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

Abstract

Compounds are provided as allosteric chromenone inhibitors of phosphoinositide 3-kinase (PI3K), useful for the treatment of diseases or disorders associated with PI3K regulation. The present disclosure provides a compound of formula (I): TIFF2026004333000763.tif53128 The present invention relates to compounds of formula (I), or pharmaceutically acceptable salts thereof, as allosteric chromenone inhibitors of phosphoinositide 3-kinase (PI3K), useful for the treatment of diseases or disorders associated with PI3K regulation.

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-related overgrowth syndrome (PROS), breast cancer, brain cancer, prostate cancer, endometrial cancer, gastric cancer, leukemia, lymphoma, sarcoma, colorectal cancer, lung cancer, ovarian cancer, skin cancer, or head and neck cancer), and uses of PI3K inhibitors in combination with one or more additional cancer therapies. [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 of genes 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, other neuroepithelial tumors, thyroid cancer, leukemia, and encapsulated glioma (Goncalves MD, Hopkins BD, Cantley LC. Phosphatidylinositol 3-Kinase, Growth Hormone Signaling, 1999). Disorders, and Cancer.N Engl J Med.2018 Nov 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 difficult to achieve 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 for selective PI3Kα inhibition. 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] [In the formula, R is —H or C1-C3 alkyl; R1 is a group having the formula: [ka] is the basis of R2 is a compound of the formula: [ka] or R2 is an optionally substituted 5-membered heteroaryl selected from pyrrole, furan, thiophene, pyrazole, isoxazole, isothiazole, imidazole, oxazole, thiazole, triazole, tetrazole, oxadiazole, and thiadiazole, and the optionally substituted 5-membered heteroaryl is selected from -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R 11 , -C(O)OC1-C3 alkyl, -CONR 11 R 11 , -NR 11 R 11 , -NR 11 CO2R 11, —OH, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C5 cycloalkyl, an optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine, or morpholine, optionally substituted phenyl, optionally substituted 1,3-benzodioxole, optionally substituted 2,3-dihydro-1,4-benzodioxine, or pyridine, pyridinone, optionally substituted 2,3-dihydro-1,4-benzodioxine, or pyridine, pyridinone, optionally substituted 2,3-dihydro-1,4-benzodioxine, or pyridine, pyridinone, optionally substituted 2,3-dihydro-1,4-benzodioxine, or pyridine, pyridinone, optionally substituted 2,3-dihydro-1,4-benzodioxine, or pyridinone, optionally substituted 2,3-dihydro-1,4-benzodioxine, optionally substituted 2,3-dihydro-1,4-benzodioxine, or pyridine, ... optionally substituted with 1 to 3 substituents independently selected from optionally substituted heteroaryl selected from imidazole, pyridazine, pyrazine, pyrazole, isoxazole, isothiazole, imidazole, oxazole, and thiazole, wherein the optionally substituted C1-C6 alkyl, the optionally substituted C2-C6 alkenyl, or the optionally substituted C2-C6 alkynyl is each independently selected from -CN, -OH, oxetanyl, C1-C3 alkoxy, or -CONR 11 R 11 and the optionally substituted C3-C5 cycloalkyl, phenyl, 1,3-benzodioxole, 2,3-dihydro-1,4-benzodioxine, heterocycle, or heteroaryl is each independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -SO2R 11 , -NR 11 R 11 , —OH, or —CN; R3 is -H, halogen, -CN, -N(H)(C-C alkyl), -N(C-C alkyl), -N(H)(CHCHCOH), -C(O)C-C alkyl, C-C alkyl, C-C haloalkyl, C-C hydroxyalkyl, C-C cycloalkyl, an optionally substituted heterocycle having 3 to 5 ring atoms including 1, 2, or 3 ring heteroatoms independently selected from N, O, or S, or an optionally substituted heteroaryl having 5 or 6 ring atoms including 1, 2, or 3 ring heteroatoms independently selected from N, O, or S, wherein the optionally substituted heterocycle or the optionally substituted heteroaryl is each optionally substituted with 1 to 3 substituents each independently selected from halogen, C-C alkyl, or C-C haloalkyl; R4, R5, and R6 are each 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; R9 is, independently at each occurrence, -H, halogen, -CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C3-C5 cycloalkyl; R 10 are each independently -H, -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R 11 , -C(O)OC1-C3 alkyl, -CONR 11 R 11 , -NR 11 R 11 , -NR 11 -CO2R 11, —OH, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C5 cycloalkyl, an optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine, or morpholine, optionally substituted phenyl, optionally substituted 1,3-benzodioxole, optionally substituted 2,3-dihydro-1,4-benzodioxine, or optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole, or thiazole, wherein the optionally substituted C1-C6 alkyl, the optionally substituted C2-C6 alkenyl, or the optionally substituted C2-C6 alkynyl is each selected from —CN, —OH, oxetanyl, C1-C3 alkoxy, or —CONR 11 R 11 and the optionally substituted C3-C5 cycloalkyl, phenyl, 1,3-benzodioxole, 2,3-dihydro-1,4-benzodioxine, heterocycle, or heteroaryl is each independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -SO2R 11 , -NR 11 R 11 , —OH, or —CN; R 11 are each independently -H or C1-C3 alkyl, or a pharmaceutically acceptable salt thereof.

[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 for 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 disease or 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, diseases or disorders associated with PI3K 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 cancer, nerve sheath cancer, and ovarian cancer. tumors, including, but not limited to, 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, other neuroepithelial tumors, 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 expressly defined otherwise, 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 specifically defined, refers to a monovalent monocyclic or polycyclic aromatic radical having 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 can contain two or more fused rings and further include two or more spiro-fused rings, e.g., bicyclic, tricyclic, tetracyclic, etc. Unless otherwise specifically defined, "fused" means two rings that share two ring atoms. Unless otherwise specifically defined, "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 "hydroxyalkyl" refers to an alkyl group, as defined herein, substituted with a hydroxy group.

[0057] The term "isomer" refers to compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the spatial arrangement of their atoms. Isomers that differ in the spatial arrangement of their atoms are called "stereoisomers." Stereoisomers that are not mirror images of each other are called "diastereomers," and stereoisomers that are non-superimposable mirror images of each other are called "enantiomers." When a compound has an asymmetric center, for example, when a compound is bonded to four different groups, a pair of enantiomers is possible. Enantiomers can be characterized by the absolute configuration of their asymmetric center and described by the R and S ordering rules of Cahn and Prelog, or by the way the molecule rotates the plane of polarized light and is designated as dextrorotatory or levorotatory (i.e., as (+) or (-)-isomers, respectively). Chiral compounds can exist as either individual enantiomers or as mixtures thereof. A mixture containing equal proportions of enantiomers is called a "racemic mixture."

[0058] The terms "modulate," "modulation," or "modulating" refer to the biological activity of a compound or substrate that inhibits and / or activates PI3K.

[0059] 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.

[0060] The term "therapeutically effective amount" when used in connection with 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 under 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 consider several factors, including, but not limited to, the patient's species; its size, age, and general health; the specific disease or disorder involved; the extent or involvement or severity of the disease or disorder; the individual patient's response; the specific compound administered; the mode of administration; the bioavailability characteristics of the administered formulation; the selected dosing regimen; the use of concomitant medications; and other relevant circumstances.

[0061] The term "treating" with respect to a subject includes inhibiting, slowing, arresting, or reversing the progression or severity of an existing condition or disorder.

[0062] 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 for formula (I).

[0063] 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 for formula (I).

[0064] In the compound of formula (I) or a pharmaceutically acceptable salt thereof, R is —H or C1-C3 alkyl; R1 is a group represented by the formula: [ka] is the basis of R2 has the formula: [ka] or R2 is an optionally substituted 5-membered heteroaryl selected from pyrrole, furan, thiophene, pyrazole, isoxazole, isothiazole, imidazole, oxazole, thiazole, triazole, oxadiazole, and thiadiazole, and the optionally substituted 5-membered heteroaryl is selected from -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R 11 , -CONR 11 R 11 , -NR 11 R 11 , -NR 11 CO2R 11, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C5 cycloalkyl, an optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine, or morpholine, optionally substituted phenyl, optionally substituted 1,3-benzodioxole, optionally substituted 2,3-dihydro-1,4-benzodioxine, or an optionally substituted heterocycle selected from pyridine, pyrimidine, pyridazine, pyrazine, pyrazole, isoxazole, isothiazole, imidazole, oxazole, or thiazole. and optionally substituted heteroaryl, each of the optionally substituted C1-C6 alkyl, the optionally substituted C2-C6 alkenyl, or the optionally substituted C2-C6 alkynyl is optionally substituted with -CN, -OH, oxetanyl, or C1-C3 alkoxy, and each of the 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; R3 is -H, halogen, -CN, C1-C6 alkyl, C1-C6 haloalkyl, C3-C5 cycloalkyl, a heterocycle having 3 to 5 ring atoms including 1, 2, or 3 ring heteroatoms independently selected from N, O, or S, or a heteroaryl having 5 ring atoms including 1, 2, or 3 ring heteroatoms independently selected from N, O, or S; R4, R5, and R6 are each 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; R9 is, independently at each occurrence, -H, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C3-C5 cycloalkyl; R 10 are each 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 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 any group selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole, or thiazole. optionally substituted heteroaryl, wherein the optionally substituted C1-C6 alkyl, the optionally substituted C2-C6 alkenyl, or the optionally substituted C2-C6 alkynyl are each optionally substituted with -CN, -OH, oxetanyl, or C1-C3 alkoxy; and the optionally substituted C3-C5 cycloalkyl, phenyl, 1,3-benzodioxole, 2,3-dihydro-1,4-benzodioxine, heterocycle, or heteroaryl are each 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; R 11 are each independently —H or C1-C3 alkyl.

[0065] In the compound of formula (I) or a pharmaceutically acceptable salt thereof, R is —H or C1-C3 alkyl; R1 is a group represented by the formula: [ka] is the basis of R2 has the formula: [ka] or R2 is an optionally substituted 5-membered heteroaryl selected from pyrrole, furan, thiophene, pyrazole, isoxazole, isothiazole, imidazole, oxazole, thiazole, triazole, oxadiazole, and thiadiazole, and the optionally substituted 5-membered heteroaryl is selected from -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R 11 , -CONR 11 R 11 , -NR 11 R 11 , -NR 11 CO2R 11 optionally substituted with 1 to 3 substituents each independently selected from optionally substituted C1-C6 alkyl, optionally substituted C3-C5 cycloalkyl, an optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine, or morpholine, optionally substituted phenyl, or an optionally substituted heteroaryl selected from pyridine, 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 independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -NR 11 R11 , —OH, or —CN; R3 is -H, -CN, C1-C6 alkyl, or C1-C6 haloalkyl; R4, R5, and R6 are each 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; R9 is, independently at each occurrence, -H, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C3-C5 cycloalkyl; R 10 are each 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, an 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; R 11are each independently —H or C1-C3 alkyl.

[0066] In the compound of formula (I) or a pharmaceutically acceptable salt thereof, R is independently —H or C1-C3 alkyl; R1 is a group represented by the formula: [ka] is the basis of R3 is -H, -CN, C1-C6 alkyl, or C1-C6 haloalkyl; R4, R5, and R6 are each 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; R9 is, independently at each occurrence, -H, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C3-C5 cycloalkyl; R 10 are each 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, an optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine, or morpholine, optionally substituted phenyl, or an 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; R 11 are each independently —H or C1-C3 alkyl.

[0067] In the compounds of formula (I) or formula (II), or pharmaceutically acceptable salts thereof, R2 is a group of the formula: [ka] is the basis of R 10 are each 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 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 any group selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole, or thiazole. optionally substituted heteroaryl, wherein the optionally substituted C1-C6 alkyl, the optionally substituted C2-C6 alkenyl, or the optionally substituted C2-C6 alkynyl are each optionally substituted with -CN, -OH, oxetanyl, or C1-C3 alkoxy; and the optionally substituted C3-C5 cycloalkyl, phenyl, 1,3-benzodioxole, 2,3-dihydro-1,4-benzodioxine, heterocycle, or heteroaryl are each 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.

[0068] In the compounds of formula (I) or formula (II), or pharmaceutically acceptable salts thereof, R2 is a group of the formula: [ka] is the basis of R 10 are each 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, an 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; R 11 are each independently —H or C1-C3 alkyl.

[0069] In the compounds of formula (I) or formula (II), or pharmaceutically acceptable salts thereof, R2 is a group of the formula: [ka] is the basis of R 10 are each 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, an optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine, or morpholine, optionally substituted phenyl, or an 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; R 11 are each independently —H or C1-C3 alkyl.

[0070] In the compounds of formula (I) or formula (II), or pharmaceutically acceptable salts thereof, R2 is a group of the formula: [ka] is the basis of

[0071] R 10 are each independently -H, -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, -SO2R 11, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C5 cycloalkyl, or optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole, or thiazole, wherein the optionally substituted C1-C6 alkyl or the optionally substituted C2-C6 alkynyl is optionally substituted with -CN, -OH, or C1-C3 alkoxy, and the optionally substituted C3-C5 cycloalkyl or the optionally substituted heteroaryl is selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -NR 11 R 11 , —OH, or —CN.

[0072] In the compounds of formula (I) or formula (II), or pharmaceutically acceptable salts thereof, R2 is a group of the formula: [ka] is the basis of R 10 are each independently -H, -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, -SO2R 11 , optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkynyl, or optionally substituted C3-C5 cycloalkyl, wherein the optionally substituted C1-C6 alkyl or the optionally substituted C2-C6 alkynyl is optionally substituted with -CN, -OH, or C1-C3 alkoxy, and the optionally substituted C3-C5 cycloalkyl is halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -NR 11 R 11 , —OH, or —CN.

[0073] In the compounds of formula (I) or formula (II), or pharmaceutically acceptable salts thereof, R2 is a group of the formula: [ka] is the basis of R 10 are each independently -H, -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, -SO2R 11 , C1-C6 alkyl, C2-C6 alkynyl optionally substituted with —OH, C3 cycloalkyl optionally substituted with —CN, or pyrazole optionally substituted with 1 to 3 substituents each independently selected from C1-C3 alkyl.

[0074] In the compounds of formula (I) or formula (II), or pharmaceutically acceptable salts thereof, R2 is a group of the formula: [ka] is the basis of R 10 are each independently -H, -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, -SO2R 11 , C1-C6 alkyl, C2-C6 alkynyl optionally substituted with -OH, or C3 cycloalkyl optionally substituted with -CN.

[0075] In the compounds of formula (I) or formula (II), or pharmaceutically acceptable salts thereof, R2 is a group of the formula: [ka] is the basis of R 10 are each independently [ka] is.

[0076] In the compound of formula (I) or formula (II), or a pharmaceutically acceptable salt thereof, R2 has the formula: [ka] is the basis of R 10 are each independently [ka] is.

[0077] In the compounds of formula (I) or formula (II), or pharmaceutically acceptable salts thereof, R2 is a group of the formula: [ka] is the basis of

[0078] In the compounds of formula (I) or formula (II), or pharmaceutically acceptable salts thereof, R2 is a group of the formula: [ka] is the basis of

[0079] In the compound of formula (I) or formula (II), or a pharmaceutically acceptable salt thereof, R2 is an optionally substituted 5-membered heteroaryl selected from pyrrole, furan, thiophene, pyrazole, isoxazole, isothiazole, imidazole, oxazole, thiazole, triazole, oxadiazole, and thiadiazole, and the optionally substituted 5-membered heteroaryl is selected from -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R 11 , -CONR 11 R 11 , -NR 11 R 11 , -NR 11 CO2R 11, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C5 cycloalkyl, an optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine, or morpholine, optionally substituted phenyl, optionally substituted 1,3-benzodioxole, optionally substituted 2,3-dihydro-1,4-benzodioxine, or an optionally substituted heterocycle selected from pyridine, pyrimidine, pyridazine, pyrazine, pyrazole, isoxazole, isothiazole, imidazole, oxazole, or thiazole. and optionally substituted heteroaryl, each of the optionally substituted C1-C6 alkyl, the optionally substituted C2-C6 alkenyl, or the optionally substituted C2-C6 alkynyl is optionally substituted with -CN, -OH, oxetanyl, or C1-C3 alkoxy, and each of the 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.

[0080] In the compound of formula (I) or formula (II), or a pharmaceutically acceptable salt thereof, R2 is an optionally substituted 5-membered heteroaryl selected from pyrrole, furan, thiophene, pyrazole, isoxazole, isothiazole, imidazole, oxazole, thiazole, triazole, oxadiazole, and thiadiazole, and the optionally substituted 5-membered heteroaryl is selected from -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R 11 , -CONR 11 R 11, -NR 11 R 11 , -NR 11 CO2R 11 optionally substituted with 1 to 3 substituents each independently selected from optionally substituted C1-C6 alkyl, optionally substituted C3-C5 cycloalkyl, an optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine, or morpholine, optionally substituted phenyl, or an optionally substituted heteroaryl selected from pyridine, 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 independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -NR 11 R 11 , —OH, or —CN; R 11 are each independently —H or C1-C3 alkyl.

[0081] In the compound of formula (I) or formula (II), or a pharmaceutically acceptable salt thereof, R2 is an optionally substituted 5-membered heteroaryl selected from pyrrole, furan, thiophene, pyrazole, isoxazole, isothiazole, imidazole, oxazole, thiazole, triazole, oxadiazole, and thiadiazole, and the optionally substituted 5-membered heteroaryl is C1-C6 haloalkyl, optionally substituted C1-C6 alkyl, optionally substituted phenyl, optionally substituted 1,3-benzodioxole, or pyridine, pyrimidine, pyridazine, pyrazine, pyrazole, isopropyl alcohol, or propyl alcohol. optionally substituted with 1 to 3 substituents independently selected from optionally substituted heteroaryl selected from isoxazole, isothiazole, imidazole, oxazole, or thiazole, wherein the optionally substituted C1-C6 alkyl is optionally substituted with -CN, -OH, oxetanyl, or C1-C3 alkoxy, and the optionally substituted phenyl, the optionally substituted 1,3-benzodioxole, or the optionally substituted heteroaryl is independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -SO2R 11 , -NR 11 R 11 , —OH, or —CN; R 11 are each independently —H or C1-C3 alkyl.

[0082] In the compound of formula (I) or formula (II), or a pharmaceutically acceptable salt thereof, R2 is an optionally substituted 5-membered heteroaryl selected from pyrrole, furan, thiophene, pyrazole, isoxazole, isothiazole, imidazole, oxazole, thiazole, triazole, oxadiazole, and thiadiazole, wherein the optionally substituted 5-membered heteroaryl is optionally substituted with 1 to 3 substituents each independently selected from C1-C6 haloalkyl, C1-C6 alkyl, optionally substituted phenyl, optionally substituted 1,3-benzodioxole, or optionally substituted heteroaryl selected from pyridine or pyrimidine, wherein the optionally substituted phenyl, the optionally substituted 1,3-benzodioxole, or the optionally substituted heteroaryl is each independently selected from halogen, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -SO2R 11 or —CN; R 11 are each independently —H or C1-C3 alkyl.

[0083] In the compound of formula (I) or formula (II), or a pharmaceutically acceptable salt thereof, R2 is an optionally substituted 5-membered heteroaryl selected from pyrrole, furan, thiophene, pyrazole, isoxazole, isothiazole, imidazole, oxazole, thiazole, triazole, oxadiazole, and thiadiazole, and the optionally substituted 5-membered heteroaryl is [ka] is optionally substituted with 1 to 3 substituents each independently selected from:

[0084] In the compound of formula (I) or formula (II), or a pharmaceutically acceptable salt thereof, R2 is an optionally substituted 5-membered heteroaryl selected from pyrrole, furan, thiophene, pyrazole, isoxazole, isothiazole, imidazole, oxazole, thiazole, triazole, oxadiazole, and thiadiazole, and the optionally substituted 5-membered heteroaryl is [ka] is optionally substituted with 1 to 3 substituents each independently selected from:

[0085] In the compounds of formula (I) or formula (II), or pharmaceutically acceptable salts thereof, R2 is a group of the formula: [ka] [ka] is the basis of

[0086] In the compounds of formula (I) or formula (II), or pharmaceutically acceptable salts thereof, R2 is a group of the formula: [ka] [ka] is the basis of

[0087] In still further compounds of Formula (I) or Formula (II), or pharmaceutically acceptable salts thereof, R3 is -H, halogen, -CN, -N(H)(CH2CH2CO2H), -C(O)C1-C3 alkyl, C1-C6 alkyl, C1-C6 haloalkyl, oxetane, isoxazole, or pyridine (preferably 3-pyridine). In still further compounds of Formula (I) or Formula (II), or pharmaceutically acceptable salts thereof, R3 is -H, halogen, -CN, C1-C6 alkyl, C1-C6 haloalkyl, C3-C5 cycloalkyl, a heterocycle having 3 to 5 ring atoms containing 1, 2, or 3 ring heteroatoms independently selected from N, O, or S, or a heteroaryl having 5 ring atoms containing 1, 2, or 3 ring heteroatoms independently selected from N, O, or S. In still further compounds of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, R3 is -H, halogen, -CN, C1-C6 alkyl, C1-C6 haloalkyl, oxetane, or isoxazole. In still further compounds of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, R3 is -H, -CN, C1-C6 alkyl, or C1-C6 haloalkyl. In still further compounds of Formula (I) or Formula (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 most preferably, R3 is -H or methyl. Also preferably, R3 is -H, methyl, or trifluoromethyl.

[0088] In still further compounds of formula (I) or formula (II), or a pharmaceutically acceptable salt thereof, R4 is -H or halogen, preferably R4 is -H.

[0089] In still further compounds of formula (I) or formula (II), or a pharmaceutically acceptable salt thereof, R5 is -H, -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.

[0090] In still further compounds of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, R6 is -H or halogen.

[0091] In still further compounds of Formula (I) or Formula (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 a group of the formula: [ka] or R2 is an optionally substituted 5-membered heteroaryl selected from pyrrole, furan, thiophene, pyrazole, isoxazole, isothiazole, imidazole, oxazole, thiazole, triazole, oxadiazole, and thiadiazole, and the optionally substituted 5-membered heteroaryl is selected from -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R 11 , -CONR 11 R 11 , -NR 11 R 11 , -NR 11 CO2R 11optionally substituted with 1 to 3 substituents each independently selected from optionally substituted C1-C6 alkyl, optionally substituted C3-C5 cycloalkyl, an optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine, or morpholine, optionally substituted phenyl, or an optionally substituted heteroaryl selected from pyridine, 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 independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -NR 11 R 11 , —OH, or —CN; R 10 are each 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, an optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine, or morpholine, optionally substituted phenyl, or an 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, —NR11 R 11 , —OH, or —CN; R 11 are each independently —H or C1-C3 alkyl.

[0092] In still further compounds of Formula (I) or Formula (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 a group of the formula: [ka] is the basis of R 10 are each 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, an optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine, or morpholine, optionally substituted phenyl, or an 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; R 11 are each independently —H or C1-C3 alkyl.

[0093] In still further compounds of formula (I) or formula (II), or a pharmaceutically acceptable salt thereof, R4 is -H or halogen (preferably, R4 is -H) and R2 is a group of the formula: [ka] or R2 is an optionally substituted 5-membered heteroaryl selected from pyrrole, furan, thiophene, pyrazole, isoxazole, isothiazole, imidazole, oxazole, thiazole, triazole, oxadiazole, and thiadiazole, and the optionally substituted 5-membered heteroaryl is selected from -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R 11 , -CONR 11 R 11 , -NR 11 R 11 , -NR 11 CO2R 11 optionally substituted with 1 to 3 substituents each independently selected from optionally substituted C1-C6 alkyl, optionally substituted C3-C5 cycloalkyl, an optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine, or morpholine, optionally substituted phenyl, or an optionally substituted heteroaryl selected from pyridine, 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 independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -NR 11 R 11 , —OH, or —CN; R 10are each 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, an optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine, or morpholine, optionally substituted phenyl, or an 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; R 11 are each independently —H or C1-C3 alkyl.

[0094] In still further compounds of formula (I) or formula (II), or a pharmaceutically acceptable salt thereof, R4 is -H or halogen (preferably, R4 is -H) and R2 is a group of the formula: [ka] is the basis of R 10 are each independently -H, -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R 11 , -CONR 11 R 11 , -NR 11 R 11 , -NR11 -CO2R 11 , optionally substituted C1-C6 alkyl, optionally substituted C3-C5 cycloalkyl, an optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine, or morpholine, optionally substituted phenyl, or an 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; R 11 are each independently —H or C1-C3 alkyl.

[0095] In still further compounds of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, R5 is -H, halogen, C1-C6 alkyl, or C1-C6 haloalkyl, and R2 is a group of the formula: [ka] or R2 is an optionally substituted 5-membered heteroaryl selected from pyrrole, furan, thiophene, pyrazole, isoxazole, isothiazole, imidazole, oxazole, thiazole, triazole, oxadiazole, and thiadiazole, and the optionally substituted 5-membered heteroaryl is selected from -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R 11 , -CONR 11 R 11 , -NR 11 R 11 , -NR 11 CO2R11 optionally substituted with 1 to 3 substituents each independently selected from optionally substituted C1-C6 alkyl, optionally substituted C3-C5 cycloalkyl, an optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine, or morpholine, optionally substituted phenyl, or an optionally substituted heteroaryl selected from pyridine, 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 independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -NR 11 R 11 , —OH, or —CN; R 10 are each 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, an optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine, or morpholine, optionally substituted phenyl, or an 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; R 11 are each independently —H or C1-C3 alkyl.

[0096] In still further compounds of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, R5 is -H, halogen, C1-C6 alkyl, or C1-C6 haloalkyl, and R2 is a group of the formula: [ka] is the basis of R 10 are each 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, an optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine, or morpholine, optionally substituted phenyl, or an 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; R 11 are each independently —H or C1-C3 alkyl.

[0097] In still further compounds of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, R6 is -H or halogen and R2 is a group of the formula: [ka] or R2 is an optionally substituted 5-membered heteroaryl selected from pyrrole, furan, thiophene, pyrazole, isoxazole, isothiazole, imidazole, oxazole, thiazole, triazole, oxadiazole, and thiadiazole, and the optionally substituted 5-membered heteroaryl is selected from -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R 11 , -CONR 11 R 11 , -NR 11 R 11 , -NR 11 CO2R 11optionally substituted with 1 to 3 substituents each independently selected from optionally substituted C1-C6 alkyl, optionally substituted C3-C5 cycloalkyl, an optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine, or morpholine, optionally substituted phenyl, or an optionally substituted heteroaryl selected from pyridine, 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 independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -NR 11 R 11 , —OH, or —CN; R 10 are each 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, an optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine, or morpholine, optionally substituted phenyl, or an 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, —NR11 R 11 , —OH, or —CN; R 11 are each independently —H or C1-C3 alkyl.

[0098] In still further compounds of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, R6 is -H or halogen and R2 is a group of the formula: [ka] is the basis of R 10 are each 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, an optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine, or morpholine, optionally substituted phenyl, or an 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; R 11 are each independently —H or C1-C3 alkyl.

[0099] In still further compounds of formula (I) or formula (II), or a pharmaceutically acceptable salt 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.

[0100] In still further compounds of formula (I) or formula (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 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.

[0101] In still further compounds of formula (I) or formula (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 R6 is -H or halogen; more preferably, R3 is -H or methyl, and R6 is -H.

[0102] In still further compounds of formula (I) or formula (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.

[0103] In still further compounds of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, R4 is -H or halogen (preferably, R4 is -H), and R6 is -H or halogen.

[0104] 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, and R6 is -H or halogen, preferably, R5 is -H, halogen, methyl, or trifluoromethyl, and R6 is -H.

[0105] In still further compounds of Formula (I) or Formula (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), and R2 is a group of the formula: [ka] or R2 is an optionally substituted 5-membered heteroaryl selected from pyrrole, furan, thiophene, pyrazole, isoxazole, isothiazole, imidazole, oxazole, thiazole, triazole, oxadiazole, and thiadiazole, and the optionally substituted 5-membered heteroaryl is selected from -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R 11 , -CONR 11 R 11 , -NR 11 R 11 , -NR 11 CO2R 11optionally substituted with 1 to 3 substituents each independently selected from optionally substituted C1-C6 alkyl, optionally substituted C3-C5 cycloalkyl, an optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine, or morpholine, optionally substituted phenyl, or an optionally substituted heteroaryl selected from pyridine, 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 independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -NR 11 R 11 , —OH, or —CN; More preferably, R3 is -H or methyl and R4 is -H.

[0106] In still further compounds of Formula (I) or Formula (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), and R2 is a group of the formula: [ka] More preferably, R3 is -H or methyl and R4 is -H.

[0107] In still further compounds of Formula (I) or Formula (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 is a group of the formula: [ka] or R2 is an optionally substituted 5-membered heteroaryl selected from pyrrole, furan, thiophene, pyrazole, isoxazole, isothiazole, imidazole, oxazole, thiazole, triazole, oxadiazole, and thiadiazole, and the optionally substituted 5-membered heteroaryl is selected from -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R 11 , -CONR 11 R 11 , -NR 11 R 11 , -NR 11 CO2R 11 optionally substituted with 1 to 3 substituents each independently selected from optionally substituted C1-C6 alkyl, optionally substituted C3-C5 cycloalkyl, an optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine, or morpholine, optionally substituted phenyl, or an optionally substituted heteroaryl selected from pyridine, 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 independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -NR 11 R 11 , —OH, or —CN; More preferably, R3 is -H or methyl and R5 is -H, halogen, methyl, or trifluoromethyl.

[0108] In still further compounds of Formula (I) or Formula (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 is a group of the formula: [ka] More preferably, R3 is -H or methyl and R5 is -H, halogen, methyl, or trifluoromethyl.

[0109] In still further compounds of Formula (I) or Formula (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 is a group of the formula: [ka] or R2 is an optionally substituted 5-membered heteroaryl selected from pyrrole, furan, thiophene, pyrazole, isoxazole, isothiazole, imidazole, oxazole, thiazole, triazole, oxadiazole, and thiadiazole, and the optionally substituted 5-membered heteroaryl is selected from -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R 11 , -CONR 11 R 11 , -NR 11 R 11 , -NR 11 CO2R 11optionally substituted with 1 to 3 substituents each independently selected from optionally substituted C1-C6 alkyl, optionally substituted C3-C5 cycloalkyl, an optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine, or morpholine, optionally substituted phenyl, or an optionally substituted heteroaryl selected from pyridine, 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 independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -NR 11 R 11 , —OH, or —CN; More preferably, R3 is -H or methyl and R6 is -H.

[0110] In still further compounds of Formula (I) or Formula (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 is a group of the formula: [ka] More preferably, R3 is -H or methyl and R6 is -H.

[0111] In still further compounds of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, R4 is -H or halogen (preferably, R4 is -H), R5 is -H, halogen, C1-C3 alkyl, or C1-C3 haloalkyl, and R2 is a group of the formula: [ka] or R2 is an optionally substituted 5-membered heteroaryl selected from pyrrole, furan, thiophene, pyrazole, isoxazole, isothiazole, imidazole, oxazole, thiazole, triazole, oxadiazole, and thiadiazole, and the optionally substituted 5-membered heteroaryl is selected from -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R 11 , -CONR 11 R 11 , -NR 11 R 11 , -NR 11 CO2R 11 optionally substituted with 1 to 3 substituents each independently selected from optionally substituted C1-C6 alkyl, optionally substituted C3-C5 cycloalkyl, an optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine, or morpholine, optionally substituted phenyl, or an optionally substituted heteroaryl selected from pyridine, 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 independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -NR 11 R 11 , —OH, or —CN, more preferably R5 is —H, halogen, methyl, or trifluoromethyl.

[0112] In still further compounds of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, R4 is -H or halogen (preferably, R4 is -H), R5 is -H, halogen, C1-C3 alkyl, or C1-C3 haloalkyl, and R2 is a group of the formula: [ka] and more preferably, R5 is -H, halogen, methyl, or trifluoromethyl.

[0113] In the compounds of formula (I) or formula (II), or pharmaceutically acceptable salts thereof, R4 is -H or halogen (preferably, R4 is -H), R6 is -H or halogen, and R2 is a group of the formula: [ka] or R2 is an optionally substituted 5-membered heteroaryl selected from pyrrole, furan, thiophene, pyrazole, isoxazole, isothiazole, imidazole, oxazole, thiazole, triazole, oxadiazole, and thiadiazole, and the optionally substituted 5-membered heteroaryl is selected from -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R 11 , -CONR 11 R 11 , -NR 11 R 11 , -NR 11 CO2R 11optionally substituted with 1 to 3 substituents each independently selected from optionally substituted C1-C6 alkyl, optionally substituted C3-C5 cycloalkyl, an optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine, or morpholine, optionally substituted phenyl, or an optionally substituted heteroaryl selected from pyridine, 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 independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -NR 11 R 11 , —OH, or —CN; More preferably, R4 and R6 are each -H.

[0114] In the compounds of formula (I) or formula (II), or pharmaceutically acceptable salts thereof, R4 is -H or halogen (preferably, R4 is -H), R6 is -H or halogen, and R2 is a group of the formula: [ka] and more preferably, R4 and R6 are each -H.

[0115] In still further compounds of Formula (I) or Formula (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 is a group of the formula: [ka] or R2 is an optionally substituted 5-membered heteroaryl selected from pyrrole, furan, thiophene, pyrazole, isoxazole, isothiazole, imidazole, oxazole, thiazole, triazole, oxadiazole, and thiadiazole, and the optionally substituted 5-membered heteroaryl is selected from -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R 11 , -CONR 11 R 11 , -NR 11 R 11 , -NR 11 CO2R 11 optionally substituted with 1 to 3 substituents each independently selected from optionally substituted C1-C6 alkyl, optionally substituted C3-C5 cycloalkyl, an optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine, or morpholine, optionally substituted phenyl, or an optionally substituted heteroaryl selected from pyridine, 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 independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -NR 11 R 11 , —OH, or —CN; Preferably, R5 is -H, halogen, methyl, or trifluoromethyl, and R6 is -H.

[0116] In still further compounds of Formula (I) or Formula (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 is a group of the formula: [ka] Preferably, R5 is -H, halogen, methyl, or trifluoromethyl, and R6 is -H.

[0117] In still further compounds of formula (I) or formula (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), 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.

[0118] In still further compounds of Formula (I) or Formula (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 (more preferably, R4 is H), and R6 is -H or halogen, more preferably, R3 is -H or methyl, and R4 and R6 are each -H.

[0119] In still further compounds of formula (I) or formula (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-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.

[0120] In still further compounds of formula (I) or formula (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), and R6 is -H or halogen, more preferably, R5 is -H, halogen, methyl, or trifluoromethyl, and R4 and R6 are each -H.

[0121] In still further compounds of Formula (I) or Formula (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), R5 is -H, halogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 alkoxy, and R2 is a group of the formula: [ka] or R2 is an optionally substituted 5-membered heteroaryl selected from pyrrole, furan, thiophene, pyrazole, isoxazole, isothiazole, imidazole, oxazole, thiazole, triazole, oxadiazole, and thiadiazole, and the optionally substituted 5-membered heteroaryl is selected from -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R 11 , -CONR 11 R 11 , -NR 11 R 11 , -NR 11 CO2R 11optionally substituted with 1 to 3 substituents each independently selected from optionally substituted C1-C6 alkyl, optionally substituted C3-C5 cycloalkyl, an optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine, or morpholine, optionally substituted phenyl, or an optionally substituted heteroaryl selected from pyridine, 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 independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -NR 11 R 11 , —OH, or —CN; More preferably, R3 is -H or methyl, R4 is -H, and R5 is -H, halogen, methyl, or trifluoromethyl.

[0122] In still further compounds of Formula (I) or Formula (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), R5 is -H, halogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 alkoxy, and 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.

[0123] In still further compounds of Formula (I) or Formula (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 is a group of the formula: [ka] or R2 is an optionally substituted 5-membered heteroaryl selected from pyrrole, furan, thiophene, pyrazole, isoxazole, isothiazole, imidazole, oxazole, thiazole, triazole, oxadiazole, and thiadiazole, and the optionally substituted 5-membered heteroaryl is selected from -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R 11 , -CONR 11 R 11 , -NR 11 R 11 , -NR 11 CO2R 11 optionally substituted with 1 to 3 substituents each independently selected from optionally substituted C1-C6 alkyl, optionally substituted C3-C5 cycloalkyl, an optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine, or morpholine, optionally substituted phenyl, or an optionally substituted heteroaryl selected from pyridine, 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 independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -NR 11 R 11, —OH, or —CN; More preferably, R3 is -H or methyl, and R4 and R6 are each -H.

[0124] In still further compounds of Formula (I) or Formula (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 is a group of the formula: [ka] More preferably, R3 is -H or methyl, and R4 and R6 are each -H.

[0125] In still further compounds of Formula (I) or Formula (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 is a group of the formula: [ka] or R2 is an optionally substituted 5-membered heteroaryl selected from pyrrole, furan, thiophene, pyrazole, isoxazole, isothiazole, imidazole, oxazole, thiazole, triazole, oxadiazole, and thiadiazole, and the optionally substituted 5-membered heteroaryl is selected from -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R 11 , -CONR 11 R 11 , -NR 11 R 11 , -NR 11CO2R 11 optionally substituted with 1 to 3 substituents each independently selected from optionally substituted C1-C6 alkyl, optionally substituted C3-C5 cycloalkyl, an optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine, or morpholine, optionally substituted phenyl, or an optionally substituted heteroaryl selected from pyridine, 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 independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -NR 11 R 11 , —OH, or —CN; More preferably, R3 is -H or methyl, R5 is -H, halogen, methyl, or trifluoromethyl, and R6 is -H.

[0126] In still further compounds of Formula (I) or Formula (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 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.

[0127] In still further compounds of Formula (I) or Formula (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 is a group of the formula: [ka] or R2 is an optionally substituted 5-membered heteroaryl selected from pyrrole, furan, thiophene, pyrazole, isoxazole, isothiazole, imidazole, oxazole, thiazole, triazole, oxadiazole, and thiadiazole, and the optionally substituted 5-membered heteroaryl is selected from -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R 11 , -CONR 11 R 11 , -NR 11 R 11 , -NR 11 CO2R 11 optionally substituted with 1 to 3 substituents each independently selected from optionally substituted C1-C6 alkyl, optionally substituted C3-C5 cycloalkyl, an optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine, or morpholine, optionally substituted phenyl, or an optionally substituted heteroaryl selected from pyridine, 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 independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -NR 11 R 11 , —OH, or —CN; More preferably, R5 is -H, halogen, methyl, or trifluoromethyl, and R4 and R6 are each -H.

[0128] In still further compounds of Formula (I) or Formula (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 is a group of the formula: [ka] More preferably, R5 is -H, halogen, methyl, or trifluoromethyl, and R4 and R6 are each -H.

[0129] In still further compounds of Formula (I) or Formula (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 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.

[0130] In still further compounds of Formula (I) or Formula (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 or halogen, R5 is -H, halogen, C1-C3 alkyl, or C1-C3 haloalkyl, and R2 is a group of the formula: [ka] or R2 is an optionally substituted 5-membered heteroaryl selected from pyrrole, furan, thiophene, pyrazole, isoxazole, isothiazole, imidazole, oxazole, thiazole, triazole, oxadiazole, and thiadiazole, and the optionally substituted 5-membered heteroaryl is selected from -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R 11 , -CONR 11 R 11 , -NR 11 R 11 , -NR 11 CO2R 11 optionally substituted with 1 to 3 substituents each independently selected from optionally substituted C1-C6 alkyl, optionally substituted C3-C5 cycloalkyl, an optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine, or morpholine, optionally substituted phenyl, or an optionally substituted heteroaryl selected from pyridine, 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 independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -NR 11 R 11 , —OH, or —CN; More preferably, R3 is -H or methyl, R4 and R6 are each -H, and R5 is -H, halogen, methyl, or trifluoromethyl.

[0131] In still further compounds of Formula (I) or Formula (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 or halogen, R5 is -H, halogen, C1-C3 alkyl, or C1-C3 haloalkyl, and 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.

[0132] In still further compounds of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, R is —H.

[0133] In still further compounds of formula (I) or formula (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.

[0134] In still further compounds of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, R8 is -H.

[0135] In still further compounds of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, R7 is -CN, C1-C3 alkyl, or C1-C3 haloalkyl, and R is -H. In still further compounds of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, R7 is C1-C3 alkyl (preferably methyl), and R is -H.

[0136] In still further compounds of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, R and R are each -H.

[0137] In still further compounds of Formula (I) or Formula (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 Formula (II), or a pharmaceutically acceptable salt thereof, R7 is C1-C3 alkyl (preferably methyl) and R8 is -H.

[0138] In still further compounds of Formula (I) or Formula (II), or a pharmaceutically acceptable salt 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 Formula (II), or a pharmaceutically acceptable salt thereof, R7 is C1-C3 alkyl (preferably methyl), and R8 and R are -H.

[0139] In still further compounds of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, R7 is -CN, C1-C3 alkyl, or C1-C3 haloalkyl, R8 is -H, R is -H, and R2 is a group of the formula: [ka] or R2 is an optionally substituted 5-membered heteroaryl selected from pyrrole, furan, thiophene, pyrazole, isoxazole, isothiazole, imidazole, oxazole, thiazole, triazole, oxadiazole, and thiadiazole, and the optionally substituted 5-membered heteroaryl is selected from -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R 11 , -CONR 11 R 11 , -NR 11 R 11 , -NR 11 CO2R11 optionally substituted with 1 to 3 substituents each independently selected from optionally substituted C1-C6 alkyl, optionally substituted C3-C5 cycloalkyl, an optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine, or morpholine, optionally substituted phenyl, or an optionally substituted heteroaryl selected from pyridine, 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 independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -NR 11 R 11 , —OH, or —CN.

[0140] In still further compounds of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, R7 is -CN, C1-C3 alkyl, or C1-C3 haloalkyl, R8 is -H, R is -H, and R2 is a group of the formula: [ka] is the basis of

[0141] In still further compounds of formula (I) or formula (II), or a pharmaceutically acceptable salt thereof, R7 is C1-C3 alkyl (preferably methyl), R8 is -H, R is -H, and R2 is a group of the formula: [ka] or R2 is an optionally substituted 5-membered heteroaryl selected from pyrrole, furan, thiophene, pyrazole, isoxazole, isothiazole, imidazole, oxazole, thiazole, triazole, oxadiazole, and thiadiazole, and the optionally substituted 5-membered heteroaryl is selected from -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R 11 , -CONR 11 R 11 , -NR 11 R 11 , -NR 11 CO2R 11 optionally substituted with 1 to 3 substituents each independently selected from optionally substituted C1-C6 alkyl, optionally substituted C3-C5 cycloalkyl, an optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine, or morpholine, optionally substituted phenyl, or an optionally substituted heteroaryl selected from pyridine, 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 independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -NR 11 R 11 , —OH, or —CN.

[0142] In still further compounds of formula (I) or formula (II), or a pharmaceutically acceptable salt thereof, R7 is C1-C3 alkyl (preferably methyl), R8 is -H, R is -H, and R2 is a group of the formula: [ka] is the basis of

[0143] In still further compounds of Formula (I) or Formula (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), 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 Formula (II), or a pharmaceutically acceptable salt thereof, R3 is -H or methyl, R7 is C1-C3 alkyl (preferably methyl), and R8 and R are each -H.

[0144] In still further compounds of Formula (I) or Formula (II), or a pharmaceutically acceptable salt 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 Formula (II), or a pharmaceutically acceptable salt thereof, R7 is C1-C3 alkyl (preferably methyl), and R4, R8, and R are each -H.

[0145] In still further compounds of Formula (I) or Formula (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 Formula (II), or a pharmaceutically acceptable salt thereof, R5 is -H, halogen, methyl, or trifluoromethyl, R7 is methyl, and R8 and R are each -H.

[0146] In still further compounds of Formula (I) or Formula (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 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 is a group of the formula: [ka] or R2 is an optionally substituted 5-membered heteroaryl selected from pyrrole, furan, thiophene, pyrazole, isoxazole, isothiazole, imidazole, oxazole, thiazole, triazole, oxadiazole, and thiadiazole, and the optionally substituted 5-membered heteroaryl is selected from -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R 11 , -CONR 11 R 11 , -NR 11 R 11 , -NR 11 CO2R 11optionally substituted with 1 to 3 substituents each independently selected from optionally substituted C1-C6 alkyl, optionally substituted C3-C5 cycloalkyl, an optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine, or morpholine, optionally substituted phenyl, or an optionally substituted heteroaryl selected from pyridine, 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 independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -NR 11 R 11 , —OH, or —CN; 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.

[0147] In still further compounds of Formula (I) or Formula (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 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 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.

[0148] In still further compounds of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, R1 is a group of the formula: [ka] wherein each R is independently -H, halogen, -CN, C-C alkyl, C-C haloalkyl, C-C alkoxy, or C-C cycloalkyl; preferably, each R is independently -H, halogen, -CN, methyl, trifluoromethyl, methoxy, or cyclopropyl.

[0149] In still further compounds of Formula (I) or Formula (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.

[0150] In still further compounds of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, R1 is a group of the formula: [ka] wherein each R is independently -H, halogen, C-C alkyl, C-C haloalkyl, or C-C cycloalkyl; preferably, each R is independently -H, halogen, methyl, trifluoromethyl, or cyclopropyl.

[0151] In still further compounds of Formula (I) or Formula (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.

[0152] In still further compounds of Formula (I) or Formula (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.

[0153] In still further compounds of Formula (I) or Formula (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, or C3-C5 cycloalkyl. More preferably, each R9 is independently -H, halogen, methyl, trifluoromethyl, or cyclopropyl.

[0154] In still further compounds of Formula (I) or Formula (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, or C1-C3 haloalkyl. More preferably, each R9 is independently -H, halogen, or trifluoromethyl.

[0155] In still further compounds of formula (I) or formula (II), or a pharmaceutically acceptable salt thereof, R1 is a group of formula [ka] wherein each R9 is independently -H, halogen, -CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C3-C5 cycloalkyl; preferably, each R9 is independently -H, halogen, -CN, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, or C3-C5 cycloalkyl; more preferably, each R9 is independently -H, halogen, -CN, methyl, trifluoromethyl, methoxy, or cyclopropyl.

[0156] In still further compounds of formula (I) or formula (II), or a pharmaceutically acceptable salt thereof, R1 is a group of 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.

[0157] In still further compounds of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, R1 is a group of the formula: [ka] wherein each R is independently -H, halogen, -CN, C-C alkyl, C-C haloalkyl, or C-C alkoxy. Preferably, each R is independently -H, halogen, C-C alkyl, or C-C haloalkyl. More preferably, each R is independently -H, halogen, methyl, or trifluoromethyl.

[0158] In still further compounds of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, R1 is a group of the formula: [ka] wherein R9 is -H, halogen, -CN, C1-C3 haloalkyl, or C1-C3 alkoxy. Preferably, R9 is -H, halogen, or C1-C3 haloalkyl. More preferably, R9 is -H or trifluoromethyl.

[0159] In still further compounds of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, R1 is a group of the formula: [ka] wherein R9 is -H, halogen, -CN, C1-C3 haloalkyl, or C1-C3 alkoxy. Preferably, R9 is -H, halogen, or C1-C3 haloalkyl. More preferably, R9 is -H or halogen. Even more preferably, R9 is -H or fluoro.

[0160] In still further compounds of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, R1 is a group of the formula: [ka] wherein R9 is -H, halogen, -CN, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, or C3-C5 cycloalkyl. Preferably, R9 is -H, halogen, C1-C3 alkyl, C1-C3 haloalkyl, or C3-C5 cycloalkyl. More preferably, R9 is -H, halogen, methyl, trifluoromethyl, or cyclopropyl.

[0161] In still further compounds of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, R1 is a group of the formula: [ka] wherein R9 is —H, halogen, or C1-C3 haloalkyl. Preferably, R9 is halogen or trifluoromethyl. More preferably, R9 is chloro or trifluoromethyl.

[0162] In still further compounds of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, R1 is a group of the formula: [ka] wherein R9 is -H, halogen, -CN, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 alkoxy. Preferably, R9 is -H, halogen, C1-C6 alkyl, or C1-C6 haloalkyl. More preferably, R9 is -H, halogen, C1-C3 alkyl, or C1-C3 haloalkyl.

[0163] In still further compounds of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, R1 is a group of the formula: [ka] wherein R9 is -H, halogen, -CN, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, or C3-C5 cycloalkyl. Preferably, R9 is -H, halogen, C1-C3 alkyl, C1-C3 haloalkyl, or C3-C5 cycloalkyl. More preferably, R9 is -H, halogen, methyl, trifluoromethyl, or cyclopropyl.

[0164] In still further compounds of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, R1 is a group of the formula: [ka] [ka] is.

[0165] In still further compounds of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, R1 is a group of the formula: [ka] is.

[0166] In still further compounds of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, R1 is a group of the formula: [ka] is.

[0167] In still further compounds of Formula (I) or Formula (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.

[0168] In still further compounds of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, R3 is -H, -CN, or C1-C3 alkyl; R4 is -H; 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, or C1-C3 haloalkyl. Preferably, R3 is -H or methyl, R4 and R6 are each -H, R5 is -H, halogen, methyl, or trifluoromethyl, and each R9 is independently -H, halogen, methyl, or trifluoromethyl.

[0169] In still further compounds of Formula (I) or Formula (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 R is independently -H, halogen, C-C alkyl, C-C haloalkyl, or C-C cycloalkyl; more preferably, R is methyl, R and R are each -H, and each R is independently -H, halogen, methyl, trifluoromethyl, or cyclopropyl.

[0170] In still further compounds of Formula (I) or Formula (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 R is independently -H, halogen, C-C alkyl, or C-C haloalkyl; more preferably, R is methyl, R and R are each -H, and each R is independently -H, halogen, methyl, or trifluoromethyl.

[0171] In still further compounds of Formula (I) or Formula (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.

[0172] In still further compounds of Formula (I) or Formula (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] wherein each R9 is independently -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 each R9 is independently -H, halogen, methyl, or trifluoromethyl.

[0173] In still further compounds of Formula (I) or Formula (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 R9 is independently -H, halogen, methyl, or trifluoromethyl.

[0174] In still further compounds of Formula (I) or Formula (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] wherein 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 trifluoromethyl.

[0175] In still further compounds of Formula (I) or Formula (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] wherein 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.

[0176] In still further compounds of Formula (I) or Formula (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 R9 is -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, 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.

[0177] In still further compounds of Formula (I) or Formula (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] wherein 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 halogen or trifluoromethyl.

[0178] In still further compounds of Formula (I) or Formula (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] wherein 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.

[0179] In still further compounds of Formula (I) or Formula (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 R9 is -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, 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.

[0180] In still further compounds of Formula (I) or Formula (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 R2 is a group of the formula: [ka] or R2 is an optionally substituted 5-membered heteroaryl selected from pyrrole, furan, thiophene, pyrazole, isoxazole, isothiazole, imidazole, oxazole, thiazole, triazole, oxadiazole, and thiadiazole, and the optionally substituted 5-membered heteroaryl is selected from -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R 11 , -CONR 11 R 11 , -NR 11 R 11 , -NR 11 -CO2R 11optionally substituted with 1 to 3 substituents each independently selected from optionally substituted C1-C6 alkyl, optionally substituted C3-C5 cycloalkyl, an optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine, or morpholine, optionally substituted phenyl, or an optionally substituted heteroaryl selected from pyridine, 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 independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -NR 11 R 11 , —OH, or —CN; R 10 are each 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, an optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine, or morpholine, optionally substituted phenyl, or an 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, —NR11 R 11 , —OH, or —CN; R 11 are each independently —H or C1-C3 alkyl.

[0181] In still further compounds of Formula (I) or Formula (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; and R2 is a group of the formula: [ka] is the basis of In the formula, R 10 are each 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, an optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine, or morpholine, optionally substituted phenyl, or an 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; R 11 are each independently —H or C1-C3 alkyl.

[0182] In still further compounds of Formula (I) or Formula (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; and R2 is a group of the formula: [ka] or R2 is an optionally substituted 5-membered heteroaryl selected from pyrrole, furan, thiophene, pyrazole, isoxazole, isothiazole, imidazole, oxazole, thiazole, triazole, oxadiazole, and thiadiazole, and the optionally substituted 5-membered heteroaryl is selected from -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R 11 , -CONR 11 R 11 , -NR 11 R 11 , -NR 11 CO2R 11optionally substituted with 1 to 3 substituents each independently selected from optionally substituted C1-C6 alkyl, optionally substituted C3-C5 cycloalkyl, an optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine, or morpholine, optionally substituted phenyl, or an optionally substituted heteroaryl selected from pyridine, 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 independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -NR 11 R 11 , -OH, or -CN, preferably, each R9 is independently -H, halogen, C1-C3 alkyl, or C1-C3 haloalkyl. Most preferably, each R9 is independently -H, halogen, methyl, or trifluoromethyl.

[0183] In still further compounds of Formula (I) or Formula (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; and R2 is a group of the formula: [ka] Preferably, each R is independently -H, halogen, C-C alkyl, or C-C haloalkyl. Most preferably, each R is independently -H, halogen, methyl, or trifluoromethyl.

[0184] In still further compounds of Formula (I) or Formula (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; and R2 is a group of the formula: [ka] or R2 is an optionally substituted 5-membered heteroaryl selected from pyrrole, furan, thiophene, pyrazole, isoxazole, isothiazole, imidazole, oxazole, thiazole, triazole, oxadiazole, and thiadiazole, and the optionally substituted 5-membered heteroaryl is selected from -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R 11 , -CONR 11 R 11 , -NR 11 R 11 , -NR 11 CO2R 11 optionally substituted with 1 to 3 substituents each independently selected from optionally substituted C1-C6 alkyl, optionally substituted C3-C5 cycloalkyl, an optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine, or morpholine, optionally substituted phenyl, or an optionally substituted heteroaryl selected from pyridine, 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 independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -NR 11 R 11, —OH, or —CN; Preferably, each R9 is independently -H, halogen, methyl, or trifluoromethyl.

[0185] In still further compounds of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, R1 is a group of the formula: [ka] wherein R9 is —H, halogen, or C1-C3 haloalkyl, and R2 is a group of the formula: [ka] or R2 is an optionally substituted 5-membered heteroaryl selected from pyrrole, furan, thiophene, pyrazole, isoxazole, isothiazole, imidazole, oxazole, thiazole, triazole, oxadiazole, and thiadiazole, and the optionally substituted 5-membered heteroaryl is selected from -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R 11 , -CONR 11 R 11 , -NR 11 R 11 , -NR 11 CO2R 11optionally substituted with 1 to 3 substituents each independently selected from optionally substituted C1-C6 alkyl, optionally substituted C3-C5 cycloalkyl, an optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine, or morpholine, optionally substituted phenyl, or an optionally substituted heteroaryl selected from pyridine, 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 independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -NR 11 R 11 , —OH, or —CN; Preferably, R9 is -H or trifluoromethyl.

[0186] In still further compounds of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, R1 is a group of the formula: [ka] wherein R9 is —H, halogen, or C1-C3 haloalkyl, and R2 is a group of the formula: [ka] Preferably, R9 is —H or trifluoromethyl.

[0187] In still further compounds of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, R1 is a group of the formula: [ka] wherein R9 is —H, halogen, or C1-C3 haloalkyl, and R2 is a group of the formula: [ka] or R2 is an optionally substituted 5-membered heteroaryl selected from pyrrole, furan, thiophene, pyrazole, isoxazole, isothiazole, imidazole, oxazole, thiazole, triazole, oxadiazole, and thiadiazole, and the optionally substituted 5-membered heteroaryl is selected from -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R 11 , -CONR 11 R 11 , -NR 11 R 11 , -NR 11 CO2R 11 optionally substituted with 1 to 3 substituents each independently selected from optionally substituted C1-C6 alkyl, optionally substituted C3-C5 cycloalkyl, an optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine, or morpholine, optionally substituted phenyl, or an optionally substituted heteroaryl selected from pyridine, 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 independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -NR 11 R 11 , —OH, or —CN; Preferably, R9 is -H or halogen.

[0188] In still further compounds of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, R1 is a group of the formula: [ka] wherein R9 is —H, halogen, or C1-C3 haloalkyl, and R2 is a group of the formula: [ka] Preferably, R9 is —H or halogen.

[0189] In still further compounds of Formula (I) or Formula (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; and R2 is a group of the formula: [ka] or R2 is an optionally substituted 5-membered heteroaryl selected from pyrrole, furan, thiophene, pyrazole, isoxazole, isothiazole, imidazole, oxazole, thiazole, triazole, oxadiazole, and thiadiazole, and the optionally substituted 5-membered heteroaryl is selected from -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R 11 , -CONR 11 R 11 , -NR 11 R 11 , -NR 11 CO2R 11optionally substituted with 1 to 3 substituents each independently selected from optionally substituted C1-C6 alkyl, optionally substituted C3-C5 cycloalkyl, an optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine, or morpholine, optionally substituted phenyl, or an optionally substituted heteroaryl selected from pyridine, 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 independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -NR 11 R 11 , —OH, or —CN; Preferably, R9 is -H, halogen, methyl, trifluoromethyl, or cyclopropyl.

[0190] In still further compounds of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, R1 is a group of the formula: [ka] wherein R9 is halogen or C1-C3 haloalkyl and R2 is a group of the formula: [ka] is the basis of Preferably, R9 is halogen or trifluoromethyl. More preferably, R9 is chloro or trifluoromethyl.

[0191] In still further compounds of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, R1 is a group of the formula: [ka] wherein R9 is —H, halogen, C1-C3 alkyl, or C1-C3 haloalkyl; and R2 is a group of the formula: [ka] or R2 is an optionally substituted 5-membered heteroaryl selected from pyrrole, furan, thiophene, pyrazole, isoxazole, isothiazole, imidazole, oxazole, thiazole, triazole, oxadiazole, and thiadiazole, and the optionally substituted 5-membered heteroaryl is selected from -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R 11 , -CONR 11 R 11 , -NR 11 R 11 , -NR 11 CO2R 11 optionally substituted with 1 to 3 substituents each independently selected from optionally substituted C1-C6 alkyl, optionally substituted C3-C5 cycloalkyl, an optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine, or morpholine, optionally substituted phenyl, or an optionally substituted heteroaryl selected from pyridine, 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 independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -NR 11 R 11 , —OH, or —CN.

[0192] In still further compounds of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, R1 is a group of the formula: [ka] wherein R9 is —H, halogen, C1-C3 alkyl, or C1-C3 haloalkyl; and R2 is a group of the formula: [ka] is the basis of

[0193] In still further compounds of Formula (I) or Formula (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; and R2 is a group of the formula: [ka] or R2 is an optionally substituted 5-membered heteroaryl selected from pyrrole, furan, thiophene, pyrazole, isoxazole, isothiazole, imidazole, oxazole, thiazole, triazole, oxadiazole, and thiadiazole, and the optionally substituted 5-membered heteroaryl is selected from -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R 11 , -CONR 11 R 11 , -NR 11 R 11 , -NR 11 CO2R 11optionally substituted with 1 to 3 substituents each independently selected from optionally substituted C1-C6 alkyl, optionally substituted C3-C5 cycloalkyl, an optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine, or morpholine, optionally substituted phenyl, or an optionally substituted heteroaryl selected from pyridine, 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 independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -NR 11 R 11 , —OH, or —CN.

[0194] In still further compounds of formula (I) or formula (II), or a pharmaceutically acceptable salt thereof, R2 is a group of the formula: [ka] or R2 is an optionally substituted 5-membered heteroaryl selected from pyrrole, furan, thiophene, pyrazole, isoxazole, isothiazole, imidazole, oxazole, thiazole, triazole, oxadiazole, and thiadiazole, and the optionally substituted 5-membered heteroaryl is selected from -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R 11 , -CONR 11 R 11 , -NR 11 R 11 , -NR 11 CO2R 11optionally substituted with 1 to 3 substituents each independently selected from optionally substituted C1-C6 alkyl, optionally substituted C3-C5 cycloalkyl, an optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine, or morpholine, optionally substituted phenyl, or an optionally substituted heteroaryl selected from pyridine, 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 independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -NR 11 R 11 , -OH, or -CN; 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.

[0195] In still further compounds of formula (I) or formula (II), or a pharmaceutically acceptable salt thereof, R2 is a group of the formula: [ka] wherein R3 is -H, -CN, or C1-C3 alkyl; R4 is -H; 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, or C1-C3 haloalkyl. Preferably, R3 is -H or methyl, R4 and R6 are each -H, R5 is -H, halogen, methyl, or trifluoromethyl, and each R9 is independently -H, halogen, methyl, or trifluoromethyl.

[0196] In still further compounds of formula (I) or formula (II), or a pharmaceutically acceptable salt thereof, R2 is a group of the formula: [ka] or R2 is an optionally substituted 5-membered heteroaryl selected from pyrrole, furan, thiophene, pyrazole, isoxazole, isothiazole, imidazole, oxazole, thiazole, triazole, oxadiazole, and thiadiazole, and the optionally substituted 5-membered heteroaryl is selected from -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R 11 , -CONR 11 R 11 , -NR 11 R 11 , -NR 11 CO2R 11optionally substituted with 1 to 3 substituents each independently selected from optionally substituted C1-C6 alkyl, optionally substituted C3-C5 cycloalkyl, an optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine, or morpholine, optionally substituted phenyl, or an optionally substituted heteroaryl selected from pyridine, 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 independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -NR 11 R 11 , -OH, or -CN; 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.

[0197] In still further compounds of formula (I) or formula (II), or a pharmaceutically acceptable salt thereof, R2 is a group of the formula: [ka] wherein 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, or C1-C3 haloalkyl.

[0198] In still further compounds of Formula (I) or Formula (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 R2 is a group of the formula: [ka] or R2 is an optionally substituted 5-membered heteroaryl selected from pyrrole, furan, thiophene, pyrazole, isoxazole, isothiazole, imidazole, oxazole, thiazole, triazole, oxadiazole, and thiadiazole, and the optionally substituted 5-membered heteroaryl is selected from -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R 11 , -CONR 11 R 11 , -NR 11 R 11 , -NR 11 CO2R 11 optionally substituted with 1 to 3 substituents each independently selected from optionally substituted C1-C6 alkyl, optionally substituted C3-C5 cycloalkyl, an optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine, or morpholine, optionally substituted phenyl, or an optionally substituted heteroaryl selected from pyridine, 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 independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -NR 11 R 11, —OH, or —CN; R7 is C1-C3 alkyl (preferably methyl); and R8 and R are each —H.

[0199] In still further compounds of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, R1 is a group of the formula: [ka] wherein R9 is -H, halogen, or trifluoromethyl (preferably, R9 is -H or trifluoromethyl), and R2 is a group of the formula: [ka] or R2 is an optionally substituted 5-membered heteroaryl selected from pyrrole, furan, thiophene, pyrazole, isoxazole, isothiazole, imidazole, oxazole, thiazole, triazole, oxadiazole, and thiadiazole, and the optionally substituted 5-membered heteroaryl is selected from -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R 11 , -CONR 11 R 11 , -NR 11 R 11 , -NR 11 CO2R 11optionally substituted with 1 to 3 substituents each independently selected from optionally substituted C1-C6 alkyl, optionally substituted C3-C5 cycloalkyl, an optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine, or morpholine, optionally substituted phenyl, or an optionally substituted heteroaryl selected from pyridine, 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 independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -NR 11 R 11 , —OH, or —CN; R7 is C1-C3 alkyl (preferably methyl); and R8 and R are each —H.

[0200] In still further compounds of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, R1 is a group of the formula: [ka] wherein R9 is -H, halogen, or trifluoromethyl (preferably, R9 is -H or trifluoromethyl), and R2 is a group of the formula: [ka] wherein R7 is C1-C3 alkyl (preferably methyl), and R8 and R are each -H.

[0201] In still further compounds of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, R1 is a group of the formula: [ka] wherein R9 is -H, halogen, or trifluoromethyl (preferably, R9 is -H or halogen), and R2 is a group of the formula: [ka] or R2 is an optionally substituted 5-membered heteroaryl selected from pyrrole, furan, thiophene, pyrazole, isoxazole, isothiazole, imidazole, oxazole, thiazole, triazole, oxadiazole, and thiadiazole, and the optionally substituted 5-membered heteroaryl is selected from -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R 11 , -CONR 11 R 11 , -NR 11 R 11 , -NR 11 CO2R 11 optionally substituted with 1 to 3 substituents each independently selected from optionally substituted C1-C6 alkyl, optionally substituted C3-C5 cycloalkyl, an optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine, or morpholine, optionally substituted phenyl, or an optionally substituted heteroaryl selected from pyridine, 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 independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -NR 11 R 11 , —OH, or —CN; R7 is C1-C3 alkyl (preferably methyl); and R8 and R are each —H.

[0202] In still further compounds of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, R1 is a group of the formula: [ka] wherein R9 is -H, halogen, or trifluoromethyl (preferably, R9 is -H or halogen), and R2 is a group of the formula: [ka] wherein R7 is C1-C3 alkyl (preferably methyl), and R8 and R are each -H.

[0203] In still further compounds of Formula (I) or Formula (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 a group of the formula: [ka] or R2 is an optionally substituted 5-membered heteroaryl selected from pyrrole, furan, thiophene, pyrazole, isoxazole, isothiazole, imidazole, oxazole, thiazole, triazole, oxadiazole, and thiadiazole, and the optionally substituted 5-membered heteroaryl is selected from -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R 11 , -CONR 11 R 11 , -NR 11 R 11 , -NR 11 CO2R 11optionally substituted with 1 to 3 substituents each independently selected from optionally substituted C1-C6 alkyl, optionally substituted C3-C5 cycloalkyl, an optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine, or morpholine, optionally substituted phenyl, or an optionally substituted heteroaryl selected from pyridine, 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 independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -NR 11 R 11 , —OH, or —CN; R7 is C1-C3 alkyl (preferably methyl); and R8 and R are each —H.

[0204] In still further compounds of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, R1 is a group of the formula: [ka] wherein R9 is -H, halogen, or trifluoromethyl (preferably, R9 is halogen or trifluoromethyl), and R2 is a group of the formula: [ka] wherein R7 is C1-C3 alkyl (preferably methyl), and R8 and R are each -H.

[0205] In still further compounds of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, R1 is a group of the formula: [ka] wherein R9 is —H, halogen, C1-C3 alkyl, or C1-C3 haloalkyl; and R2 is a group of the formula: [ka] or R2 is an optionally substituted 5-membered heteroaryl selected from pyrrole, furan, thiophene, pyrazole, isoxazole, isothiazole, imidazole, oxazole, thiazole, triazole, oxadiazole, and thiadiazole, and the optionally substituted 5-membered heteroaryl is selected from -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R 11 , -CONR 11 R 11 , -NR 11 R 11 , -NR 11 CO2R 11 optionally substituted with 1 to 3 substituents each independently selected from optionally substituted C1-C6 alkyl, optionally substituted C3-C5 cycloalkyl, an optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine, or morpholine, optionally substituted phenyl, or an optionally substituted heteroaryl selected from pyridine, 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 independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -NR 11 R 11 , —OH, or —CN; R7 is C1-C3 alkyl (preferably methyl); and R8 and R are each —H.

[0206] In still further compounds of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, R1 is a group of the formula: [ka] wherein R9 is —H, halogen, C1-C3 alkyl, or C1-C3 haloalkyl; and R2 is a group of the formula: [ka] wherein R7 is C1-C3 alkyl (preferably methyl), and R8 and R are each -H.

[0207] In still further compounds of Formula (I) or Formula (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; and R2 is a group of the formula: [ka] or R2 is an optionally substituted 5-membered heteroaryl selected from pyrrole, furan, thiophene, pyrazole, isoxazole, isothiazole, imidazole, oxazole, thiazole, triazole, oxadiazole, and thiadiazole, and the optionally substituted 5-membered heteroaryl is selected from -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R 11 , -CONR 11 R 11 , -NR 11 R 11 , -NR 11 CO2R 11optionally substituted with 1 to 3 substituents each independently selected from optionally substituted C1-C6 alkyl, optionally substituted C3-C5 cycloalkyl, an optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine, or morpholine, optionally substituted phenyl, or an optionally substituted heteroaryl selected from pyridine, 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 independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -NR 11 R 11 , —OH, or —CN; R7 is C1-C3 alkyl (preferably methyl); and R8 and R are each —H.

[0208] In still further compounds of formula (I) or formula (II), or a pharmaceutically acceptable salt thereof, R2 is a group of the formula: [ka] or R2 is an optionally substituted 5-membered heteroaryl selected from pyrrole, furan, thiophene, pyrazole, isoxazole, isothiazole, imidazole, oxazole, thiazole, triazole, oxadiazole, and thiadiazole, and the optionally substituted 5-membered heteroaryl is selected from -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R 11 , -CONR 11 R 11 , -NR 11 R 11 , -NR 11 CO2R 11optionally substituted with 1 to 3 substituents each independently selected from optionally substituted C1-C6 alkyl, optionally substituted C3-C5 cycloalkyl, an optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine, or morpholine, optionally substituted phenyl, or an optionally substituted heteroaryl selected from pyridine, 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 independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -NR 11 R 11 , -OH, or -CN; 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.

[0209] In still further compounds of formula (I) or formula (II), or a pharmaceutically acceptable salt thereof, R2 is a group of the formula: [ka] wherein 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, C1-C3 alkyl, or C1-C3 haloalkyl.

[0210] In still further compounds of Formula (I) or Formula (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 R2 is a group of the formula: [ka] or R2 is an optionally substituted 5-membered heteroaryl selected from pyrrole, furan, thiophene, pyrazole, isoxazole, isothiazole, imidazole, oxazole, thiazole, triazole, oxadiazole, and thiadiazole, and the optionally substituted 5-membered heteroaryl is selected from -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R 11 , -CONR 11 R 11 , -NR 11 R 11 , -NR 11 CO2R 11optionally substituted with 1 to 3 substituents each independently selected from optionally substituted C1-C6 alkyl, optionally substituted C3-C5 cycloalkyl, an optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine, or morpholine, optionally substituted phenyl, or an optionally substituted heteroaryl selected from pyridine, 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 independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -NR 11 R 11 , -OH, or -CN; 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).

[0211] In still further compounds of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, R1 is a group of the formula: [ka] wherein R9 is -H, halogen, or trifluoromethyl (preferably, R9 is -H or trifluoromethyl), and R2 is a group of the formula: [ka] or R2 is an optionally substituted 5-membered heteroaryl selected from pyrrole, furan, thiophene, pyrazole, isoxazole, isothiazole, imidazole, oxazole, thiazole, triazole, oxadiazole, and thiadiazole, and the optionally substituted 5-membered heteroaryl is selected from -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R 11 , -CONR 11 R 11 , -NR 11 R 11 , -NR 11 CO2R 11 optionally substituted with 1 to 3 substituents each independently selected from optionally substituted C1-C6 alkyl, optionally substituted C3-C5 cycloalkyl, an optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine, or morpholine, optionally substituted phenyl, or an optionally substituted heteroaryl selected from pyridine, 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 independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -NR 11 R 11 , -OH, or -CN; 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).

[0212] In still further compounds of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, R1 is a group of the formula: [ka] wherein R9 is -H, halogen, or trifluoromethyl (preferably, R9 is -H or trifluoromethyl), and R2 is a group of the formula: [ka] wherein 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).

[0213] In still further compounds of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, R1 is a group of the formula: [ka] wherein R9 is -H, halogen, or trifluoromethyl (preferably, R9 is -H or halogen), and R2 is a group of the formula: [ka] or R2 is an optionally substituted 5-membered heteroaryl selected from pyrrole, furan, thiophene, pyrazole, isoxazole, isothiazole, imidazole, oxazole, thiazole, triazole, oxadiazole, and thiadiazole, and the optionally substituted 5-membered heteroaryl is selected from -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R 11 , -CONR 11 R 11 , -NR 11 R 11 , -NR 11 CO2R 11optionally substituted with 1 to 3 substituents each independently selected from optionally substituted C1-C6 alkyl, optionally substituted C3-C5 cycloalkyl, an optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine, or morpholine, optionally substituted phenyl, or an optionally substituted heteroaryl selected from pyridine, 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 independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -NR 11 R 11 , -OH, or -CN; 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).

[0214] In still further compounds of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, R1 is a group of the formula: [ka] wherein R9 is -H, halogen, or trifluoromethyl (preferably, R9 is -H or halogen), and R2 is a group of the formula: [ka] wherein 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).

[0215] In still further compounds of Formula (I) or Formula (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 a group of the formula: [ka] or R2 is an optionally substituted 5-membered heteroaryl selected from pyrrole, furan, thiophene, pyrazole, isoxazole, isothiazole, imidazole, oxazole, thiazole, triazole, oxadiazole, and thiadiazole, and the optionally substituted 5-membered heteroaryl is selected from -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R 11 , -CONR 11 R 11 , -NR 11 R 11 , -NR 11 CO2R 11 optionally substituted with 1 to 3 substituents each independently selected from optionally substituted C1-C6 alkyl, optionally substituted C3-C5 cycloalkyl, an optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine, or morpholine, optionally substituted phenyl, or an optionally substituted heteroaryl selected from pyridine, 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 independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -NR 11 R 11, -OH, or -CN; 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).

[0216] In still further compounds of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, R1 is a group of the formula: [ka] wherein R9 is -H, halogen, or trifluoromethyl (preferably, R9 is halogen or trifluoromethyl), and R2 is a group of the formula: [ka] wherein 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).

[0217] In still further compounds of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, R1 is a group of the formula: [ka] wherein R9 is —H, halogen, C1-C3 alkyl, or C1-C3 haloalkyl; and R2 is a group of the formula: [ka] or R2 is an optionally substituted 5-membered heteroaryl selected from pyrrole, furan, thiophene, pyrazole, isoxazole, isothiazole, imidazole, oxazole, thiazole, triazole, oxadiazole, and thiadiazole, and the optionally substituted 5-membered heteroaryl is selected from -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R 11 , -CONR 11 R 11 , -NR 11 R 11 , -NR 11 CO2R 11 optionally substituted with 1 to 3 substituents each independently selected from optionally substituted C1-C6 alkyl, optionally substituted C3-C5 cycloalkyl, an optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine, or morpholine, optionally substituted phenyl, or an optionally substituted heteroaryl selected from pyridine, 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 independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -NR 11 R 11 , -OH, or -CN; 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).

[0218] In still further compounds of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, R1 is a group of the formula: [ka] wherein R9 is —H, halogen, C1-C3 alkyl, or C1-C3 haloalkyl; and R2 is a group of the formula: [ka] wherein 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).

[0219] In still further compounds of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, R1 is a group of the formula: [ka] wherein each R9 is independently -H, halogen, methyl, trifluoromethyl, or cyclopropyl; and R2 is a group of the formula: [ka] or R2 is an optionally substituted 5-membered heteroaryl selected from pyrrole, furan, thiophene, pyrazole, isoxazole, isothiazole, imidazole, oxazole, thiazole, triazole, oxadiazole, and thiadiazole, and the optionally substituted 5-membered heteroaryl is selected from -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R 11 , -CONR 11 R 11 , -NR 11 R 11 , -NR 11 CO2R 11optionally substituted with 1 to 3 substituents each independently selected from optionally substituted C1-C6 alkyl, optionally substituted C3-C5 cycloalkyl, an optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine, or morpholine, optionally substituted phenyl, or an optionally substituted heteroaryl selected from pyridine, 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 independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -NR 11 R 11 , -OH, or -CN; 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).

[0220] In a further embodiment, the compound of formula (I) or (II) has formula (III), or a pharmaceutically acceptable salt thereof: [ka] wherein R1, R2, R3, R5, R6, and R7 are as defined in the Summary for formula (I) above.

[0221] In the compound of formula (III), or a pharmaceutically acceptable salt thereof, R2 is a group of the formula: [ka] or R2 is an optionally substituted 5-membered heteroaryl selected from pyrrole, furan, thiophene, pyrazole, isoxazole, isothiazole, imidazole, oxazole, thiazole, triazole, oxadiazole, and thiadiazole, and the optionally substituted 5-membered heteroaryl is selected from -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R 11 , -CONR 11 R 11 , -NR 11 R 11 , -NR 11 CO2R 11 optionally substituted with 1 to 3 substituents each independently selected from optionally substituted C1-C6 alkyl, optionally substituted C3-C5 cycloalkyl, an optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine, or morpholine, optionally substituted phenyl, or an optionally substituted heteroaryl selected from pyridine, 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 independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -NR 11 R 11 , —OH, or —CN.

[0222] In the compound of formula (III), or a pharmaceutically acceptable salt thereof, R2 is a group of the formula: [ka] is the basis of

[0223] 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.

[0224] 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.

[0225] In still further compounds of formula (III), or a pharmaceutically acceptable salt thereof, R6 is -H or halogen, preferably R6 is -H.

[0226] 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.

[0227] 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, C-C alkyl, C-C haloalkyl, or C-C cycloalkyl; preferably, each R is independently -H, halogen, methyl, trifluoromethyl, or cyclopropyl.

[0228] 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.

[0229] 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.

[0230] 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, or C1-C3 haloalkyl. More preferably, each R9 is independently -H, halogen, methyl, or trifluoromethyl.

[0231] 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, C-C alkyl, or C-C haloalkyl. Preferably, each R is independently -H, halogen, methyl, or trifluoromethyl.

[0232] 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, or C1-C3 haloalkyl. Preferably, R9 is —H or trifluoromethyl.

[0233] In still further compounds of formula (III), or a pharmaceutically acceptable salt thereof, R1 is a group of the formula: [ka] wherein R9 is independently -H, halogen, C1-C3 alkyl, or C1-C3 haloalkyl. Preferably, R9 is independently -H, halogen, methyl, or trifluoromethyl.

[0234] 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, or C1-C3 haloalkyl. Preferably, R9 is —H or halogen.

[0235] 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.

[0236] 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, or C1-C3 haloalkyl. Preferably, R9 is independently halogen or trifluoromethyl. More preferably, R9 is chloro or trifluoromethyl.

[0237] 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, or C1-C3 haloalkyl.

[0238] 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 -H, halogen, methyl, trifluoromethyl, or cyclopropyl.

[0239] 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 R2 is a group of the formula: [ka] or R2 is an optionally substituted 5-membered heteroaryl selected from pyrrole, furan, thiophene, pyrazole, isoxazole, isothiazole, imidazole, oxazole, thiazole, triazole, oxadiazole, and thiadiazole, and the optionally substituted 5-membered heteroaryl is selected from -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R 11 , -CONR 11 R 11 , -NR 11 R 11 , -NR 11 CO2R 11 optionally substituted with 1 to 3 substituents each independently selected from optionally substituted C1-C6 alkyl, optionally substituted C3-C5 cycloalkyl, an optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine, or morpholine, optionally substituted phenyl, or an optionally substituted heteroaryl selected from pyridine, 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 independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -NR 11 R 11 , —OH, or —CN; R 10are each 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, an optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine, or morpholine, optionally substituted phenyl, or an 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; R 11 are each independently —H or C1-C3 alkyl.

[0240] 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 R2 is a group of the formula: [ka] is the basis of R 10 are each independently -H, -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R11 , -CONR 11 R 11 , -NR 11 R 11 , -NR 11 -CO2R 11 , optionally substituted C1-C6 alkyl, optionally substituted C3-C5 cycloalkyl, an optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine, or morpholine, optionally substituted phenyl, or an 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; R 11 are each independently —H or C1-C3 alkyl.

[0241] 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 R2 is a group of the formula: [ka] or R2 is an optionally substituted 5-membered heteroaryl selected from pyrrole, furan, thiophene, pyrazole, isoxazole, isothiazole, imidazole, oxazole, thiazole, triazole, oxadiazole, and thiadiazole, and the optionally substituted 5-membered heteroaryl is selected from -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R 11 , -CONR 11 R 11 , -NR 11 R 11 , -NR 11 CO2R 11 optionally substituted with 1 to 3 substituents each independently selected from optionally substituted C1-C6 alkyl, optionally substituted C3-C5 cycloalkyl, an optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine, or morpholine, optionally substituted phenyl, or an optionally substituted heteroaryl selected from pyridine, 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 independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -NR 11 R 11 , -OH, or -CN. 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.

[0242] 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 R2 is a group of the formula: [ka] Preferably, each R is independently -H, halogen, C-C alkyl, or C-C haloalkyl. Most preferably, each R is independently -H, halogen, methyl, or trifluoromethyl.

[0243] 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 R2 is a group of the formula: [ka] or R2 is an optionally substituted 5-membered heteroaryl selected from pyrrole, furan, thiophene, pyrazole, isoxazole, isothiazole, imidazole, oxazole, thiazole, triazole, oxadiazole, and thiadiazole, and the optionally substituted 5-membered heteroaryl is selected from -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R 11 , -CONR 11 R 11 , -NR 11 R 11 , -NR 11 CO2R 11optionally substituted with 1 to 3 substituents each independently selected from optionally substituted C1-C6 alkyl, optionally substituted C3-C5 cycloalkyl, an optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine, or morpholine, optionally substituted phenyl, or an optionally substituted heteroaryl selected from pyridine, 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 independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -NR 11 R 11 , -OH, or -CN. Preferably, each R9 is independently -H, halogen, methyl, or trifluoromethyl.

[0244] 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, or C1-C3 haloalkyl, and R2 is a group of the formula: [ka] or R2 is an optionally substituted 5-membered heteroaryl selected from pyrrole, furan, thiophene, pyrazole, isoxazole, isothiazole, imidazole, oxazole, thiazole, triazole, oxadiazole, and thiadiazole, and the optionally substituted 5-membered heteroaryl is selected from -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R 11 , -CONR 11R 11 , -NR 11 R 11 , -NR 11 CO2R 11 optionally substituted with 1 to 3 substituents each independently selected from optionally substituted C1-C6 alkyl, optionally substituted C3-C5 cycloalkyl, an optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine, or morpholine, optionally substituted phenyl, or an optionally substituted heteroaryl selected from pyridine, 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 independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -NR 11 R 11 , -OH, or -CN, preferably R9 is -H or trifluoromethyl.

[0245] 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, or C1-C3 haloalkyl, and R2 is a group of the formula: [ka] Preferably, R9 is —H or trifluoromethyl.

[0246] 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, or C1-C3 haloalkyl, and R2 is a group of the formula: [ka] or R2 is an optionally substituted 5-membered heteroaryl selected from pyrrole, furan, thiophene, pyrazole, isoxazole, isothiazole, imidazole, oxazole, thiazole, triazole, oxadiazole, and thiadiazole, and the optionally substituted 5-membered heteroaryl is selected from -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R 11 , -CONR 11 R 11 , -NR 11 R 11 , -NR 11 CO2R 11 optionally substituted with 1 to 3 substituents each independently selected from optionally substituted C1-C6 alkyl, optionally substituted C3-C5 cycloalkyl, an optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine, or morpholine, optionally substituted phenyl, or an optionally substituted heteroaryl selected from pyridine, 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 independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -NR 11 R 11 , -OH, or -CN, preferably R9 is -H or halogen.

[0247] 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, or C1-C3 haloalkyl, and R2 is a group of the formula: [ka] Preferably, R9 is —H or halogen.

[0248] 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; and R2 is a group of the formula: [ka] or R2 is an optionally substituted 5-membered heteroaryl selected from pyrrole, furan, thiophene, pyrazole, isoxazole, isothiazole, imidazole, oxazole, thiazole, triazole, oxadiazole, and thiadiazole, and the optionally substituted 5-membered heteroaryl is selected from -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R 11 , -CONR 11 R 11 , -NR 11 R 11 , -NR 11 CO2R 11optionally substituted with 1 to 3 substituents each independently selected from optionally substituted C1-C6 alkyl, optionally substituted C3-C5 cycloalkyl, an optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine, or morpholine, optionally substituted phenyl, or an optionally substituted heteroaryl selected from pyridine, 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 independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -NR 11 R 11 , -OH, or -CN, preferably R9 is -H, halogen, methyl, trifluoromethyl, or cyclopropyl.

[0249] In still further compounds of formula (III), or a pharmaceutically acceptable salt thereof, R1 is a group of the formula: [ka] wherein R9 is halogen or C1-C3 haloalkyl and R2 is a group of the formula: [ka] Preferably, R9 is halogen or trifluoromethyl. More preferably, R9 is chloro or trifluoromethyl.

[0250] 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, or C1-C3 haloalkyl; and R2 is a group of the formula: [ka] or R2 is an optionally substituted 5-membered heteroaryl selected from pyrrole, furan, thiophene, pyrazole, isoxazole, isothiazole, imidazole, oxazole, thiazole, triazole, oxadiazole, and thiadiazole, and the optionally substituted 5-membered heteroaryl is selected from -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R 11 , -CONR 11 R 11 , -NR 11 R 11 , -NR 11 CO2R 11 optionally substituted with 1 to 3 substituents each independently selected from optionally substituted C1-C6 alkyl, optionally substituted C3-C5 cycloalkyl, an optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine, or morpholine, optionally substituted phenyl, or an optionally substituted heteroaryl selected from pyridine, 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 independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -NR 11 R 11 , —OH, or —CN.

[0251] 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, or C1-C3 haloalkyl; and R2 is a group of the formula: [ka] is the basis of

[0252] 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; and R2 is a group of the formula: [ka] or R2 is an optionally substituted 5-membered heteroaryl selected from pyrrole, furan, thiophene, pyrazole, isoxazole, isothiazole, imidazole, oxazole, thiazole, triazole, oxadiazole, and thiadiazole, and the optionally substituted 5-membered heteroaryl is selected from -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R 11 , -CONR 11 R 11 , -NR 11 R 11 , -NR 11 CO2R 11optionally substituted with 1 to 3 substituents each independently selected from optionally substituted C1-C6 alkyl, optionally substituted C3-C5 cycloalkyl, an optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine, or morpholine, optionally substituted phenyl, or an optionally substituted heteroaryl selected from pyridine, 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 independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -NR 11 R 11 , -OH, or -CN, preferably R9 is -H, halogen, methyl, trifluoromethyl, or cyclopropyl.

[0253] 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), R5 is -H, halogen, C1-C6 alkyl, or C1-C6 haloalkyl, R6 is -H or halogen, R7 is -CN, methyl, or trifluoromethyl, and R2 is a group of the formula: [ka] or R2 is an optionally substituted 5-membered heteroaryl selected from pyrrole, furan, thiophene, pyrazole, isoxazole, isothiazole, imidazole, oxazole, thiazole, triazole, oxadiazole, and thiadiazole, and the optionally substituted 5-membered heteroaryl is selected from -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R 11 , -CONR 11 R 11 , -NR 11 R 11 , -NR 11 CO2R 11 optionally substituted with 1 to 3 substituents each independently selected from optionally substituted C1-C6 alkyl, optionally substituted C3-C5 cycloalkyl, an optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine, or morpholine, optionally substituted phenyl, or an optionally substituted heteroaryl selected from pyridine, 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 independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -NR 11 R 11 , -OH, or -CN, and more preferably, R3 is -H or methyl, R5 is -H, halogen, methyl, or trifluoromethyl, R6 is -H, and R7 is methyl.

[0254] In still further compounds of formula (III), or a pharmaceutically acceptable salt thereof, R3 is -H, -CN, or C1-C3 alkyl; R5 is -H, halogen, C1-C6 alkyl, or C1-C6 haloalkyl; R7 is -CN, methyl, or trifluoromethyl; R6 is -H or halogen; and R2 is a group of the formula: [ka] Preferably, R3 is -H or methyl, R5 is -H, halogen, methyl, or trifluoromethyl, R6 is -H, R7 is methyl, and R2 is a group of the formula: [ka] is the basis of

[0255] In still further compounds of formula (III), or a pharmaceutically acceptable salt thereof, R2 is a group of the formula: [ka] or R2 is an optionally substituted 5-membered heteroaryl selected from pyrrole, furan, thiophene, pyrazole, isoxazole, isothiazole, imidazole, oxazole, thiazole, triazole, oxadiazole, and thiadiazole, and the optionally substituted 5-membered heteroaryl is selected from -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R 11 , -CONR 11 R 11 , -NR 11 R 11 , -NR 11 CO2R 11optionally substituted with 1 to 3 substituents each independently selected from optionally substituted C1-C6 alkyl, optionally substituted C3-C5 cycloalkyl, an optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine, or morpholine, optionally substituted phenyl, or an optionally substituted heteroaryl selected from pyridine, 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 independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -NR 11 R 11 , -OH, or -CN; 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.

[0256] In still further compounds of formula (III), or a pharmaceutically acceptable salt thereof, R2 is a group of the formula: [ka] wherein R3 is -H, -CN, or C1-C3 alkyl; 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, or C1-C3 haloalkyl. Preferably, R3 is -H or methyl, R5 is -H, halogen, methyl, or trifluoromethyl, R6 is -H, and each R9 is independently -H, halogen, methyl, or trifluoromethyl.

[0257] In still further compounds of formula (III), or a pharmaceutically acceptable salt thereof, R2 is a group of the formula: [ka] or R2 is an optionally substituted 5-membered heteroaryl selected from pyrrole, furan, thiophene, pyrazole, isoxazole, isothiazole, imidazole, oxazole, thiazole, triazole, oxadiazole, and thiadiazole, and the optionally substituted 5-membered heteroaryl is selected from -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R 11 , -CONR 11 R 11 , -NR 11 R 11 , -NR 11 CO2R 11optionally substituted with 1 to 3 substituents each independently selected from optionally substituted C1-C6 alkyl, optionally substituted C3-C5 cycloalkyl, an optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine, or morpholine, optionally substituted phenyl, or an optionally substituted heteroaryl selected from pyridine, 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 independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -NR 11 R 11 , -OH, or -CN; 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.

[0258] In still further compounds of formula (III), or a pharmaceutically acceptable salt thereof, R2 is a group of the formula: [ka] wherein R3 is -H, -CN, or C1-C3 alkyl; 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.

[0259] 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 R2 is a group of the formula: [ka] or R2 is an optionally substituted 5-membered heteroaryl selected from pyrrole, furan, thiophene, pyrazole, isoxazole, isothiazole, imidazole, oxazole, thiazole, triazole, oxadiazole, and thiadiazole, and the optionally substituted 5-membered heteroaryl is selected from -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R 11 , -CONR 11 R 11 , -NR 11 R 11 , -NR 11 CO2R 11optionally substituted with 1 to 3 substituents each independently selected from optionally substituted C1-C6 alkyl, optionally substituted C3-C5 cycloalkyl, an optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine, or morpholine, optionally substituted phenyl, or an optionally substituted heteroaryl selected from pyridine, 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 independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -NR 11 R 11 , -OH, or -CN; 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).

[0260] 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, or trifluoromethyl (preferably, R9 is -H or trifluoromethyl), and R2 is a group of the formula: [ka] or R2 is an optionally substituted 5-membered heteroaryl selected from pyrrole, furan, thiophene, pyrazole, isoxazole, isothiazole, imidazole, oxazole, thiazole, triazole, oxadiazole, and thiadiazole, and the optionally substituted 5-membered heteroaryl is selected from -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R 11 , -CONR 11 R 11 , -NR 11 R 11 , -NR 11 CO2R 11 optionally substituted with 1 to 3 substituents each independently selected from optionally substituted C1-C6 alkyl, optionally substituted C3-C5 cycloalkyl, an optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine, or morpholine, optionally substituted phenyl, or an optionally substituted heteroaryl selected from pyridine, 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 independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -NR 11 R 11 , -OH, or -CN; R3 is -H or methyl; R5 is -H, halogen, methyl, or trifluoromethyl; R6 is -H or halogen; and R7 is methyl.

[0261] 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, or trifluoromethyl (preferably, R9 is -H or trifluoromethyl), and R2 is a group of the formula: [ka] wherein R3 is -H or methyl, R5 is -H, halogen, methyl, or trifluoromethyl, R6 is -H or halogen, and R7 is methyl.

[0262] 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, or trifluoromethyl (preferably, R9 is -H or halogen), and R2 is a group of the formula: [ka] or R2 is an optionally substituted 5-membered heteroaryl selected from pyrrole, furan, thiophene, pyrazole, isoxazole, isothiazole, imidazole, oxazole, thiazole, triazole, oxadiazole, and thiadiazole, and the optionally substituted 5-membered heteroaryl is selected from -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R 11 , -CONR 11 R 11 , -NR 11 R 11 , -NR 11 CO2R 11optionally substituted with 1 to 3 substituents each independently selected from optionally substituted C1-C6 alkyl, optionally substituted C3-C5 cycloalkyl, an optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine, or morpholine, optionally substituted phenyl, or an optionally substituted heteroaryl selected from pyridine, 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 independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -NR 11 R 11 , -OH, or -CN; R3 is -H or methyl; R5 is -H, halogen, methyl, or trifluoromethyl; R6 is -H or halogen; and R7 is methyl.

[0263] 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, or trifluoromethyl (preferably, R9 is -H or halogen), and R2 is a group of the formula: [ka] wherein R3 is -H or methyl, R5 is -H, halogen, methyl, or trifluoromethyl, R6 is -H or halogen, and R7 is methyl.

[0264] In still further compounds of formula (III), 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 a group of the formula: [ka] or R2 is an optionally substituted 5-membered heteroaryl selected from pyrrole, furan, thiophene, pyrazole, isoxazole, isothiazole, imidazole, oxazole, thiazole, triazole, oxadiazole, and thiadiazole, and the optionally substituted 5-membered heteroaryl is selected from -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R 11 , -CONR 11 R 11 , -NR 11 R 11 , -NR 11 CO2R 11 optionally substituted with 1 to 3 substituents each independently selected from optionally substituted C1-C6 alkyl, optionally substituted C3-C5 cycloalkyl, an optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine, or morpholine, optionally substituted phenyl, or an optionally substituted heteroaryl selected from pyridine, 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 independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -NR 11 R 11, -OH, or -CN; 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).

[0265] 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, or trifluoromethyl (preferably, R9 is halogen or trifluoromethyl), and R2 is a group of the formula: [ka] wherein R3 is -H or methyl, R5 is -H, halogen, methyl, or trifluoromethyl, R6 is -H or halogen, and R7 is methyl.

[0266] 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, or C1-C3 haloalkyl; and R2 is a group of the formula: [ka] or R2 is an optionally substituted 5-membered heteroaryl selected from pyrrole, furan, thiophene, pyrazole, isoxazole, isothiazole, imidazole, oxazole, thiazole, triazole, oxadiazole, and thiadiazole, and the optionally substituted 5-membered heteroaryl is selected from -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R11 , -CONR 11 R 11 , -NR 11 R 11 , -NR 11 CO2R 11 optionally substituted with 1 to 3 substituents each independently selected from optionally substituted C1-C6 alkyl, optionally substituted C3-C5 cycloalkyl, an optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine, or morpholine, optionally substituted phenyl, or an optionally substituted heteroaryl selected from pyridine, 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 independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -NR 11 R 11 , -OH, or -CN; R3 is -H or methyl; R5 is -H, halogen, methyl, or trifluoromethyl; R6 is -H or halogen; and R7 is methyl.

[0267] 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, or C1-C3 haloalkyl; and R2 is a group of the formula: [ka] wherein R3 is -H or methyl, R5 is -H, halogen, methyl, or trifluoromethyl, R6 is -H or halogen, and R7 is methyl.

[0268] In still further compounds of formula (III), 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 a group of the formula: [ka] or R2 is an optionally substituted 5-membered heteroaryl selected from pyrrole, furan, thiophene, pyrazole, isoxazole, isothiazole, imidazole, oxazole, thiazole, triazole, oxadiazole, and thiadiazole, and the optionally substituted 5-membered heteroaryl is selected from -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R 11 , -CONR 11 R 11 , -NR 11 R 11 , -NR 11 CO2R 11 optionally substituted with 1 to 3 substituents each independently selected from optionally substituted C1-C6 alkyl, optionally substituted C3-C5 cycloalkyl, an optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine, or morpholine, optionally substituted phenyl, or an optionally substituted heteroaryl selected from pyridine, 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 independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -NR 11 R 11, -OH, or -CN; 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).

[0269] In still further compounds of formula (I), the compound is [ka] or a pharmaceutically acceptable salt of any of the foregoing; During the ceremony, * The bond at the position is as shown or [ka] or [ka] is.

[0270] In still further compounds of formula (I), the compound is [ka] [ka] [ka] or a pharmaceutically acceptable salt of any of the foregoing; During the ceremony, * The bond at the position is as shown or [ka] or [ka] is.

[0271] In still further compounds of formula (I), the compound is [ka] [ka] [ka] [ka] [ka] [ka] or a pharmaceutically acceptable salt of any of the foregoing; During the ceremony, * The bond at the position is as shown or [ka] or [ka] is.

[0272] In still further compounds of formula (I), the compound is [ka] or a pharmaceutically acceptable salt of any of the foregoing; During the ceremony, * The bond at the position is as shown or [ka] or [ka] is.

[0273] In still further compounds of formula (I), the compound is [ka] [ka] [ka] or a pharmaceutically acceptable salt of any of the foregoing; During the ceremony, * The bond at the position is as shown or [ka] or [ka] is.

[0274] A further embodiment is a compound of the formula: [ka] or a pharmaceutically acceptable salt thereof. * The bond at the position is [ka] In yet a further embodiment, * The bond at the position is [ka] is.

[0275] A further embodiment is a compound of the formula: [ka] or a pharmaceutically acceptable salt thereof. * The bond at the position is [ka] In yet a further embodiment, * The bond at the position is [ka] is.

[0276] A further embodiment is a compound of the formula: [ka] or a pharmaceutically acceptable salt thereof. * The bond at the position is [ka] In yet a further embodiment, * The bond at the position is [ka] is.

[0277] A further embodiment is a compound of the formula: [ka] or a pharmaceutically acceptable salt thereof. * The bond at the position is [ka] In yet a further embodiment, * The bond at the position is [ka] is.

[0278] A further embodiment is a compound of the formula: [ka] or a pharmaceutically acceptable salt thereof.* The bond at the position is [ka] In yet a further embodiment, * The bond at the position is [ka] is.

[0279] A further embodiment is a compound of the formula: [ka] or a pharmaceutically acceptable salt thereof. * The bond at the position is [ka] In yet a further embodiment, * The bond at the position is [ka] is.

[0280] A further embodiment is a compound of the formula: [ka] or a pharmaceutically acceptable salt thereof. * The bond at the position is [ka] In yet a further embodiment, * The bond at the position is [ka] is.

[0281] A further embodiment is a compound of the formula: [ka] or a pharmaceutically acceptable salt thereof. * The bond at the position is [ka] In yet a further embodiment, * The bond at the position is [ka] is.

[0282] A further embodiment is a compound of the formula: [ka] or a pharmaceutically acceptable salt thereof. * The bond at the position is [ka] In yet a further embodiment, * The bond at the position is [ka] is.

[0283] A further embodiment is a compound of the formula: [ka] or a pharmaceutically acceptable salt thereof. * The bond at the position is [ka] In yet a further embodiment, * The bond at the position is [ka] is.

[0284] A further embodiment is a compound of the formula: [ka] or a pharmaceutically acceptable salt thereof. * The bond at the position is [ka] In yet a further embodiment, * The bond at the position is [ka] is.

[0285] A further embodiment is a compound of the formula: [ka] or a pharmaceutically acceptable salt thereof. * The bond at the position is [ka] In yet a further embodiment, * The bond at the position is [ka] is.

[0286] A further embodiment is a compound of the formula: [ka] or a pharmaceutically acceptable salt thereof. * The bond at the position is [ka] In yet a further embodiment, * The bond at the position is [ka] is.

[0287] A further embodiment is a compound of the formula: [ka] or a pharmaceutically acceptable salt thereof. * The bond at the position is [ka] In yet a further embodiment, * The bond at the position is [ka] is.

[0288] A further embodiment is a compound of the formula: [ka] or a pharmaceutically acceptable salt thereof. * The bond at the position is [ka] In yet a further embodiment, * The bond at the position is [ka] is.

[0289] A further embodiment is a compound of the formula: [ka] or a pharmaceutically acceptable salt thereof. * The bond at the position is [ka] In yet a further embodiment,* The bond at the position is [ka] is.

[0290] A further embodiment is a compound of the formula: [ka] or a pharmaceutically acceptable salt thereof. * The bond at the position is [ka] In yet a further embodiment, * The bond at the position is [ka] is.

[0291] A further embodiment is a compound of the formula: [ka] or a pharmaceutically acceptable salt thereof. * The bond at the position is [ka] In yet a further embodiment, * The bond at the position is [ka] is.

[0292] A further embodiment is a compound of the formula: [ka] or a pharmaceutically acceptable salt thereof. * The bond at the position is [ka] In yet a further embodiment, * The bond at the position is [ka] is.

[0293] A further embodiment is a compound of the formula: [ka] or a pharmaceutically acceptable salt thereof. * The bond at the position is [ka] In yet a further embodiment, * The bond at the position is [ka] is.

[0294] A further embodiment is a compound of the formula: [ka] or a pharmaceutically acceptable salt thereof. * The bond at the position is [ka] In yet a further embodiment, * The bond at the position is [ka] is.

[0295] A further embodiment is a compound of the formula: [ka] or a pharmaceutically acceptable salt thereof. * The bond at the position is [ka] In yet a further embodiment, * The bond at the position is [ka] is.

[0296] A further embodiment is a compound of the formula: [ka] or a pharmaceutically acceptable salt thereof. * The bond at the position is [ka] In yet a further embodiment, * The bond at the position is [ka] is.

[0297] A further embodiment is a compound of the formula: [ka] or a pharmaceutically acceptable salt thereof. * The bond at the position is [ka] In yet a further embodiment, * The bond at the position is [ka] is.

[0298] A further embodiment is a compound of the formula: [ka] or a pharmaceutically acceptable salt thereof. * The bond at the position is [ka] In yet a further embodiment, * The bond at the position is [ka] is.

[0299] A further embodiment is a compound of the formula: [ka] or a pharmaceutically acceptable salt thereof. * The bond at the position is [ka] In yet a further embodiment, * The bond at the position is [ka] is.

[0300] A further embodiment is a compound of the formula: [ka] or a pharmaceutically acceptable salt thereof. * The bond at the position is [ka] In yet a further embodiment, * The bond at the position is [ka] is.

[0301] A further embodiment is a compound of the formula: [ka] or a pharmaceutically acceptable salt thereof. * The bond at the position is [ka] In yet a further embodiment, * The bond at the position is [ka] is.

[0302] A further embodiment is a compound of the formula: [ka] or a pharmaceutically acceptable salt thereof. * The bond at the position is [ka] In yet a further embodiment, * The bond at the position is [ka] is.

[0303] A further embodiment is a compound of the formula: [ka] or a pharmaceutically acceptable salt thereof. * The bond at the position is [ka] In yet a further embodiment, * The bond at the position is [ka] is.

[0304] A further embodiment is a compound of the formula: [ka] or a pharmaceutically acceptable salt thereof. * The bond at the position is [ka] In yet a further embodiment, * The bond at the position is [ka] is.

[0305] A further embodiment is a compound of the formula: [ka] or a pharmaceutically acceptable salt thereof. * The bond at the position is [ka] In yet a further embodiment, * The bond at the position is [ka] is.

[0306] A further embodiment is a compound of the formula: [ka] or a pharmaceutically acceptable salt thereof. * The bond at the position is [ka] In yet a further embodiment, * The bond at the position is [ka] is.

[0307] A further embodiment is a compound of the formula: [ka] or a pharmaceutically acceptable salt thereof. * The bond at the position is [ka] In yet a further embodiment, * The bond at the position is [ka] is.

[0308] A further embodiment is a compound of the formula: [ka] or a pharmaceutically acceptable salt thereof. * The bond at the position is [ka] In yet a further embodiment, * The bond at the position is [ka] is.

[0309] A further embodiment is a compound of the formula: [ka] or a pharmaceutically acceptable salt thereof.* The bond at the position is [ka] In yet a further embodiment, * The bond at the position is [ka] is.

[0310] A further embodiment is a compound of the formula: [ka] or a pharmaceutically acceptable salt thereof. * The bond at the position is [ka] In yet a further embodiment, * The bond at the position is [ka] is.

[0311] A further embodiment is a compound of the formula: [ka] or a pharmaceutically acceptable salt thereof. * The bond at the position is [ka] In yet a further embodiment, * The bond at the position is [ka] is.

[0312] A further embodiment is a compound of the formula: [ka] or a pharmaceutically acceptable salt thereof. * The bond at the position is [ka] In yet a further embodiment, * The bond at the position is [ka] is.

[0313] A further embodiment is a compound of the formula: [ka] or a pharmaceutically acceptable salt thereof. * The bond at the position is [ka] In yet a further embodiment, * The bond at the position is [ka] is.

[0314] A further embodiment is a compound of the formula: [ka] or a pharmaceutically acceptable salt thereof. * The bond at the position is [ka] In yet a further embodiment, * The bond at the position is [ka] is.

[0315] A further embodiment is a compound of the formula: [ka] or a pharmaceutically acceptable salt thereof. * The bond at the position is [ka] In yet a further embodiment, * The bond at the position is [ka] is.

[0316] A further embodiment is a compound of the formula: [ka] or a pharmaceutically acceptable salt thereof. * The bond at the position is [ka] In yet a further embodiment, * The bond at the position is [ka] is.

[0317] A further embodiment is a compound of the formula: [ka] or a pharmaceutically acceptable salt thereof. * The bond at the position is [ka] In yet a further embodiment, * The bond at the position is [ka] is.

[0318] A further embodiment is a compound of the formula: [ka] or a pharmaceutically acceptable salt thereof. * The bond at the position is [ka] In yet a further embodiment, * The bond at the position is [ka] is.

[0319] A further embodiment is a compound of the formula: [ka] or a pharmaceutically acceptable salt thereof. * The bond at the position is [ka] In yet a further embodiment, * The bond at the position is [ka] is.

[0320] A further embodiment is a compound of the formula: [ka] or a pharmaceutically acceptable salt thereof. * The bond at the position is [ka] In yet a further embodiment,* The bond at the position is [ka] is.

[0321] A further embodiment is a compound of the formula: [ka] or a pharmaceutically acceptable salt thereof. * The bond at the position is [ka] In yet a further embodiment, * The bond at the position is [ka] is.

[0322] A further embodiment is a compound of the formula: [ka] or a pharmaceutically acceptable salt thereof. * The bond at the position is [ka] In yet a further embodiment, * The bond at the position is [ka] is.

[0323] A further embodiment is a compound of the formula: [ka] or a pharmaceutically acceptable salt thereof. * The bond at the position is [ka] In yet a further embodiment, * The bond at the position is [ka] is.

[0324] A further embodiment is a compound of the formula: [ka] or a pharmaceutically acceptable salt thereof. * The bond at the position is [ka] In yet a further embodiment, * The bond at the position is [ka] is.

[0325] A further embodiment is a compound of the formula: [ka] or a pharmaceutically acceptable salt thereof. * The bond at the position is [ka] In yet a further embodiment, * The bond at the position is [ka] is.

[0326] A further embodiment is a compound of the formula: [ka] or a pharmaceutically acceptable salt thereof. * The bond at the position is [ka] In yet a further embodiment, * The bond at the position is [ka] is.

[0327] A further embodiment is a compound of the formula: [ka] or a pharmaceutically acceptable salt thereof. * The bond at the position is [ka] In yet a further embodiment, * The bond at the position is [ka] is.

[0328] A further embodiment is a compound of the formula: [ka] or a pharmaceutically acceptable salt thereof. * The bond at the position is [ka] In yet a further embodiment, * The bond at the position is [ka] is.

[0329] A further embodiment is a compound of the formula: [ka] or a pharmaceutically acceptable salt thereof. * The bond at the position is [ka] In yet a further embodiment, * The bond at the position is [ka] is.

[0330] A further embodiment is a compound of the formula: [ka] or a pharmaceutically acceptable salt thereof. * The bond at the position is [ka] In yet a further embodiment, * The bond at the position is [ka] is.

[0331] A further embodiment is a compound of the formula: [ka] or a pharmaceutically acceptable salt thereof. * The bond at the position is [ka] In yet a further embodiment, * The bond at the position is [ka] is.

[0332] A further embodiment is a compound of the formula: [ka] or a pharmaceutically acceptable salt thereof. * The bond at the position is [ka] In yet a further embodiment, * The bond at the position is [ka] is.

[0333] A further embodiment is a compound of the formula: [ka] or a pharmaceutically acceptable salt thereof. * The bond at the position is [ka] In yet a further embodiment, * The bond at the position is [ka] is.

[0334] A further embodiment is a compound of the formula: [ka] or a pharmaceutically acceptable salt thereof. * The bond at the position is [ka] In yet a further embodiment, * The bond at the position is [ka] is.

[0335] A further embodiment is a compound of the formula: [ka] or a pharmaceutically acceptable salt thereof. * The bond at the position is [ka] In yet a further embodiment, * The bond at the position is [ka] is.

[0336] A further embodiment is a compound of the formula: [ka] or a pharmaceutically acceptable salt thereof. * The bond at the position is [ka] In yet a further embodiment, * The bond at the position is [ka] is.

[0337] A further embodiment is a compound of the formula: [ka] or a pharmaceutically acceptable salt thereof. * The bond at the position is [ka] In yet a further embodiment, * The bond at the position is [ka] is.

[0338] A further embodiment is a compound of the formula: [ka] or a pharmaceutically acceptable salt thereof. * The bond at the position is [ka] In yet a further embodiment, * The bond at the position is [ka] is.

[0339] A further embodiment is a compound of the formula: [ka] or a pharmaceutically acceptable salt thereof. * The bond at the position is [ka] In yet a further embodiment, * The bond at the position is [ka] is.

[0340] A further embodiment is a compound of the formula: [ka] or a pharmaceutically acceptable salt thereof.* The bond at the position is [ka] In yet a further embodiment, * The bond at the position is [ka] is.

[0341] A further embodiment is a compound of the formula: [ka] or a pharmaceutically acceptable salt thereof. * The bond at the position is [ka] In yet a further embodiment, * The bond at the position is [ka] is.

[0342] A further embodiment is a compound of the formula: [ka] or a pharmaceutically acceptable salt thereof. * The bond at the position is [ka] In yet a further embodiment, * The bond at the position is [ka] is.

[0343] A further embodiment is a compound of the formula: [ka] or a pharmaceutically acceptable salt thereof. * The bond at the position is [ka] In yet a further embodiment, * The bond at the position is [ka] is.

[0344] A further embodiment is a compound of the formula: [ka] or a pharmaceutically acceptable salt thereof. * The bond at the position is [ka] In yet a further embodiment, * The bond at the position is [ka] is.

[0345] A further embodiment is a compound of the formula: [ka] or a pharmaceutically acceptable salt thereof. * The bond at the position is [ka] In yet a further embodiment, * The bond at the position is [ka] is.

[0346] A further embodiment is a compound of the formula: [ka] or a pharmaceutically acceptable salt thereof. * The bond at the position is [ka] In yet a further embodiment, * The bond at the position is [ka] is.

[0347] A further embodiment is a compound of the formula: [ka] or a pharmaceutically acceptable salt thereof. * The bond at the position is [ka] In yet a further embodiment, * The bond at the position is [ka] is.

[0348] A further embodiment is a compound of the formula: [ka] or a pharmaceutically acceptable salt thereof. * The bond at the position is [ka] In yet a further embodiment, * The bond at the position is [ka] is.

[0349] A further embodiment is a compound of the formula: [ka] or a pharmaceutically acceptable salt thereof. * The bond at the position is [ka] In yet a further embodiment, * The bond at the position is [ka] is.

[0350] A further embodiment is a compound of the formula: [ka] or a pharmaceutically acceptable salt thereof. * The bond at the position is [ka] In yet a further embodiment, * The bond at the position is [ka] is.

[0351] A further embodiment is a compound of the formula: [ka] or a pharmaceutically acceptable salt thereof. * The bond at the position is [ka] In yet a further embodiment,* The bond at the position is [ka] is.

[0352] A further embodiment is a compound of the formula: [ka] or a pharmaceutically acceptable salt thereof. * The bond at the position is [ka] In yet a further embodiment, * The bond at the position is [ka] is.

[0353] A further embodiment is a compound of the formula: [ka] or a pharmaceutically acceptable salt thereof. * The bond at the position is [ka] In yet a further embodiment, * The bond at the position is [ka] is.

[0354] A further embodiment is a compound of the formula: [ka] or a pharmaceutically acceptable salt thereof. * The bond at the position is [ka] In yet a further embodiment, * The bond at the position is [ka] is.

[0355] A further embodiment is a compound of the formula: [ka] or a pharmaceutically acceptable salt thereof. * The bond at the position is [ka] In yet a further embodiment, * The bond at the position is [ka] is.

[0356] A further embodiment is a compound of the formula: [ka] or a pharmaceutically acceptable salt thereof. * The bond at the position is [ka] In yet a further embodiment, * The bond at the position is [ka] is.

[0357] A further embodiment is a compound of the formula: [ka] or a pharmaceutically acceptable salt thereof. * The bond at the position is [ka] In yet a further embodiment, * The bond at the position is [ka] is.

[0358] A further embodiment is a compound of the formula: [ka] or a pharmaceutically acceptable salt thereof. * The bond at the position is [ka] In yet a further embodiment, * The bond at the position is [ka] is.

[0359] A further embodiment is a compound of the formula: [ka] or a pharmaceutically acceptable salt thereof. * The bond at the position is [ka] In yet a further embodiment, * The bond at the position is [ka] is.

[0360] A further embodiment is a compound of the formula: [ka] or a pharmaceutically acceptable salt thereof. * The bond at the position is [ka] In yet a further embodiment, * The bond at the position is [ka] is.

[0361] A further embodiment is a compound of the formula: [ka] or a pharmaceutically acceptable salt thereof. * The bond at the position is [ka] In yet a further embodiment, * The bond at the position is [ka] is.

[0362] A further embodiment is a compound of the formula: [ka] or a pharmaceutically acceptable salt thereof. * The bond at the position is [ka] In yet a further embodiment, * The bond at the position is [ka] is.

[0363] A further embodiment is a compound of the formula: [ka] or a pharmaceutically acceptable salt thereof. * The bond at the position is [ka] In yet a further embodiment, * The bond at the position is [ka] is.

[0364] A further embodiment is a compound of the formula: [ka] or a pharmaceutically acceptable salt thereof. * The bond at the position is [ka] In yet a further embodiment, * The bond at the position is [ka] is.

[0365] A further embodiment is a compound of the formula: [ka] or a pharmaceutically acceptable salt thereof. * The bond at the position is [ka] In yet a further embodiment, * The bond at the position is [ka] is.

[0366] A further embodiment is a compound of the formula: [ka] or a pharmaceutically acceptable salt thereof. * The bond at the position is [ka] In yet a further embodiment, * The bond at the position is [ka] is.

[0367] A further embodiment is a compound of the formula: [ka] or a pharmaceutically acceptable salt thereof. * The bond at the position is [ka] In yet a further embodiment, * The bond at the position is [ka] is.

[0368] A further embodiment is a compound of the formula: [ka] or a pharmaceutically acceptable salt thereof. * The bond at the position is [ka] In yet a further embodiment, * The bond at the position is [ka] is.

[0369] A further embodiment is a compound of the formula: [ka] or a pharmaceutically acceptable salt thereof. * The bond at the position is [ka] In yet a further embodiment, * The bond at the position is [ka] is.

[0370] A further embodiment is a compound of the formula: [ka] or a pharmaceutically acceptable salt thereof. * The bond at the position is [ka] In yet a further embodiment, * The bond at the position is [ka] is.

[0371] A further embodiment is a compound of the formula: [ka] or a pharmaceutically acceptable salt thereof.* The bond at the position is [ka] In yet a further embodiment, * The bond at the position is [ka] is.

[0372] A further embodiment is a compound of the formula: [ka] or a pharmaceutically acceptable salt thereof. * The bond at the position is [ka] In yet a further embodiment, * The bond at the position is [ka] is.

[0373] A further embodiment is a compound of the formula: [ka] or a pharmaceutically acceptable salt thereof. * The bond at the position is [ka] In yet a further embodiment, * The bond at the position is [ka] is.

[0374] A further embodiment is a compound of the formula: [ka] or a pharmaceutically acceptable salt thereof. * The bond at the position is [ka] In yet a further embodiment, * The bond at the position is [ka] is.

[0375] A further embodiment is a compound of the formula: [ka] or a pharmaceutically acceptable salt thereof. * The bond at the position is [ka] In yet a further embodiment, * The bond at the position is [ka] is.

[0376] A further embodiment is a compound of the formula: [ka] or a pharmaceutically acceptable salt thereof. * The bond at the position is [ka] In yet a further embodiment, * The bond at the position is [ka] is.

[0377] A further embodiment is a compound of the formula: [ka] or a pharmaceutically acceptable salt thereof. * The bond at the position is [ka] In yet a further embodiment, * The bond at the position is [ka] is.

[0378] A further embodiment is a compound of the formula: [ka] or a pharmaceutically acceptable salt thereof. * The bond at the position is [ka] In yet a further embodiment, * The bond at the position is [ka] is.

[0379] A further embodiment is a compound of the formula: [ka] or a pharmaceutically acceptable salt thereof. * The bond at the position is [ka] In yet a further embodiment, * The bond at the position is [ka] is.

[0380] A further embodiment is a compound of the formula: [ka] or a pharmaceutically acceptable salt thereof. * The bond at the position is [ka] In yet a further embodiment, * The bond at the position is [ka] is.

[0381] A further embodiment is a compound of the formula: [ka] or a pharmaceutically acceptable salt thereof. * The bond at the position is [ka] In yet a further embodiment, * The bond at the position is [ka] is.

[0382] A further embodiment is a compound of the formula: [ka] or a pharmaceutically acceptable salt thereof. * The bond at the position is [ka] In yet a further embodiment,* The bond at the position is [ka] is.

[0383] A further embodiment is a compound of the formula: [ka] or a pharmaceutically acceptable salt thereof. * The bond at the position is [ka] In yet a further embodiment, * The bond at the position is [ka] is.

[0384] A further embodiment is a compound of the formula: [ka] or a pharmaceutically acceptable salt thereof. * The bond at the position is [ka] In yet a further embodiment, * The bond at the position is [ka] is.

[0385] A further embodiment is a compound of the formula: [ka] or a pharmaceutically acceptable salt thereof. * The bond at the position is [ka] In yet a further embodiment, * The bond at the position is [ka] is.

[0386] A further embodiment is a compound of the formula: [ka] or a pharmaceutically acceptable salt thereof. * The bond at the position is [ka] In yet a further embodiment, * The bond at the position is [ka] is.

[0387] A further embodiment is a compound of the formula: [ka] or a pharmaceutically acceptable salt thereof. * The bond at the position is [ka] In yet a further embodiment, * The bond at the position is [ka] is.

[0388] A further embodiment is a compound of the formula: [ka] or a pharmaceutically acceptable salt thereof. * The bond at the position is [ka] In yet a further embodiment, * The bond at the position is [ka] is.

[0389] A further embodiment is a compound of the formula: [ka] or a pharmaceutically acceptable salt thereof. * The bond at the position is [ka] In yet a further embodiment, * The bond at the position is [ka] is.

[0390] A further embodiment is a compound of the formula: [ka] or a pharmaceutically acceptable salt thereof. * The bond at the position is [ka] In yet a further embodiment, * The bond at the position is [ka] is.

[0391] A further embodiment is a compound of the formula: [ka] or a pharmaceutically acceptable salt thereof. * The bond at the position is [ka] In yet a further embodiment, * The bond at the position is [ka] is.

[0392] A further embodiment is a compound of the formula: [ka] or a pharmaceutically acceptable salt thereof. * The bond at the position is [ka] In yet a further embodiment, * The bond at the position is [ka] is.

[0393] A further embodiment is a compound of the formula: [ka] or a pharmaceutically acceptable salt thereof. * The bond at the position is [ka] In yet a further embodiment, * The bond at the position is [ka] is.

[0394] A further embodiment is a compound of the formula: [ka] or a pharmaceutically acceptable salt thereof. * The bond at the position is [ka] In yet a further embodiment, * The bond at the position is [ka] is.

[0395] A further embodiment is a compound of the formula: [ka] or a pharmaceutically acceptable salt thereof. * The bond at the position is [ka] In yet a further embodiment, * The bond at the position is [ka] is.

[0396] 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. Furthermore, 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 methodologies for preparing them are well known in the art (see, for example, P. Stahl, et al., Handbook of Pharmaceutical Salts: Properties, Selection, and Use, 2002). nd Revised Edition (Wiley-VCH, 2011); S.M. Berge, et al., "Pharmaceutical Salts," Journal of Pharmaceutical Sciences, Vol. 66, No. 1, January 1977).

[0397] 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, isothiocyanate, and the like. Salts include ionate, 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 naphthoate, oleate, oxalate, palmitate, pamoate, pantothenate, phosphate / diphosphate, picrate, polygalacturonate, propionate, p-toluenesulfonate, salicylate, stearate, diacetate, succinate, sulfate, sulfosalicylate, tannate, tartrate, teoclate, tosylate, triethiodide, and valerate.

[0398] 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 schemes 1, 2, and 3.The starting materials are either commercially available or can be prepared by known procedures in the published literature or as exemplified below.

[0399] Scheme 1 [ka] Scheme 1 illustrates the preparation of compounds of formula (I) where R is -H, R is methyl, and R is -H. Acylation of substituted phenols (1) can provide esters (2). Esters (2) can undergo rearrangement under Lewis acid (e.g., AlCl) or Bronsted acid (e.g., triflic acid) conditions to provide hydroxyaryl ketones (3). Basic deprotonation of ketones (3) in the presence of carbon disulfide provides bicyclic chromene-2-thiones (4).

[0400] Alkylation of thiones (4) under basic conditions affords thiol ethers (5). Phenyl bromides (5) can be acylated with palladium catalysis to give acylchroman-4-ones (6). Aryl ketones (6) can be reduced to hydroxy compounds (7) with reagents such as sodium borohydride. Hydroxy compounds (7) can be converted to halo compounds (8) using halogenating agents such as phosphorus tribromide.

[0401] Halo compounds 8 can be used to alkylate aryl or heteroaryl amines to give aryl or heteroaryl amines 9. Thiol ethers 9 can be converted to compounds of formula I using transition metal catalysis and coupled with heteroaryl boronic acids, boronic esters, or other coupling partners, followed by hydrolysis of the ester present in R1.

[0402] Scheme 2 [ka] Scheme 2 shows an alternative preparation of compounds of formula (I) where R is -H, R7 is methyl, and R8 is -H. Oxidation of thiol ether (9) with an oxidizing agent such as m-CPBA can provide sulfoxide (10). Sulfoxide (10) can be converted to compounds of formula (I) by substitution with various heteroaryl groups.

[0403] Scheme 3 [ka] Scheme 3 illustrates the preparation of compounds of formula (II) where R is -H and R is methyl. Thiol ether (6) can be converted to 2-substituted chromenone (11) using transition metal catalysis and coupled with heteroarylboronic acids, boronic esters, or other coupling partners. Ketone (11) can be reduced to hydroxy compound (12) with a chiral catalyst such as Noyori's catalyst. Hydroxyl compound (12) can be converted to a leaving group using methanesulfonic anhydride or methanesulfonyl chloride to give mesylate (13). Mesylate (13) can be used to alkylate aryl or heteroaryl amines to give compounds of formula (II) after hydrolysis of the ester present in R.

[0404] Alternatively, ketone 11 can be reduced to hydroxy compound 14 with a chiral catalyst such as Noyori's catalyst. The hydroxyl group can be converted to chloride 15 with a chlorinating agent such as 2,4,6-trichloro-1,3,5-triazine. Chloride 15 can then be used to alkylate aryl or heteroaryl amines to give compounds of formula II after hydrolysis of the ester present in R1.

[0405] 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.

[0406] 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.

[0407] 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.

[0408] 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.

[0409] 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.

[0410] 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).

[0411] 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.

[0412] How to use In some aspects, the present disclosure provides a method of modulating PI3K (e.g., PI3Kα) activity (e.g., in vitro or in vivo), comprising contacting a cell with a therapeutically effective amount of a compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof.

[0413] 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.

[0414] 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.

[0415] In some embodiments, the disease or disorder is associated with PI3K activity being implicated. In some embodiments, the disease or disorder is a disease or disorder in which PI3K activity is implicated.

[0416] In some embodiments, the disease or disorder is cancer.

[0417] In some embodiments, the cancer is selected from the group consisting of 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, cholangiocarcinoma, chordoma, chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), and / or chronic myelogenous leukemia (CML). leukemia, CML), colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, mycosis fungoides, Sézary syndrome, ductal carcinoma in situ (DCIS), germinoma, 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 tumor, GIST), germ cell tumors, gestational trophoblastic disease, hairy cell leukemia, head and neck cancer, hepatocellular carcinoma, Langerhans cell histiocytosis, Hodgkin's lymphoma, pancreatic islet cell tumors, pancreatic neuroendocrine tumors, 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 neck cancer, midline carcinoma with nut gene alterations, mouth cancer, multiple endocrine neoplasia syndrome, multiple myeloma / plasma cell neoplasia, myelodysplastic syndrome, myelodysplastic tumor, myeloproliferative neoplasm, chronic myeloproliferative neoplasm, nasal cavity and paranasal sinus cancer, nasopharyngeal carcinoma, 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 tumor (islet cell tumor), papillomatosis, paraganglioma, sinus and nasal cancer, parathyroid cancer, penile cancer, pharyngeal cancer, pheochromocytoma, pituitary tumor, plasma cell neoplasm, multiple myeloma, pleuropulmonary blastoma, primary central nervous system tumor The cancer is selected from: lymphoma, primary peritoneal cancer, prostate cancer, rectal cancer, recurrent cancer, renal cell (kidney) cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, sarcoma, childhood vascular tumors, skin cancer, small cell lung cancer, small intestine cancer, soft tissue sarcoma, squamous cell carcinoma of the skin, testicular cancer, oropharyngeal cancer, hypopharyngeal cancer, thymoma, thymic carcinoma, thyroid cancer, tracheobronchial tumor, transitional cell carcinoma of the renal pelvis and ureter, urethral cancer, uterine sarcoma, vaginal cancer, vascular tumors, vulvar cancer, and Wilms' tumor.

[0418] 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.

[0419] In some embodiments, the cancer is breast cancer, prostate cancer, or brain cancer.

[0420] In some embodiments, the cancer is breast cancer, in some embodiments, the cancer is prostate cancer, in some embodiments, the cancer is brain cancer.

[0421] In some embodiments, the breast cancer is metastatic breast cancer. In some embodiments, the breast cancer is ductal carcinoma in situ (DCIS). In some embodiments, the breast cancer is invasive ductal carcinoma. In some embodiments, the breast cancer is triple-negative breast cancer. In some embodiments, the breast cancer is medullary carcinoma. In some embodiments, the breast cancer is tubular carcinoma. In some embodiments, the breast cancer is mucinous carcinoma. In some embodiments, the breast cancer is Paget's disease of the breast or nipple. In some embodiments, the breast cancer is inflammatory breast cancer (IBC). In some embodiments, the breast cancer is hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced or metastatic breast cancer.

[0422] 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.

[0423] 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.

[0424] 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.

[0425] In some embodiments, the PI3K-related disease or disorder is CLOVES syndrome (congenital lipomatous overgrowth, vascular malformations, epidermal nevus, scoliosis / skeletal and spinal syndrome).

[0426] In some embodiments, the PI3K-related disease or disorder is PIK3CA-associated overgrowth syndrome (PROS).

[0427] 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.

[0428] In some embodiments, the disease or disorder associated with PI3K is a breast neoplasm, a thyroid neoplasm, an ovarian neoplasm, a non-small cell lung cancer, an endometrial neoplasm, or a pancreatic neoplasm. In some embodiments, the disease or disorder associated with PI3K is a breast neoplasm. In some embodiments, the disease or disorder associated with PI3K is a thyroid neoplasm. In some embodiments, the disease or disorder associated with PI3K is an ovarian neoplasm. In some embodiments, the disease or disorder associated with PI3K is non-small cell lung cancer. In some embodiments, the disease or disorder associated with PI3K is an endometrial neoplasm. In some embodiments, the disease or disorder associated with PI3K is a pancreatic neoplasm.

[0429] 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.

[0430] In some embodiments, the PI3K-related disease or disorder is leukemia, lymphoma, or sarcoma.

[0431] In some embodiments, the cancer is endometrial cancer, head and neck cancer, or sarcoma.

[0432] 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.

[0433] 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.

[0434] 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.

[0435] 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.

[0436] 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.

[0437] 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.

[0438] 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.

[0439] 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.

[0440] 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.

[0441] 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.

[0442] 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.

[0443] In some aspects, the disclosure provides a compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof, for use in therapy.

[0444] 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 vivo or in vivo).

[0445] 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.

[0446] 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.

[0447] 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.

[0448] 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 of cancer.

[0449] 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.

[0450] 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.

[0451] 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.

[0452] 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.

[0453] 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.

[0454] 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.

[0455] 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).

[0456] 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.

[0457] 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.

[0458] 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.

[0459] 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.

[0460] 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.

[0461] 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.

[0462] 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.

[0463] 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.

[0464] 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.

[0465] 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.

[0466] 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.

[0467] In some embodiments, the PI3K modulation is an inhibition of PI3K.

[0468] In some embodiments, the PI3K inhibitor is a PI3K alpha inhibitor. In some embodiments, the PI3K inhibitor is a PI3K alpha H1047R mutation inhibitor.

[0469] The efficacy of the compounds of the present disclosure can be determined by industry-recognized assays / disease models according to standard practices that are described in the art and that elucidate the same as found in current general knowledge.

[0470] 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 treatment for the disease or disorder, comprising administering to the patient a therapeutically effective amount of a compound as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition.

[0471] 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).

[0472] 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., orally or nasally, e.g., via aerosol, e.g., by inhalation or insufflation therapy), rectal (e.g., by suppository or enema), vaginal (e.g., by pessary), parenteral (e.g., by injection, including subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcuticular, intraarticular, subarachnoid, and intrasternal), implantation of a depot or reservoir (e.g., subcutaneous or intramuscular). [Example]

[0473] 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).

[0474] Nuclear magnetic resonance (NMR) spectra were recorded at 400 MHz or 300 MHz as indicated, and at 300.3 K unless otherwise noted, and chemical shifts (δ) are reported in parts per million (ppm). Spectra were recorded using Bruker or Varian instruments with 8, 16, or 32 scans.

[0475] LC-MS chromatograms and spectra were recorded using an Agilent 1200 or Shimadzu LC-20 AD&MS 2020 instrument using a C-18 column such as a Luna-C18 2.0 x 30 mm or an Xbridge Shield RPC18 2.1 x 50 mm. The injection volume was 0.7-8.0 μl, and the flow rate was typically 0.8 or 1.2 ml / min. The detection methods were diode array (DAD) or evaporative light scattering (ELSD) and 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%).

[0476] [Table 1]

[0477] Intermediate 1: (2-Bromo-4-methyl-phenyl)acetate [ka] A mixture of 2-bromo-4-methyl-phenol (300 g, 1.6 mol) and pyridine (152 g, 1.92 mol) in DCM (2.4 L) was treated with acetyl chloride at 0 °C and stirred at 25 °C for 16 h. The mixture was diluted with water (1500 mL), the pH adjusted to 5 with HCl (2 M aqueous solution), and extracted with DCM (3 × 500 mL). The combined organic extracts were washed with brine (2 × 250 mL), dried over NaSO, filtered, and concentrated to give the product as an oil (400 g, crude). 1 H NMR(400MHz,CDCl3)δ ppm 2.24(s,3 H),2.25(s,3 H),6.91(d,J=8.4Hz,2 H),7.01-7.02(m,2 H),7.33(s,1 H).

[0478] Intermediate 2: 1-(3-bromo-2-hydroxy-5-methyl-phenyl)ethanone [ka] A mixture of (2-bromo-4-methyl-phenyl)acetate (50 g, 218 mmol) and AlCl (102 g, 764 mmol) was degassed, purged with N three times, and stirred at 140 °C for 1 h. After cooling to room temperature, the reaction was diluted with DCM (30 mL) and added dropwise to 150 mL of water at 0 °C. The mixture was filtered, and the aqueous phase was extracted with DCM (2 × 150 mL). The combined organic extracts were washed with brine, dried over anhydrous NaSO, filtered, and concentrated. The residue was triturated with petroleum ether (2 × 150 mL) to give the product as a solid (30 g, 52%). 1 H NMR(400MHz,CDCl3)δ ppm 2.30(s,3 H),2.68(s,3 H),7.73(s,1 H),7.33(s,1 H),12.64(s,1 H).

[0479] Intermediate 3: 8-Bromo-4-hydroxy-6-methyl-chromene-2-thione [ka] A solution of 1-(3-bromo-2-hydroxy-5-methyl-phenyl)ethanone (65 g, 284 mmol) in THF (800 mL) was treated with NaHMDS (851 mL, 1 M) at −50° C. over 30 min, warmed to −5° C. to 0° C., and stirred for 1 h. The reaction was cooled to −20° C., treated dropwise with CS (64.8 g, 851 mmol) over 1 h, warmed to 25° C., and stirred for an additional 16 h. The reaction was quenched with HSO (800 mL, 15%) at −50° C. over 1 h, warmed to room temperature, and extracted with EtOAc (2 × 1 L). The combined organic extracts were washed with brine (1 L), dried over anhydrous NaSO, filtered, and concentrated. The residue was triturated with EtOAc (0.5 L) to give the product as a solid (210 g crude, 64%, purity approx. 76%).

[0480] Intermediate 4: 8-Bromo-2-ethylsulfanyl-6-methyl-chromen-4-one [ka] A mixture of 8-bromo-4-hydroxy-6-methyl-chromene-2-thione (20.0 g, 73.8 mmol), EtI (46 g, 295 mmol), and KCO (12.2 g, 88.5 mmol) in acetone (200 mL) was stirred at 60 °C for 3 h. When the reaction cooled to room temperature, the mixture was diluted with water (200 mL) and extracted with DCM (2 × 200 mL). The combined organic extracts were concentrated and purified by silica gel chromatography eluting with 20% to 40% EtOAc in petroleum ether to give the product as a gum. 1 H NMR(400MHz,CDCl3)δ ppm 1.51(t,J=7.2Hz,3 H),2.45(s,3 H),3.22(q,J=7.2Hz,2 H),6.32(s,1 H),7.70(s,1 H),7.93(s,1 H).

[0481] Intermediate 5: 8-Acetyl-2-ethylsulfanyl-6-methyl-chromen-4-one [ka] A mixture of 8-bromo-2-ethylsulfanyl-6-methyl-chromen-4-one (9.00 g, 30.0 mmol), tributyl(1-ethoxyvinyl)tin (13.3 g, 36.8 mmol), and Pd(PPh3)2Cl2 (2.11 g, 3.01 mmol) in dioxane (90 mL) was stirred at 95 °C for 16 h. HCl (30 mL, 1 M) was added to the mixture and stirred at 50 °C for 0.5 h. Upon cooling to room temperature, the mixture was treated with saturated aqueous KF solution (100 mL), stirred for 0.5 h, and filtered. The filter cake was washed with EtOAc (3 × 40 mL). The filtrate was extracted with EtOAc (2 × 80 mL). The combined organic extracts were concentrated and purified on a silica gel column eluted with 0–60% EtOAc in petroleum ether to give the product as a solid (5.8 g, 60%). MS ES+m / z 263[M+H] + .

[0482] Intermediate 6: 2-Ethylsulfanyl-8-(1-hydroxyethyl)-6-methyl-chromen-4-one [ka] A solution of 8-acetyl-2-ethylsulfanyl-6-methyl-chromen-4-one (8.30 g, 31.6 mmol) in DCM (30 mL) and MeOH (30 mL) was treated with NaBH (1.32 g, 34.8 mmol) in small portions at 0 °C and stirred at 15 °C for 1 h. The mixture was diluted with water (50 mL) and extracted with DCM (2 × 100 mL). The combined organic extracts were washed with brine (80 mL), dried over anhydrous NaSO, filtered, and concentrated. The residue was purified on a silica gel column eluting with 0-4% MeOH in DCM to give the product as a solid (6.0 g, 60%). MS ES+ m / z 265 [M+H] + .

[0483] Intermediate 7: 8-(1-Bromoethyl)-2-ethylsulfanyl-6-methyl-chromen-4-one [ka] A mixture of 2-ethylsulfanyl-8-(1-hydroxyethyl)-6-methyl-chromen-4-one (5.50 g, 20.8 mmol) in DCM (50 mL) was treated dropwise with PBr (16.9 g, 62.4 mmol) at 0 °C and then stirred at 30 °C for 4 h. The reaction was quenched with water (20 mL) at 0 °C and the pH was adjusted to 8 with saturated aqueous NaHCO. The mixture was extracted with DCM (2 × 80 mL). The combined organic extracts were washed with brine, dried over anhydrous NaSO, filtered, and concentrated to give the product as an oil (4.7 g, 61%). MS ES+ m / z 329 [M+2+H] + .

[0484] Intermediate 8: tert-butyl 2-[1-(2-ethylsulfanyl-6-methyl-4-oxo-chromen-8-yl)ethylamino]benzoate [ka] 8-(1-Bromoethyl)-2-ethylsulfanyl-6-methyl-chromen-4-one (25.0 g, 76.4 mmol), tert-butyl 2-aminobenzoate (29.5 g, 153 mmol), and DIEA (14.8 g, 20.0 mL, 115 mmol) were combined with DMF (150 mL) in a 500 mL round-bottom flask and heated at 80 °C. After cooling to room temperature, the reaction was partially concentrated to approximately 100 mL, poured into 1.1 L of water, and extracted with EtOAc (2 × 350 mL). The combined organic layers were washed with brine (400 mL). The combined aqueous layers were re-extracted with fresh EtOAc. The organic layers were combined, dried over anhydrous NaSO, filtered, and concentrated to give a thick oil. The residue was purified by silica gel chromatography using EtOAc in DCM (0% to 10%) to give an off-white foam. Trituration with heptane / DCM and washing with heptane gave the product as a white solid (27.1 g, 81%). MS ES+ m / z 440 [M+H] + .

[0485] Intermediate 9: tert-butyl 2-[1-[2-(6-isopropoxy-3-pyridyl)-6-methyl-4-oxo-chromen-8-yl]ethylamino]benzoate [ka] tert-Butyl 2-[1-(2-ethylsulfanyl-6-methyl-4-oxo-chromen-8-yl)ethylamino]benzoate (0.100 g, 227 μmol), (6-isopropoxypyridin-3-yl)boronic acid (82.4 mg, 455 μmol), zinc(II) acetate (83.5 mg, 455 μmol), tris(dibenzylideneacetone)dipalladium(0) (20.8 mg, 22.7 μmol), copper(I) thiophene-2-carboxylate (86.8 mg, 455 μmol), and tri(2-furyl)phosphine (26.4 mg, 114 μmol) were combined in THF (2 mL) and degassed with argon for 5 minutes. The reaction mixture was stirred at 75 °C overnight. Silica gel was added to the reaction mixture and concentrated. Purification by silica gel chromatography using a gradient of EtOAc in heptane (0-100%) gave the product (0.151 g). MS ES+ m / z 515 [M+H] + .

[0486] Intermediate 10: tert-butyl 2-[1-[2-(2-methoxypyrimidin-5-yl)-6-methyl-4-oxo-chromen-8-yl]ethylamino]benzoate [ka] tert-Butyl 2-[1-(2-ethylsulfanyl-6-methyl-4-oxo-chromen-8-yl)ethylamino]benzoate (200 mg, 455 μmol), (2-methoxypyrimidin-5-yl)boronic acid (140 mg, 910 μmol), tris(dibenzylideneacetone)dipalladium(0) (42 mg, 46 μmol), cesium carbonate (445 mg, 1.365 mmol), and tri(2-furyl)phosphine (10.6 mg, 46 μmol) were combined in 1,4-dioxane (5 mL) and heated at 85° C. for 12 hours. The reaction mixture was filtered, concentrated, and purified by silica gel chromatography using a 10-80% ethyl acetate in heptane gradient to give the product (90 mg, 41%). MS ES+ m / z 488 [M+H] + .

[0487] Intermediate 11: Methyl 2-[1-(2-ethylsulfanyl-6-methyl-4-oxo-chromen-8-yl)ethylamino]benzoate [ka] A mixture of 8-(1-bromoethyl)-2-ethylsulfanyl-6-methyl-chromen-4-one (4.00 g, 12.2 mmol) and methyl 2-aminobenzoate (3.70 g, 24.5 mmol) in DMF (30 mL) was stirred at 80° C. for 8 hours. Upon cooling to room temperature, the mixture was diluted with water (100 mL) and extracted with EtOAc (3×80 mL). The combined organic extracts were washed with brine (3×100 mL), dried over anhydrous NaSO, filtered, and concentrated. The residue was purified by silica gel chromatography eluting with 0%-27% EtOAc in petroleum ether to give the product as a solid (4.5 g, 84%). MS ES+ m / z 398 [M+H] + .

[0488] Intermediate 12 and Intermediate 13: Methyl 2-[1-(2-ethylsulfanyl-6-methyl-4-oxo-chromen-8-yl)ethylamino]benzoate, Isomer 1 and Isomer 2 [ka] Methyl 2-[1-(2-ethylsulfanyl-6-methyl-4-oxo-chromen-8-yl)ethylamino]benzoate (13 g, 32.71 mmol) was separated by supercritical fluid chromatography (DAICEL CHIRALPAK AS, 250 mm × 50 mm, 10 μm, 30% EtOH (containing 0.1% NH4OH): 70% CO2) to give the product isomers as white solids (4.3 g, 5.6 g). Both had MS ES+ m / z 398 [M+H]. + .

[0489] Intermediate 14: Methyl 2-[1-(6-methyl-4-oxo-2-pyrimidin-2-yl-chromen-8-yl)ethylamino]benzoate, isomer 2 [ka] A mixture of methyl 2-[1-(2-ethylsulfanyl-6-methyl-4-oxo-chromen-8-yl)ethylamino]benzoate, isomer 2 (300 mg, 754.74 μmol), tributyl(pyrimidin-2-yl)stannane (613 mg, 1.66 mmol), Pd(PPh3)4 (87 mg, 75.47 μmol), and CuBr (238 mg, 1.66 mmol) in THF (6 mL) was stirred at 70 °C under N2 for 10 h to give a brown suspension. The reaction mixture was cooled to room temperature, concentrated, and purified by flash silica gel chromatography using a gradient of 0-40% EtOAc in petroleum ether to give the product as a pale yellow solid (150 mg, 48%). MS ES+ m / z 416 [M+H] + .

[0490] Intermediate 15 and Intermediate 16: tert-Butyl 2-[1-(2-ethylsulfanyl-6-methyl-4-oxo-chromen-8-yl)ethylamino]benzoate, Isomer 1 and Isomer 2 [ka] tert-Butyl 2-[1-(2-ethylsulfanyl-6-methyl-4-oxo-chromen-8-yl)ethylamino]benzoate (22.04 g, 50.14 mmol) was separated into its component isomers using a Chiralcel OJ column (8 x 34 cm, 20 microns) eluted with 100% MeOH (containing 0.2% DMEA) to give Isomer 1 (11.3 g wet) and Isomer 2 (12.9 g wet). MS ES+ m / z 440 [M+H] + .

[0491] Intermediate 17 and Intermediate 18: 2-[1-(2-ethylsulfanyl-6-methyl-4-oxo-chromen-8-yl)ethylamino]benzoic acid, Isomer 1 and Isomer 2 [ka] A mixture of 8-(1-bromoethyl)-2-ethylsulfanyl-6-methyl-chromen-4-one (10 g, 31 mmol) and 2-aminobenzoic acid (8.38 g, 61.1 mmol) in DMF (70 mL) was stirred at 80° C. for 2 hours. The reaction mixture was diluted with DCM (200 mL) and water (500 mL), and the pH was adjusted to approximately 11 with aqueous NaOH (2 M). After removing the organic layer, the aqueous layer was washed with MTBE (200 mL × 2) and the pH was adjusted to approximately 3 with aqueous HCl (2 M) to give a solid. After stirring for 0.5 h, the mixture was filtered and the filter cake was purified by chiral SFC (Daicel ChiralCel OJ-H, 250 × 30 mm, 5 μm) using a 5-50% MeOH (containing 0.1% aqueous NH) / CO gradient to give Isomer 1 (5.4 g, 45%, >99% ee) and Isomer 2 (4.9 g, 41%, >99% ee), both with MS ES+ m / z 384 [M+H]. + .

[0492] Intermediate 19: 2-[1-(2-ethylsulfinyl-6-methyl-4-oxo-chromen-8-yl)ethylamino]benzoic acid, isomer 2 [ka] A mixture of 2-[1-(2-ethylsulfanyl-6-methyl-4-oxo-chromen-8-yl)ethylamino]benzoic acid, isomer 2 (850 mg, 2.22 mmol) in DCM (10 mL) was treated with m-CPBA (585 mg, 2.88 mmol, 85% purity) at 0 °C under N. The reaction was stirred at 25 °C for 2 h. The mixture was quenched with saturated NaSO (10 mL) at 0 °C, and the aqueous layer was extracted with EtOAc (2 × 20 mL). The combined organic layers were washed with brine (3 × 20 mL), dried over anhydrous NaSO, filtered, and concentrated. The residue was purified by silica gel chromatography eluting with 0-80% EtOAc / petroleum ether to give the product as a solid (410 mg, 42%). MS ES+ m / z 400 [M+H] + .

[0493] Intermediate 20: tert-Butyl 2-[1-[6-methyl-4-oxo-2-(1H-pyrazol-4-yl)chromen-8-yl]ethylamino]benzoate, Isomer 2 [ka] tert-Butyl 2-[1-(2-ethylsulfanyl-6-methyl-4-oxo-chromen-8-yl)ethylamino]benzoate, isomer 2 (0.25 g, 0.57 mmol), (1H-pyrazol-4-yl)boronic acid (0.19 g, 1.71 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.052 g, 0.057 mmol), copper(I) thiophene-2-carboxylate (0.22 g, 1.14 mmol), zinc(II) acetate (0.21 g, 1.14 mmol), and tri(2-furyl)phosphine (0.066 g, 0.28 mmol) were combined in 2-methyltetrahydrofuran (12 mL) and heated at 95° C. for 24 hours. (1H-pyrazol-4-yl)boronic acid (0.19 g, 1.71 mmol) and tris(dibenzylideneacetone)dipalladium(0) (0.052 g, 0.057 mmol) were added and heated at 95° C. for 24 hours. The crude product mixture was quenched with water and concentrated. The residue was purified using a silica column (0-15% ethyl acetate / heptane, then 5% methanol / DCM) followed by reverse-phase chromatography (10-100% acetonitrile (containing 0.1% TFA) / water) to give the product (0.17 g, 57%). MS ES+ m / z 446 [M+H] + .

[0494] Intermediate 21: tert-Butyl 2-[1-[2-[1-(4-chlorophenyl)pyrazol-4-yl]-6-methyl-4-oxo-chromen-8-yl]ethylamino]benzoate, Isomer 2 [ka] tert-Butyl 2-[1-[6-methyl-4-oxo-2-(1H-pyrazol-4-yl)chromen-8-yl]ethylamino]benzoate, isomer 2 (0.030 g, 0.067 mmol), 1-chloro-4-iodobenzene (0.032 g, 0.13 mmol), potassium carbonate (0.020 g, 0.14 mmol), copper(I) iodide (0.26 mg, 0.02 equiv.), and (1S,2S)-N1,N2-dimethylcyclohexane-1,2-diamine (1.9 mg, 0.2 equiv.) in 1,4-dioxane (2 mL) were mixed and heated at 110 °C for 12 h. 1-Chloro-4-iodobenzene (0.032 g, 0.13 mmol), potassium carbonate (0.020 g, 0.14 mmol), copper(I) iodide (0.26 mg, 0.02 equiv.), and (1S,2S)-N1,N2-dimethylcyclohexane-1,2-diamine (1.9 mg, 0.2 equiv.) were added and heated at 110 °C for 12 h. The crude product mixture was quenched with water and concentrated. Purification using reverse-phase chromatography (10-100% acetonitrile (containing 0.1% TFA) / water) gave the product (0.016 g, 38%). MS ES+ m / z 556 [M+H] + .

[0495] Intermediate 22: tert-Butyl 2-[1-(2-ethylsulfanyl-3-iodo-6-methyl-4-oxo-chromen-8-yl)ethylamino]benzoate, Isomer 2 [ka] A dry flask equipped with a stir bar and septum was flushed with argon gas and then charged with tert-butyl 2-[1-(2-ethylsulfanyl-6-methyl-4-oxo-chromen-8-yl)ethylamino]benzoate, isomer 2 (1.00 g, 2.27 mmol) and dry THF (2 mL). The reaction was cooled in an ice bath. Upon cooling, 2,2,6,6-tetramethylpiperidinylzinc chloride / lithium chloride complex (1 M THF, 1.93 g, 6.82 mmol) was added dropwise via addition funnel over 30 minutes. After the addition was complete, the reaction was allowed to stir at 0°C. After 1 hour, iodine (1 M, 2.73 mL, 2.73 mmol) dissolved in dry THF was added dropwise via addition funnel. After the addition was complete, the reaction was allowed to stir at 0°C. After 1 hour, the reaction was cooled to -40°C and quenched with methanol (10 mL). 50 mL of ammonium chloride / ammonia solution (2M aqueous, 50 mL) was added and the reaction was stirred at room temperature for 2 hours. Extraction was performed three times with 300 mL of dichloromethane. The organics were combined, washed with aqueous sodium carbonate, collected, dried over Na2SO4, filtered, and concentrated. The residue was purified by reverse-phase chromatography (C18) eluting with 0%-80% acetonitrile (containing 0.1% TFA) / water (containing 0.1% TFA) to give the product (0.90 g, 66%). MS ES+ m / z 566 [M+H] + .

[0496] Intermediate 23: tert-Butyl 2-[1-[2-ethylsulfanyl-6-methyl-4-oxo-3-(trifluoromethyl)chromen-8-yl]ethylamino]benzoate, Isomer 2 [ka] tert-Butyl 2-[1-(2-ethylsulfanyl-3-iodo-6-methyl-4-oxo-chromen-8-yl)ethylamino]benzoate, isomer 2 (0.31 g, 0.56 mmol), copper(I) iodide (0.13 g, 0.67 mmol), and methyl difluoro(fluorosulfonyl)acetate (0.53 g, 2.78 mmol) were mixed in DMF (4 mL) and stirred at 75 °C for 6 h. The reaction mixture was cooled to room temperature and diluted with ethyl acetate (30 mL). The organic layer was washed with water (3 x 15 mL) and concentrated. The residue was purified on a silica column (0-100% ethyl acetate / heptane) to give the product (0.20 g, 71%). MS ES+ m / z 508 [M+H] + .

[0497] Intermediate 24: 8-Acetyl-2-[6-(difluoromethyl)-2-pyridyl]-3,6-dimethyl-chromen-4-one [ka] Intermediate 24 can be prepared according to the previous intermediate. MS ES+ m / z 344 [M+H] + .

[0498] Intermediate 25: 2-[6-(difluoromethyl)-2-pyridyl]-8-[(1R)-1-hydroxyethyl]-3,6-dimethyl-chromen-4-one [ka] A solution of 8-acetyl-2-[6-(difluoromethyl)-2-pyridyl]-3,6-dimethyl-chromen-4-one (0.50 g, 1.45 mmol), formic acid (0.21 g, 4.37 mmol), and RuCl(p-cymene) [(R,R)-Ts-DPEN] (CAS 192139-92-7, 0.046 g, 0.072 mmol) in DCM (10 mL) was stirred at 0 °C. 1,8-Diazabicyclo[5.4.0]undec-7-ene (0.67 g, 4.37 mmol) was added dropwise. The reaction was stirred at room temperature for 12 hours and concentrated. The residue was purified on a silica column (1:1 heptane:ethyl acetate) to give the product (0.41 g, 82%). MS ES+ m / z 346 [M+H] + .

[0499] Intermediate 26: 8-[(1S)-1-chloroethyl]-2-[6-(difluoromethyl)-2-pyridyl]-3,6-dimethyl-chromen-4-one [ka] A solution of trichloro[1,3,5]triazine (0.33 g, 1.78 mmol) in DMF (0.1 mL) was stirred at room temperature for 30 minutes. To this was added a solution of 2-[6-(difluoromethyl)-2-pyridyl]-8-[(1R)-1-hydroxyethyl]-3,6-dimethyl-chromen-4-one (0.41 g, 1.19 mmol) in DCM (10 mL). The reaction was stirred for 4 hours. It was diluted with saturated aqueous sodium carbonate (100 mL) and DCM (20 mL). The layers were separated. The organic layer was washed with brine and concentrated. The residue was purified on a silica column (2:1 heptane:ethyl acetate) to give the product (0.32 g, 74%, 89% enantiomeric excess). MS ES+ m / z 364 [M+H] + .

[0500] Example 1: 2-[1-[2-(6-isopropoxy-3-pyridyl)-6-methyl-4-oxo-chromen-8-yl]ethylamino]benzoic acid 2,2,2-trifluoroacetic acid [ka] tert-Butyl 2-[1-[2-(6-isopropoxy-3-pyridyl)-6-methyl-4-oxo-chromen-8-yl]ethylamino]benzoate (0.150 g, 291 μmol) was dissolved in TFA / DCM (1.5 mL each) and stirred at 40° C. for 3 hours. The reaction mixture was concentrated and directly purified using reverse phase (C-18 column, 10-100% acetonitrile [0.1% TFA] / water [0.1% TFA]) to give the product as the trifluoroacetate salt (0.052 g, 31%). MS ES+ m / z 459 [M+H] + .

[0501] Example 2: 2-[1-[2-(2-methoxypyrimidin-5-yl)-6-methyl-4-oxo-chromen-8-yl]ethylamino]benzoic acid 2,2,2-trifluoroacetic acid [ka] A solution of tert-butyl 2-[1-[2-(2-methoxypyrimidin-5-yl)-6-methyl-4-oxo-chromen-8-yl]ethylamino]benzoate (90.0 mg, 185 μmol) in DCM (2 mL) was treated with TFA (2.0 mL, 26 mmol) and heated at 40° C. for 3 h. The reaction mixture was concentrated and purified using a C-18 column eluted with 10-90% acetonitrile / water (0.1% TFA (additive)) to give the product as the trifluoroacetate salt (28 mg). MS ES+ m / z 432 [M+H] + .

[0502] Example 3: 2-[1-(6-methyl-4-oxo-2-pyrimidin-2-yl-chromen-8-yl)ethylamino]benzoic acid, isomer 2 [ka] A mixture of boron tribromide (180.91 mg, 722.13 μmol, 69.58 μL) in DCM (0.5 mL) was added to a mixture of methyl 2-[1-(2-ethylsulfanyl-6-methyl-4-oxo-chromen-8-yl)ethylamino]benzoate, isomer 2 (100 mg, 240.71 μmol) in DCM (2 mL) at −78° C., followed by stirring at 20° C. for 14 hours to give a yellow suspension. The reaction mixture was poured into water and extracted with DCM (2×20 mL), and the combined organic phases were concentrated to give a residue. The residue was purified by preparative HPLC using 0.225% formic acid as an additive to give the product as a pale yellow solid (6.65 mg, 6.9%). MS ES+ m / z 402 [M+H] + .

[0503] Examples 4 and 5: 2-[1-[2-(2-methoxypyrimidin-5-yl)-6-methyl-4-oxo-chromen-8-yl]ethylamino]benzoic acid, isomer 1 and isomer 2 [ka] 2-[1-[2-(2-Methoxypyrimidin-5-yl)-6-methyl-4-oxochromen-8-yl]ethylamino]benzoic acid 2,2,2-trifluoroacetic acid (22 mg) was dissolved in MeOH (2.25 mL) and DCM (2.25 mL). Separation by supercritical fluid chromatography (Chiralpak AD-H, 150 mm x 21 mm, 30% EtOH (containing 0.5% DMEA): 70% CO2) gave the product isomers (8.3 mg, 8.3 mg). Both had MS ES+ m / z 432 [M+H]. + .

[0504] The compounds in Table 1 below can be made according to Schemes 1-3 or the examples above. [Table 2-1] [Table 2-2] [Table 2-3] Table 2-4 Table 2-5 Table 2-6 Table 2-7 Table 2-8 Table 2-9 Table 2-10 Table 2-11 Table 2-12 Table 2-13 Table 2-14 Table 2-15 Table 2-16 Table 2-17 Table 2-18 Table 2-19 Table 2-20 [Table 2-21] [Table 2-22] [Table 2-23] [Table 2-24] [Table 2-25] [Table 2-26] [Table 2-27] [Table 2-28] [Table 2-29] [Table 2-30]

[0505] Example 57: 2-[1-[6-methyl-4-oxo-2-(triazol-2-yl)chromen-8-yl]ethylamino]benzoic acid, isomer 2, 2,2,2-trifluoroacetic acid [ka] 1H-1,2,3-Triazole (54.5 mg, 0.79 mmol) was dissolved in acetonitrile (2 mL), cooled to 0 °C, and treated with sodium hydride (31.5 mg, 60 wt% in oil, 0.79 mmol). After stirring at 0 °C for 15 min, the suspension was treated with 2-[1-(2-ethylsulfinyl-6-methyl-4-oxo-chromen-8-yl)ethylamino]benzoic acid, isomer 2 (150 mg, 0.38 mmol). The yellow suspension was stirred at room temperature. After 30 min, the suspension was treated with 1.5 mL of DMF to solubilize the suspension. After 5 min, the reaction was concentrated, dissolved in water (1 mL) and acetonitrile (2.3 mL), and purified using reverse phase (C-18 column, 10-100% acetonitrile [0.1% TFA] / water [0.1% TFA]) to give the product as the trifluoroacetate salt (30 mg, 15%). MS ES+ m / z 391 [M+H] + .

[0506] The compounds in Table 2 below can be made according to Schemes 1-3 or the previous examples. [Table 3]

[0507] Example 142: 2-[[(1R)-1-[2-[6-(difluoromethyl)-2-pyridyl]-3,6-dimethyl-4-oxo-chromen-8-yl]ethyl]amino]benzoic acid [ka] A solution of 8-[(1S)-1-chloroethyl]-2-[6-(difluoromethyl)-2-pyridyl]-3,6-dimethyl-chromen-4-one (0.20 g, 0.55 mmol) and 2-aminobenzoic acid (0.23 g, 1.65 mmol) in isopropanol (4 mL) was stirred at room temperature. Triethylamine (0.22 g, 2.20 mmol) was added. The reaction was stirred at reflux for 2 hours, cooled to room temperature, and concentrated. It was diluted with DCM (20 mL) and 0.1 M aqueous hydrochloric acid (10 mL). The layers were separated. The organic layer was washed with brine and concentrated. The residue was purified on a silica column (20:1 DCM:MeOH) to give the product (0.15 g, 60%). MS ES+ m / z 465 [M+H] + .

[0508] [Table 4-1] [Table 4-2] [Table 4-3] [Table 4-4] [Table 4-5] [Table 4-6] [Table 4-7] [Table 4-8] [Table 4-9] [Table 4-10] [Table 4-11]

[0509] Determination of PI3K-alpha kinase (PIK3CA) activity, wild-type and H1047R mutant, and IC50 values ​​of inhibitors

[0510] Recombinant catalytically active human full-length PIK3KA wild-type and H1047R mutant were purchased from EMD Millipore Sigma as 1:1 complexes of N-terminal 6xHis-tagged p110 α (catalytic) and untagged p85 α (regulatory subunit) (catalog numbers 14-602M and 14-792M, respectively). 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). Prior to initiating 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 MgCl, 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 a kinase buffer containing all components except ATP in the presence or absence of compounds at 27°C for 1 hour. After preincubation, 20 μL of 50 μM ATP (final concentration: 20 μM) was added to initiate the reaction. The reaction was allowed to proceed at 27°C until approximately 10% of the ATP (2 μM ADP) was converted.5 μL of the reaction mixture was then mixed with 5 μL of ADP-Kinase Glo Reagent (ADP-Glo ​​Kinase Assay Kit, Promega catalog no. V9102) supplemented with 10 mM MgCl2 to stop the reaction and deplete remaining ATP for 40 minutes at room temperature. Next, 10 μL of Kinase Detection Reagent (ADP-Glo ​​Kinase Assay Kit, Promega catalog no. V9102) was added to simultaneously convert ADP to ATP, allowing newly synthesized ATP to be measured using a luciferase / luciferin reaction. After 30 minutes 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 values ​​were 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, slope=slope 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.

[0511] 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. [Table 5-1] [Table 5-2] [Table 5-3] 1 PIP2diC8 lipid substrate * Regarding Example 12, IC 50 WT / IC 50 H1047R=16.9

[0512] In vitro cell-based assay of PI3K-alpha kinase (PIK3CA) activity and determination of IC50 values ​​for inhibitors

[0513] The MDA-MB-453 (ATCC-HTB-131) cell line was obtained from the American Type Culture Collection (Manassas, VA). Cells were maintained in Dulbecco's modified Eagle's medium (DMEM, Gibco 11965-092) supplemented with 10% heat-inactivated fetal bovine serum (FBS HI, Gibco 10082-147), 1x non-essential amino acids (NEAA, Gibco 11140-050), and 1 mM sodium pyruvate (Gibco 11360-070). Cultures were maintained in a humidified incubator at 37°C under 5% CO2 / 95% air. To test compounds in 0% FBS, MDA-MB-453 cells were plated at 1.5 x 10 cells per well in a white 384-well plate in 20 μl of Minimum Essential Media (MEM) assay medium containing 1x NEAA, 1 mM sodium pyruvate, and 1 μg / mL human insulin (Sigma I9278). 4Cells were seeded at a density of 1000 x g. Compounds dissolved in a 10 mM stock solution in DMSO were serially diluted 1:3 in DMSO to generate a 10-point dilution series and plated using an acoustic liquid handler system (Echo 550 Series Liquid Handler, Labcyte). A 5x intermediate compound dilution plate was then prepared in MEM containing 1x NEAA and 1 mM sodium pyruvate (150 µM starting compound concentration in 1.5% DMSO). Five microliters of the intermediate serially diluted compound was added to the cell plate to achieve final concentrations ranging from 30 mM to 0.0015 mM in 0.3% DMSO. 0.3% DMSO alone was used to establish the maximum (MAX) signal, and GDC-0032 at a final concentration of 1 µM was used as a reference compound for the minimum (MIN) signal. After 3 hours of treatment, the medium was removed, and the cells were lysed in 10 µL of 1x SureFire lysis buffer with shaking at room temperature for 10 minutes. The acceptor mix (reaction buffer 1 + reaction buffer 2 + activation buffer + SureFire Ultra acceptor beads) was prepared by diluting activation buffer 25-fold in the combined reaction buffer 1 and reaction buffer 2. The acceptor beads were diluted 50-fold in the combined reaction buffer. Five μL of the acceptor mix was added to each well, and the plate was sealed, covered with foil, and incubated at room temperature for 1 hour. The donor mix (dilution buffer + SureFire Ultra donor beads) was prepared by diluting donor beads 50-fold in dilution buffer. Five μL of the donor mix was added to each well, and the plate was sealed, covered with foil, and incubated at room temperature in the dark for 1 hour. The plate was read on a Biotek Neo2 plate reader instrument using standard AlphaLisa settings. Compounds were tested in duplicate and the mean % inhibition at each compound concentration was used to generate single dose-response curves. Data were processed using the Genedata-Screener tool. Relative IC 50Values ​​were determined by calculating percent inhibition relative to the "minimum" (GDC-0032 reference control) and "maximum" (DMSO) controls within the plate using luminescence units. Data were analyzed using a four-parameter nonlinear logistic equation (four-parameter logistic concentration-response curve). Y = Bottom + [(Top - Bottom) / 1 + (X / IC50) Slope] where Y = % inhibition, X = concentration of inhibitor, bottom = minimum value of y reached by the curve fit, top = maximum value of y reached by the curve fit, and slope = IC 50 The slope of the curve at % Inhibition = [(signal at X - minimum median) / (maximum median - minimum median)] x 100 I C 50 Relative IC: The concentration of a compound that reduces a given response (ligand binding, enzyme response) by 50%. 50 : The concentration that gives half the maximal response of the compound.

[0514] ICs shown in Table B 50 For values, "A" indicates an IC less than 50 nM 50 "B" means IC in the range of 50nM to 100nM. 50 "C" means IC in the range of 100nM to 500nM. 50 "D" means IC > 500 nM 50 means.

[0515] [Table 6-1]

[0516] [Table 6-2]

Claims

1. formula: 【Chemistry 1】 [In the formula, R is -H or C １ -C ３ It is alkyl, R １ The formula is: 【Chemistry 2】 It is the basis of, R ２ The formula is: 【Transformation 3】 It is the basis of, R ３ is selected independently from -H, halogen, -CN, -N(H)(C １ -C ３ alkyl), -N(C １ -C ３ alkyl), ２ , -N(H)(CH ２ CH ２ CO ２ H), -C(O)C １ -C ３ alkyl, C １ -C ６ alkyl, C １ -C ６ haloalkyl, C １ -C ６ hydroxyalkyl, C ３ -C ５ cycloalkyl, an optionally substituted heterocyclic ring having 3 to 5 ring atoms containing 1, 2, or 3 ring heteroatoms independently selected from N, O, and S, or an optionally substituted heteroaryl having 5 or 6 ring atoms containing 1, 2, or 3 ring heteroatoms independently selected from N, O, and S, where the optionally substituted heterocyclic ring or the optionally substituted heteroaryl is each optionally substituted with 1 to 3 substituents independently selected from halogen, C １ -C ３ alkyl, and C １ -C ３ haloalkyl), R ４ , R ５ , and R ６ These are, independently, -H, halogen, and C. １ -C ６ Alkyl, or C １ -C ６ It is a haloalkyl, R ７ is -CN, C １ -C ６ Alkyl, or C １ -C ６ It is a haloalkyl, R ８ is -H or C １ -C ６ It is alkyl, R ９ These are, independently, -H, halogen, -CN, and C. １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Alkoxy, or C ３ -C ５ It is a cycloalkyl, R １０ These are, independently, -H, -CN, halogen, and C. １ -C ６ Haloalkyl, C １ -C ６ Alkoxy, C １ -C ６ Haloalkoxy, -SO ２ R １１ , -C(O)OC １ -C ３ Alkyl, -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 Alkinyl, optionally substituted C ３ -C ５ A optionally substituted heterocycle selected from cycloalkyl, pyrrolidine, pyrrolidinone, piperidine, and morpholine, an optionally substituted phenyl, an optionally substituted 1,3-benzodioxole, an optionally substituted 2,3-dihydro-1,4-benzodioxin, or an optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole, and thiazole, wherein the optionally substituted C １ -C ６ Alkyl, the optionally substituted C ２ -C ６ Alkenyl, or the optionally substituted C ２ -C ６ Alkinyls are -CN, -OH, oxetanyl, and C, respectively. １ -C ３ Alkoxy, or -CONR １１ R １１ The C that is optionally replaced by the C that is optionally replaced by the C ３ -C ５ Cycloalkyl, said optionally substituted phenyl, said optionally substituted 1,3 - benzodioxole, said optionally substituted 2,3 - dihydro - 1,4 - benzodioxin, said optionally substituted heterocyclic ring, or said optionally substituted heteroaryl is each optionally substituted with 1 to 3 substituents independently selected from halogen, C １ -C ３ alkyl, C １ -C ３ haloalkyl, C １ -C ３ alkoxy, C １ -C ３ haloalkoxy, -SO ２ R １１ 、-NR １１ R １１ 、-OH, and -CN, and is optionally substituted with R １１ Each of these is independently -H or C １ -C ３ It is alkyl. Compounds thereof, or pharmaceutically acceptable salts thereof.

2. formula: 【Chemistry 4】 [In the formula, R, R １ , R ２ , R ３ , R ４ , R ５ , R ６ and R ７ This is the same as the definition in claim 1. The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

3. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R is -H.

4. R １ However, the formula is: 【Transformation 5】 The compound according to claim 1, or a pharmaceutically acceptable salt thereof, which is the base of the compound.

5. R １ However, the formula is: 【Transformation 6】 The compound according to claim 1, or a pharmaceutically acceptable salt thereof, which is the base of the compound.

6. R ９ However, each is independent of -H, halogen, and C. １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Alkoxy, or C ３ -C ５ A compound according to claim 1, which is a cycloalkyl compound, or a pharmaceutically acceptable salt thereof.

7. R ９ However, each is independent of -H, halogen, and C. １ -C ３ Alkyl, or C １ -C ３ A compound according to claim 1, which is a haloalkyl compound, or a pharmaceutically acceptable salt thereof.

8. R １ However, the formula is: 【Transformation 7】 The compound according to claim 1, or a pharmaceutically acceptable salt thereof, which is the base of the compound.

9. R ３ is -H, -CN,C １ -C ３ Alkyl, or C １ -C ３ A compound according to claim 1, which is a haloalkyl compound, or a pharmaceutically acceptable salt thereof.

10. R ３ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is -H or methyl.

11. R ４ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is -H.

12. R ５ However, -H, halogen, C １ -C ３ Alkyl, or C １ -C ３ A compound according to claim 1, which is a haloalkyl compound, or a pharmaceutically acceptable salt thereof.

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

14. R ７ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is methyl.

15. R ８ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is -H.

16. R ２ but, 【Transformation 8】 The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

17. R ２ but, 【Chemistry 9】 And R １０ However, each is independent of -H, -CN, halogen, and C. １ -C ６ Haloalkyl, C １ -C ６ Alkoxy, C １ -C ６ Alkyl, -SO ２ R １１ , pyrazolyl, C optionally substituted with -CN ３ -C ５ C is optionally substituted with a cycloalkyl group or an -OH group. ２ -C ６ The compound according to claim 1, which is an alkynyl, or a pharmaceutically acceptable salt thereof.

18. The following compounds: 【Chemistry 10】 A compound according to claim 1, or a pharmaceutically acceptable salt thereof, selected from the above.

19. The following compounds: 【Chemistry 11】 A compound according to claim 1, or a pharmaceutically acceptable salt thereof, selected from the above.

20. The following compounds: 【Chemistry 12】 A compound according to claim 1, or a pharmaceutically acceptable salt thereof, selected from the above.

21. The following compounds: 【Chemistry 13】 A compound according to claim 1, or a pharmaceutically acceptable salt thereof, selected from the above.

22. The following compounds: 【Chemistry 14】 【Chemistry 15】 A compound according to claim 1, or a pharmaceutically acceptable salt thereof, selected from the above.

23. A pharmaceutical composition comprising a compound according to any one of claims 1 to 22 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

24. A pharmaceutical agent for inhibiting phosphoinositide 3-kinase (PI3K), comprising a compound according to any one of claims 1 to 22 or a pharmaceutically acceptable salt thereof.

25. A therapeutic agent for treating cancer, comprising a compound described in any one of claims 1 to 22 or a pharmaceutically acceptable salt thereof.

26. The therapeutic agent according to claim 25, wherein the cancer is endometrial cancer, gastric cancer, leukemia, lymphoma, sarcoma, colorectal cancer, lung cancer, ovarian cancer, skin cancer, head and neck cancer, breast cancer, brain cancer, or prostate cancer.

27. The therapeutic agent according to claim 25, wherein the cancer is breast cancer.

28. The therapeutic agent according to claim 25, wherein the cancer is progressive or metastatic breast cancer that is hormone receptor-positive (HR+) and human epidermal growth factor receptor 2-negative (HER2-).

29. A therapeutic agent for treating CLOVES syndrome (congenital lipomatous hypergrowth, vascular malformations, epidermal nevi, scoliosis / skeletal and spinal cord syndrome), or PIK3CA-associated hypergrowth syndrome (PROS), comprising a compound according to any one of claims 1 to 22 or a pharmaceutically acceptable salt thereof.

30. Use of a compound according to any one of claims 1 to 22 or a pharmaceutically acceptable salt thereof in the manufacture of a pharmaceutical for the treatment of cancer.

31. The use according to claim 30, wherein the cancer is endometrial cancer, gastric cancer, leukemia, lymphoma, sarcoma, colorectal cancer, lung cancer, ovarian cancer, skin cancer, head and neck cancer, breast cancer, brain cancer, or prostate cancer.

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

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

34. Use of a compound according to any one of claims 1 to 22 or a pharmaceutically acceptable salt thereof in the manufacture of a pharmaceutical product for the treatment of CLOVES syndrome (congenital lipomatous hypergrowth, vascular malformations, epidermal nevi, scoliosis / skeletal and spinal syndrome), or PIK3CA-associated hypergrowth syndrome (PROS).

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