Allosteric chromenone inhibitors of phosphoinositide 3-kinase (PI3K) for the treatment of diseases

Abstract

The present invention relates to compounds of formula (I) as allosteric chromenone inhibitors of phosphoinositide 3-kinase (PI3K), useful for the treatment of diseases or disorders associated with PI3K regulation: [Formula 1] TIFF2024536263000257.tif48128 or a pharma- ceutically acceptable salt thereof, wherein R, R1, R2, R3, R4, R5, R6, R7, and R8 are as defined herein. The present disclosure also relates to methods of making and using the compounds of formula (I) or a pharma- ceutically acceptable salt thereof.

Description

[Technical Field]

[0001] 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]

[0002] Cellular activity can be regulated by external signals that stimulate or inhibit intracellular events. The process by which stimulatory or inhibitory signals are transmitted within and within cells to induce intracellular responses is called signal transduction. Over the past several decades, cascades of signal transduction events have been elucidated and found to play a central role in various biological responses. Defects in various components of signal transduction pathways have been found to be the cause of a vast number of diseases, including many forms of cancer, inflammatory disorders, metabolic disorders, vascular, and neurological disorders (Gaestel et al. Current Medicinal Chemistry (2007) 14:2214-2234).

[0003] Kinases represent a class of important signal transduction molecules. Kinases can generally be classified into protein kinases, lipid kinases, and certain kinases that exhibit dual specificity. Protein kinases are enzymes that phosphorylate other proteins and / or themselves (i.e., autophosphorylation). Protein kinases can generally be classified into three major groups based on their substrate utilization: tyrosine kinases (e.g., erb2, PDGF receptor, EGF receptor, VEGF receptor, src, abl), which phosphorylate substrates primarily on tyrosine residues; serine / threonine kinases (e.g., mTorC1, mTorC2, ATM, ATR, DNA-PK, Akt), which phosphorylate substrates primarily on serine and / or threonine residues; and dual specificity kinases, which phosphorylate substrates on tyrosine, serine, and / or threonine residues.

[0004] Lipid kinases are enzymes that catalyze the phosphorylation of intracellular lipids. These enzymes, the resulting phosphorylated lipids, and lipid-derived biologically active organic molecules play a role in many different physiological processes, including cell proliferation, migration, adhesion, and differentiation. A specific group of lipid kinases includes membrane lipid kinases, i.e., kinases that catalyze the phosphorylation of lipids contained in or associated with cell membranes. Examples of such enzymes include phosphoinositide kinases (such as PI3-kinase and PI4-kinase), diacylglycerol kinase, and sphingosine kinase.

[0005] 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.

[0006] 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.

[0007] 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.

[0008] 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).

[0009] 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.

[0010] 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(suppl 5)).

[0011] 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)).

[0012] 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).

[0013] 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.

[0014] Therefore, kinases, for example lipid kinases such as PI3K, are prime targets for drug development.The present invention provides a new class of kinase inhibitors. Summary of the Invention

[0015] In one aspect, the present invention provides a compound of formula (I): [ka] or a pharmaceutically acceptable salt thereof, wherein R is —H or C1-C3 alkyl; R1 is a group of the formula: [ka] R2 is 1 to 3 R 10 or R2 is a group of the formula: [ka] R3 is -H, halogen, -CN, C1-C6 alkyl, C1-C6 haloalkyl, C3-C5 cycloalkyl, a heterocycle of 3 to 5 ring atoms containing 1, 2, or 3 ring heteroatoms independently selected from N, O, or S, or a heteroaryl of 5 ring atoms containing 1, 2, or 3 ring heteroatoms independently selected from N, O, or S; each of 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, 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 , -CONR 11 R 11 , -NR11 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 pyrazole, isoxazole, isothiazole, imidazole, oxazole or thiazoline. optionally substituted C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl is optionally substituted with -CN, -OH, oxetanyl, or C1-C3 alkoxy, respectively; optionally substituted C3-C5 cycloalkyl, phenyl, 1,3-benzodioxole, 2,3-dihydro-1,4-benzodioxine, heterocycle, or heteroaryl is optionally substituted with 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 is independently —H or C1-C3 alkyl.

[0016] In another aspect, the present invention provides a pharmaceutical composition comprising a compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent or carrier.

[0017] In another aspect, the present invention provides a method for 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), or (III) or a pharmaceutically acceptable salt thereof.

[0018] 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), or (III), or a pharmaceutically acceptable salt thereof.

[0019] 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), or (III), or a pharmaceutically acceptable salt thereof.

[0020] In some aspects, the present invention 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), or (III), or a pharmaceutically acceptable salt thereof.

[0021] In some aspects, the present invention 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 pharmaceutical composition of a compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof.

[0022] In another aspect, the present invention provides a compound of formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof, for use in therapy.

[0023] In another aspect, the present invention provides a compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof, for use in modulating PI3K (e.g., PI3Kα) activity (e.g., in vitro or in vivo).

[0024] In another aspect, the present invention provides a compound of formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof, for use in the selective inhibition of mutant PI3K α over wild-type PI3K α.

[0025] In another aspect, the present invention provides a compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof, for use in the treatment or prevention of a disease or disorder disclosed herein.

[0026] In another aspect, the present invention provides a compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof, for use in the treatment of a disease or disorder disclosed herein.

[0027] In another aspect, the invention provides the use of a compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for modulating PI3K (e.g., PI3Kα) activity (e.g., in vitro or in vivo).

[0028] In another aspect, the present invention provides the use of a compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating or preventing a disease or disorder disclosed herein.

[0029] In another aspect, the present invention provides the use of a compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a disease or disorder disclosed herein.

[0030] In another aspect, the present invention provides a method for preparing a compound of formula (I), (II), or (III) or a pharmaceutically acceptable salt thereof.

[0031] In another aspect, the present invention provides a method of preparing a compound comprising one or more of the steps described herein.

[0032] In another aspect, the invention provides compounds obtainable by or obtained by a process for preparing a compound described herein (e.g., a process comprising one or more steps described in a scheme).

[0033] 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).

[0034] Other features and advantages of the invention will become apparent from the following detailed description and claims. DETAILED DESCRIPTION OF THE INVENTION

[0035] 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.

[0036] 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, PI3K-related diseases or disorders include CLOVES syndrome (congenital lipomatous overgrowth, vascular malformations, epidermal nevus, scoliosis / skeletal and spinal cord syndrome), PIK3CA-associated overgrowth 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 carcinoma, nerve sheath tumor. These include, but are not limited to, squamous cell carcinoma of the head and neck, 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, and encapsulated glioma.

[0037] 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.

[0038] 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.

[0039] The term "and / or" means either "and" or "or" unless otherwise indicated.

[0040] 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.

[0041] 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.

[0042] 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.

[0043] 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.

[0044] 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.

[0045] 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.

[0046] 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.

[0047] 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.

[0048] The term "cyano" refers to a substituent having a carbon atom attached to a nitrogen atom by a triple bond, i.e., C≡N.

[0049] 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.

[0050] The term "disorder" means, and is used interchangeably with, the terms disease, condition, or illness, unless otherwise indicated.

[0051] 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.

[0052] 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.

[0053] The term "halogen" or "halo" refers to fluorine, chlorine, bromine, or iodine.

[0054] 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.

[0055] 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.

[0056] 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 are described by the Cahn-Prelog R- and S-sequencing rules or by the way the molecule rotates the plane of polarized light and are 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."

[0057] The terms "modulate," "modulation," or "modulating" refer to the biological activity of a compound or substrate that inhibits and / or activates PI3K.

[0058] 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.

[0059] 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 undergoing diagnosis or treatment. 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 take into account, but is not limited to, the patient's species; its size, age, and general health; the particular 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 preparation; the selected dosing regimen; the use of concomitant medications; and other relevant circumstances.

[0060] The term "treating" with respect to a subject includes inhibiting, slowing, arresting, or reversing the progression or severity of an existing condition or disorder.

[0061] Compounds of the Invention In one aspect, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt thereof: [ka] wherein R, R1, R2, R3, R4, R5, R6, R7, and R8 are as defined in the Summary of the Invention for formula (I).

[0062] In a further embodiment, the compound of formula (I) where R8 is H has the formula (II): [ka] wherein R, R1, R2, R3, R4, R5, R6, and R7 are as defined in the Summary of the Invention for formula (I).

[0063] In the compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R2 is selected from 1 to 3 R 10 or R2 is a group of the formula: [ka] In the formula, R 10 are independently -H, -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R 11 , -CONR 11 R 11 , -NR 11 R 11 , -NR 11 -CO2R 11 , —OH, optionally substituted C1-C6 alkyl, optionally substituted C3-C5 cycloalkyl, optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine, or morpholine, optionally substituted phenyl, or optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole, or thiazole, wherein the optionally substituted C1-C6 alkyl is optionally substituted with —CN, —OH, or C1-C3 alkoxy, and the optionally substituted C3-C5 cycloalkyl, phenyl, heterocycle, or heteroaryl is each selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, —NR 11 R 11 , —OH, or —CN; and each R 11 are independently H or C1-C3 alkyl.

[0064] In still further compounds of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R2 is [ka] where R 10 are independently -H, halogen, C1-C6 alkyl or C1-C6 haloalkyl, preferably R 10 are independently -H, halogen or C1-C3 alkyl, more preferably R 10 is independently —H, fluoro, or methyl.

[0065] In still further compounds of formula (I) or (II) or pharmaceutically acceptable salts thereof, R3 is -H, halogen, -CN, C1-C6 alkyl, or C1-C6 haloalkyl, oxetane, oxazole, or isoxazole. In still further compounds of formula (I) or (II) or pharmaceutically acceptable salts thereof, R3 is -H, -CN, C1-C6 alkyl, or C1-C6 haloalkyl. In still further compounds of formula (I) or (II) or pharmaceutically acceptable salts thereof, R3 is H, CN, or C1-C3 alkyl, or C1-C3 haloalkyl (preferably, R3 is H, -CN, or C1-C3 alkyl), and most preferably, R3 is H or methyl.

[0066] In still further compounds of formula (I) or (II), or a pharmaceutically acceptable salt thereof, R 4 is H or halogen, preferably R 4 is H.

[0067] In still further compounds of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R5 is -H, halogen, C1-C6 alkyl, or C1-C6 haloalkyl; preferably, R5 is -H, halogen, C1-C3 alkyl, or C1-C3 haloalkyl; more preferably, R5 is H, halogen, methyl, or trifluoromethyl.

[0068] In still further compounds of Formula (I) or (II) or a pharmaceutically acceptable salt thereof, R6 is H, or halogen.

[0069] In still further compounds of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R3 is -H, -CN, C1-C3 alkyl or C1-C3 haloalkyl (preferably, R3 is H, CN, or C1-C3 alkyl), and R2 is each selected from 1 to 3 R 10 or R2 is a group of the formula: [ka] In the formula, each R 10 are independently -H, -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R 11 , -CONR 11 R 11 , -NR 11 R 11 , -NR 11 -CO2R 11 , optionally substituted C1-C6 alkyl, optionally substituted C3-C5 cycloalkyl, optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine, or morpholine, optionally substituted phenyl, or optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole, or thiazole, wherein the optionally substituted C1-C6 alkyl is optionally substituted with —CN, OH, or C1-C3 alkoxy, and the optionally substituted C3-C5 cycloalkyl, phenyl, heterocycle, or heteroaryl is each selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, —NR 11 R 11 , —OH, or —CN; and each R 11are independently H or C1-C3 alkyl. Preferably, R2 is [ka] where R 10 are independently -H, halogen, C1-C6 alkyl or C1-C6 haloalkyl, preferably R 10 are independently -H, halogen or C1-C3 alkyl, more preferably R 10 is independently —H, fluoro, or methyl.

[0070] In still further compounds of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R4 is H or halogen (preferably, R4 is H), and R2 each contains 1 to 3 R 10 or R2 is a group of the formula: [ka] In the formula, each R 10 are independently -H, -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R 11 , -CONR 11 R 11 , -NR 11 R 11 , -NR 11 -CO2R 11, optionally substituted C1-C6 alkyl, optionally substituted C3-C5 cycloalkyl, optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine, or morpholine, optionally substituted phenyl, or optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole, or thiazole, wherein the optionally substituted C1-C6 alkyl is optionally substituted with —CN, OH, or C1-C3 alkoxy, and the optionally substituted C3-C5 cycloalkyl, phenyl, heterocycle, or heteroaryl is each selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, —NR 11 R 11 , —OH, or —CN; and each R 11 are independently H or C1-C3 alkyl.

[0071] In still further compounds of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R5 is H, halogen, C1-C6 alkyl, or C1-C6 haloalkyl; R2 each represents 1 to 3 R 10 or R2 is a group of the formula: [ka] In the formula, each R 10 are independently -H, -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R 11 , -CONR 11 R 11 , -NR 11 R 11 , -NR 11 -CO2R 11, optionally substituted C1-C6 alkyl, optionally substituted C3-C5 cycloalkyl, optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine, or morpholine, optionally substituted phenyl, or optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole, or thiazole, wherein the optionally substituted C1-C6 alkyl is optionally substituted with —CN, OH, or C1-C3 alkoxy, and the optionally substituted C3-C5 cycloalkyl, phenyl, heterocycle, or heteroaryl is each selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, —NR 11 R 11 , —OH, or —CN; and each R 11 are independently H or C1-C3 alkyl. Preferably, R2 is [ka] where R 10 are independently -H, halogen, C1-C6 alkyl or C1-C6 haloalkyl, preferably R 10 are independently -H, halogen or C1-C3 alkyl, more preferably R 10 is independently —H, fluoro, or methyl.

[0072] In still further compounds of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R6 is H or halogen and R2 each represents 1 to 3 R 10 or R2 is a group of the formula: [ka] In the formula, each R 10are independently -H, -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R 11 , -CONR 11 R 11 , -NR 11 R 11 , -NR 11 -CO2R 11 , optionally substituted C1-C6 alkyl, optionally substituted C3-C5 cycloalkyl, optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine, or morpholine, optionally substituted phenyl, or optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole, or thiazole, wherein the optionally substituted C1-C6 alkyl is optionally substituted with —CN, OH, or C1-C3 alkoxy, and the optionally substituted C3-C5 cycloalkyl, phenyl, heterocycle, or heteroaryl is each selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, —NR 11 R 11 , —OH, or —CN; and each R 11 are independently H or C1-C3 alkyl. Preferably, R2 is [ka] where R 10 are independently -H, halogen, C1-C6 alkyl, or C1-C6 haloalkyl, preferably R 10 are independently -H, halogen, or C1-C3 alkyl, and more preferably, R 10 is independently —H, fluoro, or methyl.

[0073] In still further compounds of formula (I) or (II) or pharmaceutically acceptable salts thereof, R3 is -H, -CN, C1-C3 alkyl or C1-C3 haloalkyl and R4 is H or halogen, more preferably R3 is H, CN, or C1-C3 alkyl and R4 is H, most preferably R3 is H or methyl and R4 is H.

[0074] In still further compounds of formula (I) or (II) or pharmaceutically acceptable salts thereof, R3 is -H, -CN, C1-C3 alkyl or C1-C3 haloalkyl (preferably, R3 is H, CN, or C1-C3 alkyl), and R5 is H, halogen, C1-C3 alkyl or C1-C3 haloalkyl; more preferably, R3 is H or methyl and R5 is H, halogen, methyl, or trifluoromethyl.

[0075] In still further compounds of formula (I) or (II) or pharmaceutically acceptable salts thereof, R3 is -H, -CN, C1-C3 alkyl, or C1-C3 haloalkyl (preferably, R3 is H, CN, or C1-C3 alkyl), and R6 is H or halogen; more preferably, R3 is H or methyl and R6 is H.

[0076] In still further compounds of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R4 is -H or halogen (preferably, R4 is H), and R5 is H, halogen, C1-C3 alkyl, or C1-C3 haloalkyl, preferably, R5 is H, halogen, methyl, or trifluoromethyl.

[0077] In still further compounds of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R4 is H or halogen (preferably, R4 is -H) and R6 is H or halogen.

[0078] In still further compounds of formula (I) or (II) or pharmaceutically acceptable salts thereof, R5 is H, halogen, C1-C3 alkyl or C1-C3 haloalkyl and R6 is H or halogen, preferably R5 is H, halogen, methyl or trifluoromethyl and R6 is H.

[0079] In still further compounds of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R3 is -H, -CN, C1-C3 alkyl or C1-C3 haloalkyl (preferably, R3 is H, CN, or C1-C3 alkyl, more preferably, R3 is H or methyl), R4 is -H or halogen (preferably, R4 is H), and R2 each contains 1 to 3 R 10 R2 is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl optionally substituted with a substituent, or R2 is a group of the formula: [ka] Preferably, R2 is [ka] where R 10 are independently -H, halogen, C1-C6 alkyl or C1-C6 haloalkyl, preferably R 10 are independently -H, halogen or C1-C3 alkyl, more preferably R 10 is independently —H, fluoro, or methyl.

[0080] In still further compounds of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R3 is -H, -CN, C1-C3 alkyl or C1-C3 haloalkyl (preferably, R3 is H, CN, or C1-C3 alkyl), R5 is H, halogen, C1-C6 alkyl, or C1-C6 haloalkyl, and R2 each represents 1 to 3 R 10or R2 is a group of the formula: [ka] More preferably, R3 is H or methyl and R5 is H, halogen, methyl, or trifluoromethyl. [ka] where R 10 are independently -H, halogen, C1-C6 alkyl, or C1-C6 haloalkyl, preferably R 10 are independently -H, halogen, or C1-C3 alkyl, more preferably R 10 is independently —H, fluoro, or methyl.

[0081] In still further compounds of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R3 is -H, -CN, C1-C3 alkyl, or C1-C3 haloalkyl (preferably, R3 is H, CN, or C1-C3 alkyl), R6 is H or halogen, and R2 each represents 1 to 3 R 10 or R2 is a group of the formula: [ka] More preferably, R3 is H or methyl and R6 is H. Preferably, R2 is [ka] where R 10 are independently -H, halogen, C1-C6 alkyl or C1-C6 haloalkyl, preferably R 10 are independently -H, halogen or C1-C3 alkyl, more preferably R 10is independently —H, fluoro, or methyl.

[0082] In still further compounds of formula (I) or (II) or pharmaceutically acceptable salts thereof, R4 is H or halogen (preferably, R4 is H), R5 is H, halogen, C1-C3 alkyl or C1-C3 haloalkyl, and R2 each represents 1 to 3 R 10 or R2 is a group of the formula: [ka] More preferably, R5 is H, halogen, methyl, or trifluoromethyl. Preferably, R2 is [ka] where R 10 are independently -H, halogen, C1-C6 alkyl or C1-C6 haloalkyl, preferably R 10 are independently -H, halogen or C1-C3 alkyl, more preferably R 10 is independently —H, fluoro, or methyl.

[0083] In the compounds of formula (I) or (II) or pharmaceutically acceptable salts thereof, R4 is H or halogen (preferably, R4 is H), R6 is H or halogen, and R2 is each selected from 1 to 3 R 10 or R2 is a group of the formula: [ka] More preferably, R4 and R6 are each H. Preferably, R2 is [ka] where R10 are independently -H, halogen, C1-C6 alkyl, or C1-C6 haloalkyl, preferably R 10 are independently -H, halogen, or C1-C3 alkyl, and more preferably, R 10 is independently —H, fluoro, or methyl.

[0084] In still further compounds of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R5 is H, halogen, C1-C3 alkyl or C1-C3 haloalkyl; R6 is H or halogen; and R2 each represents 1 to 3 R 10 or R2 is a group of the formula: [ka] Preferably, R5 is H, halogen, methyl or trifluoromethyl and R6 is H. Preferably, R2 is [ka] where R 10 are independently -H, halogen, C1-C6 alkyl, or C1-C6 haloalkyl, preferably R 10 are independently -H, halogen, or C1-C3 alkyl, and more preferably, R 10 is independently —H, fluoro, or methyl.

[0085] In still further compounds of formula (I) or (II) or pharmaceutically acceptable salts thereof, R3 is H, CN, C1-C3 alkyl, or C1-C3 haloalkyl (preferably, R3 is H, CN, or C1-C3 alkyl), R4 is H or halogen (preferably, R4 is H), and R5 is H, halogen, C1-C3 alkyl, or C1-C3 haloalkyl; more preferably, R3 is H or methyl, R4 is H, and R5 is H, halogen, methyl, or trifluoromethyl.

[0086] In still further compounds of formula (I) or (II) or pharmaceutically acceptable salts thereof, R3 is H, CN, C1-C3 alkyl, or C1-C3 haloalkyl (preferably, R3 is H, CN, or C1-C3 alkyl), R4 is H or halogen (preferably, R4 is H), and R6 is H or halogen, more preferably, R3 is H or methyl, and R4 and R6 are each H.

[0087] In still further compounds of formula (I) or (II) or pharmaceutically acceptable salts thereof, R3 is H, CN, C1-C3 alkyl, or C1-C3 haloalkyl (preferably, R3 is H, CN, or C1-C3 alkyl), R5 is H, halogen, C1-C3 alkyl, or C1-C3 haloalkyl, and R6 is H or halogen; more preferably, R3 is H or methyl, R5 is H, halogen, methyl, or trifluoromethyl, and R6 is H.

[0088] In still further compounds of formula (I) or (II) or pharmaceutically acceptable salts thereof, R5 is H, halogen, C1-C3 alkyl or C1-C3 haloalkyl, R4 is H or halogen (R4 is H), and R6 is H or halogen, more preferably R5 is H, halogen, methyl, or trifluoromethyl, and R4 and R6 are each H.

[0089] In still further compounds of formula (I) or (II) or pharmaceutically acceptable salts thereof, R3 is -H, -CN, C1-C3 alkyl, or C1-C3 haloalkyl (preferably, R3 is H, CN, or C1-C3 alkyl), R4 is -H or halogen (preferably, R4 is H), R5 is H, halogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 alkoxy, and R2 is each selected from 1 to 3 R 10or R2 is a group of the formula: [ka] More preferably, R3 is H or methyl, R4 is H, and R5 is H, halogen, methyl, or trifluoromethyl. [ka] where R 10 are independently -H, halogen, C1-C6 alkyl or C1-C6 haloalkyl, preferably R 10 are independently -H, halogen or C1-C3 alkyl, more preferably R 10 is independently —H, fluoro, or methyl.

[0090] In still further compounds of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R3 is -H, -CN, C1-C3 alkyl, or C1-C3 haloalkyl (preferably, R3 is H, CN, or C1-C3 alkyl), R4 is -H or halogen (preferably, R4 is -H), R6 is H, and R2 each contain 1 to 3 R 10 or R2 is a group of the formula: [ka] More preferably, R3 is H or methyl, and R4 and R6 are each H. Preferably, R2 is [ka] where R 10 are independently -H, halogen, C1-C6 alkyl, or C1-C6 haloalkyl, preferably R 10are independently -H, halogen, or C1-C3 alkyl, and more preferably, R 10 is independently —H, fluoro, or methyl.

[0091] In still further compounds of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R3 is -H, -CN, C1-C3 alkyl, or C1-C3 haloalkyl (preferably, R3 is H, CN, or C1-C3 alkyl), R5 is H, halogen, C1-C6 alkyl, or C1-C6 haloalkyl, R6 is H or halogen, and R2 each contains 1 to 3 R 10 or R2 is a group of the formula: [ka] More preferably, R3 is H or methyl, R5 is H, halogen, methyl, or trifluoromethyl, and R6 is H. Preferably, R2 is [ka] where R 10 are independently -H, halogen, C1-C6 alkyl, or C1-C6 haloalkyl, preferably R 10 are independently -H, halogen, or C1-C3 alkyl, and more preferably, R 10 is independently —H, fluoro, or methyl.

[0092] In still further compounds of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R5 is H, halogen, C1-C3 alkyl or C1-C3 haloalkyl, R4 is H or halogen (preferably, R4 is H), R6 is H or halogen, and R2 each contains 1 to 3 R 10 or R2 is a group of the formula: [ka] More preferably, R5 is H, halogen, methyl, or trifluoromethyl, and R4 and R6 are each H. Preferably, R2 is [ka] where R 10 are independently -H, halogen, C1-C6 alkyl, or C1-C6 haloalkyl, preferably R 10 are independently -H, halogen, or C1-C3 alkyl, and more preferably, R 10 is independently —H, fluoro, or methyl.

[0093] In still further compounds of formula (I) or (II) or pharmaceutically acceptable salts thereof, R3 is H, CN, C1-C3 alkyl, or C1-C3 haloalkyl (preferably, R3 is H, CN, or C1-C3 alkyl), R4 is H or halogen (preferably, R4 is H), R6 is H or halogen, and R5 is H, halogen, C1-C3 alkyl, or C1-C3 haloalkyl, preferably, R3 is H or methyl, R4 and R6 are each H, and R5 is H, halogen, methyl, or trifluoromethyl.

[0094] In still further compounds of formula (I) or (II) or pharmaceutically acceptable salts thereof, R3 is -H, -CN, C1-C3 alkyl, or C1-C3 haloalkyl (preferably, R3 is H, CN, or C1-C3 alkyl), R4 is -H or halogen (preferably, R4 is H), R6 is H or halogen, R5 is H, halogen, C1-C3 alkyl, or C1-C3 haloalkyl, and R2 each represents 1 to 3 R 10 or R2 is a group of the formula: [ka] More preferably, R3 is H or methyl, R4 and R6 are each H, and R5 is H, halogen, methyl, or trifluoromethyl. [ka] where R 10 are independently -H, halogen, C1-C6 alkyl or C1-C6 haloalkyl, preferably R 10 are independently -H, halogen or C1-C3 alkyl, more preferably R 10 is independently —H, fluoro, or methyl.

[0095] In still further compounds of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R is H.

[0096] In still further compounds of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R7 is CN, C1-C6 alkyl, or C1-C6 haloalkyl, preferably R7 is CN, C1-C3 alkyl, or C1-C3 haloalkyl, more preferably R7 is CN, methyl, or trifluoromethyl.

[0097] In still further compounds of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R8 is H.

[0098] In still further compounds of formula (I) or (II) or pharmaceutically acceptable salts thereof, R7 is CN, C1-C3 alkyl or C1-C3 haloalkyl and R is H. In still further compounds of formula (I) or (II) or pharmaceutically acceptable salts thereof, R7 is C1-C3 alkyl (preferably methyl) and R is H.

[0099] In still further compounds of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R and R are each H.

[0100] In still further compounds of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R7 is CN, C1-C3 alkyl or C1-C3 haloalkyl and R8 is H. In still further compounds of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R7 is C1-C3 alkyl (preferably methyl) and R8 is H.

[0101] In still further compounds of formula (I) or (II) or pharmaceutically acceptable salts thereof, R7 is CN, C1-C3 alkyl or C1-C3 haloalkyl, and R8 and R are each H. In still further compounds of formula (I) or (II) or pharmaceutically acceptable salts thereof, R7 is C1-C3 alkyl (preferably methyl), and R8 and R are H.

[0102] In still further compounds of formula (I) or (II) or pharmaceutically acceptable salts thereof, R7 is CN, C1-C3 alkyl or C1-C3 haloalkyl, R8 is H, R is H, and R2 each contains 1 to 3 R 10 R2 is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl optionally substituted with a substituent, or R2 is a group of the formula: [ka] Preferably, R2 is [ka] where R 10 are independently -H, halogen, C1-C6 alkyl or C1-C6 haloalkyl, preferably R 10 are independently -H, halogen or C1-C3 alkyl, more preferably R 10 is independently —H, fluoro, or methyl.

[0103] In still further compounds of formula (I) or (II) or pharmaceutically acceptable salts thereof, R7 is C1-C3 alkyl (preferably methyl), R8 is H, R is H, and R2 each contains 1 to 3 R 10 R2 is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl optionally substituted with a substituent, or R2 is a group of the formula: [ka] Preferably, R2 is [ka] where R 10 are independently -H, halogen, C1-C6 alkyl or C1-C6 haloalkyl, preferably R 10 are independently -H, halogen or C1-C3 alkyl, more preferably R 10 is independently —H, fluoro, or methyl.

[0104] In still further compounds of formula (I) or (II) or pharmaceutically acceptable salts thereof, R3 is -H, -CN, C1-C3 alkyl, or C1-C3 haloalkyl (preferably, R3 is H, CN, or C1-C3 alkyl), R7 is CN, C1-C3 alkyl, or C1-C3 haloalkyl, and R8 and R are each H. In still further compounds of formula (I) or (II) or pharmaceutically acceptable salts thereof, R3 is H or methyl, R7 is C1-C3 alkyl (preferably methyl), and R8 and R are each H.

[0105] In still further compounds of formula (I) or (II) or pharmaceutically acceptable salts thereof, R7 is CN, C1-C3 alkyl or C1-C3 haloalkyl, and R4, R8 and R are each H. In still further compounds of formula (I) or (II) or pharmaceutically acceptable salts thereof, R7 is C1-C3 alkyl (preferably methyl), and R4, R8 and R are each H.

[0106] In still further compounds of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R5 is H, halogen, C1-C3 alkyl or C1-C3 haloalkyl, R7 is CN, methyl or trifluoromethyl, and R8 and R are each H. In still further compounds of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R5 is H, halogen, methyl or trifluoromethyl, R7 is methyl, and R8 and R are each H.

[0107] In still further compounds of formula (I) or (II) or pharmaceutically acceptable salts thereof, R3 is -H, -CN, C1-C3 alkyl, or C1-C3 haloalkyl (preferably, R3 is H, CN, or C1-C3 alkyl), R4 is -H or halogen (preferably, R4 is H), R6 is H or halogen, R5 is H, halogen, C1-C6 alkyl, or C1-C6 haloalkyl, R7 is CN, methyl, or trifluoromethyl, R8 is H, R is H, and R2 each represents 1 to 3 R 10 or R2 is a group of the formula: [ka] More preferably, R3 is H or methyl, R4 and R6 are each H, R5 is H, halogen, methyl, or trifluoromethyl, R7 is methyl, and R8 and R are each H. Preferably, R2 is [ka] where R 10 are independently -H, halogen, C1-C6 alkyl, or C1-C6 haloalkyl, preferably R 10 are independently -H, halogen, or C1-C3 alkyl, and more preferably, R 10 is independently —H, fluoro, or methyl.

[0108] In still further compounds of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R1 is a group of the formula: [ka] wherein each R9 is independently -H, halogen, C1-C3 alkyl, C1-C3 haloalkyl, or C3-C5 cycloalkyl; preferably, each R9 is independently -H, halogen, methyl, trifluoromethyl, or cyclopropyl; more preferably, each R9 is independently -H, halogen, methyl, or trifluoromethyl.

[0109] In still further compounds of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R1 is a group of the formula: [ka] wherein each R9 is independently -H, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C3-C5 cycloalkyl; preferably, each R9 is independently -H, halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, or C3-C5 cycloalkyl; more preferably, each R9 is independently -H, halogen, methyl, trifluoromethyl, methoxy, or cyclopropyl.

[0110] In still further compounds of formula (I) or (II) 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 C1-C3 haloalkyl. Preferably, each R9 is independently -H, halogen, methyl, or trifluoromethyl.

[0111] In still further compounds of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R1 is a group of the formula: [ka] In the formula, R9 is H, halogen, or C1-C3 haloalkyl. Preferably, R9 is H or trifluoromethyl.

[0112] In still further compounds of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R1 is a group of the formula: [ka] In the formula, R9 is -H, halogen, or C1 to C3 haloalkyl. Preferably, R9 is -H or halogen. More preferably, R9 is -H or fluoro.

[0113] In still further compounds of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R1 is a group of the formula: [ka] wherein R9 is -H, halogen, C1-C3 alkyl, C1-C3 haloalkyl, or C3-C5 cycloalkyl. Preferably, R9 is independently -H, halogen, methyl, trifluoromethyl, or cyclopropyl.

[0114] In still further compounds of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R1 is a group of the formula: [ka] In the formula, R9 is H, halogen, C1-C3 alkyl, or C1-C3 haloalkyl.

[0115] In still further compounds of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R1 is a group of the formula: [ka] In the formula, R9 is —H, halogen, C1 to C3 alkyl, C1 to C3 haloalkyl, or C3 to C5 cycloalkyl. Preferably, R9 is —H, halogen, methyl, trifluoromethyl, or cyclopropyl.

[0116] In still further compounds of formula (I) or (II), or a pharmaceutically acceptable salt thereof, R3 is -H, -CN, C1-C3 alkyl, or C1-C3 haloalkyl, R4 is -H or halogen, R6 is -H or halogen, R5 is -H, halogen, C1-C3 alkyl, or C1-C3 haloalkyl, and R1 is a group of the formula: [ka] wherein each R9 is independently -H, halogen, C1-C3 alkyl, C1-C3 haloalkyl, or C3-C5 cycloalkyl. More preferably, each R9 is independently -H, halogen, methyl, trifluoromethyl, or cyclopropyl. Preferably, R3 is -H, methyl, or trifluoromethyl, R4 is -H or halogen, R6 is -H or halogen, R5 is -H, halogen, methyl, or trifluoromethyl, and each R9 is independently -H, halogen, methyl, trifluoromethyl, or cyclopropyl.

[0117] In still further compounds of formula (I) or (II), or a pharmaceutically acceptable salt thereof, R7 is -CN, methyl, or trifluoromethyl, R8 and R are each -H, and R1 is a group of the formula: [ka] wherein each R9 is independently -H, halogen, C1-C3 alkyl, C1-C3 haloalkyl, or C3-C5 cycloalkyl; more preferably, R7 is methyl, R8 and R are each -H, and each R9 is independently -H, halogen, methyl, trifluoromethyl, or cyclopropyl.

[0118] In still further compounds of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R3 is -H, -CN, C1-C3 alkyl, or C1-C3 haloalkyl; R4 is -H or halogen; R8 and R are each -H; R5 is -H, halogen, C1-C3 alkyl, or C1-C3 haloalkyl; R6 is -H or halogen; R7 is -CN, methyl, or trifluoromethyl; and R1 is a group of the formula: [ka] wherein each R9 is independently -H, halogen, C1-C3 alkyl, C1-C3 haloalkyl, or C3-C5 cycloalkyl; more preferably, R3 is -H, methyl, or trifluoromethyl, R4 is -H or halogen, R6 is -H or halogen, R8 and R are each -H, R5 is -H, halogen, methyl, or trifluoromethyl, R7 is methyl, and each R9 is independently -H, halogen, methyl, trifluoromethyl, or cyclopropyl.

[0119] In still further compounds of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R3 is -H, -CN, C1-C3 alkyl, or C1-C3 haloalkyl; R4 is -H or halogen; R8 and R are each -H; R5 is -H, halogen, C1-C3 alkyl, or C1-C3 haloalkyl; R6 is -H or halogen; R7 is -CN, methyl, or trifluoromethyl; and R1 is a group of the formula: [ka] wherein each R9 is independently -H, halogen, C1-C3 alkyl or C1-C3 haloalkyl, preferably, R3 is -H, methyl or trifluoromethyl, R4 is -H or halogen, R6 is -H or halogen, R8 and R are each -H, R5 is -H, halogen, methyl or trifluoromethyl, R7 is methyl, and each R9 is independently -H, halogen, methyl or trifluoromethyl.

[0120] In still further compounds of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R3 is H, CN, or C1-C3 alkyl; R4, R6, R8 and R are each H; R5 is H, halogen, C1-C3 alkyl or C1-C3 haloalkyl; R7 is CN, methyl or trifluoromethyl; and R1 is a group of the formula: [ka] In the formula, R9 is H, halogen, or C1-C3 haloalkyl, and preferably, R3 is H or methyl, R4, R6, R8, and R are each H, R5 is H, halogen, methyl, or trifluoromethyl, R7 is methyl, and R9 is H or trifluoromethyl.

[0121] In still further compounds of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R3 is H, CN, or C1-C3 alkyl; R4, R6, R8 and R are each H; R5 is H, halogen, C1-C3 alkyl or C1-C3 haloalkyl; R7 is CN, methyl or trifluoromethyl; and R1 is a group of the formula: [ka] In the formula, R9 is -H, halogen, or C1-C3 haloalkyl, preferably R3 is H or methyl, R4, R6, R8, and R are each H, R5 is H, halogen, methyl, or trifluoromethyl, R7 is methyl, and R9 is -H or halogen. More preferably, R9 is -H or fluoro.

[0122] In still further compounds of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R3 is -H, -CN, C1-C3 alkyl, or C1-C3 haloalkyl; R4 is -H or halogen; R8 and R are each -H; R5 is -H, halogen, C1-C3 alkyl, or C1-C3 haloalkyl; R6 is -H or halogen; R7 is -CN, methyl, or trifluoromethyl; and R1 is a group of the formula: [ka] In the formula, R9 is -H, halogen, C1-C3 alkyl, C1-C3 haloalkyl, or C3-C5 cycloalkyl, and preferably, R3 is -H, methyl, or trifluoromethyl, R4 is -H or halogen, R6 is -H or halogen, R8 and R are each -H, R5 is -H, halogen, methyl, or trifluoromethyl, R7 is methyl, and R9 is -H, halogen, methyl, trifluoromethyl, or cyclopropyl.

[0123] In still further compounds of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R3 is H, CN, or C1-C3 alkyl; R4, R6, R8 and R are each H; R5 is H, halogen, C1-C3 alkyl or C1-C3 haloalkyl; R7 is CN, methyl or trifluoromethyl; and R1 is a group of the formula: [ka] In the formula, R9 is H, halogen, C1-C3 alkyl or C1-C3 haloalkyl, preferably, R3 is H or methyl, R4, R6, R8 and R are each H, R5 is H, halogen, methyl or trifluoromethyl, R7 is methyl, and R9 is H, halogen, C1-C3 alkyl or C1-C3 haloalkyl.

[0124] In still further compounds of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R3 is -H, -CN, C1-C3 alkyl, or C1-C3 haloalkyl; R4 is -H or halogen; R8 and R are each -H; R5 is -H, halogen, C1-C3 alkyl, or C1-C3 haloalkyl; R6 is -H or halogen; R7 is -CN, methyl, or trifluoromethyl; and R1 is a group of the formula: [ka] In the formula, R9 is -H, halogen, C1-C3 alkyl, C1-C3 haloalkyl, or C3-C5 cycloalkyl, and preferably, R3 is -H, methyl, or trifluoromethyl, R4 is -H or halogen, R6 is -H or halogen, R8 and R are each -H, R5 is -H, halogen, methyl, or trifluoromethyl, R7 is methyl, and R9 is -H, halogen, methyl, trifluoromethyl, or cyclopropyl.

[0125] In still further compounds of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R1 is a group of the formula: [ka] wherein each R9 is independently —H, halogen, C1-C3 alkyl, C1-C3 haloalkyl, or C3-C5 cycloalkyl; and each R2 is selected from 1 to 3 R 10or R2 is a group of the formula: [ka] In the formula, each R 10 are independently H, CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R 11 , -CONR 11 R 11 , -NR 11 R 11 , -NR 11 -CO2R 11 , optionally substituted C1-C6 alkyl, optionally substituted C3-C5 cycloalkyl, optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine, or morpholine, optionally substituted phenyl, or optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole, or thiazole, wherein the optionally substituted C1-C6 alkyl is optionally substituted with —CN, OH, or C1-C3 alkoxy, and the optionally substituted C3-C5 cycloalkyl, phenyl, heterocycle, or heteroaryl is each selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, —NR 11 R 11 , —OH, or —CN; and each R 11 are independently H or C1-C3 alkyl. Preferably, R2 is [ka] where R 10 are independently -H, halogen, C1-C6 alkyl or C1-C6 haloalkyl, preferably R 10 are independently -H, halogen or C1-C3 alkyl, more preferably R 10is independently —H, fluoro, or methyl.

[0126] In still further compounds of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R1 is a group of the formula: [ka] wherein each R9 is independently —H, halogen, or C1-C3 alkyl or C1-C3 haloalkyl; and each R2 is selected from 1 to 3 R 10 or R2 is a group of the formula: [ka] Preferably, each R9 is independently -H, halogen, methyl, or trifluoromethyl. Preferably, R2 is [ka] where R 10 are independently -H, halogen, C1-C6 alkyl or C1-C6 haloalkyl, preferably R 10 are independently -H, halogen or C1-C3 alkyl, more preferably R 10 is independently —H, fluoro, or methyl.

[0127] In still further compounds of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R1 is a group of the formula: [ka] In the formula, R9 is H, halogen, or C1-C3 haloalkyl, and R2 is each 1 to 3 R 10 or R2 is a group of the formula: [ka] Preferably, R9 is H or trifluoromethyl. Preferably, R2 is [ka] where R 10 are independently -H, halogen, C1-C6 alkyl or C1-C6 haloalkyl, preferably R 10 are independently -H, halogen or C1-C3 alkyl, more preferably R 10 is independently —H, fluoro, or methyl.

[0128] In still further compounds of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R1 is a group of the formula: [ka] In the formula, R9 is H, halogen, or C1-C3 haloalkyl, and R2 is each 1 to 3 R 10 or R2 is a group of the formula: [ka] Preferably, R9 is H or halogen. Preferably, R2 is [ka] where R 10 are independently -H, halogen, C1-C6 alkyl or C1-C6 haloalkyl, preferably R 10 are independently -H, halogen or C1-C3 alkyl, more preferably R 10 is independently —H, fluoro, or methyl.

[0129] In still further compounds of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R1 is a group of the formula: [ka] In the formula, R9 is H, halogen, C1-C3 alkyl, C1-C3 haloalkyl, or C3-C5 cycloalkyl, and R2 is each 1 to 3 R 10 or R2 is a group of the formula: [ka] Preferably, R9 is -H, halogen, methyl, trifluoromethyl, or cyclopropyl. Preferably, R2 is [ka] where R 10 are independently -H, halogen, C1-C6 alkyl, or C1-C6 haloalkyl, preferably R 10 are independently -H, halogen, or C1-C3 alkyl, and more preferably, R 10 is independently —H, fluoro, or methyl.

[0130] In still further compounds of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R1 is a group of the formula: [ka] In the formula, R9 is H, halogen, C1-C3 alkyl, or C1-C3 haloalkyl, and R2 is each 1 to 3 R 10 R2 is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl optionally substituted with a substituent, or R2 is a group of the formula: [ka] Preferably, R2 is [ka] where R 10 are independently -H, halogen, C1-C6 alkyl or C1-C6 haloalkyl, preferably R 10 are independently -H, halogen or C1-C3 alkyl, more preferably R 10 is independently —H, fluoro, or methyl.

[0131] In still further compounds of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R1 is a group of the formula: [ka] In the formula, R9 is —H, halogen, C1-C3 alkyl, C1-C3 haloalkyl, or C3-C5 cycloalkyl, and R2 is each 1 to 3 R 10 R2 is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl optionally substituted with a substituent, or R2 is a group of the formula: [ka] Preferably, R2 is [ka] where R 10 are independently -H, halogen, C1-C6 alkyl, or C1-C6 haloalkyl, preferably R 10 are independently -H, halogen, or C1-C3 alkyl, and more preferably, R 10 is independently —H, fluoro, or methyl.

[0132] In still further compounds of formula (I) or (II) or pharmaceutically acceptable salts thereof, R2 is selected from 1 to 3 R 10or R2 is a group of the formula: [ka] R3 is -H, -CN, C1-C3 alkyl, or C1-C3 haloalkyl; R4 is -H or halogen; R6 is -H or halogen; R5 is -H, halogen, C1-C3 alkyl, or C1-C3 haloalkyl; and R1 is a group of the formula: [ka] wherein each R9 is independently -H, halogen, C1-C3 alkyl, C1-C3 haloalkyl, or C3-C5 cycloalkyl. Preferably, R3 is -H, methyl, or trifluoromethyl, R4 is -H or halogen, R6 is -H or halogen, R5 is -H, halogen, methyl, or trifluoromethyl, and each R9 is independently -H, halogen, methyl, trifluoromethyl, or cyclopropyl. Preferably, R2 is [ka] where R 10 are independently -H, halogen, C1-C6 alkyl or C1-C6 haloalkyl, preferably R 10 are independently -H, halogen or C1-C3 alkyl, more preferably R 10 is independently —H, fluoro, or methyl.

[0133] In still further compounds of formula (I) or (II) or pharmaceutically acceptable salts thereof, R2 is selected from 1 to 3 R 10 or R2 is a group of the formula: [ka] R7 is -CN, methyl or trifluoromethyl, R8 and R are each -H, and R1 is a group of the formula: [ka] wherein each R9 is independently -H, halogen, methyl, C1-C3 haloalkyl, or cyclopropyl. Preferably, R2 is [ka] where R 10 are independently -H, halogen, C1-C6 alkyl, or C1-C6 haloalkyl, preferably R 10 are independently -H, halogen, or C1-C3 alkyl, and more preferably, R 10 is independently —H, fluoro, or methyl.

[0134] In still further compounds of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R1 is a group of the formula: [ka] wherein each R9 is independently —H, halogen, methyl, or trifluoromethyl; and each R2 is selected from 1 to 3 R 10 or R2 is a group of the formula: [ka] R7 is C1-C3 alkyl (preferably methyl), and R8 and R are each -H. Preferably, R2 is [ka] where R 10 are independently -H, halogen, C1-C6 alkyl, or C1-C6 haloalkyl, preferably R 10are independently -H, halogen, or C1-C3 alkyl, and more preferably, R 10 is independently —H, fluoro, or methyl.

[0135] In still further compounds of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R1 is a group of the formula: [ka] In the formula, R9 is H, halogen, or trifluoromethyl (preferably, R9 is H or trifluoromethyl), and R2 is each 1 to 3 R 10 or R2 is a group of the formula: [ka] R7 is C1-C3 alkyl (preferably methyl), and R8 and R are each H. Preferably, R2 is [ka] where R 10 are independently -H, halogen, C1-C6 alkyl, or C1-C6 haloalkyl, preferably R 10 are independently -H, halogen, or C1-C3 alkyl, and more preferably, R 10 is independently —H, fluoro, or methyl.

[0136] In still further compounds of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R1 is a group of the formula: [ka] In the formula, R9 is H, halogen, or trifluoromethyl (preferably, R9 is H or halogen), and R2 is each 1 to 3 R 10or R2 is a group of the formula: [ka] R7 is C1-C3 alkyl (preferably methyl), and R8 and R are each H. Preferably, R2 is [ka] where R 10 are independently -H, halogen, C1-C6 alkyl, or C1-C6 haloalkyl, preferably R 10 are independently -H, halogen, or C1-C3 alkyl, and more preferably, R 10 is independently —H, fluoro, or methyl.

[0137] In still further compounds of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R1 is a group of the formula: [ka] wherein R9 is —H, halogen, methyl, trifluoromethyl, or cyclopropyl; and R2 is each 1 to 3 R 10 or R2 is a group of the formula: [ka] R7 is C1-C3 alkyl (preferably methyl), and R8 and R are each H. Preferably, R2 is [ka] where R 10 are independently -H, halogen, C1-C6 alkyl, or C1-C6 haloalkyl, preferably R 10are independently -H, halogen, or C1-C3 alkyl, and more preferably, R 10 is independently —H, fluoro, or methyl.

[0138] In still further compounds of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R1 is a group of the formula: [ka] In the formula, R9 is H, halogen, C1-C3 alkyl, or C1-C3 haloalkyl, and R2 is each 1 to 3 R 10 or R2 is a group of the formula: [ka] R7 is C1-C3 alkyl (preferably methyl), and R8 and R are each H. Preferably, R2 is [ka] where R 10 are independently -H, halogen, C1-C6 alkyl, or C1-C6 haloalkyl, preferably R 10 are independently -H, halogen, or C1-C3 alkyl, and more preferably, R 10 is independently —H, fluoro, or methyl.

[0139] In still further compounds of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R1 is a group of the formula: [ka] In the formula, R9 is —H, halogen, C1-C3 alkyl, C1-C3 haloalkyl, or C3-C5 cycloalkyl, and R2 is each 1 to 3 R 10or R2 is a group of the formula: [ka] R7 is C1-C3 alkyl (preferably methyl), and R8 and R are each H. Preferably, R2 is [ka] where R 10 are independently -H, halogen, C1-C6 alkyl, or C1-C6 haloalkyl, preferably R 10 are independently -H, halogen, or C1-C3 alkyl, and more preferably, R 10 is independently —H, fluoro, or methyl.

[0140] In still further compounds of formula (I) or (II) or pharmaceutically acceptable salts thereof, R2 is selected from 1 to 3 R 10 or R2 is a group of the formula: [ka] R3 is H, CN, or C1-C3 alkyl; R4, R6, R8, and R are each H; R5 is H, halogen, C1-C3 alkyl, or C1-C3 haloalkyl; R7 is CN, methyl, or trifluoromethyl; and R1 is a group of the formula: [ka] wherein each R9 is independently -H, halogen, methyl, C1-C3 haloalkyl, or cyclopropyl. Preferably, R2 is [ka] where R 10are independently -H, halogen, C1-C6 alkyl, or C1-C6 haloalkyl, preferably R 10 are independently -H, halogen, or C1-C3 alkyl, and more preferably, R 10 is independently —H, fluoro, or methyl.

[0141] In still further compounds of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R1 is a group of the formula: [ka] wherein each R9 is independently —H, halogen, methyl, or trifluoromethyl; and each R2 is selected from 1 to 3 R 10 or R2 is a group of the formula: [ka] R3 is -H, methyl, or trifluoromethyl, R4 is -H or halogen, R8 and R are each -H, R5 is -H, halogen, methyl, or trifluoromethyl, R6 is -H or halogen, and R7 is C1-C3 alkyl (preferably methyl). Preferably, R2 is [ka] where R 10 are independently -H, halogen, C1-C6 alkyl or C1-C6 haloalkyl, preferably R 10 are independently -H, halogen or C1-C3 alkyl, more preferably R 10 is independently —H, fluoro, or methyl.

[0142] In still further compounds of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R1 is a group of the formula: [ka] In the formula, R9 is H, halogen, or trifluoromethyl (preferably, R9 is H or trifluoromethyl), and R2 is each 1 to 3 R 10 or R2 is a group of the formula: [ka] R3 is H or methyl, R4, R6, R8 and R are each H, R5 is H, halogen, methyl or trifluoromethyl, and R7 is C1-C3 alkyl (preferably methyl). Preferably, R2 is [ka] where R 10 are independently -H, halogen, C1-C6 alkyl or C1-C6 haloalkyl, preferably R 10 are independently -H, halogen or C1-C3 alkyl, more preferably R 10 is independently —H, fluoro, or methyl.

[0143] In still further compounds of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R1 is a group of the formula: [ka] In the formula, R9 is H, halogen, or trifluoromethyl (preferably, R9 is H or halogen), and R2 is each 1 to 3 R 10 or R2 is a group of the formula: [ka] R3 is H or methyl, R4, R6, R8 and R are each H, R5 is H, halogen, methyl or trifluoromethyl, and R7 is C1-C3 alkyl (preferably methyl). Preferably, R2 is [ka] where R 10 are independently -H, halogen, C1-C6 alkyl or C1-C6 haloalkyl, preferably R 10 are independently -H, halogen or C1-C3 alkyl, more preferably R 10 is independently —H, fluoro, or methyl.

[0144] In still further compounds of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R1 is a group of the formula: [ka] wherein R9 is independently —H, halogen, methyl, trifluoromethyl, or cyclopropyl; and R2 is each 1 to 3 R 10 or R2 is a group of the formula: [ka] R3 is -H, methyl, or trifluoromethyl, R4 is -H or halogen, R8 and R are each -H, R5 is -H, halogen, methyl, or trifluoromethyl, R6 is -H or halogen, and R7 is C1-C3 alkyl (preferably methyl). Preferably, R2 is [ka] where R 10 are independently -H, halogen, C1-C6 alkyl or C1-C6 haloalkyl, preferably R 10are independently -H, halogen or C1-C3 alkyl, more preferably R 10 is independently —H, fluoro, or methyl.

[0145] In still further compounds of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R1 is a group of the formula: [ka] In the formula, R9 is H, halogen, C1-C3 alkyl, or C1-C3 haloalkyl, and R2 is each 1 to 3 R 10 or R2 is a group of the formula: [ka] R3 is H or methyl, R4, R6, R8 and R are each H, R5 is H, halogen, methyl or trifluoromethyl, and R7 is C1-C3 alkyl (preferably methyl). Preferably, R2 is [ka] where R 10 are independently -H, halogen, C1-C6 alkyl or C1-C6 haloalkyl, preferably R 10 are independently -H, halogen or C1-C3 alkyl, more preferably R 10 is independently —H, fluoro, or methyl.

[0146] In still further compounds of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R1 is a group of the formula: [ka] wherein each R is independently —H, halogen, methyl, trifluoromethyl, or cyclopropyl; and each R is selected from 1 to 3 R10 or R2 is a group of the formula: [ka] R3 is -H, methyl, or trifluoromethyl, R4 is -H or halogen, R8 and R are each -H, R5 is -H, halogen, methyl, or trifluoromethyl, R6 is -H or halogen, and R7 is C1-C3 alkyl (preferably methyl). Preferably, R2 is [ka] where R 10 are independently -H, halogen, C1-C6 alkyl or C1-C6 haloalkyl, preferably R 10 are independently -H, halogen or C1-C3 alkyl, more preferably R 10 is independently —H, fluoro, or methyl.

[0147] In a further embodiment, the compound of formula (I) or (II) has the formula (III): [ka] wherein R1, R2, R3, R5, R6, and R7 are as defined above in the Summary of the Invention for formula (I).

[0148] In still further compounds of formula (III) or a pharmaceutically acceptable salt thereof, R3 is -H, -CN, C1-C3 alkyl, C1-C3 haloalkyl, preferably R3 is H, CN, or C1-C3 alkyl, and most preferably R3 is H or methyl.

[0149] In still further compounds of formula (III) or pharmaceutically acceptable salts thereof, R5 is H, halogen, C1-C6 alkyl, or C1-C6 haloalkyl, preferably R5 is H, halogen, C1-C3 alkyl, or C1-C3 haloalkyl, more preferably R5 is H, halogen, methyl, or trifluoromethyl.

[0150] In still further compounds of formula (III) or a pharmaceutically acceptable salt thereof, R6 is H or halogen, preferably R6 is H.

[0151] In still further compounds of formula (III) or pharmaceutically acceptable salts thereof, R7 is CN, C1-C6 alkyl, or C1-C6 haloalkyl, preferably R7 is CN, C1-C3 alkyl, or C1-C3 haloalkyl, more preferably R7 is CN, methyl, or trifluoromethyl.

[0152] In still further compounds of formula (III) or a pharmaceutically acceptable salt thereof, R1 is a group of the formula: [ka] wherein each R9 is independently -H, halogen, C1-C3 alkyl, C1-C3 haloalkyl, or C3-C5 cycloalkyl; preferably, each R9 is independently -H, halogen, methyl, trifluoromethyl, or cyclopropyl.

[0153] In still further compounds of formula (III) or a pharmaceutically acceptable salt thereof, R1 is a group of the formula: [ka] wherein each R9 is independently H, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C3-C5 cycloalkyl. Preferably, each R9 is independently -H, halogen, C1-C3 alkyl, C1-C3 haloalkyl, or C3-C5 cycloalkyl. More preferably, each R9 is independently -H, halogen, methyl, trifluoromethyl, or cyclopropyl.

[0154] In still further compounds of formula (III) 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 C1-C3 haloalkyl. Preferably, each R9 is independently -H, halogen, methyl, or trifluoromethyl.

[0155] In still further compounds of formula (III) or a pharmaceutically acceptable salt thereof, R1 is a group of the formula: [ka] In the formula, R9 is H, halogen, or C1-C3 haloalkyl. Preferably, R9 is H or trifluoromethyl.

[0156] In still further compounds of formula (III) 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 C1-C3 haloalkyl. Preferably, each R9 is independently -H, halogen, methyl, or trifluoromethyl.

[0157] In still further compounds of formula (III) or a pharmaceutically acceptable salt thereof, R1 is a group of the formula: [ka] wherein R9 is -H, halogen, C1-C3 alkyl, C1-C3 haloalkyl, or C3-C5 cycloalkyl. Preferably, R9 is independently -H, halogen, methyl, trifluoromethyl, or cyclopropyl.

[0158] In still further compounds of formula (III) or a pharmaceutically acceptable salt thereof, R1 is a group of the formula: [ka] In the formula, R9 is H, halogen, C1-C3 alkyl, or C1-C3 haloalkyl.

[0159] In still further compounds of formula (III) or a pharmaceutically acceptable salt thereof, R1 is a group of the formula: [ka] In the formula, R9 is —H, halogen, C1 to C3 alkyl, C1 to C3 haloalkyl, or C3 to C5 cycloalkyl. Preferably, R9 is —H, halogen, methyl, trifluoromethyl, or cyclopropyl.

[0160] In still further compounds of formula (III) or a pharmaceutically acceptable salt thereof, R1 is a group of the formula: [ka] wherein each R9 is independently —H, halogen, C1-C3 alkyl, C1-C3 haloalkyl, or C3-C5 cycloalkyl; and each R2 is selected from 1 to 3 R 10 or R2 is a group of the formula: [ka] In the formula, each R 10are independently -H, -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R 11 , -CONR 11 R 11 , -NR 11 R 11 , -NR 11 -CO2R 11 , optionally substituted C1-C6 alkyl, optionally substituted C3-C5 cycloalkyl, optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine, or morpholine, optionally substituted phenyl, or optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole, or thiazole, wherein the optionally substituted C1-C6 alkyl is optionally substituted with —CN, OH, or C1-C3 alkoxy, and the optionally substituted C3-C5 cycloalkyl, phenyl, heterocycle, or heteroaryl is each selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, —NR 11 R 11 , —OH, or —CN; and each R 11 are independently H or C1-C3 alkyl. Preferably, R2 is [ka] where R 10 are independently -H, halogen, C1-C6 alkyl or C1-C6 haloalkyl, preferably R 10 are independently -H, halogen or C1-C3 alkyl, more preferably R 10 is independently —H, fluoro, or methyl.

[0161] In still further compounds of formula (III) or a pharmaceutically acceptable salt thereof, R1 is a group of the formula: [ka] wherein each R9 is independently —H, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C3-C5 cycloalkyl; and each R2 is selected from 1 to 3 R 10 or R2 is a group of the formula: [ka] Preferably, each R9 is independently -H, halogen, C1-C3 alkyl, C1-C3 haloalkyl, or C3-C5 cycloalkyl. Most preferably, each R9 is independently -H, halogen, methyl, trifluoromethyl, or cyclopropyl. Preferably, R2 is [ka] where R 10 are independently -H, halogen, C1-C6 alkyl or C1-C6 haloalkyl, preferably R 10 are independently -H, halogen or C1-C3 alkyl, more preferably R 10 is independently —H, fluoro, or methyl.

[0162] In still further compounds of formula (III) 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 C1-C3 haloalkyl; and each R2 is 1 to 3 R 10 or R2 is a group of the formula: [ka] Preferably, each R9 is independently -H, halogen, methyl, or trifluoromethyl. Preferably, R2 is [ka] where R 10 are independently -H, halogen, C1-C6 alkyl or C1-C6 haloalkyl, preferably R 10 are independently -H, halogen or C1-C3 alkyl, more preferably R 10 is independently —H, fluoro, or methyl.

[0163] In still further compounds of formula (III) or a pharmaceutically acceptable salt thereof, R1 is a group of the formula: [ka] In the formula, R9 is H, halogen, or C1-C3 haloalkyl, and R2 is each 1 to 3 R 10 or R2 is a group of the formula: [ka] Preferably, R9 is H or trifluoromethyl. Preferably, R2 is [ka] where R 10 are independently -H, halogen, C1-C6 alkyl or C1-C6 haloalkyl, preferably R 10 are independently -H, halogen or C1-C3 alkyl, more preferably R 10 is independently —H, fluoro, or methyl.

[0164] In still further compounds of formula (III) or a pharmaceutically acceptable salt thereof, R1 is a group of the formula: [ka] In the formula, R9 is H, halogen, or C1-C3 haloalkyl, and R2 is each 1 to 3 R 10 or R2 is a group of the formula: [ka] Preferably, R9 is H or halogen. Preferably, R2 is [ka] where R 10 are independently -H, halogen, C1-C6 alkyl or C1-C6 haloalkyl, preferably R 10 are independently -H, halogen or C1-C3 alkyl, more preferably R 10 is independently —H, fluoro, or methyl.

[0165] In still further compounds of formula (III) or a pharmaceutically acceptable salt thereof, R1 is a group of the formula: [ka] In the formula, R9 is —H, halogen, C1-C3 alkyl, C1-C3 haloalkyl, or C3-C5 cycloalkyl, and R2 is each 1 to 3 R 10 or R2 is a group of the formula: [ka] Preferably, R9 is -H, halogen, methyl, trifluoromethyl, or cyclopropyl. Preferably, R2 is [ka] where R10 are independently -H, halogen, C1-C6 alkyl, or C1-C6 haloalkyl, preferably R 10 are independently -H, halogen, or C1-C3 alkyl, and more preferably, R 10 is independently —H, fluoro, or methyl.

[0166] In still further compounds of formula (III) or a pharmaceutically acceptable salt thereof, R1 is a group of the formula: [ka] In the formula, R9 is H, halogen, C1-C3 alkyl, or C1-C3 haloalkyl, and R2 is each 1 to 3 R 10 R2 is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl optionally substituted with a substituent, or R2 is a group of the formula: [ka] Preferably, R2 is [ka] where R 10 are independently -H, halogen, C1-C6 alkyl or C1-C6 haloalkyl, preferably R 10 are independently -H, halogen or C1-C3 alkyl, more preferably R 10 is independently —H, fluoro, or methyl.

[0167] In still further compounds of formula (III) or a pharmaceutically acceptable salt thereof, R1 is a group of the formula: [ka] In the formula, R9 is —H, halogen, C1-C3 alkyl, C1-C3 haloalkyl, or C3-C5 cycloalkyl, and R2 is each 1 to 3 R 10or R2 is a group of the formula: [ka] Preferably, R9 is -H, halogen, methyl, trifluoromethyl, or cyclopropyl. Preferably, R2 is [ka] where R 10 are independently -H, halogen, C1-C6 alkyl, or C1-C6 haloalkyl, preferably R 10 are independently -H, halogen, or C1-C3 alkyl, and more preferably, R 10 is independently —H, fluoro, or methyl.

[0168] In still further compounds of formula (III) or pharmaceutically acceptable salts thereof, R3 is -H, -CN, C1-C3 alkyl, C1-C3 haloalkyl (preferably, R3 is -H, -CN, or C1-C3 alkyl), R5 is -H, halogen, C1-C6 alkyl, or C1-C6 haloalkyl, R6 is -H or halogen, R7 is -CN, methyl, or trifluoromethyl, and R2 each represents 1 to 3 R 10 or R2 is a group of the formula: [ka] More preferably, R3 is -H or methyl, R5 is -H, halogen, methyl, or trifluoromethyl, R6 is -H, and R7 is methyl. [ka] where R 10are independently -H, halogen, C1-C6 alkyl or C1-C6 haloalkyl, preferably R 10 are independently -H, halogen or C1-C3 alkyl, more preferably R 10 is independently —H, fluoro, or methyl.

[0169] In still further compounds of formula (III) or pharmaceutically acceptable salts thereof, R2 is selected from 1 to 3 R 10 or R2 is a group of the formula: [ka] R3 is -H, -CN, C1-C3 alkyl, or C1-C3 haloalkyl; R5 is -H, halogen, C1-C3 alkyl, or C1-C3 haloalkyl; R6 is -H or halogen; and R1 is a group of the formula: [ka] wherein each R9 is independently -H, halogen, C1-C3 alkyl, C1-C3 haloalkyl, or C3-C5 cycloalkyl. Preferably, R3 is -H, methyl, or trifluoromethyl, R5 is -H, halogen, methyl, or trifluoromethyl, R6 is -H or halogen, and each R9 is independently -H, halogen, methyl, trifluoromethyl, or cyclopropyl. Preferably, R2 is [ka] where R 10 are independently -H, halogen, C1-C6 alkyl or C1-C6 haloalkyl, preferably R 10 are independently -H, halogen or C1-C3 alkyl, more preferably R 10 is independently —H, fluoro, or methyl.

[0170] In still further compounds of formula (III) or pharmaceutically acceptable salts thereof, R2 is selected from 1 to 3 R 10 or R2 is a group of the formula: [ka] R3 is -H, -CN, C1-C3 alkyl, or C1-C3 haloalkyl; R5 is -H, halogen, C1-C3 alkyl, or C1-C3 haloalkyl; R6 is -H or halogen; R7 is -CN, methyl, or trifluoromethyl; and R1 is a group of the formula: [ka] wherein each R9 is independently -H, halogen, C1-C3 alkyl, C1-C3 haloalkyl, or C3-C5 cycloalkyl. Preferably, R2 is [ka] where R 10 are independently -H, halogen, C1-C6 alkyl or C1-C6 haloalkyl, preferably R 10 are independently -H, halogen or C1-C3 alkyl, more preferably R 10 is independently —H, fluoro, or methyl.

[0171] In still further compounds of formula (III) or a pharmaceutically acceptable salt thereof, R1 is a group of the formula: [ka] wherein each R9 is independently —H, halogen, methyl, or trifluoromethyl; and each R2 is selected from 1 to 3 R 10 or R2 is a group of the formula: [ka] R3 is -H, methyl, or trifluoromethyl, R5 is -H, halogen, methyl, or trifluoromethyl, R6 is -H, or halogen, and R7 is C1-C3 alkyl (preferably methyl). Preferably, R2 is [ka] where R 10 are independently -H, halogen, C1-C6 alkyl or C1-C6 haloalkyl, preferably R 10 are independently -H, halogen or C1-C3 alkyl, more preferably R 10 is independently —H, fluoro, or methyl.

[0172] In still further compounds of formula (III) or a pharmaceutically acceptable salt thereof, R1 is a group of the formula: [ka] In the formula, R9 is H, halogen, or trifluoromethyl (preferably, R9 is H or trifluoromethyl), and R2 is each 1 to 3 R 10 or R2 is a group of the formula: [ka] R3 is H or methyl, R5 is H, halogen, methyl, or trifluoromethyl, R6 is H or halogen, and R7 is methyl. Preferably, R2 is [ka] where R 10 are independently -H, halogen, C1-C6 alkyl or C1-C6 haloalkyl, preferably R10 are independently -H, halogen or C1-C3 alkyl, more preferably R 10 is independently —H, fluoro, or methyl.

[0173] In still further compounds of formula (III) or a pharmaceutically acceptable salt thereof, R1 is a group of the formula: [ka] In the formula, R9 is H, halogen, or trifluoromethyl (preferably, R9 is H or halogen), and R2 is each 1 to 3 R 10 or R2 is a group of the formula: [ka] R3 is H or methyl, R5 is H, halogen, methyl, or trifluoromethyl, R6 is H or halogen, and R7 is methyl. Preferably, R2 is [ka] where R 10 are independently -H, halogen, C1-C6 alkyl or C1-C6 haloalkyl, preferably R 10 are independently -H, halogen or C1-C3 alkyl, more preferably R 10 is independently —H, fluoro, or methyl.

[0174] In still further compounds of formula (III) or a pharmaceutically acceptable salt thereof, R1 is a group of the formula: [ka] wherein each R is independently —H, halogen, methyl, trifluoromethyl, or cyclopropyl; and each R is selected from 1 to 3 R 10or R2 is a group of the formula: [ka] R3 is -H, methyl, or trifluoromethyl, R5 is -H, halogen, methyl, or trifluoromethyl, R6 is -H, or halogen, and R7 is C1-C3 alkyl (preferably methyl). Preferably, R2 is [ka] where R 10 are independently -H, halogen, C1-C6 alkyl or C1-C6 haloalkyl, preferably R 10 are independently -H, halogen or C1-C3 alkyl, more preferably R 10 is independently —H, fluoro, or methyl.

[0175] In still further compounds of formula (III) or a pharmaceutically acceptable salt thereof, R1 is a group of the formula: [ka] In the formula, R9 is H, halogen, C1-C3 alkyl, or C1-C3 haloalkyl, and R2 is each 1 to 3 R 10 or R2 is a group of the formula: [ka] R3 is H or methyl, R5 is H, halogen, methyl, or trifluoromethyl, R6 is H or halogen, and R7 is methyl. Preferably, R2 is [ka] where R 10are independently -H, halogen, C1-C6 alkyl or C1-C6 haloalkyl, preferably R 10 are independently -H, halogen or C1-C3 alkyl, more preferably R 10 is independently —H, fluoro, or methyl.

[0176] In still further compounds of formula (III) or a pharmaceutically acceptable salt thereof, R1 is a group of the formula: [ka] wherein each R is independently —H, halogen, methyl, trifluoromethyl, or cyclopropyl; and each R is selected from 1 to 3 R 10 or R2 is a group of the formula: [ka] R3 is -H, methyl, or trifluoromethyl, R5 is -H, halogen, methyl, or trifluoromethyl, R6 is -H, or halogen, and R7 is C1-C3 alkyl (preferably methyl). Preferably, R2 is [ka] where R 10 are independently -H, halogen, C1-C6 alkyl or C1-C6 haloalkyl, preferably R 10 are independently -H, halogen or C1-C3 alkyl, more preferably R 10 is independently —H, fluoro, or methyl.

[0177] In still further compounds of formula (I), the compound is [ka] or a pharmaceutically acceptable salt of any of the foregoing, wherein:* The bond at the position is as shown, or [ka] or [ka] is.

[0178] A further embodiment is a compound of the formula: [ka] or a pharmaceutically acceptable salt thereof. * The bond at the position is [ka] In still further embodiments, * The bond at the position is [ka] is.

[0179] A further embodiment is a compound of the formula: [ka] or a pharmaceutically acceptable salt thereof. * The bond at the position is [ka] In still further embodiments, * The bond at the position is [ka] is.

[0180] A further embodiment is a compound of the formula: [ka] or a pharmaceutically acceptable salt thereof. * The bond at the position is [ka] In still further embodiments, * The bond at the position is [ka] is.

[0181] A further embodiment is a compound of the formula: [ka] or a pharmaceutically acceptable salt thereof. * The bond at the position is [ka] In still further embodiments, * The bond at the position is [ka] is.

[0182] A further embodiment is a compound of the formula: [ka] or a pharmaceutically acceptable salt thereof. * The bond at the position is [ka] In still further embodiments, * The bond at the position is [ka] is.

[0183] A further embodiment is a compound of the formula: [ka] or a pharmaceutically acceptable salt thereof. * The bond at the position is [ka] In still further embodiments, * The bond at the position is [ka] is.

[0184] A further embodiment is a compound of the formula: [ka] or a pharmaceutically acceptable salt thereof. * The bond at the position is [ka] In still further embodiments, * The bond at the position is [ka] is.

[0185] A further embodiment is a compound of the formula: [ka] or a pharmaceutically acceptable salt thereof. * The bond at the position is [ka] In still further embodiments, * The bond at the position is [ka] is.

[0186] 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 Revised Edition (Wiley-VCH, 2011); see S.M. Berge, et al., "Pharmaceutical Salts," Journal of Pharmaceutical Sciences, Vol. 66, No. 1, January 1977).

[0187] 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.

[0188] 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 field 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.The compounds of the present invention can be synthesized according to the steps outlined in General Scheme 1.Starting materials are either commercially available or can be prepared by known procedures in published literature or as exemplified below. [ka]

[0189] Scheme 1 illustrates the preparation of compounds of formula (I), where R is H, R7 is methyl, and R8 is H. Acylation of substituted phenols (1) can provide esters (2). Esters (2) can undergo rearrangement under Lewis acid conditions to provide hydroxyaryl ketones (3). Basic addition of the ester to aryl ketones (3) can provide diketo compounds (4).

[0190] Acidic cyclization can provide the chromen-4-one core (5). Phenyl bromide (5) can be acylated by palladium catalysis to generate acyl chromen-4-one (6). Aryl ketone (6) can be reduced to hydroxy compound (7) with a reagent such as sodium borohydride. Hydroxy compound (7) can be converted to halo compound (8) using a halogenating agent such as phosphorus tribromide.

[0191] Halo compounds (8) can be used to alkylate arylamines to give compounds of formula (I), followed by hydrolysis of the ester present at R1.

[0192] Pharmaceutical Composition In some aspects, the present disclosure provides pharmaceutical compositions comprising a compound of Formula (I), (II), or (III) as an active ingredient. In some embodiments, the present disclosure provides pharmaceutical compositions comprising a compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or excipients.

[0193] 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.

[0194] The compounds of Formula (I), (II), or (III) can be formulated for oral administration in forms such as tablets, capsules (each of which includes sustained-release or extended-release formulations), pills, powders, granules, elixirs, tinctures, suspensions, syrups, and emulsions. The compounds of Formula (I), (II), or (III) can also be formulated for intravenous (bolus or 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.

[0195] 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.

[0196] 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, hydrate, or solvate thereof, together with a pharmaceutically acceptable diluent or carrier.

[0197] 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).

[0198] 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.

[0199] How to use In some aspects, the disclosure provides a method for 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), or (III) or a pharmaceutically acceptable salt thereof.

[0200] 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), or (III), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0201] 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), or (III), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0202] 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.

[0203] In some embodiments, the disease or disorder is cancer.

[0204] 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.

[0205] 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.

[0206] In some embodiments, the cancer is breast cancer, prostate cancer, or brain cancer.

[0207] In some embodiments, the cancer is breast cancer, in some embodiments, the cancer is prostate cancer, in some embodiments, the cancer is brain cancer.

[0208] 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).

[0209] 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.

[0210] 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.

[0211] In some embodiments, the PI3K-related disease or disorder includes, but is not limited to, 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.

[0212] In some embodiments, the disease or disorder associated with PI3K is CLOVES syndrome (congenital lipomatous overgrowth, vascular malformations, epidermal nevus, scoliosis / skeletal and spinal syndrome).

[0213] In some embodiments, the disease or disorder associated with PI3K is PIK3CA-associated overgrowth syndrome (PROS).

[0214] 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.

[0215] 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.

[0216] In some embodiments, the disease or disorder associated with PI3K is leukemia, lymphoma, or sarcoma.

[0217] In some embodiments, the cancer is endometrial cancer, head and neck cancer, or sarcoma.

[0218] 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.

[0219] 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.

[0220] 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.

[0221] 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), or (III), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the disclosure.

[0222] 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), or (III), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0223] 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), or (III), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the disclosure.

[0224] 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), or (III), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the disclosure.

[0225] In some aspects, the present disclosure provides a method 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), or (III), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the disclosure.

[0226] 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), or (III), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the disclosure.

[0227] 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), or (III), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the disclosure.

[0228] 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), or (III), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0229] In some aspects, the disclosure provides a compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof, for use in therapy.

[0230] In some aspects, the disclosure provides a compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof, for use in modulating PI3K (e.g., PI3Kα) activity (e.g., in vitro or in vivo).

[0231] In some aspects, the present disclosure provides a compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof, for use in the treatment or prevention of a disease or disorder disclosed herein.

[0232] In some aspects, the present disclosure provides a compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof, for use in treating a disease or disorder disclosed herein.

[0233] In some aspects, the disclosure provides a compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof, for use in treating or preventing cancer.

[0234] In some aspects, the disclosure provides a compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer.

[0235] In some aspects, the disclosure provides a compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof, for use in treating or preventing breast cancer.

[0236] In some aspects, the disclosure provides a compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof, for use in the treatment of breast cancer.

[0237] In some aspects, the disclosure provides a compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof, for use in treating or preventing prostate cancer.

[0238] In some aspects, the disclosure provides a compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof, for use in the treatment of prostate cancer.

[0239] In some aspects, the disclosure provides a compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof, for use in treating or preventing brain cancer.

[0240] In some aspects, the disclosure provides a compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof, for use in the treatment of brain cancer.

[0241] In some aspects, the disclosure provides the use of a compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for modulating PI3K (e.g., PI3Kα) activity (e.g., in vitro or in vivo).

[0242] In some aspects, the disclosure provides the use of a compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating or preventing a disease or disorder disclosed herein.

[0243] In some aspects, the disclosure provides the use of a compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating a disease or disorder disclosed herein.

[0244] In some aspects, the disclosure provides the use of a compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating or preventing cancer in a subject in need thereof.

[0245] In some aspects, the disclosure provides the use of a compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating cancer in a subject in need thereof.

[0246] In some aspects, the disclosure provides the use of a compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating or preventing breast cancer in a subject in need thereof.

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

[0248] In some aspects, the disclosure provides the use of a compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating or preventing prostate cancer in a subject in need thereof.

[0249] In some aspects, the disclosure provides the use of a compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating prostate cancer in a subject in need thereof.

[0250] In some aspects, the disclosure provides the use of a compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating or preventing brain cancer in a subject in need thereof.

[0251] In some aspects, the disclosure provides the use of a compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating brain cancer in a subject in need thereof.

[0252] 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.

[0253] In some embodiments, the PI3K modulation is an inhibition of PI3K.

[0254] In some embodiments, the PI3K inhibitor is a PI3K alpha inhibitor. In some embodiments, the PI3K inhibitor is a PI3K alpha H1047R mutation inhibitor.

[0255] 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.

[0256] 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.

[0257] Administration route Compounds of formula (I), (II), or (III), 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).

[0258] 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); ophthalmic (e.g., by eye drops); pulmonary (e.g., via aerosol, e.g., used 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, including, e.g., by injection, including subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcuticular, intraarticular, subarachnoid, and intrasternal; by implantation of a depot or reservoir, e.g., subcutaneously or intramuscularly. [Example]

[0259] Exemplary compounds of formulas (I), (II), and (III) are synthesized and tested in the Examples. It is understood that the compounds of formulas (I), (II), and (III) can be converted to their corresponding pharmaceutically acceptable salts using techniques conventional in the art (e.g., by saponification of an ester to a carboxylate salt, or by hydrolyzing an amide to form the corresponding carboxylic acid and then converting the carboxylic acid to a carboxylate salt).

[0260] Nuclear magnetic resonance (NMR) spectra were recorded at 400 MHz or 300 MHz as indicated and 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.

[0261] 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. Positive detection methods were 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%).

[0262] [Table 1]

[0263] Intermediate 1: (2-bromo-4-methyl-phenyl)propanoate [ka]

[0264] 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 added to propanoyl chloride (5.44 g, 58.8 mmol) at 0 °C and stirred at 25 °C for 16 h. The mixture was then diluted with water (100 mL), adjusted to pH 5 with HCl (2 M), and extracted with DCM (100 mL × 2). The combined extracts were washed with brine (150 mL × 2), dried over anhydrous NaSO, filtered, and concentrated to give the product as an oil (13 g, crude). 1 H NMR(400MHz,DMSO-d6)δppm 1.17(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).

[0265] Intermediate 2: 1-(3-bromo-2-hydroxy-5-methyl-phenyl)propan-1-one [ka]

[0266] A mixture of (2-bromo-4-methyl-phenyl)propanoate (12.5 g, 51.4 mmol) and AlCl (24.0 g, 180 mmol) was stirred at 140 °C for 1 h. When cooled to room temperature, the mixture was quenched by dropwise addition of water (80 mL) and stirred for 30 min. The mixture was then extracted with EtOAc (100 mL × 3). The combined extracts were washed with brine (200 mL × 2), 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 H NMR(400MHz,DMSO-d6)δppm 1.10(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).

[0267] Intermediate 3: 1-(3-bromo-2-hydroxy-5-methyl-phenyl)ethanone [ka]

[0268] A mixture of 1-(2-hydroxy-5-methyl-phenyl)ethanone in acetic acid (80 mL) was treated with sodium acetate (6.56 g, 79.91 mmol). The reaction was cooled to 0 °C and treated dropwise with bromine (12.77 g, 79.91 mmol). After the addition was complete, the reaction was stirred at room temperature for 20 hours. The reaction was poured into 400 mL of ice water and the suspension was filtered to give the product (13 g, 85%) as a yellow solid. 1H NMR (400MHz, CDCl3) δppm 2.33 (s, 3H), 2.65 (s, 3H), 7.50 (s, 1H), 7.60 (s, 1H), 12.64 (s, 1H).

[0269] Intermediate 4: Methyl 1-phenylcyclopropanecarboxylate [ka]

[0270] 1-Phenylcyclopropanecarboxylic acid (5.3 g, 33 mmol) was dissolved in 50 mL of methanol and treated portionwise with acetyl chloride. After the addition was complete, the reaction was stirred at room temperature for 18 hours. The reaction was concentrated, and the residue was diluted with water and ethyl acetate. Saturated aqueous sodium bicarbonate was added to neutralize the residue, and the layers were separated. The aqueous layer was re-extracted three times with 100 mL of ethyl acetate. The organics were combined, dried over MgSO4, filtered, and concentrated to give the product (4.5 g, 66%) as a clear liquid. MS ES+ m / z 177 [M+H] + .

[0271] Intermediate 5: Methylindan-2-carboxylate [ka]

[0272] A mixture of indan-2-carboxylic acid (3 g, 18.50 mmol) in 30 mL of methanol was treated with sulfuric acid (0.18 g, 1.85 mmol) and stirred at 60 °C for 12 h. The reaction was concentrated, and the residue was dissolved in 100 mL of dichloromethane, washed with saturated aqueous sodium bicarbonate, collected, dried over Na2SO4, filtered, and concentrated to give the product (3.15 g, 17.88 mmol), which was used without purification. MS ES+ m / z 177 [M+H] + .

[0273] Intermediate 45: Indan-2-carbonyl chloride [ka]

[0274] A mixture of indan-2-carboxylic acid (6.0 g, 37.0 mmol) in 60 mL of dichloromethane was treated with DMF (0.27 g, 0.28 mL, 3.70 mmol) and cooled to 0° C. Once cooled, the reaction was treated with oxalyl chloride (7.04 g, 55.49 mmol) and then stirred at 25° C. for 2 hours. The resulting yellow solution was concentrated and used in the next synthetic step without purification.

[0275] Intermediate 6: (2-bromo-4-methyl-6-propanoyl-phenyl) 4,4-difluorocyclohexanecarboxylate [ka]

[0276] 1-(3-Bromo-2-hydroxy-5-methyl-phenyl)propan-1-one (5.0 g, 20.57 mmol) was dissolved in 50 mL of dichloromethane and cooled to 0 °C. The solution was treated with triethylamine (10.41 g, 102.84 mmol), 4-dimethylaminopyridine (3.77 g, 30.85 mmol), and difluorocyclohexanecarbonyl chloride (7.50 g, 41.02 mmol) and then stirred under nitrogen at 15 °C for 16 hours. The yellow suspension was diluted with 50 mL of water, the pH adjusted to 3 with 1 M aqueous hydrogen chloride, and extracted with 50 mL of dichloromethane. The organic layer was washed with 50 mL of saturated aqueous sodium bicarbonate, brine, collected, dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography eluting with 0% to 10% ethyl acetate in petroleum ether to give the compound as a yellow oil (7.85 g, 98%).

[0277] The following compounds in Table 1 were prepared in a similar manner to that described in Intermediate 6. [Table 2]

[0278] Intermediate 7: 1-(3-bromo-2-hydroxy-5-methyl-phenyl)-3-cyclohexyl-propane-1,3-dione [ka]

[0279] A mixture of 1-(3-bromo-2-hydroxy-5-methyl-phenyl)ethanone (1 g, 4.37 mmol) in 10 mL of THF was cooled to 0 °C in an ice bath. Once cooled, the reaction was treated with lithium diisopropylamide (2 M, 1.40 g, 13.10 mmol) and stirred at 0 °C. After 30 min, the reaction was treated with a solution of methylcyclohexanecarboxylate (1.24 g, 8.73 mmol) in 5 mL of THF. After the addition was complete, the reaction was stirred at room temperature for 16 h. The resulting yellow solution was diluted with saturated aqueous ammonium chloride (20 mL) and extracted twice with 20 mL of ethyl acetate. The combined organics were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography, eluting with 0% to 5% ethyl acetate in petroleum ether, to give the product (0.70 g, 48%) as a yellow oil. MS ES+m / z 339[M+H] + .

[0280] Intermediate 8: 1-(3-bromo-2-hydroxy-5-methyl-phenyl)-3-(4,4-dimethylcyclohexyl)propane-1,3-dione [ka]

[0281] A solution of 1-(3-bromo-2-hydroxy-5-methyl-phenyl)ethanone (0.50 g, 2.18 mmol) and methyl 4,4-dimethylcyclohexanecarboxylate (0.45 g, 2.62 mmol) in 20 mL of THF was cooled to 0 °C and treated portionwise with sodium hydride (0.26 g, 60%, 6.55 mmol). After the addition was complete, the reaction was stirred at room temperature for 32 h. The reaction was carefully quenched with 20 mL of water and extracted three times with 20 mL of dichloromethane. The combined organics were washed with brine, collected, dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography eluting with 0% to 17% ethyl acetate in petroleum ether to give the product as a yellow solid (0.50 g, 62%). MS ES+ m / z 369 [M+H] + .

[0282] The following compounds in Table 2 were prepared in a similar manner to that described in Intermediate 8. [Table 3]

[0283] Intermediate 13: 8-Bromo-2-(4,4-difluorocyclohexyl)-3,6-dimethyl-chromen-4-one [ka]

[0284] (2-Bromo-4-methyl-6-propanoyl-phenyl) 4,4-difluorocyclohexanecarboxylate (4.0 g, 10.28 mmol) was dissolved in 40 mL of 2-methyltetrahydrofuran and cooled to 0 °C. Once cooled, the reaction was treated with sodium hydride (1.23 g, 60 wt%, 30.83 mmol), then removed from the cooling bath and stirred at 80 °C for 1 hour. The reaction was quenched with 80 mL of saturated aqueous ammonium chloride solution and extracted three times with 80 mL of ethyl acetate. The organic layers were combined, washed with 100 mL of brine, collected, dried over Na SO , filtered, and concentrated to give the product (4 g, crude) without further purification. MS ES+ m / z 373 [M+H] + .

[0285] Intermediate 14: 8-Bromo-2-cyclohexyl-6-methyl-chromen-4-one [ka]

[0286] A mixture of 1-(3-bromo-2-hydroxy-5-methyl-phenyl)-3-cyclohexyl-propane-1,3-dione (0.50 g, 1.47 mmol) in acetic acid (5 mL) was treated with sulfuric acid (1 mL) and stirred at 100 °C for 1 h. The reaction was cooled to room temperature, poured into 20 mL of ice water, and extracted three times with 20 mL of ethyl acetate. The combined organics were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography eluting with 0% to 5% ethyl acetate in petroleum ether to give the product (0.24 g, 51%) as a light yellow solid, which was used in the next synthetic step without spectral analysis.

[0287] The following compounds in Table 3 were prepared in a similar manner to that described in Intermediate 14. [Table 4]

[0288] Intermediate 20: 8-Acetyl-2-cyclohexyl-6-methyl-chromen-4-one [ka]

[0289] A mixture of 8-bromo-2-cyclohexyl-6-methyl-chromen-4-one (0.34 mg, 1.06 mmol) in 1,4-dioxane (8 mL) was treated with tributyl(1-ethoxyvinyl)stannane (1.14 g, 3.16 mmol) and bis(triphenylphosphine)palladium(II) chloride (0.074 g, 0.011 mmol) under a nitrogen atmosphere, and the reaction was stirred at 95 °C for 16 h. The resulting black suspension was treated with 4 mL of aqueous hydrogen chloride (2 M) and stirred at 25 °C for 1 h. The reaction was then diluted with 20 mL of saturated aqueous potassium fluoride and 20 mL of ethyl acetate, filtered, and the solid washed with 20 mL of ethyl acetate. The layers of the filtrate were separated, and the aqueous layer was re-extracted with 20 mL of ethyl acetate. The combined organics were washed with saturated aqueous sodium bicarbonate (30 mL), brine (30 mL), collected, dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography eluting with 0% to 25% ethyl acetate in petroleum ether to give the product as a white solid (0.24 g, 80%). MS ES+ m / z 285 [M+H] + .

[0290] The following compounds in Table 4 were prepared in a similar manner to that described in Intermediate 20. [Table 5]

[0291] Intermediate 27: 2-Cyclohexyl-8-(1-hydroxyethyl)-6-methyl-chromen-4-one [ka]

[0292] A solution of 8-acetyl-2-cyclohexyl-6-methyl-chromen-4-one (0.24 g, 0.84 mmol) in dichloromethane (4 mL) and methanol (2 mL) was treated with sodium borohydride (0.035 g, 0.93 mmol), and the reaction was stirred at room temperature for 1 hour. The reaction was quenched with 15 mL of water and then extracted twice with 20 mL of dichloromethane. The combined organics were washed with 30 mL of brine, collected, dried over Na2SO4, filtered, and concentrated to give the product (0.24 g, 99%) as a white solid. MS ES+ m / z 287 [M+H] + .

[0293] The following compounds in Table 5 were prepared in a similar manner to that described in Intermediate 27. [Table 6]

[0294] Intermediate 34: 8-(1-Bromoethyl)-2-cyclohexyl-6-methyl-chromen-4-one [ka]

[0295] A mixture of 2-cyclohexyl-8-(1-hydroxyethyl)-6-methyl-chromen-4-one (0.12 g, 0.42 mmol) in 5 mL of dichloromethane was cooled to 0 °C and treated dropwise with phosphorus tribromide (0.34 g, 1.26 mmol). After the addition was complete, the reaction was stirred at room temperature for 16 hours. The reaction was cooled to 0 °C, treated with 2 mL of water, and the pH was adjusted to 8 with saturated aqueous sodium bicarbonate. The mixture was extracted twice with 15 mL of dichloromethane. The combined organics were washed with 20 mL of brine, collected, dried over Na2SO4, filtered, and concentrated to give the product (0.13 g, 90%) as a green solid. MS ES+ m / z 351 [M+H] + .

[0296] The following compounds in Table 6 were prepared in a similar manner to that described in Intermediate 34. [Table 7]

[0297] Intermediate 41: Methyl 2-[1-(2-cyclohexyl-4-oxo-chromen-8-yl)ethylamino]benzoate [ka]

[0298] A mixture of 8-(1-bromoethyl)-2-cyclohexyl-chromen-4-one (0.10 g, 0.30 mmol) and methyl 2-aminobenzoate (0.09 g, 0.60 mmol) in 2 mL of DMF was stirred at 80 °C for 16 h. It was combined with an equal amount of the second reaction and concentrated. The residue was purified by silica gel chromatography eluting with 0% to 22% ethyl acetate in petroleum ether to give the product as a yellow oil (0.25 g, 82%). MS ES+ m / z 406 [M+H] + .

[0299] Intermediate 42: tert-butyl 2-[1-[2-(4,4-difluorocyclohexyl)-6-methyl-4-oxo-chromen-8-yl]ethylamino]benzoate [ka]

[0300] 8-(1-Bromoethyl)-2-(4,4-difluorocyclohexyl)-6-methyl-chromen-4-one (0.10 g, 0.26 mmol) was dissolved in 3 mL of DMF, treated with tert-butyl 2-aminobenzoate (0.075 g, 0.39 mmol), and stirred at 80 °C for 16 h. The mixture was diluted with 10 mL of ice water and filtered to give a gray solid. The solid was diluted with ethyl acetate, dried over Na SO , filtered, and concentrated to give the product (0.10 g, 77%) as a gray solid. MS ES+ m / z 498 [M+H] + .

[0301] The following compounds in Table 7 were prepared in a similar manner to that described in Intermediate 42. [Table 8]

[0302] Example 1: 2-[1-(2-cyclohexyl-4-oxo-chromen-8-yl)ethylamino]benzoic acid [ka]

[0303] A mixture of methyl 2-[1-(2-cyclohexyl-4-oxo-chromen-8-yl)ethylamino]benzoate (0.20 g, 0.48 mmol) in 3 mL of methanol and 0.5 mL of water was treated with sodium hydroxide (0.08 g, 1.93 mmol) and stirred at 45° C. for 16 hours. The reaction was concentrated and purified by preparative HPLC using acetonitrile and water (containing 0.05% ammonia hydroxide) to give the product (0.13 g, 69%) as a white solid. MS ES+ m / z 392 [M+H] + .

[0304] Example 2: 2-[1-[2-(4,4-difluorocyclohexyl)-6-methyl-4-oxo-chromen-8-yl]ethylamino]benzoic acid [ka]

[0305] tert-Butyl 2-[1-[2-(4,4-difluorocyclohexyl)-6-methyl-4-oxo-chromen-8-yl]ethylamino]benzoate (0.10 g, 0.20 mmol) was dissolved in 10 mL of dichloromethane, treated with trifluoroacetic acid (3.08 g, 27.01 mmol), and stirred at 20 °C for 16 h. The reaction was concentrated, and the residue was purified by reverse-phase chromatography (C18-6, 30 x 100 mm, 5 μm) eluting with 52% to 82% acetonitrile in water (with trifluoroacetic acid) to give the product (0.06 g, 66%) as a white solid. MS ES + m / z 442[M+H] + .

[0306] The following compounds in Table 8 were prepared in a manner similar to that described in Example 2. [Table 9]

[0307] Example 5: 2-[1-(2-cyclohexyl-6-methyl-4-oxo-chromen-8-yl)ethylamino]benzoic acid [ka]

[0308] A mixture of 8-(1-bromoethyl)-2-cyclohexyl-6-methyl-chromen-4-one (0.12 g, 0.34 mmol) and 2-aminobenzoic acid (0.094 g, 0.69 mmol) in 1 mL of DMF was stirred at 80° C. for 14 h. The resulting brown suspension was diluted with 1 mL of DMF and purified by preparative HPLC to give the product (0.06 g, 43%) as a white solid. MS ES+ m / z 406 [M+H] + .

[0309] The following compounds in Table 9 were prepared in a manner similar to that described in Example 5. [Table 10]

[0310] Examples 8 and 9: 2-[1-(2-cyclohexyl-6-methyl-4-oxo-chromen-8-yl)ethylamino]benzoic acid, isomer 1 and isomer 2 [ka]

[0311] 2-[1-(2-Cyclohexyl-6-methyl-4-oxo-chromen-8-yl)ethylamino]benzoic acid (0.06 g, 0.15 mmol) was separated by reverse-phase chromatography using a Phenomenex Gemini-NX C18 column (75 x 30 mm, 3 um) eluted with 41% to 81% acetonitrile in water (containing 0.225% TFA) to give Isomer 1 (17.2 mg, 29%) and Isomer 2 (16.7 mg, 28%) as white solids. MS ES+ m / z 406 [M+H] + .

[0312] The following compounds in Table 10 were prepared in a manner similar to that described in Examples 8 and 9. [Table 11-1] [Table 11-2] a Compounds were separated using a Daicel Chiralpak AD-H (250 x 30 mm, 10 um) column eluted with 25% EtOH (containing 0.1% NH4OH) in CO2. b Compounds were separated using a Daicel Chiralcel OJ (250 x 30 mm, 10 um) column eluted with 20% MeOH (containing 0.1% NH4OH) in CO2. c Compounds were separated using a Daicel Chiralpak AS (250 x 30 mm, 10 um) column eluted with 45% EtOH (containing 0.1% NH4OH) in CO2. dCompounds were separated using a (S,S) Whelk-O1 (250 x 30 mm, 5 um) column eluted with 40% EtOH (containing 0.1% NH4OH) in CO2. e Compounds were separated using a Daicel Chiralpak AS (250 x 30 mm, 10 um) column eluted with 40% EtOH (containing 0.1% NH4OH) in CO2. f Compounds were separated using a Daicel Chiralcel OD (250 x 30 mm, 10 um) column eluted with 50% MeOH (containing 0.1% NH4OH) in CO2.

[0313] Determination of PI3K-alpha kinase (PIK3CA) activity, wild-type and H1047R mutant, and IC50 values ​​of inhibitors Recombinant, catalytically active human full-length PIK3KA wild-type and H1047R mutant were purchased from EMD Millipore Sigma (catalyst, catalog numbers 14-602M and 14-792M, respectively) as 1:1 complexes of N-terminal 6xHis-tagged p110α (catalytic) and untagged p85α (regulatory subunit). PIP2diC8 (Avanti Polar Lipids Inc., catalog number 850185) or Soy PI (Avanti Polar Lipids Inc., catalog number 840044P) were used as lipid substrates. PIP2diC8 or PI lyophilized powder was dissolved in milliQ water to a concentration of 1 mM immediately before use. 10 mM stock compounds in DMSO were serially diluted 1:3 to generate 10-point curves and plated using an acoustic liquid handler system (Echo 550 series instrument, Labcyte). Before starting the reaction, a 10x intermediate compound plate (starting compound concentration 200 μM and 10% DMSO) was prepared. A typical reaction mixture (50 μL) contained 40 mM HEPES buffer, pH 7.4, 25 mM MgCl2, 0.01% v / v Triton-X-100, 1% v / v DMSO, 20 mM NaCl, 1–5 nM WT or H1047R PI3K protein, 20 μM ATP, and 50 μM PIP2diC8 or SoyPI. 1% DMSO buffer alone without test compound served as a maximum control (full activity in the absence of inhibitor), and a no enzyme control was used to determine background adenosine 5'-diphosphate (ADP) levels (minimum control). First, wild-type (WT) and H1047R mutant proteins were incubated in kinase buffer containing all components except ATP in the presence or absence of compounds at 27°C for 1 h. After preincubation, the reaction was initiated by adding 20 μL of 50 μM ATP (final concentration 20 μM). The reaction was allowed to proceed at 27°C until approximately 10% conversion of ATP (2 μM ADP). The reaction was then stopped by mixing 5 μL of the reaction with 5 μL of ADP-Kinase Glo Reagent (ADP-Glo ​​Kinase Assay Kit, Promega catalog no. V9102) supplemented with 10 mM MgCl2 and allowing the remaining ATP to deplete for 40 min at room temperature.Next, 10 μL of kinase detection reagent (ADP-Glo ​​Kinase Assay Kit, Promega catalog number V9102) was added to simultaneously convert ADP to ATP, allowing the measurement of newly synthesized ATP using a luciferase / luciferin reaction. After 30 min at room temperature, light generated was measured using a luminometer (EnVision plate reader, Perkin Elmer). Data were processed using the Genedata-Screener tool. Relative IC was calculated. 50 Values ​​are determined by calculating percent inhibition relative to the "min" and "max" controls on 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 / IC50) slope] where Y = % inhibition, X = concentration resulting in y % inhibition, bottom = minimum value of y reached by the curve, top = maximum value of y reached by the curve, and slope = gradient of the curve at IC50. Inhibition % = [(Maximum Median - x / Maximum Median - Minimum Median)] 100 IC50: The concentration of a compound that reduces a given response (ligand binding, enzyme response) by 50%. Relative IC50: The concentration that gives half the maximal response of a compound.

[0314] ICs shown in Table A 50 For values, "A" indicates an IC less than 0.5 μM 50 "B" means IC in the range of 0.5 μM to 1.0 μM 50 "C" means IC in the range of 1 μM to 5 μM 50 "D" means IC in the range of 5 μM to 10 μM. 50 "E" means IC > 10 μM 50 means.

[0315] [Table 12] 1 PIP2diC8 lipid substrate *Regarding Example 9, IC 50 WT / IC 50 H1047R=5.5 The present invention includes the following aspects. [Item 1] formula: [ka] or a pharmaceutically acceptable salt thereof, wherein R is -H or C 1 ~C 3 is alkyl, R 1 is a group of the formula: [ka] R 2 are 1 to 3 R 10 cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl optionally substituted by substituents, or R 2 is a group of the formula: [ka] R 3 -H, halogen, -CN, C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 3 ~C 5 a cycloalkyl, a heterocycle of 3 to 5 ring atoms containing 1, 2, or 3 ring heteroatoms independently selected from N, O, or S, or a heteroaryl of 5 ring atoms containing 1, 2, or 3 ring heteroatoms independently selected from N, O, or S; R 4 、R 5 , and R 6 each independently represents -H, a halogen, or C 1 ~C 6 Alkyl, or C 1 ~C 6 is haloalkyl, R 7 But -CN, C 1 ~C 6 Alkyl or C 1 ~C 6 is haloalkyl, R 8 is -H or C 1 ~C 6 is alkyl, Each R 9 are independently -H, halogen, C 1 ~C 6 Alkyl, C 1 ~C6 Haloalkyl, C 1 ~C 6 Alkoxy or C 3 ~C 5 is cycloalkyl, Each R 10 are independently -H, -CN, halogen, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Alkoxy, C 1 ~C 6 Haloalkoxy, -SO 2 R 11 , -CONR 11 R 11 , -NR 11 R 11 , -NR 11 -CO 2 R 11 , —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 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-benzodioxine, or an optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole, or thiazole, wherein said optionally substituted C 1 ~C 6 Alkyl, C 2 ~C 6 Alkenyl, or C 2 ~C 6 Alkynyl is -CN, -OH, oxetanyl, or C 1 ~C 3 Optionally substituted with alkoxy, said optionally substituted C 3 ~C 5 Cycloalkyl, phenyl, 1,3-benzodioxole, 2,3-dihydro-1,4-benzodioxine, heterocycle, or heteroaryl may each be 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 R 11 are independently -H or C 1 ~C 3 alkyl, or a pharmaceutically acceptable salt thereof. [Item 2] formula:

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Claims

1. formula: 【Chemical 1】 or a pharmaceutically acceptable salt thereof, wherein R is —H; R １ is a group of the formula: 【Chemistry 2】 R ２ is a group of the formula: 【Chemistry 3】 R ３ is —H or methyl; R 4 is —H; R 5 is —H or methyl; R 6 is —H; R ７ is methyl, R ８ is -H, Each R ９ is -H, Each R １０ is independently —H, fluoro, or methyl, or a pharmaceutically acceptable salt thereof.

2. formula: 【Chemistry 4】 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, having the formula:

3. The compound of claim 1 selected from: 【Chemistry 5】 or a pharmaceutically acceptable salt thereof.

4. The compound of claim 1 selected from: 【Chemistry 6】 or a pharmaceutically acceptable salt thereof.

5. A pharmaceutical composition comprising the compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

6. A drug for treating a disease or disorder associated with the regulation of phosphoinositide 3-kinase (PI3K), comprising a compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof.

7. The agent according to claim 6, wherein the PI3K is PI3Kα.

8. The method of claim 7, wherein the PI3K associated with the disease or disorder has an H1047R mutation.

9. The method of claim 6 , wherein the disease or disorder is cancer.

10. 10. The method of claim 9, 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.

11. 7. The method of claim 6, wherein the disease or disorder is CLOVES syndrome (congenital lipomatous overgrowth, vascular malformations, epidermal nevi, scoliosis / skeletal and spinal syndrome) or PIK3CA-associated overgrowth syndrome (PROS).

12. A drug for inhibiting phosphoinositide 3-kinase (PI3K), comprising the compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof.

13. A medicament for treating cancer or a disorder, comprising a compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof.

14. 14. The method of claim 13, 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.

15. 14. The method of claim 13, wherein the disorder is CLOVES syndrome (congenital lipomatous overgrowth, vascular malformations, epidermal nevi, scoliosis / skeletal and spinal syndrome) or PIK3CA-associated overgrowth syndrome (PROS).

16. 10. Use of a compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a disease associated with the modulation of PI3K.

17. The use according to claim 16, wherein the disease associated with the regulation of PI3K is cancer.

18. 18. The use of claim 17, 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.

19. 17. The use according to claim 16, wherein the disease is CLOVES syndrome (congenital lipomatous overgrowth, vascular malformations, epidermal nevi, scoliosis / skeletal and spinal syndrome) or PIK3CA-associated overgrowth syndrome (PROS).

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