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

Abstract

The disclosure relates to compounds of Formula (I) as allosteric chromenone inhibitors of phosphoinositide 3-kinase (PI3K) useful in the treatment of diseases or disorders associated with PI3K modulation, Formula (I): or pharmaceutically acceptable salts thereof wherein R, R1, R 2,R

Description

[Technical Field]

[0001] This invention relates to PI3K eochromone inhibitors suitable for treating diseases or conditions related to phosphoinositol 3-kinase (PI3K) regulation. The invention relates to compounds and compositions that inhibit PI3K, methods for treating diseases or conditions related to PI3K (e.g., CLOVES syndrome (congenital lipomatous overgrowth, vascular malformations, epidermal nevi, scoliosis / skeletal and spinal syndromes), 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 methods for using PI3K inhibitors in combination with one or more other cancer therapies or for their use. [Previous Technology]

[0002] Cellular activity can be regulated by external signals that stimulate or inhibit intracellular events. The process by which stimulating or inhibiting signals are transmitted into the cell and elicit intracellular responses is called signal transduction. Over the past few decades, the cascade of signal transduction events has been elucidated, and their major role in a variety of biological responses has been discovered. Defects in various components of signal transduction pathways have been found to cause a wide range of diseases, including various forms of cancer, inflammatory diseases, metabolic disorders, vascular and neuronal diseases (Gaestel et al. Current Medicinal Chemistry (2007) 14:2214-2234).

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

[0004] Lipid kinases are enzymes that catalyze the phosphorylation of lipids within cells. These enzymes, along with the resulting phosphorylated lipids and lipid-derived bioactive organic molecules, play roles in many different physiological processes, including cell proliferation, migration, adhesion, and differentiation. Certain groups of lipid kinases include membrane lipid kinases, i.e., kinases that catalyze the phosphorylation of lipids contained in or associated with the cell membrane. Examples of such enzymes include phosphoinositol kinases (such as PI3-kinase and PI4-kinase), diacylglycerol kinase, and sphingosine kinase.

[0005] The phosphoinositol 3-kinase (PI3K) signaling pathway is one of the most mutated systems in human cancer. PI3K signaling is involved in many other disease conditions, including allergic contact dermatitis, rheumatoid arthritis, osteoarthritis, inflammatory bowel disease, chronic obstructive pulmonary disease, psoriasis, multiple sclerosis, asthma, conditions associated with diabetic complications, and inflammatory complications of the cardiovascular system, such as acute coronary syndrome.

[0006] PI3K is a member of a unique and conserved family of intracellular lipid kinases that phosphorylate the 3'-OH group on phosphatidylinositol or phosphoinositol. The PI3K family comprises 15 kinases with different receptor specificities, expression patterns, and regulatory patterns (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 produce PIP3, which binds to downstream effectors such as Akt / PDK1, mTOR, Tec family kinases, and Rho family GTPases. Class II and III PI3Ks play a key role in intracellular migration via the synthesis of PI(3)P and PI(3,4)P2.

[0007] PI3K isoforms have been involved in various human cancers and diseases. It is believed that mutations in the gene encoding PI3K isoforms, or mutations that cause upregulation of PI3K isoforms, exist in many human cancers. Mutations in the gene encoding PI3K isoforms are point mutations clustered in several hotspots within the helical and kinase domains. Due to the high mutation rate of PI3K, targeting this pathway may provide valuable therapeutic opportunities.

[0008] It is believed that gene alterations in PI3K signaling are involved in a range of cancers, such as endometrial cancer, breast cancer, esophageal squamous cell carcinoma, cervical squamous cell carcinoma, cervical adenocarcinoma, colorectal adenocarcinoma, cystourethral epithelial carcinoma, glioblastoma, ovarian cancer, non-small cell lung cancer, esophageal and gastric cancer, nerve sheath tumors, head and neck squamous cell carcinoma, melanoma, esophageal and gastric adenocarcinoma, soft tissue sarcoma, prostate cancer, fibrous carcinoma, hepatocellular carcinoma, diffuse glioma, colorectal cancer, pancreatic cancer, bile duct cancer, B-cell lymphoma, mesothelioma, adrenal cortical carcinoma, non-clear cell renal carcinoma, clear cell renal carcinoma, germ cell carcinoma, thymic tumor, pheochromocytoma, miscellaneous neuroepithelial tumor, thyroid cancer, leukemia, and encapsulated glioma (Goncalves MD, Hopkins BD, Cantley LC. Phosphatidylinositol). 3-Kinase, Growth Disorders, and Cancer. N Engl J Med. 2018 Nov 22;379(21):2052-2062).

[0009] PI3K alpha isoforms have been involved in various human cancers. Angiogenesis has been shown to selectively require PI3K alpha isoforms to control endothelial cell migration (Graupera et al., Nature 2008; 453; 662-6). Mutations in the PI3Kα gene, or mutations that upregulate PI3Kα, are believed to exist in many human cancers, such as lung cancer, gastric cancer, endometrial cancer, ovarian cancer, bladder cancer, breast cancer, colon cancer, brain cancer, prostate cancer, and skin cancer. Mutations in the PI3Kα gene are point mutations clustered in several hotspots within the helix and kinase domain, such as E542K, E545K, and H1047R. Many of these mutations have been shown to be gain-of-function mutations. Due to the high mutation rate of PI3Kα, targeting this pathway could provide valuable therapeutic opportunities. Although other PI3K isoforms, such as PI3Kδ or PI3Kγ, are primarily expressed in hematopoietic cells, PI3Kα is constitutively expressed together with PI3Kβ.

[0010] Mutated PI3Kα has been involved in brain metastases in HR+ / HER2- metastatic breast cancer. The development of brain-penetrating PI3Kα inhibitors could provide improved therapeutic benefits compared to 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 (Supplement 5)).

[0011] Due to the major role of PI3Kα in regulating organismal glucose homeostasis, 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 may potentially have mitogenic and / or anti-apoptotic effects on cancer cells, thus counteracting the antiproliferative effects of PI3K inhibitors (Blouin MJ et al., Abstract 4615: the hyperinsulinemia caused by PI3K inhibitors attenuates their antineoplastic efficacy, but can be minimized by co-administration of metformin. Cancer Res 2013;73:4615).

[0012] In cancer settings with PI3Kα mutations, one way to overcome the problem of compensatory insulin and / or glucose production after systemic PI3Kα inhibition is to develop inhibitors that are more selective for mutant PI3Kα than wild-type PI3Kα. This results in a widened dosing window, selectively inhibiting the pathological signaling of mutant PI3Kα in cancer cells without affecting wild-type PI3Kα in host tissues that control systemic metabolism (Okkenhaug K, Graupera M, Vanhaesebroeck B. Targeting PI3K in Cancer: Impact on Tumor Cells, Their Protective Stroma, Angiogenesis, and Immunotherapy. Cancer Discov. 2016 Oct; 6(10):1090-1105), thereby limiting toxicity and 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 are almost equivalent for wild-type and mutant PI3Kα. Because the PI3Kα mutation site is far from the active site, selective inhibitors for mutants are still difficult to achieve. Therefore, inhibitors targeting the second peripheral binding bag near known mutations (e.g., H1047R) could provide a pathway for selective PI3Kα inhibition. Thus, targeting the mutant peripheral binding bag of PI3Kα provides a valuable therapeutic target for drug development.

[0014] Therefore, kinases, such as lipid kinases like PI3K, are a primary target for drug development. This invention provides a novel class of kinase inhibitors. [Summary of the Invention]

[0015] In one embodiment, the present invention relates to a compound of formula (I): or a pharmaceutically acceptable salt thereof, wherein: R is -H or C1-C3 alkyl; R1 is a group of the following formula:; R2 is a group of the following formula:; or R2 is a substituted 5-membered heteroaryl group selected from pyrrole, furan, thiophene, pyrazole, isothiazolium, isothiazole, imidazole, acetazole, thiazole, triazole, tetraazole, acediazole and thiadiazole; wherein the substituted 5-membered heteroaryl group is substituted with one to three substituents, each independently selected from -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R1 1. -C(O)OC1-C3 alkyl, -CONR11R11, -NR11R11, -NR11CO2R11, -OH, C1-C6 alkyl (subject to substitution), C2-C6 alkenyl (subject to substitution), C2-C6 alkynyl (subject to substitution), C3-C5 cycloalkyl (subject to substitution), heterocyclic (subject to substitution) selected from pyrrolidine, pyrrolidone, piperidine or morpholine, phenyl (subject to substitution), etc. The substituted aryl group is 1,3-benzodioxane, or, as appropriate, 2,3-dihydro-1,4-benzodioxane, or, as appropriate, a heteroaryl group selected from pyridine, pyrimidine, pyrazine, pyridine, pyrazine, pyrazole, isothiazolium, isothiazole, imidazole, thiazolium, or thiazole; wherein the substituted C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl group is respectively, as appropriate, prefixed with -CN, -OH, oxetyl, C1-C3 alkoxy, or -CON. R11R11 substitution; depending on the case, the substituted C3-C5 cycloalkyl, phenyl, 1,3-benzodioxane, 2,3-dihydro-1,4-benzodioxane, heterocyclic or heteroaryl group is substituted by one or three substituents independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -SO2R11, -NR11R11, -OH or -CN; R3 is -H, halogen, -CN, -N(H)(C1-C3 alkyl), -N(C1-C3 alkyl)2, -N(H)(CH2CH2CO2H), -C(O)C1-C3 alkyl, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C3-C5 cycloalkyl, a heterocycle containing, as appropriate, 3 to 5 ring atoms independently selected from N, O, or S, or a heteroaryl containing, as appropriate, 5 to 6 ring atoms independently selected from N, O, or S; wherein each heterocycle or heteroaryl is, as appropriate, substituted with one to three substituents independently selected from halogen, C1-C3 alkyl, or C1-C3 haloalkyl; each of R4, R5, and R6 is independently -H, halogen, C1-C6 alkyl, or C1-C6 haloalkyl;R7 is -CN, C1-C6 alkyl, or C1-C6 haloalkyl; R8 is -H or C1-C6 alkyl; each R9 is independently -H, halogen, -CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C3-C5 cycloalkyl; Each R10 is independently -H, -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R11, -C(O)OC1-C3 alkyl, -CONR11R11, -NR11R11, -NR11-CO2R11, -OH, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C5 cycloalkyl, optionally substituted heterocyclic selected from pyrrolidine, pyrrolidone, piperidine or morpholine, optionally substituted phenyl, optionally substituted 1,3-benzodioxane, optionally substituted 2,3-dihydro-1,4-benzodioxane, or selected from pyrazole, isothiazolyl, isothiazine, etc. The azole, imidazole, thiazole, or thiazole may be substituted with a heteroaryl group, wherein the substituted C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl group may be substituted with -CN, -OH, oxetyl, C1-C3 alkoxy, or -CONR11R11, as appropriate; the substituted C3-C5 cycloalkyl, phenyl, 1,3-benzodioxane, 2,3-dihydro-1,4-benzodioxane, heterocyclic, or heteroaryl group may be substituted with one or three substituents independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -SO2R11, -NR11R11, -OH, or -CN, as appropriate; and each R11 may be independently -H or C1-C3 alkyl.

[0016] In another embodiment, 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 embodiment, the present invention provides a method for regulating PI3K (e.g., PI3Kα) activity (e.g., in vitro or in vivo), comprising contacting cells with a therapeutically effective amount of a compound of formula (I), (II) or (III) or a medically acceptable salt thereof.

[0018] In some embodiments, the present invention provides a method for treating or preventing a disease or ailment disclosed herein in an individual in need, comprising administering to the individual a therapeutically effective amount of a compound of formula (I), (II) or (III) or a medically acceptable salt thereof.

[0019] In some embodiments, the present invention provides a method for treating or preventing a disease or ailment disclosed herein in an individual in need, comprising administering to the individual a therapeutically effective amount of a compound of formula (I), (II) or (III) or a pharmaceutically acceptable salt thereof.

[0020] In some embodiments, the present invention provides a method for treating an individual in need of a disease or ailment disclosed herein, comprising administering to the individual a therapeutically effective amount of a compound of formula (I), (II) or (III) or a medically acceptable salt thereof.

[0021] In some embodiments, the present invention provides a method for treating an individual in need of a disease or ailment disclosed herein, comprising administering to the individual a therapeutically effective amount of a compound of formula (I), (II) or (III) or a pharmaceutically acceptable salt thereof.

[0022] In another embodiment, the present invention provides compounds of formula (I), (II) or (III) for use in therapeutics, or medically acceptable salts thereof.

[0023] In another embodiment, the present invention provides compounds of formula (I), (II) or (III) or pharmaceutically acceptable salts thereof for modulating PI3K (e.g., PI3Kα) activity (e.g., in vitro or in vivo).

[0024] In another embodiment, the present invention provides a compound of formula (I), (II) or (III) or a pharmaceutically acceptable salt thereof for selectively inhibiting mutant PI3Kα relative to wild-type PI3Kα.

[0025] In another embodiment, the present invention provides compounds of formula (I), (II) or (III) or their pharmaceutically acceptable salts for the treatment or prevention of the diseases or conditions disclosed herein.

[0026] In another embodiment, the present invention provides compounds of formula (I), (II) or (III) or their pharmaceutically acceptable salts for use in treating the diseases or conditions disclosed herein.

[0027] In another embodiment, the present invention provides the use of compounds of formula (I), (II) or (III) or pharmaceutically acceptable salts thereof for the manufacture of agents that modulate the activity of PI3K (e.g., PI3Kα) (e.g., in vitro or in vivo).

[0028] In another embodiment, the present invention provides the use of compounds of formula (I), (II) or (III) or pharmaceutically acceptable salts thereof for the manufacture of medicaments for the treatment or prevention of the diseases or conditions disclosed herein.

[0029] In another embodiment, the present invention provides the use of compounds of formula (I), (II) or (III) or pharmaceutically acceptable salts thereof for the manufacture of medicaments for treating the diseases or conditions disclosed herein.

[0030] In another embodiment, 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 embodiment, the present invention provides a method for preparing a compound comprising one or more of the steps described herein.

[0032] In another embodiment, the present invention provides a compound that can be obtained by or by a method for preparing a compound as described herein (e.g., a method comprising one or more steps described in the process).

[0033] In another embodiment, the present invention provides an intermediate as described herein, which is suitable for a method of preparing a compound as described herein (e.g., the intermediate is selected from the intermediates described in the examples).

[0034] Other features and advantages of the present invention will be apparent from the following embodiments and the scope of the claims.

Implementation Method

[0035] This application claims the rights under 35 USC §119(e) to U.S. Provisional Application Serial No. 63 / 183,366 filed May 3, 2021; Serial No. 63 / 227,652 filed July 30, 2021; Serial No. 63 / 250,564 filed September 30, 2021; Serial No. 63 / 253,282 filed October 7, 2021; and Serial No. 63 / 253,412 filed October 7, 2021; the disclosures of these applications are incorporated herein by reference.

[0036] This invention provides a method (or use in treating, preventing, or improving a disease or condition) for treating, preventing, or improving a disease or condition, wherein PI3K works by administering a therapeutically effective amount of the PI3K inhibitor of this invention to a patient in need of it. The method (or use) of this invention can be used to treat a variety of PI3K-dependent diseases and conditions.

[0037] In some embodiments, the disease or condition is cancer (e.g., breast cancer, brain cancer, prostate cancer, endometrial cancer, stomach cancer, leukemia, lymphoma, sarcoma, colorectal cancer, lung cancer, ovarian cancer, skin cancer, or head and neck cancer). In some embodiments, PI3K-related diseases or conditions include, but are not limited to, CLOVES syndrome (congenital lipomatous overgrowth, vascular malformation, epidermal nevus, scoliosis / skeletal and spinal syndrome), PIK3CA-associated overgrowth syndrome (PROS), endometrial cancer, breast cancer, esophageal squamous cell carcinoma, cervical squamous cell carcinoma, cervical adenocarcinoma, colorectal adenocarcinoma, cystourethral epithelial carcinoma, glioblastoma, ovarian cancer, non-small cell lung cancer, esophageal and gastric cancer, nerve sheath tumors, head and neck squamous cell carcinoma, melanoma, esophageal and gastric adenocarcinoma, soft tissue sarcoma, prostate cancer, fibrous carcinoma, hepatocellular carcinoma, diffuse glioma, colorectal cancer, pancreatic cancer, bile duct cancer, B-cell lymphoma, mesothelioma, adrenocortical carcinoma, non-clear cell renal carcinoma, clear cell renal carcinoma, germ cell carcinoma, thymic tumor, pheochromocytoma, mixed neuroepithelial tumor, thyroid cancer, leukemia, and encapsulated glioma.

[0038] Details of the invention are set forth in the following appended description. Although methods and materials similar to or equivalent to those described herein may be used in the practice or testing of the invention, illustrative methods and materials are described here. Other features, objects, and advantages of the invention will be apparent from the implementation and from the claims. Unless the context clearly indicates otherwise, the singular form includes the plural in the specification and the appended claims. 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 pertains. All patents and publications referenced in this specification are incorporated herein by reference in their entirety. Definitions

[0039] The article "a / an" refers to one or more of the grammatical objects of the article (i.e., at least one). By way of example, "element" means one element or more elements.

[0040] Unless otherwise specified, the term "and / or" means "and" or "or".

[0041] The term "administer / administering / administration" refers to the direct administration of the disclosed compound, or a medically acceptable salt of the disclosed compound, or a combination thereof, to an individual.

[0042] The term "alkenyl" refers to a straight-chain or branched unsaturated hydrocarbon containing 2 to 12 carbon atoms. An "alkenyl" contains at least one double bond in the chain. The double bond of an alkenyl may be non-conjugated or conjugated to another unsaturated group. Examples of alkenyl include vinyl, propenyl, n-butenyl, isobutenyl, pentenyl, or hexenyl.

[0043] The term "alkoxy" refers to a straight-chain or branched saturated hydrocarbon containing 1 to 12 carbon atoms, which has a terminal "O" in the chain, i.e., -O (alkyl). Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, tert-butoxy, or pentoxy.

[0044] The term "alkyl" refers to a straight-chain or branched saturated hydrocarbon containing 1 to 12 carbon atoms, preferably 1 to 6 carbon atoms. Examples of (C1-C6) alkyl include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, secondary butyl, tertiary butyl, isopentyl, neopentyl and isohexyl.

[0045] The term "alkynyl" refers to a straight-chain or branched unsaturated hydrocarbon containing 2 to 12 carbon atoms. An "alkynyl" contains at least one parabonding bond in the chain. Examples of alkynyl groups include ethynyl, propynyl, n-butynyl, isobutynyl, pentynyl, or hexynyl.

[0046] The term "aromatic" means a planar ring with 4n+2 electrons in a conjugated system. As used herein, "conjugated system" means a system with p orbitals to which nonlocal electrons are attached, and the system may include isolated electron pairs.

[0047] Unless otherwise explicitly defined, the term "aryl" refers to a cyclic aromatic hydrocarbon group having one to three aromatic rings, including monocyclic or bicyclic groups such as phenyl, biphenyl, or naphthyl. In the case of two aromatic rings (bicyclic, etc.), the aromatic rings of the aryl group may be joined (e.g., biphenyl) or fused (e.g., naphthyl) at a single position. Furthermore, when containing two fused rings, the aryl group as defined herein may have one or more saturated or partially unsaturated rings fused to fully unsaturated aromatic rings. Exemplary ring systems of such aryl groups include, but are not limited to, phenyl, biphenyl, naphthyl, anthracene, propenyl naphthyl, phenanthryl, dihydroindenyl, indenyl, tetrahydronaphthyl, and tetrahydrobenzoannulenyl.

[0048] The term "carrier" encompasses carriers, excipients and diluents, and means a material, composition or medium relating to carrying or delivering a pharmaceutical agent from one organ or part of an individual's body to another organ or part of the body, such as liquid or solid fillers, diluents, excipients, solvents or encapsulating materials.

[0049] The term "cyano" means a substituent that has a carbon atom bonded to a nitrogen atom by a paratactic bond, that is, C≡N.

[0050] The term "cycloalkyl" means a monocyclic or polycyclic saturated carbon ring containing 3 to 18 carbon atoms, preferably 3 to 10 carbon atoms. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, noroyl, norborenyl, bicyclo[2.2.2]octyl, and bicyclo[2.2.2]octenyl.

[0051] Unless otherwise specified, the term “symptom” means the term disease, illness or ailment and is used interchangeably with it.

[0052] As defined herein, the term "haloalkoxy" refers to an alkoxy group substituted with one or more halogens. Examples of haloalkoxy groups include, but are not limited to, trifluoromethoxy, difluoromethoxy, pentafluoroethoxy, and trichloromethoxy.

[0053] As defined herein, the term "haloalkyl" refers to an alkyl group substituted with one or more halogens. Examples of haloalkyl groups include, but are not limited to, trifluoromethyl, difluoromethyl, pentafluoroethyl, and trichloromethyl.

[0054] The term "halogen" or "halogen group" refers to fluorine, chlorine, bromine or iodine.

[0055] Unless otherwise explicitly defined, the term "heteroaryl" means a monovalent monocyclic or polycyclic aromatic group 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 groups include two or more fused rings, and may further include two or more spirofused rings, such as bicyclic, tricyclic, tetracyclic, and similar rings. Unless otherwise explicitly defined, "fused" means that two rings share two ring atoms. Unless otherwise explicitly defined, "spiro-fused" means that two rings share one ring atom. As defined herein, heteroaryl also means a bicyclic heteroaryl group, wherein the heteroatom is selected from N, O, S, P, or B, preferably N, O, or S. As defined herein, a heteroaryl group also means a tricyclic heteroaryl group containing one or more cyclic heteroatoms selected from N, O, S, P, or B, preferably N, O, or S. As defined herein, a heteroaryl group also means a tetracyclic heteroaryl group containing one or more cyclic heteroatoms selected from N, O, S, P, or B, preferably N, O, or S.Examples of heteroaromatic groups include, but are not limited to, furanyl, thiophene, pyrrolyl, pyridyl, pyrazolyl, pyrimidinyl, imidazole, isozolyl, acezolyl, acediazole, pyroflavone, indole, thiophene-2-yl, quinolinyl, benzopiperanyl, isothiazolyl, thiazolyl, thiadiazole, indazole, benzimidazolyl, thieno[3,2-b]thiophene, triazolyl, trioflavone, imidazo[1,2-b]pyrazolyl, furan[2,3-c]pyridyl, imidazo[1,2-a]pyridyl, indazole, pyrrolo[2,3-c]pyridyl, pyrrolo[3,2-c]pyridyl, pyrazolo[3,4-c]pyridyl, thieno[3,2-c]pyridyl Thiophene[2,3-c]pyridyl, thieneno[2,3-b]pyridyl, benzothiazolyl, indole, indolinyl, indolinone, dihydrobenzothienyl, dihydrobenzofuranyl, benzofuranyl, alkyl, thioalkyl, tetrahydroquinolinyl, dihydrobenzothiazolyl, quinolinyl, isoquinolinyl, 1,6-pyridyl, benzo[de]isoquinolinyl, pyrido[4,3-b][1,6]pyridyl, thieneno[2,3-b]pyridyl, quinazolinyl, tetrazo[1,5-a]pyridyl, [1,2,4]triazo[4,3-a]pyridyl, isoindolyl, pyrrolo[2,3-b]pyridyl, pyrrolo[ [3,4-b]pyridyl, pyrrolo[3,2-b]pyridyl, imidazo[5,4-b]pyridyl, pyrrolo[1,2-a]pyrimidinyl, tetrahydropyrrolo[1,2-a]pyrimidinyl, 3,4-dihydro-2H-1-pyrrolo[2,1-b]pyrimidinyl, dibenzo[b,d]thiophene, pyridin-2-one, furano[3,2-c]pyridyl, furano[2,3-c]pyridyl, 1H-pyrido[3,4-b][1,4]thiazolyl, benzoxazolyl, benzoisoxazolyl, furano[2,3-b]pyridyl, benzothiophene, 1,5-pyridyl, furano[3,2-b]pyridine, [1,2,4]triazole [1,5-a]pyridyl, benzo[1,2,3]triazolyl, imidazo[1,2-a]pyrimidinyl, [1,2,4]triazol[4,3-b]pyridyl, benzo[c][1,2,5]thiadiazolyl, benzo[c][1,2,5]pyridazole, 1,3-dihydro-2H-benzo[d]imidazol-2-one, 3,4-dihydro-2H-pyrazolo[1,5-b][1,2]pyridyl, 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridyl, thiazo[5,4-d]thiazolyl, imidazo[2,1-b][1,3,4]thiadiazolyl, thieno[2,3-b]pyrroleyl, and 3H-indolyl. Furthermore, when containing two or more fused rings, the heteroaryl group defined herein may have one or more saturated or partially unsaturated rings fused with one or more fully unsaturated aromatic rings.In heteroaryl ring systems containing more than two fused rings, a saturated or partially unsaturated ring may be further fused with a saturated or partially unsaturated ring as described herein. Furthermore, when three or more fused rings are present, the heteroaryl group as defined herein may have one or more saturated or partially unsaturated spirofused rings. Any saturated or partially unsaturated ring described herein may be substituted with one or more side oxygen groups, depending on the case. Exemplary ring systems of these heteroaryl groups include, for example, indololinyl, indololinone, dihydrobenzothiophene, dihydrobenzofuran, alkyl, thioalkyl, tetrahydroquinolinyl, dihydrobenzothiophene, 3,4-dihydro-1H-isoquinolinyl, 2,3-dihydrobenzofuranyl, benzofuranone, hydroxyindolyl, indolyl, 1,6-dihydro-7H-pyrazole[3,4-c]pyridin-7-one, 7,8-dihydro-6H-pyrido[3,2-b]pyrrolizinyl, 8H-pyrido[3,2-b]pyrrolyl, 1,5,6,7-tetrahydrocyclopentano[b]pyrazole[4,3-e]pyridinyl, 7, 8-Dihydro-6H-pyrido[3,2-b]pyryl, pyrazolo[1,5-a]pyrimidin-7(4H)-keto, 3,4-dihydropiperano[1,2-a]indole-1(2H)-keto, benzo[c][1,2]oxaborol-1(3H)-olyl, 6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]pyrol-9-keto, and 6a',7'-dihydro-6'H,9'H-spiro[cyclopropane-1,8'-pyrido[2,3-b]pyrrolo[1,2-d][1,4]pyrol]-9'-keto.

[0056] The terms "heterocyclic", "heterocyclic" or "heterocyclic alkyl" mean monocyclic or polycyclic, 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 heterocyclic rings include, but are not limited to, oxoheterocyclic butyl, azetidinyl, tetrahydrofuranyl, tetrahydropiperanyl, pyrrolidyl, azolinyl, azolinyl, thiazolinyl, thiazolinyl, piperanyl, thiopiperanyl, tetrahydropiperanyl, diazolinyl, piperidinyl, morpholinyl, thiomorpholinyl, thiomorpholinyl S-oxide, thiomorpholinyl S-dioxide, piperanyl, azepyl, oxopyl, diazolinyl, tropanyl, azolinyl ketone, and homotropanyl.

[0057] As defined herein, the term "hydroxyalkyl" refers to an alkyl group that has been substituted with a hydroxyl group.

[0058] The term "isomer" refers to compounds that have the same molecular formula but differ in the nature or order of their atomic bonding or in the spatial arrangement of their atoms. Isomers that differ in their atomic spatial arrangement are called "stereoisomers." Stereoisomers that are not mirror images of each other are called "diastereomers," and stereoisomers that are non-overlapping mirror images of each other are called "enantiomers." When a compound has an asymmetry center, for example, when it is bonded to four different groups, a pair of enantiomers may exist. Enantiomers can be characterized by the absolute configuration of their asymmetry center and described by the R and S sequence rules of Cahn and Prelog, or by the rotation of the molecule around the plane of polarized light and designated as dextrorotatory or levorotatory (i.e., (+) or (-)- isomers, respectively). Enantiomers can exist individually as enantiomers or as mixtures thereof. A mixture containing equal proportions of enantiomers is called a "racemic mixture."

[0059] The term "modulate / modulation / modulating" refers to the biological activity of compounds or receptors that inhibit and / or activate PI3K.

[0060] The term "patient" or "individual" refers to a mammal, such as a human, mouse, rat, guinea pig, dog, cat, horse, cow, pig, or a non-human primate, such as a monkey, chimpanzee, baboon, or rhesus monkey. Preferably, the mammal is a human.

[0061] When used in combination with a compound, the term "therapeutic effective amount" refers to the amount or dose of the compound intended to act on a patient in the context of diagnosis or treatment, following a single or multiple dose administration. The effective amount can be determined by a person skilled in the art using known techniques and based on observations obtained in similar situations. In determining the effective amount for a patient, the attending physician considers several factors, including but not limited to: the patient's species; their body type, age, and general health condition; the specific disease or condition involved; the extent or severity of the disease or condition; the individual patient's response; the specific compound administered; the administration method; the bioavailability characteristics of the administered formulation; the chosen dosing regimen; the use of concomitant medications; and other relevant factors.

[0062] In an individual context, the term "treatment" includes limiting, alleviating, stopping, or reversing the worsening or severity of existing symptoms or conditions. The compounds of this invention...

[0063] In one embodiment, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R, R1, R2, R3, R4, R5, R6, R7 and R8 are as defined in the description of the invention with respect to formula (I).

[0064] In another state, the compound of formula (I) having formula (II), or a pharmaceutically acceptable salt thereof, wherein R, R1, R2, R3, R4, R5, R6 and R7 are as defined in the description of the invention with respect to formula (I).

[0065] In a compound of formula (I) or a pharmaceutically acceptable salt thereof, R is -H or C1-C3 alkyl; R1 is a group of the following formula:; R2 is a group of the following formula:; or R2 is a substituted 5-membered heteroaryl group selected from pyrrole, furan, thiophene, pyrazole, isothiazolium, isothiazole, imidazole, acetazole, thiazole, triazole, acediazole and thiadiazole; wherein the substituted 5-membered heteroaryl group is substituted by one to three substituents selected independently from the following: -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R11, -CONR11R11, -NR11R11, -NR11CO2R11, substituted C1-C6 alkyl, substituted C2-C6 alkenyl, substituted C2-C6 ynyl, substituted C3-C5 cycloalkyl, substituted heterocyclic selected from pyrrolidine, pyrrolidone, piperidine or morpholine, substituted phenyl, substituted 1, 3-Benzodioxane, 2,3-dihydro-1,4-benzodioxane (subject to substitution), or heteroaryl groups (subject to substitution) selected from pyridine, pyrimidine, pyrazine, pyridine, pyrazine, pyrazole, isothiazolium, isothiazole, imidazole, thiazolium, or thiazole; wherein the C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl groups (subject to substitution) are respectively, as appropriate, substituted with -CN, -OH, oxetyl, or C1-C3 alkoxy groups. Substitution; depending on the case, the C3-C5 cycloalkyl, phenyl, 1,3-benzodioxane, 2,3-dihydro-1,4-benzodioxane, heterocyclic or heteroaryl group is substituted by one or three substituents independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -SO2R11, -NR11R11, -OH or -CN; R3 is -H, halogen, -CN, C1-C6 alkyl, C1-C6 haloalkyl, C3-C5 cycloalkyl, a heterocycle containing 3 to 5 ring atoms independently selected from 1, 2 or 3 ring heteroatoms of N, O or S, or a heteroaryl group containing 5 ring atoms independently selected from 1, 2 or 3 ring heteroatoms of N, O or S; each of R4, R5 and R6 is independently -H, halogen, C1-C6 alkyl or C1-C6 haloalkyl; R7 is -CN, C1-C6 alkyl or C1-C6 haloalkyl; R8 is -H or C1-C6 alkyl; each of R9 is independently -H, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy or C3-C5 cycloalkyl;Each R10 is independently -H, -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R11, -CONR11R11, -NR11R11, -NR11-CO2R11, -OH, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C5 cycloalkyl, optionally substituted heterocyclic selected from pyrrolidine, pyrrolidone, piperidine or morpholine, optionally substituted phenyl, optionally substituted 1,3-benzodioxane, optionally substituted 2,3-dihydro-1,4-benzodioxane, or selected from pyrazole, isothiazole, isothiazole The heteroaryl group of imidazole, acetazole, or thiazole may be substituted, as appropriate; wherein the substituted C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl group may be substituted, as appropriate, with -CN, -OH, oxetyl, or C1-C3 alkoxy groups; wherein the substituted C3-C5 cycloalkyl, phenyl, 1,3-benzodioxane, 2,3-dihydro-1,4-benzodioxane, heterocyclic, or heteroaryl group may be substituted, as appropriate, with one to three substituents independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -SO2R11, -NR11R11, -OH, or -CN; and each R11 may be independently -H or C1-C3 alkyl.

[0066] In a compound of formula (I) or a pharmaceutically acceptable salt thereof, R is -H or C1-C3 alkyl; R1 is a group of the following formula:; R2 is a group of the following formula:; or R2 is a substituted 5-membered heteroaryl group selected from pyrrole, furan, thiophene, pyrazole, isothiazolium, isothiazole, imidazole, acetazole, thiazole, triazole, acediazole and thiadiazole; wherein the substituted 5-membered heteroaryl group is substituted by one to three substituents selected independently from the following: -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R11, -CONR11R11, -NR11R11, -NR11CO2R11, substituted C1-C6 alkyl, substituted C3-C5 cycloalkyl The substituted heterocycle selected from pyrrolidone, piperidine, or morpholine, the substituted phenyl group selected from pyridine, pyrazole, isothiazolium, isothiazole, imidazole, thiazolium, or thiazole, the substituted heteroaryl group selected from pyridine, pyrazole, isothiazole, imidazole, thiazolium, or thiazole, wherein the substituted C1-C6 alkyl group is substituted with -CN, -OH, or C1-C3 alkoxy group, and the substituted C3-C5 cycloalkyl, phenyl, heterocyclic, or heteroaryl group is substituted with one or three substituents selected independently from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -NR11R11, -OH, or -CN. R3 is -H, -CN, C1-C6 alkyl, or C1-C6 haloalkyl; each of R4, R5, and R6 is independently -H, halogen, C1-C6 alkyl, or C1-C6 haloalkyl; R7 is -CN, C1-C6 alkyl, or C1-C6 haloalkyl; R8 is -H or C1-C6 alkyl; each of R9 is independently -H, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C3-C5 cycloalkyl; Each R10 is independently -H, -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R11, -CONR11R11, -NR11R11, -NR11-CO2R11, -OH, substituted C1-C6 alkyl, substituted C3-C5 cycloalkyl, substituted heterocycle selected from pyrrolidone, pyrrolidone, piperidine or morpholine, substituted phenyl, or selected from pyrazole or isothazole. The heteroaryl group of isothiazole, imidazole, thiazole or thiazole is substituted as appropriate; wherein the C1-C6 alkyl group is substituted as appropriate is substituted with -CN, -OH or C1-C3 alkoxy; and the C3-C5 cycloalkyl, phenyl, heterocyclic or heteroaryl group is substituted as appropriate is substituted with one or three substituents selected independently from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -NR11R11, -OH or -CN.And each R11 is independently -H or C1-C3 alkyl.

[0067] In a compound of formula (I) or a pharmaceutically acceptable salt thereof, R is independently -H or C1-C3 alkyl; R1 is a group of the following formula:; R2 is a group of the following formula:; R3 is -H, -CN, C1-C6 alkyl or C1-C6 haloalkyl; each of R4, R5 and R6 is independently -H, halogen, C1-C6 alkyl or C1-C6 haloalkyl; R7 is -CN, C1-C6 alkyl or C1-C6 haloalkyl; R8 is -H or C1-C6 alkyl; each of R9 is independently -H, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy or C3-C5 cycloalkyl; Each R10 is independently -H, -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R11, -CONR11R11, -NR11R11, -NR11-CO2R11, a C1-C6 alkyl group as appropriate, a C3-C5 cycloalkyl group as appropriate, a heterocyclic group selected from pyrrolidine, pyrrolidone, piperidine or morpholine as appropriate, a phenyl group as appropriate, or a group selected from pyrazole, isothiazole, isothiazole, imidazole, thiazole or thiazoline. The azole is optionally substituted with a heteroaryl group; wherein the optionally substituted C1-C6 alkyl group is optionally substituted with -CN, -OH or C1-C3 alkoxy; wherein the optionally substituted C3-C5 cycloalkyl, phenyl, heterocyclic or heteroaryl group is optionally substituted with one to three substituents independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -NR11R11, -OH or -CN; and each R11 is independently -H or C1-C3 alkyl.

[0068] In compounds of formula (I) or (II) or their pharmaceutically acceptable salts, R2 is a group of the following formula:; and each R10 is independently -H, -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R11, -CONR11R11, -NR11R11, -NR11-CO2R11, -OH, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C5 cycloalkyl, optionally substituted heterocyclic selected from pyrrolidine, pyrrolidone, piperidine or morpholine, optionally substituted phenyl, optionally substituted 1,3-benzodioxane, optionally substituted 2 3-Dihydro-1,4-benzodioxane, or a heteroaryl group selected from pyrazole, isothiazolium, isothiazole, imidazole, thiazolium, or thiazole, substituted as appropriate; wherein the substituted C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl group is substituted as appropriate by -CN, -OH, oxetyl, or C1-C3 alkoxy; and the substituted C3-C5 cycloalkyl, phenyl, 1,3-benzodioxane, 2,3-dihydro-1,4-benzodioxane, heterocyclic, or heteroaryl group is substituted as appropriate by one or three substituents selected independently from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -SO2R11, -NR11R11, -OH, or -CN.

[0069] In compounds of formula (I) or (II) or their pharmaceutically acceptable salts, R2 is a group of the following formula:; and each R10 is independently -H, -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R11, -CONR11R11, -NR11R11, -NR11-CO2R11, -OH, substituted C1-C6 alkyl, substituted C3-C5 cycloalkyl, substituted heterocycle selected from pyrrolidine, pyrrolidone, piperidine or morpholine, substituted heterocycle, etc. The phenyl group, or a heteroaryl group selected from pyrazole, isothiazolium, isothiazole, imidazole, thiazolium or thiazole, may be substituted as appropriate; wherein the C1-C6 alkyl group may be substituted as appropriate with -CN, -OH or C1-C3 alkoxy; the C3-C5 cycloalkyl, phenyl, heterocyclic or heteroaryl group may be substituted as appropriate with one to three substituents selected independently from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -NR11R11, -OH or -CN; and each R11 may be independently H or C1-C3 alkyl.

[0070] In compounds of formula (I) or (II) or their pharmaceutically acceptable salts, R2 is a group of the following formula:; and each R10 is independently -H, -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R11, -CONR11R11, -NR11R11, -NR11-CO2R11, substituted C1-C6 alkyl, substituted C3-C5 cycloalkyl, substituted heterocycle selected from pyrrolidine, pyrrolidone, piperidine or morpholine, substituted benzene. The alkyl group, or a heteroaryl group selected from pyrazole, isothiazolium, isothiazole, imidazole, thiazolium or thiazole, may be substituted as appropriate; wherein the C1-C6 alkyl group may be substituted as appropriate with -CN, -OH or C1-C3 alkoxy; the C3-C5 cycloalkyl, phenyl, heterocyclic or heteroaryl group may be substituted as appropriate with one or three substituents selected independently from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -NR11R11, -OH or -CN; and each R11 may be independently H or C1-C3 alkyl.

[0071] In compounds of formula (I) or (II) or their pharmaceutically acceptable salts, R2 is a group of the following formula:; and each R10 is independently -H, -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, -SO2R11, substituted C1-C6 alkyl, substituted C2-C6 alkynyl, substituted C3-C5 cycloalkyl, or selected from pyrazole, isothiazole, isothiazole, imidazole, thiazole or thiazolyl. The azole is optionally substituted with a heteroaryl group; wherein the optional substituted C1-C6 alkyl or C2-C6 alkynyl group is optionally substituted with -CN, OH or C1-C3 alkoxy; and the optional substituted C3-C5 cycloalkyl or heteroaryl group is optionally substituted with one or three substituents each independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -NR11R11, -OH or -CN.

[0072] In a compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R2 is a group of the following formula:; and each R10 is independently -H, -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, -SO2R11, substituted C1-C6 alkyl, substituted C2-C6 alkynyl, or substituted C3-C5 cycloalkyl; wherein the substituted C1-C6 alkyl or C2-C6 alkynyl is substituted with -CN, -OH or C1-C3 alkoxy as appropriate; and the substituted C3-C5 cycloalkyl is substituted with one or three substituents independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -NR11R11, -OH or -CN as appropriate.

[0073] In the compound of formula (I) or (II) or its pharmaceutically acceptable salt, R2 is a group of the following formula:; and each R10 is independently -H, -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, -SO2R11, C1-C6 alkyl, C2-C6 alkynyl substituted with -OH as appropriate, C3 cycloalkyl substituted with -CN as appropriate, or a heteroaryl group selected from pyrazoles substituted with one to three substituents independently selected from C1-C3 alkyl groups as appropriate.

[0074] In the compound of formula (I) or (II) or its pharmaceutically acceptable salt, R2 is a group of the following formula:; and each R10 is independently -H, -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, -SO2R11, C1-C6 alkyl, C2-C6 alkynyl substituted with -OH as appropriate, or C3 cycloalkyl substituted with -CN as appropriate.

[0075] In the compound of formula (I) or (II) or its pharmaceutically acceptable salt, R2 is a group of the following formula:; and each R10 is independently:.

[0076] In the compound of formula (I) or (II) or its pharmaceutically acceptable salt, R2 is a group of the following formula:; and each R10 is independently:.

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

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

[0079] In compounds of formula (I) or (II) or their pharmaceutically acceptable salts, R2 is, where appropriate, a substituted 5-membered heteroaryl group selected from pyrrole, furan, thiophene, pyrazole, isoflavone, isothiazole, imidazole, acetazole, thiazole, triazole, acediazole, and thiadiazole; wherein the substituted 5-membered heteroaryl group is, where appropriate, substituted by one to three substituents selected independently from the following: -CN, halogen, C1-C6 haloalkyl, C1 -C6 alkoxy, C1-C6 haloalkoxy, -SO2R11, -CONR11R11, -NR11R11, -NR11CO2R11, substituted C1-C6 alkyl, substituted C2-C6 alkenyl, substituted C2-C6 alkynyl, substituted C3-C5 cycloalkyl, substituted heterocycles selected from pyrrolidine, pyrrolidone, piperidine, or morpholine, substituted benzene. The substituted 1,3-benzodioxane, substituted 2,3-dihydro-1,4-benzodioxane, or a heteroaryl group selected from pyridine, pyrimidine, pyrazine, pyridine, pyrazole, isothiazolium, isothiazole, imidazole, thiazolium, or thiazole, substituted heteroaryl group; wherein the substituted C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 ynyl group is substituted with -CN, -OH, oxetyl, or C1-C... 3. Alkoxy substitution; depending on the case, the substituted C3-C5 cycloalkyl, phenyl, 1,3-benzodioxane, 2,3-dihydro-1,4-benzodioxane, heterocyclic or heteroaryl group is substituted by one or three substituents independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -SO2R11, -NR11R11, -OH or -CN.

[0080] In compounds of formula (I) or (II) or their pharmaceutically acceptable salts, R2 is, where appropriate, a substituted 5-membered heteroaryl group selected from pyrrole, furan, thiophene, pyrazole, isothiazolium, isothiazole, imidazole, acetazole, thiazole, triazole, acediazole, and thiadiazole; wherein the substituted 5-membered heteroaryl group is, where appropriate, substituted with one to three substituents selected independently from the following: -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R11, -CONR11R11, -NR11R11, -NR11CO2R11, where appropriate, a substituted C1-C6 alkyl, and where appropriate, a substituted C3-C5 cycloalkyl. The alkyl group, a heterocyclic group selected from pyrrolidone, piperidine or morpholine, a phenyl group selected from pyridine, pyrazole, isothiazolium, isothiazole, imidazole, thiazolium or thiazole, a heteroaryl group selected from pyridine, pyrazole, isothiazole, imidazole or thiazole, wherein the C1-C6 alkyl group selected from pyrrolidone, isothiazolium or C1-C3 alkoxy ...

[0081] In compounds of formula (I) or (II) or their pharmaceutically acceptable salts, R2 is, where appropriate, a substituted 5-membered heteroaryl group selected from pyrrole, furan, thiophene, pyrazole, isothiazolium, isothiazole, imidazole, acetazole, thiazole, triazole, acediazole, and thiadiazole; wherein the substituted 5-membered heteroaryl group is, where appropriate, substituted with one to three substituents selected independently from: C1-C6 haloalkyl, where appropriate, a substituted C1-C6 alkyl, where appropriate, a substituted phenyl, where appropriate, a substituted 1,3-benzodioxane, or selected from pyridine, pyrimidine, pyrazine, pyridine, pyrazole, pyridine ...idine, pyridine, pyridine, pyridine, pyridine, pyridine, pyridine, pyridine, The isothiazolium, isothiazole, imidazole, thiazolium or thiazole is optionally substituted with a heteroaryl group; wherein the optional substituted C1-C6 alkyl group is optionally substituted with -CN, -OH, oxetyl or C1-C3 alkoxy; and the optional substituted phenyl, 1,3-benzodioxacyclopentene or heteroaryl group is optionally substituted with one or three substituents independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -SO2R11, -NR11R11, -OH or -CN; and each R11 is independently H or C1-C3 alkyl.

[0082] In compounds of formula (I) or (II) or their pharmaceutically acceptable salts, R2 is, where appropriate, a substituted 5-membered heteroaryl group selected from pyrrole, furan, thiophene, pyrazole, isothiazolium, isothiazole, imidazole, thiazolium, triazole, thiadiazole, and thiadiazole; wherein the substituted 5-membered heteroaryl group is, where appropriate, substituted by one to three substituents selected independently from the following: C1-C6 haloalkyl, C1-C6 alkyl, and so on. Furthermore, the substituted phenyl group, the substituted 1,3-benzodioxane, or the substituted heteroaryl group selected from pyridine or pyrimidine, wherein the substituted phenyl group, the 1,3-benzodioxane, or the heteroaryl group are each independently selected from halogen, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -SO2R11, or -CN; and each R11 is independently H or C1-C3 alkyl.

[0083] In the compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R2 is, where appropriate, a substituted 5-membered heteroaryl group selected from pyrrole, furan, thiophene, pyrazole, isothiazolium, isothiazole, imidazole, thiazolium, triazole, thiadiazole and thiadiazole; wherein the substituted 5-membered heteroaryl group is, where appropriate, substituted by one to three substituents selected independently from the following:

[0084] In the compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R2 is a substituted 5-membered heteroaryl group selected from pyrrole, furan, thiophene, pyrazole, isothiazolium, isothiazole, imidazole, thiazolium, triazole, thiadiazole and thiadiazole; wherein the substituted 5-membered heteroaryl group is substituted by one to three substituents selected independently from the following:

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

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

[0087] In another compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R3 is -H, halogen, -CN, C1-C6 alkyl, C1-C6 haloalkyl, C3-C5 cycloalkyl, a heterocycle containing 3 to 5 ring atoms independently selected from 1, 2 or 3 ring heteroatoms of N, O or S, or a heteroaryl group containing 5 ring atoms independently selected from 1, 2 or 3 ring heteroatoms of N, O or S. In another compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R3 is -H, halogen, -CN, C1-C6 alkyl, C1-C6 haloalkyl, oxetane or isozolol. In another compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R3 is -H, -CN, C1-C6 alkyl or C1-C6 haloalkyl. In another compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R3 is H, -CN, or a C1-C3 alkyl or C1-C3 haloalkyl (preferably R3 is H, -CN, or C1-C3 alkyl); most preferably R3 is H or methyl. Also preferably, R3 is H, methyl, or trifluoromethyl.

[0088] In another compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R4 is H or a halogen, preferably R4 is H.

[0089] In another compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R5 is H, halogen, C1-C6 alkyl or C1-C6 haloalkyl; preferably R5 is H, halogen, C1-C3 alkyl or C1-C3 haloalkyl; even more preferably R5 is H, halogen, methyl or trifluoromethyl.

[0090] In another compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R6 is H or a halogen.

[0091] In another compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R3 is -H, -CN, C1-C3 alkyl or C1-C3 haloalkyl (preferably R3 is H, CN or C1-C3 alkyl), and R2 is a group of the following formula:; or R2 is a substituted 5-membered heteroaryl group selected from pyrrole, furan, thiophene, pyrazole, isothiazolium, isothiazole, imidazole, acetazole, thiazole, triazole, acediazole and thiadiazole; wherein the substituted 5-membered heteroaryl group is substituted by one to three substituents selected independently from the following: -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R11, -CONR11R11, -NR11R11, - NR11CO2R11, a C1-C6 alkyl group as appropriate, a C3-C5 cycloalkyl group as appropriate, a heterocyclic group as appropriate selected from pyrrolidone, pyrrolidone, piperidine or morpholine, a phenyl group as appropriate, or a heteroaryl group as appropriate selected from pyridine, pyrazole, isothiazolium, isothiazole, imidazole, thiazolium or thiazole; wherein the C1-C6 alkyl group as appropriate is substituted with -CN, -OH or C1-C3 alkoxy as appropriate; and the C3-C5 cycloalkyl, phenyl, heterocyclic or heteroaryl group as appropriate is substituted with one or three substituents selected independently from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -NR11R11, -OH or -CN as appropriate. Each R10 is independently H, CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R11, -CONR11R11, -NR11R11, -NR11-CO2R11, a substituted C1-C6 alkyl, a substituted C3-C5 cycloalkyl, a substituted heterocycle selected from pyrrolidine, pyrrolidone, piperidine, or morpholine, a substituted phenyl, or a substituted pyrazole, isothiazolium, isothiazole, imidazole, pyrazole, or... The thiazole is optionally substituted with a heteroaryl group; wherein the optionally substituted C1-C6 alkyl group is optionally substituted with CN, -OH or C1-C3 alkoxy; wherein the optionally substituted C3-C5 cycloalkyl, phenyl, heterocyclic or heteroaryl group is optionally substituted with one to three substituents independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -NR11R11, -OH or -CN; and each R11 is independently H or C1-C3 alkyl.

[0092] In another compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R3 is -H, -CN, C1-C3 alkyl or C1-C3 haloalkyl (preferably R3 is H, CN or C1-C3 alkyl), and R2 is a group of the following formula:; wherein each R10 is independently H, CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R11, -CONR11R11, -NR11R11, -NR11-CO2R11, optionally substituted C1-C6 alkyl, optionally substituted C3-C5 cycloalkyl, optionally substituted heterocyclic selected from pyrrolidine, pyrrolidone, piperidine or morpholine, optionally substituted phenyl, or selected from pyrazole, isothiazole, isothiazole, imidazole, pyrazole or The thiazole is optionally substituted with a heteroaryl group; wherein the optionally substituted C1-C6 alkyl group is optionally substituted with CN, -OH or C1-C3 alkoxy; wherein the optionally substituted C3-C5 cycloalkyl, phenyl, heterocyclic or heteroaryl group is optionally substituted with one to three substituents independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -NR11R11, -OH or -CN; and each R11 is independently H or C1-C3 alkyl.

[0093] In another compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R4 is H or a halogen (preferably R4 is H), and R2 is a group of the following formula:; or R2 is a substituted 5-membered heteroaryl group selected from pyrrole, furan, thiophene, pyrazole, isothiazolium, isothiazole, imidazole, acetazole, thiazole, triazole, acediazole and thiadiazole; wherein the substituted 5-membered heteroaryl group is substituted by one to three substituents selected independently from the following: -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R11, -CONR11R11, -NR11R11, -NR11CO2R11, as appropriate. The substituted C1-C6 alkyl group, the optionally substituted C3-C5 cycloalkyl group, the optionally substituted heterocyclic group selected from pyrrolidone, pyrrolidone, piperidine or morpholine, the optionally substituted phenyl group, or the optionally substituted heteroaryl group selected from pyridine, pyrazole, isothiazolium, isothiazole, imidazole, thiazolium or thiazole; wherein the optionally substituted C1-C6 alkyl group is optionally substituted with -CN, -OH or C1-C3 alkoxy; and the optionally substituted C3-C5 cycloalkyl group, phenyl group, heterocyclic group or heteroaryl group is optionally substituted with one or three substituents independently selected from halogen, C1-C3 alkyl group, C1-C3 haloalkyl group, C1-C3 alkoxy group, C1-C3 haloalkoxy group, -NR11R11 group, -OH or -CN. Each R10 is independently H, CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R11, -CONR11R11, -NR11R11, -NR11-CO2R11, a substituted C1-C6 alkyl, a substituted C3-C5 cycloalkyl, a substituted heterocycle selected from pyrrolidine, pyrrolidone, piperidine, or morpholine, a substituted phenyl, or a substituted pyrazole, isothiazolium, isothiazole, imidazole, pyrazole, or... The thiazole is optionally substituted with a heteroaryl group; wherein the optionally substituted C1-C6 alkyl group is optionally substituted with CN, -OH or C1-C3 alkoxy; wherein the optionally substituted C3-C5 cycloalkyl, phenyl, heterocyclic or heteroaryl group is optionally substituted with one to three substituents independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -NR11R11, -OH or -CN; and each R11 is independently H or C1-C3 alkyl.

[0094] In another compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R4 is H or a halogen (preferably R4 is H), and R2 is a group of the following formula:; wherein each R10 is independently H, CN, a halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R11, -CONR11R11, -NR11R11, -NR11-CO2R11, a substituted C1-C6 alkyl, a substituted C3-C5 cycloalkyl, a substituted heterocyclic ring selected from pyrrolidine, pyrrolidone, piperidine or morpholine, a substituted phenyl, or a pyrazole, isozolazole, isothiazole, imidazole, succinate or The thiazole is optionally substituted with a heteroaryl group; wherein the optionally substituted C1-C6 alkyl group is optionally substituted with CN, -OH or C1-C3 alkoxy; wherein the optionally substituted C3-C5 cycloalkyl, phenyl, heterocyclic or heteroaryl group is optionally substituted with one to three substituents independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -NR11R11, -OH or -CN; and each R11 is independently H or C1-C3 alkyl.

[0095] In another compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R5 is H, a halogen, a C1-C6 alkyl or a C1-C6 haloalkyl, and R2 is a group of the following formula:; or R2 is a substituted 5-membered heteroaryl group selected from pyrrole, furan, thiophene, pyrazole, isothiazolium, isothiazole, imidazole, succinazole, thiazole, triazole, succinyl diazole and thiadiazole; wherein the substituted 5-membered heteroaryl group is substituted by one to three substituents selected independently from the following: -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R11, -CONR11R11, -NR11R11, -NR11CO2R11 The substituted C1-C6 alkyl group, the substituted C3-C5 cycloalkyl group, the substituted heterocyclic group selected from pyrrolidone, pyrrolidone, piperidine or morpholine, the substituted phenyl group, or the substituted heteroaryl group selected from pyridine, pyrazole, isothiazolium, isothiazole, imidazole, thiazolium or thiazole; wherein the substituted C1-C6 alkyl group is substituted with -CN, -OH or C1-C3 alkoxy group as appropriate; and the substituted C3-C5 cycloalkyl group, phenyl group, heterocyclic group or heteroaryl group is substituted with one or three substituents selected independently from halogen, C1-C3 alkyl group, C1-C3 haloalkyl group, C1-C3 alkoxy group, C1-C3 haloalkoxy group, -NR11R11 group, -OH or -CN group as appropriate. Each R10 is independently H, CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R11, -CONR11R11, -NR11R11, -NR11-CO2R11, a substituted C1-C6 alkyl, a substituted C3-C5 cycloalkyl, a substituted heterocycle selected from pyrrolidine, pyrrolidone, piperidine, or morpholine, a substituted phenyl, or a substituted pyrazole, isothiazolium, isothiazole, imidazole, pyrazole, or... The thiazole is optionally substituted with a heteroaryl group; wherein the optionally substituted C1-C6 alkyl group is optionally substituted with CN, -OH or C1-C3 alkoxy; wherein the optionally substituted C3-C5 cycloalkyl, phenyl, heterocyclic or heteroaryl group is optionally substituted with one to three substituents independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -NR11R11, -OH or -CN; and each R11 is independently H or C1-C3 alkyl.

[0096] In another compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R5 is H, a halogen, a C1-C6 alkyl or a C1-C6 haloalkyl, and R2 is a group of the following formula:; wherein each R10 is independently H, CN, a halogen, a C1-C6 haloalkyl, a C1-C6 alkoxy, a C1-C6 haloalkoxy, -SO2R11, -CONR11R11, -NR11R11, -NR11-CO2R11, a C1-C6 alkyl group substituted as appropriate, a C3-C5 cycloalkyl group substituted as appropriate, a heterocyclic group substituted as appropriate selected from pyrrolidine, pyrrolidone, piperidine or morpholine, a phenyl group substituted as appropriate, or a group selected from pyrazole, isothiazole, isothiazole, imidazole, pyrazole or The thiazole is optionally substituted with a heteroaryl group; wherein the optionally substituted C1-C6 alkyl group is optionally substituted with CN, -OH or C1-C3 alkoxy; wherein the optionally substituted C3-C5 cycloalkyl, phenyl, heterocyclic or heteroaryl group is optionally substituted with one to three substituents independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -NR11R11, -OH or -CN; and each R11 is independently H or C1-C3 alkyl.

[0097] In another compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R6 is H or a halogen, and R2 is a group of the following formula:; or R2 is a substituted 5-membered heteroaryl group selected from pyrrole, furan, thiophene, pyrazole, isothiazolium, isothiazole, imidazole, acetazole, thiazole, triazole, acediazole and thiadiazole; wherein the substituted 5-membered heteroaryl group is substituted by one to three substituents selected independently from the following: -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R11, -CONR11R11, -NR11R11, -NR11CO2R11, substituted C 1-C6 alkyl, optionally substituted C3-C5 cycloalkyl, optionally substituted heterocyclic selected from pyrrolidone, pyrrolidone, piperidine or morpholine, optionally substituted phenyl, or optionally substituted heteroaryl selected from pyridine, pyrazole, isothiazolium, isothiazole, imidazole, thiazolium or thiazole; wherein the optionally substituted C1-C6 alkyl is optionally substituted with -CN, -OH or C1-C3 alkoxy; the optionally substituted C3-C5 cycloalkyl, phenyl, heterocyclic or heteroaryl is optionally substituted with one or three substituents independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -NR11R11, -OH or -CN; Each R10 is independently H, CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R11, -CONR11R11, -NR11R11, -NR11-CO2R11, a substituted C1-C6 alkyl, a substituted C3-C5 cycloalkyl, a substituted heterocycle selected from pyrrolidine, pyrrolidone, piperidine, or morpholine, a substituted phenyl, or a substituted pyrazole, isothiazolium, isothiazole, imidazole, pyrazole, or... The thiazole is optionally substituted with a heteroaryl group; wherein the optionally substituted C1-C6 alkyl group is optionally substituted with CN, -OH or C1-C3 alkoxy; wherein the optionally substituted C3-C5 cycloalkyl, phenyl, heterocyclic or heteroaryl group is optionally substituted with one to three substituents independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -NR11R11, -OH or -CN; and each R11 is independently H or C1-C3 alkyl.

[0098] In another compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R6 is H or a halogen, and R2 is a group of the following formula:; wherein each R10 is independently H, CN, a halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R11, -CONR11R11, -NR11R11, -NR11-CO2R11, a substituted C1-C6 alkyl, a substituted C3-C5 cycloalkyl, a substituted heterocyclic ring selected from pyrrolidine, pyrrolidone, piperidine or morpholine, a substituted phenyl, or a pyrazole, isozolazole, isothiazole, imidazole, succinate or The thiazole is optionally substituted with a heteroaryl group; wherein the optionally substituted C1-C6 alkyl group is optionally substituted with CN, -OH or C1-C3 alkoxy; wherein the optionally substituted C3-C5 cycloalkyl, phenyl, heterocyclic or heteroaryl group is optionally substituted with one to three substituents independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -NR11R11, -OH or -CN; and each R11 is independently H or C1-C3 alkyl.

[0099] In another compound of formula (I) or (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 another compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R3 is -H, -CN, C1-C3 alkyl or C1-C3 haloalkyl (preferably R3 is H, CN or C1-C3 alkyl), and 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 another compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R3 is -H, -CN, C1-C3 alkyl or C1-C3 haloalkyl (preferably R3 is H, CN or C1-C3 alkyl), and R6 is H or halogen; more preferably R3 is H or methyl, and R6 is H.

[0102] In another compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R4 is -H or a halogen (preferably R4 is H), and R5 is H, a halogen, a C1-C3 alkyl or a C1-C3 haloalkyl; preferably R5 is H, a halogen, a methyl or a trifluoromethyl.

[0103] In another compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R4 is H or a halogen (preferably R4 is -H) and R6 is H or a halogen.

[0104] In another compound 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 another compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R3 is -H, -CN, C1-C3 alkyl or C1-C3 haloalkyl (preferably R3 is H, CN or C1-C3 alkyl), R4 is -H or halogen (preferably R4 is H), and R2 is a group of the following formula:; or R2 is a substituted 5-membered heteroaryl group selected from pyrrole, furan, thiophene, pyrazole, isothiazolium, isothiazole, imidazole, acetazole, thiazole, triazole, acediazole and thiadiazole; wherein the substituted 5-membered heteroaryl group is substituted by one to three substituents selected independently from the following: -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R11, -CONR11R11. -NR11R11, -NR11CO2R11, a C1-C6 alkyl group as appropriate, a C3-C5 cycloalkyl group as appropriate, a heterocyclic group selected from pyrrolidone, pyrrolidone, piperidine or morpholine as appropriate, a phenyl group as appropriate, or a heteroaryl group selected from pyridine, pyrazole, isothiazol, isothiazole, imidazole, thiazol or thiazole as appropriate; wherein the C1-C6 alkyl group as appropriate is substituted with CN, -OH or C1-C3 alkoxy as appropriate; the C3-C5 cycloalkyl, phenyl, heterocyclic or heteroaryl group as appropriate is substituted with one or three substituents selected independently from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -NR11R11, -OH or -CN as appropriate; preferably R3 is H or methyl, and R4 is H.

[0106] In another compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R3 is -H, -CN, C1-C3 alkyl or C1-C3 haloalkyl (preferably R3 is H, CN or C1-C3 alkyl), R4 is -H or halogen (preferably R4 is H), and R2 is a group of the following formula:; more preferably R3 is H or methyl, and R4 is H.

[0107] In another compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R3 is -H, -CN, C1-C3 alkyl or C1-C3 haloalkyl (preferably R3 is H, CN or C1-C3 alkyl), R5 is H, halogen, C1-C6 alkyl or C1-C6 haloalkyl, and R2 is a group of the following formula:; or R2 is a substituted 5-membered heteroaryl group selected from pyrrole, furan, thiophene, pyrazole, isothiazolium, isothiazole, imidazole, acetazole, thiazole, triazole, acediazole and thiadiazole; wherein the substituted 5-membered heteroaryl group is substituted by one to three substituents selected independently from the following: -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R11, -CONR11R 11. -NR11R11, -NR11CO2R11, a C1-C6 alkyl group substituted as appropriate, a C3-C5 cycloalkyl group substituted as appropriate, a heterocyclic group substituted as appropriate from pyrrolidone, piperidine, or morpholine, a phenyl group substituted as appropriate, or a heteroaryl group substituted as appropriate from pyridine, pyrazole, isothiazolium, isothiazole, imidazole, thiazolium, or thiazole; wherein the C1-C6 alkyl group substituted as appropriate is substituted with -CN, -OH, or C1-C3 alkoxy; and the C3-C5 cycloalkyl, phenyl, heterocyclic, or heteroaryl group substituted as appropriate is substituted with one or three substituents independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -NR11R11, -OH, or -CN; Preferably, R3 is H or methyl, and R5 is H, halogen, methyl or trifluoromethyl.

[0108] In another compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R3 is -H, -CN, C1-C3 alkyl or C1-C3 haloalkyl (preferably R3 is H, CN or C1-C3 alkyl), R5 is H, halogen, C1-C6 alkyl or C1-C6 haloalkyl, and R2 is a group of the following formula:; more preferably R3 is H or methyl, and R5 is H, halogen, methyl or trifluoromethyl.

[0109] In another compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R3 is -H, -CN, C1-C3 alkyl or C1-C3 haloalkyl (preferably R3 is H, CN or C1-C3 alkyl), and R6 is H or halogen, and R2 is a group of the following formula:; or R2 is a substituted 5-membered heteroaryl group selected from pyrrole, furan, thiophene, pyrazole, isothiazolium, isothiazole, imidazole, acetazole, thiazole, triazole, acediazole and thiadiazole; wherein the substituted 5-membered heteroaryl group is substituted by one to three substituents selected independently from the following: -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R11, -CONR11R11, -NR11 R11, -NR11CO2R11, a C1-C6 alkyl group as appropriate, a C3-C5 cycloalkyl group as appropriate, a heterocyclic group selected from pyrrolidone, pyrrolidone, piperidine or morpholine as appropriate, a phenyl group as appropriate, or a heteroaryl group selected from pyridine, pyrazole, isothiazol, isothiazole, imidazole, thiazol or thiazole as appropriate; wherein the C1-C6 alkyl group as appropriate is substituted with -CN, -OH or C1-C3 alkoxy as appropriate; the C3-C5 cycloalkyl group, phenyl group, heterocyclic group or heteroaryl group as appropriate is substituted with one or three substituents selected independently from halogen, C1-C3 alkyl group, C1-C3 haloalkyl group, C1-C3 alkoxy group, C1-C3 haloalkoxy group, -NR11R11, -OH or -CN as appropriate; preferably R3 is H or methyl, and R6 is H.

[0110] In another compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R3 is -H, -CN, C1-C3 alkyl or C1-C3 haloalkyl (preferably R3 is H, CN or C1-C3 alkyl), and R6 is H or halogen, and R2 is a group of the following formula:; more preferably R3 is H or methyl, and R6 is H.

[0111] In another compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R4 is H or a halogen (preferably R4 is H), R5 is H, a halogen, a C1-C3 alkyl or a C1-C3 haloalkyl, and R2 is a group of the following formula:; or R2 is a substituted 5-membered heteroaryl group selected from pyrrole, furan, thiophene, pyrazole, isothiazolium, isothiazole, imidazole, acetazole, thiazole, triazole, acediazole and thiadiazole; wherein the substituted 5-membered heteroaryl group is substituted by one to three substituents selected independently from the following: -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R11, -CONR11R11, -NR11R11, -NR11CO2R11. The C1-C6 alkyl group may be substituted, the C3-C5 cycloalkyl group may be substituted, the heterocyclic group may be substituted from pyrrolidone, piperidine or morpholine, the phenyl group may be substituted, or the heteroaryl group may be substituted from pyridine, pyrazole, isothiazol, imidazole, thiazol or thiazole; wherein the C1-C6 alkyl group may be substituted with -CN, -OH or C1-C3 alkoxy; the C3-C5 cycloalkyl, phenyl, heterocyclic or heteroaryl group may be substituted with one or three substituents selected independently from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -NR11R11, -OH or -CN; preferably R5 is H, halogen, methyl or trifluoromethyl.

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

[0113] In compounds of formula (I) or (II) or their pharmaceutically acceptable salts, R4 is H or a halogen (preferably R4 is H) and R6 is H or a halogen, and R2 is a group of the following formula:; or R2 is a substituted 5-membered heteroaryl group selected from pyrrole, furan, thiophene, pyrazole, isothiazolium, isothiazole, imidazole, succinazole, thiazole, triazole, succinyl diazole and thiadiazole; wherein the substituted 5-membered heteroaryl group is substituted by one to three substituents selected independently from the following: -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R11, -CONR11R11, -NR11R11, -NR11CO2R11, ... The substituted C1-C6 alkyl group, optionally substituted C3-C5 cycloalkyl group, optionally substituted heterocyclic group selected from pyrrolidone, pyrrolidone, piperidine or morpholine, optionally substituted phenyl group, or optionally substituted heteroaryl group selected from pyridine, pyrazole, isothiazolium, isothiazole, imidazole, thiazolium or thiazole; wherein the optionally substituted C1-C6 alkyl group is optionally substituted with CN, -OH or C1-C3 alkoxy group; the optionally substituted C3-C5 cycloalkyl group, phenyl group, heterocyclic group or heteroaryl group is optionally substituted with one or three substituents independently selected from halogen, C1-C3 alkyl group, C1-C3 haloalkyl group, C1-C3 alkoxy group, C1-C3 haloalkoxy group, -NR11R11 group, -OH or -CN group; preferably R4 and R6 are each H.

[0114] In the compound of formula (I) or (II) or its pharmaceutically acceptable salt, R4 is H or a halogen (preferably R4 is H) and R6 is H or a halogen, and R2 is a group of the following formula:; more preferably R4 and R6 are each H.

[0115] In another compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R5 is H, a halogen, a C1-C3 alkyl or a C1-C3 haloalkyl, R6 is H or a halogen, and R2 is a group of the following formula:; or R2 is a substituted 5-membered heteroaryl group selected from pyrrole, furan, thiophene, pyrazole, isothiazolium, isothiazole, imidazole, succinazole, thiazole, triazole, succinyl diazole and thiadiazole; wherein the substituted 5-membered heteroaryl group is substituted by one to three substituents selected independently from the following: -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R11, -CONR11R11, -NR11R11, -NR11CO2 R11, optionally substituted C1-C6 alkyl, optionally substituted C3-C5 cycloalkyl, optionally substituted heterocyclic selected from pyrrolidone, pyrrolidone, piperidine or morpholine, optionally substituted phenyl, or optionally substituted heteroaryl selected from pyridine, pyrazole, isothiazolium, isothiazole, imidazole, thiazolium or thiazole; wherein optionally substituted C1-C6 alkyl is optionally substituted with -CN, -OH or C1-C3 alkoxy; optionally substituted C3-C5 cycloalkyl, phenyl, heterocyclic or heteroaryl is optionally substituted with one or three substituents independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -NR11R11, -OH or -CN; preferably R5 is H, halogen, methyl or trifluoromethyl, and R6 is H.

[0116] In another compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R5 is H, halogen, C1-C3 alkyl or C1-C3 haloalkyl, R6 is H or halogen, and R2 is a group of the following formula:; preferably R5 is H, halogen, methyl or trifluoromethyl, and R6 is H.

[0117] In another compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R3 is H, CN, C1-C3 alkyl or C1-C3 haloalkyl (preferably R3 is H, CN or C1-C3 alkyl), R4 is H or halogen (preferably R4 is H), 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 another compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R3 is H, CN, C1-C3 alkyl or C1-C3 haloalkyl (preferably R3 is H, CN or C1-C3 alkyl), R4 is H or halogen (preferably R4 is H) and R6 is H or halogen; more preferably R3 is H or methyl, and R4 and R6 are each H.

[0119] In another compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R3 is H, CN, C1-C3 alkyl or C1-C3 haloalkyl (preferably R3 is H, CN or C1-C3 alkyl), R5 is H, halogen, C1-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 another compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R5 is H, halogen, C1-C3 alkyl or C1-C3 haloalkyl, R4 is H or halogen (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 another compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R3 is -H, -CN, C1-C3 alkyl or C1-C3 haloalkyl (preferably R3 is H, CN or C1-C3 alkyl), R4 is -H or halogen (preferably R4 is H), R5 is H, halogen, C1-C6 alkyl, C1-C6 haloalkyl or C1-C6 alkoxy, and R2 is a group of the following formula. R2 is a substituted 5-membered heteroaryl group selected from pyrrole, furan, thiophene, pyrazole, isothiazolium, isothiazole, imidazole, thiazolium, triazole, thiadiazole, and thiadiazole; wherein the substituted 5-membered heteroaryl group is substituted by one to three substituents selected independently from the following: -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO 2R11, -CONR11R11, -NR11R11, -NR11CO2R11, a C1-C6 alkyl group substituted as appropriate, a C3-C5 cycloalkyl group substituted as appropriate, a heterocyclic group substituted as appropriate from pyrrolidone, pyrrolidone, piperidine or morpholine, a phenyl group substituted as appropriate, or a heteroaryl group substituted as appropriate from pyridine, pyrazole, isothiazolium, isothiazole, imidazole, thiazolium or thiazole; wherein the C1-C6 alkyl group substituted as appropriate is substituted with -CN, -OH or C1-C3 alkoxy; and the C3-C5 cycloalkyl, phenyl, heterocyclic or heteroaryl group substituted as appropriate is substituted with one or three substituents independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -NR11R11, -OH or -CN; Preferably, R3 is H or methyl, R4 is H, and R5 is H, halogen, methyl, or trifluoromethyl.

[0122] In another compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R3 is -H, -CN, C1-C3 alkyl or C1-C3 haloalkyl (preferably R3 is H, CN or C1-C3 alkyl), R4 is -H or halogen (preferably R4 is H), R5 is H, halogen, C1-C6 alkyl, C1-C6 haloalkyl or C1-C6 alkoxy, and R2 is a group of the following formula:; more preferably R3 is H or methyl, R4 is H, and R5 is H, halogen, methyl or trifluoromethyl.

[0123] In another compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R3 is -H, -CN, C1-C3 alkyl or C1-C3 haloalkyl (preferably R3 is H, CN or C1-C3 alkyl), R4 is -H or halogen (preferably R4 is -H), R6 is H, and R2 is a group of the following formula:; or R2 is a substituted 5-membered heteroaryl group selected from pyrrole, furan, thiophene, pyrazole, isothiazolium, isothiazole, imidazole, acetazole, thiazole, triazole, acediazole and thiadiazole; wherein the substituted 5-membered heteroaryl group is substituted by one to three substituents selected independently from the following: -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R11, -CONR11R1 1. -NR11R11, -NR11CO2R11, a C1-C6 alkyl group substituted as appropriate, a C3-C5 cycloalkyl group substituted as appropriate, a heterocyclic group substituted as appropriate from pyrrolidone, piperidine, or morpholine, a phenyl group substituted as appropriate, or a heteroaryl group substituted as appropriate from pyridine, pyrazole, isothiazolium, isothiazole, imidazole, thiazolium, or thiazole; wherein the C1-C6 alkyl group substituted as appropriate is substituted with -CN, -OH, or C1-C3 alkoxy; and the C3-C5 cycloalkyl, phenyl, heterocyclic, or heteroaryl group substituted as appropriate is substituted with one or three substituents independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -NR11R11, -OH, or -CN; Preferably, R3 is H or methyl, and R4 and R6 are each H.

[0124] In another compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R3 is -H, -CN, C1-C3 alkyl or C1-C3 haloalkyl (preferably R3 is H, CN or C1-C3 alkyl), R4 is -H or halogen (preferably R4 is -H), R6 is H, and R2 is a group of the following formula:; more preferably R3 is H or methyl, and R4 and R6 are each H.

[0125] In another compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R3 is -H, -CN, C1-C3 alkyl or C1-C3 haloalkyl (preferably R3 is H, CN or C1-C3 alkyl), R5 is H, halogen, C1-C6 alkyl or C1-C6 haloalkyl, R6 is H or halogen, and R2 is a group of the following formula:; or R2 is a substituted 5-membered heteroaryl group selected from pyrrole, furan, thiophene, pyrazole, isothiazolium, isothiazole, imidazole, acetazole, thiazole, triazole, acediazole and thiadiazole; wherein the substituted 5-membered heteroaryl group is substituted by one to three substituents selected independently from the following: -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R11, -CON R11R11, -NR11R11, -NR11CO2R11, a C1-C6 alkyl group substituted as appropriate, a C3-C5 cycloalkyl group substituted as appropriate, a heterocyclic group substituted as appropriate from pyrrolidone, pyrrolidone, piperidine or morpholine, a phenyl group substituted as appropriate, or a heteroaryl group substituted as appropriate from pyridine, pyrazole, isothiazolium, isothiazole, imidazole, thiazolium or thiazole; wherein the C1-C6 alkyl group substituted as appropriate is substituted with -CN, -OH or C1-C3 alkoxy; and the C3-C5 cycloalkyl, phenyl, heterocyclic or heteroaryl group substituted as appropriate is substituted with one or three substituents independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -NR11R11, -OH or -CN; Preferably, R3 is H or methyl, R5 is H, halogen, methyl or trifluoromethyl, and R6 is H.

[0126] In another compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R3 is -H, -CN, C1-C3 alkyl or C1-C3 haloalkyl (preferably R3 is H, CN or C1-C3 alkyl), R5 is H, halogen, C1-C6 alkyl or C1-C6 haloalkyl, R6 is H or halogen, and R2 is a group of the following formula:; more preferably R3 is H or methyl, R5 is H, halogen, methyl or trifluoromethyl, and R6 is H.

[0127] In another compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R5 is H, a halogen, a C1-C3 alkyl or a C1-C3 haloalkyl, R4 is -H or a halogen (preferably R4 is H), R6 is H or a halogen, and R2 is a group of the following formula:; or R2 is a substituted 5-membered heteroaryl group selected from pyrrole, furan, thiophene, pyrazole, isothiazolium, isothiazole, imidazole, acetazole, thiazole, triazole, acediazole and thiadiazole; wherein the substituted 5-membered heteroaryl group is substituted by one to three substituents selected independently from the following: -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R11, -CONR11R11, -NR11R11 -NR11CO2R11, a C1-C6 alkyl group as appropriate, a C3-C5 cycloalkyl group as appropriate, a heterocyclic group selected from pyrrolidone, pyrrolidone, piperidine or morpholine as appropriate, a phenyl group as appropriate, or a heteroaryl group selected from pyridine, pyrazole, isothiazolium, isothiazole, imidazole, thiazolium or thiazole as appropriate; wherein the C1-C6 alkyl group as appropriate is substituted with -CN, -OH or C1-C3 alkoxy as appropriate; and the C3-C5 cycloalkyl, phenyl, heterocyclic or heteroaryl group as appropriate is substituted with one or three substituents selected independently from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -NR11R11, -OH or -CN as appropriate. Preferably, R5 is H, halogen, methyl or trifluoromethyl, and R4 and R6 are each H.

[0128] In another compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R5 is H, halogen, C1-C3 alkyl or C1-C3 haloalkyl, R4 is -H or halogen (preferably R4 is H), R6 is H or halogen, and R2 is a group of the following formula:; more preferably R5 is H, halogen, methyl or trifluoromethyl, and R4 and R6 are each H.

[0129] In another compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R3 is H, CN, C1-C3 alkyl or C1-C3 haloalkyl (preferably R3 is H, CN or C1-C3 alkyl), R4 is H or halogen (preferably R4 is H), R6 is H 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 another compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R3 is -H, -CN, C1-C3 alkyl or C1-C3 haloalkyl (preferably R3 is H, CN or C1-C3 alkyl), R4 is -H or halogen (preferably R4 is H), R6 is H or halogen, R5 is H, halogen, C1-C3 alkyl or C1-C3 haloalkyl, and R2 is a group of the following formula: ; or R2 is a substituted 5-membered heteroaryl group selected from pyrrole, furan, thiophene, pyrazole, isothiazolium, isothiazole, imidazole, thiazolium, triazole, thiadiazole, and thiadiazole; wherein the substituted 5-membered heteroaryl group is substituted by one to three substituents selected independently from the following: -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2 R11, -CONR11R11, -NR11R11, -NR11CO2R11, a C1-C6 alkyl group substituted as appropriate, a C3-C5 cycloalkyl group substituted as appropriate, a heterocyclic group substituted as appropriate from pyrrolidone, piperidine, or morpholine, a phenyl group substituted as appropriate, or a heteroaryl group substituted as appropriate from pyridine, pyrazole, isothiazolium, isothiazole, imidazole, thiazolium, or thiazole; wherein the C1-C6 alkyl group substituted as appropriate is substituted with -CN, -OH, or C1-C3 alkoxy; and each of the C3-C5 cycloalkyl, phenyl, heterocyclic, or heteroaryl group substituted as appropriate is substituted with one or three substituents independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -NR11R11, -OH, or -CN; Preferably, R3 is H or methyl, R4 and R6 are each H, and R5 is H, halogen, methyl or trifluoromethyl.

[0131] In another compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R3 is -H, -CN, C1-C3 alkyl or C1-C3 haloalkyl (preferably R3 is H, CN or C1-C3 alkyl), R4 is -H or halogen (preferably R4 is H), R6 is H or halogen, R5 is H, halogen, C1-C3 alkyl or C1-C3 haloalkyl, and R2 is a group of the following formula:; more preferably R3 is H or methyl, R4 and R6 are each H, and R5 is H, halogen, methyl or trifluoromethyl.

[0132] In another compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R is H.

[0133] In another compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R7 is CN, C1-C6 alkyl or C1-C6 haloalkyl; preferably R7 is CN, C1-C3 alkyl or C1-C3 haloalkyl; more preferably R7 is CN, methyl or trifluoromethyl.

[0134] In another compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R8 is H.

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

[0136] In another compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R8 and R are each H.

[0137] In another compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R7 is CN, C1-C3 alkyl or C1-C3 haloalkyl, and R8 is H. In another compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R7 is C1-C3 alkyl (preferably methyl), and R8 is H.

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

[0139] In another compound of formula (I) or (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 following formula:; or R2 is a substituted 5-membered heteroaryl group selected from pyrrole, furan, thiophene, pyrazole, isothiazolium, isothiazole, imidazole, acetazole, thiazole, triazole, acediazole and thiadiazole; wherein the substituted 5-membered heteroaryl group is substituted by one to three substituents selected independently from the following: -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R11, -CONR11R11, -NR11R11, -NR11CO2 R11, a C1-C6 alkyl group, a C3-C5 cycloalkyl group, a heterocyclic group selected from pyrrolidone, pyrrolidone, piperidine or morpholine, a phenyl group, or a heteroaryl group selected from pyridine, pyrazole, isothiazol, isothiazole, imidazole, thiazol or thiazole; wherein the C1-C6 alkyl group is substituted with -CN, -OH or C1-C3 alkoxy as appropriate; and each of the C3-C5 cycloalkyl, phenyl, heterocyclic or heteroaryl group is substituted with one or three substituents selected independently from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -NR11R11, -OH or -CN as appropriate.

[0140] In another compound of formula (I) or (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 following formula:

[0141] In another compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R7 is a C1-C3 alkyl (preferably methyl), R8 is H, R is H, and R2 is a group of the following formula:; or R2 is a substituted 5-membered heteroaryl group selected from pyrrole, furan, thiophene, pyrazole, isothiazolium, isothiazole, imidazole, succinazole, thiazole, triazole, succinyl diazole and thiadiazole; wherein the substituted 5-membered heteroaryl group is substituted by one to three substituents selected independently from the following: -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R11, -CONR11R11, -NR11R11, -NR11CO2R11 The substituted C1-C6 alkyl group, the substituted C3-C5 cycloalkyl group, the substituted heterocyclic group selected from pyrrolidone, pyrrolidone, piperidine or morpholine, the substituted phenyl group, or the substituted heteroaryl group selected from pyridine, pyrazole, isothiazol, isothiazole, imidazole, thiazol or thiazole; wherein the substituted C1-C6 alkyl group is substituted with -CN, -OH or C1-C3 alkoxy group as appropriate; and the substituted C3-C5 cycloalkyl group, phenyl group, heterocyclic group or heteroaryl group is substituted with one or three substituents selected independently from halogen, C1-C3 alkyl group, C1-C3 haloalkyl group, C1-C3 alkoxy group, C1-C3 haloalkoxy group, -NR11R11 group, -OH or -CN group as appropriate.

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

[0143] In yet another compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R3 is -H, -CN, C1-C3 alkyl or C1-C3 haloalkyl (preferably R3 is H, CN or C1-C3 alkyl), R7 is CN, C1-C3 alkyl or C1-C3 haloalkyl, and R8 and R are each H. In yet another compound of formula (I) or (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 yet another compound of formula (I) or (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 yet another compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R7 is C1-C3 alkyl (preferably methyl), and R4, R8 and R are each H.

[0145] In yet another compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R5 is H, a halogen, a C1-C3 alkyl group or a C1-C3 haloalkyl group, R7 is CN, a methyl group or a trifluoromethyl group, and R8 and R are each H. In yet another compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R5 is H, a halogen, a methyl group or a trifluoromethyl group, R7 is methyl, and R8 and R are each H.

[0146] In another compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R3 is -H, -CN, C1-C3 alkyl or C1-C3 haloalkyl (preferably R3 is H, CN or C1-C3 alkyl), R4 is -H or halogen (preferably R4 is H), R6 is H or halogen, R5 is H, halogen, C1-C6 alkyl or C1-C6 haloalkyl, R7 is CN, methyl or trifluoromethyl, R 8 is H, R is H, and R2 is a group of the following formula:; or R2 is a substituted 5-membered heteroaryl group selected from pyrrole, furan, thiophene, pyrazole, isothiazolium, isothiazole, imidazole, acetazole, thiazole, triazole, acediazole, and thiadiazole; wherein the substituted 5-membered heteroaryl group is substituted by one to three substituents selected independently from the following: -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1 -C6 haloalkoxy, -SO2R11, -CONR11R11, -NR11R11, -NR11CO2R11, substituted C1-C6 alkyl, substituted C3-C5 cycloalkyl, substituted heterocyclic rings selected from pyrrolidone, pyrrolidone, piperidine or morpholine, substituted phenyl, or substituted pyridine, pyrazole, isothiazolium, isothiazole, imidazole, thiazolium or thiazole, substituted The heteroaryl group; wherein the substituted C1-C6 alkyl group is substituted with -CN, -OH or C1-C3 alkoxy as appropriate; wherein the substituted C3-C5 cycloalkyl, phenyl, heterocyclic or heteroaryl group is substituted with one to three substituents selected independently from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -NR11R11, -OH or -CN as appropriate; 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 another compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R3 is -H, -CN, C1-C3 alkyl or C1-C3 haloalkyl (preferably R3 is H, CN or C1-C3 alkyl), R4 is -H or halogen (preferably R4 is H), R6 is H 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 following formula:; 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 another compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R1 is a group of the following formula:; wherein each R9 is independently -H, halogen, -CN, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy or C3-C5 cycloalkyl; preferably each R9 is independently -H, halogen, -CN, methyl, trifluoromethyl, methoxy or cyclopropyl.

[0149] In another compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R1 is a group of the following formula:; 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 another compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R1 is a group of the following formula:; wherein each R9 is independently -H, halogen, C1-C3 alkyl, C1-C3 haloalkyl or C3-C5 cycloalkyl; preferably each R9 is independently -H, halogen, methyl, trifluoromethyl or cyclopropyl.

[0151] In another compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R1 is a group of the following formula:; 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 another compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R1 is a group of the following formula:; 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 another compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R1 is a group of the following formula: ; 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 another compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R1 is a group of the following formula: ; wherein each R9 is independently H, a halogen, a C1-C6 alkyl, a C1-C6 haloalkyl, a C1-C6 alkoxy, or a C3-C5 cycloalkyl. Preferably, each R9 is independently H, a halogen, a C1-C3 alkyl, or a C1-C3 haloalkyl. More preferably, each R9 is independently H, a halogen, or a trifluoromethyl group.

[0155] In another compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R1 is a group of the following formula:; 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 another compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R1 is a group of the following formula:; 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 another compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R1 is a group of the following formula: ; wherein each R9 is independently -H, halogen, -CN, C1-C3 alkyl, C1-C3 haloalkyl, or C1-C3 alkoxy. 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.

[0158] In another compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R1 is a group of the following formula: ; 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 another compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R1 is a group of the following formula: ; 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 fluorine.

[0160] In another compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R1 is a group of the following formula: ; 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 another compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R1 is a group of the following formula: ; wherein R9 is H, a halogen, or a C1-C3 haloalkyl group. Preferably, R9 is a halogen or trifluoromethyl. More preferably, R9 is chlorine or trifluoromethyl.

[0162] In another compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R1 is a group of the following formula: ; 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 another compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R1 is a group of the following formula: ; 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 another compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R1 is a group of the following formula:

[0165] In another compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R1 is a group of the following formula:

[0166] In another compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R1 is a group of the following formula:

[0167] In another compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R3 is -H, -CN, C1-C3 alkyl or C1-C3 haloalkyl, R4 is -H or halogen, R6 is -H or halogen, R5 is -H, halogen, C1-C3 alkyl or C1-C3 haloalkyl, and R1 is a group of the following formula:; 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. More 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 another compound of formula (I) or (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 following formula:; 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 another compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R7 is -CN, methyl or trifluoromethyl, R8 and R are each -H, and R1 is a group of the following formula:; wherein each R9 is independently -H, halogen, C1-C3 alkyl, C1-C3 haloalkyl or C3-C5 cycloalkyl; preferably R7 is methyl, R8 and R are each -H, and each R9 is independently -H, halogen, methyl, trifluoromethyl or cyclopropyl.

[0170] In another compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R7 is CN, methyl or trifluoromethyl, R8 and R are H, and R1 is a group of the following formula:; wherein each R9 is independently H, halogen, C1-C3 alkyl or C1-C3 haloalkyl; preferably R7 is methyl, R8 and R are each H, and each R9 is independently H, halogen, methyl or trifluoromethyl.

[0171] In another compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R3 is -H, -CN, C1-C3 alkyl or C1-C3 haloalkyl, R4 is -H or halogen, R8 and R are each -H, R5 is -H, halogen, C1-C3 alkyl or C1-C3 haloalkyl, R6 is -H or halogen, R7 is -CN, methyl or trifluoromethyl, and R1 is a group of the following formula:; 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, 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 another compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R3 is H, CN or C1-C3 alkyl, R4, R6, R8 and R are each H, R5 is H, halogen, C1-C3 alkyl or C1-C3 haloalkyl, R7 is CN, methyl or trifluoromethyl, and R1 is a group of the following formula:; 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 another compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R3 is -H, -CN, C1-C3 alkyl or C1-C3 haloalkyl, R4 is -H or halogen, R8 and R are each -H, R5 is -H, halogen, C1-C3 alkyl or C1-C3 haloalkyl, R6 is -H or halogen, R7 is -CN, methyl or trifluoromethyl, and R1 is a group of the following formula:; wherein each R9 is independently -H, halogen, C1-C3 alkyl or C1-C3 haloalkyl; preferably R3 is -H, methyl or trifluoromethyl, R4 is -H or halogen, R6 is -H or halogen, R8 and R are each -H, R5 is -H, halogen, methyl or trifluoromethyl, R7 is methyl, and each R9 is independently -H, halogen, methyl or trifluoromethyl.

[0174] In another compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R3 is H, CN or C1-C3 alkyl, R4, R6, R8 and R are each H, R5 is H, halogen, C1-C3 alkyl or C1-C3 haloalkyl, R7 is CN, methyl or trifluoromethyl, and R1 is a group of the following formula:; 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 another compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R3 is H, CN, or C1-C3 alkyl, R4, R6, R8, and R are each H, R5 is H, halogen, C1-C3 alkyl, or C1-C3 haloalkyl, R7 is CN, methyl, or trifluoromethyl, and R1 is a group of the following formula:; 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 fluorine.

[0176] In another compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R3 is -H, -CN, C1-C3 alkyl or C1-C3 haloalkyl, R4 is -H or halogen, R8 and R are each -H, R5 is -H, halogen, C1-C3 alkyl or C1-C3 haloalkyl, R6 is -H or halogen, R7 is -CN, methyl or trifluoromethyl, and R1 is a group of the following formula:; 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 another compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R3 is H, CN or C1-C3 alkyl, R4, R6, R8 and R are each H, R5 is H, halogen, C1-C3 alkyl or C1-C3 haloalkyl, R7 is CN, methyl or trifluoromethyl, and R1 is a group of the following formula:; 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 another compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R3 is H, CN or C1-C3 alkyl, R4, R6, R8 and R are each H, R5 is H, halogen, C1-C3 alkyl or C1-C3 haloalkyl, R7 is CN, methyl or trifluoromethyl, and R1 is a group of the following formula:; 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 another compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R3 is -H, -CN, C1-C3 alkyl or C1-C3 haloalkyl, R4 is -H or halogen, R8 and R are each -H, R5 is -H, halogen, C1-C3 alkyl or C1-C3 haloalkyl, R6 is -H or halogen, R7 is -CN, methyl or trifluoromethyl, and R1 is a group of the following formula:; 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 another compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R1 is a group of the following formula:; wherein each R9 is independently -H, halogen, C1-C3 alkyl, C1-C3 haloalkyl or C3-C5 cycloalkyl, and R2 is a group of the following formula:; or R2 is a substituted 5-membered heteroaryl group selected from pyrrole, furan, thiophene, pyrazole, isothiazolium, isothiazole, imidazole, succinate, thiazole, triazole, succinyl diazole and thiadiazole; wherein the substituted 5-membered heteroaryl group is substituted by one to three substituents independently selected from the following: CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R11, -CONR11R11, -NR11R11 -NR11-CO2R11, C1-C6 alkyl group as appropriate, C3-C5 cycloalkyl group as appropriate, heterocyclic group as appropriate selected from pyrrolidone, pyrrolidone, piperidine or morpholine, phenyl group as appropriate, or heteroaryl group as appropriate selected from pyridine, pyrazole, isothiazolium, isothiazole, imidazole, thiazolium or thiazole; wherein the C1-C6 alkyl group as appropriate is substituted with CN, -OH or C1-C3 alkoxy group as appropriate; and the C3-C5 cycloalkyl group, phenyl group, heterocyclic group or heteroaryl group as appropriate is substituted with one or three substituents selected independently from halogen, C1-C3 alkyl group, C1-C3 haloalkyl group, C1-C3 alkoxy group, C1-C3 haloalkoxy group, -NR11R11, -OH or -CN group as appropriate. Each R10 is independently H, CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R11, -CONR11R11, -NR11R11, -NR11-CO2R11, a substituted C1-C6 alkyl, a substituted C3-C5 cycloalkyl, a substituted heterocycle selected from pyrrolidine, pyrrolidone, piperidine, or morpholine, a substituted phenyl, or a substituted pyrazole, isothiazolium, isothiazole, imidazole, etc. The azole, acetazole or thiazole is optionally substituted with a heteroaryl group; wherein the optional substituted C1-C6 alkyl group is optionally substituted with CN, -OH or C1-C3 alkoxy; the optional substituted C3-C5 cycloalkyl, phenyl, heterocyclic or heteroaryl group is optionally substituted with one to three substituents independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -NR11R11, -OH or -CN; and each R11 is independently H or C1-C3 alkyl.

[0181] In another compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R1 is a group of the following formula:; wherein each R9 is independently H, a halogen, a C1-C3 alkyl or a C1-C3 haloalkyl, and R2 is a group of the following formula:; wherein each R10 is independently H, CN, a halogen, a C1-C6 haloalkyl, a C1-C6 alkoxy, a C1-C6 haloalkoxy, -SO2R11, -CONR11R11, -NR11R11, -NR11-CO2R11, a substituted C1-C6 alkyl, a substituted C3-C5 cycloalkyl, a substituted heterocyclic ring selected from pyrrolidine, pyrrolidone, piperidine or morpholine, a substituted phenyl, or a pyrazole, isozolazole, isothiazole, imidazole, succinate or The thiazole is optionally substituted with a heteroaryl group; wherein the optionally substituted C1-C6 alkyl group is optionally substituted with CN, -OH or C1-C3 alkoxy; wherein the optionally substituted C3-C5 cycloalkyl, phenyl, heterocyclic or heteroaryl group is optionally substituted with one to three substituents independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -NR11R11, -OH or -CN; and each R11 is independently H or C1-C3 alkyl.

[0182] In another compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R1 is a group of the following formula:; 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 following formula:; or R2 is, where appropriate, a substituted 5-membered heteroaryl group selected from pyrrole, furan, thiophene, pyrazole. Isotriazole, isothiazole, imidazole, succinazole, thiazole, triazole, succinidazole, and thiadiazole; wherein the 5-membered heteroaryl group, as appropriate, is substituted by one to three substituents independently selected from the following: -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R11, -CONR11R11, -NR11R11, -NR11CO2R 11. A C1-C6 alkyl group, a C3-C5 cycloalkyl group, a heterocyclic group selected from pyrrolidone, pyrrolidone, piperidine or morpholine, a phenyl group, or a heteroaryl group selected from pyridine, pyrazole, isothiazol, isothiazole, imidazole, thiazol or thiazole; wherein the C1-C6 alkyl group is substituted with CN, -OH or C1-C3 alkoxy; the C3-C5 cycloalkyl, phenyl, heterocyclic or heteroaryl group is substituted with one or three substituents selected independently from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -NR11R11, -OH or -CN; preferably each R9 is independently H, halogen, C1-C3 alkyl or C1-C3 haloalkyl. Ideally, each R9 is independently H, halogen, methyl, or trifluoromethyl.

[0183] In another compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R1 is a group of the following formula:; wherein each R9 is independently H, a halogen, a C1-C6 alkyl, a C1-C6 haloalkyl, a C1-C6 alkoxy, or a C3-C5 cycloalkyl, and R2 is a group of the following formula:; preferably each R9 is independently H, a halogen, a C1-C3 alkyl, or a C1-C3 haloalkyl. Most preferably, each R9 is independently H, a halogen, a methyl, or a trifluoromethyl.

[0184] In another compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R1 is a group of the following formula:; wherein each R9 is independently -H, halogen, C1-C3 alkyl or C1-C3 haloalkyl, and R2 is a group of the following formula:; or R2 is a substituted 5-membered heteroaryl group selected from pyrrole, furan, thiophene, pyrazole, isothiazolium, isothiazole, imidazole, acetazole, thiazole, triazole, acediazole and thiadiazole; wherein the substituted 5-membered heteroaryl group is substituted by one to three substituents independently selected from the following: -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R11, -CONR11R11, -NR11R11, -N R11CO2R11, optionally substituted C1-C6 alkyl, optionally substituted C3-C5 cycloalkyl, optionally substituted heterocyclic selected from pyrrolidone, pyrrolidone, piperidine or morpholine, optionally substituted phenyl, or optionally substituted heteroaryl selected from pyridine, pyrazole, isothiazolium, isothiazole, imidazole, thiazolium or thiazole; wherein the optionally substituted C1-C6 alkyl is optionally substituted with CN, -OH or C1-C3 alkoxy; the optionally substituted C3-C5 cycloalkyl, phenyl, heterocyclic or heteroaryl is optionally substituted with one or three substituents independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -NR11R11, -OH or -CN; preferably each R9 is independently -H, halogen, methyl or trifluoromethyl.

[0185] In another compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R1 is a group of the following formula:; wherein R9 is H, a halogen or a C1-C3 haloalkyl, and R2 is a group of the following formula:; or R2 is a substituted 5-membered heteroaryl group selected from pyrrole, furan, thiophene, pyrazole, isothiazolium, isothiazole, imidazole, acetazole, thiazole, triazole, acediazole and thiadiazole; wherein the substituted 5-membered heteroaryl group is substituted by one to three substituents selected independently from the following: -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R11, -CONR11R11, -NR11R11, -NR11CO2R 11. A C1-C6 alkyl group, a C3-C5 cycloalkyl group, a heterocyclic group selected from pyrrolidone, pyrrolidone, piperidine or morpholine, a phenyl group, or a heteroaryl group selected from pyridine, pyrazole, isothiazol, isothiazole, imidazole, thiazol or thiazole, wherein the C1-C6 alkyl group is substituted with CN, -OH or C1-C3 alkoxy; the C3-C5 cycloalkyl, phenyl, heterocyclic or heteroaryl group is substituted with one or three substituents selected independently from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -NR11R11, -OH or -CN, wherein R9 is preferably H or trifluoromethyl.

[0186] In another compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R1 is a group of the following formula:; wherein R9 is H, a halogen or a C1-C3 haloalkyl group, and R2 is a group of the following formula:;; preferably R9 is H or trifluoromethyl.

[0187] In another compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R1 is a group of the following formula:; wherein R9 is H, a halogen or a C1-C3 haloalkyl, and R2 is a group of the following formula:; or R2 is a substituted 5-membered heteroaryl group selected from pyrrole, furan, thiophene, pyrazole, isothiazolium, isothiazole, imidazole, succinazole, thiazole, triazole, succinyl diazole and thiadiazole; wherein the substituted 5-membered heteroaryl group is substituted by one to three substituents selected independently from the following: -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R11, -CONR11R11, -NR11R11, -NR11CO2R 11. A C1-C6 alkyl group, a C3-C5 cycloalkyl group, a heterocyclic group selected from pyrrolidone, pyrrolidone, piperidine, or morpholine, a phenyl group, or a heteroaryl group selected from pyridine, pyrazole, isothiazol, isothiazole, imidazole, thiazol, or thiazole, wherein the C1-C6 alkyl group is substituted with CN, -OH, or C1-C3 alkoxy; and each of the C3-C5 cycloalkyl, phenyl, heterocyclic, or heteroaryl group is substituted with one or three substituents selected independently from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -NR11R11, -OH, or -CN, wherein R9 is preferably H or a halogen.

[0188] In another compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R1 is a group of the following formula:; wherein R9 is H, a halogen or a C1-C3 haloalkyl group, and R2 is a group of the following formula:; preferably R9 is H or a halogen.

[0189] In another compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R1 is a group of the following formula:; wherein R9 is H, halogen, C1-C3 alkyl, C1-C3 haloalkyl or C3-C5 cycloalkyl, and R2 is a group of the following formula:; or R2 is a substituted 5-membered heteroaryl group selected from pyrrole, furan, thiophene, pyrazole, isothiazolium, isothiazole, imidazole, succinate, thiazole, triazole, succinyl diazole and thiadiazole; wherein the substituted 5-membered heteroaryl group is substituted by one to three substituents selected independently from the following: -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R11, -CONR11R11, -NR11R11. -NR11CO2R11, optionally substituted C1-C6 alkyl, optionally substituted C3-C5 cycloalkyl, optionally substituted heterocyclic selected from pyrrolidone, pyrrolidone, piperidine or morpholine, optionally substituted phenyl, or optionally substituted heteroaryl selected from pyridine, pyrazole, isothiazol, isothiazole, imidazole, thiazol or thiazole; wherein optionally substituted C1-C6 alkyl is optionally substituted with CN, -OH or C1-C3 alkoxy; optionally substituted C3-C5 cycloalkyl, phenyl, heterocyclic or heteroaryl is optionally substituted with one or three substituents independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -NR11R11, -OH or -CN; preferably R9 is -H, halogen, methyl, trifluoromethyl or cyclopropyl.

[0190] In another compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R1 is a group of the following formula:; wherein R9 is a halogen or C1-C3 haloalkyl, and R2 is a group of the following formula:. Preferably, R9 is a halogen or trifluoromethyl. More preferably, R9 is chlorine or trifluoromethyl.

[0191] In another compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R1 is a group of the following formula:; wherein R9 is H, halogen, C1-C3 alkyl or C1-C3 haloalkyl, and R2 is a group of the following formula:; or R2 is a substituted 5-membered heteroaryl group selected from pyrrole, furan, thiophene, pyrazole, isothiazolium, isothiazole, imidazole, succinate, thiazole, triazole, succinyl diazole and thiadiazole; wherein the substituted 5-membered heteroaryl group is substituted by one to three substituents selected independently from the following: -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R11, -CONR11R11, -NR11R11, -NR11 CO2R11, a C1-C6 alkyl group as appropriate, a C3-C5 cycloalkyl group as appropriate, a heterocyclic group as appropriate selected from pyrrolidone, pyrrolidone, piperidine or morpholine, a phenyl group as appropriate, or a heteroaryl group as appropriate selected from pyridine, pyrazole, isothiazol, isothiazole, imidazole, thiazol or thiazole; wherein the C1-C6 alkyl group as appropriate is substituted with CN, -OH or C1-C3 alkoxy as appropriate; and each of the C3-C5 cycloalkyl, phenyl, heterocyclic or heteroaryl group as appropriate is substituted with one or three substituents selected independently from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -NR11R11, -OH or -CN as appropriate.

[0192] In another compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R1 is a group of the following formula:; wherein R9 is H, halogen, C1-C3 alkyl or C1-C3 haloalkyl, and R2 is a group of the following formula:.

[0193] In another compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R1 is a group of the following formula:; wherein R9 is -H, halogen, C1-C3 alkyl, C1-C3 haloalkyl or C3-C5 cycloalkyl, and R2 is a group of the following formula:; or R2 is a substituted 5-membered heteroaryl group selected from pyrrole, furan, thiophene, pyrazole, isothiazolium, isothiazole, imidazole, acetazole, thiazole, triazole, acediazole and thiadiazole; wherein the substituted 5-membered heteroaryl group is substituted by one to three substituents selected independently from the following: -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R11, -CONR11R11, -NR11R11. -NR11CO2R11, a C1-C6 alkyl group as appropriate, a C3-C5 cycloalkyl group as appropriate, a heterocyclic group as appropriate selected from pyrrolidone, pyrrolidone, piperidine or morpholine, a phenyl group as appropriate, or a heteroaryl group as appropriate selected from pyridine, pyrazole, isothiazol, isothiazole, imidazole, thiazol or thiazole; wherein the C1-C6 alkyl group as appropriate is substituted with -CN, -OH or C1-C3 alkoxy as appropriate; and each of the C3-C5 cycloalkyl, phenyl, heterocyclic or heteroaryl group as appropriate is substituted with one or three substituents selected independently from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -NR11R11, -OH or -CN as appropriate.

[0194] In another compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R2 is a group of the following formula:; or R2 is a substituted 5-membered heteroaryl group selected from pyrrole, furan, thiophene, pyrazole, isothiazolium, isothiazole, imidazole, thiazolium, triazole, thiadiazole and thiadiazole; wherein the substituted 5-membered heteroaryl group is substituted by one to three substituents selected independently from the following: -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R11, -CONR11R11, -NR11R11, -NR11CO2R11, substituted C1-C6 alkyl, substituted C3-C5 cycloalkyl, substituted heterocycle selected from pyrrolidine, pyrrolidone, piperidine or morpholine, substituted phenyl, or selected from pyridine The pyrazole, isothiazol, isothiazole, imidazole, pyrazole, or thiazole may be substituted with a heteroaryl group, wherein the substituted C1-C6 alkyl group may be substituted with -CN, -OH, or C1-C3 alkoxy, and the substituted C3-C5 cycloalkyl, phenyl, heterocyclic, or heteroaryl group may be substituted with a group selected independently from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, - One to three substituents of NR11R11, -OH, or -CN are used; 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 following formula: ; 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 another compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R2 is a group of the following formula:; 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 following formula:; 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 another compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R2 is a group of the following formula:; or R2 is a substituted 5-membered heteroaryl group selected from pyrrole, furan, thiophene, pyrazole, isothiazolium, isothiazole, imidazole, thiazole, triazole, thiazolium diazole and thiadiazole; wherein the substituted 5-membered heteroaryl group is substituted by one to three substituents selected independently from the following: -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R11, -CONR11R11, -NR11R11, -NR11CO2R11, substituted C1-C6 alkyl, substituted C3-C5 cycloalkyl, selected from pyrrolidine, pyrrolidone, piperidine or morphine. The porphyrin is optionally substituted with a heterocyclic ring, optionally substituted with a phenyl group, or optionally substituted with a heteroaryl group selected from pyridine, pyrazole, isothiazol, isothiazole, imidazole, thiazol, or thiazole; wherein the optionally substituted C1-C6 alkyl group is optionally substituted with -CN, -OH, or C1-C3 alkoxy; wherein the optionally substituted C3-C5 cycloalkyl, phenyl, heterocyclic, or heteroaryl group is optionally substituted with one to three substituents independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -NR11R11, -OH, or -CN; R7 is -CN, methyl, or trifluoromethyl; R8 and R are each -H; and R1 is a group of the following formula:; wherein each R9 is independently -H, halogen, methyl, C1-C3 haloalkyl, or cyclopropyl.

[0197] In another compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R2 is a group of the following formula:; R7 is CN, methyl or trifluoromethyl, R8 and R are each H, and R1 is a group of the following formula:; wherein each R9 is independently H, halogen, C1-C3 alkyl or C1-C3 haloalkyl.

[0198] In another compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R1 is a group of the following formula:; wherein each R9 is independently -H, halogen, methyl or trifluoromethyl, and R2 is a group of the following formula:; or R2 is a substituted 5-membered heteroaryl group selected from pyrrole, furan, thiophene, pyrazole, isothiazolium, isothiazole, imidazole, succinate, thiazole, triazole, succinyl diazole and thiadiazole; wherein the substituted 5-membered heteroaryl group is substituted by one to three substituents independently selected from the following: -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R11, -CONR11R11, -NR11R11, -NR11CO2R11, substituted C1- C6 alkyl, optionally substituted C3-C5 cycloalkyl, optionally substituted heterocyclic selected from pyrrolidone, pyrrolidone, piperidine or morpholine, optionally substituted phenyl, or optionally substituted heteroaryl selected from pyridine, pyrazole, isothiazol, isothiazole, imidazole, thiazol or thiazole; wherein optionally substituted C1-C6 alkyl is optionally substituted with -CN, -OH or C1-C3 alkoxy; optionally substituted C3-C5 cycloalkyl, phenyl, heterocyclic or heteroaryl is optionally substituted with one or three substituents independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -NR11R11, -OH or -CN; R7 is C1-C3 alkyl (preferably methyl), and R8 and R are each -H.

[0199] In another compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R1 is a group of the following formula:; wherein R9 is H, a halogen, or a trifluoromethyl group (preferably R9 is H or a trifluoromethyl group), and R2 is a group of the following formula:; or R2 is a substituted 5-membered heteroaryl group selected from pyrrole, furan, thiophene, pyrazole, isothiazolium, isothiazole, imidazole, acetazole, thiazole, triazole, acediazole, and thiadiazole; wherein the substituted 5-membered heteroaryl group is substituted by one to three substituents selected independently from the following: -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R11, -CONR11R11, -NR11R11, -NR11CO2R11, substituted as appropriate C1-C6 alkyl, optionally substituted C3-C5 cycloalkyl, optionally substituted heterocyclic selected from pyrrolidone, pyrrolidone, piperidine or morpholine, optionally substituted phenyl, or optionally substituted heteroaryl selected from pyridine, pyrazole, isothiazol, isothiazole, imidazole, thiazol or thiazole; wherein the optionally substituted C1-C6 alkyl is optionally substituted with -CN, -OH or C1-C3 alkoxy; the optionally substituted C3-C5 cycloalkyl, phenyl, heterocyclic or heteroaryl is optionally substituted with one or three substituents independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -NR11R11, -OH or -CN; R7 is C1-C3 alkyl (preferably methyl), and R8 and R are each H.

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

[0201] In another compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R1 is a group of the following formula:; wherein R9 is H, a halogen, or a trifluoromethyl group (preferably R9 is H or a halogen), and R2 is a group of the following formula:; or R2 is a substituted 5-membered heteroaryl group selected from pyrrole, furan, thiophene, pyrazole, isothiazolium, isothiazole, imidazole, acetazole, thiazole, triazole, acediazole, and thiadiazole; wherein the substituted 5-membered heteroaryl group is substituted by one to three substituents selected independently from the following: -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R11, -CONR11R11, -NR11R11, -NR11CO2R11, substituted C 1-C6 alkyl, optionally substituted C3-C5 cycloalkyl, optionally substituted heterocyclic selected from pyrrolidone, pyrrolidone, piperidine or morpholine, optionally substituted phenyl, or optionally substituted heteroaryl selected from pyridine, pyrazole, isothiazol, isothiazole, imidazole, thiazol or thiazole; wherein the optionally substituted C1-C6 alkyl is optionally substituted with -CN, -OH or C1-C3 alkoxy; the optionally substituted C3-C5 cycloalkyl, phenyl, heterocyclic or heteroaryl is optionally substituted with one or three substituents independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -NR11R11, -OH or -CN; R7 is C1-C3 alkyl (preferably methyl), and R8 and R are each H.

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

[0203] In another compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R1 is a group of the following formula:; wherein R9 is -H, halogen, methyl, trifluoromethyl or cyclopropyl, and R2 is a group of the following formula:; or R2 is a substituted 5-membered heteroaryl group selected from pyrrole, furan, thiophene, pyrazole, isothiazolium, isothiazole, imidazole, succinate, thiazole, triazole, succinyl diazole and thiadiazole; wherein the substituted 5-membered heteroaryl group is substituted by one to three substituents selected independently from the following: -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R11, -CONR11R11, -NR11R11, -NR11CO2R11, substituted C1- C6 alkyl, optionally substituted C3-C5 cycloalkyl, optionally substituted heterocyclic selected from pyrrolidone, pyrrolidone, piperidine or morpholine, optionally substituted phenyl, or optionally substituted heteroaryl selected from pyridine, pyrazole, isothiazol, isothiazole, imidazole, thiazol or thiazole; wherein optionally substituted C1-C6 alkyl is optionally substituted with -CN, -OH or C1-C3 alkoxy; optionally substituted C3-C5 cycloalkyl, phenyl, heterocyclic or heteroaryl is optionally substituted with one or three substituents independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -NR11R11, -OH or -CN; R7 is C1-C3 alkyl (preferably methyl), and R8 and R are each -H.

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

[0205] In another compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R1 is a group of the following formula:; wherein R9 is H, halogen, C1-C3 alkyl or C1-C3 haloalkyl, and R2 is a group of the following formula:; or R2 is a substituted 5-membered heteroaryl group selected from pyrrole, furan, thiophene, pyrazole, isothiazolium, isothiazole, imidazole, acetazole, thiazole, triazole, acediazole and thiadiazole; wherein the substituted 5-membered heteroaryl group is substituted by one to three substituents selected independently from the following: -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R11, -CONR11R11, -NR11R11, -NR11CO2R11, substituted C 1-C6 alkyl, optionally substituted C3-C5 cycloalkyl, optionally substituted heterocyclic selected from pyrrolidone, pyrrolidone, piperidine or morpholine, optionally substituted phenyl, or optionally substituted heteroaryl selected from pyridine, pyrazole, isothiazol, isothiazole, imidazole, thiazol or thiazole; wherein the optionally substituted C1-C6 alkyl is optionally substituted with -CN, -OH or C1-C3 alkoxy; the optionally substituted C3-C5 cycloalkyl, phenyl, heterocyclic or heteroaryl is optionally substituted with one or three substituents independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -NR11R11, -OH or -CN; R7 is C1-C3 alkyl (preferably methyl), and R8 and R are each H.

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

[0207] In another compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R1 is a group of the following formula:; wherein R9 is -H, halogen, C1-C3 alkyl, C1-C3 haloalkyl or C3-C5 cycloalkyl, and R2 is a group of the following formula:; or R2 is a substituted 5-membered heteroaryl group selected from pyrrole, furan, thiophene, pyrazole, isothiazolium, isothiazole, imidazole, succinate, thiazole, triazole, succinyl diazole and thiadiazole; wherein the substituted 5-membered heteroaryl group is substituted by one to three substituents selected independently from the following: -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R11, -CONR11R11, -NR11R11, -NR11CO2R11, as appropriate. The substituted C1-C6 alkyl group, the optionally substituted C3-C5 cycloalkyl group, the optionally substituted heterocyclic group selected from pyrrolidone, pyrrolidone, piperidine or morpholine, the optionally substituted phenyl group, or the optionally substituted heteroaryl group selected from pyridine, pyrazole, isothiazolium, isothiazole, imidazole, thiazolium or thiazole; wherein the optionally substituted C1-C6 alkyl group is optionally substituted with -CN, -OH or C1-C3 alkoxy; the optionally substituted C3-C5 cycloalkyl group, phenyl group, heterocyclic group or heteroaryl group is optionally substituted with one or three substituents independently selected from halogen, C1-C3 alkyl group, C1-C3 haloalkyl group, C1-C3 alkoxy group, C1-C3 haloalkoxy group, -NR11R11 group, -OH or -CN; R7 is a C1-C3 alkyl group (preferably methyl group), and R8 and R are each -H.

[0208] In another compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R2 is a group of the following formula:; or R2 is a substituted 5-membered heteroaryl group selected from pyrrole, furan, thiophene, pyrazole, isoflavone, isothiazole, imidazole, acetazole, thiazole, triazole, acediazole and thiadiazole; wherein the substituted 5-membered heteroaryl group is selected independently from one to three of the following substituents. Substitution: -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R11, -CONR11R11, -NR11R11, -NR11CO2R11, C1-C6 alkyl substituted as appropriate, C3-C5 cycloalkyl substituted as appropriate, heterocycles substituted as appropriate selected from pyrrolidine, pyrrolidone, piperidine or morpholine, phenyl substituted as appropriate. Alternatively, a heteroaryl group selected from pyridine, pyrazole, isothiazol, isothiazole, imidazole, thiazol, or thiazole, substituted as appropriate; wherein the substituted C1-C6 alkyl group is substituted with -CN, -OH, or C1-C3 alkoxy as appropriate; and the substituted C3-C5 cycloalkyl, phenyl, heterocyclic, or heteroaryl group is substituted with a substituted alkyl group, substituted independently, selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1- One to three substituents of C3 haloalkoxy, -NR11R11, -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 following formula:; wherein each R9 is independently -H, halogen, methyl, C1-C3 haloalkyl or cyclopropyl.

[0209] In another compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R2 is a group of the following formula:; 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 following formula:; wherein each R9 is independently H, halogen, C1-C3 alkyl or C1-C3 haloalkyl.

[0210] In another compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R1 is a group of the following formula:; wherein each R9 is independently -H, halogen, methyl or trifluoromethyl, and R2 is a group of the following formula:; or R2 is, where appropriate, a substituted 5-membered heteroaryl group selected from pyrrole, furan, thiophene, pyrazole, isothiazolium, isothiazole, imidazole, thiazolium, triazole, thiadiazole and thiadiazole; wherein, where appropriate Furthermore, the substituted 5-membered heteroaryl group is optionally substituted by one to three substituents selected independently from the following: -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R11, -CONR11R11, -NR11R11, -NR11CO2R11, optionally substituted C1-C6 alkyl, optionally substituted C3-C5 cycloalkyl, optionally substituted heterocycle selected from pyrrolidone, pyrrolidone, piperidine or morpholine, optionally substituted phenyl, or optionally substituted heteroaryl selected from pyridine, pyrazole, isothiazolium, isothiazole, imidazole, thiazolium or thiazole; wherein the optionally substituted C1-C6 alkyl group is optionally substituted by -CN, -OH or C1-C3 alkoxy; and the optionally substituted C3-C5 cycloalkyl, phenyl, heterocycle or heteroaryl group is optionally substituted by one to three substituents selected independently. The substituted group is selected from one to three substituents of halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -NR11R11, -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 another compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R1 is a group of the following formula:; wherein R9 is H, a halogen, or a trifluoromethyl group (preferably R9 is H or a trifluoromethyl group), and R2 is a group of the following formula:; or R2 is, where appropriate, a substituted 5-membered heteroaryl group selected from pyrrole, furan, thiophene, pyrazole, isothiazolium, isothiazole, imidazole, thiazolium, triazole, acetylene ... Azoles and thiadiazoles; wherein the 5-membered heteroaryl group, depending on the case, is substituted by one to three substituents independently selected from the following: -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R11, -CONR11R11, -NR11R11, -NR11CO2R11, C1-C6 alkyl group depending on the case, and substituents depending on the case. The C3-C5 cycloalkyl group, a heterocyclic group selected from pyrrolidone, pyrrolidone, piperidine or morpholine, a phenyl group selected from pyridine, pyrazole, isothiazolium, isothiazole, imidazole, thiazolium or thiazole, a heteroaryl group selected from pyridine, pyrazole, isothiazole, imidazole or thiazole, a heteroaryl group selected from pyridine, pyrazole, isothi ...

[0212] In another compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R1 is a group of the following formula:; wherein R9 is H, a halogen or a trifluoromethyl (preferably R9 is H or a trifluoromethyl), R2 is a group of the following formula:; R3 is H or a methyl, R4, R6, R8 and R are each H, R5 is H, a halogen, a methyl or a trifluoromethyl, and R7 is a C1-C3 alkyl (preferably methyl).

[0213] In another compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R1 is a group of the following formula:; wherein R9 is H, a halogen, or a trifluoromethyl group (preferably R9 is H or a halogen), and R2 is a group of the following formula:; or R2 is, where appropriate, a substituted 5-membered heteroaryl group selected from pyrrole, furan, thiophene, pyrazole, isofenazole, isothiazole, imidazole, thiazole, triazole, diazole, and Thiadiazole; wherein the 5-membered heteroaryl group, which is substituted as appropriate, is substituted independently by one to three of the following substituents: -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R11, -CONR11R11, -NR11R11, -NR11CO2R11, substituted C1-C6 alkyl group, substituted... C3-C5 cycloalkyl, a heterocyclic ring selected from pyrrolidone, pyrrolidone, piperidine or morpholine, a phenyl ring selected from pyridine, pyrazole, isothiazolium, isothiazole, imidazole, thiazolium or thiazole, a heteroaryl group selected from pyridine, pyrazole, isothiazole, imidazole or thiazole, wherein the C1-C6 alkyl group selected from pyrrolidone, isothiazolium or C1-C3 alkoxy group selected from pyrrolidone, isothiazolium or C1-C3 alkoxy group selected from pyrrolidone, isothiazolium or C1-C3 alkoxy group selected from pyrrolidone, isothiazolium or C1-C5 cycloalkyl, phenyl, heterocyclic or heteroaryl group selected from pyrrolidone, isothiazolium or C1-C5 cycloalkyl, phenyl, heterocyclic or heteroaryl group selected from pyrrolidone, isothiazolium or C1-C5 cycloalkyl, isothiazolium or C1-C5 alkoxy, isothiazolium or C1-C5 alkoxy, isothiazolium or C1-C5 cycloalkyl, isothiazolium or C1-C5 alkyl (preferably methyl).

[0214] In another compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R1 is a group of the following formula:; wherein R9 is H, a halogen or a trifluoromethyl (preferably R9 is H or a halogen), R2 is a group of the following formula:; R3 is H or a methyl, R4, R6, R8 and R are each H, R5 is H, a halogen, a methyl or a trifluoromethyl, and R7 is a C1-C3 alkyl (preferably methyl).

[0215] In another compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R1 is a group of the following formula:; wherein R9 is independently -H, halogen, methyl, trifluoromethyl or cyclopropyl, and R2 is a group of the following formula:; or R2 is, where appropriate, a substituted 5-membered heteroaryl group selected from pyrrole, furan, thiophene, pyrazole, isothiazolium, isothiazole, imidazole, thiazolium, triazole, thiadiazole and thiadiazole; wherein The substituted 5-membered heteroaryl group is, as appropriate, substituted by one to three substituents selected independently from the following: -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R11, -CONR11R11, -NR11R11, -NR11CO2R11, substituted C1-C6 alkyl, substituted C3-C5 cycloalkyl, substituted heterocycle selected from pyrrolidone, pyrrolidone, piperidine or morpholine, substituted phenyl, or substituted heteroaryl group selected from pyridine, pyrazole, isothiazolium, isothiazole, imidazole, pyrazole or thiazole; wherein the substituted C1-C6 alkyl group is substituted by -CN, -OH or C1-C3 alkoxy; and the substituted C3-C5 cycloalkyl, phenyl, heterocycle or heteroaryl group is substituted by one to three substituents selected independently from the following. The substituted group is selected from one to three substituents of halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -NR11R11, -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 another compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R1 is a group of the following formula:; wherein R9 is H, a halogen or a trifluoromethyl group (preferably R9 is a halogen or a trifluoromethyl group), R2 is a group of the following formula:; R3 is H or a methyl group, R4, R6, R8 and R are each H, R5 is H, a halogen, a methyl group or a trifluoromethyl group, and R7 is a C1-C3 alkyl group (preferably methyl).

[0217] In another compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R1 is a group of the following formula:; wherein R9 is H, a halogen, a C1-C3 alkyl group or a C1-C3 haloalkyl group, and R2 is a group of the following formula:; or R2 is, where appropriate, a substituted 5-membered heteroaryl group selected from pyrrole, furan, thiophene, pyrazole, isothiazolium, isothiazole, imidazole, thiazolium, triazole, diazole and Thiadiazole; wherein the 5-membered heteroaryl group, which is substituted as appropriate, is substituted independently by one to three of the following substituents: -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R11, -CONR11R11, -NR11R11, -NR11CO2R11, substituted C1-C6 alkyl group, substituted... C3-C5 cycloalkyl, a heterocyclic ring selected from pyrrolidone, pyrrolidone, piperidine or morpholine, a phenyl ring selected from pyridine, pyrazole, isothiazolium, isothiazole, imidazole, thiazolium or thiazole, a heteroaryl group selected from pyridine, pyrazole, isothiazole, imidazole or thiazole, wherein the C1-C6 alkyl group selected from pyrrolidone, isothiazolium or C1-C3 alkoxy group selected from pyrrolidone, isothiazolium or C1-C3 alkoxy group selected from pyrrolidone, isothiazolium or C1-C3 alkoxy group selected from pyrrolidone, isothiazolium or C1-C5 cycloalkyl, phenyl, heterocyclic or heteroaryl group selected from pyrrolidone, isothiazolium or C1-C5 cycloalkyl, phenyl, heterocyclic or heteroaryl group selected from pyrrolidone, isothiazolium or C1-C5 cycloalkyl, isothiazolium or C1-C5 alkoxy, isothiazolium or C1-C5 alkoxy, isothiazolium or C1-C5 cycloalkyl, isothiazolium or C1-C5 alkyl (preferably methyl).

[0218] In another compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R1 is a group of the following formula:; wherein R9 is H, halogen, C1-C3 alkyl or C1-C3 haloalkyl, R2 is a group of the following formula:; 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 another compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, R1 is a group of the following formula:; wherein each R9 is independently -H, halogen, methyl, trifluoromethyl or cyclopropyl, and R2 is a group of the following formula:; or R2 is, where appropriate, a substituted 5-membered heteroaryl group selected from pyrrole, furan, thiophene, pyrazole, isothiazolium, isothiazole, imidazole, acetazole, thiazole, triazole, acediazole and thiadiazole; The 5-membered heteroaryl group, depending on the substituted group, is substituted by one to three substituents selected independently from the following: -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R11, -CONR11R11, -NR11R11, -NR11CO2R11, the substituted C1-C6 alkyl group, the substituted C3-C5 cycloalkyl group, the substituted heterocycle selected from pyrrolidone, pyrrolidone, piperidine, or morpholine, the substituted phenyl group, or the substituted heteroaryl group selected from pyridine, pyrazole, isothiazolium, isothiazole, imidazole, pyrazole, or thiazole; wherein the substituted C1-C6 alkyl group is substituted by -CN, -OH, or C1-C3 alkoxy; and the substituted C3-C5 cycloalkyl, phenyl, heterocycle, or heteroaryl group is substituted by one or three substituents selected independently from the following. The substituted group is selected from one to three substituents of halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -NR11R11, -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 another embodiment, the compound of formula (I) or (II) has formula (III), or a pharmaceutically acceptable salt thereof: wherein R1, R2, R3, R5, R6 and R7 are as defined in the invention description relating to formula (I) above.

[0221] In a compound of formula (III) or a pharmaceutically acceptable salt thereof, R2 is a group of the following formula:; or R2 is a substituted 5-membered heteroaryl group selected from pyrrole, furan, thiophene, pyrazole, isothiazolium, isothiazole, imidazole, succinazole, thiazole, triazole, succinyl diazole and thiadiazole; wherein the substituted 5-membered heteroaryl group is substituted by one to three substituents selected independently from the following: -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R11, -CONR11R11, -NR11R11, -NR11CO2R11, substituted C1-C6 alkyl, substituted The substituted C3-C5 cycloalkyl group, the substituted heterocyclic group selected from pyrrolidone, pyrrolidone, piperidine or morpholine, the substituted phenyl group, or the substituted heteroaryl group selected from pyridine, pyrazole, isothiazol, isothiazole, imidazole, thiazol or thiazole; wherein the substituted C1-C6 alkyl group is substituted with -CN, -OH or C1-C3 alkoxy; and the substituted C3-C5 cycloalkyl, phenyl, heterocyclic or heteroaryl group is substituted with one or three substituents selected independently from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -NR11R11, -OH or -CN.

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

[0223] In yet another compound 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; most preferably R3 is H or methyl.

[0224] In yet another compound of formula (III) or a pharmaceutically acceptable salt thereof, R5 is H, halogen, C1-C6 alkyl or C1-C6 haloalkyl; preferably R5 is H, halogen, C1-C3 alkyl or C1-C3 haloalkyl; even more preferably R5 is H, halogen, methyl or trifluoromethyl.

[0225] In yet another compound of formula (III) or a pharmaceutically acceptable salt thereof, R6 is H or a halogen; preferably R6 is H.

[0226] In yet another compound of formula (III) 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; even more preferably R7 is CN, methyl or trifluoromethyl.

[0227] In yet another compound of formula (III) or a pharmaceutically acceptable salt thereof, R1 is a group of the following formula:; wherein each R9 is independently -H, halogen, C1-C3 alkyl, C1-C3 haloalkyl or C3-C5 cycloalkyl; preferably each R9 is independently -H, halogen, methyl, trifluoromethyl or cyclopropyl.

[0228] In yet another compound of formula (III) or a pharmaceutically acceptable salt thereof, R1 is a group of the following formula:; 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 yet another compound of formula (III) or a pharmaceutically acceptable salt thereof, R1 is a group of the following formula: ; 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 yet another compound of formula (III) or a pharmaceutically acceptable salt thereof, R1 is a group of the following formula: ; wherein each R9 is independently H, a halogen, a C1-C6 alkyl, a C1-C6 haloalkyl, a C1-C6 alkoxy, or a C3-C5 cycloalkyl. Preferably, each R9 is independently H, a halogen, a C1-C3 alkyl, or a C1-C3 haloalkyl. More preferably, each R9 is independently H, a halogen, a methyl, or a trifluoromethyl.

[0231] In yet another compound of formula (III) or a pharmaceutically acceptable salt thereof, R1 is a group of the following formula:; wherein each R9 is independently -H, halogen, C1-C3 alkyl or C1-C3 haloalkyl. Preferably, each R9 is independently -H, halogen, methyl or trifluoromethyl.

[0232] In yet another compound of formula (III) or a pharmaceutically acceptable salt thereof, R1 is a group of the following formula:; wherein R9 is H, a halogen, or a C1-C3 haloalkyl group. Preferably, R9 is H or a trifluoromethyl group.

[0233] In yet another compound of formula (III) or a pharmaceutically acceptable salt thereof, R1 is a group of the following formula:; wherein R9 is independently -H, halogen, C1-C3 alkyl or C1-C3 haloalkyl. Preferably, R9 is independently -H, halogen, methyl or trifluoromethyl.

[0234] In yet another compound of formula (III) or a pharmaceutically acceptable salt thereof, R1 is a group of the following formula:; wherein R9 is H, a halogen, or a C1-C3 haloalkyl group. Preferably, R9 is H or a halogen.

[0235] In yet another compound of formula (III) or a pharmaceutically acceptable salt thereof, R1 is a group of the following formula:; 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 yet another compound of formula (III) or a pharmaceutically acceptable salt thereof, R1 is a group of the following formula:; wherein R9 is H, a halogen, or a C1-C3 haloalkyl group. Preferably, R9 is independently a halogen or a trifluoromethyl group. More preferably, R9 is chlorine or a trifluoromethyl group.

[0237] In yet another compound of formula (III) or a pharmaceutically acceptable salt thereof, R1 is a group of the following formula:; wherein R9 is H, halogen, C1-C3 alkyl or C1-C3 haloalkyl.

[0238] In yet another compound of formula (III) or a pharmaceutically acceptable salt thereof, R1 is a group of the following formula:; 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 another compound of formula (III) or a pharmaceutically acceptable salt thereof, R1 is a group of the following formula:; wherein each R9 is independently H, halogen, C1-C3 alkyl, C1-C3 haloalkyl or C3-C5 cycloalkyl, and R2 is a group of the following formula:; or R2 is a substituted 5-membered heteroaryl group selected from pyrrole, furan, thiophene, pyrazole, isothiazolium, isothiazole, imidazole, acetazole, thiazole, triazole, acediazole and thiadiazole; wherein the substituted 5-membered heteroaryl group is substituted by one to three substituents independently selected from the following: -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R11, -CONR11R11, -NR11R11, - NR11CO2R11, a C1-C6 alkyl group as appropriate, a C3-C5 cycloalkyl group as appropriate, a heterocyclic group as appropriate selected from pyrrolidone, pyrrolidone, piperidine or morpholine, a phenyl group as appropriate, or a heteroaryl group as appropriate selected from pyridine, pyrazole, isothiazolium, isothiazole, imidazole, thiazolium or thiazole; wherein the C1-C6 alkyl group as appropriate is substituted with -CN, -OH or C1-C3 alkoxy as appropriate; and the C3-C5 cycloalkyl, phenyl, heterocyclic or heteroaryl group as appropriate is substituted with one or three substituents selected independently from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -NR11R11, -OH or -CN as appropriate. Each R10 is independently H, CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R11, -CONR11R11, -NR11R11, -NR11-CO2R11, a substituted C1-C6 alkyl, a substituted C3-C5 cycloalkyl, a substituted heterocycle selected from pyrrolidine, pyrrolidone, piperidine, or morpholine, a substituted phenyl, or a substituted pyrazole, isothiazolium, isothiazole, imidazole, pyrazole, or... The thiazole is optionally substituted with a heteroaryl group; wherein the optionally substituted C1-C6 alkyl group is optionally substituted with CN, -OH or C1-C3 alkoxy; wherein the optionally substituted C3-C5 cycloalkyl, phenyl, heterocyclic or heteroaryl group is optionally substituted with one to three substituents independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -NR11R11, -OH or -CN; and each R11 is independently H or C1-C3 alkyl.

[0240] In yet another compound of formula (III) or a pharmaceutically acceptable salt thereof, R1 is a group of the following formula:; wherein each R9 is independently H, a halogen, a C1-C3 alkyl or a C1-C3 haloalkyl, and R2 is a group of the following formula:; wherein each R10 is independently H, CN, a halogen, a C1-C6 haloalkyl, a C1-C6 alkoxy, a C1-C6 haloalkoxy, -SO2R11, -CONR11R11, -NR11R11, -NR11-CO2R11, a substituted C1-C6 alkyl, a substituted C3-C5 cycloalkyl, a substituted heterocyclic ring selected from pyrrolidine, pyrrolidone, piperidine or morpholine, a substituted phenyl, or a pyrazole, isozolazole, isothiazole, imidazole, succinate or The thiazole is optionally substituted with a heteroaryl group; wherein the optionally substituted C1-C6 alkyl group is optionally substituted with CN, -OH or C1-C3 alkoxy; wherein the optionally substituted C3-C5 cycloalkyl, phenyl, heterocyclic or heteroaryl group is optionally substituted with one to three substituents independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -NR11R11, -OH or -CN; and each R11 is independently H or C1-C3 alkyl.

[0241] In another compound of formula (III) or a pharmaceutically acceptable salt thereof, R1 is a group of the following formula:; 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 following formula:; or R2 is a substituted 5-membered heteroaryl group selected from pyrrole, furan, thiophene, pyrazole, isothiazolium, isothiazole, imidazole, succinate, thiazole, triazole, succinyl diazole and thiadiazole; wherein the substituted 5-membered heteroaryl group is substituted by one to three substituents independently selected from the following: -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R11, -CONR11R11, -NR11 R11, -NR11CO2R11, a C1-C6 alkyl group as appropriate, a C3-C5 cycloalkyl group as appropriate, a heterocyclic group as appropriate selected from pyrrolidone, pyrrolidone, piperidine or morpholine, a phenyl group as appropriate, or a heteroaryl group as appropriate selected from pyridine, pyrazole, isothiazol, isothiazole, imidazole, thiazol or thiazole; wherein the C1-C6 alkyl group as appropriate is substituted with -CN, -OH or C1-C3 alkoxy as appropriate; and each of the C3-C5 cycloalkyl, phenyl, heterocyclic or heteroaryl group as appropriate is substituted with one or three substituents selected independently from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -NR11R11, -OH or -CN as appropriate. 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 yet another compound of formula (III) or a pharmaceutically acceptable salt thereof, R1 is a group of the following formula:; wherein each R9 is independently H, a halogen, a C1-C6 alkyl, a C1-C6 haloalkyl, a C1-C6 alkoxy, or a C3-C5 cycloalkyl, and R2 is a group of the following formula:; preferably each R9 is independently H, a halogen, a C1-C3 alkyl, or a C1-C3 haloalkyl. Most preferably, each R9 is independently H, a halogen, a methyl, or a trifluoromethyl.

[0243] In another compound of formula (III) or a pharmaceutically acceptable salt thereof, R1 is a group of the following formula:; wherein each R9 is independently -H, halogen, C1-C3 alkyl or C1-C3 haloalkyl, and R2 is a group of the following formula:; or R2 is a substituted 5-membered heteroaryl group selected from pyrrole, furan, thiophene, pyrazole, isothiazolium, isothiazole, imidazole, acetazole, thiazole, triazole, acediazole and thiadiazole; wherein the substituted 5-membered heteroaryl group is substituted by one to three substituents independently selected from the following: -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R11, -CONR11R11, -NR11R11, -NR11 CO2R11, optionally substituted C1-C6 alkyl, optionally substituted C3-C5 cycloalkyl, optionally substituted heterocyclic selected from pyrrolidone, pyrrolidone, piperidine or morpholine, optionally substituted phenyl, or optionally substituted heteroaryl selected from pyridine, pyrazole, isothiazolium, isothiazole, imidazole, thiazolium or thiazole; wherein the optionally substituted C1-C6 alkyl is optionally substituted with -CN, -OH or C1-C3 alkoxy; the optionally substituted C3-C5 cycloalkyl, phenyl, heterocyclic or heteroaryl is optionally substituted with one or three substituents independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -NR11R11, -OH or -CN. Preferably, each R9 is independently -H, halogen, methyl or trifluoromethyl.

[0244] In another compound of formula (III) or a pharmaceutically acceptable salt thereof, R1 is a group of the following formula:; wherein R9 is H, a halogen or a C1-C3 haloalkyl, and R2 is a group of the following formula:; or R2 is a substituted 5-membered heteroaryl group selected from pyrrole, furan, thiophene, pyrazole, isothiazolium, isothiazole, imidazole, succinazole, thiazole, triazole, succinyl diazole and thiadiazole; wherein the substituted 5-membered heteroaryl group is substituted by one to three substituents selected independently from the following: -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R11, -CONR11R11, -NR11R11, -NR11CO2R11, or substituted by the following substituents. The alternative is a C1-C6 alkyl group, a C3-C5 cycloalkyl group that is substituted as appropriate, a heterocyclic group selected from pyrrolidone, pyrrolidone, piperidine or morpholine that is substituted as appropriate, a phenyl group that is substituted as appropriate, or a heteroaryl group selected from pyridine, pyrazole, isothiazolium, isothiazole, imidazole, thiazolium or thiazole that is substituted as appropriate; wherein the C1-C6 alkyl group that is substituted as appropriate is substituted with -CN, -OH or C1-C3 alkoxy; the C3-C5 cycloalkyl group, phenyl group, heterocyclic group or heteroaryl group that is substituted as appropriate is substituted with one or three substituents selected independently from halogen, C1-C3 alkyl group, C1-C3 haloalkyl group, C1-C3 alkoxy group, C1-C3 haloalkoxy group, -NR11R11 group, -OH or -CN; preferably R9 is H or trifluoromethyl.

[0245] In yet another compound of formula (III) or a pharmaceutically acceptable salt thereof, R1 is a group of the following formula:; wherein R9 is H, a halogen or a C1-C3 haloalkyl group, and R2 is a group of the following formula:; preferably R9 is H or trifluoromethyl.

[0246] In another compound of formula (III) or a pharmaceutically acceptable salt thereof, R1 is a group of the following formula:; wherein R9 is H, a halogen or a C1-C3 haloalkyl, and R2 is a group of the following formula:; or R2 is a substituted 5-membered heteroaryl group selected from pyrrole, furan, thiophene, pyrazole, isothiazolium, isothiazole, imidazole, succinazole, thiazole, triazole, succinyl diazole and thiadiazole; wherein the substituted 5-membered heteroaryl group is substituted by one to three substituents selected independently from the following: -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R11, -CONR11R11, -NR11R11, -NR11CO2R11, as appropriate. The substituted C1-C6 alkyl group, optionally substituted C3-C5 cycloalkyl group, optionally substituted heterocyclic group selected from pyrrolidone, pyrrolidone, piperidine or morpholine, optionally substituted phenyl group, or optionally substituted heteroaryl group selected from pyridine, pyrazole, isothiazolium, isothiazole, imidazole, thiazolium or thiazole; wherein the optionally substituted C1-C6 alkyl group is optionally substituted with -CN, -OH or C1-C3 alkoxy group; the optionally substituted C3-C5 cycloalkyl group, phenyl group, heterocyclic group or heteroaryl group is optionally substituted with one or three substituents independently selected from halogen, C1-C3 alkyl group, C1-C3 haloalkyl group, C1-C3 alkoxy group, C1-C3 haloalkoxy group, -NR11R11 group, -OH or -CN group; preferably R9 is H or halogen.

[0247] In yet another compound of formula (III) or a pharmaceutically acceptable salt thereof, R1 is a group of the following formula:; wherein R9 is H, a halogen or a C1-C3 haloalkyl group, and R2 is a group of the following formula:; preferably R9 is H or a halogen.

[0248] In another compound of formula (III) or a pharmaceutically acceptable salt thereof, R1 is a group of the following formula:; wherein R9 is -H, halogen, C1-C3 alkyl, C1-C3 haloalkyl or C3-C5 cycloalkyl, and R2 is a group of the following formula:; or R2 is a substituted 5-membered heteroaryl group selected from pyrrole, furan, thiophene, pyrazole, isothiazolium, isothiazole, imidazole, acetazole, thiazole, triazole, acediazole and thiadiazole; wherein the substituted 5-membered heteroaryl group is substituted by one to three substituents selected independently from the following: -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R11, -CONR11R11, -NR11R11, -NR11CO2R11, as appropriate. Furthermore, the substituted C1-C6 alkyl group, optionally substituted C3-C5 cycloalkyl group, optionally substituted heterocyclic group selected from pyrrolidone, pyrrolidone, piperidine or morpholine, optionally substituted phenyl group, or optionally substituted heteroaryl group selected from pyridine, pyrazole, isothiazolium, isothiazole, imidazole, thiazolium or thiazole; wherein the optionally substituted C1-C6 alkyl group is optionally substituted with -CN, -OH or C1-C3 alkoxy group; the optionally substituted C3-C5 cycloalkyl group, phenyl group, heterocyclic group or heteroaryl group is optionally substituted with one or three substituents independently selected from halogen, C1-C3 alkyl group, C1-C3 haloalkyl group, C1-C3 alkoxy group, C1-C3 haloalkoxy group, -NR11R11 group, -OH or -CN group; preferably R9 is -H, halogen, methyl, trifluoromethyl or cyclopropyl.

[0249] In yet another compound of formula (III) or a pharmaceutically acceptable salt thereof, R1 is a group of the following formula:; wherein R9 is a halogen or C1-C3 haloalkyl, and R2 is a group of the following formula:; preferably R9 is a halogen or trifluoromethyl. More preferably, R9 is chlorine or trifluoromethyl.

[0250] In another compound of formula (III) or a pharmaceutically acceptable salt thereof, R1 is a group of the following formula:; wherein R9 is H, halogen, C1-C3 alkyl or C1-C3 haloalkyl, and R2 is a group of the following formula:; or R2 is a substituted 5-membered heteroaryl group selected from pyrrole, furan, thiophene, pyrazole, isothiazolium, isothiazole, imidazole, acetazole, thiazole, triazole, acediazole and thiadiazole; wherein the substituted 5-membered heteroaryl group is substituted by one to three substituents selected independently from the following: -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R11, -CONR11R11, -NR11R11, -NR11CO 2R11, a C1-C6 alkyl group as appropriate, a C3-C5 cycloalkyl group as appropriate, a heterocyclic group as appropriate selected from pyrrolidone, pyrrolidone, piperidine or morpholine, a phenyl group as appropriate, or a heteroaryl group as appropriate selected from pyridine, pyrazole, isothiazolium, isothiazole, imidazole, thiazolium or thiazole; wherein the C1-C6 alkyl group as appropriate is substituted with -CN, -OH or C1-C3 alkoxy as appropriate; and each of the C3-C5 cycloalkyl, phenyl, heterocyclic or heteroaryl group as appropriate is substituted with one or three substituents selected independently from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -NR11R11, -OH or -CN as appropriate.

[0251] In yet another compound of formula (III) or a pharmaceutically acceptable salt thereof, R1 is a group of the following formula:; wherein R9 is H, halogen, C1-C3 alkyl or C1-C3 haloalkyl, and R2 is a group of the following formula:.

[0252] In another compound of formula (III) or a pharmaceutically acceptable salt thereof, R1 is a group of the following formula:; wherein R9 is -H, halogen, C1-C3 alkyl, C1-C3 haloalkyl or C3-C5 cycloalkyl, and R2 is a group of the following formula:; or R2 is a substituted 5-membered heteroaryl group selected from pyrrole, furan, thiophene, pyrazole, isothiazolium, isothiazole, imidazole, succinate, thiazole, triazole, succinyl diazole and thiadiazole; wherein the substituted 5-membered heteroaryl group is substituted by one to three substituents selected independently from the following: -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R11, -CONR11R11, -NR11R11, -NR11CO2R11, as appropriate. Furthermore, the substituted C1-C6 alkyl group, optionally substituted C3-C5 cycloalkyl group, optionally substituted heterocyclic group selected from pyrrolidone, pyrrolidone, piperidine or morpholine, optionally substituted phenyl group, or optionally substituted heteroaryl group selected from pyridine, pyrazole, isothiazolium, isothiazole, imidazole, thiazolium or thiazole; wherein the optionally substituted C1-C6 alkyl group is optionally substituted with -CN, -OH or C1-C3 alkoxy group; the optionally substituted C3-C5 cycloalkyl group, phenyl group, heterocyclic group or heteroaryl group is optionally substituted with one or three substituents independently selected from halogen, C1-C3 alkyl group, C1-C3 haloalkyl group, C1-C3 alkoxy group, C1-C3 haloalkoxy group, -NR11R11 group, -OH or -CN group; preferably R9 is -H, halogen, methyl, trifluoromethyl or cyclopropyl.

[0253] In yet another compound 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 following formula:; or R2 is substituted as appropriate. The 5-membered heteroaryl group is selected from pyrrole, furan, thiophene, pyrazole, isothiazolium, isothiazole, imidazole, thiazolium, triazole, thiadiazole, and thiadiazole; wherein the substituted 5-membered heteroaryl group is, as appropriate, substituted by one to three substituents selected independently from the following: -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R11, -CONR11R11, -NR11R 11, -NR11CO2R11, a C1-C6 alkyl group as appropriate, a C3-C5 cycloalkyl group as appropriate, a heterocyclic group selected from pyrrolidone, pyrrolidone, piperidine or morpholine as appropriate, a phenyl group as appropriate, or a heteroaryl group selected from pyridine, pyrazole, isothiazolium, isothiazole, imidazole, thiazolium or thiazole as appropriate; wherein the C1-C6 alkyl group as appropriate is optionally substituted with -CN, -OH or C1-C 3. Alkoxy substitution; wherein the substituted C3-C5 cycloalkyl, phenyl, heterocyclic or heteroaryl group is substituted by one or three substituents selected independently from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -NR11R11, -OH or -CN; preferably R3 is -H or methyl, R5 is -H, halogen, methyl or trifluoromethyl, R6 is -H and R7 is methyl.

[0254] In yet another compound 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 following formula:; 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 following formula:.

[0255] In another compound of formula (III) or a pharmaceutically acceptable salt thereof, R2 is a group of the following formula:; or R2 is a substituted 5-membered heteroaryl group selected from pyrrole, furan, thiophene, pyrazole, isothiazolium, isothiazole, imidazole, thiazolium, triazole, thiadiazole and thiadiazole; wherein the substituted 5-membered heteroaryl group is substituted by one to three substituents selected independently from the following: -C N, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R11, -CONR11R11, -NR11R11, -NR11CO2R11, substituted C1-C6 alkyl, substituted C3-C5 cycloalkyl, substituted heterocycle selected from pyrrolidine, pyrrolidone, piperidine or morpholine, substituted phenyl, or selected from pyridine The pyrazole, isothiazol, isothiazole, imidazole, pyrazole, or thiazole may be substituted with a heteroaryl group, wherein the substituted C1-C6 alkyl group may be substituted with -CN, -OH, or C1-C3 alkoxy group, and the substituted C3-C5 cycloalkyl, phenyl, heterocyclic, or heteroaryl group may be substituted with a group selected independently from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, or C1-C3 haloalkoxy group, as appropriate. The R3 group is substituted with one or three substituents: -NR11R11, -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 following formula: ; wherein each R9 group 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 group is independently -H, halogen, methyl, trifluoromethyl, or cyclopropyl.

[0256] In yet another compound of formula (III) or a pharmaceutically acceptable salt thereof, R2 is a group of the following formula:; 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 following formula:; 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 another compound of formula (III) or a pharmaceutically acceptable salt thereof, R2 is a group of the following formula:; or R2 is a substituted 5-membered heteroaryl group selected from pyrrole, furan, thiophene, pyrazole, isothiazolium, isothiazole, imidazole, thiazolium, triazole, thiadiazole and thiadiazole; wherein the substituted 5-membered heteroaryl group is substituted by one to three substituents selected independently from the following: -CN, Halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R11, -CONR11R11, -NR11R11, -NR11CO2R11, substituted C1-C6 alkyl, substituted C3-C5 cycloalkyl, substituted heterocyclic rings selected from pyrrolidine, pyrrolidone, piperidine or morpholine, substituted phenyl rings, or substituted pyridine, pyrazole, iso... The substituted heteroaryl group of acetazole, isothiazole, imidazole, acetazole, or thiazole, as appropriate; wherein the substituted C1-C6 alkyl group is substituted with -CN, -OH, or C1-C3 alkoxy as appropriate; and the substituted C3-C5 cycloalkyl, phenyl, heterocyclic, or heteroaryl group is substituted with a radical selected independently from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, or -NR11R1 as appropriate. 1. One to three substituents of -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 following formula:; wherein each R9 is independently -H, halogen, C1-C3 alkyl, C1-C3 haloalkyl or C3-C5 cycloalkyl.

[0258] In yet another compound of formula (III) or a pharmaceutically acceptable salt thereof, R2 is a group of the following formula:; 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 following formula:; wherein each R9 is independently H, halogen, C1-C3 alkyl or C1-C3 haloalkyl.

[0259] In another compound of formula (III) or a pharmaceutically acceptable salt thereof, R1 is a group of the following formula:; wherein each R9 is independently -H, halogen, methyl or trifluoromethyl, and R2 is a group of the following formula:; or R2 is a substituted 5-membered heteroaryl group selected from pyrrole, furan, thiophene, pyrazole, isothiazolium, isothiazole, imidazole, succinazole, thiazole, triazole, succinyl diazole and thiadiazole; wherein the substituted 5-membered heteroaryl group is substituted by one to three substituents independently selected from the following: -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R11, -CONR11R11, -NR11R11, -NR11CO2R11, substituted C1-C6 alkyl, substituted C3-C5 The cycloalkyl group, a heterocyclic group selected from pyrrolidone, pyrrolidone, piperidine or morpholine, a phenyl group selected from pyridine, pyrazole, isothiazolium, isothiazole, imidazole, thiazolium or thiazole, a heteroaryl group selected from pyridine, pyrazole, isothiazole, imidazole or thiazole, wherein the C1-C6 alkyl group selected from pyrrolidone, isothiazolium or C1-C3 alkoxy ...

[0260] In another compound of formula (III) or a pharmaceutically acceptable salt thereof, R1 is a group of the following formula:; wherein R9 is H, a halogen, or a trifluoromethyl group (preferably R9 is H or a trifluoromethyl group), and R2 is a group of the following formula:; or R2 is a substituted 5-membered heteroaryl group selected from pyrrole, furan, thiophene, pyrazole, isothiazolium, isothiazole, imidazole, succinazole, thiazole, triazole, succinyl diazole, and thiadiazole; wherein the substituted 5-membered heteroaryl group is substituted by one to three substituents selected independently from the following: -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R11, -CONR11R11, -NR11R11, -NR11CO2R11, or substituted C1-C6 alkyl group. The C3-C5 cycloalkyl group may be substituted, a heterocyclic group may be substituted, selected from pyrrolidone, piperidine or morpholine, a phenyl group may be substituted, or a heteroaryl group may be substituted, selected from pyridine, pyrazole, isothiazol, isothiazole, imidazole, thiazol or thiazole; wherein the C1-C6 alkyl group may be substituted, selected from -CN, -OH or C1-C3 alkoxy; each of the C3-C5 cycloalkyl, phenyl, heterocyclic or heteroaryl group may be substituted, selected from one or three substituents independently, selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -NR11R11, -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 yet another compound of formula (III) or a pharmaceutically acceptable salt thereof, R1 is a group of the following formula:; wherein R9 is H, a halogen or a trifluoromethyl group (preferably R9 is H or a trifluoromethyl group), R2 is a group of the following formula:; R3 is H or a methyl group, R5 is H, a halogen, a methyl group or a trifluoromethyl group, R6 is H or a halogen group, and R7 is a methyl group.

[0262] In another compound of formula (III) or a pharmaceutically acceptable salt thereof, R1 is a group of the following formula:; wherein R9 is H, a halogen, or a trifluoromethyl group (preferably R9 is H or a halogen), and R2 is a group of the following formula:; or R2 is a substituted 5-membered heteroaryl group selected from pyrrole, furan, thiophene, pyrazole, isothiazolium, isothiazole, imidazole, acetazole, thiazole, triazole, acediazole, and thiadiazole; wherein the substituted 5-membered heteroaryl group is substituted by one to three substituents selected independently from the following: -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R11, -CONR11R11, -NR11R11, -NR11CO2R11, substituted C1-C6 alkyl, The C3-C5 cycloalkyl group may be substituted, a heterocyclic group selected from pyrrolidone, pyrrolidone, piperidine, or morpholine may be substituted, a phenyl group may be substituted, or a heteroaryl group selected from pyridine, pyrazole, isothiazol, isothiazole, imidazole, succinazole, or thiazole may be substituted; wherein the C1-C6 alkyl group may be substituted with -CN, -OH, or C1-C3 alkoxy; each of the C3-C5 cycloalkyl, phenyl, heterocyclic, or heteroaryl group may be substituted with one or three substituents selected independently from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -NR11R11, -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 another compound of formula (III) or a pharmaceutically acceptable salt thereof, R1 is a group of the following formula:; wherein R9 is H, halogen or trifluoromethyl (preferably R9 is H or halogen), R2 is a group of the following formula:; R3 is H or methyl, R5 is H, halogen, methyl or trifluoromethyl, R6 is H or halogen, and R7 is methyl.

[0264] In another compound of formula (III) or a pharmaceutically acceptable salt thereof, R1 is a group of the following formula:; wherein each R9 is independently -H, halogen, methyl, trifluoromethyl or cyclopropyl, and R2 is a group of the following formula:; or R2 is a substituted 5-membered heteroaryl group selected from pyrrole, furan, thiophene, pyrazole, isothiazolium, isothiazole, imidazole, succinazole, thiazole, triazole, succinyl diazole and thiadiazole; wherein the substituted 5-membered heteroaryl group is substituted by one to three substituents independently selected from the following: -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R11, -CONR11R11, -NR11R11, -NR11CO2R11, substituted C1-C6 alkyl group ... The C3-C5 cycloalkyl group is replaced by a heterocyclic group selected from pyrrolidone, pyrrolidone, piperidine, or morpholine, or a phenyl group selected from pyridine, pyrazole, isothiazolium, isothiazole, imidazole, thiazolium, or thiazole, or a heteroaryl group selected from pyridine, pyrazole, isothiazole, imidazole, or thiazole, wherein the C1-C6 alkyl group selected from pyrrolidone, isothiazole, or morpholine is selected from -CN, -OH, or C1-C3 alkoxy, and the C3-C5 cycloalkyl, phenyl, heterocyclic, or heteroaryl group selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -NR11R11, -OH, or -CN, wherein 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 another compound of formula (III) or a pharmaceutically acceptable salt thereof, R1 is a group of the following formula:; wherein R9 is H, a halogen or a trifluoromethyl group (preferably R9 is a halogen or a trifluoromethyl group), R2 is a group of the following formula:; R3 is H or a methyl group, R5 is H, a halogen, a methyl group or a trifluoromethyl group, R6 is H or a halogen group, and R7 is a methyl group.

[0266] In another compound of formula (III) or a pharmaceutically acceptable salt thereof, R1 is a group of the following formula:; wherein R9 is H, halogen, C1-C3 alkyl or C1-C3 haloalkyl, and R2 is a group of the following formula:; or R2 is a substituted 5-membered heteroaryl group selected from pyrrole, furan, thiophene, pyrazole, isothiazolium, isothiazole, imidazole, acetazole, thiazole, triazole, acediazole and thiadiazole; wherein the substituted 5-membered heteroaryl group is substituted by one to three substituents selected independently from the following: -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R11, -CONR11R11, -NR11R11, -NR11CO2R11, substituted C1-C6 alkyl group, as appropriate. The C3-C5 cycloalkyl group may be substituted, a heterocyclic group selected from pyrrolidone, pyrrolidone, piperidine, or morpholine may be substituted, a phenyl group may be substituted, or a heteroaryl group selected from pyridine, pyrazole, isothiazol, isothiazole, imidazole, succinazole, or thiazole may be substituted; wherein the C1-C6 alkyl group may be substituted with -CN, -OH, or C1-C3 alkoxy; each of the C3-C5 cycloalkyl, phenyl, heterocyclic, or heteroaryl group may be substituted with one or three substituents selected independently from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -NR11R11, -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 yet another compound of formula (III) or a pharmaceutically acceptable salt thereof, R1 is a group of the following formula:; wherein R9 is H, halogen, C1-C3 alkyl or C1-C3 haloalkyl, R2 is a group of the following formula:; R3 is H or methyl, R5 is H, halogen, methyl or trifluoromethyl, R6 is H or halogen, and R7 is methyl.

[0268] In another compound of formula (III) or a pharmaceutically acceptable salt thereof, R1 is a group of the following formula:; wherein each R9 is independently -H, halogen, methyl, trifluoromethyl or cyclopropyl, and R2 is a group of the following formula:; or R2 is a substituted 5-membered heteroaryl group selected from pyrrole, furan, thiophene, pyrazole, isothiazolium, isothiazole, imidazole, succinazole, thiazole, triazole, succinyl diazole and thiadiazole; wherein the substituted 5-membered heteroaryl group is substituted by one to three substituents independently selected from the following: -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R11, -CONR11R11, -NR11R11, -NR11CO2R11, substituted C1-C6 alkyl, substituted C3- C5 cycloalkyl, a heterocyclic ring selected from pyrrolidone, pyrrolidone, piperidine or morpholine, a phenyl ring selected from pyridine, pyrazole, isothiazolium, isothiazole, imidazole, thiazolium or thiazole, a heteroaryl ring selected from pyridine, pyrazole, isothiazole, imidazole or thiazole, wherein the C1-C6 alkyl ring selected from pyrrolidone, isothiazolium or C1-C3 alkoxy ...

[0269] In yet another compound of formula (I), the compound is selected from:; or a pharmaceutically acceptable salt of any of the foregoing; wherein the bond at the * position is as indicated, or.

[0270] In yet another compound of formula (I), the compound is selected from:; or a pharmaceutically acceptable salt of any of the foregoing; wherein the bond at the * position is as indicated, or.

[0271] In yet another compound of formula (I), the compound is selected from:; or a pharmaceutically acceptable salt of any of the foregoing; wherein the bond at the * position is as indicated, or.

[0272] In yet another compound of formula (I), the compound is selected from:; or a pharmaceutically acceptable salt of any of the foregoing; wherein the bond at the * position is as indicated, or.

[0273] In yet another compound of formula (I), the compound is selected from:; or a pharmaceutically acceptable salt of any of the foregoing; wherein the bond at the * position is as indicated, or.

[0274] Another embodiment is a compound of the following formula: ; or a pharmaceutically acceptable salt thereof. In yet another embodiment, the bond at the * position is . In yet another embodiment, the bond at the * position is .

[0275] Another embodiment is a compound of the following formula: ; or a pharmaceutically acceptable salt thereof. In yet another embodiment, the bond at the * position is . In yet another embodiment, the bond at the * position is .

[0276] Another embodiment is a compound of the following formula: ; or a pharmaceutically acceptable salt thereof. In yet another embodiment, the bond at the * position is . In yet another embodiment, the bond at the * position is .

[0277] Another embodiment is a compound of the following formula: ; or a pharmaceutically acceptable salt thereof. In yet another embodiment, the bond at the * position is . In yet another embodiment, the bond at the * position is .

[0278] Another embodiment is a compound of the following formula: ; or a pharmaceutically acceptable salt thereof. In yet another embodiment, the bond at the * position is . In yet another embodiment, the bond at the * position is .

[0279] Another embodiment is a compound of the following formula: ; or a pharmaceutically acceptable salt thereof. In yet another embodiment, the bond at the * position is . In yet another embodiment, the bond at the * position is .

[0280] Another embodiment is a compound of the following formula: ; or a pharmaceutically acceptable salt thereof. In yet another embodiment, the bond at the * position is . In yet another embodiment, the bond at the * position is .

[0281] Another embodiment is a compound of the following formula: ; or a pharmaceutically acceptable salt thereof. In yet another embodiment, the bond at the * position is . In yet another embodiment, the bond at the * position is .

[0282] Another embodiment is a compound of the following formula: ; or a pharmaceutically acceptable salt thereof. In yet another embodiment, the bond at the * position is . In yet another embodiment, the bond at the * position is .

[0283] Another embodiment is a compound of the following formula: ; or a pharmaceutically acceptable salt thereof. In yet another embodiment, the bond at the * position is . In yet another embodiment, the bond at the * position is .

[0284] Another embodiment is a compound of the following formula: ; or a pharmaceutically acceptable salt thereof. In yet another embodiment, the bond at the * position is . In yet another embodiment, the bond at the * position is .

[0285] Another embodiment is a compound of the following formula: ; or a pharmaceutically acceptable salt thereof. In yet another embodiment, the bond at the * position is . In yet another embodiment, the bond at the * position is .

[0286] Another embodiment is a compound of the following formula: ; or a pharmaceutically acceptable salt thereof. In yet another embodiment, the bond at the * position is . In yet another embodiment, the bond at the * position is .

[0287] Another embodiment is a compound of the following formula: ; or a pharmaceutically acceptable salt thereof. In yet another embodiment, the bond at the * position is . In yet another embodiment, the bond at the * position is .

[0288] Another embodiment is a compound of the following formula: ; or a pharmaceutically acceptable salt thereof. In yet another embodiment, the bond at the * position is . In yet another embodiment, the bond at the * position is .

[0289] Another embodiment is a compound of the following formula: ; or a pharmaceutically acceptable salt thereof. In yet another embodiment, the bond at the * position is . In yet another embodiment, the bond at the * position is .

[0290] Another embodiment is a compound of the following formula: ; or a pharmaceutically acceptable salt thereof. In yet another embodiment, the bond at the * position is . In yet another embodiment, the bond at the * position is .

[0291] Another embodiment is a compound of the following formula: ; or a pharmaceutically acceptable salt thereof. In yet another embodiment, the bond at the * position is . In yet another embodiment, the bond at the * position is .

[0292] Another embodiment is a compound of the following formula: ; or a pharmaceutically acceptable salt thereof. In yet another embodiment, the bond at the * position is . In yet another embodiment, the bond at the * position is .

[0293] Another embodiment is a compound of the following formula: ; or a pharmaceutically acceptable salt thereof. In yet another embodiment, the bond at the * position is . In yet another embodiment, the bond at the * position is .

[0294] Another embodiment is a compound of the following formula: ; or a pharmaceutically acceptable salt thereof. In yet another embodiment, the bond at the * position is . In yet another embodiment, the bond at the * position is .

[0295] Another embodiment is a compound of the following formula: ; or a pharmaceutically acceptable salt thereof. In yet another embodiment, the bond at the * position is . In yet another embodiment, the bond at the * position is .

[0296] Another embodiment is a compound of the following formula: ; or a pharmaceutically acceptable salt thereof. In yet another embodiment, the bond at the * position is . In yet another embodiment, the bond at the * position is .

[0297] Another embodiment is a compound of the following formula: ; or a pharmaceutically acceptable salt thereof. In yet another embodiment, the bond at the * position is . In yet another embodiment, the bond at the * position is .

[0298] Another embodiment is a compound of the following formula: ; or a pharmaceutically acceptable salt thereof. In yet another embodiment, the bond at the * position is . In yet another embodiment, the bond at the * position is .

[0299] Another embodiment is a compound of the following formula: ; or a pharmaceutically acceptable salt thereof. In yet another embodiment, the bond at the * position is . In yet another embodiment, the bond at the * position is .

[0300] Another embodiment is a compound of the following formula: ; or a pharmaceutically acceptable salt thereof. In yet another embodiment, the bond at the * position is . In yet another embodiment, the bond at the * position is .

[0301] Another embodiment is a compound of the following formula: ; or a pharmaceutically acceptable salt thereof. In yet another embodiment, the bond at the * position is . In yet another embodiment, the bond at the * position is .

[0302] Another embodiment is a compound of the following formula: ; or a pharmaceutically acceptable salt thereof. In yet another embodiment, the bond at the * position is . In yet another embodiment, the bond at the * position is .

[0303] Another embodiment is a compound of the following formula: ; or a pharmaceutically acceptable salt thereof. In yet another embodiment, the bond at the * position is . In yet another embodiment, the bond at the * position is .

[0304] Another embodiment is a compound of the following formula: ; or a pharmaceutically acceptable salt thereof. In yet another embodiment, the bond at the * position is . In yet another embodiment, the bond at the * position is .

[0305] Another embodiment is a compound of the following formula: ; or a pharmaceutically acceptable salt thereof. In yet another embodiment, the bond at the * position is . In yet another embodiment, the bond at the * position is .

[0306] Another embodiment is a compound of the following formula: ; or a pharmaceutically acceptable salt thereof. In yet another embodiment, the bond at the * position is . In yet another embodiment, the bond at the * position is .

[0307] Another embodiment is a compound of the following formula: ; or a pharmaceutically acceptable salt thereof. In yet another embodiment, the bond at the * position is . In yet another embodiment, the bond at the * position is .

[0308] Another embodiment is a compound of the following formula: ; or a pharmaceutically acceptable salt thereof. In yet another embodiment, the bond at the * position is . In yet another embodiment, the bond at the * position is .

[0309] Another embodiment is a compound of the following formula: ; or a pharmaceutically acceptable salt thereof. In yet another embodiment, the bond at the * position is . In yet another embodiment, the bond at the * position is .

[0310] Another embodiment is a compound of the following formula: ; or a pharmaceutically acceptable salt thereof. In yet another embodiment, the bond at the * position is . In yet another embodiment, the bond at the * position is .

[0311] Another embodiment is a compound of the following formula: ; or a pharmaceutically acceptable salt thereof. In yet another embodiment, the bond at the * position is . In yet another embodiment, the bond at the * position is .

[0312] Another embodiment is a compound of the following formula: ; or a pharmaceutically acceptable salt thereof. In yet another embodiment, the bond at the * position is . In yet another embodiment, the bond at the * position is .

[0313] Another embodiment is a compound of the following formula: ; or a pharmaceutically acceptable salt thereof. In yet another embodiment, the bond at the * position is . In yet another embodiment, the bond at the * position is .

[0314] Another embodiment is a compound of the following formula: ; or a pharmaceutically acceptable salt thereof. In yet another embodiment, the bond at the * position is . In yet another embodiment, the bond at the * position is .

[0315] Another embodiment is a compound of the following formula: ; or a pharmaceutically acceptable salt thereof. In yet another embodiment, the bond at the * position is . In yet another embodiment, the bond at the * position is .

[0316] Another embodiment is a compound of the following formula: ; or a pharmaceutically acceptable salt thereof. In yet another embodiment, the bond at the * position is . In yet another embodiment, the bond at the * position is .

[0317] Another embodiment is a compound of the following formula: ; or a pharmaceutically acceptable salt thereof. In yet another embodiment, the bond at the * position is . In yet another embodiment, the bond at the * position is .

[0318] Another embodiment is a compound of the following formula: ; or a pharmaceutically acceptable salt thereof. In yet another embodiment, the bond at the * position is . In yet another embodiment, the bond at the * position is .

[0319] Another embodiment is a compound of the following formula: ; or a pharmaceutically acceptable salt thereof. In yet another embodiment, the bond at the * position is . In yet another embodiment, the bond at the * position is .

[0320] Another embodiment is a compound of the following formula: ; or a pharmaceutically acceptable salt thereof. In yet another embodiment, the bond at the * position is . In yet another embodiment, the bond at the * position is .

[0321] Another embodiment is a compound of the following formula: ; or a pharmaceutically acceptable salt thereof. In yet another embodiment, the bond at the * position is . In yet another embodiment, the bond at the * position is .

[0322] Another embodiment is a compound of the following formula: ; or a pharmaceutically acceptable salt thereof. In yet another embodiment, the bond at the * position is . In yet another embodiment, the bond at the * position is .

[0323] Another embodiment is a compound of the following formula: ; or a pharmaceutically acceptable salt thereof. In yet another embodiment, the bond at the * position is . In yet another embodiment, the bond at the * position is .

[0324] Another embodiment is a compound of the following formula: ; or a pharmaceutically acceptable salt thereof. In yet another embodiment, the bond at the * position is . In yet another embodiment, the bond at the * position is .

[0325] Another embodiment is a compound of the following formula: ; or a pharmaceutically acceptable salt thereof. In yet another embodiment, the bond at the * position is . In yet another embodiment, the bond at the * position is .

[0326] Another embodiment is a compound of the following formula: ; or a pharmaceutically acceptable salt thereof. In yet another embodiment, the bond at the * position is . In yet another embodiment, the bond at the * position is .

[0327] Another embodiment is a compound of the following formula: ; or a pharmaceutically acceptable salt thereof. In yet another embodiment, the bond at the * position is . In yet another embodiment, the bond at the * position is .

[0328] Another embodiment is a compound of the following formula: ; or a pharmaceutically acceptable salt thereof. In yet another embodiment, the bond at the * position is . In yet another embodiment, the bond at the * position is .

[0329] Another embodiment is a compound of the following formula: ; or a pharmaceutically acceptable salt thereof. In yet another embodiment, the bond at the * position is . In yet another embodiment, the bond at the * position is .

[0330] Another embodiment is a compound of the following formula: ; or a pharmaceutically acceptable salt thereof. In yet another embodiment, the bond at the * position is . In yet another embodiment, the bond at the * position is .

[0331] Another embodiment is a compound of the following formula: ; or a pharmaceutically acceptable salt thereof. In yet another embodiment, the bond at the * position is . In yet another embodiment, the bond at the * position is .

[0332] Another embodiment is a compound of the following formula: ; or a pharmaceutically acceptable salt thereof. In yet another embodiment, the bond at the * position is . In yet another embodiment, the bond at the * position is .

[0333] Another embodiment is a compound of the following formula: ; or a pharmaceutically acceptable salt thereof. In yet another embodiment, the bond at the * position is . In yet another embodiment, the bond at the * position is .

[0334] Another embodiment is a compound of the following formula: ; or a pharmaceutically acceptable salt thereof. In yet another embodiment, the bond at the * position is . In yet another embodiment, the bond at the * position is .

[0335] Another embodiment is a compound of the following formula: ; or a pharmaceutically acceptable salt thereof. In yet another embodiment, the bond at the * position is . In yet another embodiment, the bond at the * position is .

[0336] Another embodiment is a compound of the following formula: ; or a pharmaceutically acceptable salt thereof. In yet another embodiment, the bond at the * position is . In yet another embodiment, the bond at the * position is .

[0337] Another embodiment is a compound of the following formula: ; or a pharmaceutically acceptable salt thereof. In yet another embodiment, the bond at the * position is . In yet another embodiment, the bond at the * position is .

[0338] Another embodiment is a compound of the following formula: ; or a pharmaceutically acceptable salt thereof. In yet another embodiment, the bond at the * position is . In yet another embodiment, the bond at the * position is .

[0339] Another embodiment is a compound of the following formula: ; or a pharmaceutically acceptable salt thereof. In yet another embodiment, the bond at the * position is . In yet another embodiment, the bond at the * position is .

[0340] Another embodiment is a compound of the following formula: ; or a pharmaceutically acceptable salt thereof. In yet another embodiment, the bond at the * position is . In yet another embodiment, the bond at the * position is .

[0341] Another embodiment is a compound of the following formula: ; or a pharmaceutically acceptable salt thereof. In yet another embodiment, the bond at the * position is . In yet another embodiment, the bond at the * position is .

[0342] Another embodiment is a compound of the following formula: ; or a pharmaceutically acceptable salt thereof. In yet another embodiment, the bond at the * position is . In yet another embodiment, the bond at the * position is .

[0343] Another embodiment is a compound of the following formula: ; or a pharmaceutically acceptable salt thereof. In yet another embodiment, the bond at the * position is . In yet another embodiment, the bond at the * position is .

[0344] Another embodiment is a compound of the following formula: ; or a pharmaceutically acceptable salt thereof. In yet another embodiment, the bond at the * position is . In yet another embodiment, the bond at the * position is .

[0345] Another embodiment is a compound of the following formula: ; or a pharmaceutically acceptable salt thereof. In yet another embodiment, the bond at the * position is . In yet another embodiment, the bond at the * position is .

[0346] Another embodiment is a compound of the following formula: ; or a pharmaceutically acceptable salt thereof. In yet another embodiment, the bond at the * position is . In yet another embodiment, the bond at the * position is .

[0347] Another embodiment is a compound of the following formula: ; or a pharmaceutically acceptable salt thereof. In yet another embodiment, the bond at the * position is . In yet another embodiment, the bond at the * position is .

[0348] Another embodiment is a compound of the following formula: ; or a pharmaceutically acceptable salt thereof. In yet another embodiment, the bond at the * position is . In yet another embodiment, the bond at the * position is .

[0349] Another embodiment is a compound of the following formula: ; or a pharmaceutically acceptable salt thereof. In yet another embodiment, the bond at the * position is . In yet another embodiment, the bond at the * position is .

[0350] Another embodiment is a compound of the following formula: ; or a pharmaceutically acceptable salt thereof. In yet another embodiment, the bond at the * position is . In yet another embodiment, the bond at the * position is .

[0351] Another embodiment is a compound of the following formula: ; or a pharmaceutically acceptable salt thereof. In yet another embodiment, the bond at the * position is . In yet another embodiment, the bond at the * position is .

[0352] Another embodiment is a compound of the following formula: ; or a pharmaceutically acceptable salt thereof. In yet another embodiment, the bond at the * position is . In yet another embodiment, the bond at the * position is .

[0353] Another embodiment is a compound of the following formula: ; or a pharmaceutically acceptable salt thereof. In yet another embodiment, the bond at the * position is . In yet another embodiment, the bond at the * position is .

[0354] Another embodiment is a compound of the following formula: ; or a pharmaceutically acceptable salt thereof. In yet another embodiment, the bond at the * position is . In yet another embodiment, the bond at the * position is .

[0355] Another embodiment is a compound of the following formula: ; or a pharmaceutically acceptable salt thereof. In yet another embodiment, the bond at the * position is . In yet another embodiment, the bond at the * position is .

[0356] Another embodiment is a compound of the following formula: ; or a pharmaceutically acceptable salt thereof. In yet another embodiment, the bond at the * position is . In yet another embodiment, the bond at the * position is .

[0357] Another embodiment is a compound of the following formula: ; or a pharmaceutically acceptable salt thereof. In yet another embodiment, the bond at the * position is . In yet another embodiment, the bond at the * position is .

[0358] Another embodiment is a compound of the following formula: ; or a pharmaceutically acceptable salt thereof. In yet another embodiment, the bond at the * position is . In yet another embodiment, the bond at the * position is .

[0359] Another embodiment is a compound of the following formula: ; or a pharmaceutically acceptable salt thereof. In yet another embodiment, the bond at the * position is . In yet another embodiment, the bond at the * position is .

[0360] Another embodiment is a compound of the following formula: ; or a pharmaceutically acceptable salt thereof. In yet another embodiment, the bond at the * position is . In yet another embodiment, the bond at the * position is .

[0361] Another embodiment is a compound of the following formula: ; or a pharmaceutically acceptable salt thereof. In yet another embodiment, the bond at the * position is . In yet another embodiment, the bond at the * position is .

[0362] Another embodiment is a compound of the following formula: ; or a pharmaceutically acceptable salt thereof. In yet another embodiment, the bond at the * position is . In yet another embodiment, the bond at the * position is .

[0363] Another embodiment is a compound of the following formula: ; or a pharmaceutically acceptable salt thereof. In yet another embodiment, the bond at the * position is . In yet another embodiment, the bond at the * position is .

[0364] Another embodiment is a compound of the following formula: ; or a pharmaceutically acceptable salt thereof. In yet another embodiment, the bond at the * position is . In yet another embodiment, the bond at the * position is .

[0365] Another embodiment is a compound of the following formula: ; or a pharmaceutically acceptable salt thereof. In yet another embodiment, the bond at the * position is . In yet another embodiment, the bond at the * position is .

[0366] Another embodiment is a compound of the following formula: ; or a pharmaceutically acceptable salt thereof. In yet another embodiment, the bond at the * position is . In yet another embodiment, the bond at the * position is .

[0367] Another embodiment is a compound of the following formula: ; or a pharmaceutically acceptable salt thereof. In yet another embodiment, the bond at the * position is . In yet another embodiment, the bond at the * position is .

[0368] Another embodiment is a compound of the following formula: ; or a pharmaceutically acceptable salt thereof. In yet another embodiment, the bond at the * position is . In yet another embodiment, the bond at the * position is .

[0369] Another embodiment is a compound of the following formula: ; or a pharmaceutically acceptable salt thereof. In yet another embodiment, the bond at the * position is . In yet another embodiment, the bond at the * position is .

[0370] Another embodiment is a compound of the following formula: ; or a pharmaceutically acceptable salt thereof. In yet another embodiment, the bond at the * position is . In yet another embodiment, the bond at the * position is .

[0371] Another embodiment is a compound of the following formula: ; or a pharmaceutically acceptable salt thereof. In yet another embodiment, the bond at the * position is . In yet another embodiment, the bond at the * position is .

[0372] Another embodiment is a compound of the following formula: ; or a pharmaceutically acceptable salt thereof. In yet another embodiment, the bond at the * position is . In yet another embodiment, the bond at the * position is .

[0373] Another embodiment is a compound of the following formula: ; or a pharmaceutically acceptable salt thereof. In yet another embodiment, the bond at the * position is . In yet another embodiment, the bond at the * position is .

[0374] Another embodiment is a compound of the following formula: ; or a pharmaceutically acceptable salt thereof. In yet another embodiment, the bond at the * position is . In yet another embodiment, the bond at the * position is .

[0375] Another embodiment is a compound of the following formula: ; or a pharmaceutically acceptable salt thereof. In yet another embodiment, the bond at the * position is . In yet another embodiment, the bond at the * position is .

[0376] Another embodiment is a compound of the following formula: ; or a pharmaceutically acceptable salt thereof. In yet another embodiment, the bond at the * position is . In yet another embodiment, the bond at the * position is .

[0377] Another embodiment is a compound of the following formula: ; or a pharmaceutically acceptable salt thereof. In yet another embodiment, the bond at the * position is . In yet another embodiment, the bond at the * position is .

[0378] Another embodiment is a compound of the following formula: ; or a pharmaceutically acceptable salt thereof. In yet another embodiment, the bond at the * position is . In yet another embodiment, the bond at the * position is .

[0379] Another embodiment is a compound of the following formula: ; or a pharmaceutically acceptable salt thereof. In yet another embodiment, the bond at the * position is . In yet another embodiment, the bond at the * position is .

[0380] Another embodiment is a compound of the following formula: ; or a pharmaceutically acceptable salt thereof. In yet another embodiment, the bond at the * position is . In yet another embodiment, the bond at the * position is .

[0381] Another embodiment is a compound of the following formula: ; or a pharmaceutically acceptable salt thereof. In yet another embodiment, the bond at the * position is . In yet another embodiment, the bond at the * position is .

[0382] Another embodiment is a compound of the following formula: ; or a pharmaceutically acceptable salt thereof. In yet another embodiment, the bond at the * position is . In yet another embodiment, the bond at the * position is .

[0383] Another embodiment is a compound of the following formula: ; or a pharmaceutically acceptable salt thereof. In yet another embodiment, the bond at the * position is . In yet another embodiment, the bond at the * position is .

[0384] Another embodiment is a compound of the following formula: ; or a pharmaceutically acceptable salt thereof. In yet another embodiment, the bond at the * position is . In yet another embodiment, the bond at the * position is .

[0385] Another embodiment is a compound of the following formula: ; or a pharmaceutically acceptable salt thereof. In yet another embodiment, the bond at the * position is . In yet another embodiment, the bond at the * position is .

[0386] Another embodiment is a compound of the following formula: ; or a pharmaceutically acceptable salt thereof. In yet another embodiment, the bond at the * position is . In yet another embodiment, the bond at the * position is .

[0387] Another embodiment is a compound of the following formula: ; or a pharmaceutically acceptable salt thereof. In yet another embodiment, the bond at the * position is . In yet another embodiment, the bond at the * position is .

[0388] Another embodiment is a compound of the following formula: ; or a pharmaceutically acceptable salt thereof. In yet another embodiment, the bond at the * position is . In yet another embodiment, the bond at the * position is .

[0389] Another embodiment is a compound of the following formula: ; or a pharmaceutically acceptable salt thereof. In yet another embodiment, the bond at the * position is . In yet another embodiment, the bond at the * position is .

[0390] Another embodiment is a compound of the following formula: ; or a pharmaceutically acceptable salt thereof. In yet another embodiment, the bond at the * position is . In yet another embodiment, the bond at the * position is .

[0391] Another embodiment is a compound of the following formula: ; or a pharmaceutically acceptable salt thereof. In yet another embodiment, the bond at the * position is . In yet another embodiment, the bond at the * position is .

[0392] Another embodiment is a compound of the following formula: ; or a pharmaceutically acceptable salt thereof. In yet another embodiment, the bond at the * position is . In yet another embodiment, the bond at the * position is .

[0393] Another embodiment is a compound of the following formula: ; or a pharmaceutically acceptable salt thereof. In yet another embodiment, the bond at the * position is . In yet another embodiment, the bond at the * position is .

[0394] Another embodiment is a compound of the following formula: ; or a pharmaceutically acceptable salt thereof. In yet another embodiment, the bond at the * position is . In yet another embodiment, the bond at the * position is .

[0395] Another embodiment is a compound of the following formula: ; or a pharmaceutically acceptable salt thereof. In yet another embodiment, the bond at the * position is . In yet another embodiment, the bond at the * position 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 having sufficient basicity, such as acid addition salts of inorganic or organic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, trifluoroacetic acid, formic acid, citric acid, methanesulfonic acid, or maleic acid. Additionally, pharmaceutically acceptable salts of the compounds of the present invention having sufficient acidity are alkali metal salts, such as sodium or potassium salts; alkaline earth metal salts, such as calcium or magnesium salts; ammonium salts; or salts of organic bases that yield pharmaceutically acceptable cations, such as salts of methylamine, dimethylamine, diethylamine, trimethylamine, piperidine, morpholine, or tris(2-hydroxyethyl)amine. Pharmaceutically acceptable salts and common methods for their preparation are well known in this technique (see, for example, P. Stahl et al., Handbook of Pharmaceutical Salts: Properties, Selection, and Use, 2nd revised edition (Wiley-VCH, 2011); SM Berge et al., "Pharmaceutical Salts", Journal of Pharmaceutical Sciences, Vol. 66, No. 1, January 1977).

[0397] Other representative “medically acceptable salts” include, for example, water-soluble and non-water-soluble salts such as acetates, amsonate (4,4-diaminostilbene-2,2-disulfonate), benzenesulfonate, benzoate, bicarbonate, bisulfate, tartrate, borate, bromide, butyrate, calcium salt, calcium ethylenediaminetetraacetate, camphorsulfonate, carbonate, chloride, citrate, clavulanate, dihydrochloride, ethylenediaminetetraacetate, ethanesulfonate, estolate, ethanesulfonate, fumarate, glucohepanoate, glucuronate, glutamate, acetylamine benzoarsylate, hexafluorophosphate, hexylresorcinate, hydrabamine salts, hydrobromide, hydrochloride, hydroxyl Naphthyl carboxylates, iodides, hydroxyethanesulfonates, lactates, lactobionates, laurates, magnesium salts, malates, maleate, amygdalinate, methanesulfonates, methyl bromide, methyl nitrates, methyl sulfates, galactosidates, naphthalenesulfonates, nitrates, N-methylglucosamine ammonium salts, 3-hydroxy-2-naphthyl carboxylates, oleates, oxalates, palmitates, dihydroxynaphthyl salts, pantothenates, phosphates / bisphosphates, picrates, polygalacturonic acids, propionates, p-toluenesulfonates, salicylates, stearates, hypoacetates, succinates, sulfates, sulfosalicylates, tannates, tartrates, theochloroate, toluenesulfonates, triethyl iodide, and valerates.

[0398] The compounds of the present invention can be prepared in a variety of ways well known to those skilled in organic synthesis. By way of example, the compounds of the present invention can be synthesized using the methods described below and synthetic methods known in organic synthetic chemistry, or variations thereof as understood by those skilled in the art. Preferred methods include, but are not limited to, those described below. The compounds of the present invention can be synthesized by following the steps outlined in general procedures 1, 2, and 3. The starting materials are commercially available or obtained by known procedures in reported literature or as described below. Procedure 1

[0399] Procedure 1 describes the preparation of the compound of formula (I), wherein R is H, R7 is methyl and R8 is H. The esterification of the substituted phenol (1) provides an ester (2). The ester (2) may undergo recombination under Lewis acid (e.g., AlCl3) or Brønsted acid (e.g., trifluoromethanesulfonic acid) conditions to give a hydroxyaryl ketone (3). The ketone (3) is subjected to basic deprotonation in the presence of carbon disulfide to give a bicyclic chromene-2-thione (4).

[0400] Thione (4) is alkylated under basic conditions to give thioether (5). Phenyl bromide (5) can be acylated via palladium catalysis to produce acetylen-4-one (6). Aryl ketone (6) can be reduced to hydroxy compound (7) by a reagent such as sodium borohydride. Halogenating agents (such as phosphorus tribromide) can be used to convert hydroxy compound (7) into halogen compound (8).

[0401] The halogenated compound (8) can be used to alkylate aromatic or heteroarylamines to obtain aromatic or heteroarylamines (9). Thiol ethers (9) can be converted to compounds of formula (I) using transition metal catalysis to couple heteroaryl acids, esters, or other coupling complexes, followed by hydrolysis of the ester present at R1. Process 2

[0402] Step 2 describes another preparation of the compound of formula (I), wherein R is H, R7 is methyl and R8 is H. The thiol ether (9) is oxidized with an oxidizing agent (such as m-CPBA) to give a monoxide (10). The monoxide (10) can be converted into the compound of formula (I) by substitution with various aryl groups. Step 3

[0403] Process 3 describes the preparation of compound (II), wherein R is H and R7 is methyl. Thiol ether (6) can be converted to 2-substituted chromenone (11) by transition metal catalysis to couple heteroaryl acid, ester or other coupling complex. Ketone (11) can be reduced to hydroxy compound (12) by a palm-like catalyst such as Noyori catalyst. Hydroxy compound (12) can be converted to a detached group by methanesulfonic anhydride or methanesulfonyl chloride to give methanesulfonate (13). Methanesulfonate (13) can be used to alkylate aromatic amine or heteroaryl amine after hydrolysis of ester present on R1 to give compound (II).

[0404] Alternatively, the ketone (11) can be reduced to a hydroxy compound (14) by a catalytic catalyst such as a nori catalyst. The hydroxyl group can be converted to a chloride (15) by a chlorinating agent such as 2,4,6-trichloro-1,3,5-triazine. The chloride (15) can then be used to alkylate an aromatic amine or heteroaryl amine after hydrolysis of the ester present on R1 to obtain a compound of formula (II). Pharmaceutical Composition

[0405] In some embodiments, the present invention provides a pharmaceutical composition comprising a compound of formula (I), (II) or (III) as an active ingredient. In some embodiments, the present invention provides a pharmaceutical composition comprising a compound of formula (I), (II) or (III) or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers or excipients.

[0406] As used herein, the term "composition" is intended to cover a product comprising a specified amount of a specified ingredient, and any product produced directly or indirectly from a combination of a specified amount of a specified ingredient.

[0407] Compounds of formula (I), (II), or (III) may be formulated for oral administration in the form of tablets, capsules (each of which includes sustained-release or timed-release formulations), pills, powders, granules, elixirs, tinctures, suspensions, syrups, and emulsions. Compounds of formula (I), (II), or (III) may also be formulated for intravenous (bolus or infusion), intraperitoneal, topical, subcutaneous, intramuscular, or transdermal (e.g., patch) administration, all in forms well known to those skilled in the art of medicine.

[0408] The formulations of the present invention may be in the form of an aqueous solution containing an aqueous mediator. The aqueous mediator component may contain water and at least one pharmaceutically acceptable excipient. Suitable acceptable excipients include those selected from the group consisting of: solubilizers, chelating agents, preservatives, tensioning agents, viscosity / suspending agents, buffers and pH adjusters, and mixtures thereof.

[0409] According to another aspect of the present invention, a pharmaceutical composition is provided comprising a compound of any of the formulas disclosed herein or a pharmaceutically acceptable salt, hydrate or solvate thereof, and a pharmaceutically acceptable diluent or carrier.

[0410] The compositions of the present invention may be in the following forms: oral (e.g., in the form of tablets, lozenges, hard capsules or soft capsules, aqueous suspensions or oil suspensions, emulsions, dispersible powders or granules, syrups or elixirs), topical (e.g., in the form of creams, ointments, gels, or aqueous or oil solutions or suspensions), inhalation (e.g., in the form of fine powders or liquid aerosols), inhalation (e.g., in the form of fine powders), or non-entericidal (e.g., in the form of sterile aqueous or oil solutions for intravenous, subcutaneous, intramuscular, intraperitoneal or intramuscular administration, or in the form of suppositories for rectal administration).

[0411] The compositions of the present invention can be obtained by conventional procedures using conventional pharmaceutical excipients well known in the art. Therefore, compositions intended for oral use may contain, for example, one or more colorants, sweeteners, flavorings, and / or preservatives. Method of Use

[0412] In some embodiments, the present invention provides a method for regulating PI3K (e.g., PI3Kα) activity (e.g., in vitro or in vivo), comprising contacting cells with a therapeutically effective amount of a compound of formula (I), (II) or (III) or a medically acceptable salt thereof.

[0413] In some embodiments, the present invention provides a method for treating or preventing a disease or ailment disclosed herein in an individual in need, comprising administering to the individual 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 invention.

[0414] In some embodiments, the present invention provides a method for treating an individual in need of a disease or ailment disclosed herein, comprising administering to the individual 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 invention.

[0415] In some embodiments, the disease or condition is related to the PI3K activity involved. In some embodiments, the disease or condition is a disease or condition involving PI3K activity.

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

[0417] In some embodiments, the cancer is selected from 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 lymphoma, carcinoid tumor, cancer of unknown primary cardiac tumor, atypical teratoid / rhabdoid tumor, primary CNS lymphoma, cervical cancer, cholangiocarcinoma, chordoma, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, mycosis fungoides, and Sézary syndrome. Syndrome, ductal carcinoma in situ (DCIS), embryonal tumors, neuroblastoma, endometrial cancer, ependymoma, esophageal cancer, sensitive neuroblastoma, Ewing sarcoma, extracranial germ cell tumors, gonadal extragerminal tumors, fallopian tube cancer, gallbladder cancer, gastric cancer, gastrointestinal carcinoid tumors, malignant gastrointestinal stromal tumors (GIST), germ cell tumors, gestational trophoblastic disease, hairy cell leukemia, head and neck cancer, hepatocellular carcinoma, Langerhans cell histiocytosis, Hodgkin lymphoma, islet cell tumor, pancreatic neuroendocrine tumor, Kaposi sarcoma, kidney cancer, laryngeal cancer, leukemia, liver cancer, lung cancer, lymphoma, male breast cancer, intraocular melanoma, Merkel cell carcinoma. Carcinoma, malignant mesothelioma, metastatic carcinoma, metastatic squamous neck carcinoma, midline tract carcinoma with nut gene changes, mouth cancer, multiple endocrine tumor syndrome, multiple myeloma / plasmocytoma, myelodyplastic syndrome, myelodyplastic lesion, myeloproliferative neoplasm, chronic myeloproliferative neoplasm, nasal cavity and sinus carcinoma, nasopharyngeal carcinoma, neuroblastoma, non-Hodgkin's lymphoma, non-small cell lung cancer, oral cancer.Cancer, lip and oral cavity cancer, oropharyngeal cancer, malignant fibrous histiocytoma of bone, ovarian cancer, pancreatic cancer, pancreatic neuroendocrine tumor (islet cell tumor), papilloma, paraganglioma, paranasal sinus and nasal cavity cancer, parathyroid cancer, penile cancer, pharyngeal cancer, pheochromocytoma, pituitary tumor, plasmacytoma, multiple myeloma, pleural pulmonary blastoma, primary central nervous system (CNS) lymphoma, primary peritoneal cancer, prostate cancer, rectal cancer, recurrent cancer, renal cell carcinoma, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, sarcoma, juvenile vascular tumor, 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 Carcinoma, thyroid cancer, tracheobronchial tumors, 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, cystourethral epithelial carcinoma, glioblastoma, ovarian cancer, non-small cell lung cancer, esophageal and gastric cancer, nerve sheath tumor, head and neck squamous cell carcinoma, melanoma, esophageal and gastric adenocarcinoma, soft tissue sarcoma, prostate cancer, fibrous carcinoma, hepatocellular carcinoma, diffuse glioma, colorectal cancer, pancreatic cancer, bile duct cancer, B-cell lymphoma, mesothelioma, adrenocortical carcinoma, non-clear cell renal carcinoma, clear cell renal carcinoma, germ cell carcinoma, thymic tumor, pheochromocytoma, mixed 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 adenocarcinoma. In some embodiments, the prostate cancer is small cell carcinoma. In some embodiments, the prostate cancer is a neuroendocrine tumor. In some embodiments, the prostate cancer is transitional cell carcinoma. In some embodiments, the prostate cancer is 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 metastatic brain cancer. 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 an embryonal tumor. In some embodiments, the brain cancer is an ependymoma. In some embodiments, the brain cancer is a glioblastoma. In some embodiments, the brain cancer is a glioma. In some embodiments, the brain cancer is a neuroblastoma. 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, PI3K-related diseases or conditions include, but are not limited to, CLOVES syndrome (congenital lipomatous overgrowth, vascular malformation, epidermal nevus, 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 disease or condition associated with PI3K is CLOVES syndrome (congenital lipomatous overgrowth, vascular malformation, epidermal nevus, scoliosis / skeletal and spinal syndrome).

[0426] In some embodiments, the disease or condition associated with PI3K is PIK3CA-associated hyperglycemia (PROS).

[0427] In some embodiments, diseases or conditions associated with PI3K include 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 PI3K-related disease or condition is a breast fibroadenoma, thyroid fibroadenoma, ovarian fibroadenoma, non-small cell lung cancer, endometrial fibroadenoma, or pancreatic fibroadenoma. In some embodiments, the PI3K-related disease or condition is a breast fibroadenoma. In some embodiments, the PI3K-related disease or condition is a thyroid fibroadenoma. In some embodiments, the PI3K-related disease or condition is an ovarian fibroadenoma. In some embodiments, the PI3K-related disease or condition is non-small cell lung cancer. In some embodiments, the PI3K-related disease or condition is an endometrial fibroadenoma. In some embodiments, the PI3K-related disease or condition is a pancreatic fibroadenoma.

[0429] In some embodiments, the diseases or conditions associated with PI3K are 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 disease or condition associated with PI3K 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 a soft tissue sarcoma, osteosarcoma, chondrosarcoma, Ewing's sarcoma, hemangioendothelioma, angiosarcoma, fibrosarcoma, myofibrosarcoma, chordoma, amelioma, 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 a liposarcoma, atypical lipomatous tumor, dermatofibrosarcoma protuberans, malignant solitary fibrous tumor, inflammatory myofibroblastic tumor, low-grade myofibroblastic sarcoma, fibrosarcoma, myxofibrosarcoma, low-grade fibromyxoid nodular sarcoma, soft tissue giant cell tumor, leiomyosarcoma, malignant glomus tumor, rhabdomyosarcoma, hemangioendothelioma, soft tissue angiosarcoma, extraosseous osteosarcoma, gastrointestinal stromal tumor, malignant gastrointestinal stromal tumor (GIST), malignant peripheral nerve sheath tumor, malignant Triton tumor. Malignant granular cell tumor, malignant ossifying fibromyxoid nodule tumor, stromal sarcoma, myoepithelial carcinoma, malignant hyperphosphatemic mesenchymal tumor, synovial sarcoma, epithelioid sarcoma, soft tissue alveolar sarcoma, clear cell soft tissue sarcoma, extraosseous myxoid chondrosarcoma, extraosseous Ewing's sarcoma, pro-connective tissue proliferative small round cell tumor, extrarenal rhabdomyosarcoma, perivascular epithelioid cell tumor, endometrial sarcoma, undifferentiated spindle cell sarcoma, undifferentiated pleomorphic sarcoma, undifferentiated round cell sarcoma, undifferentiated epithelioid sarcoma, or nonspecific undifferentiated sarcoma.

[0435] In some embodiments, the present invention provides a method for treating or preventing cancer in an individual in need, comprising administering to the individual 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 invention.

[0436] In some embodiments, the present invention provides a method of treating cancer in an individual in need, comprising administering to the individual 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 invention.

[0437] In some embodiments, the present invention provides a method for treating or preventing breast cancer in an individual in need, comprising administering to the individual 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 invention.

[0438] In some embodiments, the present invention provides a method for treating breast cancer in an individual in need, comprising administering to the individual 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 invention.

[0439] In some embodiments, the present invention provides a method for treating or preventing prostate cancer in an individual in need, comprising administering to the individual 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 invention.

[0440] In some embodiments, the present invention provides a method for treating prostate cancer in an individual in need, comprising administering to the individual 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 invention.

[0441] In some embodiments, the present invention provides a method for treating or preventing brain cancer in an individual in need, comprising administering to the individual 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 invention.

[0442] In some embodiments, the present invention provides a method for treating brain cancer in an individual in need, comprising administering to the individual 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 invention.

[0443] In some embodiments, the present invention provides compounds of formula (I), (II) or (III) for use in therapeutics, or pharmaceutically acceptable salts thereof.

[0444] In some embodiments, the present invention provides compounds of formula (I), (II) or (III) or their pharmaceutically acceptable salts for regulating PI3K (e.g., PI3Kα) activity (e.g., in vitro or in vivo).

[0445] In some embodiments, the present invention provides compounds of formula (I), (II) or (III) or their pharmaceutically acceptable salts for treating or preventing the diseases or conditions disclosed herein.

[0446] In some embodiments, the present invention provides compounds of formula (I), (II) or (III) or their pharmaceutically acceptable salts for treating the diseases or conditions disclosed herein.

[0447] In some embodiments, the present invention provides compounds of formula (I), (II) or (III) or their pharmaceutically acceptable salts for the treatment or prevention of cancer.

[0448] In some embodiments, the present invention provides compounds of formula (I), (II) or (III) for the treatment of cancer, or medically acceptable salts thereof.

[0449] In some embodiments, the present invention provides compounds of formula (I), (II) or (III) or their pharmaceutically acceptable salts for the treatment or prevention of breast cancer.

[0450] In some embodiments, the present invention provides compounds of formula (I), (II) or (III) or their pharmaceutically acceptable salts for treating breast cancer.

[0451] In some embodiments, the present invention provides compounds of formula (I), (II) or (III) or their pharmaceutically acceptable salts for the treatment or prevention of prostate cancer.

[0452] In some embodiments, the present invention provides compounds of formula (I), (II) or (III) for the treatment of prostate cancer, or pharmaceutically acceptable salts thereof.

[0453] In some embodiments, the present invention provides compounds of formula (I), (II) or (III) or their pharmaceutically acceptable salts for the treatment or prevention of brain cancer.

[0454] In some embodiments, the present invention provides compounds of formula (I), (II) or (III) for the treatment of brain cancer, or pharmaceutically acceptable salts thereof.

[0455] In some embodiments, the present invention provides the use of compounds of formula (I), (II) or (III) or pharmaceutically acceptable salts thereof for the manufacture of agents that modulate PI3K (e.g., PI3Kα) activity (e.g., in vitro or in vivo).

[0456] In some embodiments, the present invention provides the use of compounds of formula (I), (II) or (III) or pharmaceutically acceptable salts thereof for the manufacture of medicaments for the treatment or prevention of the diseases or conditions disclosed herein.

[0457] In some embodiments, the present invention provides the use of compounds of formula (I), (II) or (III) or pharmaceutically acceptable salts thereof for the manufacture of medicaments for treating the diseases or conditions disclosed herein.

[0458] In some embodiments, the present invention provides the use of compounds of formula (I), (II) or (III) or their pharmaceutically acceptable salts for the manufacture of medicaments for the treatment or prevention of cancer in individuals in need.

[0459] In some embodiments, the present invention provides the use of compounds of formula (I), (II) or (III) or pharmaceutically acceptable salts thereof for the manufacture of medicaments for treating cancer in individuals in need.

[0460] In some embodiments, the present invention provides the use of compounds of formula (I), (II) or (III) or their pharmaceutically acceptable salts for the manufacture of medicaments for the treatment or prevention of breast cancer in individuals in need.

[0461] In some embodiments, the present invention provides the use of compounds of formula (I), (II) or (III) or pharmaceutically acceptable salts thereof for the manufacture of medicaments for the treatment of breast cancer in individuals in need.

[0462] In some embodiments, the present invention provides the use of compounds of formula (I), (II) or (III) or pharmaceutically acceptable salts thereof for the manufacture of medicaments for the treatment or prevention of prostate cancer in individuals in need.

[0463] In some embodiments, the present invention provides the use of compounds of formula (I), (II) or (III) or pharmaceutically acceptable salts thereof for the manufacture of medicaments for the treatment of prostate cancer in individuals in need.

[0464] In some embodiments, the present invention provides the use of compounds of formula (I), (II) or (III) or pharmaceutically acceptable salts thereof for the manufacture of medicaments for the treatment or prevention of brain cancer in individuals in need.

[0465] In some embodiments, the present invention provides the use of compounds of formula (I), (II) or (III) or pharmaceutically acceptable salts thereof for the manufacture of medicaments for the treatment of brain cancer in individuals in need.

[0466] This invention provides compounds that act as regulators of PI3K activity. Therefore, this invention provides a method for regulating PI3K activity in vitro or in vivo, the method comprising contacting cells with a therapeutically effective amount of the compound or a pharmaceutically acceptable salt thereof as defined herein.

[0467] In some embodiments, PI3K is regulated to PI3K suppression.

[0468] In some embodiments, the PI3K inhibitor is a PI3Kα inhibitor. In some embodiments, the PI3K inhibitor is a PI3Kα H1047R mutant inhibitor.

[0469] The effectiveness of the compounds of the present invention can be determined by industry-recognized analytical / disease models that explain the standard operating procedures described in this art and are found in current common knowledge.

[0470] The present invention also provides a method for treating a disease or condition involving PI3K activity in a patient requiring such treatment, the method comprising administering to the patient a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition, as defined herein. Administration route

[0471] Compounds of formula (I), (II) or (III) or pharmaceutical compositions containing such compounds may be administered to an individual by any convenient route of administration, whether systemic / peripheral or local (i.e., at the site of action).

[0472] Routes of administration include, but are not limited to, oral (e.g., by ingestion); buccal; sublingual; transdermal (e.g., by patches, ointments, etc.); transmucosal (e.g., by patches, ointments, etc.); intranasal (e.g., by nasal spray); ocular (e.g., by eye drops); pulmonary (e.g., by inhalation or blowing therapy, using, for example, via aerosols, such as through the mouth or nose); rectal (e.g., by suppositories or enemas); vaginal (e.g., by a pessary); non-intestinal, such as by injection, including subcutaneous, intradermal, intramuscular, intravenous, intraarticular, intracardiac, intrasheath, intraspinal, intrabursal, subbursal, intraorbital, intraperitoneal, intratracheal, subcutaneous, intra-articular, subarachnoid, and intrasternal; and by implantation of a drug depot or reservoir, such as subcutaneous or intramuscular. Examples

[0473] In the examples, illustrative compounds of formulas (I), (II), and (III) were synthesized and tested. It should be understood that compounds of formulas (I), (II), and (III) can be converted into the corresponding pharmaceutically acceptable salts of the compounds using conventional techniques in this art (e.g., by saponifying esters to carboxylates, or by hydrolyzing amides to form the corresponding carboxylic acids and subsequently converting the carboxylic acids to carboxylates).

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

[0475] LC-MS chromatograms and spectra were recorded using C-18 columns such as Luna-C18 2.0 x 30 mm or Xbridge Shield RPC18 2.1 x 50 mm, and an Agilent 1200 or Shimadzu LC-20 AD&MS 2020 instrument. Injection volumes ranged from 0.7 to 8.0 µl, and flow rates were typically 0.8 or 1.2 ml / min. Detection methods included diode array (DAD), evaporative light scattering (ELSD), and cation electrospray ionization. MS ranges were from 100 to 1000 Da. Solvents were water and acetonitrile, each containing a gradient of modifiers such as trifluoroacetic acid or ammonium carbonate (typically 0.01-0.04%).

[0476] Abbreviations: AcOH / HOAc Acetic acid ADP Adenosine diphosphate ATP Adenosine triphosphate CDCl3 Chloroform-d DCM Dichloromethane DIEA N,N-diisopropylethylamine DMF N,N-dimethylformamide DMSO Dimethyl sulfoxide DMSO-d6 Hexadeuterated dimethyl sulfoxide eq. Equivalent EtI Ethyl iodide EtOAc Ethyl acetate h Hours HEPES 4-(2-hydroxyethyl)-1-piperazine ethanesulfonic acid 1H NMR Proton nuclear magnetic resonance spectroscopy LC-MS Liquid chromatography-mass spectrometry MeOH Methanol min Minutes NaHMDS Bis(trimethylsilyl)amino sodium PIP2 Phosphatidylinositol 4,5-bisphosphate PPh3 Triphenylphosphine ppm Parts per million rt Room temperature TFA Trifluoroacetic acid THF Tetrahydrofuran Ti(i-PrO)4 Titanium isopropoxide (IV)

[0477] Intermediate 1: (2-bromo-4-methyl-phenyl)acetate

[0478] A mixture of 2-bromo-4-methylphenol (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 hours. The mixture was diluted with water (1500 mL), the pH was adjusted to 5 with HCl (2 M aqueous solution), and extracted with DCM (3 x 500 mL). The combined organic extracts were washed with brine (2 x 250 mL), dried over Na2SO4, filtered, and concentrated to give an oily product (400 g, crude product). 1H NMR (400 MHz, CDCl3) δ ppm 2.24 (s, 3 H), 2.25 (s, 3 H), 6.91 (d, J=8.4 Hz, 2 H), 7.01-7.02 (m, 2 H), 7.33 (s, 1 H).

[0479] Intermediate 2: 1-(3-bromo-2-hydroxy-5-methyl-phenyl) ethyl ketone

[0480] A mixture of (2-bromo-4-methyl-phenyl)acetate (50 g, 218 mmol) and AlCl3 (102 g, 764 mmol) was degassed, purged three times with N2, and stirred at 140 °C for 1 hour. After cooling to room temperature, the reactants were 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 Na2SO4, filtered, and concentrated. The residue was wet-milled with petroleum ether (2 × 150 mL) to give a solid product (30 g, 52%). 1H NMR (400 MHz, 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).

[0481] Intermediate 3: 8-Bromo-4-hydroxy-6-methyl-chromene-2-thione

[0482] A solution of 1-(3-bromo-2-hydroxy-5-methyl-phenyl)ethyl ketone (65 g, 284 mmol) in THF (800 mL) was treated with NaHMDS (851 mL, 1 M) at -50 °C for 30 min, allowing the temperature to rise between -5 °C and 0 °C, and stirred for 1 h. The reactants were cooled to -20 °C and treated dropwise with CS2 (64.8 g, 851 mmol) for 1 h, allowing the temperature to rise to 25 °C, and stirred for another 16 h. The reactants were quenched with H2SO4 (800 mL, 15%) at -50 °C for 1 h, allowing the temperature to rise to room temperature, and extracted with EtOAc (2 × 1 L). The combined organic extracts were washed with brine (1 L), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was wet-milled with EtOAc (0.5 L) to obtain a solid product (210 g crude product, 64%, purity approximately 76%).

[0483] Intermediate 4: 8-Bromo-2-ethylthio-6-methyl-chromene-4-one

[0484] A mixture of 20.0 g (73.8 mmol) of 8-bromo-4-hydroxy-6-methyl-chromene-2-thione, 46 g (295 mmol) of EtI, and 12.2 g (88.5 mmol) of K₂CO₃ in 200 mL of acetone was stirred at 60 °C for 3 hours. When the reaction mixture was cooled to room temperature, it was diluted with 200 mL of water and extracted with DCM (2 × 200 mL). The combined organic extracts were concentrated and purified by silica gel chromatography, and dissolved in 20% to 40% EtOAc / petroleum ether to give a gel-like product. 1H NMR (400 MHz, CDCl3) δ ppm 1.51 (t, J=7.2 Hz, 3 H), 2.45 (s, 3 H), 3.22 (q, J=7.2 Hz, 2 H), 6.32 (s, 1 H), 7.70 (s, 1 H), 7.93 (s, 1 H).

[0485] Intermediate 5: 8-acetyl-2-ethylthio-6-methyl-chromene-4-one

[0486] A mixture of 8-bromo-2-ethylthio-6-methylchromone-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 dimethyl ether (90 mL) was stirred at 95 °C for 16 hours. HCl (30 mL, 1 M) was added to the mixture and the mixture was stirred at 50 °C for 0.5 hours. When cooled to room temperature, the mixture was treated with 100 mL of saturated KF aqueous solution and stirred for 0.5 hours, followed by filtration. 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 silicone column dissolved in 0 to 60% EtOAc / petroleum ether to give a solid product (5.8 g, 60%). MS ES+m / z 263 [M+H]+.

[0487] Intermediate 6: 2-Ethylthio-8-(1-hydroxyethyl)-6-methyl-chromene-4-one

[0488] A solution of 8-acetyl-2-ethylthio-6-methyl-chromone-4-one (8.30 g, 31.6 mmol) in DCM (30 mL) and MeOH (30 mL) was treated fractionally with NaBH4 (1.32 g, 34.8 mmol) at 0 °C and stirred at 15 °C for 1 hour. 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 Na2SO4, filtered, and concentrated. The residue was purified on a silicone column dissociated with 0 to 4% MeOH / DCM to give a solid product (6.0 g, 60%). MS ES+m / z 265 [M+H]+.

[0489] Intermediate 7: 8-(1-bromoethyl)-2-ethylthio-6-methyl-chromene-4-one

[0490] A mixture of 2-ethylthio-8-(1-hydroxyethyl)-6-methyl-chromone-4-one (5.50 g, 20.8 mmol) in DCM (50 mL) was treated dropwise with PBr3 (16.9 g, 62.4 mmol) at 0 °C, followed by stirring at 30 °C for 4 h. The reaction mixture was quenched with water (20 mL) at 0 °C and the pH was adjusted to 8 with a saturated aqueous solution of NaHCO3. The mixture was extracted with DCM (2 × 80 mL). The combined organic extracts were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated to give an oily product (4.7 g, 61%). MS ES+m / z 329 [M+2+H]+.

[0491] Intermediate 8: 2-[1-(2-ethylthio-6-methyl-4-sideoxy-chromen-8-yl)ethylamino]benzoate, tert-butyl ester

[0492] 8-(1-bromoethyl)-2-ethylthio-6-methyl-chromone-4-one (25.0 g, 76.4 mmol), tributyl 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 reactants were partially concentrated to about 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 extracted again with fresh EtOAc. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated to give a viscous oil. The residue was purified by silica gel chromatography using EtOAc / DCM (0% to 10%) to give a grayish-white foam. Wet milling with heptane / DCM and washing with heptane yielded a white solid product (27.1 g, 81%). MS ES+m / z 440 [M+H]+.

[0493] Intermediate 9: 2-[1-[2-(6-isopropoxy-3-pyridyl)-6-methyl-4-sideoxy-chromen-8-yl]ethylamino]terephthalate

[0494] Teryl 2-[1-(2-ethylthio-6-methyl-4-sideoxy-chromene-8-yl)ethylamino]benzoate (0.100 g, 227 µmol), (6-isopropoxypyridin-3-yl) acid (82.4 mg, 455 µmol), zinc acetate (II) (83.5 mg, 455 µmol), tris(diphenylmethyleneacetone)dipalladium (O) (20.8 mg, 22.7 µmol), methylcopper thiophene-2-carboxylate (I) (86.8 mg, 455 µmol), and tris(2-furanyl)phosphine (26.4 mg, 114 µmol) were combined in THF (2 mL) and degassed with argon for 5 minutes. The reaction mixture was stirred overnight at 75°C. Silicone was added to the reactants and the mixture was concentrated. The product (0.151 g) was purified by silica gel chromatography using a gradient of EtOAc (0 to 100%) in heptane to obtain a product. MS ES+m / z 515 [M+H]+.

[0495] Intermediate 10: 2-[1-[2-(2-methoxypyrimidin-5-yl)-6-methyl-4-sideoxy-chromen-8-yl]ethylamino]terephthalate

[0496] Tributyl 2-[1-(2-ethylthio-6-methyl-4-sideoxy-chromene-8-yl)ethylamino]benzoate (200 mg, 455 µmol), (2-methoxypyrimidin-5-yl) acid (140 mg, 910 µmol), tris(diphenylmethyleneacetone)palladium(O) (42 mg, 46 µmol), cesium carbonate (445 mg, 1.365 mmol), and tris(2-furanyl)phosphine (10.6 mg, 46 µmol) were combined in 1,4-dimethylacetone (5 mL) and heated at 85 °C for 12 hours. The reaction mixture was filtered, concentrated, and purified by silica gel chromatography using a gradient of 10 to 80% ethyl acetate / heptane to give the product (90 mg, 41%). MS ES+m / z 488 [M+H]+.

[0497] Intermediate 11: Methyl 2-[1-(2-ethylthio-6-methyl-4-sideoxy-chromen-8-yl)ethylamino]benzoate

[0498] A mixture of 8-(1-bromoethyl)-2-ethylthio-6-methyl-chromene-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 x 100 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated. The residue was purified by silica gel chromatography with 0% to 27% EtOAc / petroleum ether to give a solid product (4.5 g, 84%). MS ES + m / z 398 [M + H] +.

[0499] Intermediate 12 and Intermediate 13: Methyl 2-[1-(2-ethylthio-6-methyl-4-sideoxy-chromen-8-yl)ethylamino]benzoate, isomer 1 and isomer 2

[0500] Methyl 2-[1-(2-ethylthio-6-methyl-4-sideoxy-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 w / 0.1% NH4OH: 70% CO2) to obtain the product isomer (4.3 g, 5.6 g) as a white solid. MS ES+m / z 398 [M+H]+, both present.

[0501] Intermediate 14: Methyl 2-[1-(6-methyl-4-sideoxy-2-pyrimidin-2-yl-chromen-8-yl)ethylamino]benzoate, isomer 2

[0502] A mixture of methyl 2-[1-(2-ethylthio-6-methyl-4-sideoxy-chromen-8-yl)ethylamino]benzoate, isomer 2 (300 mg, 754.74 μmol), tributyl(pyrimidin-2-yl)stanane (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 hours to give a brown suspension. The reaction mixture was cooled to room temperature, concentrated, and purified by rapid silica gel chromatography using a gradient of EtOAc (0 to 40%) / petroleum ether to give a pale yellow solid (150 mg, 48%). MS ES+m / z 416 [M+H]+.

[0503] Intermediate 15 and Intermediate 16: 2-[1-(2-ethylthio-6-methyl-4-sideoxy-chromen-8-yl)ethylamino]benzoate, isomer 1 and isomer 2

[0504] 2-[1-(2-ethylthio-6-methyl-4-sideoxy-chromen-8-yl)ethylamino]benzoate tributyl ester (22.04 g, 50.14 mmol) was separated into fractional isomers using a Chiralcel OJ column (8 × 34 cm; 20 μm) dissociated with 100% MeOH containing 0.2% DMEA, yielding isomer 1 (wet 11.3 g) and isomer 2 (wet 12.9 g). MS ES+ m / z 440 [M+H]+.

[0505] Intermediate 17 and Intermediate 18: 2-[1-(2-ethylthio-6-methyl-4-sideoxy-chromen-8-yl)ethylamino]benzoic acid, isomer 1 and isomer 2

[0506] The mixture of 8-(1-bromoethyl)-2-ethylthio-6-methyl-chromone-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 an aqueous solution of 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 an aqueous solution of HCl (2 M) to obtain a solid. After stirring for 0.5 hours, the mixture was filtered and the filter cake was purified by a gradient of 5 to 50% MeOH containing 0.1% NH3 aqueous solution / CO2 using a palmar SFC (Daicel ChiralCel OJ-H; 250 × 30 mm; 5 µm) to obtain isomer 1 (5.4 g; 45%, >99% ee) and isomer 2 (4.9 g, 41%, >99% ee). MS ES+m / z 384 [M+H]+, both present.

[0507] Intermediate 19: 2-[1-(2-ethylsulfinyl-6-methyl-4-sideoxy-chromen-8-yl)ethylamino]benzoic acid, isomer 2

[0508] A mixture of 2-[1-(2-ethylthio-6-methyl-4-sideoxy-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 N2. The reaction mixture was stirred at 25 °C for 2 h. The mixture was quenched at 0 °C with saturated Na2S2O3 (10 mL) 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 Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography with dissolution in 0 to 80% EtOAc / petroleum ether to give a product in solid form (410 mg, 42%). MS ES+ m / z 400 [M+H]+.

[0509] Intermediate 20: 2-[1-[6-methyl-4-sideoxy-2-(1H-pyrazol-4-yl)chromen-8-yl]ethylamino]benzoate, isomer 2

[0510] 2-[1-(2-ethylthio-6-methyl-4-sideoxy-chromene-8-yl)ethylamino]benzoate, isomer 2 (0.25 g, 0.57 mmol), (1H-pyrazol-4-yl) acid (0.19 g, 1.71 mmol), tris(diphenylmethyleneacetone)palladium(0) (0.052 g, 0.057 mmol), methylcopper(I) thiophene-2-carboxylate (0.22 g, 1.14 mmol), zinc(II) acetate (0.21 g, 1.14 mmol) and tris(2-furanyl)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) acid (0.19 g, 1.71 mmol) and triphenylmethyleneacetone dipalladium(0) (0.052 g, 0.057 mmol) were added and the mixture was heated at 95 °C for 24 h. The crude product mixture was quenched with water and concentrated. The residue was purified using a silicone column (0 to 15% ethyl acetate / heptane, followed by 5% methanol / DCM) and then by reverse-phase chromatography (10 to 100% acetonitrile / water with 0.1% TFA) to give the product (0.17 g, 57%). MS ES+m / z 446 [M+H]+.

[0511] Intermediate 21: 2-[1-[2-[1-(4-chlorophenyl)pyrazol-4-yl]-6-methyl-4-sideoxy-chromen-8-yl]ethylamino]tributyl benzoate, isomer 2

[0512] 2-[1-[6-methyl-4-sideoxy-2-(1H-pyrazol-4-yl)chromen-8-yl]ethylamino]benzoate tributyl ester, 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 iodide (I) (0.26 mg, 0.02 eq) and (1S,2S)-N1,N2-dimethylcyclohexane-1,2-diamine (1.9 mg, 0.2 eq) were combined in 1,4-dimethylethane (2 mL) and heated at 110 °C for 12 hours. 1-Chloro-4-iodobenzene (0.032 g, 0.13 mmol), potassium carbonate (0.020 g, 0.14 mmol), copper iodide (I) (0.26 mg, 0.02 eq), and (1S,2S)-N1,N2-dimethylcyclohexane-1,2-diamine (1.9 mg, 0.2 eq) were added, and the mixture was heated at 110 °C for 12 h. The crude product mixture was quenched with water and concentrated. Purification was performed by reverse-phase chromatography (10 to 100% acetonitrile / water with 0.1% TFA) to give the product (0.016 g, 38%). MS ES+m / z 556 [M+H]+.

[0513] Intermediate 22: 2-[1-(2-ethylthio-3-iodo-6-methyl-4-semi-oxy-chromen-8-yl)ethylamino]benzoate, isomer 2

[0514] Rinse a dry flask equipped with a stir bar and septum with argon gas, and then add 2-[1-(2-ethylthio-6-methyl-4-sideoxy-chromen-8-yl)ethylamino]benzoate, isomer 2 (1.00 g, 2.27 mmol) and 2 mL of anhydrous THF. Cool the reaction mixture in an ice bath. While cooling, add dropwise via a feeding funnel 2,2,6,6-tetramethylpiperidinylzinc chloride lithium chloride complex (1 M in THF, 1.93 g, 6.82 mmol) for 30 minutes. After the addition is complete, stir the reaction mixture at 0°C. After 1 hour, add dropwise via a feeding funnel iodine dissolved in anhydrous THF (1 M, 2.73 mL, 2.73 mmol). After addition, the reaction mixture was stirred at 0°C. After 1 hour, the reaction mixture was cooled to -40°C and quenched with methanol (10 mL). 50 mL of ammonium chloride / ammonia solution (2 M aqueous solution; 50 mL) was added and the reaction mixture was stirred at room temperature for 2 hours. Extraction was performed three times with 300 mL of dichloromethane. The organic matter was combined, washed with aqueous sodium carbonate solution, collected, dried over Na2SO4, filtered, and concentrated. The residue was purified by reverse-phase chromatography (C18) with dissolution in 0% to 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]+.

[0515] Intermediate 23: 2-[1-[2-ethylthio-6-methyl-4-sideoxy-3-(trifluoromethyl)chromen-8-yl]ethylamino]benzoate, isomer 2

[0516] Tributyl 2-[1-(2-ethylthio-3-iodo-6-methyl-4-sideoxy-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 combined in DMF (4 mL) and stirred at 75 °C for 6 hours. The reaction mixture was cooled to room temperature and diluted with ethyl acetate (30 mL). The organic matter was washed with water (3 × 15 mL) and concentrated. The residue was purified by a silicone column (0 to 100% ethyl acetate / heptane) to give the product (0.20 g, 71%). MS ES+m / z 508 [M+H]+.

[0517] Intermediate 24: 8-acetyl-2-[6-(difluoromethyl)-2-pyridyl]-3,6-dimethyl-chromene-4-one

[0518] Intermediate 24 can be prepared from the aforementioned intermediate. MS ES+m / z344 [M+H]+.

[0519] Intermediate 25: 2-[6-(difluoromethyl)-2-pyridyl]-8-[(1R)-1-hydroxyethyl]-3,6-dimethyl-chromene-4-one

[0520] A solution of 8-acetyl-2-[6-(difluoromethyl)-2-pyridyl]-3,6-dimethyl-chromene-4-one (0.50 g, 1.45 mmol), formic acid (0.21 g, 4.37 mmol), and RuCl (p-isopropyltoluene) [(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 mixture was stirred at room temperature for 12 hours and concentrated. The residue was purified by a silicone column (1:1 heptane:ethyl acetate) to give the product (0.41 g, 82%). MS ES+m / z346 [M+H]+.

[0521] Intermediate 26: 8-[(1S)-1-chloroethyl]-2-[6-(difluoromethyl)-2-pyridyl]-3,6-dimethyl-chromen-4-one

[0522] Stir a solution of trichloro[1,3,5]triazine (0.33 g, 1.78 mmol) in DMF (0.1 mL) at room temperature for 30 minutes. Add to this a solution of 2-[6-(difluoromethyl)-2-pyridyl]-8-[(1R)-1-hydroxyethyl]-3,6-dimethyl-chromone-4-one (0.41 g, 1.19 mmol) in DCM (10 mL). Stir the reaction mixture for 4 hours. Dilute with saturated aqueous sodium carbonate solution (100 mL) and DCM (20 mL). Separate the layers. Wash the organic matter with brine and concentrate. Purify the residue by a silicone column (2:1 heptane:ethyl acetate) to give the product (0.32 g, 74%, 89% ee). MS ES+m / z 364 [M+H]+.

[0523] Example 1: 2-[1-[2-(6-isopropoxy-3-pyridyl)-6-methyl-4-sideoxy-chromen-8-yl]ethylamino]benzoic acid 2,2,2-trifluoroacetic acid

[0524] Teryl 2-[1-[2-(6-isopropoxy-3-pyridyl)-6-methyl-4-sideoxy-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 purified directly using reverse-phase (C-18 column, 10 to 100% acetonitrile [0.1% TFA] in water [0.1% TFA]) to give the product as trifluoroacetate (0.052 g, 31%). MS ES+ m / z 459 [M+H]+.

[0525] Example 2: 2-[1-[2-(2-methoxypyrimidin-5-yl)-6-methyl-4-sideoxy-chromen-8-yl]ethylamino]benzoic acid 2,2,2-trifluoroacetic acid

[0526] A solution of 2-[1-[2-(2-methoxypyrimidin-5-yl)-6-methyl-4-sideoxy-chromen-8-yl]ethylamino]benzoate tributyl ester (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 hours. The reaction mixture was concentrated and purified using a C-18 column dissociated with 10 to 90% acetonitrile / water (0.1% TFA additive) to give the product as trifluoroacetate (28 mg). MS ES+m / z 432 [M+H]+.

[0527] Example 3: 2-[1-(6-methyl-4-sideoxy-2-pyrimidin-2-yl-chromen-8-yl)ethylamino]benzoic acid, isomer 2

[0528] 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-ethylthio-6-methyl-4-sideoxy-chromen-8-yl)ethylamino]benzoate, isomer 2 (100 mg, 240.71 μmol) in DCM (2 mL), and the mixture was stirred 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 the residue. The residue was purified by preparative HPLC using 0.225% formic acid as an additive to give a product as a pale yellow solid (6.65 mg; 6.9%). MS ES+m / z 402 [M+H]+.

[0529] Examples 4 and 5: 2-[1-[2-(2-methoxypyrimidin-5-yl)-6-methyl-4-sideoxy-chromen-8-yl]ethylamino]benzoic acid, isomer 1 and isomer 2

[0530] 2,2,2-trifluoroacetic acid (22 mg) of 2-[1-[2-(2-methoxypyrimidin-5-yl)-6-methyl-4-sideoxy-chromen-8-yl]ethylamino]benzoic acid was dissolved in MeOH (2.25 mL) and DCM (2.25 mL). The product isomers (8.3 mg and 8.3 mg) were obtained by supercritical fluid chromatography (Chiralpak AD-H, 150 mm × 21 mm; 30% EtOH w / 0.5% DMEA: 70% CO2). MS ES+m / z 432 [M+H]+, both present.

[0531] The following compounds in Table 1 can be prepared according to procedures 1 to 3 or the foregoing examples.

[0532] Table 1 Instance number Chemical name structure MS ES+ m / z 6 2-[1-[2-(2-isopropoxypyrimidin-5-yl)-6-methyl-4-sideoxy-chromen-8-yl]ethylamino]benzoic acid 2,2,2-trifluoroacetic acid 460 [M+H] + 7 2-[1-[6-methyl-2-(6-methanesulfonyl-3-pyridyl)-4-sideoxy-chromen-8-yl]ethylamino]benzoic acid 2,2,2-trifluoroacetic acid 479 [M+H] + 8 2-[1-[6-methyl-4-sideoxy-2-[6-(trifluoromethyl)-3-pyridyl]chromen-8-yl]ethylamino]benzoic acid 2,2,2-trifluoroacetic acid 469 [M+H] + 9 2-[1-[2-(6-fluoro-3-pyridyl)-6-methyl-4-sideoxy-chromen-8-yl]ethylamino]benzoic acid 2,2,2-trifluoroacetic acid 419 [M+H] + 10 2-[1-[2-(4-cyano-2-pyridyl)-6-methyl-4-sideoxy-chromen-8-yl]ethylamino]benzoic acid 2,2,2-trifluoroacetic acid 426 [M+H] + 11 2-[1-[2-(6-methoxy-2-pyridyl)-6-methyl-4-sideoxy-chromen-8-yl]ethylamino]benzoic acid 2,2,2-trifluoroacetic acid 431 [M+H] + 12 2-[1-[2-(6-methoxy-3-pyridyl)-6-methyl-4-sideoxy-chromen-8-yl]ethylamino]benzoic acid 2,2,2-trifluoroacetic acid 431 [M+H] + 13 2-[1-[6-methyl-2-(2-methylpyrimidin-5-yl)-4-sideoxy-chromen-8-yl]ethylamino]benzoic acid 2,2,2-trifluoroacetic acid 416 [M+H] + 14 2-[1-[6-methyl-4-sideoxy-2-(3-pyridyl)chromen-8-yl]ethylamino]benzoic acid, isomer 2 401 [M+H] + 15 2-[1-(6-methyl-4-sideoxy-2-pyridine-2-yl-chromene-8-yl)ethylamino]benzoic acid, isomer 1 402 [M+H] + 16 2-[1-(6-methyl-4-sideoxy-2-pyridine-2-yl-chromene-8-yl)ethylamino]benzoic acid, isomer 2 402 [M+H] + 17 2-[1-[6-methyl-4-sideoxy-2-(2-pyridyl)chromen-8-yl]ethylamino]benzoic acid, isomer 1 401 [M+H] + 18 2-[1-[6-methyl-4-sideoxy-2-(2-pyridyl)chromen-8-yl]ethylamino]benzoic acid, isomer 2 401 [M+H] + 19 2-[1-[2-(6-methoxy-3-pyridyl)-6-methyl-4-sideoxy-chromen-8-yl]ethylamino]benzoic acid, isomer 1 431 [M+H] + 20 2-[1-[2-(6-methoxy-3-pyridyl)-6-methyl-4-sideoxy-chromen-8-yl]ethylamino]benzoic acid, isomer 2 431 [M+H] + twenty one 2-[1-[2-(6-methoxy-2-pyridyl)-6-methyl-4-sideoxy-chromen-8-yl]ethylamino]benzoic acid, isomer 1 431 [M+H] + twenty two 2-[1-[2-(6-methoxy-2-pyridyl)-6-methyl-4-sideoxy-chromen-8-yl]ethylamino]benzoic acid, isomer 2 431 [M+H] + twenty three 2-[1-[2-(5-fluoro-2-pyridyl)-6-methyl-4-sideoxy-chromen-8-yl]ethylamino]benzoic acid 2,2,2-trifluoroacetic acid 419 [M+H] + twenty four 2-[1-[3,6-dimethyl-4-sideoxy-2-(2-pyridyl)chromen-8-yl]ethylamino]benzoic acid, isomer 1 415 [M+H] + 25 2-[1-[3,6-dimethyl-4-sideoxy-2-(3-pyridyl)chromen-8-yl]ethylamino]benzoic acid, isomer 1 415 [M+H] + 26 2-[1-[2-(2-cyclopropylpyrimidin-5-yl)-6-methyl-4-sideoxy-chromen-8-yl]ethylamino]benzoic acid, isomer 2 442 [M+H] + 27 6-Chloro-3-[1-[6-methyl-4-sideoxy-2-(2-pyridyl)chromen-8-yl]ethylamino]pyridine-2-carboxylic acid, isomer 1 436 [M+H] + 28 6-Chloro-3-[1-(6-methyl-4-sideoxy-2-pyridine-2-yl-chromene-8-yl)ethylamino]pyridine-2-carboxylic acid, isomer 1 437 [M+H] + 29 2-[1-[6-methyl-2-(3-methylpyridine-2-yl)-4-sideoxy-chromene-8-yl]ethylamino]benzoic acid, isomer 2 416 [M+H] + 30 2-[1-[2-(6-isopropoxy-3-pyridyl)-6-methyl-4-sideoxy-chromen-8-yl]ethylamino]benzoic acid, isomer 1 459 [M+H] + 31 2-[1-[2-(6-isopropoxy-3-pyridyl)-6-methyl-4-sideoxy-chromen-8-yl]ethylamino]benzoic acid, isomer 2 459 [M+H] + 32 2-[1-[6-methyl-2-(2-methylpyrimidin-5-yl)-4-sideoxy-chromen-8-yl]ethylamino]benzoic acid, isomer 1 416 [M+H] + 33 2-[1-[6-methyl-2-(2-methylpyrimidin-5-yl)-4-sideoxy-chromen-8-yl]ethylamino]benzoic acid, isomer 2 416 [M+H] + 34 2-[1-(3,6-dimethyl-4-sideoxy-2-pyrimidin-2-yl-chromene-8-yl)ethylamino]benzoic acid, isomer 1 416 [M+H] + 35 2-[1-[2-(6-fluoro-3-pyridyl)-6-methyl-4-sideoxy-chromen-8-yl]ethylamino]benzoic acid, isomer 1 419 [M+H] + 36 2-[1-[2-(6-fluoro-3-pyridyl)-6-methyl-4-sideoxy-chromen-8-yl]ethylamino]benzoic acid, isomer 2 419 [M+H] + 37 2-[1-[6-methyl-4-sideoxy-2-[6-(trifluoromethyl)-3-pyridyl]chromen-8-yl]ethylamino]benzoic acid, isomer 1 469 [M+H] + 38 2-[1-[6-methyl-4-sideoxy-2-[6-(trifluoromethyl)-3-pyridyl]chromen-8-yl]ethylamino]benzoic acid, isomer 2 469 [M+H] + 39 2-[1-[6-methyl-2-(6-methanesulfonyl-3-pyridyl)-4-sideoxy-chromen-8-yl]ethylamino]benzoic acid, isomer 1 479 [M+H] + 40 2-[1-[6-methyl-2-(6-methanesulfonyl-3-pyridyl)-4-sideoxy-chromene-8-yl]ethylamino]benzoic acid, isomer 2 479 [M+H] + 41 2-[1-[2-(2-isopropoxypyrimidin-5-yl)-6-methyl-4-sideoxy-chromen-8-yl]ethylamino]benzoic acid, isomer 1 460 [M+H] + 42 2-[1-[2-(2-isopropoxypyrimidin-5-yl)-6-methyl-4-sideoxy-chromene-8-yl]ethylamino]benzoic acid, isomer 2 460 [M+H] + 43 2-[1-[2-(4-methoxy-2-pyridyl)-6-methyl-4-sideoxy-chromen-8-yl]ethylamino]benzoic acid, isomer 2,2,2,2-trifluoroacetic acid 431 [M+H] + 44 2-[1-[2-(5-fluoro-3-pyridyl)-6-methyl-4-sideoxy-chromen-8-yl]ethylamino]benzoic acid, isomer 2,2,2,2-trifluoroacetic acid 419 [M+H] + 45 2-[1-[2-(5-fluoro-3-pyridyl)-3,6-dimethyl-4-sideoxy-chromen-8-yl]ethylamino]benzoic acid, isomer 1 433 [M+H] + 46 2-[1-[6-fluoro-4-sideoxy-2-(2-pyridyl)chromen-8-yl]ethylamino]benzoic acid, isomer 1,2,2,2-trifluoroacetic acid 405 [M+H] + 47 2-[1-[6-methyl-2-(1-methylpyrazol-4-yl)-4-sideoxy-chromene-8-yl]ethylamino]benzoic acid 404 [M+H] + 48 2-[1-[6-methyl-4-sideoxy-2-[1-(3-pyridyl)pyrazol-4-yl]chromen-8-yl]ethylamino]benzoic acid 2,2,2-trifluoroacetic acid 467 [M+H] + 49 2-[1-[6-methyl-4-sideoxy-2-[1-(3-pyridyl)pyrazol-4-yl]chromen-8-yl]ethylamino]benzoic acid, isomer 1 467 [M+H] + 50 2-[1-[6-methyl-4-sideoxy-2-[1-(3-pyridyl)pyrazol-4-yl]chromen-8-yl]ethylamino]benzoic acid, isomer 2 467 [M+H] + 51 2-[1-[6-methyl-4-sideoxy-2-(1H-pyrazol-4-yl)chromen-8-yl]ethylamino]benzoic acid, isomer 2,2,2,2-trifluoroacetic acid 390 [M+H] + 52 2-[1-[2-[1-(difluoromethyl)pyrazol-4-yl]-6-methyl-4-sideoxy-chromene-8-yl]ethylamino]benzoic acid, isomer 2,2,2,2-trifluoroacetic acid 440 [M+H] + 53 2-[1-[2-[1-(3-methoxyphenyl)pyrazol-4-yl]-6-methyl-4-sideoxy-chromen-8-yl]ethylamino]benzoic acid, isomer 2,2,2,2-trifluoroacetic acid 496 [M+H] + 54 2-[1-[2-[1-(3-cyanophenyl)pyrazol-4-yl]-6-methyl-4-sideoxy-chromene-8-yl]ethylamino]benzoic acid, isomer 2,2,2,2-trifluoroacetic acid 491 [M+H] + 55 2-[1-[6-fluoro-4-sideoxy-2-[1-(3-pyridyl)pyrazol-4-yl]chromen-8-yl]ethylamino]benzoic acid, isomer 1,2,2,2-trifluoroacetic acid 471 [M+H] + 56 2-[1-[6-methyl-4-sideoxy-2-(6-sideoxy-1H-pyroxy-3-yl)chromen-8-yl]ethylamino]methyl benzoate, isomer 2 432 [M+H] + 60 6-Chloro-3-[1-[3,6-dimethyl-4-sideoxy-2-(2-pyridyl)chromen-8-yl]ethylamino]pyridine-2-carboxylic acid, isomer 1 450 [M+H] + 61 6-Chloro-3-[1-[3-methyl-4-sideoxy-2-(2-pyridinyl)-6-(trifluoromethyl)chromen-8-yl]ethylamino]pyridine-2-carboxylic acid, isomer 1 504 [M+H] + 62 6-Chloro-3-[1-[4-Semi-oxy-2-(2-pyridinyl)-6-(trifluoromethyl)chromen-8-yl]ethylamino]pyridine-2-carboxylic acid, isomer 1 490 [M+H] + 63 2-[1-[3,6-dimethyl-4-sideoxy-2-[1-(3-pyridyl)pyrazol-4-yl]chromen-8-yl]ethylamino]benzoic acid, isomer 1,2,2,2-trifluoroacetic acid 481 [M+H] + 64 2-[1-[2-[1-(4-cyanophenyl)pyrazol-4-yl]-6-methyl-4-sideoxy-chromen-8-yl]ethylamino]benzoic acid, isomer 2,2,2,2-trifluoroacetic acid 491 [M+H] + 65 2-[1-[2-(6-methoxy-3-pyridyl)-3,6-dimethyl-4-sideoxy-chromen-8-yl]ethylamino]benzoic acid, isomer 1,2,2,2-trifluoroacetic acid 445 [M+H] + 66 2-[1-[2-[1-(3-methoxyphenyl)pyrazol-4-yl]-3,6-dimethyl-4-sideoxy-chromene-8-yl]ethylamino]benzoic acid, isomer 1,2,2,2-trifluoroacetic acid 510 [M+H] + 67 2-[1-[6-methyl-4-sideoxy-2-(2-pyridyl)-3-(trifluoromethyl)chromen-8-yl]ethylamino]benzoic acid, isomer 1,2,2,2-trifluoroacetic acid 469 [M+H] + 68 2-[1-[6-fluoro-3-methyl-4-sideoxy-2-(2-pyridyl)chromen-8-yl]ethylamino]benzoic acid, isomer 1,2,2,2-trifluoroacetic acid 419 [M+H] + 69 2-[1-[2-[1-(4-methoxyphenyl)pyrazol-4-yl]-3,6-dimethyl-4-sideoxy-chromene-8-yl]ethylamino]benzoic acid, isomer 1,2,2,2-trifluoroacetic acid 510 [M+H] + 70 2-[1-[2-[1-(2-methoxyphenyl)pyrazol-4-yl]-3,6-dimethyl-4-sideoxy-chromene-8-yl]ethylamino]benzoic acid, isomer 1,2,2,2-trifluoroacetic acid 510 [M+H] + 71 2-[1-[2-[6-(difluoromethyl)-2-pyridyl]-6-methyl-4-sideoxy-chromen-8-yl]ethylamino]benzoic acid, isomer 2 451 [M+H] + 72 2-[1-[2-[1-(2-methoxypyrimidin-5-yl)pyrazol-4-yl]-3,6-dimethyl-4-sideoxy-chromene-8-yl]ethylamino]benzoic acid, isomer 1,2,2,2-trifluoroacetic acid 512 [M+H] + 73 2-[1-[2-[1-(4-cyanophenyl)pyrazol-4-yl]-3,6-dimethyl-4-sideoxy-chromene-8-yl]ethylamino]benzoic acid, isomer 1,2,2,2-trifluoroacetic acid 505 [M+H] + 74 2-[1-[2-[1-(3-cyanophenyl)pyrazol-4-yl]-3,6-dimethyl-4-sideoxy-chromene-8-yl]ethylamino]benzoic acid, isomer 1,2,2,2-trifluoroacetic acid 505 [M+H] + 75 2-[1-[6-methyl-2-(3-methyl-1H-pyrazol-5-yl)-4-sideoxy-chromene-8-yl]ethylamino]benzoic acid, isomer 2,2,2,2-trifluoroacetic acid 404 [M+H] + 76 2-[1-[4-Semi-oxy-2-(2-pyridyl)-6-(trifluoromethyl)chromen-8-yl]ethylamino]benzoic acid, isomer 1 455 [M+H] + 77 2-[1-[2-[6-(difluoromethyl)-2-pyridyl]-3,6-dimethyl-4-sideoxy-chromen-8-yl]ethylamino]benzoic acid, isomer 1,2,2,2-trifluoroacetic acid 465 [M+H] + 78 3-Chloro-2-fluoro-6-[1-[6-methyl-4-sideoxy-2-(2-pyridyl)chromen-8-yl]ethylamino]benzoic acid, isomer 1 453 [M+H] + 79 2-[1-[2-[1-(4-methoxyphenyl)pyrazol-4-yl]-6-methyl-4-sideoxy-chromene-8-yl]ethylamino]benzoic acid, isomer 2,2,2,2-trifluoroacetic acid 496 [M+H] + 80 2-[1-[6-methyl-4-sideoxy-2-(1-phenylpyrazol-4-yl)chromen-8-yl]ethylamino]benzoic acid, isomer 2,2,2,2-trifluoroacetic acid 466 [M+H] + 81 2-[1-[2-[1-(6-methoxy-3-pyridyl)pyrazol-4-yl]-6-methyl-4-sideoxy-chromene-8-yl]ethylamino]benzoic acid, isomer 2,2,2,2-trifluoroacetic acid 497 [M+H] + 82 2-[1-[2-[1-(6-cyano-3-pyridyl)pyrazol-4-yl]-6-methyl-4-sideoxy-chromene-8-yl]ethylamino]benzoic acid, isomer 2,2,2,2-trifluoroacetic acid 492 [M+H] + 83 2-[1-[2-[1-(5-cyano-2-pyridyl)pyrazol-4-yl]-6-methyl-4-sideoxy-chromene-8-yl]ethylamino]benzoic acid, isomer 2,2,2,2-trifluoroacetic acid 492 [M+H] + 84 2-[1-[2-[5-(3-methoxyphenyl)-1,3,4-diazol-2-yl]-6-methyl-4-sideoxy-chromen-8-yl]ethylamino]benzoic acid, isomer 2 498 [M+H] + 85 2-[1-[2-[1-(4-cyano-3-fluoro-phenyl)pyrazol-4-yl]-6-methyl-4-sideoxy-chromene-8-yl]ethylamino]benzoic acid, isomer 2,2,2,2-trifluoroacetic acid 509 [M+H] + 86 2-[1-[2-[1-(3-cyano-4-methoxy-phenyl)pyrazol-4-yl]-6-methyl-4-sideoxy-chromene-8-yl]ethylamino]benzoic acid, isomer 2,2,2,2-trifluoroacetic acid 521 [M+H] + 87 2-[1-[6-methyl-4-sideoxy-2-[1-[4-(trifluoromethyl)phenyl]pyrazol-4-yl]chromen-8-yl]ethylamino]benzoic acid, isomer 2,2,2,2-trifluoroacetic acid 534 [M+H] + 88 2-[1-[6-methyl-2-[1-(4-methanesulfonylphenyl)pyrazol-4-yl]-4-sideoxy-chromene-8-yl]ethylamino]benzoic acid, isomer 2,2,2,2-trifluoroacetic acid 544 [M+H] + 89 2-[1-[2-[6-(1-cyanocyclopropyl)-3-pyridyl]-3,6-dimethyl-4-sideoxy-chromen-8-yl]ethylamino]benzoic acid, isomer 1,2,2,2-trifluoroacetic acid 480 [M+H] + 90 2-[1-[2-[5-(4-cyanophenyl)-1,3,4-diazol-2-yl]-6-methyl-4-sideoxy-chromen-8-yl]ethylamino]benzoic acid, isomer 2 493 [M+H] + 91 2-[1-[2-[1-(2,2-difluoro-1,3-benzodioxacyclopenten-5-yl)pyrazol-4-yl]-6-methyl-4-sideoxy-chromen-8-yl]ethylamino]benzoic acid, isomer 2,2,2,2-trifluoroacetic acid 546 [M+H] + 92 2-[1-[2-[1-(3-fluoro-4-methoxy-phenyl)pyrazol-4-yl]-6-methyl-4-sideoxy-chromen-8-yl]ethylamino]benzoic acid, isomer 2,2,2,2-trifluoroacetic acid 514 [M+H] + 93 2-[1-[6-methyl-4-sideoxy-2-[1-[4-(trifluoromethoxy)phenyl]pyrazol-4-yl]chromen-8-yl]ethylamino]benzoic acid, isomer 2,2,2,2-trifluoroacetic acid 550 [M+H] + 94 2-[1-[2-[1-(4-cyano-3-methoxy-phenyl)pyrazol-4-yl]-6-methyl-4-sideoxy-chromene-8-yl]ethylamino]benzoic acid, isomer 2,2,2,2-trifluoroacetic acid 521 [M+H] + 95 2,3-Difluoro-6-[1-[2-[1-(4-cyanophenyl)pyrazol-4-yl]-6-methyl-4-sideoxy-chromen-8-yl]ethylamino]benzoic acid, isomer 1,2,2,2-trifluoroacetic acid 527 [M+H] + 96 6-Chloro-3-[1-[2-[1-(4-cyanophenyl)pyrazol-4-yl]-4-sideoxy-6-(trifluoromethyl)chromen-8-yl]ethylamino]pyridine-2-carboxylic acid, isomer 1 580 [M+H] + 97 6-Chloro-3-[1-[2-(5-fluoro-3-pyridyl)-3-methyl-4-sideoxy-6-(trifluoromethyl)chromen-8-yl]ethylamino]pyridine-2-carboxylic acid, isomer 1 522 [M+H] + 98 2-[1-[2-[1-(3-methoxyphenyl)triazol-4-yl]-6-methyl-4-sideoxy-chromen-8-yl]ethylamino]benzoic acid, isomer 2 497 [M+H] + 99 2-[1-[2-[1-(4-cyanophenyl)pyrazol-4-yl]-4-sideoxy-6-(trifluoromethyl)chromen-8-yl]ethylamino]benzoic acid, isomer 1 545 [M+H] + 100 2-Fluoro-6-[1-[6-methyl-4-sideoxy-2-(2-pyridyl)chromen-8-yl]ethylamino]benzoic acid 2,2,2-trifluoroacetic acid 419 [M+H] + 101 2-[1-[2-[1-(4-cyanophenyl)pyrazol-4-yl]-6-methyl-4-sideoxy-chromen-8-yl]ethylamino]-6-fluorobenzoic acid 2,2,2-trifluoroacetic acid 509 [M+H] + 102 2-[1-[2-[2-(3-hydroxy-3-methyl-but-1-ynyl)pyrimidin-5-yl]-6-methyl-4-sideoxy-chromen-8-yl]ethylamino]benzoic acid, isomer 2,2,2,2-trifluoroacetic acid 484 [M+H] + 103 2-[1-[2-[1-(4-cyanophenyl)imidazol-4-yl]-6-methyl-4-sideoxy-chromen-8-yl]ethylamino]benzoic acid, isomer 2,2,2,2-trifluoroacetic acid 491 [M+H] + 104 2-[1-[2-[1-(4-cyano-2-fluoro-phenyl)pyrazol-4-yl]-6-methyl-4-sideoxy-chromene-8-yl]ethylamino]benzoic acid, isomer 2,2,2,2-trifluoroacetic acid 509 [M+H] + 105 2-[1-[2-[1-(2-methoxypyrimidin-5-yl)pyrazol-4-yl]-6-methyl-4-sideoxy-chromene-8-yl]ethylamino]benzoic acid, isomer 2,2,2,2-trifluoroacetic acid 498 [M+H] + 106 2-[1-[2-[1-(4-chlorophenyl)pyrazol-4-yl]-6-methyl-4-sideoxy-chromene-8-yl]ethylamino]benzoic acid, isomer 2,2,2,2-trifluoroacetic acid 500 [M+H] + 107 2-[[(1R)-1-[2-[1-(2-cyanophenyl)pyrazol-4-yl]-6-methyl-4-sideoxy-chromen-8-yl]ethylamino]benzoic acid, isomer 2,2,2,2-trifluoroacetic acid 491 [M+H] + 108 2-[1-[6-methyl-4-sideoxy-2-[1-(2-pyridyl)pyrazol-4-yl]chromen-8-yl]ethylamino]benzoic acid, isomer 2,2,2,2-trifluoroacetic acid 467 [M+H] + 109 2-[1-[2-[1-(4-cyanophenyl)-3-methylpyrazol-4-yl]-6-methyl-4-sideoxy-chromen-8-yl]ethylamino]benzoic acid, isomer 2,2,2,2-trifluoroacetic acid 505 [M+H] + 110 2-Fluoro-6-[1-[6-methyl-4-sideoxy-2-(2-pyridyl)chromen-8-yl]ethylamino]benzoic acid, isomer 1 419 [M+H] + 111 2-Fluoro-6-[1-[6-methyl-4-sideoxy-2-(2-pyridyl)chromen-8-yl]ethylamino]benzoic acid, isomer 2 419 [M+H] + 112 2-[1-[2-[1-(4-cyanophenyl)pyrazol-4-yl]-6-methyl-4-sideoxy-chromen-8-yl]ethylamino]-6-fluorobenzoic acid, isomer 1 509 [M+H] + 113 2-[1-[2-[1-(4-cyanophenyl)pyrazol-4-yl]-6-methyl-4-sideoxy-chromen-8-yl]ethylamino]-6-fluorobenzoic acid, isomer 2 509 [M+H] + 114 6-[1-[2-[1-(4-cyanophenyl)pyrazol-4-yl]-6-methyl-4-sideoxy-chromen-8-yl]ethylamino]-2,3-difluorobenzoic acid, isomer 1 527 [M+H] + 115 6-Chloro-3-[1-[3,6-dimethyl-4-sideoxy-2-(3-pyridyl)chromen-8-yl]ethylamino]pyridine-2-carboxylic acid, isomer 1 450 [M+H] + 116 3-[1-[3,6-dimethyl-4-sideoxy-2-(3-pyridyl)chromen-8-yl]ethylamino]pyridine-2-carboxylic acid, isomer 1 416 [M+H] + 117 3-[1-[3,6-dimethyl-4-sideoxy-2-(3-pyridyl)chromen-8-yl]ethylamino]-6-(trifluoromethyl)pyridine-2-carboxylic acid, isomer 1 484 [M+H] + 118 3-[1-[3,6-dimethyl-4-sideoxy-2-(3-pyridyl)chromen-8-yl]ethylamino]-6-methyl-pyridin-2-carboxylic acid, isomer 1 430 [M+H] + 119 2-[1-[3,6-dimethyl-4-sideoxy-2-(3-pyridyl)chromen-8-yl]ethylamino]-5-(trifluoromethyl)benzoic acid, isomer 1 483 [M+H] + 120 2-[1-[3,6-dimethyl-4-sideoxy-2-(3-pyridyl)chromen-8-yl]ethylamino]-5-fluorobenzoic acid, isomer 1 433 [M+H] + 121 6-Chloro-3-[1-[3,6-dimethyl-4-sideoxy-2-(2-pyridyl)chromen-8-yl]ethylamino]pyridine-2-carboxylic acid, isomer 1,2,2,2-trifluoroacetic acid 450 [M+H] + 122 3-[1-[3,6-dimethyl-4-sideoxy-2-(2-pyridyl)chromen-8-yl]ethylamino]-6-methyl-pyridin-2-carboxylic acid, isomer 1 430 [M+H] + 123 3-[1-[2-(5-fluoro-3-pyridyl)-3,6-dimethyl-4-sideoxy-chromen-8-yl]ethylamino]-6-methyl-pyridin-2-carboxylic acid, isomer 1 448 [M+H] + 124 2-[1-[2-[1-(4-cyanophenyl)triazol-4-yl]-6-methyl-4-sideoxy-chromen-8-yl]ethylamino]benzoic acid, isomer 2,2,2,2-trifluoroacetic acid 492 [M+H] + 125 2-[1-[2-(5-cyano-3-pyridyl)-3,6-dimethyl-4-sideoxy-chromen-8-yl]ethylamino]benzoic acid, isomer 1,2,2,2-trifluoroacetic acid 440 [M+H] + 126 2-[1-[3,6-dimethyl-4-sideoxy-2-(2-phenylthiazolyl-5-yl)chromen-8-yl]ethylamino]benzoic acid, isomer 1,2,2,2-trifluoroacetic acid 497 [M+H] + 127 2-[1-[3,6-dimethyl-4-sideoxy-2-(5-pyrazol-1-yl-3-pyridyl)chromen-8-yl]ethylamino]benzoic acid, isomer 1,2,2,2-trifluoroacetic acid 481 [M+H] + 128 6-[1-[3,6-dimethyl-4-sideoxy-2-(2-pyridyl)chromen-8-yl]ethylamino]-2,3-difluorobenzoic acid, isomer 1 451 [M+H] + 129 6-Bromo-3-[1-[3,6-dimethyl-4-sideoxy-2-(3-pyridyl)chromen-8-yl]ethylamino]pyridine-2-carboxylic acid, isomer 1 496 [M+H] + 130 2-[1-[2-[2-(dimethylamino)thiazolyl-5-yl]-3,6-dimethyl-4-sideoxy-chromene-8-yl]ethylamino]benzoic acid, isomer 1 464 [M+H] + 131 3-[1-[2-(5-fluoro-3-pyridyl)-3,6-dimethyl-4-sideoxy-chromen-8-yl]ethylamino]pyridine-2-carboxylic acid, isomer 1 434 [M+H] + 132 5-Chloro-2-[1-[3,6-dimethyl-4-sideoxy-2-(3-pyridyl)chromen-8-yl]ethylamino]benzoic acid, isomer 1 449 [M+H] + 133 2-[1-[2-[1-(3,4-dimethoxyphenyl)triazol-4-yl]-6-methyl-4-sideoxy-chromen-8-yl]ethylamino]benzoic acid, isomer 2,2,2,2-trifluoroacetic acid 527 [M+H] + 134 2-[1-[2-[3-(3,4-dimethoxyphenyl)triazol-4-yl]-6-methyl-4-sideoxy-chromene-8-yl]ethylamino]benzoic acid, isomer 2,2,2,2-trifluoroacetic acid 527 [M+H] + 135 2-[1-[2-[6-(1-cyanocyclopropyl)-3-pyridyl]-3,6-dimethyl-4-sideoxy-chromen-8-yl]ethylamino]benzoic acid, isomer 1 480 [M+H] + 136 2-[1-[3,6-dimethyl-2-(1-methylpyrazol-4-yl)-4-sideoxy-chromene-8-yl]ethylamino]benzoic acid, isomer 1 418 [M+H] + 137 3-[1-[2-[6-(difluoromethyl)-2-pyridyl]-3,6-dimethyl-4-sideoxy-chromen-8-yl]ethylamino]-6-methyl-pyridin-2-carboxylic acid, isomer 1 480 [M+H] + 138 6-Chloro-3-[1-[2-(5-fluoro-3-pyridyl)-3,6-dimethyl-4-sideoxy-chromen-8-yl]ethylamino]pyridine-2-carboxylic acid, isomer 1 468 [M+H] + 139 3-[1-[2-[6-(difluoromethyl)-2-pyridyl]-3,6-dimethyl-4-sideoxy-chromen-8-yl]ethylamino]pyridine-2-carboxylic acid; 2,2,2-trifluoroacetic acid, isomer 1 466 [M+H] + 140 2-[1-[3,6-dimethyl-4-sideoxy-2-(2-pyridyl)chromen-8-yl]ethylamino]-6-fluorobenzoic acid, isomer 1 433 [M+H] + 141 6-Chloro-3-[1-[2-[6-(difluoromethyl)-2-pyridyl]-3,6-dimethyl-4-sideoxy-chromen-8-yl]ethylamino]pyridine-2-carboxylic acid, isomer 1 500 [M+H] +

[0533] Example 57: 2-[1-[6-methyl-4-sideoxy-2-(triazol-2-yl)chromen-8-yl]ethylamino]benzoic acid, isomer 2,2,2,2-trifluoroacetic acid

[0534] 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-sideoxy-chromene-8-yl)ethylamino]benzoic acid, isomer 2 (150 mg, 0.38 mmol). A yellow suspension was stirred at room temperature. After 30 min, the suspension was treated with 1.5 mL of DMF to dissolve it. After 5 minutes, the reactants were concentrated and dissolved in water (1 mL) and acetonitrile (2.3 mL), and purified using reverse-phase (C-18 column, 10 to 100% acetonitrile [0.1% TFA] in water [0.1% TFA]) to give the product as trifluoroacetate (30 mg, 15%). MS ES+m / z 391 [M+H]+.

[0535] The following compounds in Table 2 can be prepared according to procedures 1 to 3 or the aforementioned examples. Table 2 Instance number Chemical name structure MS ES+ m / z 58 2-[1-(6-methyl-4-sideoxy-2-pyrazol-1-yl-chromene-8-yl)ethylamino]benzoic acid, isomer 2,2,2,2-trifluoroacetic acid 390 [M+H] + 59 2-[1-(2-imidazol-1-yl-6-methyl-4-sideoxy-chromen-8-yl)ethylamino]benzoic acid, isomer 2,2,2,2-trifluoroacetic acid 390 [M+H] +

[0536] Example 142: 2-[[(1R)-1-[2-[6-(difluoromethyl)-2-pyridyl]-3,6-dimethyl-4-sideoxy-chromen-8-yl]ethyl]amino]benzoic acid

[0537] A solution of 8-[(1S)-1-chloroethyl]-2-[6-(difluoromethyl)-2-pyridyl]-3,6-dimethyl-chromene-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 mixture was stirred under reflux for 2 hours, cooled to room temperature, and concentrated. It was diluted with DCM (20 mL) and 0.1 M hydrochloric acid aqueous solution (10 mL). The layers were separated. The organic matter was washed with brine and concentrated. The residue was purified by a silicone column (20:1 DCM:MeOH) to give the product (0.15...

Claims

1. A compound of the following formula: or its isomer, hydrate, or pharmaceutically acceptable salt, wherein: R is -H or C1-C3 alkyl; R1 is a group of the following formula:; R2 is a group of the following formula:; or R2 is a substituted 5-membered heteroaryl group selected from pyrrole, furan, thiophene, pyrazole, isothiazolium, isothiazole, imidazole, acetazole, thiazole, triazole, tetraazole, acediazole, and thiadiazole; wherein the substituted 5-membered heteroaryl group is substituted by one to three substituents selected independently from the following: -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R 11. -C(O)OC1-C3 alkyl, -CONR11R11, -NR11R11, -NR11CO2R11, -OH, C1-C6 alkyl (subject to substitution), C2-C6 alkenyl (subject to substitution), C2-C6 alkynyl (subject to substitution), C3-C5 cycloalkyl (subject to substitution), heterocyclic (subject to substitution) selected from pyrrolidine, pyrrolidone, piperidine or morpholine, phenyl (subject to substitution), etc. The alternative is 1,3-benzodioxane, or optionally substituted 2,3-dihydro-1,4-benzodioxane, or optionally substituted heteroaryl groups selected from pyridine, pyrimidine, pyrazine, pyridine, pyrazine, pyrazole, isothiazolium, isothiazole, imidazole, thiazolium, or thiazole; wherein the optionally substituted C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl group is optionally prefixed with -CN, -OH, oxetyl, C1-C3 alkoxy, or -CON. R11R11 substitution; the substituted C3-C5 cycloalkyl, phenyl, 1,3-benzodioxane, 2,3-dihydro-1,4-benzodioxane, heterocyclic or heteroaryl group is substituted, as appropriate, by one or three substituents independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -SO2R11, -NR11R11, -OH or -CN; R3 is -H, halogen, -CN, -N(H)(C1-C3 alkyl), -N(C1-C3 alkyl)2, -N(H)(CH2CH2CO2H), -C(O)C1-C3 alkyl, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C3-C5 cycloalkyl, a heterocycle containing, as appropriate, 3 to 5 ring atoms independently selected from N, O, or S, or a heteroaryl containing, as appropriate, 5 to 6 ring atoms independently selected from N, O, or S; wherein each of the heterocycles or heteroaryls is, as appropriate, substituted with one to three substituents independently selected from halogen, C1-C3 alkyl, or C1-C3 haloalkyl; each of R4, R5, and R6 is independently -H, halogen, C1-C6 alkyl, or C1-C6 haloalkyl; R7 is -CN, C1-C6 alkyl, or C1-C6 haloalkyl; R8 is -H or C1-C6 alkyl;Each R9 is independently -H, halogen, -CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C3-C5 cycloalkyl; Each R10 is independently -H, -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R11, -C(O)OC1-C3 alkyl, -CONR11R11, -NR11R11, -NR11-CO2R11, -OH, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C5 cycloalkyl, optionally substituted heterocyclic selected from pyrrolidine, pyrrolidone, piperidine or morpholine, optionally substituted phenyl, optionally substituted 1,3-benzodioxane, optionally substituted 2,3-dihydro-1,4-benzodioxane, or selected from pyrazole, isothiazole, isothiazole The heteroaryl group of imidazole, thiazole, or thiazole is optionally substituted; wherein the optionally substituted C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl group is optionally substituted with -CN, -OH, oxetyl, C1-C3 alkoxy, or -CONR11R11; the optionally substituted C3-C5 cycloalkyl, phenyl, 1,3-benzodioxane, 2,3-dihydro-1,4-benzodioxane, heterocyclic, or heteroaryl group is optionally substituted with one to three substituents independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -SO2R11, -NR11R11, -OH, or -CN; and each R11 is independently -H or C1-C3 alkyl.

2. The compound or its isomers, hydrates or pharmaceutically acceptable salts of claim 1 have the following formula:

3. The compound or its isomer, hydrate or pharmaceutically acceptable salt of claim 1 or claim 2 has the following formula:

4. A compound or isomer, hydrate or pharmaceutically acceptable salt of claim 1 or claim 2, wherein R is -H.

5. A compound or isomer, hydrate or pharmaceutically acceptable salt of any of claims 1 to 4, wherein R1 is a group of the following formula:

6. A compound or isomer, hydrate or pharmaceutically acceptable salt of any of claims 1 to 5, wherein R1 is a group of the following formula:

7. A compound or isomer, hydrate or pharmaceutically acceptable salt of any of claims 1 to 6, wherein R1 is a group of the following formula:

8. A compound or isomer, hydrate or pharmaceutically acceptable salt of any of claims 1 to 4, wherein R1 is a group of the following formula:

9. A compound or its isomer, hydrate or pharmaceutically acceptable salt of any of claims 1 to 8, wherein each R9 is independently -H, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy or C3-C5 cycloalkyl.

10. A compound or its isomer, hydrate or pharmaceutically acceptable salt of any of claims 1 to 9, wherein each R9 is independently -H, halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy or C3-C5 cycloalkyl.

11. A compound or its isomer, hydrate or pharmaceutically acceptable salt of any of claims 1 to 10, wherein each R9 is independently -H, halogen, C1-C3 alkyl, C1-C3 haloalkyl or C3-C5 cycloalkyl.

12. A compound or its isomer, hydrate or pharmaceutically acceptable salt of any of claims 1 to 11, wherein each R9 is independently -H, halogen, C1-C3 alkyl or C1-C3 haloalkyl.

13. A compound or isomer, hydrate or pharmaceutically acceptable salt of any of claims 1 to 4, wherein R1 is a group of the following formula:

14. A compound or isomer, hydrate or pharmaceutically acceptable salt of any of claims 1 to 4, wherein R1 is a group of the following formula:

15. A compound or isomer, hydrate or pharmaceutically acceptable salt of any of claims 1 to 4, wherein R1 is a group of the following formula:

16. A compound or a pharmaceutically acceptable salt thereof, as claimed in any of claims 1 to 15, wherein R3 is -H, halogen, -CN, C1-C6 alkyl, C1-C6 haloalkyl, C3-C5 cycloalkyl, a heterocycle containing 3 to 5 ring atoms independently selected from 1, 2 or 3 ring heteroatoms of N, O or S, or a heteroaryl group containing 5 ring atoms independently selected from 1, 2 or 3 ring heteroatoms of N, O or S.

17. A compound or isomer, hydrate or pharmaceutically acceptable salt of any of claims 1 to 16, wherein R3 is -H, -CN, C1-C6 alkyl or C1-C6 haloalkyl.

18. A compound or isomer, hydrate or pharmaceutically acceptable salt of any of claims 1 to 17, wherein R3 is -H, -CN, C1-C3 alkyl or C1-C3 haloalkyl.

19. A compound or isomer, hydrate or pharmaceutically acceptable salt of any of claims 1 to 18, wherein R3 is -H, -CN or C1-C3 alkyl.

20. A compound or isomer, hydrate or pharmaceutically acceptable salt of any of claims 1 to 18, wherein R3 is -H, methyl or trifluoromethyl.

21. A compound or isomer, hydrate or pharmaceutically acceptable salt of any of claims 1 to 20, wherein R3 is -H or methyl.

22. A compound or its isomer, hydrate or pharmaceutically acceptable salt of any of claims 1, 2 or 4 through 21, wherein R4 is -H or a halogen.

23. A compound or its isomer, hydrate or pharmaceutically acceptable salt of any of claims 1, 2 or 4 through 22, wherein R4 is -H.

24. A compound or isomer, hydrate or pharmaceutically acceptable salt of any of claims 1 to 23, wherein R5 is -H, halogen, C1-C3 alkyl or C1-C3 haloalkyl.

25. A compound or isomer, hydrate or pharmaceutically acceptable salt of any of claims 1 to 24, wherein R6 is -H or a halogen.

26. A compound or isomer, hydrate or pharmaceutically acceptable salt of any of claims 1 to 25, wherein R7 is -CN, C1-C3 alkyl or C1-C3 haloalkyl.

27. A compound or isomer, hydrate or pharmaceutically acceptable salt of any of claims 1 to 26, wherein R7 is -CN, methyl or trifluoromethyl.

28. A compound or isomer, hydrate or pharmaceutically acceptable salt of any of claims 1 to 27, wherein R7 is methyl.

29. A compound or its isomer, hydrate or pharmaceutically acceptable salt as claimed in any of claims 1 or 4 to 28, wherein R8 is H.

30. A compound or isomer, hydrate or pharmaceutically acceptable salt thereof, as claimed in any of claims 1 to 29, wherein each R10 is independently -H, -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R11, -CONR11R11, -NR11R11, -NR11-CO2R11, -OH, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C5 cycloalkyl, optionally substituted heterocyclic selected from pyrrolidine, pyrrolidone, piperidine or morpholine, optionally substituted phenyl, optionally substituted 1,3-benzodioxane, optionally substituted 2,3-cyclopentene, etc. -dihydro-1,4-benzodioxane, or a heteroaryl group selected from pyrazole, isothiazolium, isothiazole, imidazole, thiazolium, or thiazole, wherein the C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl group is substituted with -CN, -OH, oxetyl, or C1-C3 alkoxy, as appropriate; and the C3-C5 cycloalkyl, phenyl, 1,3-benzodioxane, 2,3-dihydro-1,4-benzodioxane, heterocyclic, or heteroaryl group is substituted with one or three substituents selected independently from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -SO2R11, -NR11R11, -OH, or -CN, as appropriate.

31. A compound or its isomer, hydrate or pharmaceutically acceptable salt of any of claims 1 to 30, wherein each R10 is independently -H, -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R11, -CONR11R11, -NR11R11, -NR11-CO2R11, -OH, optionally substituted C1-C6 alkyl, optionally substituted C3-C5 cycloalkyl, optionally substituted heterocycle selected from pyrrolidine, pyrrolidone, piperidine or morpholine. The substituted phenyl group, or a heteroaryl group selected from pyrazole, isothiazolium, isothiazole, imidazole, thiazolium, or thiazole, may be substituted as appropriate; wherein the substituted C1-C6 alkyl group is substituted with -CN, -OH, or C1-C3 alkoxy group as appropriate; and each of the substituted C3-C5 cycloalkyl, phenyl, heterocyclic, or heteroaryl group is substituted with one or three substituents selected independently from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -NR11R11, -OH, or -CN as appropriate.

32. A compound or its isomer, hydrate or pharmaceutically acceptable salt of any of claims 1 to 31, wherein each R10 is independently -H, -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R11, -CONR11R11, -NR11R11, -NR11-CO2R11, a substituted C1-C6 alkyl, a substituted C3-C5 cycloalkyl, a substituted heterocycle selected from pyrrolidine, pyrrolidone, piperidine or morpholine, or a substituted heterocycle. The substituted phenyl group, or a heteroaryl group selected from pyrazole, isothiazolium, isothiazole, imidazole, thiazolium, or thiazole, may be substituted as appropriate; wherein the substituted C1-C6 alkyl group is substituted with -CN, -OH, or C1-C3 alkoxy group as appropriate; and each of the substituted C3-C5 cycloalkyl, phenyl, heterocyclic, or heteroaryl group is substituted with one or three substituents selected independently from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -NR11R11, -OH, or -CN as appropriate.

33. A compound or its isomers, hydrates or pharmaceutically acceptable salts of any of claims 1 to 29, wherein R2 is a group of the following formula: ; and each R10 is independently -H, -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, -SO2R11, substituted C1-C6 alkyl, substituted C2-C6 alkynyl, substituted C3-C5 cycloalkyl, or selected from pyrazole, isothiazole, isothiazole, imidazole, acet ... The azole or thiazole is optionally substituted with a heteroaryl group; wherein the optionally substituted C1-C6 alkyl or C2-C6 alkynyl group is optionally substituted with -CN, -OH or C1-C3 alkoxy; and the optionally substituted C3-C5 cycloalkyl or heteroaryl group is optionally substituted with one or three substituents each independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -NR11R11, -OH or -CN.

34. A compound or its isomer, hydrate or pharmaceutically acceptable salt of any of claims 1 to 29, wherein R2 is a group of the following formula:; and each R10 is independently -H, -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, -SO2R11, substituted C1-C6 alkyl, substituted C2-C6 alkynyl, or substituted C3-C5 cycloalkyl; wherein the substituted C1-C6 alkyl or C2-C6 alkynyl is substituted with -CN, -OH or C1-C3 alkoxy as appropriate; and the substituted C3-C5 cycloalkyl is substituted with one or three substituents each independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -NR11R11, -OH or -CN.

35. A compound or its isomers, hydrates or pharmaceutically acceptable salts of any of claims 1 to 29, wherein R2 is a group of the following formula:; and each R10 is independently -H, -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, -SO2R11, C1-C6 alkyl, C2-C6 alkynyl substituted with -OH as appropriate, C3 cycloalkyl substituted with -CN as appropriate, or a heteroaryl group selected from pyrazoles substituted with one to three substituents independently selected from C1-C3 alkyl groups as appropriate.

36. A compound or its isomer, hydrate or pharmaceutically acceptable salt of any of claims 1 to 29, wherein R2 is a group of the following formula:; and each R10 is independently -H, -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, -SO2R11, C1-C6 alkyl, C2-C6 alkynyl substituted with -OH as appropriate, or C3 cycloalkyl substituted with -CN as appropriate.

37. A compound or its isomer, hydrate or pharmaceutically acceptable salt of any of claims 1 to 29, wherein R2 is a group of the following formula: and each R10 is independently:

38. A compound or its isomer, hydrate or pharmaceutically acceptable salt of any of claims 1 to 29, wherein R2 is a group of the following formula: and each R10 is independently:

39. A compound or isomer, hydrate or pharmaceutically acceptable salt of any of claims 1 to 29, wherein R2 is a group of the following formula:

40. A compound or isomer, hydrate or pharmaceutically acceptable salt of any of claims 1 to 29, wherein R2 is a group of the following formula:

41. A compound or its isomers, hydrates or pharmaceutically acceptable salts of any of claims 1 to 29, wherein R2 is a 5-membered heteroaryl group selected from the group that is substituted, as appropriate: pyrrole, furan, thiophene, pyrazole, isothiazolium, isothiazole, imidazole, thiazole, triazole, thiadiazole and thiadiazole; wherein the 5-membered heteroaryl group that is substituted, as appropriate, is substituted by one to three substituents selected independently from the group that are: -CN, halogen, C1- C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R11, -CONR11R11, -NR11R11, -NR11CO2R11, substituted C1-C6 alkyl, substituted C2-C6 alkenyl, substituted C2-C6 alkynyl, substituted C3-C5 cycloalkyl, substituted heterocycles selected from pyrrolidine, pyrrolidone, piperidine or morpholine, substituted heterocycles ... The substituted phenyl group, the substituted 1,3-benzodioxane, the substituted 2,3-dihydro-1,4-benzodioxane, or the substituted heteroaryl group selected from pyridine, pyrimidine, pyrazine, pyridine, pyrazole, isothiazolium, isothiazole, imidazole, thiazolium, or thiazole; wherein the substituted C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 ynynyl group is respectively substituted with -CN, -OH, oxetyl, or C... 1-C3 alkoxy substitution; the substituted C3-C5 cycloalkyl, phenyl, 1,3-benzodioxane, 2,3-dihydro-1,4-benzodioxane, heterocyclic or heteroaryl group is, as appropriate, substituted by one or three substituents independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -SO2R11, -NR11R11, -OH or -CN.

42. A compound or its isomers, hydrates or pharmaceutically acceptable salts of any of claims 1 to 29, wherein R2 is a 5-membered heteroaryl group selected from the group that is substituted, as appropriate: pyrrole, furan, thiophene, pyrazole, isothiazolium, isothiazole, imidazole, acetazole, thiazole, triazole, acediazole and thiadiazole; wherein the 5-membered heteroaryl group that is substituted is substituted, as appropriate, by one to three substituents selected independently from the group that are: -CN, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -SO2R11, -CONR11R11, -NR11R11, -NR11CO2R11, or a substituted C1-C6 alkyl group. The C3-C5 cycloalkyl group may be substituted, a heterocyclic group selected from pyrrolidone, pyrrolidone, piperidine or morpholine may be substituted, a phenyl group may be substituted, or a heteroaryl group selected from pyridine, pyrazole, isothiazol, isothiazole, imidazole, thiazol or thiazole may be substituted; wherein the substituted C1-C6 alkyl group may be substituted with -CN, -OH or C1-C3 alkoxy; and each of the substituted C3-C5 cycloalkyl, phenyl, heterocyclic or heteroaryl group may be substituted with one or three substituents selected independently from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -NR11R11, -OH or -CN.

43. A compound or isomer, hydrate, or pharmaceutically acceptable salt thereof, as claimed in any of claims 1 to 29, wherein R2 is a 5-membered heteroaryl group selected from the group to which it is substituted, as appropriate: pyrrole, furan, thiophene, pyrazole, isothiazolium, isothiazole, imidazole, acetazole, thiazole, triazole, acediazole, and thiadiazole; wherein the 5-membered heteroaryl group to which it is substituted is, as appropriate, substituted by one to three substituents selected independently from the group to which it is substituted: C1-C6 haloalkyl, C1-C6 alkyl, phenyl, 1,3-benzodioxane, or pyrrole. The heteroaryl group of pyrimidine, pyrimidine, pyrazine, pyridine, pyrazole, isothiazolium, isothiazolium, imidazole, thiazolium or thiazole is optionally substituted; wherein the optionally substituted C1-C6 alkyl group is optionally substituted with -CN, -OH, oxetyl or C1-C3 alkoxy; and the optionally substituted phenyl, 1,3-benzodioxacyclopentene or heteroaryl group is optionally substituted with one or three substituents independently selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -SO2R11, -NR11R11, -OH or -CN.

44. A compound or its isomers, hydrates or pharmaceutically acceptable salts of any of claims 1 to 29, wherein R2 is a 5-membered heteroaryl group selected from the group that is substituted, as appropriate: pyrrole, furan, thiophene, pyrazole, isothiazolium, isothiazole, imidazole, thiazolium, triazole, thiadiazole and thiadiazole; wherein the 5-membered heteroaryl group that is substituted, as appropriate, is substituted by one to three substituents selected independently from the group that are C1-C6 haloalkyl, C1-C6 alkyl, optionally substituted phenyl, optionally substituted 1,3-benzodioxane, or optionally substituted heteroaryl selected from pyridine or pyrimidine; wherein each optionally substituted phenyl, 1,3-benzodioxane, or heteroaryl is optionally substituted by one or three substituents independently selected from halogen, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -SO2R11, or -CN.

45. A compound or its isomers, hydrates or pharmaceutically acceptable salts of any of claims 1 to 29, wherein R2 is a 5-membered heteroaryl group selected from the group that is substituted as appropriate: pyrrole, furan, thiophene, pyrazole, isothiazolium, isothiazole, imidazole, thiazolium, triazole, thiadiazole and thiadiazole; wherein the 5-membered heteroaryl group that is substituted as appropriate is substituted by one to three substituents selected independently from the group that are substituted as appropriate:

46. ​​A compound or its isomer, hydrate or pharmaceutically acceptable salt of any of claims 1 to 29, wherein R2 is a 5-membered heteroaryl group selected from the group that is substituted as appropriate: pyrrole, furan, thiophene, pyrazole, isothiazolium, isothiazole, imidazole, acetazole, thiazole, triazole, acediazole and thiadiazole; wherein the 5-membered heteroaryl group that is substituted as appropriate is substituted by one to three substituents selected independently from the group that are substituted as appropriate:

47. A compound or isomer, hydrate or pharmaceutically acceptable salt of any of claims 1 to 29, wherein R2 is a group of the following formula:

48. A compound or isomer, hydrate or pharmaceutically acceptable salt of any of claims 1 to 29, wherein R2 is a group of the following formula:

49. The compound or its isomers, hydrates or pharmaceutically acceptable salts as claimed in claim 1, wherein the compound is selected from:

50. The compound or its isomers, hydrates or pharmaceutically acceptable salts as claimed in claim 1, wherein the compound is selected from:

51. The compound or its isomers, hydrates or pharmaceutically acceptable salts of claim 1, wherein the compound is selected from:

52. The compound or its isomers, hydrates or pharmaceutically acceptable salts as claimed in claim 1, wherein the compound is selected from:

53. The compound or its isomers, hydrates or pharmaceutically acceptable salts as claimed in claim 1, wherein the compound is selected from:

54. A pharmaceutical composition comprising a compound or isomer thereof, hydrate or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, as claimed in any one of claims 1 to 53.

55. Use of a compound, or an isomer, hydrate, or pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 53, or a pharmaceutical composition thereof, as claimed in claim 54, for the manufacture of an agent for treating a disease or condition related to the regulation of phosphoinositol 3-kinase (PI3K).

56. As used in request item 55, wherein the PI3K is PI3Kα.

57. As used in claim 55 or claim 56, wherein the PI3K associated with the disease or condition has an H1047R mutation.

58. The use of any of the claims 55 to 57, wherein the disease or ailment is cancer.

59. As claimed in claim 58, 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.

60. As used in claim 58, wherein the cancer is breast cancer.

61. As claimed in claim 58, wherein the cancer is hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced or metastatic breast cancer.

62. For any of the uses in claims 55 to 57, wherein the disease or condition is CLOVES syndrome (congenital lipomatous overgrowth, vascular malformations, epidermal naevi, scoliosis / skeletal and spinal syndrome) or PIK3CA-related overgrowth syndrome (PROS).

63. Use of a compound, or an isomer, hydrate, or pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 53, or a pharmaceutical composition thereof, as claimed in claim 54, for the manufacture of an agent that inhibits phosphoinositol 3-kinase (PI3K).

64. Use of a compound, or an isomer, hydrate, or pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 53, or a pharmaceutical composition as claimed in claim 54, for the manufacture of an agent for treating cancer or a disease.

65. As claimed in claim 64, 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.

66. As used in claim 64, wherein the cancer is breast cancer.

67. As claimed in claim 64, wherein the cancer is hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced or metastatic breast cancer.

68. As claimed in claim 64, wherein the condition is CLOVES syndrome (congenital lipomatous overgrowth, vascular malformation, epidermal lentigines, scoliosis / skeletal and spinal syndrome) or PIK3CA-associated overgrowth syndrome (PROS).