B-12B, 14B, 15B, 17B-20B, 22B, 24B-27B, 29B, 30B, 7C~10 C, 12C, 19C, 22C-25C, 31C, 36C-38C, 40C-43C, 45C, 46C, 48C, 52C-55C, 58C-63C, 64C-66C, 68C-70C, 72C-77C, 79C-85C, 94C, 98C, 99C-101C, 103C-105C, 107C, 109C, 110C, 114C, 115C, 117C, 119C, 120C, 122C-124C, 126C, 127C, 129C, 130C, 132C, 133C, and 136C had an IC of less than 500 nM for the MCF-7PI3Kα E545K mutant. 50 The values ​​were shown.

[0481] Efficacy of test compounds in MDA-MB-361 (ATCC-HTB-22) cell line (PI3KαE545K) Selected compounds of the Examples were tested in the cell-based MDA-MB-361 PI3Kα E545K mutant assay described above. Examples 11A, 13A, 14A, 15A, 16A, 17A, 25A, 26A, 28A, 29A, 30A, 37A, 40A, 46A, 48A, 50A, 51A, 52A, 57A, 58A, 59A, 60A, 61A, 63A, 66A, 68A, 74A, 104A, 119A, 120A, 123A, 146A, 149A, 2B, 3B, 4B, 6B, 7B, 12B, 17B, 22B, 24B, 25B, 27B, 29B, 30B, 18C, 22C, 23C, 31C, 36C, 38C , 40C, 43C, 50C, 53C, 58C, 61C, 63C, 65C, 66C, 69C, 72C, 74C, 75C, 76C, 77C, 79C, 80C, 81C, 83C, 84C, 85C, 90C, 98C, 99C, 100C, 101C, 102C, 105C, 106C, 107C, 110C, 115C, 117C, 118C, 119C, 121C, 122C, 124C, 126C, 129C, 130C, 132C, 133C, and 134C had IC<500 nM for the MDA-MB-361 PI3Kα E545K mutant. 50 The values ​​were shown.

[0482] Metabolic stability and intrinsic clearance in liver microsomes (MICS) One purpose of this assay is to measure the in vitro metabolic stability of a test compound in liver microsomes of one or more different species. The concentration of a reference compound in the reaction system is assessed by LC / MS / MS to calculate the intrinsic clearance of the test compound and to estimate the stability of the reference and test compounds in liver microsomes of one or more different species.

[0483] 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 from commercial sources at a concentration of 20 mg / mL protein and stored in a -80°C freezer. Prior to use, liver microsomes are removed from the freezer, thawed in a 37°C water bath, and then stored on wet ice.

[0484] Prepare a test compound (TC) stock solution in DMSO at a concentration of 10 mM and store it for later use. Prepare a positive control (PC) stock solution of verapamil.HCl (FW: 491.1 g / mol) in DMSO at a concentration of 10 mM (4.91 mg / mL) and store it under the same conditions as the test compound stock solution.

[0485] Phosphate Buffer Phosphate buffer (100 mM, pH 7.4) is prepared by combining solution A and solution B as follows:

[0486] To prepare solution A, 7.098 g of disodium hydrogen phosphate was mixed with 500 mL of purified water and sonicated to dissolve. To prepare solution B, 3.400 g of potassium dihydrogen phosphate was mixed with 250 mL of purified water and sonicated to dissolve. Solution A was placed on a stirrer and solution B was slowly added to solution A until the pH reached 7.4.

[0487] NADPH solution: Prepare a 10 mM NADPH solution by dissolving NADPH (MW: 833.4 g / mol) at 8.334 mg / mL in phosphate buffer (100 mM, pH 7.4).

[0488] Microsome Master Solution: Prepare microsome master solution by adding 6.25 μL of microsomes (20 mg / mL) to 216.25 μL of phosphate buffer (100 mM). The final concentrations are phosphate buffer (100 mM); microsomes (0.5 mg / mL).

[0489] Dilution of Stock Solutions Dilute the TC stock solution (10 mM in DMSO) and PC stock solution (10 mM in DMSO) by adding 3 μL of TC or PC stock solution to 297 μL of 50% acetonitrile / 50% water.

[0490] Incubations were performed in two separate experiments as follows: a) with cofactor (NADPH): 25 μL of 10 mM NADPH was added to the incubation. The final concentrations of microsomes and NADPH were: The concentrations were 0.5 mg / mL and 1 mM, respectively. b) No cofactor (NADPH): 25 μL of 100 mM phosphate buffer was added to the incubation. The final concentration of microsomes was 0.5 mg / mL. The mixture was preheated to 37°C for 10 minutes.

[0491] The reaction was initiated by adding 2.5 μL of 100 μM PC or TC solution. Verapamil was used as PC in this study. The final concentration of the test compound or control compound was 1 μM. The incubation solution was incubated in a 37°C water bath.

[0492] End of reaction 30 μL aliquots were taken from the reaction solution at 0.5, 5, 15, 30, and 60 minutes and added to the plate. The reaction was stopped by adding 5 volumes of cold acetonitrile and a solution containing 100 nM alprazolam, 200 nM caffeine, and 100 nM tolbutamide.

[0493] The plate containing the sampled and stopped reactions was centrifuged at 4000 rpm for 30 minutes. Supernatants (40 μL) from each compound were transferred to a 96-well assay plate. Four compound samples were pooled together in one cassette and diluted by adding 160 μL of pure water. All incubations were performed in duplicate.

[0494] Analysis and Data Processing: Quantitative LC-MS analysis was performed to determine peak areas from extracted ion chromatograms. The percent parent remaining was calculated from the TC or PC peak area. The slope value k was determined by linear regression of the natural logarithm of the percent parent remaining versus incubation time curve.

[0495] In vitro half-life (in vitro t 1 / 2 ) is determined from the slope value.

number

[0496] In vitro t 1 / 2 (in minutes) In vitro intrinsic clearance (in vitro CL int (µL / min / mg protein) is calculated using the following formula:

number

[0497] Scaled-up CL hep (mL / min / kg), predicted CL int Calculations of (mL / min / kg) and EH can be made using formulas and scaling factors for human, monkey, dog, rat, and mouse microsomes known in the art.

[0498] Intrinsic clearance of test compounds In the above assays, the compounds of the examples presented herein were tested in human MICS and showed metabolic stability as determined by calculating intrinsic clearance values. Examples 2-6: 1A-8A, 10A, 11A, 13A-16A, 18A, 20A, 23A, 24A, 26A, 27A, 31A, 33A-36A, 38A, 39A, 41A, 42A, 46A, 47A, 50A-56A, 58A-61A, 64A, 66A, 67A, 83A, 102A, 105A, 128A, 130A, 137A, 141A, 147A, 149A, 1B, 2B, 4B, 5B, 7B-9B, 16B, 17B, 19B, 23B-26B, 1C-6C, 8C, 10C, 14C ~17C, 19C, 21C, 22C, 24C, 25C, 27C-35C, 37C, 39C, 42C, 44C, 46C, 47C, 52C, 58C, 60C-6C, 73C, 74C, 75C, 78C, 79C, 80C, 81C, 86C-98C, 99C, 103C, 109C, 101C, 105C, 108C, 110C, 111C, 115C, 119C, 122C-126C, 128C, and 135C showed intrinsic clearance of less than about 50 μL / min / mg in human MICS.

[0499] Metabolic stability and intrinsic clearance in hepatocytes (HEPS) One purpose of this assay is to measure the in vitro metabolic stability of a test compound in hepatocytes of one or more different species. The concentration of a reference compound in the reaction system is assessed by LC / MS / MS to calculate the intrinsic clearance of the test compound and estimate the stability of the reference and test compounds in hepatocytes of one or more different species.

[0500] Hepatocytes (HEPS) Hepatocytes were purchased from a commercial source and stored below -150°C.

[0501] Prepare a test compound (TC) stock solution in DMSO at a concentration of 10 mM and store it for later use. Prepare a positive control (PC) stock solution of verapamil.HCl (FW: 491.1 g / mol) in DMSO at a concentration of 10 mM (4.91 mg / mL) and store it under the same conditions as the test compound stock solution.

[0502] Preparation of hepatocytes Incubation medium (Williams E medium supplemented with GlutaMAX) and hepatocyte thawing medium were warmed in a 37°C water bath for at least 30 minutes before use.

[0503] A vial of cryopreserved hepatocytes was removed from storage, depressurized, and thawed in a 37°C water bath. The contents were poured into a 50 mL conical tube containing Hepatocyte Thawing Medium preheated to 37°C. The vial was centrifuged at 100 g for 5 minutes at room temperature. The thawing medium was aspirated, and the hepatocytes were resuspended in 3-4 mL of serum-free incubation medium.

[0504] Cell viability and density were counted and the cell density was adjusted to 0.5 x 10 by dilution with serum-free incubation medium. 6 A working cell density of viable cells / mL was achieved.

[0505] Dilution of Stock Solutions Dilute TC stock solution (10 mM in DMSO) and PC stock solution (10 mM in DMSO) to 100 μM by adding 2 μL of TC or PC stock solution to 198 μL of 50% acetonitrile / 50% water.

[0506] incubation The hepatocyte suspension (247.5 μL) was pipetted into each well of a 96-well non-coated plate. The plate was placed in an incubator and the hepatocytes were allowed to warm for 10 minutes. TC (2.5 μL of a 100 μM TC solution) or PC (2.5 μL of a 100 μM PC solution) was pipetted into each well of the 96-well non-coated plate to initiate the reaction. The plate was returned to the incubator, and samples were taken at the designated time points.

[0507] The contents of the reaction-terminated wells were transferred to the plate in 25 μL aliquots at 0.5, 30, 60, 90, 120, and 240 minutes, and the reactions were then stopped by mixing the aliquots with 12 volumes (300 μL) of acetonitrile containing internal standards (100 nM alprazolam, 200 nM caffeine, and 100 nM tolbutamide).

[0508] The plate containing the sampled and stopped reactions was centrifuged at 4000 rpm for 40 minutes. Supernatants (100 μL) from each compound were transferred to a 96-well analysis plate. Four compound samples were pooled together in one cassette and diluted by adding 160 μL of pure water. All incubations were performed in duplicate. A 100 μL aliquot of the supernatant was diluted with 100 μL of ultrapure water and used for LC / MS / MS analysis. All incubations were performed in duplicate.

[0509] Analysis and Data Processing: Quantitative LC-MS analysis was performed to determine peak areas from extracted ion chromatograms. The percent parent remaining was calculated from the TC or PC peak area. The slope value k was determined by linear regression of the natural logarithm of the percent parent remaining versus incubation time curve.

[0510] In vitro half-life (in vitro t 1 / 2 ) is determined from the slope value.

number

[0511] In vitro t 1 / 2 (in minutes) In vitro intrinsic clearance (in vitro CL int (µL / min / mg protein) is calculated using the following formula:

number

[0512] Scaled-up CLhep (mL / min / kg), predicted CL int Calculations of (mL / min / kg) and EH can be made using formulas and scaling factors for human, monkey, dog, rat, and mouse microsomes known in the art.

[0513] Intrinsic clearance of test compounds In the above assay, the compounds of the examples presented herein were tested in human HEPS and showed metabolic stability as determined by calculating intrinsic clearance values. Examples 1-7: 1A-11A, 13A, 14A, 16A-21A, 23A-28A, 31A, 33A-43A, 46A, 47A, 49A-64A, 66A-71A, 74A, 83A, 102A, 105A, 108A, 111A-114A, 116A, 119A-121A, 123A, 126A, 128A, 130A, 132A , 137A, 141A, 147A, 149A, 1B to 10B, 12B-17B, 19B-31B, 1C to 7C to 10C, 12C to 35C, 37C to 90C, 91C, 93C to 99C, 102C to 105C, 108C, 111C, 113C, 114C, 116C to 131C, and 133C to 136C are approximately 50 μL / min / 1 × 10 6 Subcellular intrinsic clearance was demonstrated.

[0514] In vitro evaluation of CYP1A2, CYP2B6, and CYP3A4 induction potency in primary human hepatocytes One purpose of this assay is to investigate the potential of test compounds to modulate the expression of CYP1A2, CYP2B6, and CYP2A4 in plate cultures of cryopreserved human hepatocytes.

[0515] material Hepatocytes were purchased from a commercial source and stored below -150°C.

[0516] Preparation of compound working solutions Stock solutions of test compounds (TC) and the positive control chlorpromazine (PC) are prepared in DMSO at 1000x stock concentration and diluted to their respective working concentrations in hepatocyte incubation medium at 37°C. The final DMSO concentration in the assay is 0.1%.

[0517] Hepatocyte seeding and treatment A vial of cryopreserved hepatocytes was 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 Hepatocyte Thawing Medium preheated to 37°C. The vial was centrifuged at 100 g for 10 minutes at room temperature. The thawing medium was aspirated, and the hepatocytes were resuspended in sufficient plating medium (preheated to 37°C) to obtain a plate of approximately 1.0 x 10 6 The viable cell density was determined and the cells were diluted with plating medium to obtain a cell density of 0.55 x 10 cells / mL. 6 Transfer an aliquot of cells (100 μL) to each well of a collagen I-coated 96-well plate. Place the plate in an incubator (37°C, 5% CO2, 95% relative humidity) for 4-5 hours. After incubation, check cell morphology and monolayer integrity to ensure that the cells are attached to the plate. Replace the medium in the wells with 125 μL of Matrigel incubation medium with a concentration of 0.5-0.75 mg protein / mL. Place the plate in the incubator for 18 hours. Remove the plate from the incubator and replace the medium with 125 μL of 0.1% DMSO, TC solution, or PC solution, each in triplicate. Refresh the TC solution or PC solution every 24 hours.

[0518] Determination of cell viability After 72 hours of treatment, cell morphology is checked under a microscope and samples are removed to determine cell viability.

[0519] Enzyme activity assay Stock solutions of the marker substrates phenacetin and midazolam were prepared in DMSO at 1:1000 for CYP1A2 and CYP3A4, respectively, and bupropion was prepared in pure water at 1:100 for CYP2B6. The substrate solutions were prepared by diluting the stock solutions with incubation medium preheated to 37°C to final concentrations of phenacetin (CYP1A2) (100 μM), bupropion (CYP2B6) (500 μM), and midazolam (CYP3A4) (10 μM). The final concentration of DMSO in the substrate solution was ≤0.1%. The medium was removed from the cell plate, the cell monolayer was washed with PBS, and 125 μL of preheated incubation medium was added to the plate. The assay plate was incubated at 37°C, 5% CO2, and 95% RH for 10 hours. After incubation, the contents of the plate wells are replaced with 125 μL of probe substrate solution. The plate is incubated for 30 minutes (37°C, 5% CO2, 95% relative humidity). At the end of the incubation period, aliquots (100 μL) are removed directly from the wells to a new 96-well plate. The contents of the new plate wells are mixed with 400 μL of quenching solution (acetonitrile containing 0.5 μM tolbutamide), vortexed for 10 minutes, and then centrifuged at 3,000 × g and 4°C for 30 minutes. For UPLC-MS / MS analysis, a 150 μL aliquot of the supernatant is mixed with 150 μL of purified water. The marker metabolites acetaminophen, hydroxybupropion, and 1-hydroxymidazolam are diluted to their respective concentrations in William's E medium to generate calibration curves. Quality control samples of the marker metabolites are also prepared. Metabolite stock solution (1 µL of 100x DMSO stock solution) is added to 99 µL incubation medium and mixed with 400 µL of acetonitrile containing an internal standard (0.5 µM tolbutamide) to generate samples for calibration curves and QC. The samples are centrifuged in the plate at 3000 x g for 30 min at 4 °C to precipitate proteins. 150 µL of supernatant sample is transferred to a new 96-well plate and then analyzed by UPLC-MS / MS after adding 150 µL of pure water. All incubations are performed in triplicate.CYP activity is expressed as pmol / min / million cells, where pmol is the amount of metabolite formed in the reaction. The fold induction of CYP activity for TC relative to vehicle is determined.

[0520] mRNA level assay After extracting samples for enzyme activity assay, mRNA was extracted using a commercially available kit. The mRNA levels of CYP1A2, CYP2A6, and CYP3A4 were measured by quantitative fluorescent RT-PCR, and the mRNA content was expressed as the number of cycles required for the fluorescent signal to exceed a selected threshold. The fold induction of CYP mRNA levels for TCs relative to the control was determined.

[0521] The compounds of the examples presented herein were tested in the above assay to determine the fold induction level for CYP3A4 mRNA after administration of the compounds at a concentration of 1 μM. Examples 10, 2A, 3A, 10A-16A, 23A, 25A, 26A, 29A, 30A, 32A, 35A, 38A, 41A, 42A, 44A, 47A, 54A, 56A, 61A, 65A, 67A, 69A-71A, 83A, 104A-106A, 108A, 110A-112A, 114A, 116A, 120A, 123A, 126A, 128A, 132A, 137A, 140A, 147A, 2B, 5B-7B, 11 B, 18B, 21B, 23B, 25B, 26B, 28B, 30B, 1C, 2C, 10C, 12C, 18C, 19C, 22C, 38C, 39C, 41C, 43C, 71C, 72C, 77C, 85C-90C, 92C-94C, 99C, 111C-113C, 115C, 117C, 118C, 121C, 125C, 126C, 128C, and 129C showed CYP3A4 mRNA induction fold levels of less than about 3.0-fold.

Claims

1. A compound of the formula: 【Chemical Formula 1】 or a pharmaceutically acceptable salt thereof, wherein R １ is an optionally substituted bicyclic ring selected from isobenzofuranone, benzofuranone, isoindolinone, indolinone, quinazolinone, 3,4-dihydro-2H-isoquinolin-1-one, 2H-isoquinolin-1-one, or benzothiazolone, wherein the optionally substituted bicyclic ring is optionally substituted with 1 to 3 substituents independently selected from oxo, -CN, halogen, C １ to C ６ alkyl, C １ to C ６ haloalkyl, -OH, or C １ to C ６ alkoxy, or R １ is the basis of the following formula, 【Chemical 2】 R' is hydrogen, halogen, C １ -C ３ alkyl, C １ -C ３ haloalkyl, C １ -C ３ alkoxy, C １ -C ３ haloalkoxy, -OH, -CH(OH)-CH ２ OH, -CO-CH ２ OH, C ３ -C ６ cycloalkyl, -NO ２ , -N(R １１ )-CO ２ C １ -C ３ alkyl, -N(R １１ )-SO ２ C １ -C ３ alkyl, -N(R １１ )-SO ２ R １５ , -SO ２ C １ -C ３ alkyl, -SO ２ NR １１ R １１ , -SO ２ NR １１ R １２ , -SO ２ N(R １１ )-CO-C １ -C ３ alkyl, -SO ２ N(R １１ )-CN, -C(=N-OH)-NH ２ , -CN, -CONR １１ R １２ , -CON(R １１ )(CH ２ ) ｎ -R １３ , -CO-SR １２ or a group of the following formula, [Chemical Formula 3] ring A is pyrrolidine optionally substituted with -CN, or R' is selected from oxetane, pyrrolidine, tetrahydrofuran, morpholine, piperidine, piperazine, pyrrole, furan, thiophene, pyrazole, imidazole, isoxazole, oxazole, isothiazole, thiazole, triazole, oxadiazole, thiadiazole, tetrazole, phenyl, pyridine, pyridazine, pyrimidine, pyrazine, or triazine, each of which is oxo, -OH, -NR １１ R １１ , -N(R １１ )-CO-R １１ , -N(R １１ )-CN, -OR １１ , -CN, halogen, C １ ~C ６ haloalkyl, or C １ ~C ６ alkyl optionally substituted with 1 to 3 substituents independently selected from alkyl optionally substituted with aryl, 5-membered heteroaryl, or 6-membered heteroaryl, or R' is a group of the following formula 【Chemical Formula 4】 R ２ is the basis of the following formula, [Chemical Formula 5] R ２ is the basis of the following formula, [Chemical Formula 6] R ２ is an optionally substituted 5-membered heteroaryl selected from pyrrole, furan, thiophene, pyrazole, isoxazole, isothiazole, imidazole, oxazole, thiazole, triazole, tetrazole, oxadiazole, and thiadiazole, and the optionally substituted 5-membered heteroaryl is -CN, halogen, C １ ~C ６ haloalkyl, C １ ~C ６ alkoxy, C １ ~C ６ haloalkoxy, -SO ２ R １１ 、-CO ２ C １ ~C ３ alkyl, -CONR １１ R １１ 、-OH、-NR １１ R １１ 、-NR １１ CO ２ R １１ 、optionally substituted C １ ~C ６ alkyl, optionally substituted C ２ ~C ６ alkenyl, optionally substituted C ２ ~C ６ alkynyl, optionally substituted C ３ ~C ５ cycloalkyl, an optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine or morpholine, an optionally substituted phenyl, an optionally substituted 1,3-benzodioxole, an optionally substituted 2,3-dihydro-1,4-benzodioxin, or an optionally substituted heteroaryl selected from pyridine, pyrimidine, pyridazine, pyrazine, pyrazole, isoxazole, isothiazole, imidazole, oxazole or thiazole, and is optionally substituted with 1 to 3 substituents each independently selected therefrom, and the optionally substituted C １ ~C ６ alkyl, C ２ ~C ６ alkenyl, or C ２ ~C ６ Each alkynyl is independently selected from -CN, -OH, halogen, oxetanyl, 2-oxabicyclo[2.1.1]hexane, C １ ~C ３ alkoxy, optionally substituted C ３ ~C ５ cycloalkyl, -CONR １１ R １１ or -S(O) ２ CH ３ optionally substituted by, and the optionally substituted C ３ ~C ５ Each cycloalkyl, phenyl, 1,3-benzodioxole, 2,3-dihydro-1,4-benzodioxine, heterocyclic ring, or heteroaryl is independently selected from halogen, C １ ~C ３ alkyl, C １ ~C ３ haloalkyl, C １ ~C ３ alkoxy, C １ ~C ３ haloalkoxy, -SO ２ R １１ -NR １１ R １１ optionally substituted by 1 to 3 substituents independently selected from -OH, or -CN, or R ２ is 1,3 - benzodioxole, 2,3 - dihydro - 1,4 - benzodioxin, quinoxaline, quinazoline, indole, indazole, isoindazole, benzimidazole, benzotriazole, benzothiazole, benzoxazole, benzotriazole, benzofuran, benzofurazan, pyridofurazan, quinoline, 1,5 - naphthyridine, isoindolin - 1 - one, indolin - 2 - one, benzomorpholine, benzo[d]oxazol - 2(3H) - one, imidazo[1,2 - a]pyridine, 1,3 - dihydro - 2H - pyrrolo[2,3 - b]pyridin - 2 - one, [1,3]dioxolo[4,5 - b]pyridine, 6,7 - dihydro - 4H - pyrazolo[5,1 - c][1,4]oxazine, 1,2,3,4 - tetrahydroisoquinoline, 4,5,6,7 - tetrahydropyrazolo[1,5 - a]pyrazine, pyrazolo[4,3 - b]pyridine, pyrazolo[3,4 - b]pyridine, pyrazolo[3,4 - c]pyridine, pyrazolo[1,5 - a]pyrimidine, oxazolo[4,5 - b]pyridine, oxazolo[5,4 - b]pyridine, thiazolo[5,4 - b]pyridine, 2,1,3 - benzothiadiazole, imidazo[1,2 - a]pyrimidine, 2,3 - dihydro - [1,4]dioxino[2,3 - b]pyridine, 6,7 - dihydro - 5H - cyclopenta[b]pyridine, 5,6 - dihydro - 4H - pyrrolo[1,2 - b]pyrazole, 3,4 - dihydro - 2(1H)quinolinone, 2H - 1,4 - benzoxazin - 3(4H) - one, 2 - hydroxyquinoline, 3,4 - dihydroisoquinolin - 1(2H) - one, 1 - hydroxyisoquinoline, 1,4 - dihydro - 3(2H) - isoquinolinone, 3H - imidazo[4,5 - b]pyridine, 4,5 - dihydro - 7H - pyrazolo[1,5 - c][1,3]oxazine, 6,7 - dihydro - 5H - pyrazolo[5,1 - b][1,3]oxazine, furo[3,2 - c]pyridine, furo[3,2 - b]pyridine, 2,3 - dihydropyrazolo[5,1 - b]oxazole, 5H,6H,8H - imidazo[2,1 - c][1,4]oxazine, pyrazolo[1,5 - b]pyridazine, imidazo[1,2 - b]pyridazine, 2,4 - dihydro - 1H - benzo[d][1,3]oxazine, 5 - oxaspiro[2,3]hexane, imidazo[1,5 - a]pyridine, or pyrazolo[1,A bicyclic ring optionally substituted from pyridine, or an optionally substituted bicyclic heteroaryl having 8 to 10 ring atoms containing 1, 2, 3, 4, or 5 ring heteroatoms independently selected from N, O, or S, wherein the optionally substituted bicyclic heteroaryl is -CN, halogen, C, １ ~C ６ haloalkyl, C １ ~C ６ alkoxy, C １ ~C ６ haloalkoxy, -SO ２ R １１ 、-CO ２ C １ ~C ３ alkyl, -CONR １１ R １１ 、-NR １１ R １１ 、-NR １１ CO ２ R １１ 、-NR １１ C(O)R １１ 、-OH, oxetanyl, optionally substituted C １ ~C ６ alkyl, optionally substituted C ２ ~C ６ alkenyl, optionally substituted C ２ ~C ６ alkynyl, optionally substituted C ３ ~C ５ cycloalkyl, pyrrolidine, pyrrolidinone, piperidine or morpholine, an optionally substituted heterocyclic ring selected therefrom, an optionally substituted phenyl, an optionally substituted 1,3 - benzodioxole, an optionally substituted 2,3 - dihydro - 1,4 - benzodioxin, or pyridine, pyrimidine, pyridazine, pyrazine, pyrazole, isoxazole, isothiazole, imidazole, oxazole or thiazole, an optionally substituted heteroaryl selected therefrom, each independently selected from 1 to 3 substituents, and the optionally substituted C １ ~C ６ alkyl, C ２ ~C ６ Alkenyl, or C ２ ~C ６ Alkynyl is each independently -CN, -OH, oxetanyl, C １ ~C ３ Alkoxy, or -CONR １１ R １１ , phenyl, or optionally substituted C ３ ~C ５ Cycloalkyl optionally substituted with, said optionally substituted C ３ ~C ５ Cycloalkyl, phenyl, 1,3 - benzodioxole, 2,3 - dihydro - 1,4 - benzodioxin, heterocycle, or heteroaryl is each independently halogen, C １ ~C ３ Alkyl, C １ ~C ３ Haloalkyl, C １ ~C ３ Alkoxy, C １ ~C ３ Haloalkoxy, -SO ２ R １１ ,-NR １１ R １１ , -OH, or -CN and is optionally substituted with 1 to 3 substituents each independently selected from, or R ２ where each of one to three R １０ is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl optionally substituted with one to three R substituents, or R ２ is a group of the following formula: 【Chemical Formula 7】 R ３ is selected independently from -H, halogen, -CN, -N(H)(C １ ~C ３ alkyl), -N(C １ ~C ３ alkyl), ２ , -N(H)(CH ２ CH ２ CO ２ H), -CO-C １ ~C ３ alkyl, C １ ~C ６ alkyl, C １ ~C ６ haloalkyl, C １ ~C ６ hydroxyalkyl, C ３ ~C ５ cycloalkyl, a heterocyclic ring containing 3 to 5 ring atoms optionally substituted with 1, 2, or 3 ring heteroatoms independently selected from N, O, or S, or a heteroaryl containing 5 or 6 ring atoms optionally substituted with 1, 2, or 3 ring heteroatoms independently selected from N, O, or S, wherein the optionally substituted heterocyclic ring or heteroaryl is substituted with 1 to 3 substituents each independently selected from halogen, C １ ~C ３ alkyl, or C １ ~C ３ haloalkyl, each optionally substituted, R ４ 、R ５ 、and R ６ each of which is independently -H, halogen, C １ ~C ６ alkyl, or C １ ~C ６ haloalkyl, and R ７ is -CN, C １ ~C ６ alkyl, or C １ ~C ６ haloalkyl, and R ８ is -H or C １ ~C ６ alkyl, Each R ９ is independently, -H, halogen, -CN, C １ ~C ６ alkyl, C １ ~C ６ haloalkyl, C １ ~C ６ alkoxy, or C ３ ~C ５ cycloalkyl, and Each R １０ is independently -H, -CN, halogen, C １ ~C ６ haloalkyl, C １ ~C ６ alkoxy, C １ ~C ６ haloalkoxy, -SO ２ R １１ 、-SONR １１ R １１ 、-CO ２ H, -CO ２ C １ ~C ３ alkyl, -CONR １１ R １２ 、 -NR １１ R １１ 、 -NR １１ -CO ２ R １１ 、 -OH, optionally substituted C １ ~C ６ alkyl, optionally substituted C ２ ~C ６ alkenyl, optionally substituted C ２ ~C ６ alkynyl, optionally substituted C ３ ~C ５ a heterocyclic ring optionally selected from cycloalkyl, pyrrolidine, pyrrolidinone, piperidine, or morpholine, an optionally substituted phenyl, an optionally substituted 1,3 - benzodioxole, an optionally substituted 2,3 - dihydro - 1,4 - benzodioxin, pyrazole, isoxazole, isothiazole, imidazole, oxazole, thiazole, or pyridine, an optionally substituted heteroaryl, or a group of the following formula, 【Chemical 8】 The optionally substituted C １ to C ６ alkyl, C ２ to C ６ alkenyl, or C ２ to C ６ alkynyl is each optionally substituted with -CN, -OH, oxetanyl, C １ to C ３ alkoxy, or -CONR １１ R １１ and the optionally substituted C ３ to C ５ cycloalkyl, phenyl, 1,3 - benzodioxole, 2,3 - dihydro - 1,4 - benzodioxine, heterocycle, or heteroaryl is each halogen, C １ to C ３ alkyl, C １ to C ３ haloalkyl, C １ to C ３ alkoxy, C １ to C ３ haloalkoxy, -SO ２ R １１ , -NR １１ R １１ , -OH, or -CN, and Each R １１ is independently -H or C １ ~C ３ alkyl, Each R １２ is independently -H, optionally substituted C １ to C ３ alkyl, C ３ to C ６ cycloalkyl, -SO ２ C １ to C ３ alkyl, -SO ２ C １ to C ３ haloalkyl, -SO ２ NR １１ R １１ 、 -NR １１ R １１ 、 -OR １１ 、 -O-CH ２ -CH(OH)-CH ２ OH, -CN, oxetane, tetrahydrofuran, aryl, 5-membered heteroaryl optionally substituted with methyl, 6-membered heteroaryl, or a group of the following formula, 【Chemical Formula 9】 The optionally substituted C １ -C ３ alkyl is optionally substituted with -OH, C ３ -C ６ cycloalkyl, oxetane, tetrahydrofuran, aryl, 5-membered heteroaryl, 6-membered heteroaryl, or indole, R １３ is -NR １１ R １１ , -OR １１ , -SO ２ C １ ~C ３ alkyl, or a ring selected from oxetane, tetrahydrofuran, or oxadiazole, wherein the ring is optionally substituted with -NR １１ R １１ or -OR １１ and is optionally substituted with R １４ is -H, optionally substituted C １ ~C ３ alkyl, -SO ２ C １ ~C ３ alkyl, aryl, 5-membered heteroaryl, or 6-membered heteroaryl, and the optionally substituted C １ ~C ３ alkyl is optionally substituted with aryl, 5-membered heteroaryl, or 6-membered heteroaryl, R １５ is optionally substituted aryl or optionally substituted 6-membered heteroaryl, and the optionally substituted aryl or the optionally substituted 6-membered heteroaryl is each independently selected from 1 to 3 substituents selected from halogen, C １ ~C ３ alkyl, or C １ ~C ３ haloalkyl and is optionally substituted with n is 0, 1, or 2, a compound or a pharmaceutically acceptable salt thereof.

2. R １ is an optionally substituted bicyclic ring selected from isobenzofuranone, benzofuranone, isoindolinone, indolinone, quinazolinone, 3,4-dihydro-2H-isoquinolin-1-one, 2H-isoquinolin-1-one, or benzothiazolone, and the optionally substituted bicyclic ring is oxo, -CN, halogen, C １ to C ６ alkyl, C １ to C ６ haloalkyl, -OH, or C １ to C ６ alkoxy, each independently selected from 1 to 3 substituents, and optionally substituted, or R １ is the basis of the following formula, 【Chemical 10】 R' is hydrogen, halogen, C １ -C ３ -C alkyl, C １ -C ３ -C haloalkyl, C １ -C ３ -C alkoxy, C １ -C ３ -C haloalkoxy, -OH, -CH(OH)-CH ２ -OH, -CO-CH ２ -OH, C ３ -C ６ -C cycloalkyl, -NO ２ -N(R １１ )-CO ２ C １ -C ３ -C alkyl, -N(R １１ )-SO ２ C １ -C ３ -C alkyl, -N(R １１ )-SO ２ R １５ -SO ２ C １ -C ３ -C alkyl, -SO ２ -SO NR １１ R １１ -SO ２ -SO N(R １１ )-CO-C １ -C ３ -C alkyl, -SO ２ -SO N(R １１ )-CN, -C(=N-OH)-NH ２ -CN, -CONR １１ R １２ -CON(R １１ )-(CH ２ ) ｎ -R １３ -CO-SR １２ or a group of the following formula, 【Chemical 11】 The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein ring A is pyrrolidine optionally substituted with -CN, or R' is selected from oxetane, pyrrolidine, tetrahydrofuran, morpholine, piperidine, piperazine, pyrrole, furan, thiophene, pyrazole, imidazole, isoxazole, oxazole, isothiazole, thiazole, triazole, oxadiazole, thiadiazole, tetrazole, phenyl, pyridine, pyridazine, pyrimidine, pyrazine, or triazine, each of which is oxo, -OH, -NR １１ R １１ , -N(R １１ ), -CO-R １１ , -N(R １１ ), -CN, -OR １１ , -CN, halogen, C １ ~C ６ haloalkyl, or C optionally substituted with 1 to 3 substituents independently selected from aryl, 5-membered heteroaryl, or 6-membered heteroaryl １ ~C ６ alkyl, or is optionally substituted with R' is a group of the following formula 【Chemical Formula 12】 R ２ is based on the following formula, 【Chemical 13】 R ２ is the basis of the following formula, 【Chemical Formula 14】 R ２ is an optionally substituted 5-membered heteroaryl selected from pyrrole, furan, thiophene, pyrazole, isoxazole, isothiazole, imidazole, oxazole, thiazole, triazole, tetrazole, oxadiazole, and thiadiazole, and the optionally substituted 5-membered heteroaryl is -CN, halogen, C １ to C ６ haloalkyl, C １ to C ６ alkoxy, C １ to C ６ haloalkoxy, -SO ２ R １１ , -CO ２ C １ to C ３ alkyl, -CONR １１ R １１ , -OH, -NR １１ R １１ , -NR １１ CO ２ R １１ , optionally substituted C １ to C ６ alkyl, optionally substituted C ２ to C ６ alkenyl, optionally substituted C ２ to C ６ alkynyl, optionally substituted C ３ to C ５ cycloalkyl, pyrrolidine, pyrrolidinone, piperidine or morpholine, an optionally substituted heterocyclic ring selected therefrom, an optionally substituted phenyl, an optionally substituted 1,3-benzodioxole, an optionally substituted 2,3-dihydro-1,4-benzodioxin, or pyridine, pyrimidine, pyridazine, pyrazine, pyrazole, isoxazole, isothiazole, imidazole, oxazole or thiazole, each independently selected from 1 to 3 substituents selected from optionally substituted heteroaryl, and the optionally substituted C １ to C ６ alkyl, C ２ to C ６ alkenyl, or C ２ to C ６ each alkynyl is independently -CN, -OH, oxetanyl, C １ to C ３ alkoxy, or -CONR １１ R １１ optionally substituted with, and the optionally substituted C ３ to C ５ cycloalkyl, phenyl, 1,3 - benzodioxole, 2,3 - dihydro - 1,4 - benzodioxine, heterocyclic ring, or heteroaryl is each independently halogen, C １ to C ３ alkyl, C １ to C ３ haloalkyl, C １ to C ３ alkoxy, C １ to C ３ haloalkoxy, -SO ２ R １１ , -NR １１ R １１ optionally substituted with 1 to 3 substituents each independently selected from -OH, or -CN, or R ２ is an optionally substituted bicyclic ring selected from 1,3 - benzodioxole, 2,3 - dihydro - 1,4 - benzodioxin, isoindolin - 1 - one, indolin - 2 - one, benzo[d]oxazol - 2(3H) - one, 1,3 - dihydro - 2H - pyrrolo[2,3 - b]pyridin - 2 - one, or 2,3 - dihydro - [1,4]dioxino[2,3 - b]pyridine, or an optionally substituted bicyclic heteroaryl containing 8 to 10 ring atoms and 1, 2, 3, 4, or 5 ring heteroatoms independently selected from N, O, or S, wherein the optionally substituted bicyclic ring is optionally substituted with 1 to 3 substituents each independently selected from halogen and C １ to C ６ alkyl, and the optionally substituted bicyclic heteroaryl is - CN, halogen, C １ to C ６ haloalkyl, C １ to C ６ alkoxy, C １ to C ６ haloalkoxy, - SO ２ R １１ -, - CO ２ C １ to C ３ alkyl, - CONR １１ R １１ -, - NR １１ R １１ -, - NR １１ CO ２ R １１ -, - OH, optionally substituted C １ to C ６ alkyl, optionally substituted C ２ to C ６ alkenyl, optionally substituted C ２ to C ６ alkynyl, optionally substituted C ３ to C ５ Optionally substituted by 1 to 3 substituents each independently selected from an optionally substituted heterocycle selected from cycloalkyl, pyrrolidine, pyrrolidinone, piperidine or morpholine, an optionally substituted phenyl, an optionally substituted 1,3-benzodioxole, an optionally substituted 2,3-dihydro-1,4-benzodioxin, or an optionally substituted heteroaryl selected from pyridine, pyrimidine, pyridazine, pyrazine, pyrazole, isoxazole, isothiazole, imidazole, oxazole or thiazole, and said optionally substituted C １ -C ６ alkyl, C ２ -C ６ alkenyl, or C ２ -C ６ alkynyl is each, -CN, -OH, oxetanyl, C １ -C ３ alkoxy, -CONR １１ R １１ , or optionally substituted with phenyl, and said optionally substituted C ３ -C ５ cycloalkyl, phenyl, 1,3-benzodioxole, 2,3-dihydro-1,4-benzodioxin, heterocycle, or heteroaryl is each, halogen, C １ -C ３ alkyl, C １ -C ３ haloalkyl, C １ -C ３ alkoxy, C １ -C ３ haloalkoxy, -SO ２ R １１ , -NR １１ R １１ , -OH, or -CN, each optionally substituted with 1 to 3 substituents independently selected therefrom, or R ２ where each of one to three R １０ is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl optionally substituted with one to three R substituents, or R ２ is a group of the following formula: 【Chemical Formula 15】 R ３ is -H, halogen, -CN, -N(H)(C １ ~C ３ alkyl), -N(C １ ~C ３ alkyl), ２ , -N(H)(CH ２ CH ２ CO ２ H), -CO-C １ ~C ３ alkyl, C １ ~C ６ alkyl, C １ ~C ６ haloalkyl, C １ ~C ６ hydroxyalkyl, C ３ ~C ５ cycloalkyl, N, O, or S, a optionally substituted heterocyclic ring containing 3 to 5 ring atoms containing 1, 2, or 3 ring heteroatoms independently selected from N, O, or S, or a optionally substituted heteroaryl containing 5 or 6 ring atoms containing 1, 2, or 3 ring heteroatoms independently selected from N, O, or S, wherein the optionally substituted heterocyclic ring or heteroaryl is halogen, C １ ~C ３ alkyl, or C １ ~C ３ haloalkyl, each independently selected from 1 to 3 substituents and each optionally substituted, Each R １０ is independently, -H, -CN, halogen, C １ to C ６ haloalkyl, C １ to C ６ alkoxy, C １ to C ６ haloalkoxy, -SO ２ R １１ , -SONR １１ R １１ , -CO ２ H, -CO ２ C １ to C ３ alkyl, -CONR １１ R １２ , -NR １１ R １１ , -NR １１ , -CO ２ R １１ , -OH, optionally substituted C １ ~C ６ alkyl, optionally substituted C ２ ~C ６ alkenyl, optionally substituted C ２ ~C ６ alkynyl, optionally substituted C ３ ~C ５ a heterocyclic ring optionally selected from cycloalkyl, pyrrolidine, pyrrolidinone, piperidine, or morpholine, an optionally substituted phenyl, an optionally substituted 1,3-benzodioxole, an optionally substituted 2,3-dihydro-1,4-benzodioxin, pyrazole, isoxazole, isothiazole, imidazole, oxazole, thiazole, or pyridine, an optionally substituted heteroaryl, or a group of the following formula, 【Chemical 16】 The optionally substituted C １ to C ６ alkyl, C ２ to C ６ alkenyl, or C ２ to C ６ alkynyl is each optionally substituted with -CN, -OH, oxetanyl, C １ to C ３ alkoxy, or -CONR １１ R １１ and the optionally substituted C ３ to C ５ cycloalkyl, phenyl, 1,3 - benzodioxole, 2,3 - dihydro - 1,4 - benzodioxin, heterocyclic ring, or heteroaryl is each optionally substituted with 1 to 3 substituents independently selected from halogen, C １ to C ３ alkyl, C １ to C ３ haloalkyl, C １ to C ３ alkoxy, C １ to C ３ haloalkoxy, -SO ２ R １１ , -NR １１ R １１ and is each optionally substituted with 1 to 3 substituents independently selected from -OH, or -CN, Each R １１ is independently -H or C １ to C ３ alkyl, Each R １２ is independently -H, optionally substituted C １ to C ３ alkyl, C ３ to C ６ cycloalkyl, -SO ２ C １ to C ３ alkyl, -SO ２ C １ to C ３ haloalkyl, -SO ２ NR １１ R １１ 、-NR １１ R １１ 、-OR １１ 、-O-CH ２ -CH(OH)-CH ２ OH, -CN, oxetane, tetrahydrofuran, aryl, 5-membered heteroaryl optionally substituted with methyl, 6-membered heteroaryl, or a group of the following formula, 【Chemical 17】 The optionally substituted C １ ~C ３ alkyl is optionally substituted with -OH, C ３ ~C ６ cycloalkyl, oxetane, tetrahydrofuran, aryl, 5-membered heteroaryl, 6-membered heteroaryl, or indole, R １３ is -NR １１ R １１ 、 -OR １１ 、 -SO ２ C １ ~C ３ alkyl, or a ring selected from oxetane, tetrahydrofuran, or oxadiazole, wherein the ring is optionally substituted with -NR １１ R １１ or -OR １１ and is optionally substituted with R １４ is -H, optionally substituted C １ to C ３ alkyl, -SO ２ C １ to C ３ alkyl, aryl, 5-membered heteroaryl, or 6-membered heteroaryl, wherein the optionally substituted C １ to C ３ alkyl is optionally substituted with aryl, 5-membered heteroaryl, or 6-membered heteroaryl, R １５ is optionally substituted aryl or optionally substituted 6-membered heteroaryl, and the optionally substituted aryl or the optionally substituted 6-membered heteroaryl is each independently selected from 1 to 3 substituents selected from halogen, C １ to C ３ alkyl, or C １ to C ３ haloalkyl, and is optionally substituted with n is 0, 1, or 2.

3. The compound or a pharmaceutically acceptable salt thereof according to claim 1, having the following formula 【Chemical 18】

4. The compound or a pharmaceutically acceptable salt thereof according to claim 1, having the following formula 【Chemical 19】

5. R １ The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R is based on the following formula. 【Chemical 20】

6. Each R ９ The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein each R is -H or halogen.

7. R' is hydrogen, C １ ~C ３ alkyl, -CONH-SO ２ C １ ~C ３ alkyl, or oxadiazolinone, the compound according to claim 1 or a pharmaceutically acceptable salt thereof.

8. R′ is —SO ２ NR １１ R １１ —SO ２ N(R １１ (R １３ )—C(O)NR １１ R １２ —C(O)N(R １１ )—(CH ２ ) ｎ —R １３ or —C(O)—NHSO ２ R １６ The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

9. R ２ The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R is bonded to the chromenone core of carbon via a ring carbon of a cycloalkyl group, via a ring carbon of a heterocycloalkyl group, via a ring carbon of an aryl group, or via a ring carbon of a heteroaryl group.

10. R ２ is based on the following formula, 【Chemical 21】 In the formula, each R １０ is independently -H, -CN, halogen, C １ to C ６ alkyl, or C １ to C ６ haloalkyl, or R ２ is each independently optionally substituted with 1 to 3 substituents selected from -CN, halogen, C １ to C ６ alkyl, or C １ to C ６ haloalkyl, or is an optionally substituted indazole or an optionally substituted pyrazole, the compound according to claim 1 or a pharmaceutically acceptable salt thereof.

11. R ２ is the basis of the following formula, 【Chemical 22】 In the formula, each R １０ is independently -H, -CN, halogen, C １ to C ６ alkyl, or C １ to C ６ haloalkyl, the compound according to claim 1 or a pharmaceutically acceptable salt thereof.

12. R ２ is C １ -C ３ alkyl or C １ -C ６ 1H-indazol-5-yl, 1H-indazol-6-yl, or 1H-pyrazol-4-yl N-substituted with hydroxyalkyl, the compound according to claim 1 or a pharmaceutically acceptable salt thereof.

13. The compound or a pharmaceutically acceptable salt thereof according to claim 1, selected from the following 【Chemical 23】 【Chemical 24】 【Chemical 25】 【Chemical 26】 【Chemical 27】 【Chemical Formula 28】 【Chemical 29】 【Chemical 30】 【Chemical 31】 【Chemical Formula 32】 【Chemical 33】 【Chemical 34】 【Chemical 35】 【Chemical 36】 【Chemical 37】 【Chemical Formula 38】 【Chemical Formula 39】 【Chemical Formula 40】 【Chemical 41】 【Chemical 42】 【Chemical Formula 43】 【Chemical 44】 【Chemical Formula 45】 【Chemical Formula 46】 【Chemical 47】 【Chemical Formula 48】 【Chemical 49】 【Chemical Formula 50】

14. A pharmaceutical composition comprising the compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 13 and a pharmaceutically acceptable carrier.

15. A pharmaceutical composition for treating a disease or disorder associated with the regulation of phosphoinositide 3-kinase (PI3K), comprising the compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 13.

16. The pharmaceutical composition according to claim 15, wherein the PI3K is PI3Kα.

17. The pharmaceutical composition according to claim 16, wherein the PI3K associated with the disease or disorder has an H1047R mutation, an E575K mutation, or both an H1047R mutation and an E575K mutation.

18. The pharmaceutical composition according to claim 15, wherein the disease or disorder is cancer.

19. The pharmaceutical composition according to claim 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.

20. The pharmaceutical composition according to claim 18, wherein the cancer is breast cancer.

21. The pharmaceutical composition according to claim 18, wherein the cancer is hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2-) advanced or metastatic breast cancer.

22. The pharmaceutical composition according to claim 15, wherein the disorder is CLOVES syndrome (Congenital Lipomatous Overgrowth, Vascular Malformations, Epidermal Nevus, Scoliosis / Skeletal and Spinal Syndrome), or PIK3CA-related overgrowth syndrome (PROS).

23. A pharmaceutical composition for inhibiting phosphoinositide 3-kinase (PI3K), comprising the compound according to any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof.

24. A pharmaceutical composition for treating cancer or a disorder associated with the regulation of phosphoinositide 3-kinase (PI3K), comprising the compound according to any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof.

25. The pharmaceutical composition according to claim 24, 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.

26. The pharmaceutical composition according to claim 24, wherein the cancer is breast cancer.

27. The pharmaceutical composition according to claim 24, wherein the cancer is hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced or metastatic breast cancer.

28. The pharmaceutical composition according to claim 24, wherein the disorder is CLOVES syndrome or PROS.

29. Use of the compound according to any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating a disease or disorder associated with the regulation of PI3K.

30. The use according to claim 29, wherein the disease or disorder associated with the regulation of PI3K is cancer.

31. The use according to claim 30, 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.

32. The use according to claim 30, wherein the cancer is breast cancer.

33. The use according to claim 30, wherein the cancer is hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced or metastatic breast cancer.

34. The use according to claim 29, wherein the disease is CLOVES syndrome (Congenital Lipomatous Overgrowth, Vascular Malformations, Epidermal Nevus, Scoliosis / Skeletal and Spinal Syndrome), or PIK3CA-related overgrowth syndrome (PROS).

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