PYRIDOPYRIMIDINONE DERIVATIVES AS ARYL HYDROCARBON RECEPTOR MODULATORS AND THEIR USE - Patent application

Abstract

The present invention relates to novel compounds effective as aryl hydrocarbon receptor (AhR) modulators, and pharmaceutical compositions containing said compounds as active ingredients for modulating AhR or for preventing or treating diseases, disorders, or conditions associated with AhR activity. Thus, the present invention may be useful as a medicament for preventing or treating diseases, disorders, or conditions associated with AhR activity, particularly cancer, cancerous conditions, tumors, fibrosis, or conditions involving dysregulated immune responses.

Description

[Technical field]

[0001] The present invention relates to novel pyridopyrimidinone derivatives capable of modulating the activity of aryl hydrocarbon receptor (AhR). The compounds of the present invention represented by formula (I) can be used (as a single drug or in combination with another active ingredient) to inhibit the proliferation of cancer cells, the metastasis and invasion of tumor cells, and to treat diseases associated with dysregulation of immune response associated with AhR signaling. [Background technology]

[0002] The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor and is well known as an important intracellular chemical sensor that responds to both natural and artificial environmental compounds. AhR is known to be a member of the PER (periodic circadian protein)-ARNT (AhR nuclear translocator)-SIM (single-minded protein) transcription factor superfamily, and the PER-ARNT-SIM (PAS) domain of this transcription factor senses ligands (Burbach et al, PNAS September 1, 1992 89 (17) 8185-8189). Activated by binding to various ligands, AhR translocates into the nucleus and dimerizes with its partner protein ARNT. This heterodimeric complex directly or indirectly regulates the expression of AhR-associated genes by interacting with xenobiotic response elements (XREs). Kynurenine is an endogenous ligand of AhR that has been thoroughly characterized. Kynurenine is produced by TDO (Opitz et al, Nature, 2011 Oct 5; 478(7368):197-203) or IDO (Mezrich, J Immunol. 2010 Sep 15;185(6):3190-8.). Recent studies have found that high plasma kynurenine concentrations and high serum Kyn / Trp ratios after PD-1 inhibition correlate with poor prognosis in patients with various types of cancer, including lung cancer, melanoma, and renal cell carcinoma (Haoxin Li et al, Nat Commun. 2019 Sep 25;10(1):4346).

[0003] It has recently become well known that AhR regulates the function of a great many types of cells in both the innate and adaptive immune systems. Activated AhR suppresses the induction of cytokines that promote the polarization of pathogenic T cell subsets and reduces MHC class II expression. Activated AhR by agonists and modulators also suppresses the differentiation of helper Th17 cells and stabilizes regulatory T cells. Activated AhR also induces the generation of AhR ligands through a positive feed-forward loop involving indoleamine 2,3-dioxygenase 1 (IDO1) (Nguyen et al., PNAS, 2010, 107(46):19961-19966, Mascanfroni, ID et al. Nat. Med., 2015, 21:638-646). In addition, repopulating tumor cells (TRCs) upregulate PD-1 on CD8+ T cells via the Kyn-AhR pathway as an immune evasion mechanism (Yuying Liu et al, Cancer cell, 2018).

[0004] Furthermore, several studies have revealed that AhR signaling plays an important role in various diseases, including autoimmune diseases, infectious diseases, and cancer. It has been suggested that AhR signaling may be related to autoimmune diseases, such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and multiple sclerosis (MS) (Xiao-Song Wang et al, Inflammopharmacology, 2020 Feb; 28(1):63-81). Constitutive AhR activation reduces the antiviral response of type I interferon (IFN-I) (Yamada et al, Nat immunol, 2016 Jun; 17(6):687-94). In addition, some types of viruses induce AhR activation to evade the host immune response, and by taking advantage of this evasion mechanism, we have succeeded in suppressing the replication of Zika virus and SARS-COV-2 in mouse models (Federico Giovannoni et al, Cell Research, 2021 Dec., 31:1-2). AhR may also affect cancer cell proliferation, tissue invasion, metastasis and angiogenesis (Jae Eun Cheong et al, Trends in Pharmacological Sciences, 2018 Mar; 39(3):307-325). In addition, it is known that various types of cancer evade recognition by the immune system through the AhR pathway. If we can develop therapeutic drugs that target AhR, it may be possible to overcome immune-related diseases. Summary of the Invention [Problem to be solved by the invention]

[0005] It is therefore an object of the present invention to provide novel compounds or their enantiomers, diastereomers, racemates, solvates, hydrates or pharma- ceutically acceptable salts as modulators of AhR.

[0006] Another object of the present invention is to provide a pharmaceutical composition for regulating the activity of AhR, comprising the compound as an AhR modulator.

[0007] The present invention also aims to provide a pharmaceutical composition for preventing or treating diseases, disorders or conditions associated with AhR activity (e.g., cancer, autoimmune diseases, etc.), comprising the above-mentioned compound as a modulator of AhR.

[0008] It is also an object of the present invention to provide a method of regulating the activity of the AhR by administering said compounds as modulators of the AhR.

[0009] It is also an object of the present invention to provide a method for preventing or treating prostaglandin-related diseases by administering said compounds as modulators of AhR.

[0010] It is a further object of the present invention to provide the use of prostaglandin analogues for modulating the activity of AhR or for the prevention or treatment of a disease, disorder or condition associated with AhR. [Means for solving the problem]

[0011] The present invention provides novel compounds and pharma- ceutically acceptable compositions useful as modulators or inhibitors of the aryl hydrocarbon receptor (AhR). The compounds have the formula (I): [ka] (In the formula, Ar 1 and Ar 2 is halo, substituted or unsubstituted monocyclic or bicyclic C 6-10 Aryl, substituted or unsubstituted monocyclic or bicyclic C 5-10 Heteroaryl and substituted or unsubstituted monocyclic or bicyclic C 3-10 heterocycloalkyl; L is absent (direct bond) or is H, halo, cyano, hydroxy, amino, nitro, ether (-O-), thioether (-S-), sulfinyl (-SO-), sulfonyl (-SO2-), sulfonylamido (-SO2NR 2 -), aminosulfonyl (-NR 2 SO2-), carbonyl (-(CO)-), amide (-(CO)NR 2 -), reverse amide (-NR 2 (CO)-), esters (-(CO)O-), substituted or unsubstituted C 1-5 Alkyl, substituted or unsubstituted monocyclic or bicyclic C 3-10 Cycloalkyl, substituted or unsubstituted monocyclic or bicyclic C 4-10 Heterocycloalkyl, substituted or unsubstituted monocyclic or bicyclic C 6-10 Aryl or substituted or unsubstituted monocyclic or bicyclic C 5-10 is heteroaryl; R 1 is absent (direct bond) or H, halo, cyano, hydroxy, amino, NHR 3 , OR 3 , phosphate, substituted or unsubstituted C 1-3 Alkyl phosphates, substituted or unsubstituted C 1-5 Alkyl, sulfinic acid (-SO-H), sulfonic acid (-SO2-H), sulfonyl amide (-SO2NR 2 2), aminosulfonic acid (-NR 2 SO2-H), carboxylic acid (-(CO)-H), carbonyl (-(CO)R 2 ), amide (-(CO)NR 2 2) Reverse alkyl amide (-NH(CO)-R 2 ), alkyl ester (-(CO)OR 2 ), sulfonates (-SO2-R 2 ), C 3-10 Cycloalkyl, C 1-5 Alkyl hydroxy, C 1-5 Alkenylhydroxy, C 1-5 Alkynylhydroxy, C 1-5 Alkylamines, C1-5 Alkenylamines, C 1-5 Alkynylamines, substituted or unsubstituted monocyclic or bicyclic C 3-10 Heterocycloalkyl or substituted or unsubstituted monocyclic or bicyclic C 5-10 is heteroaryl; R 2 is H, halo, hydroxy, amino, substituted or unsubstituted C 1-5 Alkyl, substituted or unsubstituted C 1-5 Alkoxy, substituted or unsubstituted C 3-8 Cycloalkyl, or substituted or unsubstituted C 1-5 It is an alkyl carboxylic acid; R 3 is H, substituted or unsubstituted, C 1-5 Alkyl, C 1-5 Alkylacetyl (alkyl-CO-), C 1-5 Sulfonylalkyl (alkyl-SO2-), C 1-5 Sulfonylamidoalkyl (alkyl-SO2NR 2 2) C 1-5 Amidoalkyl (alkyl-(CO)NR 2 2) or C 1-5 Reverse Amido Alkyl (Alkyl-NR 2 (CO)-), substituted or unsubstituted C 1-5 Alkoxy, or substituted or unsubstituted C 1-5 (Alkyl carboxylic acid) As shown in the figure.

[0012] In some embodiments of these and such aspects described herein, the AhR modulator of formula (I) is a modulator of AhR or an antagonist of AhR.

[0013] In some embodiments, a method for regulating the activity of AhR is described. More specifically, a method for regulating constitutive AhR activity is described in a subject that needs to regulate constitutive AhR activity. The method comprises administering a therapeutically effective amount of an AhR modulator, such as an AhR antagonist of formula (I) as described herein, to a subject that has constitutive AhR activity. In some embodiments of these and such aspects described herein, the method further comprises selecting a subject that has constitutive AhR activity.

[0014] The compound of formula (I) of the present invention has been shown to have a beneficial pharmacological spectrum of action that was not anticipated before.Surprisingly, it has been found that the compound of the present invention can effectively inhibit AhR, and therefore the compound of the present invention can be used to treat or prevent diseases or conditions mediated by aryl hydrocarbon receptor (AhR) in humans and animals, and preferably can be used to treat or prevent cancer, cancerous conditions, tumors, fibrotic diseases, conditions involving dysregulation of immune response, or other disorders related to the abnormal signal transduction of AhR.

[0015] Examples of diseases associated with dysregulation of immune responses related to AhR signaling include sepsis (SIRS), multiple organ dysfunction syndrome (MODS, MOF), inflammatory kidney disease, chronic enteritis (IBD, Crohn's disease, UC), pancreatitis, peritonitis, inflammatory skin diseases, inflammatory eye diseases, and autoimmune diseases (rheumatic diseases such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and multiple sclerosis (MS)).

[0016] Examples of fibrotic disease include fibrotic disease of internal organs such as lung, heart, kidney, bone marrow, etc., particularly liver fibrosis, skin fibrosis and eye fibrosis.In the present invention, "fibrotic disease" specifically includes liver fibrosis, liver cirrhosis, pulmonary fibrosis, endomyocardial fibrosis, nephropathy, glomerulonephritis, interstitial renal fibrosis, fibrotic disorder associated with diabetes, myelofibrosis and fibrotic diseases similar thereto; and scleroderma, patchy scleroderma, keloid, hypertrophic scar (hypertrophic scar after surgery), nevus, diabetic retinopathy, proliferative vitreoretinopathy and connective tissue disorder (e.g., sarcoidosis).

[0017] In another embodiment, a method for treating cancer or cancerous condition by regulating the activity of AhR is described.The method comprises administering to a subject having cancer or cancerous condition a therapeutically effective amount of a pharmaceutical composition comprising an AhR modulator, such as the AhR antagonist of formula (I) as described herein.

[0018] In some embodiments, a method of suppressing tumor cell invasion in a subject having cancer, a cancerous condition or a tumor is described, comprising administering to the subject having cancer or a tumor a therapeutically effective amount of a pharmaceutical composition comprising an AhR modulator, such as an AhR antagonist of formula (I) as described herein.

[0019] In some embodiments of these and such aspects described herein, the method further comprises selecting a subject with cancer, a cancerous condition, or a tumor.

[0020] Cancers, cancerous conditions or tumors that are particularly suitable for treatment with the AhR inhibitors of the present invention include liquid and solid tumors such as breast cancer, respiratory cancer, brain cancer, reproductive cancer, gastrointestinal cancer, urinary tract cancer, eye cancer, liver cancer, skin cancer, head and neck cancer, thyroid cancer, parathyroid cancer, distant metastases thereof, etc. These cancers, cancerous conditions or tumors further include lymphomas, sarcomas and leukemias.

[0021] Examples of breast cancer include, but are not limited to, triple-negative breast cancer, invasive ductal carcinoma, invasive lobular carcinoma, ductal carcinoma in situ, and lobular carcinoma in situ.

[0022] Examples of respiratory cancers include, but are not limited to, small cell and non-small cell lung carcinoma, as well as bronchial adenoma and pleuropulmonary blastoma.

[0023] Examples of brain tumors include, but are not limited to, brain stem and hypothalamic gliomas, cerebellar and cerebral astrocytomas, glioblastomas, medulloblastomas, ependymomas, as well as neuroectodermal and pineal tumors.

[0024] Tumors of the male reproductive organs include, but are not limited to, prostate and testicular cancer.

[0025] Tumors of the female reproductive organs include, but are not limited to, endometrial, cervical, ovarian, vaginal, and vulvar cancer, as well as uterine sarcoma.

[0026] Examples of ovarian cancer include, but are not limited to, serous tumor, endometrioid tumor, mucinous cystadenocarcinoma, granulosa cell tumor, Sertoli-Leydig cell tumor, and androgenic tumor.

[0027] Examples of cervical cancer include, but are not limited to, squamous cell carcinoma, adenocarcinoma, adenosquamous carcinoma, small cell carcinoma, neuroendocrine tumors, ground glass cell carcinoma, and villous tubular adenocarcinoma.

[0028] Digestive tract tumors include, but are not limited to, anal cancer, colon cancer, colorectal cancer, esophageal cancer, gallbladder cancer, gastric cancer, pancreatic cancer, rectal cancer, small intestine cancer, and salivary gland cancer.

[0029] Examples of esophageal cancer include, but are not limited to, esophageal cell carcinoma and esophageal adenocarcinoma, as well as squamous cell carcinoma, leiomyosarcoma, malignant melanoma, rhabdomyosarcoma, and lymphoma.

[0030] Examples of gastric cancer include, but are not limited to, intestinal-type adenocarcinoma and diffuse gastric-type adenocarcinoma.

[0031] Examples of pancreatic cancer include, but are not limited to, intraductal adenocarcinoma, adenosquamous carcinoma, and pancreatic endocrine tumors.

[0032] Urinary tract tumors include, but are not limited to, bladder cancer, penile cancer, kidney cancer, renal pelvis cancer, ureter cancer, urethral cancer, and human papillary renal cancer.

[0033] Examples of kidney cancer include, but are not limited to, renal cell carcinoma, urothelial cell carcinoma, juxtaglomerular tumor (nephroma), angiomyolipoma, renal oncocytoma, Bellini duct carcinoma, clear cell sarcoma of the kidney, mesodermal nephroma, and Wilms' tumor.

[0034] Examples of bladder cancer include, but are not limited to, transitional cell carcinoma, squamous cell carcinoma, adenocarcinoma, sarcoma, and small cell carcinoma.

[0035] Eye cancers include, but are not limited to, intraocular melanoma and retinoblastoma.

[0036] Examples of liver cancer include, but are not limited to, hepatocellular carcinoma (fibrolamellar or non-fibrolamellar), cholangiocarcinoma (intrahepatic cholangiocarcinoma), and mixed hepatocellular carcinoma and cholangiocarcinoma.

[0037] Skin cancers include, but are not limited to squamous cell carcinoma, Kaposi's sarcoma, malignant melanoma, Merkel cell skin cancer, and non-malignant melanoma skin cancer.

[0038] Head and neck cancers include, but are not limited to, squamous cell carcinoma of the head and neck, laryngeal cancer, hypopharyngeal cancer, nasopharyngeal cancer, oropharyngeal cancer, salivary gland cancer, lip and oral cavity cancer, and squamous cell carcinoma.

[0039] Lymphomas include, but are not limited to, AIDS-related lymphoma, non-Hodgkin's lymphoma, cutaneous T-cell lymphoma, Burkitt lymphoma, Hodgkin's disease, and central nervous system lymphoma.

[0040] Sarcomas include, but are not limited to, soft tissue sarcoma, osteosarcoma, malignant fibrous histiocytoma, lymphosarcoma, and rhabdomyosarcoma.

[0041] Leukemias include, but are not limited to, acute myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, and hairy cell leukemia.

[0042] The terms "treat" or "treatment" as used throughout this specification are used in their ordinary sense, e.g., to refer to the management or medical care of a subject for the purpose of addressing the condition of a disease or disorder, such as carcinoma, or to alleviate, inhibit, relieve or ameliorate the condition of a disease or disorder, such as carcinoma.

[0043] The compounds of the present invention can be used in particular for the treatment and prevention (i.e. prophylactic treatment) of tumor growth and metastasis, and in particular for the treatment and prevention of solid tumor growth and metastasis of any indication and any stage, with or without prior treatment against tumor growth.The tumor is breast cancer, squamous cell carcinoma, lung cancer, peritoneal cancer, hepatocellular carcinoma, gastric cancer, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, hepatoma, colon cancer, colorectal cancer, endometrial cancer, uterine cancer, salivary gland cancer, kidney cancer, prostate cancer, vulvar cancer, thyroid cancer, head and neck cancer, B-cell lymphoma, chronic lymphocytic leukemia (CLL), acute lymphoblastic leukemia (ALL), hairy cell leukemia or chronic myeloblastic leukemia.In some of these embodiments, the cancer is hepatocellular carcinoma.

[0044] Some embodiments of the method may further comprise the concomitant administration or treatment of one or more additional anti-cancer therapies, in some such embodiments, the additional anti-cancer therapies comprise surgery, radiation therapy, biological therapy, immunotherapy, chemotherapy, or any combination thereof.

[0045] Some embodiments of the method may further comprise administering or treating with one or more anti-cancer therapeutic agents, in some such embodiments, the anti-cancer therapeutic agent is a chemotherapeutic agent, an antiproliferative agent, an anti-angiogenic agent, a cytotoxic agent, an anti-hormonal agent, a prodrug, or a cytokine.

[0046] In another embodiment of the present invention, the compound of the present invention represented by formula (I) may be used to enhance the sensitivity of cells to radiation. That is, by treating cells with the compound of the present invention before performing radiation therapy, the sensitivity of cells to DNA damage and cell death can be enhanced compared to the case where the compound of the present invention is not treated. In one embodiment, cells are treated with at least one compound of the present invention represented by general formula (I).

[0047] Thus, the present invention provides a method for killing cells comprising administering to the cells one or more compounds of the present invention in combination with conventional radiation therapy.

[0048] The present invention further provides a method of increasing the susceptibility of a cell to cell death, comprising treating the cell with one or more compounds of the present invention represented by formula (I) prior to administering a treatment that induces or induces cell death. In one embodiment, after treating the cell with one or more compounds of the present invention represented by formula (I), the cell is treated with at least one compound or at least one method or a combination thereof to induce DNA damage and inhibit normal cell function or kill the cell.

[0049] In another embodiment of the present invention, cells are killed by treating cells with at least one DNA damaging agent.That is, cells are treated with one or more of the compounds of the present invention represented by formula (I) to enhance the sensitivity of cells to cell death, and then cells are killed by treating cells with at least one DNA damaging agent.The DNA damaging agent useful in the present invention includes, but is not limited to, chemotherapeutic agents (e.g., cisplatin), ionizing radiation (X-rays, ultraviolet light), carcinogens and mutagens.

[0050] In another embodiment, cells are killed by treating cells with at least one method of inducing or inducing DNA damage.Such methods include but are not limited to DNA damage caused by activating cell signaling pathway, DNA damage caused by suppressing cell signaling pathway, and DNA damage caused by inducing biochemical changes in cells.For example, DNA damage repair can be prevented by suppressing cell DNA repair pathway, resulting in abnormal accumulation of DNA damage in cells.

[0051] In one embodiment of the present invention, the compound of the present invention represented by formula (I) is administered to a cell before inducing DNA damage in the cell by irradiation or other methods. In another embodiment of the present invention, the compound of the present invention represented by general formula (I) is administered to a cell simultaneously with inducing DNA damage in the cell by irradiation or other methods. In yet another embodiment of the present invention, the compound of the present invention represented by formula (I) is administered to a cell immediately after inducing DNA damage in the cell by irradiation or other methods.

[0052] In another embodiment, the cell is an in vitro cell.In another embodiment, the cell is an in vivo cell.The compound of the present invention can be administered as a single pharmaceutical agent or can be administered in combination with one or more other active pharmaceutical ingredients, and does not cause undesirable adverse effects when combined with one or more other active pharmaceutical ingredients.

[0053] The present invention also includes combinations of pharmaceutical agents as described above. For example, pharmaceutical agents that can be combined with the compounds of the present invention include: 131I-chTNT, abarelix, abiraterone, aclarubicin, adalimumab, ado-trastuzumab emtansine, afatinib, aflibercept, aldesleukin, alectinib, alemtuzumab, alendronate, alitretinoin, altretamine, amifostine, aminoglutethimide, hexaminolevulinic acid, amrubicin, amsacrine, anastrozole, ancestim, anetholedithiourethion, anetumab ravtansine, angiotensin II, antithrombin cerebrospinal fluid III, aprepitant, arcitumomab, arglavin, arsenic trioxide, asparaginase, atezolizumab, axitinib, azacitidine, basiliximab, belotecan, bendamustine, besilesomab, belinostat, bevacizumab, bexarotene, bicalutamide, bisantrene, bleomycin, blinatumomab, bortezomib, buserelin, bosutinib, brentuximab Vedotin, busulfan, cabazitaxel, cabozantinib, calcitonin, calcium folinate, calcium levofolinate, capecitabine, capromab, carbamazepine, carboplatin, carboquin, carfilzomib, carmofur, carmustine, catumaxomab, celecoxib, cermoleukin, ceritinib, cetuximab, chlorambucil, chlormadinone, chlormethine, cidofovir, cinacalcet, cisplatin, cladribine, clodronic acid, clofarabine, cobimetinib, copanlisib, crisantaspase, crizotinib, cyclophosphamide, cyproterone, cytarabine, dacarbazine, dactinomycin, daratumumab, darbepoetin Alfa, dabrafenib, dasatinib, daunorubicin, decitabine, degarelix, denileukin diftitox, denosumab, depreotide, deslorelin, dianhydrogalactitol, dexrazoxane, dibrospidiumchloride, dianhydrogalactitol, diclofenac, dinutuximab, docetaxel, dolasetron, doxifluridine, doxorubicin, doxorubicin + estrone, dronabinol, eculizumab, edrecolomab, elliptinium acetate, elotuzumab, eltrombopag, endostatin, enocitabine, enzalutamide, epirubicin, epithiostanol, epoetin alfa, epoetin beta, epoetin zeta, peptaplatin, eribulin, erlotinib, esomeprazole, estradiol, estramustine, ethinyl estradiol, etoposide, everolimus, exemestane, fadrozole, fentanyl, filgrastim, fluoxymesterone, floxuridine, fludarabine, fluorouracil, flutamide, fo Phosphate, formestane, fosaprepitant, fotemustine, fulvestrant, gadobutrol, gadoteridol, gadoterate meglumine, gadoversetamide, gadoxetic acid, gallium nitrate, ganirelix, gefitinib, gemcitabine, gemtuzumab, glucarpidase, glutoxim, GM-CSF, goserelin, granisetron, granulocyte colony-stimulating factor, histamine dihydrochloride, histamine Strelin, hydroxycarbamide, I-125 seed source, lansoprazole, ibandronic acid, ibritumomab tiuxetan, ibrutinib, idarubicin, ifosfamide, imatinib, imiquimod, improsulfan, indisetron, incadronic acid, ingenol mebutate, interferon alpha, interferon beta, interferon gamma, iobitridol, iobenguane ( 123I), iomeprol, ipilimumab, irinotecan, itraconazole, ixabepilone, ixazomib, lanreotide, lansoprazole, lapatinib, lasocholine, lenalidomide, lenvatinib, lenograstim, lentinan, letrozole, leuprorelin, levamisole, levonorgestrel, levothyroxine sodium, lisuride, lobaplatin, lomustine, lonidamine, masoprocol, medroxyprogesterone, megestrol, melarsoprol, melphalan, mepitiostane, mercaptopurine, mesna, Methadone, methotrexate, methoxsalen, methyl aminolevulinate, methylprednisolone, methyltestosterone, metyrosine, mifamurtide, miltefosine, miriplatin, mitobronitol, mitoguazone, mitolactol, mitomycin, mitotane, mitoxantrone, mogamulizumab, molgramostim, mopidamol, morphine hydrochloride, morphine sulfate, nabilone, nabiximols, nafarelin, naloxone + pentazocine, naltrexone, nartograstim, necitumumab, nedaplatin, nelarabine, neridronic acid, nets Pitant / palonosetron, nivolumab, pentetreotide, nilotinib, nilutamide, nimorazole, nimotuzumab, nimustine, nintedanib, nitracrine, nivolumab, obinutuzumab, octreotide, ofatumumab, olaparib, olaratumab, omacetaxine mepesuxinate, omeprazole, ondansetron, oprelvekin, orgotein, olilotimod, osimertinib, oxaliplatin, oxycodone, oxymetholone, ozogamicin, p53 gene therapy, paclitaxel, palbociclib, palifermin, para Zinc-103 seed source, palonosetron, pamidronic acid, panitumumab, panobinostat, pantoprazole, pazopanib, pegaspargase, PEG-epoetin beta (methoxy-PEG-epoetin beta), pembrolizumab, pegfilgrastim, peginterferon alpha-2b, pembrolizumab, pemetrexed, pentazocine, pentostatin, peplomycin, perflubutane, perfosfamide, pertuzumab, picibanil, pilocarpine, pirarubicin, pixantrone, plerixafor, plicamycin, poliglusum,Polyestradiol phosphate, polyvinylpyrrolidone + sodium hyaluronate, polysaccharide K, pomalidomide, ponatinib, porfimer sodium, pralatrexate, prednimustine, prednisone, procarbazine, procodazole, propranolol, quinagolide, rabeprazole, racotumomab, radium 223 chloride, radotinib, raloxifene, raltitrexed, ramosetron, ramucirumab, ranimustine, rasburicase, razoxane, refametinib, regorafenib, risedronate, rhenium 186 etidronate, rituximab, rolapitant, romidepsin, romiplostim, romultide, roniciclib, samarium (, 153 Sm) Lexidonam, Sargramostim, Satumomab, Secretin, Siltuximab, Sipuleucel-T, Sizofiran, Sobuzoxane, Sodium glycididazole, Sonidegib, Sorafenib, Stanozolol, Streptozocin, Sunitinib, Talaporfin, Talimogene Laherparepvec, Tamibarotene, Tamoxifen, Tapentadol, Tasonermin, Teceleukin, Technetium ( 99m Tc) nofetumomab merpentane, 99m Tc-HYNIC-[Tyr 3]-Octreotide, tegafur, tegafur + gimeracil + oteracil, temoporfin, temozolomide, temsirolimus, teniposide, testosterone, tetrofosmin, thalidomide, thiotepa, thymalfasin, thyrotropin alfa, thioguanine, tocilizumab, topotecan, toremifene, tositumomab, trabectedin, trametinib, tramadol, trastuzumab, trastuzumab These include emtansine, treosulfan, tretinoin, trifluridine + tipiracil, trilostane, triptorelin, trametinib, trofosfamide, thrombopoietin, tryptophan, ubenimex, valatinib, valrubicin, vandetanib, vapreotide, vemurafenib, vinblastine, vincristine, vindesine, vinflunine, vinorelbine, vismodegib, vorinostat, vorozole, yttrium-90 glass microspheres, zinostatin, zinostatin stimalamer, zoledronic acid, and zorubicin.

[0054] The compounds of the invention can also be combined with other agents that target the immune system, for example immune checkpoint inhibitors, such as antagonists against the PD-1 / PD-L1 axis.

[0055] PD-1 and its ligands PD-L1 and PD-L2 act as negative regulators of T cell activation. AhR suppresses immune cell function and enhances cancer cell proliferation and motility. PD-L1 is overexpressed in a variety of cancers, and overexpression of PD-1 often coincides with T cell infiltration into tumors. This results in impaired T cell activation and evasion from immune surveillance, thus reducing antitumor immune responses (Keir ME et al. (2008) Annu. Rev. Immunol. 26:677).

[0056] Simultaneous targeting of the PD-1 / PD-L1 axis and AhR can enhance antitumor immune responses compared with additive approaches and, unexpectedly, suppress tumor growth.

[0057] Thus, it has surprisingly been found that a composition comprising an antagonist against the PD-1 / PD-L1 axis and an AhR antagonist is effective in enhancing immune responses and treating cancer.

[0058] Furthermore, the compounds of the present invention can also be used as therapeutic agents for various other diseases in which AhR is involved.

[0059] Other examples of disorders associated with inflammation through aberrant AhR signaling include vaccination against infectious diseases, cancer, viral infections, obesity and diet-induced obesity, steatosis, metabolic diseases, hepatic steatosis, uterine fibroids in women (uterine leiomyomas or fibroids), chronic renal injury, acute and chronic renal failure, diabetic nephropathy, inflammatory nephropathy, hypertensive nephropathy, heart failure, angina pectoris, hypertension, pulmonary hypertension, ischemia, vascular disorders, thromboembolic disorders, arteriosclerosis, sickle cell anemia, erectile dysfunction, benign prostatic hyperplasia, voiding disorders associated with benign prostatic hyperplasia, Huntington's disease, dementia, Alzheimer's disease, and Creutzfeldt-Jakob disease.

[0060] Additionally, in another aspect, there is provided a pharmaceutical composition comprising an AhR modulator, such as an AhR antagonist of formula (I), and a pharma- ceutically acceptable excipient.

[0061] In some embodiments, a pharmaceutical composition is provided comprising an AhR modulator (e.g., an AhR antagonist represented by formula (I)) for use in modulating constitutive AhR activity in a subject in need thereof.

[0062] In some embodiments, a pharmaceutical composition is provided comprising an AhR modulator (e.g., an AhR antagonist of Formula (I)) for use in treating cancer or a cancerous condition by modulating the activity of AhR.

[0063] In some embodiments, a pharmaceutical composition comprising an AhR modulator (e.g., an AhR antagonist of Formula (I)) is provided for use in inhibiting cancer cell proliferation, tissue invasion, metastasis and angiogenesis in a subject having cancer, a cancerous condition or a tumor.

[0064] In some embodiments of these aspects and such aspects described herein, the use further comprises selecting a subject with cancer, cancerous condition or tumor.In some such embodiments, the cancer is breast cancer, squamous cell carcinoma, lung cancer, peritoneal cancer, hepatocellular carcinoma, gastric cancer, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, hepatoma, colon cancer, colorectal cancer, endometrial cancer, uterine cancer, salivary gland cancer, kidney cancer, prostate cancer, vulvar cancer, thyroid cancer, head and neck cancer, B-cell lymphoma, chronic lymphocytic leukemia (CLL), acute lymphoblastic leukemia (ALL), hairy cell leukemia or chronic myeloblastic leukemia.In some such embodiments, the cancer is hepatocellular carcinoma.

[0065] In some embodiments of these and such aspects described herein, the use further comprises one or more additional anti-cancer therapies. In some such embodiments, the additional anti-cancer therapy comprises surgery, radiation therapy, biological therapy, immunotherapy, or chemotherapy.

[0066] In some embodiments of these and such aspects described herein, the use further comprises one or more anti-cancer therapeutic agents. In some such embodiments, the anti-cancer therapeutic agent is a chemotherapeutic agent, an antiproliferative agent, an anti-angiogenic agent, a cytotoxic agent, an anti-hormonal agent, a prodrug, or a cytokine. Effect of the Invention

[0067] The novel compounds of the present invention represented by formula (I) can effectively modulate the activity of AhR and are therefore useful as therapeutic or prophylactic agents for various diseases, disorders or conditions associated with AhR activity, such as cancer, cancerous conditions, tumors, fibrosis, conditions involving dysregulated immune responses (including, for example, autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus (SLE), multiple sclerosis (MS) and the like), or other disorders associated with abnormal signaling of AhR. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0068] The present invention will now be described in further detail.

[0069] Unless otherwise specified, all technical terms used herein have the meanings commonly understood by those skilled in the art to which the present invention belongs. In addition, although the present invention has been described with reference to specific methods and specific samples, similar or equivalents thereof are also included within the scope of the present invention. Furthermore, numerical values ​​described herein are interpreted to include the meaning of "about" unless otherwise specified. All publications and other references mentioned herein are incorporated by reference in their entirety.

[0070] The definitions of groups used herein are explained in detail. Unless otherwise specified, each group has the following definition and is used in the sense that is generally understood by those skilled in the art.

[0071] As used herein, "halo", "halogen" and "halide" include fluoro, chloro, bromo or iodo.

[0072] As used herein, "alkyl" refers to an aliphatic hydrocarbon group, including straight-chain and branched hydrocarbon groups. For example, C 1-6Alkyl is an aliphatic hydrocarbon having 1 to 6 carbon atoms, and specific examples thereof include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, and 2-ethylbutyl. Unless otherwise specified, alkyl is an aliphatic hydrocarbon having 1 to 6 carbon atoms, and specific examples thereof include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, and 2-ethylbutyl. 1-6 Refers to alkyl, C 1-4 Preferably it is alkyl, C 1-3 It is more preferably an alkyl group.

[0073] As used herein, "alkenyl" refers to an aliphatic hydrocarbon group containing at least one carbon-carbon double bond, including straight-chain and branched hydrocarbon groups. Examples of "alkenyl" include, but are not limited to, vinyl, allyl, but-1-enyl, or but-2-enyl.

[0074] As used herein, "alkynyl" refers to an aliphatic hydrocarbon group containing at least one carbon-carbon triple bond, including straight-chain and branched hydrocarbon groups. Examples of "alkynyl" include, but are not limited to, ethynyl, propargyl, but-1-ynyl, or but-2-ynyl.

[0075] As used herein, "haloalkyl" refers to an alkyl group substituted with one or more halogen atoms, and the alkyl group is defined as above. "Halo" refers to F, Cl, Br or I, and is used interchangeably with "halogen". Unless otherwise specified, haloalkyl refers to fluoromethyl, difluoromethyl, chloromethyl, trifluoromethyl or 2,2,2-trifluoromethyl.

[0076] As used herein, "alkoxy" refers to an -O-alkyl group or an alkyl-O- group, where the alkyl group is as defined above. For example, examples of "alkoxy" include methoxy, ethoxy, n-propoxy, n-butoxy, and t-butoxy.

[0077] As used herein, "alkoxyalkyl" refers to an alkyl-O-alkyl group, where the alkyl group is as defined above. Examples of "alkoxyalkyl" include, but are not limited to, methoxymethyl, ethoxymethyl, methoxyethyl, or isopropoxymethyl.

[0078] As used herein, "hydroxy" or "hydroxyl," used alone or in combination with another term, refers to --OH.

[0079] As used herein, "cyano" refers to -CN and "cyanoalkyl" refers to an alkyl substituted with -CN. The alkyl group is as defined above.

[0080] As used herein, "amino" refers to --NH.sub.2 and "nitro" refers to --NO.sub.2.

[0081] As used herein, "carboxy" refers to the group -C(O)-OH.

[0082] As used herein, "ester" refers to the group -C(O)-OR, where R is alkyl and C 1-10 may be alkyl, C 1-8 Alkyl, C 1-6 Alkyl or C 1-4 Preferably, it is alkyl. Such ester groups may be unsubstituted or substituted with one or more suitable substituents.

[0083] As used herein, "cycloalkyl" refers to a substituted or unsubstituted cyclic alkyl. For example, C 3-20 Cycloalkyl refers to a monovalent saturated hydrocarbon ring system having 3 to 20 carbon atoms. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like. Cycloalkyl, unless otherwise specified, is preferably C 3-8 Cycloalkyl or C3-6 It may also be cycloalkyl.

[0084] As used herein, "aryl" refers to, for example, an aromatic ring system having 6 to 20 carbon atoms (C 6-20 Aryl refers to a monovalent aromatic hydrocarbon of any one of the following formulas: Aryl may include bicyclic groups containing an aromatic ring fused to a saturated or partially unsaturated ring. Examples of aryl groups include groups derived from benzene (phenyl), substituted phenyl, biphenyl, naphthyl, toluyl, naphthalenyl, anthracenyl, indenyl, indanyl, and the like. Unless otherwise specified, aryl refers to any one of the following formulas: 6-12 Aryl, C 6-10 It is preferably aryl.

[0085] In the present specification, "heteroaryl" refers to a monovalent or divalent substituent derived from a heteromonocyclic aromatic hydrocarbon or heteropolycyclic aromatic hydrocarbon having a 1-10 carbon member ring containing one or more (preferably 1 to 3) heteroatoms selected from N, O, and S. Examples of heteroaryl include thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,4-thiadiazolyl, 1,3 ... Examples of heteroaryl include, but are not limited to, 3,4-thiadiazolyl, triazolyl, tetrazolyl, triazinyl, indolyl, and the like. Examples of bicyclic heteroaryl include, but are not limited to, indolyl, benzothiophenyl, benzofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzthiazolyl, benzthiadiazolyl, quinolinyl, isoquinolinyl, purinyl, furopyridinyl, octahydropyranopyridine, benzodioxolyl, and the like. Unless otherwise specified, heteroaryl is a C 3-10 Heteroaryl, C 3-7 Heteroaryl is preferred, C 3-5 More preferably, it is heteroaryl.

[0086] In the present specification, "heterocycloalkyl" refers to a 3-10 carbon membered monocyclic alkyl, bicyclic alkyl, tricyclic alkyl or alkyl having more rings containing one or more (e.g., 1 to 4) heteroatoms selected from N, O and S. Furthermore, the heterocycloalkyl in the present invention may be a fused heterocycloalkyl or a bridged heterocycloalkyl. Examples of non-aromatic rings include azetidinyl, oxetanyl, tetrahydrothienyl, tetrahydrofuranyl, pyrrolinyl, pyrrolidinyl, imidazolinyl, imidazolidinyl, oxazolinyl, oxazolidinyl, oxapiperazinyl, oxapiperidinyl, pyrazolinyl, pyrazolidinyl, thiazolinyl, thiazolidinyl, tetrahydrofuranyl, tetrahydrofuryl, tetrahydroisothiazolyl, tetrahydrooxazolyl, tetrahydroisoxazolyl, piperidinyl, piperazinyl, tetrahydropyranyl, dihydropyranyl, tetrahydropyridinyl, dihydropyridinyl, dihydrothiopyranyl, tetrahydropyrimidinyl, Examples of heterocycloalkyl include, but are not limited to, tetrahydropyridazinyl, dihydropyranyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, indolinyl, indolinylmethyl, thiomorpholinyl, azepanyl, diazepanyl, N-oxide, azaadamantanyl, and diazamatanyl. Substitution by heterocycloalkyl may be via a carbon atom or a heteroatom. Heterocycloalkyl groups may be substituted with one or more suitable groups via one or more of the above groups. Unless otherwise specified, heterocycloalkyl refers to a heterocycloalkyl having 3 to 10 carbon members, and includes C 3-7 Heterocycloalkyl is preferable, and heterocycloalkyl having 3 to 5 carbon members is more preferable.

[0087] "Substituted" means, unless otherwise specified, a halogen atom (e.g., F, Cl, Br, or I), a cyano group, a hydroxyl group, a thiol group, a nitro group, an amino group, an imino group, an azide group, an amidino group, a hydrazino group, a hydrazono group, an oxo group, a carbonyl group, a carbamyl group, an ester group, an ether group, a carboxyl group or a salt thereof, a sulfonic acid group or a salt thereof, a phosphoric acid group or a salt thereof, a C 1-6 Alkyl group, haloC 1-6 Alkyl group, C 2-6 Alkenyl group, haloC 2-6 Alkenyl group, C 2-6 Alkynyl group, haloC 2-6 Alkynyl group, C 1-6 Alkoxy group, haloC 1-6 Alkoxy group, C 1-20 Alkylthio group, C 3-20 Carbocyclic groups (e.g., C 3-9 Cycloalkyl groups, haloC 3-9 Cycloalkyl groups, C 3-9 Cycloalkenyl group, haloC 3-9 Cycloalkenyl group, C 1-9 Heterocycloalkyl groups, haloC 1-9 Heterocycloalkyl groups, C 2-9 Heterocycloalkenyl group, haloC 2-9 Heterocycloalkenyl group) and C 1-20 Heterocyclic groups (e.g., C 6-20 Aryl group, C 6-20 Aryloxy group, C 6-20 Arylthio group, C 2-20 Heteroaryl groups, C 2-20 Heteroaryloxy group, C 2-20 It means that at least one hydrogen atom is substituted with 1 to 3 substituents selected from the group consisting of heteroarylthio groups.

[0088] Aryl Hydrocarbon Receptor The aryl hydrocarbon receptor ("AhR") is a ligand-dependent member of the basic helix-loop-helix transcription factor family that is known to be activated by a large number of structurally diverse synthetic and natural compounds, including polycyclic aromatic hydrocarbons, indoles, and flavonoids. In the unliganded state, AhR resides in a cytoplasmic compartment in a latent state associated with two molecular chaperones, heat shock protein 90 ("hsp90"), the immunophilin-like protein XAP2, and the hsp90-interacting protein p23.

[0089] As used herein, "aryl hydrocarbon receptor" or "AhR" refers to an 848 amino acid long polypeptide, e.g., designated NP_001612, as well as naturally occurring allelic variants, naturally occurring splice variants, and processed forms thereof. AhR generally refers to human AhR. Additionally, "AhR" refers to truncated forms or fragments of the AhR polypeptide, e.g., truncated forms or fragments that contain a particular AhR domain. Such forms of AhR are referred to herein, e.g., as "AhR(122-224)".

[0090] AhR Modulators The present inventors have found that the novel AhR modulator compounds described herein (e.g., small molecule compounds of formula (I)) can modulate the activity of constitutive AhR by acting as AhR antagonists. Furthermore, the present inventors have found that the AhR modulator compounds can inhibit cancer cell proliferation, as well as tumor invasion, metastasis and angiogenesis. Thus, the present invention describes novel modulators of AhR and novel modulators of constitutive AhR signaling for use in therapeutic compositions and methods for treating and inhibiting cancer proliferation and tumor cell invasion, as well as immune-related diseases, such as autoimmune diseases.

[0091] AhR mediates various functional responses. AhR-mediated functional responses include, but are not limited to, de novo transcription of target genes and AhR gene batteries that have response elements such as DRE and XRE with the sequence 5'-TNGCGTG-3'. Alternative AhR signaling pathways have also been reported, including binding to retinoblastoma protein, estrogen receptor (ER) or transcription factor E2F1, and binding to NFκB pathway subunits RelA and RelB. AhR also acts as a ubiquitin ligase. Thus, AhR-mediated signaling includes multiple pathways, including, for example, constitutive and non-constitutive AhR signaling pathways, or constitutive and non-constitutive signaling activity (as these terms are defined herein).

[0092] As used herein, "constitutive AhR signaling" refers to one or more AhR-mediated or AhR-regulated signaling pathways activated or induced by one or more endogenous AhR ligands or one or more environmental factors (e.g., toxins or pollutants) that result in constitutive or long-term nuclear translocation of AhR, or that result in activation or regulation of one or more AhR gene batteries involved in unregulated cell growth and proliferation, tumor cell invasion, or a combination thereof.

[0093] As used herein, "non-constitutive AhR signaling" refers to one or more AhR-mediated or AhR-induced signaling pathways that do not result in constitutive or long-term nuclear translocation of AhR, nor in activation or modulation of one or more AhR gene batteries involved in unregulated cell growth and proliferation, tumor cell invasion, or a combination thereof. In some embodiments, non-constitutive AhR signaling does not result in upregulation of expression of CYP1A1 or CYP1B1, or a combination thereof.

[0094] Thus, as used herein, "AhR modulator" refers to an agent (e.g., a compound of formula (I)) that modulates, induces, or promotes a qualitative or quantitative change, alteration, or regulation of one or more processes, mechanisms, effects, reactions, functions, activities, or pathways mediated by the AhR receptor. Such changes mediated by AhR modulators (e.g., antagonists of AhR as described herein) may refer to a decrease, inhibition, or conversion of the constitutive activity of AhR. "Expression" refers to the cellular processes involved in the production of RNA and proteins (secreted proteins, as the case may be), including, but not limited to, transcription, translation, folding, modification, and processing. "Expression product" includes RNA transcribed from a gene, and polypeptides obtained by translation of mRNA transcribed from a gene.

[0095] The term "modulation" as used in connection with AhR modulators is used in the same sense as it is used in the art, for example, to mean inducing or promoting a qualitative or quantitative change, alteration or regulation of one or more biological processes, mechanisms, effects, responses, functions, activities, pathways or other phenomena of interest. Thus, as used herein, "modulation" refers to a qualitative or quantitative change, alteration or regulation of one or more processes, mechanisms, effects, responses, functions, activities or pathways mediated by the AhR receptor.

[0096] The term "agent" as used herein in relation to AhR modulators refers to any compound or substance, including, but not limited to, small molecules, nucleic acids, polypeptides, peptides, drugs, ions, etc. An "agent" can be any chemical, substance, or moiety, including, but not limited to, synthetic or natural proteinaceous or non-proteinaceous substances. In some embodiments, the agent is a nucleic acid, a nucleic acid analog, a protein, an antibody, a peptide, an aptamer, a nucleic acid oligomer, an amino acid, or a sugar chain, including, but not limited to, a protein, an oligonucleotide, a ribozyme, a DNAzyme, a glycoprotein, an siRNA, a lipoprotein, an aptamer, variants thereof, combinations thereof, etc. In certain embodiments, as described herein, the agent is a small molecule having a chemical moiety, including, for example, a substituted or unsubstituted alkyl moiety, an aromatic moiety, or a heterocyclyl moiety. The compound may be a compound known to have a desired activity and / or property, e.g., a compound known to be capable of modulating the activity of AhR, and may be selected from a library containing various compounds, e.g., by using the screening methods described herein.

[0097] In some embodiments, the AhR modulator selectively binds to AhR. As used herein, "selectively binds" or "specifically binds" refers to an AhR antagonist as described herein that selectively binds to AhR. -5 K below M(10000nM) D , e.g., 10 -6 M or less, 10 -7 M or less, 10 -8 M or less, 10 -9 M or less, 10 -10 M or less, 10 -11 M or less or 10 -12 K below M D For example, the antagonists described herein can bind to a target (e.g., AhR) at 10 -5 K below MD The antagonist is said to specifically bind to AhR if it binds to AhR at the target site but not to other molecules or related homologues. Specific binding may be influenced, for example, by the affinity and avidity of the antagonist, as well as the concentration of the antagonist used. Those skilled in the art can use suitable methods, such as titration of AhR antagonists using suitable cell binding assays, as described herein, to determine suitable conditions under which the antagonists described herein selectively bind.

[0098] In some embodiments of the compositions and methods described herein, the AhR modulator is an AhR antagonist having the chemical structure shown in formula (I) described herein.

[0099] In the present specification, AhR is an "AhR antagonist". An AhR antagonist refers to an AhR inhibitor that does not induce a biological response by itself when specifically bound to AhR, but can block or reduce the response mediated by AhR agonist or AhR ligand. That is, an AhR antagonist can bind to AhR, but does not activate AhR, and by binding to AhR, it disrupts the interaction with AhR agonist, replaces AhR agonist, and / or suppresses the function of AhR agonist. Thus, as described herein, an AhR antagonist does not function as an inducer of AhR activity when bound to AhR, i.e., it functions as a pure AhR inhibitor. In some embodiments, an AhR antagonist selectively binds to AhR.

[0100] In some embodiments of these aspects, the AhR antagonists described herein, such as, for example, compounds of formula (I), block constitutive AhR effector functions that mediate established tumor growth and progression. In another embodiment, the small molecule AhR antagonists of formula (I) described herein act as chemical inhibitors by inhibiting AhR-mediated CYP1A1 induction and mutagenesis upon exposure to environmental factors (ligands).

[0101] In some embodiments of these aspects, the AhR antagonists of formula (I) described herein suppress the induction of early malignant transformation by constitutively active AhR. In some embodiments, the compounds of formula (I) described herein suppress the proliferation of cancer cells or tumor cells via constitutive AhR signaling. In some embodiments, the compounds of formula (I) described herein suppress the induction of malignant transformation by tumor invasion via constitutive AhR signaling.

[0102] Thus, there is provided an AhR antagonist according to formula (I) for use in the various embodiments described herein.

[0103] One aspect of the present invention relates to novel compounds capable of modulating the human aryl hydrocarbon receptor (AhR), which specifically bind to the AhR.

[0104] In some embodiments, the compound or an enantiomer, diastereomer, racemate, solvate, hydrate, or pharma- ceutically acceptable salt thereof has the formula (I): [ka] (In the formula, Ar 1 and Ar 2 is halo, substituted or unsubstituted monocyclic or bicyclic C 6-10 Aryl, substituted or unsubstituted monocyclic or bicyclic C 5-10Heteroaryl and substituted or unsubstituted monocyclic or bicyclic C 3-10 heterocycloalkyl; L is absent (direct bond) or is H, halo, cyano, hydroxy, amino, nitro, ether (-O-), thioether (-S-), sulfinyl (-SO-), sulfonyl (-SO2-), sulfonylamido (-SO2NR 2 -), aminosulfonyl (-NR 2 SO2-), carbonyl (-(CO)-), amide (-(CO)NR 2 -), reverse amide (-NR 2 (CO)-), esters (-(CO)O-), substituted or unsubstituted C 1-5 Alkyl, substituted or unsubstituted monocyclic or bicyclic C 3-10 Cycloalkyl, substituted or unsubstituted monocyclic or bicyclic C 4-10 Heterocycloalkyl, substituted or unsubstituted monocyclic or bicyclic C 6-10 Aryl or substituted or unsubstituted monocyclic or bicyclic C 5-10 is heteroaryl; R 1 is absent (direct bond) or H, halo, cyano, hydroxy, amino, NHR 3 , OR 3 , phosphate, substituted or unsubstituted C 1-3 Alkyl phosphates, substituted or unsubstituted C 1-5 Alkyl, sulfinic acid (-SO-H), sulfonic acid (-SO2-H), sulfonyl amide (-SO2NR 2 2), aminosulfonic acid (-NR 2 SO2-H), carboxylic acid (-(CO)-H), carbonyl (-(CO)R 2 ), amide (-(CO)NR 2 2) Reverse alkyl amide (-NH(CO)-R 2 ), alkyl ester (-(CO)OR 2 ), sulfonates (-SO2-R 2 ), C 3-10 Cycloalkyl, C 1-5 Alkyl hydroxy, C1-5 Alkenylhydroxy, C 1-5 Alkynylhydroxy, C 1-5 Alkylamines, C 1-5 Alkenylamines, C 1-5 Alkynylamines, substituted or unsubstituted monocyclic or bicyclic C 3-10 Heterocycloalkyl or substituted or unsubstituted monocyclic or bicyclic C 5-10 is heteroaryl; R 2 is H, halo, hydroxy, amino, substituted or unsubstituted C 1-5 Alkyl, substituted or unsubstituted C 1-5 Alkoxy, substituted or unsubstituted C 3-8 Cycloalkyl, or substituted or unsubstituted C 1-5 It is an alkyl carboxylic acid; R 3 is H, substituted or unsubstituted, C 1-5 Alkyl, C 1-5 Alkylacetyl (alkyl-CO-), C 1-5 Sulfonylalkyl (alkyl-SO2-), C 1-5 Sulfonylamidoalkyl (alkyl-SO2NR 2 2) C 1-5 Amidoalkyl (alkyl-(CO)NR 2 2) or C 1-5 Reverse Amido Alkyl (Alkyl-NR 2 (CO)-), substituted or unsubstituted C 1-5 Alkoxy, or substituted or unsubstituted C 1-5 (Alkyl carboxylic acid) It has a structure shown below.

[0105] In one preferred embodiment, Ar 1 and Ar 2 each independently represents halo, a substituted or unsubstituted monocyclic or bicyclic C 6-10 Substituted or unsubstituted monocyclic C containing one or more heteroatoms selected from the group consisting of aryl, N, O and S 5-7Heteroaryl or substituted or unsubstituted monocyclic C containing one or more heteroatoms selected from the group consisting of N, O and S 5-7 More preferably, Ar 1 and Ar 2 each independently represents a monocyclic C ring containing 1 or 2 heteroatoms selected from the group consisting of phenyl, N, O and S; 5-6 Heteroaryl or monocyclic C containing 1 or 2 heteroatoms selected from the group consisting of N, O and S 5-6 These groups may be unsubstituted or substituted with halo, hydroxyl, amino, C 1-3 Alkyl or C 1-3 The C may be substituted with alkoxy. 1-3 Alkyl or the C 1-3 The alkoxy may be unsubstituted or substituted with 1 to 3 halo.

[0106] More preferably, Ar 1 and Ar 2 may each independently be phenyl, imidazole, pyridine, pyrimidine, piperidine or morpholine. More preferably, Ar 1 and Ar 2 may be unsubstituted or substituted with Cl, CH3 or CF3.

[0107] In a preferred embodiment, L is absent (direct bond) or is H, halo, cyano, hydroxy, amino, nitro, ether (-O-), thioether (-S-), sulfinyl (-SO-), sulfonyl (-SO2-), sulfonylamido (-SO2NR 2 -), aminosulfonyl (-NR 2 SO2-), carbonyl (-(CO)-), amide (-(CO)NR 2 -), reverse amide (-NR 2 (CO)-), esters (-(CO)O-), substituted or unsubstituted monocyclic or bicyclic C 3-8Cycloalkyl, substituted or unsubstituted monocyclic or bicyclic C 3-8 Heterocycloalkyl, substituted or unsubstituted monocyclic or bicyclic C 6-10 Aryl or substituted or unsubstituted monocyclic or bicyclic C 5-8 heteroaryl; said monocyclic or bicyclic C 3-8 Heterocycloalkyl and the monocyclic or bicyclic C 5-8 The heteroaryl contains one or more (preferably 1 to 3) heteroatoms selected from the group consisting of N, O and S.

[0108] More preferably, L is absent (direct bond) or H, substituted or unsubstituted C. 1-5 Alkyl, 1,1-dioxide tetrahydrothiopyran, piperidine, or substituted or unsubstituted monocyclic or bicyclic C 3-6 cycloalkyl; 1-5 Alkyl and the substituted or unsubstituted monocyclic or bicyclic C 3-6 Cycloalkyl is hydroxyl, halo, haloC 1-3 Alkyl and C 1-3 It may be substituted with one or more (preferably 1 to 3) substituents selected from the group consisting of alkyl.

[0109] In a preferred embodiment, R 1 is absent or is H, halo, cyano, hydroxy, amino, N(R 3 )2, OR 3 , substituted or unsubstituted C 1-4 Alkyl, carbonyl ((-(CO)R 2 ), C 3-8 Cycloalkyl, C 1-4 Alkyl hydroxy, C 1-4 Alkenylhydroxy, C 1-4 Alkynylhydroxy, C 1-4 Alkylamines, C 1-4 Alkenylamines, C 1-4 Alkynylamines, substituted or unsubstituted monocyclic or bicyclic C 3-8Heterocycloalkyl or substituted or unsubstituted monocyclic or bicyclic C 5-8 heteroaryl; said monocyclic or bicyclic C 3-8 Heterocycloalkyl and the monocyclic or bicyclic C 5-8 Heteroaryl contains one or more (preferably 1 to 3) heteroatoms selected from the group consisting of N, O and S. More preferably, R 1 is absent, H, hydroxyl, -NH, -NH-C(O)CH, -NH-SO-CH, -C(O)OH, -SO-CH, -OC(O)-CH, -OP(=O)(OCHCH), -C(O)CH or hydroxyl.

[0110] Moreover, in a more specific embodiment, the compound of formula (I) is 1. 3-(3-hydroxycyclohexyl)-8-(1-methyl-1H-pyrazol-4-yl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one; 2. 3-(3-hydroxycyclohexyl)-6,8-bis(1-methyl-1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; 3. 3-(1-hydroxypropan-2-yl)-6,8-bis(1-methyl-1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; 4. 3-(1-hydroxypropan-2-yl)-6-(1-methyl-1H-pyrazol-4-yl)-8-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one; 5. 8-(4-chlorophenyl)-3-(1-hydroxypropan-2-yl)-6-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; 6. 3-(1-hydroxypropan-2-yl)-6,8-bis(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one; 7. 2-(6-chloro-8-(4-chlorophenyl)-4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)propyl acetate; 8. 3-((1r,4r)-4-hydroxycyclohexyl)-8-(1-methyl-1H-pyrazol-4-yl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one; 9. 3-((1r,4r)-4-hydroxycyclohexyl)-6,8-bis(1-methyl-1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; 10. 6-(4-chlorophenyl)-3-((1r,4r)-4-hydroxycyclohexyl)-8-(1-methyl-1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; 11. 3-(2-hydroxypropyl)-6,8-bis(1-methyl-1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; 12. 3-(2-hydroxypropyl)-8-(1-methyl-1H-pyrazol-4-yl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one; 13. 6-(4-chlorophenyl)-3-(2-hydroxypropyl)-8-(1-methyl-1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; 14. 3-(2-hydroxypropyl)-8-(1-methyl-1H-pyrazol-4-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; 15. 3-((1S,2R)-2-hydroxycyclohexyl)-8-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one; 16. 3-((1R,2S)-2-Hydroxycyclohexyl)-8-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one; 17. 3-((1S,2R)-2-hydroxycyclohexyl)-8-(1-methyl-1H-pyrazol-4-yl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one; 18. 3-((1R,2S)-2-hydroxycyclohexyl)-8-(1-methyl-1H-pyrazol-4-yl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one; 19. 3-((1R,2S)-2-hydroxycyclohexyl)-8-(1-methyl-1H-pyrazol-4-yl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one; 20. 6-(4-chlorophenyl)-3-((1S,2R)-2-hydroxycyclohexyl)-8-(1-methyl-1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; 21. 6-(4-chlorophenyl)-3-((1S,2R)-2-hydroxycyclohexyl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; 22. 8-(1-methyl-1H-pyrazol-4-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one; 23. 6-(4-chlorophenyl)-8-(1-methyl-1H-pyrazol-4-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)pyrido[3,4-d]pyrimidin-4(3H)-one; 24. 6-(4-chlorophenyl)-8-(pyridin-3-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)pyrido[3,4-d]pyrimidin-4(3H)-one; 25. 8-(Pyridin-3-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one; 26. 6-(4-chlorophenyl)-3-(3-hydroxyphenyl)-8-(1-methyl-1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; 27. 3-(3-hydroxyphenyl)-8-(1-methyl-1H-pyrazol-4-yl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one; 28. 6-(4-chlorophenyl)-3-((1R,3S)-3-hydroxycyclopentyl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; 29. 3-((1R,3S)-3-Hydroxycyclopentyl)-8-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one; 30. 6-(4-chlorophenyl)-3-((1R,3S)-3-hydroxycyclopentyl)-8-(1-methyl-1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; 31. 3-((1R,3S)-3-hydroxycyclopentyl)-8-(1-methyl-1H-pyrazol-4-yl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one; 32. 6-(4-chlorophenyl)-3-((1S,3R)-3-hydroxycyclopentyl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; 33. 3-((1S,3R)-3-hydroxycyclopentyl)-8-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one; 34. 6-(4-chlorophenyl)-3-((1S,3R)-3-hydroxycyclopentyl)-8-(1-methyl-1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; 35. 3-((1S,3R)-3-hydroxycyclopentyl)-8-(1-methyl-1H-pyrazol-4-yl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one; 36. 1-(6-(4-chlorophenyl)-4-oxo-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-3(4H)-yl)-2-methylpropan-2-yl acetate; 37. 2-methyl-1-(4-oxo-8-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidin-3(4H)-yl)propan-2-yl acetate; 38. 6-(4-chlorophenyl)-3-(2-hydroxy-2-methylpropyl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; 39. 3-(2-Hydroxy-2-methylpropyl)-8-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one; 40. 3-(2-hydroxy-2-methylpropyl)-8-(pyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; 41. 6-(4-chlorophenyl)-3-(1-hydroxy-3-methylbutan-2-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; 42. 3-(1-hydroxy-3-methylbutan-2-yl)-8-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one; 43. 3-(1-hydroxy-3-methylbutan-2-yl)-8-(pyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; 44. (S)-2-((6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)amino)propan-1-ol; 44. 3-(1-hydroxypropan-2-yl)-8-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one; 45. 3-(1-hydroxypropan-2-yl)-8-(1-methyl-1H-pyrazol-4-yl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one; 46. ​​6-(4-chlorophenyl)-3-(1-hydroxypropan-2-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; 47. Diethyl 2-(6-(4-chlorophenyl)-4-oxo-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-3(4H)-yl)propyl phosphate; 48. 6-(4-chlorophenyl)-3-(1-hydroxypropan-2-yl)-8-(1-methyl-1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; 49. 3-(1-hydroxypropan-2-yl)-8-(pyridin-3-yl)-6-(4-(trifluoromethoxy)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one; 50. 3-(1-hydroxypropan-2-yl)-8-(pyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; 51. 6-(4-chlorophenyl)-3-(1-hydroxybutan-2-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; 52. 6-(4-chlorophenyl)-3-(1-hydroxybutan-2-yl)-8-(1-methyl-1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; 53. 3-(1-Hydroxybutan-2-yl)-8-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one; 54. 3-(1-hydroxybutan-2-yl)-8-(1-methyl-1H-pyrazol-4-yl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one; 55. 6-(4-chlorophenyl)-8-(3-fluorophenyl)-3-(1-hydroxybutan-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; 56. 6-(4-Chlorophenyl)-3-((1r,4r)-4-hydroxycyclohexyl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; 57. 3-((1r,4r)-4-Hydroxycyclohexyl)-8-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one; 58. 6-(4-Chlorophenyl)-3-((1s,4s)-4-hydroxycyclohexyl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; 59. 3-(1-hydroxypropan-2-yl)-8-(1-methyl-1H-pyrazol-4-yl)-6-(4-(trifluoromethyl)phenyl)-2,3-dihydropyrido[3,4-d]pyrimidin-4(1H)-one; 60. 6-(4-chlorophenyl)-3-(2,3-dihydroxypropyl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; 61. 6-(4-chlorophenyl)-3-(3-hydroxyphenyl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; 62. 3-(3-hydroxyphenyl)-8-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one; 63. 6-(4-chlorophenyl)-3-(3-hydroxycyclohexyl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; 64. 6-(4-chlorophenyl)-3-(3-hydroxycyclohexyl)-8-(1-methyl-1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; 65. 3-((1R,3S)-3-Hydroxycyclopentyl)-8-(pyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; 65. 3-((1R,3S)-3-Hydroxycyclopentyl)-8-(pyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; 66. 3-(2,3-dihydroxypropyl)-8-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one; 67. 6-(4-chlorophenyl)-3-(2,3-dihydroxypropyl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; 68. 3-(2,3-dihydroxypropyl)-6-(4-(4-methylpiperazin-1-yl)phenyl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; 69. 3-(1,3-dihydroxypropan-2-yl)-8-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one; 70. 6-(4-chlorophenyl)-3-(1,3-dihydroxypropan-2-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; 71. 6-(6-chloropyridin-3-yl)-3-((1R,3S)-3-hydroxycyclopentyl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; 72. 3-((1R,3S)-3-Hydroxycyclopentyl)-8-(pyridin-3-yl)-6-(2-(trifluoromethyl)pyrimidin-5-yl)pyrido[3,4-d]pyrimidin-4(3H)-one TFA salt; 73. 3-((1R,3S)-3-Hydroxycyclopentyl)-6-(4-morpholinophenyl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; 74. 6-(4'-chloro-[1,1'-biphenyl]-4-yl)-3-(1-hydroxypropan-2-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; 75. 3-(1-hydroxypropan-2-yl)-6-(4-morpholinophenyl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; 76. 3-(2-(methylsulfonyl)ethyl)-8-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one; 76. 3-(2-(methylsulfonyl)ethyl)-8-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one; 77. 6-(4-chlorophenyl)-3-(2-(methylsulfonyl)ethyl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; 78. 3-(1,1-dioxidetetrahydro-2H-thiopyran-4-yl)-6-(4-morpholinophenyl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; 79. 3-(2-(methylsulfonyl)ethyl)-6-(4-morpholinophenyl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; 80. 3-(1,3-dihydroxypropan-2-yl)-6-(4-morpholinophenyl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; 80. 3-(1,3-dihydroxypropan-2-yl)-6-(4-morpholinophenyl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; 81.(R)-3-(2,3-dihydroxypropyl)-8-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one; 82. 3-(2,3-dihydroxypropyl)-6-(4-morpholinophenyl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; 83. 2-(6-(4-chlorophenyl)-4-oxo-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-3(4H)-yl)propanoic acid 2,2,2-trifluoroacetate; 84. 2-(4-oxo-8-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidin-3(4H)-yl)propanoic acid 2,2,2-trifluoroacetate; 86. N-(2-(4-oxo-8-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidin-3(4H)-yl)propyl)acetamide; 85. 3-(1-aminopropan-2-yl)-8-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one; 86. N-(2-(4-oxo-8-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidin-3(4H)-yl)propyl)acetamide; 87. 3-(1-aminopropan-2-yl)-6-(4-chlorophenyl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; 88.N-(2-(6-(4-chlorophenyl)-4-oxo-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-3(4H)-yl)propyl)acetamide; 89. N-(2-(6-(4-chlorophenyl)-4-oxo-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-3(4H)-yl)propyl)methanesulfonamide; 90. 3-(1-aminopropan-2-yl)-6-(4-morpholinophenyl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; 91. N-(2-(6-(4-morpholinophenyl)-4-oxo-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-3(4H)-yl)propyl)methanesulfonamide; 92. N-(2-(6-(4-morpholinophenyl)-4-oxo-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-3(4H)-yl)propyl)acetamide; 93. 3-(piperidin-4-yl)-8-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one; 94. 6-(4-chlorophenyl)-3-(1-(methylsulfonyl)piperidin-4-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; 95. 6-(4-chlorophenyl)-3-(1-(cyclopropylsulfonyl)piperidin-4-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; and 96. 3-(1-Acetylpiperidin-4-yl)-6-(4-chlorophenyl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one The compound may be a compound selected from the group consisting of:

[0111] The compounds of the present invention may be synthesized by methods known in the art or as illustrated in Examples 1-96 below.

[0112] Pharmaceutical Compositions, Methods and Uses In one particular embodiment, the pharmaceutical compositions and methods of the invention comprise a compound of formula (I), or an enantiomer, diastereomer, racemate, solvate, hydrate, or a pharma- ceutically acceptable salt thereof.

[0113] The subject may be a mammal, including a human cell or a mammalian cell, for example a mammal (e.g., a human) suffering from a disease, disorder or condition associated with activity of the AhR as described above, or a mammalian cell isolated from such a mammal.

[0114] The compound of the present invention as an active ingredient or the pharmaceutical composition of the present invention may be administered orally or parenterally. For example, parenteral administration may be performed by any of intravenous injection, subcutaneous injection, intramuscular injection, intraperitoneal injection, intradermal administration, topical administration, intranasal administration, intrapulmonary administration, and intrarectal administration.

[0115] An effective amount may refer to a pharma- ceutical effective amount and / or a therapeutically effective amount, and may be formulated depending on factors such as the type of preparation, route of administration, age, weight, sex, and / or medical condition of the patient.

[0116] Pharmaceutically acceptable salts of the compounds of formula (I) include, but are not limited to, addition salts formed with inorganic acids, such as hydrochloride, sulfate, phosphate, hydrobromide, hydroiodide, nitrate, pyrosulfate, metaphosphate, and the like; addition salts formed with organic acids, such as citrate, oxalate, benzoate, acetate, trifluoroacetate, propionate, succinate, fumarate, lactate, maleate, tartrate, glutarate, sulfonate, and the like; and metal salts, such as lithium, sodium, potassium, magnesium, calcium salts.

[0117] The pharmaceutical composition of the present invention can be formulated into an appropriate form together with a commonly used pharma- ceutically acceptable carrier. "Pharmaceutically acceptable" refers to being physiologically acceptable, and when administered to humans, it usually does not cause allergic reactions or similar reactions (such as gastrointestinal disorders or dizziness). Furthermore, the pharmaceutical composition of the present invention may be formulated into oral preparations such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, and aerosols, or parenteral preparations such as transdermal preparations, suppositories, and sterile injections, according to conventional methods, before use.

[0118] Examples of carriers, additives and diluents that can be added to the composition of the present invention include, but are not limited to, lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gum arabic, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methylcellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methyl hydroxybenzoate, propyl hydroxybenzoate, talc, magnesium stearate, and mineral oil. When preparing a formulation, diluents and additives such as commonly used fillers, stabilizers, binders, disintegrants, surfactants, etc. can be used. Solid preparations for oral administration include tablets, pills, powders, granules, capsules, etc., and such solid preparations may be prepared by mixing the compound of the present invention with at least one additive such as starch, microcrystalline cellulose, sucrose, lactose, low-substituted hydroxypropyl cellulose, and hypromellose. In addition to simple additives, lubricants such as magnesium stearate and talc are also used. Liquid preparations for oral administration include suspensions, oral liquids, emulsions, syrups, etc. In addition to commonly used simple diluents such as water and liquid paraffin, various additives such as moisturizers, sweeteners, flavors, and preservatives may be added. Preparations for parenteral administration include sterile aqueous solutions, non-aqueous solutions, suspensions, emulsions, freeze-dried preparations, and suppositories. Non-aqueous solutions or suspensions may contain propylene glycol, polyethylene glycol, vegetable oils such as olive oil, injectable esters such as ethyl oleate, etc. As bases for suppositories, witepsol, macrogol, tween 61, cacao butter, laurin butter, glycerogelatin, etc. may be used. In preparing a formulation for parenteral administration, a compound of formula (I) or a pharma- ceutically acceptable salt thereof may be mixed in sterile water with auxiliary substances such as preservatives, stabilizers, adjuvants such as wetting agents and emulsifiers, salts and / or buffers for adjusting osmotic pressure, and other substances useful for treatment to prepare a solution or suspension, and the resulting solution or suspension is manufactured into a unit dosage form in an ampoule or vial.

[0119] Pharmaceutical compositions containing as an active ingredient a compound of formula (I) disclosed herein may be administered by various routes to mammals, such as mice, livestock, and humans, for the purposes of modulating the activity of the AhR or preventing or treating a disease, disorder, or condition associated with the activity of the AhR.

[0120] In some embodiments, the disease, disorder or condition associated with activity of AhR may be a cancer, a cancerous condition, a tumor, a fibrotic disease, an immune-related disease or other disease associated with AhR signaling.

[0121] In some embodiments, the disease associated with dysregulation of immune response associated with AhR signaling is selected from the group consisting of sepsis (SIRS), multiple organ failure (MODS, MOF), inflammatory kidney disease, chronic bowel inflammation (IBD, Crohn's disease, UC), pancreatitis, peritonitis, inflammatory skin disease, inflammatory eye disease, and autoimmune diseases (rheumatic diseases such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE) and multiple sclerosis (MS)).

[0122] In some embodiments, the fibrotic disease is selected from the group consisting of fibrotic disease of internal organs such as lung, heart, kidney, bone marrow (particularly liver fibrosis), skin fibrosis and eye fibrotic disease.In the present invention, "fibrotic disease" specifically includes liver fibrosis, liver cirrhosis, pulmonary fibrosis, endomyocardial fibrosis, nephropathy, glomerulonephritis, renal interstitial fibrosis, fibrotic disorder associated with diabetes, myelofibrosis and fibrotic diseases similar thereto; and scleroderma, mottled scleroderma, keloid, hypertrophic scar (hypertrophic scar after surgery), nevus, diabetic retinopathy, proliferative vitreoretinopathy and connective tissue disorder (e.g., sarcoidosis).

[0123] In some embodiments, cancers, cancerous conditions or tumors that are particularly suitable for treatment with the AhR antagonists of the invention are liquid and solid tumors, such as breast cancer, squamous cell carcinoma, lung cancer, peritoneal cancer, hepatocellular carcinoma, gastric cancer, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, hepatoma, colon cancer, colorectal cancer, endometrial cancer, uterine cancer, salivary gland cancer, kidney cancer, prostate cancer, vulvar cancer, thyroid cancer, head and neck cancer, B-cell lymphoma, chronic lymphocytic leukemia (CLL), acute lymphoblastic leukemia (ALL), hairy cell leukemia, chronic myeloblastic leukemia, and the like.

[0124] In some embodiments, the pharmaceutical compositions of the present invention can be used in combination with one or more additional anti-cancer therapies. In some such embodiments, the additional anti-cancer therapies include surgery, radiation therapy, biological therapy, immunotherapy, chemotherapy, or any combination thereof.

[0125] In some embodiments, the pharmaceutical compositions of the present invention can be used in combination with an anti-cancer therapeutic agent, which in some such embodiments is a chemotherapeutic agent, an anti-proliferative agent, an anti-angiogenic agent, a cytotoxic agent, an anti-hormonal agent, a prodrug, or a cytokine.

[0126] Other examples of disorders associated with inflammation through aberrant AhR signaling include vaccination against infectious diseases, cancer, viral infections, obesity and diet-induced obesity, steatosis, metabolic diseases, hepatic steatosis, uterine fibroids in women (uterine leiomyomas or fibroids), chronic renal injury, acute and chronic renal failure, diabetic nephropathy, inflammatory nephropathy, hypertensive nephropathy, heart failure, angina pectoris, hypertension, pulmonary hypertension, ischemia, vascular disorders, thromboembolic disorders, arteriosclerosis, sickle cell anemia, erectile dysfunction, benign prostatic hyperplasia, voiding disorders associated with benign prostatic hyperplasia, Huntington's disease, dementia, Alzheimer's disease, and Creutzfeldt-Jakob disease.

[0127] Further, in another aspect, a pharmaceutical composition is provided comprising an AhR modulator and a pharma- ceutically acceptable excipient, the AhR modulator being, for example, an AhR antagonist of formula (I), or an enantiomer, diastereomer, racemate, solvate, hydrate or pharma- ceutically acceptable salt thereof.

[0128] In some embodiments, a pharmaceutical composition is provided comprising an AhR modulator, for example an AhR antagonist of formula (I), or an enantiomer, diastereomer, racemate, solvate, hydrate or pharma- ceutically acceptable salt thereof, for use in modulating constitutive AhR activity in a subject in need thereof.

[0129] In some embodiments, a pharmaceutical composition is provided comprising an AhR modulator, for example an AhR antagonist of formula (I), or an enantiomer, diastereomer, racemate, solvate, hydrate or pharma- ceutically acceptable salt thereof, for use in treating cancer or a cancerous condition by modulating the activity of AhR.

[0130] Pharmaceutical compositions are provided comprising an AhR modulator, for example an AhR antagonist of formula (I), or an enantiomer, diastereomer, racemate, solvate, hydrate or pharma- ceutically acceptable salt thereof, for use in inhibiting cancer cell proliferation, tissue invasion, metastasis and angiogenesis in a subject having cancer, a cancerous condition or a tumor.

[0131] In some embodiments, the pharmaceutical compositions of the invention may be for use in inhibiting cancer cell proliferation, tissue invasion, metastasis and angiogenesis in a subject with cancer, a cancerous condition or a tumor.

[0132] The pharmaceutical formulations described herein can be administered to a subject via a variety of multiple routes of administration, including, but not limited to, oral, parenteral (e.g., intravenous, subcutaneous, intramuscular, rectal, endometrial, intracerebrovascular), intranasal, buccal, topical, or transdermal.

[0133] In some embodiments, the compound of Formula (I), or an enantiomer, diastereomer, racemate, solvate, hydrate, or pharma- ceutically acceptable salt thereof, is administered orally.

[0134] Another aspect of the present invention relates to a method of stimulating the immune system in a patient in need thereof, for example, a patient suffering from cancer or an infectious disease (e.g., a viral, bacterial or parasitic infection). The method comprises administering to the patient a therapeutically effective amount of one compound described herein or a therapeutically effective amount of a combination of compounds described herein. In some embodiments, the patient undergoing this administration step has an increased number of white blood cells, T and / or B lymphocytes, macrophages, dendritic cells, neutrophils, natural killer (NK) cells and / or platelets. In some embodiments, the compound of the present invention reduces the IL-21 level in the patient. The patient may be a patient suffering from cancer or an immunocompromised patient.

[0135] "Treat", "treating" or "treatment" refers to a method of alleviating or preventing a biological disorder and / or at least one symptom associated therewith. As used herein, "alleviating" a disease, disorder or condition means reducing the severity and / or frequency of occurrence of a symptom of the disease, disorder or condition. Additionally, as used herein, "treatment" includes treatment for the purpose of cure, palliative or prophylaxis. Treatment of cancer includes inhibiting cancer growth (including inhibiting cancer growth that induces partial or complete regression of the cancer), inhibiting cancer progression or metastasis, preventing cancer recurrence or residual disease, and / or prolonging patient survival. A "therapeutically effective amount" is an amount of a pharmaceutical agent capable of producing a desired therapeutic, palliative or prophylactic effect on the condition being treated.

[0136] In some embodiments, the effective dosage range of the compound is determined by carrying out a predetermined administration schedule and measuring the concentration of the compound in the blood of the patient to establish the relationship between the concentration and time of the compound; then, establish and examine the correlation between the concentration and time of the compound and the suppressive or eradicating effect on the cancer observed during the clinical trial; and further take into account the health condition or physical endurance of the patient, to balance the therapeutic effect that can be obtained with the toxicity to the patient. The frequency of administration of the compound may also be determined in a similar manner. Administration of the compound may continue until the cancer of the patient is eradicated.

[0137] In some embodiments, the effective amount for treating a tumor may be determined based on the effect of slowing the progression of the disease and / or alleviating symptoms in a patient, and preferably based on the effect of reversing the progression of the disease, such as by reducing tumor volume. In some embodiments, maintenance administration after the patient's cancer disappears may completely eliminate or eradicate the cancer, or may prevent the recurrence of residual disease. The duration of the maintenance administration may be determined based on clinical trial data.

[0138] In some embodiments, the compound of the present invention may be administered in combination with one or more other cancer therapeutic agents that target AhR or target molecules other than AhR. The compound of the present invention and the other cancer therapeutic agent may be prepared as separate formulations, or a formulation containing the compound of the present invention and the other cancer therapeutic agent may be prepared. The compound of the present invention and the other cancer therapeutic agent may be administered in the same dosage regimen, or the compound of the present invention and the other cancer therapeutic agent may be administered in different dosage regimens. The ratio of the compound of the present invention and the other cancer therapeutic agent may be determined based on the results of clinical trials. The compound of the present invention may be combined with another cancer therapeutic agent to improve the efficacy of the compound of the present invention and the other cancer therapeutic agent. For example, the compound of the present invention may be administered in combination with an immune checkpoint inhibitor, such as an inhibitor of PD-1, PD-L1 or PD-L2 (e.g., pembrolizumab, nivolumab or atezolizumab), or in combination with CAR-T therapy (e.g., axicabtageneciloreucel), which may provide additive or synergistic effects on cancer.

[0139] The dosage regimen may be adjusted to obtain the optimum desired response. As used herein, unit dosage form refers to a physically distinct unit suitable for administering a unitary dose to a patient or subject to be treated, each unit dosage form containing a predetermined amount of active compound calculated to obtain the desired therapeutic effect, and the required pharmaceutical carrier.

[0140] It should be noted that dosages may vary depending on the type and severity of the condition to be alleviated, and may include single or multiple administrations. It should also be noted that the specific dosing regimen for a particular subject should be adjusted over time according to the individual's needs and the professional judgment of the person administering or supervising the administration of the compositions of the invention. Also, the dosage ranges described herein are exemplary and do not limit the scope or practice of the compositions specifically described herein. Furthermore, the dosing regimen when using the compositions of the invention may be determined according to a variety of factors, such as the type of disease; the age, weight, sex, and condition of the patient; the severity of the condition, the route of administration, the particular antibody used, and the like. Thus, the dosing regimen may vary over a wide range, but can be routinely determined using standard methods. For example, the dosage may be adjusted according to pharmacokinetic or pharmacodynamic parameters, which may include clinical effects, such as toxicity and / or laboratory values.

[0141] The suitable dosage of the compound of the present invention may be in the range of 0.001 to 200 mg / kg body weight per day, preferably about 0.01 mg / kg body weight to about 20 mg / kg body weight per day, for example, about 0.5 to 50 mg / kg, for example, about 1 to 20 mg / kg. The compound of the present invention may be administered at a dose of, for example, at least 0.25 mg / kg, for example, at least 0.5 mg / kg, for example, at least 1 mg / kg, for example, at least 1.5 mg / kg, for example, at least 2 mg / kg, for example, at least 3 mg / kg, for example, at least 4 mg / kg, for example, at least 5 mg / kg; for example, at most 50 mg / kg or less, for example, at most 30 mg / kg or less, for example, at most 20 mg / kg or less, for example, at most 15 mg / kg or less. Administration is usually repeated at appropriate intervals, for example, twice a day, three times a day, once a day, once a week, once every two weeks, or once every three weeks, for a period of time determined to be appropriate by the responsible physician, and the dosage may be increased or decreased as necessary at the discretion of the responsible physician.

[0142] Basic compositing method The compounds of the invention can be prepared according to one or more of the schemes illustrated below.

[0143] The following methods can be used as is or with easy modification by the skilled chemist to prepare key intermediates and specific compounds of the present invention.

[0144] The appropriate synthetic sequence can be easily selected according to the specific structure of the present invention within the technical scope known to those skilled in the art who perform organic synthesis, such as methods compiled in available chemical databases such as CAS Scifinder and Elesevier Reaxys. The compounds of the present invention can be easily produced based on such general methods, and the production method of the compounds of the present invention can be carried out within the scope of general expertise. The basic synthetic method for preparing the compounds of the present invention is shown in the following Schemes 1 to 3 (General Procedures A to C).

[0145] The basic synthesis method of the compound of the present invention is shown in Basic Scheme 1. [ka] Scheme 1. General Procedure A a) N-iodosuccinimide, DMF; b) NH2-R 1 , EDC, HOBt, TEA, DMF; c) (EtO)3CH, acetic acid; d) Pd2(dba)3.CHCl3, K2CO3, Sphos, 1,4-dioxane / H2O(4 / 1); e) Pd(dppf)Cl2.CH2Cl2, K2CO3, 1,4-dioxane / H2O(4 / 1), heating, microwave

[0146] Another basic method for synthesizing the compounds of the present invention is shown in Basic Scheme 2. [ka] Scheme 2. General Procedure B a)NH2-R 2-OTBDPS, EDC, HOBt, TEA, DMF; b) Pd(dppf)Cl2.CH2Cl2, K2CO3, 1,4-dioxane / H2O (4 / 1), heating, microwave; c) N-bromosuccinimide, DMF; d) (EtO)3CH, acetic acid; e) Pd2(dba)3.CHCl3, K2CO3, Sphos, 1,4-dioxane / H2O (4 / 1); f) TBAF, THF

[0147] Another basic method for synthesizing the compounds of the present invention is shown in General Scheme 3. [ka] Scheme 3. General Procedure C a)NH2-R 2 -OTBDPS, EDC, HOBt, TEA, DMF; b) Pd(dppf)Cl2. CH2Cl2, K2CO3, 1,4-dioxane / H2O (4 / 1), heating, microwave; c) N-bromosuccinimide, DMF; d) (EtO)3CH, acetic acid; e) Pd2(dba)3. CHCl3, K2CO3, Sphos, 1,4-dioxane / H2O (4 / 1); f) NaBH4, THF; g) TBAF, THF

[0148] Another basic method for synthesizing the compounds of the present invention is shown in General Scheme 4. [ka] Scheme 4. General Procedure D a) N-iodosuccinimide, DMF; b) NH2-R 1 , EDC, HOBt, TEA, DMF; c) (EtO)3CH, acetic acid; d) Pd(dppf)Cl2.CH2Cl2, K2CO3, 1,4-dioxane / H2O, heating; e) Pd(dppf)Cl2.CH2Cl2, K2CO3, 1,4-dioxane / H2O (4 / 1), heating, microwave

[0149] Another basic method for synthesizing the compounds of the present invention is shown in General Scheme 5. [ka] Scheme 5. General Procedure E a) K2CO3, MeI, DMF; b) PdCl2(dtbpf), K2CO3, 1,4-dioxane / H2O (4 / 1), heating, microwave, or Pd(dppf)Cl2.CH2Cl2, K2CO3, 1,4-dioxane / H2O (4 / 1), heating, microwave; c) NH2-R 1 , EDC, HOBt, TEA, DMF; d) (EtO)3CH, acetic acid

[0150] Another basic method for synthesizing the compounds of the present invention is shown in General Scheme 6. [ka] Scheme 6. General Procedure F a)NH2-R 1 , EDC, HOBt, TEA, DMF; b) (EtO)3CH, acetic acid; c) Pd(dppf)Cl2.CH2Cl2, K2CO3, 1,4-dioxane / H2O (4 / 1), heating, microwave

[0151] Another basic method for synthesizing the compounds of the present invention is shown in General Scheme 7. [ka] Scheme 7. General Procedure G a) N-iodosuccinimide, DMF; b) NH2-R 1 -NH-Boc, EDC, HOBt, TEA, DMF; c) (EtO)3CH, acetic acid; d) Pd(dppf)Cl2.CH2Cl2, K2CO3, 1,4-dioxane / H2O (4 / 1), heating, microwave; e) Pd(dppf)Cl2.CH2Cl2, K2CO3, 1,4-dioxane / H2O (4 / 1), heating, microwave; f) 4M HCl in 1,4-dioxane; g) R 2 -Cl, TEA, DCM EXAMPLES

[0152] Embodiments of the present invention are described in the following examples, which are intended for illustrative purposes and are not intended to limit the scope of the invention. Common abbreviations known to those skilled in the synthetic arts are used throughout the following examples.

[0153] All chemical reagents were commercially available. Flash column chromatography refers to silica gel chromatography unless otherwise stated and was performed using a Teledyne Combiflash-RF200 system. 1 H NMR spectra (δ, ppm) were recorded using a 400 MHz or 600 MHz spectrometer. Mass spectrometry data was provided using the positive ionization method. Preparative HPLC was performed using an Agilent Technologies G1361A Preparative HPLC System or a Gilson Preparative HPLC System.

[0154] Example 1 and Example 2 3-(3-hydroxycyclohexyl)-8-(1-methyl-1H-pyrazol-4-yl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one and 3-(3-hydroxycyclohexyl)-6,8-bis(1-methyl-1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one Scheme for preparing the compound of Example 1: [ka]

[0155] Intermediate 1. 3-Amino-6-chloro-2-iodoisonicotinic acid [ka] 5-Amino-2-chloroisonicotinic acid (1) (2 g, 14.5 mmol, 1 equiv.) and N-iodosuccinimide (4.9 g, 21.7 mmol, 1.5 equiv.) were dissolved in DMF (50 mL, 0.3 M) and stirred at 100 °C for 12 h. The reaction mixture was diluted with water (50 mL), extracted with EtOAc (50 mL x 3), washed with brine (20 mL x 3), dried over Na2SO4, and filtered through a glass filter. The filtrate was concentrated under reduced pressure to give 3-amino-6-chloro-2-iodoisonicotinic acid (intermediate 1) 6.89 g (80% yield), which was used in the next step without further purification. 1H NMR (400 MHz, CDCl3) δ [ppm] = 7.69 (s, 1H); MS (ESI, m / z): 298.90 [M+H] +

[0156] Intermediate 2. 3-Amino-6-chloro-N-(3-hydroxycyclohexyl)-2-iodoisonicotinamide [ka] A mixture of 3-amino-6-chloro-2-iodoisonicotinic acid (intermediate 1) (1.24 g, 4.15 mmol, 1 equiv.), EDC (0.96 g, 4.99 mmol, 1.2 equiv.), HOBT (0.76 g, 4.99 mmol, 1.2 equiv.), and TEA (0.87 mL, 6.23 mmol, 1.5 equiv.) was dissolved in DMF (10 mL, 0.4 M) and stirred for 5 min. Then, 3-aminocyclohexanol (0.53 g, 4.57 mmol, 1.1 equiv.) was added to the reaction and stirred at 60 °C for 12 h. The reaction was diluted with water (50 mL), extracted with EtOAc (20 mL × 3), washed with brine (20 mL × 3), dried over Na2SO4, and filtered through a glass filter. The filtrate was concentrated under reduced pressure and purified by medium pressure liquid chromatography (MPLC) (silica gel, 0-50% EtOAc / hexanes) to give 0.75 g of 3-amino-6-chloro-N-(3-hydroxycyclohexyl)-2-iodoisonicotinamide (Intermediate 2) (46% yield). 1H NMR (400 MHz, MeOD) δ [ppm] = 7.40 (s, 1H), 3.91 (tt, J = 11.5, 3.7 Hz, 1H), 3.66 (tt, J = 10.6, 4.1 Hz, 1H), 2.19 (d, J = 11.7 Hz, 1H), 1.95 (d, J = 12.8 Hz, 1H), 1.87 - 1.81 (m, 2H), 1.69 - 1.61 (m, 1H), 1.55 - 1.50 (m, 1H), 1.40 (ddd, J = 12.9, 6.3, 3.2 Hz, 1H). 1.25 - 1.16 (m, 1H); MS (ESI, m / z): 395.90 [M+H]+

[0157] Intermediate 3. 6-Chloro-3-(3-hydroxycyclohexyl)-8-iodopyrido[3,4-d]pyrimidin-4(3H)-one [ka] 3-Amino-6-chloro-N-(3-hydroxycyclohexyl)-2-iodoisonicotinamide (Intermediate 2) (0.75 g, 1.90 mmol, 1 equiv) was dissolved in a solution of (EtO)3CH (2.9 mL, 17.1 mmol, 9 equiv) and CH3CO2H (2.9 mL, 49.8 mmol, 26.2 equiv). The reaction was heated and stirred at 150 °C for 1 h in a Biotage Microwave Synthesizer Initiator. The reaction was diluted with water (20 mL), extracted with EtOAc (20 mL x 3), washed with brine (20 mL x 3), dried over Na2SO4, and filtered through a glass filter. The filtrate was concentrated under reduced pressure and purified by MPLC (silica gel, 0-50% EtOAc / hexanes) to give 0.28 g of 6-chloro-3-(3-hydroxycyclohexyl)-8-iodopyrido[3,4-d]pyrimidin-4(3H)-one (Intermediate 3) (36% yield). 1H NMR (400 MHz, CDCl3) δ [ppm] = 8.26 (s, 1H), 8.03 (s, 1H), 4.77 (tt, J = 12.1, 3.6 Hz, 1H), 3.90 - 3.80 (m, 1H), 2.29 (d, J = 11.2 Hz, 1H), 2.11 (d, J = 11.7 Hz, 1H), 2.04 - 1.92 (m, 2H), 1.70 - 1.65 (m, 1H), 1.65 - 1.58 (m, 1H), 1.53 - 1.49 (m, 1H), 1.33 (ddd, J = 23.8, 12.5, 3.9 Hz, 1H); MS (ESI, m / z): 405.83 [M+H] +

[0158] Intermediate 4 and Example 2. 6-Chloro-3-(3-hydroxycyclohexyl)-8-(1-methyl-1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one and 3-(3-hydroxycyclohexyl)-6,8-bis(1-methyl-1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one [ka] 6-Chloro-3-(3-hydroxycyclohexyl)-8-iodopyrido[3,4-d]pyrimidin-4(3H)-one (intermediate 3) (68 mg, 0.168 mmol, 1 equiv.), (1-methyl-1H-pyrazol-4-yl)boronic acid (23.2 mg, 0.184 mmol, 1.1 equiv.), K2CO3 (93 mg, 0.671 mmol, 4 equiv.), Sphos (6.9 mg, 0.017 mmol, 0.1 equiv.) and Pd2(dba)3·CHCl3 (8.68 mg, 8.38 μmol, 0.05 equiv.) were dissolved in 1,4-dioxane / water (4 mL / 1 mL, 0.3 M) and stirred at 50 °C for 12 h. The reaction solution was concentrated under reduced pressure and then directly purified by MPLC (silica gel, 0-10% MeOH / DCM) to obtain 30 mg (50% yield) of 6-chloro-3-(3-hydroxycyclohexyl)-8-(1-methyl-1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (Intermediate 4) and 13 mg (19% yield) of 3-(3-hydroxycyclohexyl)-6,8-bis(1-methyl-1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (Example 2). Intermediate 4 1H NMR (400 MHz, CDCl3) δ [ppm] = 8.53 (s, 1H), 8.50 (s, 1H), 8.19 (s, 1H), 7.88 (s, 1H), 4.82 (t, J = 12.3 Hz, 1H), 3.99 (s, 3H), 3.87 (t, J = 10.5 Hz, 1H), 2.31 (d, J = 11.0 Hz, 1H), 2.12 (d, J = 11.6 Hz, 1H), 2.05 - 1.94 (m, 2H), 1.79 (s, 1H), 1.74 - 1.66 (m, 1H), 1.51 (dd, J = 18.2, 8.3 Hz, 1H), 1.33 (ddd, J = 24.3, 12.7, 3.4 Hz, 1H); MS (ESI, m / z):360.00 [M+H] + Example 2 1H-NMR (400 MHz, CDCl3): δ [ppm] = 8.57 (s, 1H), 8.52 (s, 1H), 8.15 (s, 1H), 8.10 (s, 1H), 8.06 (s, 1H), 8.00 (s, 1H), 4.90 - 4.83 (m, 1H), 4.02 (s, 3H), 4.00 (s, 3H), 3.92 - 3.85 (m, 1H), 2.33 (d, J = 11.3 Hz, 1H), 2.13 (d, J = 11.5 Hz, 1H), 2.01 (d, J = 10.2 Hz, 2H), 1.76 - 1.67 (m, 2H), 1.64 - 1.53 (m, 1H), 1.39 - 1.30 (m, 1H); MS (ESI, m / z):406.07 [M+H] +

[0159] Example 1. 3-(3-Hydroxycyclohexyl)-8-(1-methyl-1H-pyrazol-4-yl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one [ka] 6-Chloro-3-(3-hydroxycyclohexyl)-8-(1-methyl-1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (Intermediate 4) (30 mg, 0.083 mmol, 1 equiv.), (4-(trifluoromethyl)phenyl)boronic acid (32 mg, 0.17 mmol, 2 equiv.), K2CO3 (35 mg, 0.25 mmol, 3 equiv.) and Pd(dppf)Cl2·CH2Cl2 (6.8 mg, 8.34 μmol, 0.1 equiv.) were dissolved in 1,4-dioxane / water (4 mL / 1 mL, 0.02 M). The reaction mixture was heated and stirred at 130 °C for 30 min in a Biotage Microwave Synthesizer Initiator. The reaction solution was concentrated under reduced pressure and then directly purified by MPLC (Chromatorex silica gel NH-DM1020 (NH-SiO2), 0-70% MeOH / DCM) to obtain 16 mg of 3-(3-hydroxycyclohexyl)-8-(1-methyl-1H-pyrazol-4-yl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one (Example 2) (yield 40%). 1H-NMR (400 MHz, CDCl3): δ [ppm] = 8.62 (s, 1H), 8.59 (s, 1H), 8.38 (s, 1H), 8.33 (d, J = 8.3 Hz, 2H), 8.24 (s, 1H), 7.78 (d, J = 8.3 Hz, 2H), 4.92 - 4.86 (m, 1H), 4.03 (s, 3H), 3.93 - 3.86 (m, 1H), 2.35 (d, J = 11.6 Hz, 1H), 2.14 (d, J = 11.2 Hz, 1H), 2.03 (d, J = 10.6 Hz, 2H), 1.78 - 1.69 (m, 2H), 1.65 - 1.56 (m, 1H), 1.41 - 1.31 (m, 1H); MS (ESI, m / z): 470.06 [M+H] +

[0160] Example 3. 3-(1-hydroxypropan-2-yl)-6,8-bis(1-methyl-1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one [ka] The title compound was obtained in the same manner as in Example 2, except that 2-aminopropan-1-ol was used (Scheme 1. General Procedure A). 1H-NMR (400 MHz, CD3OD): δ [ppm] = 8.62 (s, 1H), 8.40 (s, 1H), 8.28 (s, 1H), 8.15 (s, 1H), 7.99 (s, 1H), 7.86 (s, 1H), 4.93 - 4.85 (m, MS (ESI, m / z): 366.06 [M+H] +

[0161] Example 4. 3-(1-hydroxypropan-2-yl)-6-(1-methyl-1H-pyrazol-4-yl)-8-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one [ka] The title compound was obtained in the same manner as in Example 1, except that 2-aminopropan-1-ol was used (Scheme 1. General Procedure A). 1H-NMR (400 MHz, CDCl3): δ [ppm] = 8.26 - 8.16 (m, 2H), 8.04 (dd, J = 20.2, 13.9 Hz, 2H), 7.77 (d, J = 8.2 Hz, 1H), 7.53 (s, 1H), 7.42 (s, MS (ESI, m / z): 430.00 [M+H] +

[0162] Example 5. 8-(4-chlorophenyl)-3-(1-hydroxypropan-2-yl)-6-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one [ka] The title compound was obtained in the same manner as in Example 1, except that 2-aminopropan-1-ol, (4-chlorophenyl)boronic acid and pyridin-3-ylboronic acid were used (Scheme 1. General Procedure A). 1H-NMR (400 MHz, CDCl3): δ [ppm] = 9.41 (s, 1H), 8.67 (d, J = 3.7 Hz, 1H), 8.56 (s, 1H), 8.50 (d, J = 8.1 Hz, 1H), 8.31 (s, 1H), 8.19 (d, J = 8.6 Hz, 2H), 7.51 (d, J = 8.6 Hz, 2H), 7.47 - 7.41 (m, 2H), 5.10 (dd, J = 11.9, 4.9 Hz, 1H), 4.00 (d, J = 4.5 Hz, 1H), 1.60 (d, J = 7.3 Hz, 3H); MS (ESI, m / z): 393.02 [M+H] +

[0163] Example 6. 3-(1-Hydroxypropan-2-yl)-6,8-bis(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one [ka] The title compound was obtained in the same manner as in Example 2, except that 2-aminopropan-1-ol and (4-(trifluoromethyl)phenyl)boronic acid were used (Scheme 1. General Procedure A). 1H-NMR (400 MHz, CD3OD): δ [ppm] = 8.46 (s, 1H), 8.31 (s, 1H), 8.27 (dd, J = 7.8, 5.1 Hz, 4H), 7.68 (d, J = 8.3 Hz, 4H), 4.94 - 4.83 (m, MS (ESI, m / z): 494.04 [M+H] +

[0164] Example 7. Acetic acid 2-(6-chloro-8-(4-chlorophenyl)-4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)propyl [ka] The title compound was obtained in a manner similar to the preparation of Intermediate 4 in Example 1, except that 2-aminopropyl acetate and (4-chlorophenyl)boronic acid were used (Scheme 1. General Procedure A). 1H-NMR (400 MHz, CDCl3): δ [ppm] = 8.15 (s, 1H), 8.09 (d, J = 8.2 Hz, 2H), 7.48 (d, J = 8.5 Hz, 2H), 5.18 (dd, J = 11.1, 6.9 Hz, 1H), 4.47 - 4.32 (m, 2H), 2.04 (s, 3H), 1.59 (d, J = 7.2 Hz, 3H); MS (ESI, m / z): 391.95 [M+H] +

[0165] Example 8. 3-((1r,4r)-4-Hydroxycyclohexyl)-8-(1-methyl-1H-pyrazol-4-yl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one [ka] The title compound was obtained in the same manner as in Example 1 except that (1r,4r)-4-aminocyclohexan-1-ol was used (Scheme 1. General Procedure A). 1H-NMR (400 MHz, CDCl3): δ [ppm] = 8.60 (s, 1H), 8.59 (s, 1H), 8.37 (s, 1H), 8.32 (d, J = 8.2 Hz, 1H), 8.20 (s, 1H), 7.77 (d, J = 8.3 Hz, 1H), 4.88 - 4.78 (m, 1H), 4.03 (s, 3H), 3.85 - 3.74 (m, 1H), 2.27 - 2.19 (m, 2H), 2.15 - 2.06 (m, 2H), 1.94 - 1.81 (m, 2H), 1.70 - 1.57 (m, 2H); MS (ESI, m / z): 470.02 [M+H] +

[0166] Example 9. 3-((1r,4r)-4-Hydroxycyclohexyl)-6,8-bis(1-methyl-1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one [ka] The title compound was obtained in the same manner as in Example 2, except that (1r,4r)-4-aminocyclohexan-1-ol was used (Scheme 1. General Procedure A). 1H-NMR (400 MHz, CDCl3): δ [ppm] = 8.55 (s, 1H), 8.52 (s, 1H), 8.11 (s, 1H), 8.10 (s, 1H), 8.05 (s, 1H), 7.99 (s, 1H), 4.87 - 4.76 (m, 1H), 4.01 (s, 3H), 4.00 (s, 3H), 3.83 - 3.72 (m, 1H), 2.26 - 2.16 (m, 2H), 2.11 - 2.02 (m, 2H), 1.91 - 1.77 (m, 2H), 1.67 - 1.56 (m, 2H); MS (ESI, m / z): 406.04 [M+H] +

[0167] Example 10. 6-(4-chlorophenyl)-3-((1r,4r)-4-hydroxycyclohexyl)-8-(1-methyl-1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one [ka] The title compound was obtained in the same manner as in Example 1 except that (1r,4r)-4-aminocyclohexan-1-ol and (4-chlorophenyl)boronic acid were used (Scheme 1. General Procedure A). 1H-NMR (400 MHz, CDCl3): δ [ppm] = 8.59 (s, 1H), 8.58 (s, 1H), 8.31 (s, 1H), 8.18 (s, 1H), 8.16 (d, J = 8.8 Hz, 2H), 7.49 (d, J = 8.6 Hz, 2H), 4.88 - 4.78 (m, 1H), 4.02 (s, 3H), 3.84 - 3.74 (m, 1H), 2.26 - 2.18 (m, 2H), 2.14 - 2.02 (m, 2H), 1.93 - 1.80 (m, 2H), 1.70 - 1.61 (m, 2H); MS (ESI, m / z): 436.01 [M+H] +

[0168] Example 11. 3-(2-hydroxypropyl)-6,8-bis(1-methyl-1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one [ka] The title compound was obtained in the same manner as in Example 2, except that 1-aminopropan-2-ol was used (Scheme 1. General Procedure A). 1H-NMR (400 MHz, CD3OD): δ [ppm] = 8.75 (s, 1H), 8.51 (s, 1H), 8.29 (s, 1H), 8.26 (s, 1H), 8.11 (s, 1H), 8.01 (s, 1H), 4.28 (dd, J = MS (ESI, m / z): 366.01 [M+H] +

[0169] Example 12. 3-(2-hydroxypropyl)-8-(1-methyl-1H-pyrazol-4-yl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one [ka] The title compound was obtained in the same manner as in Example 1, except that 1-aminopropan-2-ol was used (Scheme 1. General Procedure A). 1H-NMR (400 MHz, CDCl3): δ [ppm] = 8.50 (s, 1H), 8.49 (s, 1H), 8.32 (s, 1H), 8.24 (d, J = 8.2 Hz, 2H), 8.18 (s, 1H), 7.72 (d, J = 8.3 Hz, 2H), 4.38 (dd, J = 13.6, 2.5 Hz, 1H), 4.30 (br, 1H), 3.99 (s, 3H), 3.70 (dd, J = 13.6, 8.5 Hz, 1H), 2.78 (d, J = 4.4 Hz, 1H), 1.38 (d, J = 6.3 Hz, 3H); MS (ESI, m / z): 430.00 [M+H] +

[0170] Example 13. 6-(4-chlorophenyl)-3-(2-hydroxypropyl)-8-(1-methyl-1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one [ka] The title compound was obtained in the same manner as in Example 1, except that 1-aminopropan-2-ol and (4-chlorophenyl)boronic acid were used (Scheme 1. General Procedure A). 1H-NMR (400 MHz, CDCl3): δ [ppm] = 8.55 (s, 1H), 8.53 (s, 1H), 8.28 (s, 1H), 8.17 (s, 1H), 8.12 (d, J = 8.6 Hz, 2H), 7.47 (d, J = 8.5 Hz, 2H), 4.36 (dd, J = 13.7, 2.6 Hz, 1H), 4.28 (br, 1H), 4.00 (s, 3H), 3.73 (dd, J = 13.6, 8.3 Hz, 1H), 2.43 (d, J = 4.5 Hz, 1H), 1.37 (d, J = 6.3 Hz, 3H); MS (ESI, m / z): 396.00 [M+H] +

[0171] Example 14. 3-(2-hydroxypropyl)-8-(1-methyl-1H-pyrazol-4-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one [ka] The title compound was obtained in the same manner as in Example 1, except that 1-aminopropan-2-ol and (6-(trifluoromethyl)pyridin-3-yl)boronic acid were used (Scheme 1. General Procedure A). 1H-NMR (400 MHz, CDCl3): δ [ppm] = 9.48 (s, 1H), 8.62 (m, 1H), 8.59 (s, 1H), 8.52 (s, 1H), 8.36 (s, 1H), 8.25 (s, 1H), 7.81 (d, J = 8.2 Hz, 1H), 4.39 (dd, J = 13.5, 2.5 Hz, 1H), 4.30 (br, 1H), 4.01 (s, 3H), 3.73 (dd, J = 13.6, 8.4 Hz, 1H), 2.41 (d, J = 4.2 Hz, 1H), 1.39 (d, J = 6.3 Hz, 3H); MS (ESI, m / z): 431.00 [M+H] +

[0172] Example 15. 3-((1S,2R)-2-Hydroxycyclohexyl)-8-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one [ka] The title compound was obtained in the same manner as in Example 1 except that (1R,2S)-2-aminocyclohexanol, pyridin-3-ylboronic acid and (4-(trifluoromethyl)phenyl)boronic acid were used (Scheme 1. General Procedure A). 1H-NMR (400 MHz, MeOD): δ [ppm] = 9.42 (s, 1H), 8.73 (d, J = 8.0 Hz, 1H), 8.64 (d, J = 4.8 Hz, 1H), 8.62 (s, 1H), 8.51 (s, 1H), 8.41 (d, J = 8.2 Hz, 2H), 7.83 (d, J = 8.3 Hz, 2H), 7.61 (dd, J = 7.9, 4.9 Hz, 1H), 4.90 - 4.85 (m, 1H), 4.09 (s, 1H), 2.41 - 2.27 (m, 1H), 2.06 - 1.93 (m, 2H), 1.76 (d, J = 9.3 Hz, 2H), 1.71 (s, 1H), 1.59 (dt, J = 17.5, 8.6 Hz, 2H); MS (ESI, m / z): 467.15 [M+H]+

[0173] Example 16. 3-((1R,2S)-2-Hydroxycyclohexyl)-8-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one [ka] The title compound was obtained in the same manner as in Example 1, except that (1S,2R)-2-aminocyclohexanol hydrochloride, pyridin-3-ylboronic acid and (4-(trifluoromethyl)phenyl)boronic acid were used (Scheme 1. General Procedure A). 1H-NMR (400 MHz, MeOD): δ [ppm] = 9.41 (s, 1H), 8.75 - 8.66 (m, 1H), 8.63 (d, J = 4.7 Hz, 1H), 8.58 (d, J = 6.5 Hz, 1H), 8.49 (d, J = 1.9 Hz, 1H), 8.38 (dd, J = 8.1, 3.9 Hz, 2H), 7.81 (d, J = 6.8 Hz, 2H), 7.63 (d, J = 8.9 Hz, 1H), 7.61 - 7.57 (m, 1H), 4.86 (dd, J = 13.3, 2.6 Hz, 1H), 4.08 (s, 1H), 2.34 MS (ESI, m / z): 467.13 [M+H] +

[0174] Example 17. 3-((1S,2R)-2-Hydroxycyclohexyl)-8-(1-methyl-1H-pyrazol-4-yl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one [ka] The title compound was obtained in the same manner as in Example 1, except that (1R,2S)-2-aminocyclohexanol, (1-methyl-1H-pyrazol-4-yl)boronic acid and (4-(trifluoromethyl)phenyl)boronic acid were used (Scheme 1. General Procedure A). 1H-NMR (400 MHz, CDCl3): δ [ppm] = 8.48 (s, 1H), 8.37 (s, 1H), 8.33 (s, 1H), 8.27 (s, 1H), 8.14 (d, J = 8.1 Hz, 2H), 7.67 (d, J = 8.3 Hz, 2H), 4.95 (dd, J = 10.2, 2.4 Hz, 1H), 4.30 (s, 1H), 3.99 (s, 3H), 3.23 (s, 1H), 2.39 - 2.27 (m, 1H), 2.03 (d, J = 12.2 Hz, 2H), 1.89 - 1.74 (m, 2H), 1.68 (dd, J = 24.7, 13.2 Hz, 3H); MS (ESI, m / z): 470.18 [M+H] +

[0175] Example 18. 3-((1R,2S)-2-Hydroxycyclohexyl)-8-(1-methyl-1H-pyrazol-4-yl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one [ka] The title compound was obtained in the same manner as in Example 1, except that (1S,2R)-2-aminocyclohexanol hydrochloride, (1-methyl-1H-pyrazol-4-yl)boronic acid and (4-(trifluoromethyl)phenyl)boronic acid were used (Scheme 1. General Procedure A). 1H-NMR (400 MHz, CDCl3): δ [ppm] = 8.50 (s, 1H), 8.37 (d, J = 9.4 Hz, 2H), 8.28 (s, 1H), 8.17 (d, J = 8.2 Hz, 2H), 7.69 (d, J = 8.2 Hz, 2H), 4.96 (d, J = 13.3 Hz, 1H), 4.29 (s, 1H), 3.99 (s, 3H), 3.06 (s, 1H), 2.34 (dd, J = 22.1, 12.5 Hz, 1H), 2.06 - 1.98 (m, 2H), 1.90 - 1.78 (m, 2H), 1.75 - 1.63 (m, 3H); MS (ESI, m / z): 470.18 [M+H] +

[0176] Example 19. 6-(4-chlorophenyl)-3-((1R,2S)-2-hydroxycyclohexyl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one [ka] The title compound was obtained in the same manner as in Example 1, except that (1S,2R)-2-aminocyclohexanol hydrochloride, pyridin-3-ylboronic acid and (4-chlorophenyl)boronic acid were used (Scheme 1. General Procedure A). 1H-NMR (400 MHz, CDCl3): δ [ppm] = 9.34 (d, J = 1.6 Hz, 1H), 8.60 (dd, J = 4.9, 1.5 Hz, 1H), 8.48 - 8.43 (m, 1H), 8.43 (s, 1H), 8.40 (s, 1H), 8.07 (d, J = 8.6 Hz, 2H), 7.45 (d, J = 8.6 Hz, 2H), 7.38 (dd, J = 7.7, 4.9 Hz, 1H), 4.93 (d, J = 12.8 Hz, 1H), 4.19 (s, 1H), 3.09 (s, 1H), 2.32 (ddd, J = 25.3, MS (ESI, m / z): 433.14 [M+H] +

[0177] Example 20. 6-(4-chlorophenyl)-3-((1S,2R)-2-hydroxycyclohexyl)-8-(1-methyl-1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one [ka] The title compound was obtained in the same manner as in Example 1, except that (1R,2S)-2-aminocyclohexanol, (1-methyl-1H-pyrazol-4-yl)boronic acid and (4-chlorophenyl)boronic acid were used (Scheme 1. General Procedure A). 1H-NMR (400 MHz, CDCl3): δ [ppm] = 8.48 (s, 1H), 8.37 (d, J = 9.2 Hz, 2H), 8.21 (s, 1H), 8.03 (d, J = 8.6 Hz, 2H), 7.42 (d, J = 8.6 Hz, 2H), 4.94 (d, J = 13.0 Hz, 1H), 4.27 (s, 1H), 2.85 (d, J = 4.2 Hz, 1H), 2.33 (dt, J = 21.6, 10.7 Hz, 1H), 2.06 - 1.94 (m, 2H), 1.89 - 1.75 (m, 2H), 1.75 - 1.66 (m, 2H), 1.63 (d, J = 16.2 Hz, 1H); MS (ESI, m / z): 436.15 [M+H] +

[0178] Example 21. 6-(4-chlorophenyl)-3-((1S,2R)-2-hydroxycyclohexyl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one [ka] The title compound was obtained in the same manner as in Example 1, except that (1R,2S)-2-aminocyclohexanol, pyridin-3-ylboronic acid and (4-chlorophenyl)boronic acid were used (Scheme 1. General Procedure A). 1H-NMR (400 MHz, CDCl3): δ [ppm] = 9.33 (d, J = 1.8 Hz, 1H), 8.59 (dd, J = 4.8, 1.6 Hz, 1H), 8.47 - 8.43 (m, 1H), 8.42 (s, 1H), 8.38 (s, 1H), 8.05 (d, J = 8.6 Hz, 2H), 7.44 (d, J = 8.6 Hz, 2H), 4.93 (d, J = 12.7 Hz, 1H), 4.18 (s, 1H), 3.31 (s, 1H), 2.38 - 2.26 (m, 1H), 2.06 - 1.95 (m, 2H), 1.87 - 1.75 (m, 2H), 1.75 - 1.67 (m, 2H), 1.63 (d, J = 13.8 Hz, 1H); MS (ESI, m / z): 433.17 [M+H] +

[0179] Example 22. 8-(1-Methyl-1H-pyrazol-4-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one [ka] The title compound was obtained in the same manner as in Example 1, except that 3-amino-1,1,1-trifluoropropan-2-ol, (1-methyl-1H-pyrazol-4-yl)boronic acid and (4-(trifluoromethyl)phenyl)boronic acid were used (Scheme 1. General Procedure A). 1H-NMR (400 MHz, CDCl3): δ [ppm] = 8.34 (s, 1H), 8.25 (s, 1H), 8.24 (s, 1H), 8.10 (s, 1H), 8.09 (s, 2H), 7.65 (d, J = 8.3 Hz, 2H), 5.44 MS (ESI, m / z): 484.14 [M+H] +

[0180] Example 23. 6-(4-chlorophenyl)-8-(1-methyl-1H-pyrazol-4-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)pyrido[3,4-d]pyrimidin-4(3H)-one [ka] The title compound was obtained in the same manner as in Example 1, except that 3-amino-1,1,1-trifluoropropan-2-ol, (1-methyl-1H-pyrazol-4-yl)boronic acid and (4-chlorophenyl)boronic acid were used (Scheme 1. General Procedure A). 1H-NMR (400 MHz, CDCl3): δ [ppm] = 8.31 (s, 1H), 8.17 (s, 1H), 8.13 (s, 1H), 8.04 (s, 1H), 7.91 (d, J = 8.5 Hz, 2H), 7.37 (d, J = 8.4 Hz, MS (ESI, m / z): 450.10 [M+H] +

[0181] Example 24. 6-(4-chlorophenyl)-8-(pyridin-3-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)pyrido[3,4-d]pyrimidin-4(3H)-one [ka] The title compound was obtained in the same manner as in Example 1, except that 3-amino-1,1,1-trifluoropropan-2-ol, pyridin-3-ylboronic acid and (4-chlorophenyl)boronic acid were used (Scheme 1. General Procedure A). 1H-NMR (400 MHz, CDCl3): δ [ppm] = δ 9.21 (d, J = 1.5 Hz, 1H), 8.42 (dd, J = 4.9, 1.4 Hz, 1H), 8.40 - 8.35 (m, 1H), 8.18 (d, J = 8.1 Hz, 2H), 7.87 (d, J = 8.6 Hz, 2H), 7.38 (d, J = 8.6 Hz, 2H), 7.36 - 7.32 (m, 1H), 4.76 (d, J = 13.5 Hz, 1H), 4.70 - 4.55 (m, 1H), 3.75 (dd, J = 13.5, 10.1 Hz, 1H); MS (ESI, m / z): 447.09 [M+H] +

[0182] Example 25. 8-(Pyridin-3-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one [ka] The title compound was obtained in the same manner as in Example 1, except that 3-amino-1,1,1-trifluoropropan-2-ol, pyridin-3-ylboronic acid, and (4-(trifluoromethyl)phenyl)boronic acid were used (Scheme 1. General Procedure A). 1H-NMR (400 MHz, CDCl3): δ [ppm] = 9.29 (d, J = 1.6 Hz, 1H), 8.48 (dd, J = 4.9, 1.5 Hz, 1H), 8.45 - 8.39 (m, 1H), 8.29 (s, 1H), 8.23 ​​(s, 1H), 8.08 (d, J = 8.2 Hz, 2H), 7.67 (d, J = 8.3 Hz, 2H), 7.39 (dd, J = 8.0, 4.9 Hz, 1H), 4.77 (dd, J = 13.6, 2.5 Hz, 1H), 4.71 - 4.62 (m, 1H), 3.81 (dd, J = 13.5, 9.9 Hz, 1H); MS (ESI, m / z): 480.90 [M+H] +

[0183] Example 26. 6-(4-chlorophenyl)-3-(3-hydroxyphenyl)-8-(1-methyl-1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one [ka] The title compound was obtained in the same manner as in Example 1, except that 3-aminophenol, (1-methyl-1H-pyrazol-4-yl)boronic acid and (4-chlorophenyl)boronic acid were used (Scheme 1. General Procedure A). 1H NMR (400 MHz, CDCl3): δ [ppm] = 8.62 (s, 1H), 8.62 (s, 1H), 8.35 (s, 1H), 8.19 (s, 1H), 8.17 (d, J = 8.5 Hz, 2H), 7.49 (d, J = 8.5 Hz, MS (ESI, m / z): 430.08 [M+H] +

[0184] Example 27. 3-(3-hydroxyphenyl)-8-(1-methyl-1H-pyrazol-4-yl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one [ka] The title compound was obtained in the same manner as in Example 1, except that 3-aminophenol, (1-methyl-1H-pyrazol-4-yl)boronic acid and (4-(trifluoromethyl)phenyl)boronic acid were used (Scheme 1. General Procedure A). 1H NMR (400 MHz, MeOD): δ [ppm] = 8.80 (s, 1H), 8.58 (s, 1H), 8.47 - 8.33 (m, 4H), 7.82 (d, J = 8.3 Hz, 2H), 7.45 - 7.38 (m, 1H), 7.05 - 6.92 (m, 3H), 4.00 (s, 3H); MS (ESI, m / z): 464.1 [M+H] +

[0185] Example 28. 6-(4-chlorophenyl)-3-((1R,3S)-3-hydroxycyclopentyl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one [ka] The title compound was obtained in the same manner as in Example 1, except that (1S,3R)-3-aminocyclopentanol, pyridin-3-ylboronic acid and (4-chlorophenyl)boronic acid were used (Scheme 1. General Procedure A). 1H NMR (400 MHz, CDCl3): δ [ppm] = 9.46 (d, J = 1.8 Hz, 1H), 8.71 (dd, J = 4.8, 1.6 Hz, 1H), 8.60 (s, 1H), 8.56 (dd, J = 1.9, 1.9 Hz, 1H), 8.54 (s, 1H), 8.19 (d, J = 8.6 Hz, 2H), 7.49 (d, J = 8.5 Hz, 2H), 7.48 - 7.44 (m, 1H), 5.33 - 5.23 (m, 1H), 4.58 - 4.48 (m, 1H), 2.84 (br, 1H), 2.59 - 2.49 (m, 1H), 2.40 - 2.31 (m, 1H), 2.29 - 2.18 (m, 1H), 2.07 - 1.95 (m, 2H), 1.88 - 1.78 (m, 1H); MS (ESI, m / z): 419.1 [M+H] +

[0186] Example 29. 3-((1R,3S)-3-Hydroxycyclopentyl)-8-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one [ka] The title compound was obtained in the same manner as in Example 1, except that (1S,3R)-3-aminocyclopentanol, pyridin-3-ylboronic acid, and (4-(trifluoromethyl)phenyl)boronic acid were used (Scheme 1. General Procedure A). 1H NMR (400 MHz, CDCl3): δ [ppm] = 9.48 (s, 1H), 8.74 (d, J = 3.9 Hz, 1H), 8.64 (s, 1H), 8.62 (s, 1H), 8.58 (d, J = 8.1 Hz, 1H), 8.36 (d, J = 8.2 Hz, 2H), 7.78 (d, J = 8.3 Hz, 2H), 7.53 - 7.46 (m, 1H), 5.35 - 5.26 (m, 1H), 4.57 - 4.51 (m, 1H), 2.72 (br, 1H), 2.60 - 2.51 (m, 1H), 2.43 - 2.33 (m, 1H), 2.29 - 2.20 (m, 1H), 2.05 - 1.98 (m, 2H), 1.89 - 1.79 (m, 1H); MS (ESI, m / z): 453.15 [M+H] +

[0187] Example 30. 6-(4-chlorophenyl)-3-((1R,3S)-3-hydroxycyclopentyl)-8-(1-methyl-1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one [ka] The title compound was obtained in the same manner as in Example 1, except that (1S,3R)-3-aminocyclopentanol, (1-methyl-1H-pyrazol-4-yl)boronic acid and (4-chlorophenyl)boronic acid were used (Scheme 1. General Procedure A). 1H NMR (400 MHz, CDCl3): δ [ppm] = 8.64 (s, 1H), 8.60 (s, 1H), 8.57 (s, 1H), 8.33 (s, 1H), 8.18 (d, J = 8.5 Hz, 2H), 7.50 (d, J = 8.5 Hz, 2H), 5.29 - 5.20 (m, 1H), 4.58 - 4.51 (m, 1H), 4.04 (s, 3H), 2.61 - 2.51 (m, 1H), 2.39 - 2.22 (m, 2H), 2.10 - 1.97 (m, 2H), 1.90 - 1.79 (m, 1H); MS (ESI, m / z): 422.15 [M+H] +

[0188] Example 31. 3-((1R,3S)-3-Hydroxycyclopentyl)-8-(1-methyl-1H-pyrazol-4-yl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one [ka] The title compound was obtained in the same manner as in Example 1, except that (1S,3R)-3-aminocyclopentanol, (1-methyl-1H-pyrazol-4-yl)boronic acid and (4-(trifluoromethyl)phenyl)boronic acid were used (Scheme 1. General Procedure A). 1H NMR (400 MHz, CDCl3): δ [ppm] = 8.66 (s, 1H), 8.62 (s, 1H), 8.61 (s, 1H), 8.40 (s, 1H), 8.35 (d, J = 8.1 Hz, 2H), 7.79 (d, J = 8.2 Hz, 2H), 5.33 - 5.24 (m, 1H), 4.58 - 4.52 (m, 1H), 4.05 (s, 3H), 2.83 - 2.75 (m, 1H), 2.63 - 2.53 (m, 1H), 2.41 - 2.33 (m, 1H), 2.31 - 2.22 (m, 1H), 2.11 - 2.02 (m, 1H), 1.91 - 1.81 (m, 1H); MS (ESI, m / z): 456.18 [M+H] +

[0189] Example 32. 6-(4-chlorophenyl)-3-((1S,3R)-3-hydroxycyclopentyl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one [ka] The title compound was obtained in the same manner as in Example 1, except that (1R,3S)-3-aminocyclopentanol hydrochloride, pyridin-3-ylboronic acid and (4-chlorophenyl)boronic acid were used (Scheme 1. General Procedure A). 1H NMR (400 MHz, CDCl3): δ [ppm] = 9.46 (s, 1H), 8.71 (d, J = 4.1 Hz, 1H), 8.61 (s, 1H), 8.58 - 8.48 (m, 2H), 8.18 (d, J = 8.5 Hz, 2H), 7.53 - 7.42 (m, 3H), 5.35 - 5.24 (m, 1H), 4.57 - 4.48 (m, 1H), 2.60 - 2.48 (m, 1H), 2.41 - 2.31 (m, 1H), 2.29 - 2.17 (m, 1H), 2.10 - 1.94 (m, 2H), 1.89 - 1.77 (m, 1H); MS (ESI, m / z): 419.13 [M+H] +

[0190] Example 33. 3-((1S,3R)-3-Hydroxycyclopentyl)-8-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one [ka] The title compound was obtained in the same manner as in Example 1, except that (1R,3S)-3-aminocyclopentanol hydrochloride, pyridin-3-ylboronic acid, and (4-(trifluoromethyl)phenyl)boronic acid were used (Scheme 1. General Procedure A). 1H NMR (400 MHz, CDCl3): δ [ppm] = 9.47 (d, J = 1.6 Hz, 1H), 8.73 (dd, J = 4.8, 1.2 Hz, 1H), 8.63 (s, 1H), 8.62 (s, 1H), 8.60 - 8.52 (m, 1H), 8.36 (d, J = 8.2 Hz, 2H), 7.78 (d, J = 8.3 Hz, 2H), 7.48 (dd, J = 7.9, 4.9 Hz, 1H), 5.35 - 5.24 (m, 1H), 4.57 - 4.48 (m, 1H), 2.67 (d, J = 4.4 Hz, 1H), 2.61 - 2.47 (m, 1H), 2.44 - 2.32 (m, 1H), 2.30 - 2.16 (m, 1H), 2.09 - 1.92 (m, 2H), 1.91 - 1.77 (m, J = 12.6, 6.2 Hz, 1H); MS (ESI, m / z): 453.16 [M+H] +

[0191] Example 34. 6-(4-chlorophenyl)-3-((1S,3R)-3-hydroxycyclopentyl)-8-(1-methyl-1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one [ka] The title compound was obtained in the same manner as in Example 1, except that (1R,3S)-3-aminocyclopentanol hydrochloride, (1-methyl-1H-pyrazol-4-yl)boronic acid and (4-chlorophenyl)boronic acid were used (Scheme 1. General Procedure A). 1H NMR (400 MHz, CDCl3): δ [ppm] = 8.63 (s, 1H), 8.58 (s, 1H), 8.56 (s, 1H), 8.32 (s, 1H), 8.17 (d, J = 8.6 Hz, 2H), 7.49 (d, J = 8.7 Hz, 2H), 5.27 - 5.21 (m, 1H), 4.56 - 4.51 (m, 1H), 4.02 (s, 3H), 2.78 (d, J = 5.0 Hz, 1H), 2.58 - 2.52 (m, 1H), 2.34 - 2.19 (m, 2H), 2.07 - 1.97 (m, 2H), 1.88 - 1.81 (m, 1H); MS (ESI, m / z): 422.15 [M+H] +

[0192] Example 35. 3-((1S,3R)-3-Hydroxycyclopentyl)-8-(1-methyl-1H-pyrazol-4-yl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one [ka] The title compound was obtained in the same manner as in Example 1, except that (1R,3S)-3-aminocyclopentanol hydrochloride, (1-methyl-1H-pyrazol-4-yl)boronic acid and (4-(trifluoromethyl)phenyl)boronic acid were used (Scheme 1. General Procedure A). 1H NMR (400 MHz, CDCl3): δ [ppm] = 8.64 (s, 1H), 8.60 (s, 1H), 8.59 (s, 1H), 8.38 (s, 1H), 8.33 (d, J = 8.2 Hz, 2H), 7.77 (d, J = 8.3 Hz, 2H), 5.30 - 5.22 (m, 1H), 4.58 - 4.49 (m, 1H), 4.03 (s, 3H), 2.77 (d, J = 4.8 Hz, 1H), 2.60 - 2.52 (m, 1H), 2.39 - 2.31 (m, 1H), 2.30 - 2.21 (m, 1H), 2.09 - 1.98 (m, 2H), 1.90 - 1.80 (m, 1H); MS (ESI, m / z): 456.20 [M+H] +

[0193] Example 36. Acetic acid 1-(6-(4-chlorophenyl)-4-oxo-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-3(4H)-yl)-2-methylpropan-2-yl [ka] General procedure A (Scheme 1) was carried out using 1-amino-2-methylpropan-2-ol, pyridin-3-ylboronic acid and (4-chlorophenyl)boronic acid. LC-MS analysis and 1 H NMR analysis confirmed that the hydroxyl group was further acetylated in the cyclization step c. The title compound was obtained in analogy to Example 1 (Scheme 1. General Procedure A). 1H NMR (400 MHz, CDCl3): δ [ppm] = 9.47 (s, 1H), 8.73 (d, J = 4.1 Hz, 1H), 8.59 - 8.51 (m, 2H), 8.19 (d, J = 8.6 Hz, 2H), 8.15 (s, 1H), 7.54 - 7.44 (m, 3H), 4.36 (s, 2H), 2.06 (s, 3H), 1.57 (s, 6H); MS (ESI, m / z): 449.20 [M+H] +

[0194] Example 37. 2-Methyl-1-(4-oxo-8-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidin-3(4H)-yl)propan-2-yl acetate [ka] General procedure A (Scheme 1) was carried out using 1-amino-2-methylpropan-2-ol, pyridin-3-ylboronic acid and (4-(trifluoromethyl)phenyl)boronic acid. LC-MS analysis and 1 H NMR analysis confirmed that the hydroxyl group was further acetylated in the cyclization step c. The title compound was obtained in analogy to Example 1 (Scheme 1. General Procedure A). 1H NMR (400 MHz, CDCl3): δ [ppm] = 9.49 (s, 1H), 8.74 (d, J = 4.0 Hz, 1H), 8.62 (s, 1H), 8.56 (ddd, J = 7.9, 1.8, 1.8 Hz, 1H), 8.35 (d, J = MS (ESI, m / z): 483.12 [M+H] +

[0195] Example 38. 6-(4-chlorophenyl)-3-(2-hydroxy-2-methylpropyl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one [ka] General procedure A (Scheme 1) was carried out using 1-amino-2-methylpropan-2-ol, pyridin-3-ylboronic acid and (4-chlorophenyl)boronic acid. LC-MS analysis and 1 H NMR analysis confirmed that the hydroxyl group was further acetylated in the cyclization step c. After a second Suzuki coupling reaction, the acetylated intermediate was deprotected by addition of K2CO3 in MeOH:water (5:1) at room temperature to give the title compound of Example 1 (Scheme 1. General Procedure A). 1H NMR (400 MHz, CDCl3): δ [ppm] = 9.43 (s, 1H), 8.69 (d, J = 3.8 Hz, 1H), 8.55 (d, J = 8.0 Hz, 1H), 8.52 (s, 1H), 8.27 (s, 1H), 8.16 (d, J = MS (ESI, m / z): 407.24 [M+H] +

[0196] Example 39. 3-(2-hydroxy-2-methylpropyl)-8-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one [ka] General procedure A (Scheme 1) was carried out using 1-amino-2-methylpropan-2-ol, pyridin-3-ylboronic acid and (4-(trifluoromethyl)phenyl)boronic acid. LC-MS analysis and 1 H NMR analysis confirmed that the hydroxyl group was further acetylated in the cyclization step c. After a second Suzuki coupling reaction, the acetylated intermediate was deprotected by addition of K2CO3 in MeOH:water (5:1) at room temperature to give the title compound of Example 1 (Scheme 1. General Procedure A). 1H NMR (400 MHz, CDCl3): δ [ppm] = 9.47 (s, 1H), 8.73 (d, J = 3.2 Hz, 1H), 8.62 (s, 1H), 8.58 (d, J = 8.0 Hz, 1H), 8.35 (d, J = 8.2 Hz, 2H), 8.30 (s, 1H), 7.78 (d, J = 8.3 Hz, 2H), 7.51 - 7.44 (m, 1H), 4.15 (s, 2H), 1.37 (s, 6H); MS (ESI, m / z): 441.31 [M+H] +

[0197] Example 40. 3-(2-hydroxy-2-methylpropyl)-8-(pyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one [ka] General procedure A (Scheme 1) was carried out using 1-amino-2-methylpropan-2-ol, pyridin-3-ylboronic acid and (6-(trifluoromethyl)pyridin-3-yl)boronic acid. LC-MS analysis confirmed that the hydroxyl group was further acetylated in the cyclization step c. After the second Suzuki coupling reaction, the acetylated intermediate was deprotected by adding K2CO3 in MeOH:water (5:1) at room temperature to give the title compound of Example 1 (Scheme 1. General procedure A). 1H NMR (400 MHz, CDCl3): δ [ppm] = 9.52 (d, J = 1.9 Hz, 1H), 9.48 (d, J = 1.8 Hz, 1H), 8.76 - 8.67 (m, 2H), 8.65 (s, 1H), 8.60 - 8.55 (m, MS (ESI, m / z): 442.17 [M+H] +

[0198] Example 41. 6-(4-chlorophenyl)-3-(1-hydroxy-3-methylbutan-2-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one [ka] The title compound was obtained in the same manner as in Example 1, except that 2-amino-3-methylbutan-1-ol, pyridin-3-ylboronic acid and (4-chlorophenyl)boronic acid were used (Scheme 1. General Procedure A). 1H-NMR (400 MHz, CDCl3): δ [ppm] = 9.43 (d, J = 1.8 Hz, 1H), 8.68 (dd, J = 4.8, 1.5 Hz, 1H), 8.54 (dt, J = 7.8, 1.9 Hz, 1H), 8.50 (s, 1H), 8.30 (s, 1H), 8.15 (d, J = 8.6 Hz, 2H), 7.48 (d, J = 8.6 Hz, 2H), 7.45 (dd, J = 8.2, 5.2 Hz, 1H), 4.51 (br, 1H), 4.25 - 4.16 (m, 1H), 4.01 (dd, J = 11.8, 2.2 Hz, 1H), 2.57 - 2.43 (m, 2H), 1.20 (d, J = 6.5 Hz, 3H), 0.89 (d, J = 6.6 Hz, 3H); MS (ESI, m / z): 421.20 [M+H] +

[0199] Example 42. 3-(1-hydroxy-3-methylbutan-2-yl)-8-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one [ka] The title compound was obtained in the same manner as in Example 1, except that 2-amino-3-methylbutan-1-ol, pyridin-3-ylboronic acid and (4-(trifluoromethyl)phenyl)boronic acid were used (Scheme 1. General Procedure A). 1H-NMR (400 MHz, CDCl3): δ [ppm] = 9.42 (s, 1H), 8.67 (dd, J = 4.8, 1.4 Hz, 1H), 8.55 - 8.52 (m, 1H), 8.54 (s, 1H), 8.33 (s, 1H), 8.29 (d, J = 8.2 Hz, 2H), 7.75 (d, J = 8.3 Hz, 2H), 7.44 (dd, J = 7.7, 5.1 Hz, 1H), 4.52 (br, 1H), 4.26 - 4.18 (m, 1H), 4.02 (dd, J = 11.9, 2.2 Hz, 1H), 2.91 - 2.74 (m, 1H), 2.55 - 2.44 (m, 1H), 1.20 (d, J = 6.5 Hz, 3H), 0.89 (d, J = 6.7 Hz, 3H); MS (ESI, m / z): 455.21 [M+H] +

[0200] Example 43. 3-(1-hydroxy-3-methylbutan-2-yl)-8-(pyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one [ka] The title compound was obtained in the same manner as in Example 1, except that 2-amino-3-methylbutan-1-ol, pyridin-3-ylboronic acid and (6-(trifluoromethyl)pyridin-3-yl)boronic acid were used (Scheme 1. General Procedure A). 1H-NMR (400 MHz, CDCl3): δ [ppm] = 9.50 (d, J = 1.5 Hz, 1H), 9.46 (d, J = 1.6 Hz, 1H), 8.72 (dd, J = 4.8, 1.4 Hz, 1H), 8.68 (dd, J = 8.3, 1.7 Hz, 1H), 8.62 (s, 1H), 8.56 (dt, J = 8.0, 1.9 Hz, 1H), 8.37 (s, 1H), 7.83 (d, J = 8.2 Hz, 1H), 7.47 (dd, J = 7.9, 4.9 Hz, 1H), 4.55 (br, 1H), 4.26 - 4.17 (m, 1H), MS (ESI, m / z): 456.19 [M+H] +

[0201] Example 44. (S)-2-((6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)amino)propan-1-ol Scheme for preparing the compound of Example 44: [ka]

[0202] Intermediate 5. 5-Amino-N-(1-((tert-butyldiphenylsilyl)oxy)propan-2-yl)-2-chloroisonicotinamide [ka] 5-Amino-2-chloroisonicotinic acid (1 g, 5.79 mmol, 1 equiv.), EDC (1.33 g, 6.95 mmol, 1.2 equiv.), HOBT (1.06 g, 6.95 mmol, 1.2 equiv.) and TEA (1.21 mL, 8.69 mmol, 1.5 equiv.) were dissolved in DMF (10 mL, 0.6 M) and stirred for 5 min. Then, 1-((tert-butyldiphenylsilyl)oxy)propan-2-amine (2.73 g, 8.69 mmol, 1.5 equiv.) was added to the reaction and stirred at 60° C. for 12 h. The reaction was diluted with water (50 mL), extracted with EtOAc (50 mL×3), washed with brine (20 mL×3), dried over Na2SO4, and filtered through a glass filter. The filtrate was concentrated under reduced pressure and purified by MPLC (silica gel, 0-30% EtOAc / hexanes) to give 0.87 g of 5-amino-N-(1-((tert-butyldiphenylsilyl)oxy)propan-2-yl)-2-chloroisonicotinamide (Intermediate 5) (32% yield). MS (ESI, m / z): 468.04 [M+H] +

[0203] Intermediate 6. 5-Amino-N-(1-((tert-butyldiphenylsilyl)oxy)propan-2-yl)-2-(4-(trifluoromethyl)phenyl)isonicotinamide [ka] 5-Amino-N-(1-((tert-butyldiphenylsilyl)oxy)propan-2-yl)-2-chloroisonicotinamide (Intermediate 5) (0.64 g, 1.37 mmol, 1 equiv.), (4-(trifluoromethyl)phenyl)boronic acid (0.52 g, 2.73 mmol, 2 equiv.), K2CO3 (0.57 g, 4.10 mmol, 3 equiv.) and Pd(dppf)Cl2·CH2Cl2 (0.11 g, 0.14 mmol, 0.1 equiv.) were dissolved in 1,4-dioxane / water (4 mL / 1 mL, 0.4 M). The reaction was heated and stirred at 130 °C for 1 h in a Biotage Initiator microwave synthesizer. The reaction mixture was concentrated under reduced pressure and then directly purified by MPLC (silica gel, 0-30% EtOAc / hexane) to give 0.48 g of 5-amino-N-(1-((tert-butyldiphenylsilyl)oxy)propan-2-yl)-2-(4-(trifluoromethyl)phenyl)isonicotinamide (intermediate 6) (yield 61%). MS (ESI, m / z): 578.16 [M+H] +

[0204] Intermediate 7. 3-Amino-2-bromo-N-(1-((tert-butyldiphenylsilyl)oxy)propan-2-yl)-6-(4-(trifluoromethyl)phenyl)isonicotinamide [ka] 5-Amino-N-(1-((tert-butyldiphenylsilyl)oxy)propan-2-yl)-2-(4-(trifluoromethyl)phenyl)isonicotinamide (Intermediate 6) (0.1 g, 0.17 mmol, 1 equiv.) and N-bromosuccinimide (0.046 g, 0.26 mmol, 1.5 equiv.) were dissolved in DMF (5 mL, 0.035 M) and stirred at room temperature for 1 h. The reaction mixture was diluted with water (20 mL), extracted with EtOAc (20 mL×3), washed with brine (10 mL×3), dried over Na2SO4, and filtered through a glass filter. The filtrate was concentrated under reduced pressure to give 0.082 g of 3-amino-2-bromo-N-(1-((tert-butyldiphenylsilyl)oxy)propan-2-yl)-6-(4-(trifluoromethyl)phenyl)isonicotinamide (Intermediate 7) (72% yield). MS (ESI, m / z): 656.14 [M+H] +

[0205] Intermediate 8. 8-Bromo-3-(1-((tert-butyldiphenylsilyl)oxy)propan-2-yl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one [ka] 3-Amino-2-bromo-N-(1-((tert-butyldiphenylsilyl)oxy)propan-2-yl)-6-(4-(trifluoromethyl)phenyl)isonicotinamide (Intermediate 7) (82 mg, 0.125 mmol, 1 equiv) was dissolved in a solution of (EtO)3CH (1.5 mL, 9.01 mmol, 9 equiv) and CH3CO2H (1.5 mL, 26.2 mmol, 210 equiv). The reaction mixture was heated and stirred at 150 °C for 2 h in a Biotage Initiator microwave synthesis system. The reaction mixture was diluted with water (20 mL), extracted with EtOAc (20 mL x 3), washed with brine (10 mL x 3), dried over Na2SO4, and filtered through a glass filter. The filtrate was concentrated under reduced pressure to give 0.06 g of 8-bromo-3-(1-((tert-butyldiphenylsilyl)oxy)propan-2-yl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one (Intermediate 8) without further purification (72% yield). MS (ESI, m / z): 666.09 [M] +

[0206] Intermediate 9. 3-(1-((tert-butyldiphenylsilyl)oxy)propan-2-yl)-8-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one [ka] 8-Bromo-3-(1-((tert-butyldiphenylsilyl)oxy)propan-2-yl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one (Intermediate 8) (60 mg, 0.090 mmol, 1 equiv.), pyridin-3-ylboronic acid (17 mg, 0.13 mmol, 1.5 equiv.), K2CO3 (37 mg, 0.27 mmol, 3 equiv.), Sphos (3.7 mg, 9.00 μmol, 0.1 equiv.) and Pd2(dba)3·CHCl3 (9.32 mg, 9.00 μmol, 0.1 equiv.) were dissolved in 1,4-dioxane / water (4 mL / 1 mL, 0.2 M). The reaction mixture was heated and stirred at 130 °C for 1 h in a Biotage Microwave Synthesizer Initiator. The reaction mixture was concentrated under reduced pressure and then directly purified by MPLC (silica gel, 0-30% EtOAc / hexane) to give 10 mg of 3-(1-((tert-butyldiphenylsilyl)oxy)propan-2-yl)-8-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one (Intermediate 9) (yield 17%). MS (ESI, m / z): 665.15[M+H]+

[0207] Example 44. 3-(1-Hydroxypropan-2-yl)-8-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one [ka] A solution of 3-(1-((tert-butyldiphenylsilyl)oxy)propan-2-yl)-8-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one (Intermediate 9) (10 mg, 0.015 mmol, 1 equiv.) and TBAF (1.0 M in THF, 15 μL, 0.015 mmol, 1 equiv.) in THF (2 mL, 0.0075 M) was stirred at 40° C. for 12 h. The reaction mixture was diluted with water (5 mL), extracted with EtOAc (5 mL×3), washed with brine (5 mL×3), dried over Na2SO4, and filtered through a glass filter. The filtrate was concentrated under reduced pressure and purified by preparative thin layer chromatography (TLC) (silica gel, 0-50% EtOAc / hexanes) to give 1.9 mg of 3-(1-hydroxypropan-2-yl)-8-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one (Example 44) (30% yield). 1H-NMR (400 MHz, CD3OD): δ [ppm] = 9.44 (d, J = 1.6 Hz, 1H), 8.75 (d, J = 8.0 Hz, 1H), 8.69 (s, 1H), 8.66 (d, J = 4.8 Hz, 1H), 8.48 (s, 1H), 8.45 (d, J = 8.2 Hz, 2H), 7.86 (d, J = 8.3 Hz, 2H), 7.63 (dd, J = 8.0, 5.0 Hz, 1H), 5.08 - 4.99 (m, 1H), 3.99 (dd, J = 11.9, 7.0 Hz, 1H), 3.88 (dd, J = 11.9, 4.3 Hz, 1H), 1.58 (d, J = 7.1 Hz, 3H); MS (ESI, m / z): 426.94 [M+H] +

[0208] Example 45. 3-(1-hydroxypropan-2-yl)-8-(1-methyl-1H-pyrazol-4-yl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one [ka] The title compound was obtained in the same manner as in Example 44, except that (1-methyl-1H-pyrazol-4-yl)boronic acid was used (Scheme 2. General procedure B). 1H-NMR (400 MHz, CD3OD): δ [ppm] = 8.69 (s, 1H), 8.46 (s, 1H), 8.38 (s, 1H), 8.31 (s, 1H), 8.29 (d, J = 2.7 Hz, 2H), 7.71 (d, J = 8.3 Hz, MS (ESI, m / z): 430.02 [M+H] +

[0209] Example 46. 6-(4-chlorophenyl)-3-(1-hydroxypropan-2-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one [ka] The title compound was obtained in the same manner as in Example 44, except that pyridin-3-ylboronic acid was used (Scheme 2. General Procedure B). 1H-NMR (400 MHz, CD3OD): δ [ppm] = 9.31 (s, 1H), 8.65 - 8.59 (m, 1H), 8.53 (d, J = 4.2 Hz, 1H), 8.49 (s, 1H), 8.34 (s, 1H), 8.14 (d, J = 8.6 Hz, 2H), 7.51 (dd, J = 7.9, 5.0 Hz, 1H), 7.44 (d, J = 8.6 Hz, 2H), 4.95 - 4.86 (m, 1H), 3.87 (dd, J = 11.9, 7.0 Hz, 1H), 3.76 (dd, J = 11.9, 4.3 Hz, 1H), 1.46 (d, J = 7.1 Hz, 3H); MS (ESI, m / z): 392.91 [M+H] +

[0210] Example 47. Diethyl 2-(6-(4-chlorophenyl)-4-oxo-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-3(4H)-yl)propyl phosphate [ka] 6-(4-chlorophenyl)-3-(1-hydroxypropan-2-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (Example 46) (100 mg, 0.255 mmol, 1 equivalent) and sodium hydride (18.33 mg, 0.764 mmol, 3 equivalents) were dissolved in THF (1273 μl, 0.2 M) and stirred for 10 minutes. Next, a solution of diethyl chlorophosphate (73.8 μl, 0.509 mmol, 2 equivalents) and N,N-dimethylpyridin-4-amine (15.55 mg, 0.127 mmol, 0.5 equivalents) in THF (1273 μl, 0.2 M) was added dropwise to the reaction solution and stirred at room temperature for 12 hours. The reaction was quenched by adding water (10 mL), extracted with DCM (10 mL x 3), washed with brine (10 mL x 3), dried over Na2SO4, and filtered through a glass filter. The filtrate was concentrated under reduced pressure to give 79 mg of diethyl 2-(6-(4-chlorophenyl)-4-oxo-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-3(4H)-yl)propyl phosphate (Example 47) (yield 59%) without further purification. 1H-NMR (400 MHz, CDCl3): δ [ppm] = 9.45 (d, J = 1.6 Hz, 1H), 8.72 (dd, J = 4.8, 1.4 Hz, 1H), 8.55 (dt, J = 8.0, 1.9 Hz, 1H), 8.53 (s, 1H), 8.18 (d, J = 8.5 Hz, 3H), 7.49 (d, J = 8.7 Hz, 2H), 7.47 (dd, J = 5.2, 3.1, 1H), 5.15 (dd, J = 10.2, 6.3 Hz, 1H), 4.45 (ddd, J = 11.2, 7.5, 6.2 Hz, 1H), 4.37 - 4.28 (m, 1H), 4.06 (p, J = 7.3 Hz, 4H), 1.65 (d, J = 7.2 Hz, 3H), 1.29 - 1.23 (m, 6H); MS (ESI, m / z): 529.23 [M+H] +

[0211] Example 48. 6-(4-chlorophenyl)-3-(1-hydroxypropan-2-yl)-8-(1-methyl-1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one [ka] The title compound was obtained in the same manner as in Example 44, except that (1-methyl-1H-pyrazol-4-yl)boronic acid and (4-chlorophenyl)boronic acid were used (Scheme 2. General Procedure B). 1H-NMR (400 MHz, CD3OD): δ [ppm] = 8.79 (s, 1H), 8.56 (s, 1H), 8.46 (s, 1H), 8.33 (s, 1H), 8.22 (d, J = 8.4 Hz, 2H), 7.77 (s, 1H), 7.52 (d, J = 8.4 Hz, 2H), 5.03 - 4.99 (m, 1H), 4.01 (s, 3H), 3.99 - 3.93 (m, 1H), 3.86 (dd, J = 11.8, 4.3 Hz, 1H), 1.57 (d, J = 7.1 Hz, 3H); MS (ESI, m / z): 396.00 [M+H] +

[0212] Example 49. 3-(1-Hydroxypropan-2-yl)-8-(pyridin-3-yl)-6-(4-(trifluoromethoxy)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one [ka] The title compound was obtained in the same manner as in Example 44, except that pyridin-3-ylboronic acid and (4-(trifluoromethoxy)phenyl)boronic acid were used (Scheme 2. General Procedure B). 1H-NMR (400 MHz, CD3OD): δ [ppm] = 9.43 (s, 1H), 8.74 (dd, J = 6.2, 1.8 Hz, 1H), 8.68 - 8.64 (m, 1H), 8.62 (s, 1H), 8.46 (s, 1H), 8.37 (d, J = 8.8 Hz, 2H), 7.63 (dd, J = 7.9, 5.0 Hz, 1H), 7.46 (d, J = 8.4 Hz, 2H), 5.08 - 4.98 (m, 1H), 3.99 (dd, J = 11.9, 7.0 Hz, 1H), 3.88 (dd, J = 11.9, 4.3 Hz, 1H), 1.58 (d, J = 7.1 Hz, 3H); MS (ESI, m / z): 442.93 [M+H] +

[0213] Example 50. 3-(1-Hydroxypropan-2-yl)-8-(pyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one [ka] The title compound was obtained in the same manner as in Example 44, except that pyridin-3-ylboronic acid and (6-(trifluoromethyl)pyridin-3-yl)boronic acid were used (Scheme 2. General Procedure B). 1H-NMR (400 MHz, CD3OD): δ [ppm] = 9.59 (s, 1H), 9.45 (d, J = 1.9 Hz, 1H), 8.89 (d, J = 8.2 Hz, 1H), 8.79 (s, 1H), 8.76 (d, J = 8.0 Hz, 1H), 8.70 - 8.59 (m, 1H), 8.52 (s, 1H), 8.01 (d, J = 8.3 Hz, 1H), 7.65 (dd, J = 8.0, 4.9 Hz, 1H), 5.07 - 5.00 (m, 1H), 4.00 (dd, J = 11.9, 7.0 Hz, 1H), 3.88 (dd, J = 11.9, 4.3 Hz, 1H), 1.59 (d, J = 7.1 Hz, 3H); MS (ESI, m / z): 427.96 [M+H] +

[0214] Example 51. 6-(4-chlorophenyl)-3-(1-hydroxybutan-2-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one [ka] The title compound was obtained in the same manner as in Example 44, except that 2-aminobutan-1-ol, pyridin-3-ylboronic acid and (4-chlorophenyl)boronic acid were used (Scheme 2. General procedure B). 1H-NMR (400 MHz, CD3OD): δ [ppm] = 9.43 (d, J = 1.6 Hz, 1H), 8.74 (d, J = 8.0 Hz, 1H), 8.65 (d, J = 4.8 Hz, 1H), 8.61 (s, 1H), 8.44 (s, 1H), 8.26 (d, J = 8.5 Hz, 2H), 7.63 (dd, J = 8.0, 5.0 Hz, 1H), 7.56 (d, J = 8.5 Hz, 2H), 4.84 (s, 1H), 4.04 (dd, J = 12.0, 7.1 Hz, 1H), 3.89 (dd, J = 12.0, 4.0 Hz, 1H), 2.02 (p, J = 7.4 Hz, 2H), 1.00 (t, J = 7.4 Hz, 3H); MS (ESI, m / z): 406.95 [M+H] +

[0215] Example 52. 6-(4-chlorophenyl)-3-(1-hydroxybutan-2-yl)-8-(1-methyl-1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one [ka] The title compound was obtained in the same manner as in Example 44, except that 2-aminobutan-1-ol, (1-methyl-1H-pyrazol-4-yl)boronic acid and (4-chlorophenyl)boronic acid were used (Scheme 2. General Procedure B). 1H-NMR (400 MHz, CD3OD): δ [ppm] = 8.79 (s, 1H), 8.55 (s, 1H), 8.45 (s, 1H), 8.31 (s, 1H), 8.21 (d, J = 8.5 Hz, 2H), 7.53 (d, J = 8.5 Hz, 2H), 4.82 (s, 1H),4.08 - 4.03 (m, 1H), 4.02 (s, 3H), 3.89 (dd, J = 12.0, 4.0 Hz, 1H), 2.03 (p, J = 7.4 Hz, 2H), 1.00 (t, J = 7.4 Hz, 3H); MS (ESI, m / z): 409.99 [M+H] +

[0216] Example 53. 3-(1-Hydroxybutan-2-yl)-8-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one [ka] The title compound was obtained in the same manner as in Example 44, except that 2-aminobutan-1-ol, pyridin-3-ylboronic acid and (4-(trifluoromethyl)phenyl)boronic acid were used (Scheme 2. General procedure B). 1H-NMR (400 MHz, CD3OD): δ [ppm] = 9.43 (d, J = 2.0 Hz, 1H), 8.74 (dt, J = 8.0, 1.8 Hz, 1H), 8.66 (s, 1H), 8.66 - 8.63 (m, 1H), 8.46 (s, 1H),8.43 (d, J = 8.3 Hz, 2H), 7.84 (d, J = 8.4 Hz, 2H), 7.62 (dd, J = 8.0, 5.0 Hz, 1H), 4.84 (s, 1H), 4.04 (dd, J = 12.0, 7.0 Hz, 1H), 3.89 (dd, J = 12.0, 4.0 Hz, 1H), 2.07 - 1.94 (m, 2H), 1.01 (t, J = 7.4 Hz, 3H); MS (ESI, m / z): 441.00 [M+H] +

[0217] Example 54. 3-(1-hydroxybutan-2-yl)-8-(1-methyl-1H-pyrazol-4-yl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one [ka] The title compound was obtained in the same manner as in Example 44, except that 2-aminobutan-1-ol, (1-methyl-1H-pyrazol-4-yl)boronic acid and (4-(trifluoromethyl)phenyl)boronic acid were used (Scheme 2. General Procedure B). 1H-NMR (400 MHz, CD3OD): δ [ppm] = 8.78 (s, 1H), 8.55 (s, 1H), 8.47 (s, 1H), 8.41 (s, 1H), 8.38 (s, 2H), 7.82 (d, J = 8.1 Hz, 2H),4.83 MS (ESI, m / z): 444.01 [M+H] +

[0218] Example 55. 6-(4-chlorophenyl)-8-(3-fluorophenyl)-3-(1-hydroxybutan-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one [ka] The title compound was obtained in the same manner as in Example 44, except that 2-aminobutan-1-ol, (3-fluorophenyl)boronic acid and (4-chlorophenyl)boronic acid were used (Scheme 2. General procedure B). 1H-NMR (400 MHz, CD3OD): δ [ppm] = 8.56 (s, 1H), 8.41 (s, 1H), 8.24 (d, J = 8.6 Hz, 2H), 8.12 - 7.96 (m, 2H), 7.58 - 7.52 (m, 3H), 7.24 (td, J = 8.5, 2.6 Hz, 1H), 4.83 (s, 1H), 4.03 (dd, J = 12.0, 7.0 Hz, 1H), 3.88 (dd, J = 12.0, 4.1 Hz, 1H), 2.07 - 1.95 (m, 2H), 1.00 (t, J = 7.4 Hz, 3H); MS (ESI, m / z): 423.98 [M+H] +

[0219] Example 56. 6-(4-chlorophenyl)-3-((1r,4r)-4-hydroxycyclohexyl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one [ka] The title compound was obtained in the same manner as in Example 44, except that (1r,4r)-4-aminocyclohexan-1-ol, pyridin-3-ylboronic acid and (4-chlorophenyl)boronic acid were used (Scheme 2. General Procedure B). 1H-NMR (400 MHz, CDCl3): δ [ppm] = 9.45 (s, 1H), 8.72 (s, 1H), 8.58 - 8.46 (m, 2H), 8.19 (d, J = 8.6 Hz, 2H), 8.17 (s, 1H), 7.54 - 7.42 (m, 3H), 4.89 - 4.76 (m, 9H), 3.83 - 3.74 (m, 1H), 2.32 - 2.16 (m, 2H), 2.14 - 2.03 (m, 2H), 1.92 - 1.76 (m, 2H), 1.69 - 1.59 (m, 2H); MS (ESI, m / z): 433.01 [M+H] +

[0220] Example 57. 3-((1r,4r)-4-Hydroxycyclohexyl)-8-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one [ka] The title compound was obtained in the same manner as in Example 44, except that (1r,4r)-4-aminocyclohexan-1-ol, pyridin-3-ylboronic acid and (4-(trifluoromethyl)phenyl)boronic acid were used (Scheme 2. General Procedure B). 1H-NMR (400 MHz, CDCl3): δ [ppm] = 9.46 (d, J = 1.9 Hz, 1H), 8.73 (dd, J = 4.8, 1.6 Hz, 1H), 8.62 (s, 1H), 8.58 - 8.51 (m, 1H), 8.36 (d, J = 8.3 Hz, 2H), 8.20 (s, 1H), 7.79 (d, J = 8.4 Hz, 2H), 7.48 (dd, J = 7.9, 4.9 Hz, 1H), 4.87 - 4.79 (m, 1H), 3.83 - 3.75 (m, 1H), 2.28 - 2.16 (m, 2H), 2.14 - 2.03 (m, 2H), 1.92 - 1.79 (m, 2H), 1.69 - 1.60 (m, 2H); MS (ESI, m / z): 466.97 [M+H] +

[0221] Example 58. 6-(4-chlorophenyl)-3-((1s,4s)-4-hydroxycyclohexyl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one [ka] General procedure B (Scheme 2) was carried out using methyl (1r,4r)-4-aminocyclohexanol, pyridin-3-ylboronic acid and (4-chlorophenyl)boronic acid. LC-MS analysis confirmed that the hydroxyl group was further acetylated in the cyclization step c. After the second Suzuki coupling reaction, the acetylated intermediate was deprotected by adding K2CO3 in MeOH:water (5:1) at room temperature to give the title compound of Example 58 (Scheme 2. General procedure B). 1H NMR (400 MHz, CDCl3): δ [ppm] = 9.46 (s, 1H), 8.72 (s, 1H), 8.56 (d, J = 10.0 Hz, 2H), 8.29 (s, 1H), 8.22 - 8.10 (m, 2H), 7.57 - 7.36 (m, MS (ESI, m / z): 433.17 [M+H] +

[0222] Example 59. 3-(1-hydroxypropan-2-yl)-8-(1-methyl-1H-pyrazol-4-yl)-6-(4-(trifluoromethyl)phenyl)-2,3-dihydropyrido[3,4-d]pyrimidin-4(1H)-one Scheme for preparing the compound of Example 59: [ka]

[0223] Intermediate 10. 3-(1-((tert-butyldiphenylsilyl)oxy)propan-2-yl)-8-(1-methyl-1H-pyrazol-4-yl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one [ka] The title compound was obtained in a manner similar to the preparation of Intermediate 9 in Example 44, except that (1-methyl-1H-pyrazol-4-yl)boronic acid was used (Scheme 2. General Procedure B). MS (ESI, m / z): 668.31 [M+H] +

[0224] Intermediate 11. 3-(1-((tert-butyldiphenylsilyl)oxy)propan-2-yl)-8-(1-methyl-1H-pyrazol-4-yl)-6-(4-(trifluoromethyl)phenyl)-2,3-dihydropyrido[3,4-d]pyrimidin-4(1H)-one [ka] 3-(1-((tert-butyldiphenylsilyl)oxy)propan-2-yl)-8-(1-methyl-1H-pyrazol-4-yl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one (Intermediate 10) (23 mg, 0.034 mmol, 1 equiv.) was dissolved in THF (3 mL, 0.011 M) and cooled to 0° C. Then, NaBH4 (5.21 mg, 0.14 mmol, 4 equiv.) was added to the reaction solution and stirred at room temperature for 2 h. The reaction solution was quenched with MeOH (3 mL), diluted with water (3 mL), extracted with EtOAc (5 mL×3), washed with brine (5 mL×3), dried over Na2SO4, and filtered through a glass filter. The filtrate was concentrated under reduced pressure and purified by MPLC (silica gel, 0-30% EtOAc / hexanes) to give 20 mg of 3-(1-((tert-butyldiphenylsilyl)oxy)propan-2-yl)-8-(1-methyl-1H-pyrazol-4-yl)-6-(4-(trifluoromethyl)phenyl)-2,3-dihydropyrido[3,4-d]pyrimidin-4(1H)-one (Intermediate 11) (87% yield). MS (ESI, m / z): 670.26 [M+H] +

[0225] Example 59. 3-(1-hydroxypropan-2-yl)-8-(1-methyl-1H-pyrazol-4-yl)-6-(4-(trifluoromethyl)phenyl)-2,3-dihydropyrido[3,4-d]pyrimidin-4(1H)-one [ka] 3-(1-((tert-butyldiphenylsilyl)oxy)propan-2-yl)-8-(1-methyl-1H-pyrazol-4-yl)-6-(4-(trifluoromethyl)phenyl)-2,3-dihydropyrido[3,4-d]pyrimidin-4(1H)-one (intermediate 11) (20 mg, 0.03 mmol, 1 equiv.) in THF (2 mL, 0.01 M) was added with TBAF (1.0 M in THF, 30 μL, 0.03 mmol, 1 equiv.) and stirred at 40° C. for 3 hours. The reaction mixture was diluted with water (5 mL), extracted with EtOAc (5 mL×3), washed with brine (5 mL×3), dried over Na2SO4, and filtered through a glass filter. The filtrate was concentrated under reduced pressure and purified by preparative TLC (Chromatorex silica gel KP80805 (NH-SiO2), 0-70% EtOAc / Hexanes) to give 3.9 mg of 3-(1-hydroxypropan-2-yl)-8-(1-methyl-1H-pyrazol-4-yl)-6-(4-(trifluoromethyl)phenyl)-2,3-dihydropyrido[3,4-d]pyrimidin-4(1H)-one (Example 59) (30% yield). 1H-NMR (400 MHz, CDCl3): δ [ppm] = 8.17 (s, 1H), 8.15 (d, J = 8.2 Hz, 2H), 8.03 (s, 1H), 7.98 (s, 1H), 7.69 (d, J = 8.3 Hz, 2H), 4.74 (dt, J = 11.0, 3.8 Hz, 2H), 4.70 - 4.62 (m, 2H), 3.86 (dd, J = 11.6, 3.8 Hz, 1H), 3.73 (d, J = 7.8 Hz, 1H), 1.61 (s, 2H), 1.32 (d, J = 7.0 Hz, 3H); MS (ESI, m / z):432.01 [M+H] +

[0226] Example 60. 6-(4-chlorophenyl)-3-(2,3-dihydroxypropyl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one [ka] 6-(4-chlorophenyl)-3-(1-hydroxypropan-2-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (Example 48) (50 mg, 0.127 mmol, 1 eq.) was dissolved in THF (3 mL, 0.042 M) and cooled to 0° C. Then, NaBH4 (9.6 mg, 0.255 mmol, 2 eq.) was added to the reaction solution and stirred at room temperature for 2 hours. The reaction solution was quenched with MeOH (3 mL), diluted with water (3 mL), extracted with EtOAc (5 mL×3), washed with brine (5 mL×3), dried over Na2SO4, and filtered through a glass filter. The filtrate was concentrated under reduced pressure and purified by preparative TLC (silica gel, 0-10% MeOH / DCM) to give 2.9 mg of 6-(4-chlorophenyl)-3-(2,3-dihydroxypropyl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (Example 60) (yield 5.7%). 1H-NMR (400 MHz, CDCl3): δ [ppm] = 9.04 (s, 1H), 8.70 (s, 1H), 8.24 (s, 1H), 8.12 (d, J = 7.9 Hz, 1H), 7.99 (d, J = 8.6 Hz, 2H), 7.47 (dd, J = 7.6, 5.0 Hz, 1H), 7.41 (d, J = 8.5 Hz, 2H), 4.85 (s, 1H), 4.79 - 4.73 (m, 1H), 4.73 - 4.61 (m, 2H), 3.85 (dd, J = 11.6, 3.8 Hz, 1H), 3.70 (dd, J = 11.5, 7.6 Hz, 1H), 1.31 (d, J = 7.0 Hz, 3H); MS (ESI, m / z):395.15 [M+H] +

[0227] Example 61. 6-(4-chlorophenyl)-3-(3-hydroxyphenyl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one [ka] The title compound was obtained in the same manner as in Example 44, except that 3-aminophenol, pyridin-3-ylboronic acid and (4-chlorophenyl)boronic acid were used (Scheme 2. General procedure B). 1H-NMR (400 MHz, CDCl3): δ [ppm] = 9.50 (d, J = 1.7 Hz, 1H), 8.72 (dd, J = 4.9, 1.5 Hz, 1H), 8.63 - 8.59 (m, 1H), 8.57 (s, 1H), 8.17 (d, J = 8.6 Hz, 2H), 8.15 (s, 1H), 7.54 (dd, J = 7.9, 4.9 Hz, 1H), 7.49 (d, J = 8.6 Hz, 2H), 7.44 (dd, J = 8.1, 8.1 Hz, 1H), 7.04 (dd, J = 8.2, 1.8 Hz, 1H), 6.96 (d, J = 7.8 Hz, 1H), 6.93 - 6.90 (m, 1H); MS (ESI, m / z): 427.0 [M+H] +

[0228] Example 62. 3-(3-hydroxyphenyl)-8-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one [ka] The title compound was obtained in the same manner as in Example 44, except that 3-aminophenol, pyridin-3-ylboronic acid and (4-(trifluoromethyl)phenyl)boronic acid were used (Scheme 2. General procedure B). 1H-NMR (400 MHz, CDCl3): δ [ppm] = 9.50 (d, J = 2.0 Hz, 1H), 8.74 (dd, J = 4.9, 1.6 Hz, 1H), 8.66 (s, 1H), 8.62 - 8.57 (m, 1H), 8.36 (d, J = 8.1 Hz, 2H), 8.20 (s, 1H), 7.79 (d, J = 8.3 Hz, 2H), 7.53 (dd, J = 8.4, 4.5 Hz, 1H), 7.46 (dd, J = 8.1, 8.1 Hz, 1H), 7.04 (dd, J = 8.3, 2.3 Hz, 1H), 7.02 - 6.98 (m, 1H), 6.96 - 6.92 (m, 1H); MS (ESI, m / z): 461.03 [M+H] +

[0229] Example 63. 6-(4-chlorophenyl)-3-(3-hydroxycyclohexyl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one [ka] The title compound was obtained in the same manner as in Example 44, except that 3-aminocyclohexan-1-ol, pyridin-3-ylboronic acid and (4-chlorophenyl)boronic acid were used (Scheme 2. General Procedure B). 1H NMR (400 MHz, MeOD) δ [ppm] = 9.42 (s, 1H), 8.74 (d, J = 7.9 Hz, 1H), 8.65 (d, J = 4.8 Hz, 1H), 8.60 (s, 1H), 8.50 (s, 1H), 8.26 (d, J = 7.6 Hz, 2H), 7.63 (dd, J = 8.0, 4.9 Hz, 1H), 7.56 (d, J = 7.7 Hz, 2H), 4.79 (t, J = 12.5 Hz, 1H), 3.90 - 3.75 (m, 1H), 2.28 (d, J = 12.1 Hz, 1H), 2.07 - 1.98 (m, MS (ESI, m / z): 433.11 [M+H] +

[0230] Example 64. 6-(4-chlorophenyl)-3-(3-hydroxycyclohexyl)-8-(1-methyl-1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one [ka] The title compound was obtained in the same manner as in Example 44, except that 3-aminocyclohexan-1-ol, (1-methyl-1H-pyrazol-4-yl)boronic acid and (4-chlorophenyl)boronic acid were used (Scheme 2. General Procedure B). 1H NMR (400 MHz, MeOD) δ [ppm] = 8.80 (s, 1H), 8.58 (s, 1H), 8.52 (s, 1H), 8.34 (s, 1H), 8.23 ​​(d, J = 8.6 Hz, 2H), 7.54 (d, J = 8.6 Hz, 2H), 4.79 (t, J = 12.4 Hz, 1H), 4.02 (s, 3H), 3.84 - 3.73 (m, 1H), 2.28 (d, J = 11.1 Hz, 1H), 2.11 - 2.01 (m, 2H), 1.91 - 1.83 (d, J = 12.0 Hz, 2H), 1.56 (dd, J = 26.7, 13.4 Hz, 1H), 1.42 - 1.33 (m, 1H).; MS (ESI, m / z): 436.10 [M+H] +

[0231] Example 65. 3-((1R,3S)-3-Hydroxycyclopentyl)-8-(pyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one Scheme for preparing the compound of Example 65: [ka]

[0232] Intermediate 12. 3-Amino-6-chloro-N-((1R,3S)-3-hydroxycyclopentyl)-2-iodoisonicotinamide [ka] A mixture of 3-amino-6-chloro-2-iodoisonicotinic acid (2 g, 6.70 mmol, 1 equiv.), EDC (1.541 g, 8.04 mmol, 1.2 equiv.), HOBT (1.231 g, 8.04 mmol, 1.2 equiv.), and TEA (1.401 mL, 10.05 mmol, 1.5 equiv.) was dissolved in DMF (50 mL, 0.14 M) and stirred for 5 min. Then, (1S,3R)-3-aminocyclopentanol (0.746 g, 7.37 mmol, 1.1 equiv.) was added to the reaction and stirred at 50 °C for 12 h. The reaction was diluted with water (50 mL), extracted with EtOAc (20 mL x 3), washed with brine (20 mL x 3), dried over Na2SO4, and filtered through a glass filter. The filtrate was concentrated under reduced pressure and purified by MPLC (silica gel, 0-5% MeOH / DCM) to give 2 g of 3-amino-6-chloro-N-((1R,3S)-3-hydroxycyclopentyl)-2-iodoisonicotinamide (intermediate 12) (yield 78%). MS (ESI, m / z): 381.85 [M+H] +

[0233] Intermediate 13. 6-Chloro-3-((1R,3S)-3-hydroxycyclopentyl)-8-iodopyrido[3,4-d]pyrimidin-4(3H)-one [ka] 3-Amino-6-chloro-N-((1R,3S)-3-hydroxycyclopentyl)-2-iodoisonicotinamide (Intermediate 12) (1.5 g, 3.93 mmol, 1 equiv.) was dissolved in a solution of (EtO)3CH (15 mL, 90 mmol, 23 equiv.) and CH3CO2H (15 mL, 262 mmol, 67 equiv.). The reaction mixture was heated and stirred at 150 °C for 1 h in a Biotage Microwave Synthesizer Initiator. The reaction mixture was diluted with water (20 mL), extracted with EtOAc (20 mL x 3), washed with brine (10 mL x 3), dried over Na2SO4, and filtered through a glass filter. The filtrate was concentrated under reduced pressure to give 0.401 g (26% yield) of 6-chloro-3-((1R,3S)-3-hydroxycyclopentyl)-8-iodopyrido[3,4-d]pyrimidin-4(3H)-one (Intermediate 13), which was used in the next step without further purification. 1H NMR (400 MHz, CDCl3): δ [ppm] = 8.78 (s, 1H), 8.04 (s, 1H), 5.39 - 5.27 (m, 1H), 4.59 - 4.46 (m, 1H), 2.50 (ddd, J = 15.8, 11.1, 5.1 MS (ESI, m / z): 391.89 [M+H]+

[0234] Intermediate 14. 6-Chloro-3-((1R,3S)-3-hydroxycyclopentyl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one [ka] 6-Chloro-3-((1R,3S)-3-hydroxycyclopentyl)-8-iodopyrido[3,4-d]pyrimidin-4(3H)-one (Intermediate 13) (0.360 g, 0.925 mmol, 1 equiv.), pyridin-3-ylboronic acid (0.125 g, 1.018 mmol, 1.1 equiv.), K2CO3 (0.384 g, 2.78 mmol, 3 equiv.) and Pd(dppf)Cl2·CH2Cl2 (0.076 g, 9.3 μmol, 0.1 equiv.) were dissolved in 1,4-dioxane / water (4 mL / 1 mL, 0.06 M). The reaction was heated and stirred at 130 °C for 30 min in a Biotage Microwave Synthesizer Initiator. The reaction mixture was concentrated under reduced pressure and then directly purified by MPLC (silica gel, 0-10% MeOH / DCM) to obtain 0.186 g of 6-chloro-3-((1R,3S)-3-hydroxycyclopentyl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (intermediate 14) (yield 60%). MS (ESI, m / z): 343.05 [M+H] +

[0235] Example 65. 3-((1R,3S)-3-Hydroxycyclopentyl)-8-(pyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one [ka] 6-Chloro-3-((1R,3S)-3-hydroxycyclopentyl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (Intermediate 14) (30 mg, 0.088 mmol, 1 equiv.), (6-(trifluoromethyl)pyridin-3-yl)boronic acid (25 mg, 0.131 mmol, 1.5 equiv.), K2CO3 (36.6 mg, 0.263 mmol, 3 equiv.) and Pd(dppf)Cl2·CH2Cl2 (7.2 mg, 8.75 μmol, 0.1 equiv.) were dissolved in 1,4-dioxane / water (0.7 mL / 0.175 mL, 0.1 M). The reaction mixture was heated and stirred at 130 °C for 30 min in a Biotage Microwave Synthesizer Initiator. The reaction solution was concentrated under reduced pressure and then directly purified by MPLC (silica gel, 0-10% MeOH / DCM) to obtain 0.027 g of 3-((1R,3S)-3-hydroxycyclopentyl)-8-(pyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (Example 65) (yield 69%). 1H NMR (400 MHz, CDCl3): δ [ppm] = 9.55 (d, J = 0.9 Hz, 1H), 9.50 (d, J = 1.6 Hz, 1H), 8.82 - 8.70 (m, 3H), 8.67 (s, 1H), 8.62 - 8.55 (m, 1H), 7.86 (d, J = 8.2 Hz, 1H), 7.50 (dd, J = 7.8, 4.8 Hz, 1H), 5.44 - 5.32 (m, 1H), 4.62 - 4.53 (m, 1H), 2.70 (br, 1H), 2.63 - 2.53 (m, 1H), 2.48 - 2.37 (m, 1H), 2.31 - 2.16 (m, 1H), 2.12 - 1.96 (m, 2H), 1.94 - 1.80 (m, 1H); MS (ESI, m / z): 454.18 [M+H] +

[0236] Example 66. 3-(2,3-dihydroxypropyl)-8-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one [ka] The title compound was obtained in a similar manner to Example 65, except that 3-aminopropane-1,2-diol, pyridin-3-ylboronic acid and (4-(trifluoromethyl)phenyl)boronic acid were used (Scheme 4. General procedure D). 1H-NMR (400 MHz, CDCl3): δ [ppm] = 9.44 (d, J = 1.7 Hz, 1H), 8.78 - 8.74 (m, 1H), 8.73 (s, 1H), 8.67 (dd, J = 4.9, 1.5 Hz, 1H), 8.48 (d, J = 8.2 Hz, 2H), 8.39 (s, 1H), 7.87 (d, J = 8.4 Hz, 2H), 7.64 (dd, J = 8.1, 4.9 Hz, 1H), 4.49 (dd, J = 13.6, 3.2 Hz, 1H), 4.10 - 4.02 (m, 1H), 3.91 (dd, J = 13.6, 8.8 Hz, 1H), 3.66 (d, J = 5.2 Hz, 2H); MS (ESI, m / z):443.19 [M+H] +

[0237] Example 67. 6-(4-chlorophenyl)-3-(2,3-dihydroxypropyl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one [ka] General procedure D (Scheme 4) was carried out using 3-aminopropane-1,2-diol, pyridin-3-ylboronic acid and (4-chlorophenyl)boronic acid. LC-MS analysis confirmed that one of the two hydroxyl groups was further formylated in the cyclization step c. The formylated intermediate was deprotected in 2M HCl in MeOH at 40° C. for 3 h to give the title compound of Example 67. 1H-NMR (400 MHz, CDCl3): δ [ppm] = 9.42 (s, 1H), 8.65 (d, J = 3.8 Hz, 1H), 8.52 (d, J = 7.9 Hz, 1H), 8.45 (s, 1H), 8.20 (s, 1H), 8.12 (d, J = 8.5 Hz, 2H), 7.47 (d, J = 8.5 Hz, 2H), 7.43 (dd, J = 7.8, 4.9 Hz, 1H), 4.33 (dd, J = 13.7, 2.8 Hz, 1H), 4.22 - 4.15 (m, 1H), 4.09 (dd, J = 13.6, 6.8 Hz, 1H), 3.72 (ddd, J = 16.4, 11.5, 3.9 Hz, 2H); MS (ESI, m / z):409.27 [M+H] +

[0238] Example 68. 3-(2,3-dihydroxypropyl)-6-(4-(4-methylpiperazin-1-yl)phenyl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one [ka] General procedure D (Scheme 4) was carried out using 3-aminopropane-1,2-diol, pyridin-3-ylboronic acid and (4-(4-methylpiperazin-1-yl)phenyl)boronic acid. LC-MS analysis confirmed that one of the two hydroxyl groups was further formylated in the cyclization step c). The formylated intermediate was deprotected in 2M HCl in MeOH at 40° C. for 3 h to give the title compound of Example 68. 1H-NMR (400 MHz, CDCl3): δ [ppm] = 9.38 (d, J = 1.5 Hz, 1H), 8.70 (dt, J = 8.0, 1.9 Hz, 1H), 8.62 (dd, J = 4.9, 1.6 Hz, 1H), 8.45 (s, 1H), 8.26 (s, 1H), 8.13 (d, J = 8.9 Hz, 2H), 7.60 (dd, J = 7.9, 5.0 Hz, 1H), 7.10 (d, J = 9.0 Hz, 2H), 4.44 (dd, J = 13.6, 3.2 Hz, 2H), 4.08 - 4.01 (m, 1H), 3.86 (dd, J = MS (ESI, m / z):473.17 [M+H] +

[0239] Example 69. 3-(1,3-dihydroxypropan-2-yl)-8-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one [ka] General procedure D (Scheme 4) was carried out using 2,2-dimethyl-1,3-dioxan-5-amine, pyridin-3-ylboronic acid and (4-(trifluoromethyl)phenyl)boronic acid. The intermediate was deprotected in 2M HCl in MeOH at 40° C. for 3 h to give the title compound of Example 69. 1H-NMR (400 MHz, CDCl3): δ [ppm] = 9.45 (s, 1H), 8.78 - 8.74 (m, 1H), 8.71 (s, 1H), 8.66 (dd, J = 4.9, 1.6 Hz, 1H), 8.49 (s, 1H), 8.47 (d, J = 8.2 Hz, 2H), 7.86 (d, J = 8.3 Hz, 2H), 7.64 (ddd, J = 8.0, 5.0, 0.8 Hz, 1H), 4.99 - 4.92 (m, 1H), 4.13 (dd, J = 11.9, 7.2 Hz, 2H), 4.00 (dd, J = 11.9, 4.9 Hz, 2H); MS (ESI, m / z):443.17 [M+H] +

[0240] Example 70. 6-(4-chlorophenyl)-3-(1,3-dihydroxypropan-2-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one [ka] General procedure D (Scheme 4) was carried out using 2,2-dimethyl-1,3-dioxan-5-amine, pyridin-3-ylboronic acid and (4-chlorophenyl)boronic acid. The intermediate was deprotected in 2M HCl in MeOH at 40° C. for 3 h to give the title compound of Example 70. 1H-NMR (400 MHz, CDCl3): δ [ppm] = 9.45 (s, 1H), 8.75 - 8.72 (m, 1H), 8.65 (dd, J = 5.0, 1.6 Hz, 1H), 8.61 (s, 1H), 8.45 (s, 1H), 8.26 (dd, J = 6.7, 1.9 Hz, 2H), 7.64 - 7.61 (m, 1H), 7.56 (dd, J = 6.7, 1.9 Hz, 1H), 4.96 - 4.94 (m, 1H), 4.11 (dd, J = 11.9, 7.2 Hz, 2H), 3.99 (dd, J = 11.9, 4.9 Hz, 2H); MS (ESI, m / z): 409.13 [M+H] +

[0241] Example 71. 6-(6-chloropyridin-3-yl)-3-((1R,3S)-3-hydroxycyclopentyl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one [ka] The title compound was obtained in the same manner as in Example 65, except that (1S,3R)-3-aminocyclopentanol, pyridin-3-ylboronic acid and (6-chloropyridin-3-yl)boronic acid were used (Scheme 4. General procedure D). 1H NMR (400 MHz, CDCl3): δ [ppm] = 9.46 (s, 1H), 9.19 (d, J = 2.3 Hz, 1H), 8.72 (s, 1H), 8.67 (s, 1H), 8.59 - 8.52 (m, 2H), 8.50 (dd, J = 8.4, 2.5 Hz, 1H), 7.54 - 7.40 (m, 2H), 5.40 - 5.24 (m, 1H), 4.60 - 4.46 (m, 1H), 2.80 (br, 1H), 2.61 - 2.48 (m, 1H), 2.45 - 2.33 (m, 1H), 2.28 - 2.15 (m, 1H), 2.09 - 1.93 (m, 2H), 1.90 - 1.79 (m, 1H); MS (ESI, m / z): 420.13 [M+H] +

[0242] Example 72. 3-((1R,3S)-3-Hydroxycyclopentyl)-8-(pyridin-3-yl)-6-(2-(trifluoromethyl)pyrimidin-5-yl)pyrido[3,4-d]pyrimidin-4(3H)-one TFA salt [ka] The title compound was obtained in the same manner as in Example 65, except that (1S,3R)-3-aminocyclopentanol, pyridin-3-ylboronic acid and (2-(trifluoromethyl)pyrimidin-5-yl)boronic acid were used (Scheme 4. General Procedure D). 1H NMR (400 MHz, MeOD): δ [ppm] = 9.98 - 9.72 (m, 3H), 9.46 (d, J = 8.2 Hz, 1H), 9.01 - 8.83 (m, 3H), 8.13 (dd, J = 8.0, 5.8 Hz, 1H), 5.54 - 5.42 (m, 1H), 4.50 - 4.43 (m, 1H), 2.62 - 2.48 (m, 1H), 2.47 - 2.35 (m, 1H), 2.29 - 2.07 (m, 2H), 2.05 - 1.91 (m, 2H); MS (ESI, m / z): 455.10 [M+H] +

[0243] Example 73. 3-((1R,3S)-3-Hydroxycyclopentyl)-6-(4-morpholinophenyl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one [ka] The title compound was obtained in the same manner as in Example 65, except that (1S,3R)-3-aminocyclopentanol, pyridin-3-ylboronic acid and (4-morpholinophenyl)boronic acid were used (Scheme 4. General procedure D). 1H NMR (400 MHz, CDCl3): δ [ppm] = 9.46 (d, J = 1.6 Hz, 1H), 8.69 (dd, J = 4.8, 1.3 Hz, 1H), 8.59 - 8.52 (m, 1H), 8.49 (s, 1H), 8.48 (s, 1H), 8.19 (d, J = 8.9 Hz, 2H), 7.45 (dd, J = 7.8, 4.9 Hz, 1H), 7.02 (d, J = 8.9 Hz, 2H), 5.26 - 5.17 (m, 1H), 4.55 - 4.47 (m, 1H), 3.96 - 3.79 (m, 4H), 3.36 - 3.18 MS (ESI, m / z): 470.29 [M+H] +

[0244] Example 74. 6-(4'-chloro-[1,1'-biphenyl]-4-yl)-3-(1-hydroxypropan-2-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one [ka] General procedure D (Scheme 4) was carried out using 2-aminopropan-1-ol, pyridin-3-ylboronic acid and (4-chlorophenyl)boronic acid. In the Suzuki coupling reaction in step e, the title biphenyl product was obtained as a by-product and purified by preparative HPLC eluting with 0.1% TFA in ACN / water with a gradient of 20%→50%→80%. 1H-NMR (400 MHz, CDCl3): δ [ppm] = 9.46 (d, J = 1.7 Hz, 1H), 8.78 - 8.76 (m, 1H), 8.66 (d, J = 4.7 Hz, 2H), 8.46 (s, 1H), 8.38 (d, J = 8.5 Hz, 2H), 7.84 (d, J = 8.4 Hz, 2H), 7.74 (d, J = 8.6 Hz, 2H), 7.64 (dd, J = 8.2, 5.4 Hz, 1H), 7.51 (d, J = 8.6 Hz, 2H), 5.06- 5.01 (m, 1H), 4.00 (dd, J = 12.8, 7.1 Hz, MS (ESI, m / z): 469.21 [M+H] +

[0245] Example 75. 3-(1-hydroxypropan-2-yl)-6-(4-morpholinophenyl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one [ka] The title compound was obtained in a similar manner to Example 65, except that 2-aminopropan-1-ol, pyridin-3-ylboronic acid and (4-morpholinophenyl)boronic acid were used (Scheme 4. General Procedure D). 1H-NMR (400 MHz, CDCl3): δ [ppm] = 9.42 (d, J = 1.5 Hz, 1H), 8.75 - 8.70 (m, 1H), 8.64 (dd, J = 4.9, 1.6 Hz, 1H), 8.50 (s, 1H), 8.39 (s, 11H), 8.18 (d, J = 9.0 Hz, 2H), 7.62 (dd, J = 7.6, 4.6 Hz, 1H), 7.13 (d, J = 9.0 Hz, 2H), 5.05 - 4.99 (m, 1H), 3.99 (dd, J = 11.8, 7.0 Hz, 1H), 3.91 - 3.87 (m, 4H), 3.86 (d, J = 4.3 Hz, 1H), 3.31 - 3.27 (m, 4H), 1.57 (d, J = 7.1 Hz, 3H); MS (ESI, m / z):444.21[M+H] +

[0246] Example 76. 3-(2-(methylsulfonyl)ethyl)-8-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one Scheme for preparing the compound of Example 76: [ka]

[0247] Intermediate 15. 3-Amino-6-chloro-[2,3'-bipyridine]-4-carboxylate methyl [ka] A mixture of 3-amino-6-chloro-[2,3'-bipyridine]-4-carboxylic acid (0.5 g, 2.003 mmol, 1 equiv) and K2CO3 (0.415 g, 3.00 mmol, 1.5 equiv) in DMF (20 mL, 0.1 M) was stirred for 5 min. Then, MeI (0.426 g, 3.00 mmol, 1.5 equiv) was added to the reaction and stirred at room temperature for 3 h. The reaction was diluted with water (50 mL), extracted with EtOAc (20 mL x 3), washed with brine (20 mL x 3), dried over Na2SO4, and filtered through a glass filter. The filtrate was concentrated under reduced pressure and purified by MPLC (silica gel, 0-30% EtOAc / hexane) to give 0.155 g of methyl 3-amino-6-chloro-[2,3'-bipyridine]-4-carboxylate (intermediate 15) (29% yield). MS (ESI, m / z): 264.01 [M+H] +

[0248] Intermediate 16. 3-Amino-6-(4-(trifluoromethyl)phenyl)-[2,3'-bipyridine]-4-carboxylic acid [ka] Methyl 3-amino-6-chloro-[2,3'-bipyridine]-4-carboxylate (Intermediate 15) (80 mg, 0.303 mmol, 1 eq.), (4-(trifluoromethyl)phenyl)boronic acid (86 mg, 0.455 mmol, 1.5 eq.), K2CO3 (126 mg, 0.910 mmol, 3 eq.) and PdCl2(dtbpf) (20 mg, 3 μmol, 0.1 eq.) were dissolved in 1,4-dioxane / water (4 mL / 1 mL, 0.06 M). The reaction mixture was heated and stirred at 130 °C for 30 min in a Biotage microwave synthesis system Initiator. The reaction solution was concentrated under reduced pressure and then directly purified by MPLC (silica gel, 0-10% MeOH / DCM) to obtain 76 mg of 3-amino-6-(4-(trifluoromethyl)phenyl)-[2,3'-bipyridine]-4-carboxylic acid (intermediate 16) (yield 70%). MS (ESI, m / z): 360.02 [M+H] +

[0249] Intermediate 17. 3-Amino-N-(2-(methylsulfonyl)ethyl)-6-(4-(trifluoromethyl)phenyl)-[2,3'-bipyridine]-4-carboxamide [ka] A mixture of 3-amino-6-(4-(trifluoromethyl)phenyl)-[2,3'-bipyridine]-4-carboxylic acid (intermediate 16) (65 mg, 0.181 mmol, 1 equiv.), EDC (42 mg, 0.217 mmol, 1.2 equiv.), HOBT (33 mg, 0.217 mmol, 1.2 equiv.), and TEA (0.038 mL, 0.271 mmol, 1.5 equiv.) was dissolved in DMF (3 mL, 0.13 M) and stirred for 5 min. Then, 2-(methylsulfonyl)ethanamine (27 mg, 0.217 mmol, 1.2 equiv.) was added to the reaction and stirred at 50 °C for 12 h. The reaction was diluted with water (50 mL), extracted with EtOAc (20 mL x 3), washed with brine (20 mL x 3), dried over Na2SO4, and filtered through a glass filter. The filtrate was concentrated under reduced pressure and purified by MPLC (silica gel, 0-5% MeOH / DCM) to give 0.07 g of 3-amino-N-(2-(methylsulfonyl)ethyl)-6-(4-(trifluoromethyl)phenyl)-[2,3′-bipyridine]-4-carboxamide (Intermediate 17) (yield 83%). MS (ESI, m / z): 465.09 [M+H] +

[0250] Example 76. 3-(2-(methylsulfonyl)ethyl)-8-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one [ka] 3-Amino-N-(2-(methylsulfonyl)ethyl)-6-(4-(trifluoromethyl)phenyl)-[2,3'-bipyridine]-4-carboxamide (Intermediate 17) (70 mg, 0.151 mmol, 1 equiv) was dissolved in a solution of (EtO)3CH (1.5 mL, 9.04 mmol, 60 equiv) and CH3CO2H (0.43 mL, 7.54 mmol, 50 equiv). The reaction mixture was heated and stirred at 150 °C for 1 h in a Biotage Microwave Synthesizer Initiator. The reaction mixture was diluted with water (20 mL), extracted with EtOAc (20 mL x 3), washed with brine (10 mL x 3), dried over Na2SO4, and filtered through a glass filter. The filtrate was concentrated under reduced pressure and purified by MPLC (silica gel, 0-5% MeOH / DCM) to give 29 mg of 3-(2-(methylsulfonyl)ethyl)-8-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one (Example 76) (40.6% yield). 1H-NMR (400 MHz, CDCl3): δ [ppm] = 9.40 (d, J = 1.5 Hz, 1H), 8.74 - 8.70 (m, 1H), 8.68 (s, 1H), 8.64 (dd, J = 4.9, 1.5 Hz, 1H), 8.44 (t, J = 4.1 Hz, 3H), 7.84 (d, J = 8.3 Hz, 2H), 7.61 (dd, J = 8.0, 4.9 Hz, 1H), 4.58 (t, J = 6.5 Hz, 2H), 3.74 (t, J = 6.5 Hz, 2H), 3.10 (s, 3H). MS (ESI, m / z):475.00 [M] +

[0251] Example 77. 6-(4-chlorophenyl)-3-(2-(methylsulfonyl)ethyl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one [ka] The title compound was obtained in a similar manner to Example 76, except that 2-(methylsulfonyl)ethanamine and (4-chlorophenyl)boronic acid were used (Scheme 5. General Procedure E). 1H-NMR (400 MHz, CDCl3): δ = 9.39 (s, 1H), 8.70 (d, J = 8.0 Hz, 1H), 8.64 (d, J = 4.6 Hz, 1H), 8.60 (s, 1H), 8.42 (s, 1H), 8.25 (d, J = MS (ESI, m / z): 441.07 [M+H] +

[0252] Example 78. 3-(1,1-dioxidetetrahydro-2H-thiopyran-4-yl)-6-(4-morpholinophenyl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one [ka] The title compound was obtained in a similar manner to Example 76, except that 4-aminotetrahydro-2H-thiopyran 1,1-dioxide and (4-morpholinophenyl)boronic acid were used (Scheme 5. General Procedure E). 1H-NMR (400 MHz, CDCl3): δ [ppm] = 9.44 (d, J = 1.8 Hz, 1H), 8.71 (dd, J = 4.8, 1.5 Hz, 1H), 8.57 - 8.49 (m, 1H), 8.45 (s, 1H), 8.19 (d, J = 8.9 Hz, 2H), 8.14 (s, 1H), 7.46 (dd, J = 7.9, 5.1 Hz, 1H), 7.03 (d, J = 9.0 Hz, 2H), 5.19 - 5.08 (m, 1H), 3.92 - 3.86 (m, 4H), 3.39 - 3.20 (m, 8H), 2.70 (dd, J = 26.1, 13.0 Hz, 2H), 2.37 (d, J = 12.6 Hz, 2H); MS (ESI, m / z): 518.22 [M+H] +

[0253] Example 79. 3-(2-(methylsulfonyl)ethyl)-6-(4-morpholinophenyl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one [ka] The title compound was obtained in a similar manner to Example 76, except that 2-(methylsulfonyl)ethanamine and (4-morpholinophenyl)boronic acid were used (Scheme 5. General Procedure E). 1H-NMR (400 MHz, CDCl3): δ [ppm] = 9.45 (d, J = 1.6 Hz, 1H), 8.70 (dd, J = 4.8, 1.4 Hz, 1H), 8.56 (dt, J = 7.9, 1.9 Hz, 1H), 8.43 (s, 1H), 8.17 (d, J = 10.2 Hz, 2H), 7.45 (dd, J = 7.8, 4.9 Hz, 1H), 7.02 (d, J = 8.9 Hz, 2H), 4.51 (t, J = 6.2 Hz, 2H), 3.92 - 3.81 (m, 4H), 3.61 (t, J = 6.2 Hz, 2H), 3.34 - 3.21 (m, 4H), 2.98 (s, 3H); MS (ESI, m / z): 492.21 [M+H] +

[0254] Example 80. 3-(1,3-dihydroxypropan-2-yl)-6-(4-morpholinophenyl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one Scheme for preparing the compound of Example 80: [ka]

[0255] Intermediate 20. 3-(2,2-dimethyl-1,3-dioxan-5-yl)-6-(4-morpholinophenyl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one [ka] The title compound was obtained in a similar manner to the preparation of intermediate 20, except that 2-dimethyl-1,3-dioxan-5-amine and (4-morpholinophenyl)boronic acid were used (Scheme 6. General Procedure F).

[0256] Example 80. 3-(1,3-dihydroxypropan-2-yl)-6-(4-morpholinophenyl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one [ka] The intermediate was deprotected using 2,2-dimethyl-1,3-dioxan-5-amine and (4-morpholinophenyl)boronic acid in 2M HCl in MeOH at 40° C. for 3 h to give the title compound of Example 80 (Scheme 6. General Procedure F). 1 H NMR (400 MHz, DMSO): δ [ppm] = 9.33 (d, J = 1.7 Hz, 1H), 8.68 (dd, J = 4.8, 1.5 Hz, 1H), 8.54 (dt, J = 8.0, 1.8 Hz, 1H), 8.40 (d, J = 4.5 Hz, 2H), 8.15 (d, J = 8.9 Hz, 2H), 7.58 (dd, J = 7.9, 4.8 Hz, 1H), 7.10 (d, J = 8.9 Hz, 2H), 4.85 - 4.75 (m, 1H), 3.91 - 3.79 (m, 4H), 3.79 - 3.72 (m, 4H), 3.25 - 3.21 (m, 4H); MS (ESI, m / z):460.26 [M+H] +

[0257] Example 81. (R)-3-(2,3-dihydroxypropyl)-8-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one [ka] General procedure F (Scheme 6) was carried out using (R)-3-aminopropane-1,2-diol, pyridin-3-ylboronic acid and (4-(trifluoromethyl)phenyl)boronic acid. LC-MS analysis confirmed that one of the two hydroxyl groups was further formylated in the cyclization step c. The formylated intermediate was deprotected in 2M HCl in MeOH at 40° C. for 3 h to give the title compound of Example 81 (Scheme 6. General procedure F). 1H-NMR (400 MHz, CDCl3): δ [ppm] = 9.44 (s, 1H), 8.77 - 8.71 (m, 1H), 8.71 (s, 1H), 8.66 (d, J = 3.8 Hz, 1H), 8.46 (d, J = 8.2 Hz, 2H), 8.38 (s, 1H), 7.86 (d, J = 8.3 Hz, 2H), 7.63 (dd, J = 7.9, 5.0 Hz, 1H), 4.49 (dd, J = 13.6, 3.2 Hz, 1H), 4.10 - 3.99 (m, 1H), 3.91 (dd, J = 13.6, 8.8 Hz, 1H), 3.66 (d, J = 5.2 Hz, 2H); MS (ESI, m / z):443.45 [M+H] +

[0258] Example 82. 3-(2,3-dihydroxypropyl)-6-(4-morpholinophenyl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one [ka] General procedure F (Scheme 6) was carried out using 3-aminopropane-1,2-diol and (4-morpholinophenyl)boronic acid. LC-MS analysis confirmed that one of the two hydroxyl groups was further formylated in the cyclization step c. The formylated intermediate was deprotected in 2M HCl in MeOH at 40° C. for 3 h to give the title compound of Example 82 (Scheme 6. General procedure F). 1H-NMR (400 MHz, CDCl3): δ [ppm] = 9.45 (d, J = 1.8 Hz, 1H), 8.67 (d, J = 3.5 Hz, 1H), 8.55 (d, J = 7.9 Hz, 1H), 8.44 (s, 1H), 8.17 (d, J = 8.8 Hz, 2H), 8.14 (s, 1H), 7.43 (dd, J = 7.8, 5.0 Hz, 1H), 7.02 (d, J = 8.9 Hz, 2H), 4.30 (d, J = 10.2 Hz, 1H), 4.19 - 4.09 (m, 2H), 3.92 - 3.87 (m, 4H), 3.76 - 3.62 (m, 2H), 3.32 - 3.26 (m, 4H); MS (ESI, m / z):460.19 [M+H] +

[0259] Example 83. 2-(6-(4-chlorophenyl)-4-oxo-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-3(4H)-yl)propanoic acid 2,2,2-trifluoroacetate [ka] The title compound was obtained in a similar manner to Example 80, except that methyl 2-aminopropanoate hydrochloride, pyridin-3-ylboronic acid and (4-chlorophenyl)boronic acid were used (Scheme 6. General Procedure F). 1H NMR (400 MHz, DMSO): δ [ppm] = 9.38 (s, 1H), 8.75 (d, J = 3.6 Hz, 1H), 8.64 (d, J = 8.0 Hz, 1H), 8.62 (s, 1H), 8.56 (s, 1H), 8.33 (d, J = MS (ESI, m / z): 407.04 [M+H] +

[0260] Example 84. 2-(4-oxo-8-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidin-3(4H)-yl)propanoic acid 2,2,2-trifluoroacetate [ka] The title compound was obtained in a similar manner to Example 80, except that methyl 2-aminopropanoate hydrochloride, pyridin-3-ylboronic acid, and (4-(trifluoromethyl)phenyl)boronic acid were used (Scheme 6. General Procedure F). 1H NMR (400 MHz, DMSO): δ [ppm] = 9.38 (br, 1H), 8.73 (br, 1H), 8.64 (s, 2H), 8.56 (d, J = 7.9 Hz, 1H), 8.52 (d, J = 8.2 Hz, 2H), 7.91 (d, J = MS (ESI, m / z): 441.07 [M+H] +

[0261] Example 86. N-(2-(4-oxo-8-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidin-3(4H)-yl)propyl)acetamide Scheme for preparing the compound of Example 86: [ka]

[0262] Intermediate 21. tert-Butyl (2-(3-amino-6-chloro-2-iodoisonicotinamide)propyl)carbamate [ka] A mixture of 3-amino-6-chloro-2-iodoisonicotinic acid (intermediate 1) (0.8 g, 2.68 mmol, 1 equiv.), EDC (0.617 g, 3.22 mmol, 1.2 equiv.), HOBT (0.493 g, 3.22 mmol, 1.2 equiv.), and TEA (0.560 mL, 4.02 mmol, 1.5 equiv.) was dissolved in DMF (13.4 mL, 0.2 M) and stirred for 10 min. Then, tert-butyl (2-aminopropyl)carbamate (0.475 mL, 2.68 mmol, 1 equiv.) was added to the reaction and stirred at 50 °C for 12 h. The reaction was diluted with water (50 mL), extracted with EtOAc (20 mL x 3), washed with brine (20 mL x 3), dried over Na2SO4, and filtered through a glass filter. The filtrate was concentrated under reduced pressure and purified by MPLC (silica gel, 0-50% EtOAc / hexanes) to give 0.372 g of tert-butyl (2-(3-amino-6-chloro-2-iodoisonicotinamido)propyl)carbamate (Intermediate 21) (31% yield). 1H NMR (400 MHz, CDCl3): δ = 7.71 (d, J = 5.1 Hz, 1H), 7.29 (s, 1H), 6.17 (br, 2H), 5.01 - 4.90 (m, 1H), 4.13 - 4.00 (m, 1H), 3.37 - 3.19 (m, 2H), 1.45 (s, 9H), 1.23 (d, J = 6.5 Hz, 3H); MS (ESI, m / z): 455.08 [M+H] +

[0263] Intermediate 22. 6-Chloro-3-((1R,3S)-3-hydroxycyclopentyl)-8-iodopyrido[3,4-d]pyrimidin-4(3H)-one [ka] tert-Butyl (2-(3-amino-6-chloro-2-iodoisonicotinamido)propyl)carbamate (Intermediate 21) (0.372 g, 0.818 mmol, 1 equiv) was dissolved in a solution of (EtO)3CH (1.226 mL, 7.36 mmol, 9 equiv) and CH3CO2H (1.226 mL, 20.18 mmol, 25 equiv). The reaction mixture was heated and stirred at 150 °C for 1 h in a Biotage Microwave Synthesizer Initiator. The reaction mixture was diluted with water (20 mL), extracted with EtOAc (20 mL x 3), washed with brine (10 mL x 3), dried over Na2SO4, and filtered through a glass filter. The filtrate was concentrated under reduced pressure and purified by MPLC (silica gel, 0-50% EtOAc / hexanes) to give 0.135 g of tert-butyl (2-(6-chloro-8-iodo-4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)propyl)carbamate (Intermediate 22) (36% yield), which was used in the next step without further purification. 1H NMR (400 MHz, CDCl3): δ = 8.16 (s, 1H), 8.01 (s, 1H), 4.98 - 4.87 (m, 1H), 4.76 - 4.68 (m, 1H), 3.53 (t, J = 6.2 Hz, 2H), 1.54 (d, J = 7.2 Hz, 3H), 1.32 (s, 9H); MS (ESI, m / z): 465.07 [M+H] +

[0264] Intermediate 23. tert-Butyl (2-(6-chloro-4-oxo-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-3(4H)-yl)propyl)carbamate [ka] tert-Butyl (2-(6-chloro-8-iodo-4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)propyl)carbamate (Intermediate 22) (0.123 g, 0.265 mmol, 1 equiv.), pyridin-3-ylboronic acid (0.036 g, 0.291 mmol, 1.1 equiv.), K2CO3 (0.110 g, 0.794 mmol, 3 equiv.) and Pd(dppf)Cl2·CH2Cl2 (0.022 g, 0.026 mmol, 0.1 equiv.) were dissolved in 1,4-dioxane / water (2.1 mL / 0.53 mL, 0.1 M). The reaction was heated and stirred at 130 °C for 30 min in a Biotage Microwave Synthesizer Initiator. The reaction mixture was diluted with water (10 mL), extracted with EtOAc (10 mL x 3), washed with brine (10 mL x 3), dried over Na2SO4, and filtered through a glass filter. The filtrate was concentrated under reduced pressure and purified by MPLC (silica gel, 0-5% MeOH / DCM) to give tert-butyl (2-(6-chloro-4-oxo-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-3(4H)-yl)propyl)carbamate (Intermediate 23) (0.093 g, 84% yield). 1H NMR (400 MHz, CDCl3): δ = 9.37 (d, J = 1.8 Hz, 1H), 8.70 (dd, J = 4.8, 1.5 Hz, 1H), 8.44 (dt, J = 8.0, 1.8 Hz, 1H), 8.13 (s, 1H), 8.09 (s, 1H), 7.44 (dd, J = 7.9, 4.8 Hz, 1H), 5.02 - 4.91 (m, 1H), 4.81 - 4.72 (m, 1H), 3.66 - 3.47 (m, 2H), 1.56 (d, J = 7.1 Hz, 3H), 1.29 (s, 9H); MS (ESI, m / z): 416.18 [M+H] +

[0265] Intermediate 24. tert-Butyl (2-(4-oxo-8-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidin-3(4H)-yl)propyl)carbamate [ka] tert-Butyl (2-(6-chloro-4-oxo-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-3(4H)-yl)propyl)carbamate (Intermediate 23) (30 mg, 0.072 mmol, 1 equiv.), (4-(trifluoromethyl)phenyl)boronic acid (15.1 mg, 0.079 mmol, 1.1 equiv.), K2CO3 (29.9 mg, 0.216 mmol, 3 equiv.) and Pd(dppf)Cl2·CH2Cl2 (5.9 mg, 7.21 μmol, 0.1 equiv.) were dissolved in 1,4-dioxane / water (5.8 mL / 1.4 mL, 0.1 M). The reaction mixture was heated and stirred at 130 °C for 30 min in a Biotage microwave synthesizer Initiator. The reaction mixture was diluted with water (10 mL), extracted with EtOAc (10 mL x 3), washed with brine (5 mL x 3), dried over Na2SO4, and filtered through a glass filter. The filtrate was concentrated under reduced pressure and purified by MPLC (silica gel, 0-10% MeOH / DCM) to give tert-butyl (2-(4-oxo-8-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidin-3(4H)-yl)propyl)carbamate (Intermediate 24) (29 mg, 76% yield). 1H-NMR (400 MHz, CDCl3): δ = 9.53 (s, 1H), 8.75 (d, J = 3.8 Hz, 1H), 8.63 - 8.57 (m, 2H), 8.34 (d, J = 8.2 Hz, 2H), 8.11 (s, 1H), 7.78 (d, J = 8.3 Hz, 2H), 7.50 (dd, J = 7.6, 5.0 Hz, 1H), 5.05 - 4.95 (m, 1H), 4.82 - 4.74 (m, 1H), 3.69 - 3.51 (m, 2H), 1.58 (d, J = 8.0 Hz, 3H), 1.29 (s, 9H); MS (ESI, m / z): 526.22 [M+H] +

[0266] Example 85. 3-(1-aminopropan-2-yl)-8-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one [ka] Tert-butyl (2-(6-(4-chlorophenyl)-4-oxo-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-3(4H)-yl)propyl)carbamate (Intermediate 24) (29 mg, 0.055 mmol, 1 equiv.) was dissolved in 4M HCl in 1,4-dioxane (138 μl, 4.0 M, 10 equiv.). The reaction was stirred at room temperature for 30 min. The reaction was concentrated under reduced pressure and diluted with DCM (10 mL). 1M NaOH solution was carefully added to this solution to basify the aqueous layer to pH 7. The aqueous layer was further extracted with DCM (10 mL×2), and the combined organic layers were dried over Na2SO4 and filtered through a glass filter. The filtrate was concentrated under reduced pressure and purified by MPLC (0-10% MeOH / DCM) to give 12.2 mg of 3-(1-aminopropan-2-yl)-8-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl[3,4-d]pyrimidin-4(3H)-one (Example 85) (yield 51%). 1H-NMR (400 MHz, CDCl3): δ [ppm] = 9.47 (d, J = 1.7 Hz, 1H), 8.72 (dd, J = 4.8, 1.6 Hz, 1H), 8.61 (d, J = 2.7 Hz, 1H), 8.57 (dt, J = 7.9, 1.9 Hz, 1H), 8.35 (d, J = 8.2 Hz, 2H), 8.31 (s, 1H), 7.78 (d, J = 8.3 Hz, 2H), 7.47 (dd, J = 7.8, 4.9 Hz, 1H), 5.09 - 4.98 (m, 1H), 3.20 - 3.08 (m, 2H), 1.55 (d, J = 7.1 Hz, 3H); MS (ESI, m / z): 426.15 [M+H] +

[0267] Example 86. N-(2-(4-oxo-8-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidin-3(4H)-yl)propyl)acetamide [ka] 3-(1-aminopropan-2-yl)-8-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl[3,4-d]pyrimidin-4(3H)-one (Example 85) (9.8 mg, 0.023 mmol, 1 eq.) and TEA (3.85 μl, 0.028 mmol, 1.2 eq.) were dissolved in DCM (115 μl, 0.2 M) and stirred for 5 minutes. Next, acetyl chloride (1.97 μl, 0.028 mmol, 1.2 eq.) was added to the reaction solution and stirred at room temperature for 30 minutes. The reaction solution The residue was diluted with water (5 mL), extracted with DCM (5 mL x 3), washed with brine (5 mL x 3), dried over Na2SO4, and filtered through a glass filter. The filtrate was concentrated under reduced pressure and purified by MPLC (silica gel, 0-10% MeOH / DCM) to give 4.2 mg of N-(2-(4-oxo-8-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidin-3(4H)-yl)propyl)acetamide (Example 86) (yield 38%). 1H NMR (400 MHz, CDCl3): δ [ppm] = 9.46 (d, J = 1.7 Hz, 1H), 8.71 (dd, J = 4.8, 1.5 Hz, 1H), 8.59 - 8.54 (m, 2H), 8.33 (d, J = 8.2 Hz, 2H), 8.14 (s, 1H), 7.77 (d, J = 8.3 Hz, 2H), 7.46 (dd, J = 7.8, 4.7 Hz, 1H), 5.94 (t, J = 5.9 Hz, 1H), 5.06 - 4.96 (m, 1H), 3.89 - 3.77 (m, 1H), 3.71 - 3.61 (m, 1H), 1.92 (s, 3H), 1.60 (d, J = 7.1 Hz, 3H); MS (ESI, m / z): 468.20 [M+H] +

[0268] Example 87. 3-(1-aminopropan-2-yl)-6-(4-chlorophenyl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one [ka] The title compound was obtained in the same manner as in Example 85, except that tert-butyl (2-aminopropyl)carbamate, pyridin-3-ylboronic acid, and (4-chlorophenyl)boronic acid were used (Scheme 7. General Procedure G). 1H NMR (400 MHz, MeOD): δ [ppm] = 9.41 (d, J = 1.7 Hz, 1H), 8.72 (dt, J = 8.0, 1.9 Hz, 1H), 8.63 (dd, J = 4.9, 1.5 Hz, 1H), 8.58 (s, 1H), 8.39 (s, 1H), 8.23 ​​(d, J = 8.6 Hz, 2H), 7.61 (dd, J = 8.2, 4.7 Hz, 1H), 7.53 (d, J = 8.6 Hz, 2H), 5.00 - 4.91 (m, 1H), 2.36 - 2.28 (m, 1H), 2.23 - 2.13 (m, 1H), 1.58 (d, J = 7.0 Hz, 3H); MS (ESI, m / z): 392.14 [M+H] +

[0269] Example 88. N-(2-(6-(4-chlorophenyl)-4-oxo-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-3(4H)-yl)propyl)acetamide [ka] The title compound was obtained in the same manner as in Example 86, except that tert-butyl (2-aminopropyl)carbamate, pyridin-3-ylboronic acid, (4-chlorophenyl)boronic acid and acetyl chloride were used (Scheme 7. General Procedure G). 1H NMR (400 MHz, MeOD): δ [ppm] = 9.41 (s, 1H), 8.71 (dt, J = 8.0, 1.8 Hz, 1H), 8.63 (d, J = 3.5 Hz, 1H), 8.57 (s, 1H), 8.35 (s, 1H), 8.23 (d, J = 8.6 Hz, 2H), 7.61 (dd, J = 7.9, 4.9 Hz, 1H), 7.54 (d, J = 8.6 Hz, 2H), 5.08 - 4.98 (m, 1H), 3.70 - 3.63 (m, 2H), 1.84 (s, 3H), 1.59 (d, J = 7.1 Hz, 3H); MS (ESI, m / z): 434.16 [M+H] +

[0270] Example 89. N-(2-(6-(4-chlorophenyl)-4-oxo-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-3(4H)-yl)propyl)methanesulfonamide [ka] The title compound was obtained in the same manner as in Example 86, except that tert-butyl (2-aminopropyl)carbamate, pyridin-3-ylboronic acid, (4-chlorophenyl)boronic acid and methanesulfonyl chloride were used (Scheme 7. General Procedure G). 1H NMR (400 MHz, CDCl3): δ [ppm] = 9.35 (d, J = 1.5 Hz, 1H), 8.64 (dd, J = 4.7, 1.3 Hz, 1H), 8.46 (dt, J = 8.0, 1.9 Hz, 1H), 8.30 (s, 1H), 8.14 (s, 1H), 8.03 (d, J = 8.7 Hz, 2H), 7.42 (d, J = 8.7 Hz, 2H), 7.41 - 7.37 (m, 1H), 6.07 (t, J = 6.5 Hz, 1H), 4.90 - 4.79 (m, 1H), 3.70 - 3.59 (m, 1H), 3.50 - 3.40 (m, 1H), 2.99 (s, 3H), 1.56 (s, 3H); MS (ESI, m / z): 470.11 [M+H] +

[0271] Example 90. 3-(1-aminopropan-2-yl)-6-(4-morpholinophenyl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one [ka] The title compound was obtained in the same manner as in Example 85, except that tert-butyl (2-aminopropyl)carbamate, pyridin-3-ylboronic acid, and (4-morpholinophenyl)boronic acid were used (Scheme 7. General Procedure G). 1H NMR (400 MHz, MeOD): δ [ppm] = 9.39 (d, J = 1.6 Hz, 1H), 8.70 (dt, J = 8.0, 1.9 Hz, 1H), 8.61 (dd, J = 4.9, 1.6 Hz, 1H), 8.46 (s, 1H), 8.31 (s, 1H), 8.14 (d, J = 8.9 Hz, 2H), 7.59 (dd, J = 8.0, 4.9 Hz, 1H), 7.09 (d, J = 9.0 Hz, 2H), 4.96 - 4.88 (m, 1H), 3.86 (t, J = 4.8 Hz, 4H), 3.27 (t, J = 4.8 Hz, MS (ESI, m / z): 443.23 [M+H] +

[0272] Example 91. N-(2-(6-(4-morpholinophenyl)-4-oxo-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-3(4H)-yl)propyl)methanesulfonamide [ka] The title compound was obtained in the same manner as in Example 86, except that tert-butyl (2-aminopropyl)carbamate, pyridin-3-ylboronic acid, (4-morpholinophenyl)boronic acid and methanesulfonyl chloride were used (Scheme 7. General Procedure G). 1H NMR (400 MHz, MeOD): δ [ppm] = 9.37 (s, 1H), 8.68 (dt, J = 8.0, 1.8 Hz, 1H), 8.61 (d, J = 4.6 Hz, 1H), 8.42 (s, 1H), 8.27 (s, 1H), 8.11 (d, J = 8.9 Hz, 2H), 7.58 (dd, J = 7.9, 5.0 Hz, 1H), 7.07 (d, J = 8.9 Hz, 2H), 4.96 - 4.90 (m, 1H), 3.86 (t, J = 4.8, 4H), 3.63 (dd, J = 14.4, 7.9 Hz, 1H), 3.50 (dd, MS (ESI, m / z): 521.21 [M+H] +

[0273] Example 92. N-(2-(6-(4-morpholinophenyl)-4-oxo-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-3(4H)-yl)propyl)acetamide [ka] The title compound was obtained in the same manner as in Example 86, except that tert-butyl (2-aminopropyl)carbamate, pyridin-3-ylboronic acid, (4-morpholinophenyl)boronic acid and acetyl chloride were used (Scheme 7. General Procedure G). 1H NMR (400 MHz, MeOD): δ [ppm] = 9.40 (s, 1H), 8.74 - 8.69 (m, 1H), 8.62 (d, J = 4.8 Hz, 1H), 8.44 (s, 1H), 8.28 (s, 1H), 8.13 (d, J = 8.9 Hz, 2H), 7.60 (dd, J = 7.9, 4.9 Hz, 1H), 7.09 (d, J = 8.9 Hz, 2H), 5.06 - 4.98 (m, 1H), 3.86 (t, J = 4.8 Hz, 4H), 3.66 (t, J = 5.8 Hz, 2H), 3.27 (t, J = 4.8 Hz, 4H), 1.84 (s, 3H), 1.58 (d, J = 7.1 Hz, 3H); MS (ESI, m / z): 485.16 [M+H] +

[0274] Example 93. 3-(Piperidin-4-yl)-8-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one [ka] The title compound was obtained in the same manner as in Example 85, except that tert-butyl 4-aminopiperidine-1-carboxylate, pyridin-3-ylboronic acid and (4-(trifluoromethyl)phenyl)boronic acid were used (Scheme 7. General Procedure G). 1H NMR (400 MHz, MeOD): δ [ppm] = 9.42 (d, J = 1.6 Hz, 1H), 8.72 (dt, J = 8.0, 1.9 Hz, 1H), 8.63 (dd, J = 5.0, 1.5 Hz, 1H), 8.62 (s, 1H), 8.44 (s, 1H), 8.41 (d, J = 8.2 Hz, 2H), 7.82 (d, J = 8.3 Hz, 2H), 7.61 (dd, J = 8.0, 4.9 Hz, 1H), 4.85 - 4.78 (m, 1H), 3.26 (d, J = 12.9 Hz, 2H), 2.82 (td, J = 13.0, 2.8 Hz, 2H), 2.12 - 2.01 (m, 4H); MS (ESI, m / z): 452.19 [M+H] +

[0275] Example 94. 6-(4-chlorophenyl)-3-(1-(methylsulfonyl)piperidin-4-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one [ka] The title compound was obtained in the same manner as in Example 86, except that tert-butyl 4-aminopiperidine-1-carboxylate, pyridin-3-ylboronic acid, (4-chlorophenyl)boronic acid and methanesulfonyl chloride were used (Scheme 7. General Procedure G). 1H NMR (400 MHz, CDCl3): δ [ppm] = 9.44 (d, J = 1.6 Hz, 1H), 8.72 (dd, J = 4.8, 1.6 Hz, 1H), 8.56 - 8.53 (m, 2H), 8.19 (d, J = 8.7 Hz, 2H), 8.17 (s, 1H), 7.50 (d, J = 8.7 Hz, 2H), 7.49 - 7.44 (m, 1H), 5.03 - 4.93 (m, 1H), 4.09 (d, J = 12.4 Hz, 2H), 3.00 - 2.91 (m, 2H), 2.89 (s, 3H), 2.18 - 2.11 (m, 4H); MS (ESI, m / z): 496.20 [M+H] +

[0276] Example 95. 6-(4-chlorophenyl)-3-(1-(cyclopropylsulfonyl)piperidin-4-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one [ka] The title compound was obtained in the same manner as in Example 86, except that tert-butyl 4-aminopiperidine-1-carboxylate, pyridin-3-ylboronic acid, (4-chlorophenyl)boronic acid and cyclopropanesulfonyl chloride were used (Scheme 7. General Procedure G). 1H NMR (400 MHz, CDCl3): δ [ppm] = 9.48 (s, 1H), 8.74 (s, 1H), 8.59 (d, J = 7.9 Hz, 1H), 8.53 (s, 1H), 8.18 (d, J = 9.6 Hz, 3H), 7.50 (d, J = 8.6 Hz, 3H), 5.04 - 4.93 (m, 1H), 4.08 (d, J = 12.8 Hz, 2H), 3.14 - 3.03 (m, 2H), 2.38 - 2.30 (m, 1H), 2.16 - 2.07 (m, 4H), 1.25 - 1.20 (m, 2H), 1.06 (qd, J = 5.4, ​​0.6 Hz, 2H); MS (ESI, m / z): 522.16 [M] +

[0277] Example 96. 3-(1-acetylpiperidin-4-yl)-6-(4-chlorophenyl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one [ka] The title compound was obtained in a similar manner to Example 86, except that tert-butyl 4-aminopiperidine-1-carboxylate, pyridin-3-ylboronic acid, (4-chlorophenyl)boronic acid and acetyl chloride were used (Scheme 7. General Procedure G). 1H NMR (400 MHz, CDCl3): δ [ppm] = 9.43 (d, J = 2.0 Hz, 1H), 8.72 (dd, J = 4.9, 1.6 Hz, 1H), 8.55 - 8.51 (m, 2H), 8.19 (d, J = 8.6 Hz, 2H), 8.13 (s, 1H), 7.50 (d, J = 8.7 Hz, 2H), 7.49 - 7.45 (m, 1H), 5.11 - 5.01 (m, 1H), 4.94 (d, J = 13.7 Hz, 1H), 4.06 (d, J = 13.9 Hz, 1H), 3.33 (t, J = 11.8 Hz, 1H), 2.75 (td, J = 13.2, 2.1 Hz, 1H), 2.18 (s, 3H), 2.13 (d, J = 10.8 Hz, 1H), 2.06 (d, J = 10.9 Hz, 1H), 1.98 - 1.82 (m, 2H); MS (ESI, m / z): 460.19 [M+H] +

[0278] In vitro XRE-luciferase reporter assays (in vitro assay 1, in vitro assay 2 and in vitro assay 3) When activated, AhR binds to AhR-responsive DNA elements, also known as xenobiotic response elements (XREs), and induces the expression of target genes, such as CYP1A1 and CYP1B1. To measure AhR activity, luciferase assays were performed using cell lines transfected with a luciferase reporter plasmid containing an XRE upstream of a luciferase reporter gene. By assessing the induction of luciferase activity in cells transfected with the XRE-luciferase reporter (XRE-Luc) plasmid, it can be determined whether the AhR is activated or inhibited in these cells. Cells transfected with this XRE reporter vector were co-transfected with a nanoluciferase reporter gene construct (Nano-Luc) containing a constitutively active promoter as an internal control. The antagonistic effect of each compound was tested by stimulating the cells with kynurenine (an endogenous AhR agonist). The half maximal inhibitory concentration (IC) was calculated by performing nonlinear regression (four parameters) using Prism 8.0 software (GraphPad). 50 ) and median effective concentration (EC 50 ) was calculated.

[0279] In vitro assay 1: Antagonism in human cell lines HepG2 cell lines (human hepatoma cell line) (Invivogen) transiently or stably transfected with XRE-luciferase reporter were seeded in complete medium and incubated in a CO2 incubator at 37 °C. After 24 h, cells were treated with kynurenine alone (50 μM or 200 μM) (negative control) or kynurenine and test compound for 6 h. Luciferase activity was measured using commercially available kits such as the Promega Luciferase Kit and other reagents for measuring luciferase activity. The relative luciferase activity (Firefly-Luc / Nano-Luc) was used to calculate the IC 50The relative luciferase activity was then corrected using the luciferase activity of the kynurenine-only group as a control showing the maximum value, and the luciferase activity of the solvent group as a control showing the minimum value. The AhR antagonistic activity of each compound of the Examples is shown in Table 1 below. (IC 50 According to the value, they were classified into groups A, B, C and D. Group A: IC 50 <0.01μM; Group B: 0.01μM <IC 50 <0.1μM; Group C: 0.1μM <IC 50 <1.0μM; Group D: IC 50 >1.0μM.)

[0280] In vitro assay 2: Antagonism in mouse cell lines Hepa1c1c7 cells (mouse liver cancer cell line) co-transfected with XRE-Luc and Nano-Luc plasmids were seeded in complete medium and incubated overnight in a CO2 incubator at 37 °C. After incubation, cells were treated with AhR activating ligands such as kynurenic acid and kynurenine (#) for 6 h in the presence or absence of test compounds. Firefly and nano luciferase activities were measured using a Nano-glo luciferase kit (Promega), and IC was calculated from the relative luciferase activities (firefly-Luc / Nano-Luc). 50 The relative luciferase activity was then corrected using the luciferase activity of the agonist alone group as a control showing the maximum value, and the luciferase activity of the solvent group as a control showing the minimum value. The AhR antagonistic activity of each compound of the Examples is shown in Table 1 below. (IC 50 According to the value, they were classified into groups A, B, C and D. Group A: IC 50 <0.01μM; Group B: 0.01μM <IC 50 <0.1μM; Group C: 0.1μM <IC 50 <1.0μM; Group D: IC 50 >1.0μM.)

[0281] In vitro assay 3: Agonism in human cell lines HepG2 cells (human hepatoma cell line) co-transfected with XRE-Luc and Nano-Luc plasmids were seeded in tryptophan-free medium containing 1% dialyzed fetal bovine serum and incubated overnight in a CO2 incubator at 37 °C. After 24 h, the cells were treated with or without test compounds for 6 h. Firefly and nano-luciferase activities were measured using a Nano-glo luciferase kit (Promega), and the EC 50 As a positive control, cells were incubated with TCDD (EC 50 According to the value, they were classified into groups A, B, C and D. Group A: EC 50 <0.1μM; Group B: 0.1μM <EC 50 <1.0μM; Group C: 1.0μM <EC 50 <10 μM; Group D: EC 50 >10μM.)

[0282] [Table 1] TIFF0007639020000135.tif233166TIFF0007639020000136.tif157166

[0283] In vitro assay 4: Endogenous AhR activity assay HepG2 cells were seeded in 12-well plates (3 × 10 5 The day after seeding, cells were treated with TCDD alone (10 nM) or TCDD plus compounds (123 nM) for 4 h. Total RNA was extracted using Trizol (Thermo Fisher Scientific). PrimeScript was used to extract RNA according to the manufacturer's instructions. TM RT Master Mix (Takara) and TB Green TM Premix Ex Taq TMcDNA synthesis and quantitative RT-PCR (qRT-PCR) assays were performed using a PCR kit II (Takara). To measure endogenous AhR activity, the relative amounts of CYP1A1 mRNA and CYP1B1 mRNA to β-actin mRNA were determined by the comparative Ct (ΔΔCt) method. The inhibition rate was calculated by the following formula:

number

[0284] The antagonistic activity of each compound of the Examples against endogenous AhR is shown in Table 2 below.

[0285] [Table 2]

Claims

1. Formula (I) 【Chemistry 1】 (In the formula, Ar 1 and Ar 2 is a substituted or unsubstituted monocyclic or bicyclic C 6-10 Aryl, substituted or unsubstituted monocyclic or bicyclic C 5-10 Heteroaryl and substituted or unsubstituted monocyclic or bicyclic C 3-10 heterocycloalkyl; L is 1,1-dioxidotetrahydrothiopyran, piperidine, substituted or unsubstituted monocyclic or bicyclic C 3-10 Cycloalkyl, substituted or unsubstituted monocyclic or bicyclic C 6-10 Aryl or substituted or unsubstituted monocyclic or bicyclic C 5-10 is heteroaryl; R 1 is halo, cyano, hydroxy, amino, N(R 3 ) 2 , N.H.R. 3 , OR 3 , phosphate, substituted or unsubstituted C 1-3 Alkyl phosphates, substituted or unsubstituted C 1-5 Alkyl, sulfinic acid (-S(=O)-OH), sulfonic acid (-S(=O 2 )-OH), sulfonylamide (-SO 2 NR 2 2 ), aminosulfonic acid (-NR 2 SO 2 -H), carboxylic acid (-(CO)-OH), carbonyl (-(CO)R 2 ), amide (-(CO)NR 2 2 ), reverse alkylamide (-NH(CO)-R 2 ), alkyl esters (-(CO)OR 2 ), sulfonate (-SO 2 -R 2 ), C 3-10 Cycloalkyl, C 1-5 Alkyl hydroxy, C 2-5 Alkenylhydroxy, C 2-5 Alkynylhydroxy, C 1-5 Alkylamines, C 2-5 Alkenylamines, C 2-5 Alkynylamines, substituted or unsubstituted monocyclic or bicyclic C 3-10 Heterocycloalkyl or substituted or unsubstituted monocyclic or bicyclic C 5-10 is heteroaryl; R 2 is H, halo, hydroxy, amino, substituted or unsubstituted C 1-5 Alkyl, substituted or unsubstituted C 1-5 Alkoxy, substituted or unsubstituted C 3-8 Cycloalkyl, or substituted or unsubstituted C 1-5 is an alkyl carboxylic acid; R 3 is H, substituted or unsubstituted, C 1-5 Alkyl, C 1-5 Alkylacetyl (alkyl-CO-), C 1-5 Sulfonylalkyl (alkyl-SO 2 -), C 1-5 Sulfonylamidoalkyl (alkyl-SO 2 NR 2 2 ), C 1-5 Amidoalkyl (alkyl-(CO)NR 2 2 ) or C 1-5 Reverse Amidoalkyl (Alkyl-NR 2 (CO)-), substituted or unsubstituted C 1-5 Alkoxy, or substituted or unsubstituted C 1-5 It is an alkyl carboxylic acid. or an enantiomer, diastereomer, racemate, solvate, hydrate or pharma- ceutically acceptable salt thereof.

2. Ar 1 and Ar 2 each independently represents a substituted or unsubstituted monocyclic or bicyclic C 6-10 A substituted or unsubstituted monocyclic C ring containing one or more heteroatoms selected from the group consisting of aryl, N, O and S. 5-7 Heteroaryl or substituted or unsubstituted monocyclic C containing one or more heteroatoms selected from the group consisting of N, O and S 5-7 2. The compound of claim 1, or an enantiomer, diastereomer, racemate, solvate, hydrate, or pharma- ceutically acceptable salt thereof, which is a heterocycloalkyl.

3. Ar 1 and Ar 2 each independently represents a monocyclic C ring containing 1 or 2 heteroatoms selected from the group consisting of phenyl, N, O and S; 5-6 Heteroaryl or monocyclic C containing 1 or 2 heteroatoms selected from the group consisting of N, O and S 5-6 heterocycloalkyl; these groups are unsubstituted or substituted with halo, hydroxyl, amino, C 1-3 Alkyl or C 1-3 substituted with alkoxy; 1-3 Alkyl or the C 1-3 2. The compound of claim 1, wherein alkoxy is unsubstituted or substituted with 1 to 3 halo, or an enantiomer, diastereomer, racemate, solvate, hydrate or a pharma- ceutically acceptable salt thereof.

4. L is a substituted or unsubstituted monocyclic or bicyclic C 3-8 Cycloalkyl, substituted or unsubstituted monocyclic or bicyclic C 6-10 Aryl or substituted or unsubstituted monocyclic or bicyclic C 5-8 is heteroaryl; The monocyclic or bicyclic C 5-8 Heteroaryl contains one or more heteroatoms selected from the group consisting of N, O and S; 2. A compound according to claim 1, or an enantiomer, diastereomer, racemate, solvate, hydrate or pharma- ceutically acceptable salt thereof.

5. L is 1,1-dioxidotetrahydrothiopyran, piperidine, or a substituted or unsubstituted monocyclic or bicyclic C 3-6 is cycloalkyl; The substituted or unsubstituted monocyclic or bicyclic C 3-6 Cycloalkyl is hydroxyl, halo, haloC 1-3 Alkyl and C 1-3 substituted with one or more substituents selected from the group consisting of alkyl; 2. A compound according to claim 1, or an enantiomer, diastereomer, racemate, solvate, hydrate or pharma- ceutically acceptable salt thereof.

6. R 1 However, halo, cyano, hydroxy, amino, N(R 3 ) 2 , OR 3 , substituted or unsubstituted C 1-4 Alkyl, carbonyl ((-(CO)R 2 ), C 3-8 Cycloalkyl, C 1-4 Alkyl hydroxy, C 2-4 Alkenylhydroxy, C 2-4 Alkynylhydroxy, C 1-4 Alkylamines, C 2-4 Alkenylamines, C 2-4 Alkynylamines, substituted or unsubstituted monocyclic or bicyclic C 3-8 Heterocycloalkyl or substituted or unsubstituted monocyclic or bicyclic C 5-8 is heteroaryl; The monocyclic or bicyclic C 3-8 Heterocycloalkyl and the monocyclic or bicyclic C 5-8 Heteroaryl contains one or more heteroatoms selected from the group consisting of N, O and S; 2. A compound according to claim 1, or an enantiomer, diastereomer, racemate, solvate, hydrate or pharma- ceutically acceptable salt thereof.

7. R 1 But hydroxyl, -NH 2 , -NH-C(O)CH 3 , -NH-SO 2 -CH 3 , -C(O)OH, -SO 2 -CH 3 , -OC(O)-CH 3 , -OP(=O)(OCH 2 CH 3 ) 2 or -C(O)CH 3 2. The compound of claim 1, wherein:

8. 1. 3-(3-hydroxycyclohexyl)-8-(1-methyl-1H-pyrazol-4-yl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one; 2. 3-(3-hydroxycyclohexyl)-6,8-bis(1-methyl-1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; 3. 3-(1-hydroxypropan-2-yl)-6,8-bis(1-methyl-1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; 4. 3-(1-hydroxypropan-2-yl)-6-(1-methyl-1H-pyrazol-4-yl)-8-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one; 5. 8-(4-chlorophenyl)-3-(1-hydroxypropan-2-yl)-6-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; 6. 3-(1-hydroxypropan-2-yl)-6,8-bis(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one; 7. 2-(6-chloro-8-(4-chlorophenyl)-4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)propyl acetate; 8. 3-((1r,4r)-4-hydroxycyclohexyl)-8-(1-methyl-1H-pyrazol-4-yl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one; 9. 3-((1r,4r)-4-hydroxycyclohexyl)-6,8-bis(1-methyl-1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; 10. 6-(4-chlorophenyl)-3-((1r,4r)-4-hydroxycyclohexyl)-8-(1-methyl-1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; 11. 3-(2-hydroxypropyl)-6,8-bis(1-methyl-1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; 12. 3-(2-hydroxypropyl)-8-(1-methyl-1H-pyrazol-4-yl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one; 13. 6-(4-chlorophenyl)-3-(2-hydroxypropyl)-8-(1-methyl-1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; 14. 3-(2-hydroxypropyl)-8-(1-methyl-1H-pyrazol-4-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; 15. 3-((1S,2R)-2-hydroxycyclohexyl)-8-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one; 16. 3-((1R,2S)-2-hydroxycyclohexyl)-8-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one; 17. 3-((1S,2R)-2-hydroxycyclohexyl)-8-(1-methyl-1H-pyrazol-4-yl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one; 18. 3-((1R,2S)-2-hydroxycyclohexyl)-8-(1-methyl-1H-pyrazol-4-yl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one; 19. 6-(4-chlorophenyl)-3-((1R,2S)-2-hydroxycyclohexyl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; 20. 6-(4-chlorophenyl)-3-((1S,2R)-2-hydroxycyclohexyl)-8-(1-methyl-1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; 21. 6-(4-chlorophenyl)-3-((1S,2R)-2-hydroxycyclohexyl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; 22. 8-(1-methyl-1H-pyrazol-4-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one); 25. 8-(pyridin-3-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one; 26. 6-(4-chlorophenyl)-3-(3-hydroxyphenyl)-8-(1-methyl-1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; 27. 3-(3-hydroxyphenyl)-8-(1-methyl-1H-pyrazol-4-yl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one; 28. 6-(4-chlorophenyl)-3-((1R,3S)-3-hydroxycyclopentyl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; 29. 3-((1R,3S)-3-hydroxycyclopentyl)-8-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one; 30. 6-(4-chlorophenyl)-3-((1R,3S)-3-hydroxycyclopentyl)-8-(1-methyl-1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; 31. 3-((1R,3S)-3-hydroxycyclopentyl)-8-(1-methyl-1H-pyrazol-4-yl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one; 32. 6-(4-chlorophenyl)-3-((1S,3R)-3-hydroxycyclopentyl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; 33. 3-((1S,3R)-3-hydroxycyclopentyl)-8-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one; 34. 6-(4-chlorophenyl)-3-((1S,3R)-3-hydroxycyclopentyl)-8-(1-methyl-1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; 35. 3-((1S,3R)-3-hydroxycyclopentyl)-8-(1-methyl-1H-pyrazol-4-yl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one; 36. 1-(6-(4-chlorophenyl)-4-oxo-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-3(4H)-yl)-2-methylpropan-2-yl acetate; 37. 2-methyl-1-(4-oxo-8-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidin-3(4H)-yl)propan-2-yl acetate; 41. 6-(4-chlorophenyl)-3-(1-hydroxy-3-methylbutan-2-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; 42. 3-(1-hydroxy-3-methylbutan-2-yl)-8-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one; 43. 3-(1-hydroxy-3-methylbutan-2-yl)-8-(pyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; 45. 3-(1-hydroxypropan-2-yl)-8-(1-methyl-1H-pyrazol-4-yl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one; 47. Diethyl 2-(6-(4-chlorophenyl)-4-oxo-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-3(4H)-yl)propyl phosphate; 51. 6-(4-chlorophenyl)-3-(1-hydroxybutan-2-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; 52. 6-(4-chlorophenyl)-3-(1-hydroxybutan-2-yl)-8-(1-methyl-1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; 53. 3-(1-hydroxybutan-2-yl)-8-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one; 54. 3-(1-hydroxybutan-2-yl)-8-(1-methyl-1H-pyrazol-4-yl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one; 55. 6-(4-chlorophenyl)-8-(3-fluorophenyl)-3-(1-hydroxybutan-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; 56. 6-(4-chlorophenyl)-3-((1r,4r)-4-hydroxycyclohexyl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; 57. 3-((1r,4r)-4-hydroxycyclohexyl)-8-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one; 58. 6-(4-chlorophenyl)-3-((1s,4s)-4-hydroxycyclohexyl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; 59. 3-(1-hydroxypropan-2-yl)-8-(1-methyl-1H-pyrazol-4-yl)-6-(4-(trifluoromethyl)phenyl)-2,3-dihydropyrido[3,4-d]pyrimidin-4(1H)-one; 60. 6-(4-chlorophenyl)-3-(2,3-dihydroxypropyl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; 61. 6-(4-chlorophenyl)-3-(3-hydroxyphenyl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; 62. 3-(3-hydroxyphenyl)-8-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one; 63. 6-(4-chlorophenyl)-3-(3-hydroxycyclohexyl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; 64. 6-(4-chlorophenyl)-3-(3-hydroxycyclohexyl)-8-(1-methyl-1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; 65. 3-((1R,3S)-3-hydroxycyclopentyl)-8-(pyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; 66. 3-(2,3-dihydroxypropyl)-8-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one; 67. 6-(4-chlorophenyl)-3-(2,3-dihydroxypropyl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; 68. 3-(2,3-dihydroxypropyl)-6-(4-(4-methylpiperazin-1-yl)phenyl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; 69. 3-(1,3-dihydroxypropan-2-yl)-8-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one; 70. 6-(4-chlorophenyl)-3-(1,3-dihydroxypropan-2-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; 71. 6-(6-chloropyridin-3-yl)-3-((1R,3S)-3-hydroxycyclopentyl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; 72. 3-((1R,3S)-3-hydroxycyclopentyl)-8-(pyridin-3-yl)-6-(2-(trifluoromethyl)pyrimidin-5-yl)pyrido[3,4-d]pyrimidin-4(3H)-one TFA salt; 73. 3-((1R,3S)-3-hydroxycyclopentyl)-6-(4-morpholinophenyl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; 74. 6-(4'-chloro-[1,1'-biphenyl]-4-yl)-3-(1-hydroxypropan-2-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; 75. 3-(1-hydroxypropan-2-yl)-6-(4-morpholinophenyl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; 76. 3-(2-(methylsulfonyl)ethyl)-8-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one; 77. 6-(4-chlorophenyl)-3-(2-(methylsulfonyl)ethyl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; 78. 3-(1,1-dioxidetetrahydro-2H-thiopyran-4-yl)-6-(4-morpholinophenyl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; 79. 3-(2-(methylsulfonyl)ethyl)-6-(4-morpholinophenyl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; 80. 3-(1,3-dihydroxypropan-2-yl)-6-(4-morpholinophenyl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; 81. (R)-3-(2,3-dihydroxypropyl)-8-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one; 82. 3-(2,3-dihydroxypropyl)-6-(4-morpholinophenyl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; 83. 2-(6-(4-chlorophenyl)-4-oxo-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-3(4H)-yl)propanoic acid 2,2,2-trifluoroacetate; 84. 2-(4-oxo-8-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidin-3(4H)-yl)propanoic acid 2,2,2-trifluoroacetate; 85. 3-(1-aminopropan-2-yl)-8-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one; 86. N-(2-(4-oxo-8-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidin-3(4H)-yl)propyl)acetamide; 87. 3-(1-aminopropan-2-yl)-6-(4-chlorophenyl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; 88. N-(2-(6-(4-chlorophenyl)-4-oxo-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-3(4H)-yl)propyl)acetamide; 89. N-(2-(6-(4-chlorophenyl)-4-oxo-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-3(4H)-yl)propyl)methanesulfonamide; 90. 3-(1-aminopropan-2-yl)-6-(4-morpholinophenyl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; 91. N-(2-(6-(4-morpholinophenyl)-4-oxo-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-3(4H)-yl)propyl)methanesulfonamide; 92. N-(2-(6-(4-morpholinophenyl)-4-oxo-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-3(4H)-yl)propyl)acetamide; 93. 3-(piperidin-4-yl)-8-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one; 94. 6-(4-chlorophenyl)-3-(1-(methylsulfonyl)piperidin-4-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; 95. 6-(4-chlorophenyl)-3-(1-(cyclopropylsulfonyl)piperidin-4-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; and 96. 3-(1-Acetylpiperidin-4-yl)-6-(4-chlorophenyl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one Compounds selected from: 1-22, 25-37, 41-43, 45, 47 and 51-96, or enantiomers, diastereomers, racemates, solvates, hydrates or pharma- ceutically acceptable salts thereof.

9. 10. A pharmaceutical composition comprising a compound of claim 1 or claim 8 or an enantiomer, diastereomer, racemate, solvate, hydrate or pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable carrier.

10. 10. A pharmaceutical composition according to claim 9 for use in the prevention and / or treatment of a disease or condition mediated by the aryl hydrocarbon receptor (AhR).

11. The pharmaceutical composition of claim 10, wherein the disease or condition mediated by the aryl hydrocarbon receptor (AhR) is cancer, a cancerous condition, a tumor, a fibrotic disease, a condition involving dysregulated immune response, or other disorder associated with abnormal signaling of the AhR.

12. 10. The pharmaceutical composition of claim 9 for use in inhibiting cancer cell proliferation, tissue invasion, metastasis and angiogenesis in a subject having cancer, a cancerous condition or a tumor.

13. 13. The pharmaceutical composition of claim 12, wherein the cancer is selected from the group consisting of breast cancer, squamous cell carcinoma, lung cancer, peritoneal cancer, hepatocellular carcinoma, gastric cancer, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, hepatoma, colon cancer, colorectal cancer, endometrial cancer, uterine cancer, salivary gland cancer, kidney cancer, prostate cancer, vulvar cancer, thyroid cancer, head and neck cancer, B-cell lymphoma, chronic lymphocytic leukemia (CLL), acute lymphoblastic leukemia (ALL), hairy cell leukemia and chronic myeloblastic leukemia.

14. 12. The pharmaceutical composition of claim 11, wherein the fibrotic disease is selected from the group consisting of hepatic fibrosis, liver cirrhosis, pulmonary fibrosis, endomyocardial fibrosis, nephropathy, glomerulonephritis, renal interstitial fibrosis, fibrotic disorders associated with diabetes, myelofibrosis, scleroderma, mottled scleroderma, keloids, hypertrophic scars, nevi, diabetic retinopathy, proliferative vitreoretinopathy and sarcoidosis.

15. 12. The pharmaceutical composition of claim 11, wherein the condition involving dysregulated immune response is selected from the group consisting of sepsis, multiple organ failure, inflammatory kidney disease, chronic enteritis, pancreatitis, peritonitis, inflammatory skin disease, inflammatory eye disease, rheumatic disease, systemic lupus erythematosus and multiple sclerosis.

16. Use of the compound according to claim 1 or 8, or an enantiomer, diastereomer, racemate, solvate, hydrate or pharma- ceutically acceptable salt thereof, for the manufacture of an activity modulator of an aryl hydrocarbon receptor (AhR).

17. Use of a compound according to claim 1 or claim 8, or an enantiomer, diastereomer, racemate, solvate, hydrate or pharma- ceutically acceptable salt thereof, for the manufacture of an agent for the prophylaxis or treatment of a disease or condition mediated by the aryl hydrocarbon receptor (AhR).

18. 18. The use according to claim 17, wherein the disease or condition mediated by the aryl hydrocarbon receptor (AhR) is cancer, a cancerous condition, a tumor, a fibrotic disease, a condition involving dysregulated immune response, or other disorder associated with abnormal signaling of the AhR.

19. 19. The use of claim 18, wherein the cancer is selected from the group consisting of breast cancer, squamous cell carcinoma, lung cancer, peritoneal cancer, hepatocellular carcinoma, gastric cancer, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, hepatoma, colon cancer, colorectal cancer, endometrial cancer, uterine cancer, salivary gland cancer, kidney cancer, prostate cancer, vulvar cancer, thyroid cancer, head and neck cancer, B-cell lymphoma, chronic lymphocytic leukemia (CLL), acute lymphoblastic leukemia (ALL), hairy cell leukemia and chronic myeloblastic leukemia.

20. 19. The use according to claim 18, wherein the fibrotic disease is selected from the group consisting of liver fibrosis, liver cirrhosis, pulmonary fibrosis, endomyocardial fibrosis, nephropathy, glomerulonephritis, renal interstitial fibrosis, fibrotic disorders associated with diabetes, myelofibrosis, scleroderma, mottled scleroderma, keloids, hypertrophic scars, nevi, diabetic retinopathy, proliferative vitreoretinopathy and sarcoidosis.

21. 19. The use according to claim 18, wherein the condition involving dysregulated immune response is selected from the group consisting of sepsis, multiple organ failure, inflammatory kidney disease, chronic enteritis, pancreatitis, peritonitis, inflammatory skin disease, inflammatory eye disease, rheumatic disease, systemic lupus erythematosus and multiple sclerosis.

22. Use of the compound according to claim 1 or 8, or an enantiomer, diastereomer, racemate, solvate, hydrate or pharma- ceutically acceptable salt thereof, for the manufacture of an agent for inhibiting cancer cell proliferation, tissue invasion, metastasis or angiogenesis.

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