Pyridopyrimidone derivatives and their use as aryl hydrocarbon receptor modulators

Abstract

The present invention relates to novel compounds that are effective as modulators of the aryl hydrocarbon receptor (AhR), pharmaceutical compositions comprising the compounds as active ingredients, which are useful for modulating AhR, or preventing or treating diseases, disorders or conditions associated with AhR activity, and therefore, can be used as drugs for preventing or treating diseases, disorders or conditions associated with AhR activity, in particular cancers, cancerous conditions, tumors, fibrotic diseases, conditions of dysregulated immune responses, and the like.

Description

Technical Field

[0001] The present invention relates to novel pyridopyrimidone derivatives that can modulate the activity of aryl hydrocarbon receptor (AhR). The compounds of formula (I) of the present invention can also be used to inhibit the growth of cancer cells, metastasis and invasion of tumor cells, and to treat diseases involving immune response disorders associated with AhR signaling (single agent or in combination with other active ingredients). Background Art

[0002] The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that is well known as an important intracellular chemical sensor that responds to both natural and artificial environmental compounds. It is well known that AhR is a member of the periodic circadian protein (PER)-AhR nuclear translocator (ARNT)-specific protein (SIM) transcription factor superfamily, in which the PER-ARNT-SIM (PAS) domain senses ligands (Burbach et al., PNAS Sep 1, 1992 89(17) 8185-8189). AhR activated by several bound ligands translocates to the nucleus and dimerizes with its partner protein ARNT. This heterodimeric complex interacts with exogenous response elements (XREs) and directly or indirectly controls the expression of AhR-associated genes. One of the well-characterized endogenous ligands is kynurenine, which is produced by TDO (Opitz et al., Nature, 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 concentrations of kynurenine and high serum Kyn / Trp ratios in the plasma of patients with various cancers are associated with poor prognosis after PD-1 blockade in several cancer types, including lung cancer, melanoma, and renal cell carcinoma (Haoxin Li et al., Nat Commun. 2019 Sep 25; 10(1): 4346.).

[0003] It is well known recently that AhR regulates the functions of a large number of cells of the innate and adaptive immune systems. Activated AhR weakens the induction of cytokines that promote pathogenic T cell subset polarization and reduce MHC class II expression. In addition, AhR is activated by agonists or regulators, inhibiting the differentiation of auxiliary Th17 cells and stabilizing regulatory T cells. The energetic AhR also induces the production of its ligands through a positive feedforward 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). As an immune escape mechanism, tumor regenerative cells (TRC) drive PD-1 upregulation in CD8+T cells through the Kyn-AhR pathway (Yuying Liu et al., Cancer cell, 2018).

[0004] In addition, some studies have shown that AhR signaling plays an important role in a variety of diseases, such as autoimmunity, infection, and cancer. AhR signaling may be associated with autoimmune diseases, including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and multiple sclerosis (MS) (Xiao-Song Wang et al., Inflammopharmacology, February 2020; 28 (1): 63-81). Constitutive AhR activation reduces type I IFN (IFN-I) antiviral response (Yamada et al., Nat Immunol, June 2016; 17 (6): 687-94). A variety of viruses induce AhR activation to evade the host's immune response, which is a strategy used to limit Zika virus replication and SARS-COV-2 infection in mouse models (Federico Giovannoni et al., Cell Research, December 2021, 31: 1-2). AhR may affect cancer cell proliferation, tissue invasion, metastasis, and angiogenesis (Jae Eun Cheong et al., Trends in Pharmacological Sciences, 2018 March; 39(3): 307-325). In addition, many cancer types can escape immune recognition through the AhR pathway. Developing therapies targeting AhR may be a potential opportunity to overcome immune-related diseases. Summary of the invention

[0005] Technical issues

[0006] Therefore, one object of the present invention is to provide novel compounds, or enantiomers, diastereomers, racemates, solvates, hydrates or pharmaceutically acceptable salts thereof as modulators of AhR.

[0007] One object of the present invention is to provide a pharmaceutical composition for modulating AhR activity, comprising a compound as an AhR modulator.

[0008] It is an object of the present invention to provide a pharmaceutical composition for preventing or treating a disease, disorder or condition associated with AhR activity, such as cancer or autoimmune disease, comprising a compound that is an AhR modulator.

[0009] It is an object of the present invention to provide a method of modulating AhR activity by administering a compound that is an AhR modulator.

[0010] It is an object of the present invention to provide a method for preventing or treating prostaglandin-related diseases by administering a compound that is an AhR modulator.

[0011] One object of the present invention is to provide the use of prostaglandin analogs for modulating AhR activity, or preventing or treating diseases, disorders or conditions associated with AhR.

[0012] Solution to the problem SUMMARY OF THE INVENTION

[0014] The present invention provides novel compounds and pharmaceutically acceptable compositions that are effective as modulators or inhibitors of AhR. The compound is represented by formula (I):

[0015]

[0016] in:

[0017] Ar 1 and Ar 2 are each independently selected from the group consisting of halogen, 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;

[0018] L is absent (direct bond), H, halogen, cyano, hydroxyl, amino, nitro, ether (-O-), thioether (-S-), sulfinyl (-SO-), sulfonyl (-SO 2 -), sulfonylamino (-SO 2 NR 2 -), aminosulfonyl (-NR 2 SO 2 -), 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 and substituted or unsubstituted monocyclic or bicyclic C 5-10 heteroaryl;

[0019] R 1 Is not present (direct bonding), H, halogen, cyano, hydroxyl, 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 (-SO 2 -H), sulfonamide (-SO 2 NR 2 2 ), aminosulfonic acid (-NR 2 SO 2 -H), carboxylic acid (-(CO)-H), carbonyl (-(CO)R 2 ), amide (-(CO)NR 2 2 ), trans-alkylamide (-NH(CO)-R 2 ), alkyl esters (-(CO)OR 2 ), sulfonate (-SO 2 -R 2 ), C 3-10 Cycloalkyl, C 1-5 Alkyl hydroxyl, C 1-5 Alkenyl hydroxyl, C 1-5 Alkynyl hydroxyl, C 1-5 Alkylamine, C 1-5 Alkenylamine, C 1-5 Alkynylamine, substituted or unsubstituted monocyclic or bicyclic C 3-10 Heterocycloalkyl and substituted or unsubstituted monocyclic or bicyclic C 5-10 heteroaryl;

[0020] R 2 is H, halogen, hydroxy, amino, substituted or unsubstituted C 1-5 Alkyl, substituted or unsubstituted C 1-5 Alkoxy, substituted or unsubstituted C 3-8 Cycloalkyl and substituted or unsubstituted C 1-5 Alkyl carboxylic acids;

[0021] R 3 is H, substituted or unsubstituted C1-5 Alkyl, C 1-5 Alkyl acetyl (alkyl-CO-), C 1-5 Sulfonylalkyl (alkyl-SO 2 -), C 1-5 Sulfonylaminoalkyl (alkyl-SO 2 NR 2 2 ), C 1-5 Amide alkyl (alkyl-(CO)NR 2 2 ), C 1-5 Reverse amide alkyl (alkyl-NR 2 (CO)-), substituted or unsubstituted C 1-5 Alkoxy and substituted or unsubstituted C 1-5 Alkyl carboxylic acid.

[0022] In some embodiments of these and all of these aspects described herein, the AhR modulator of Formula (I) is an AhR modulator or an AhR antagonist.

[0023] In some aspects, described herein are methods of modulating AhR activity, more specifically, modulating constitutive AhR activity in a subject in need thereof. Such methods include administering to a subject having constitutive AhR activity a therapeutically effective amount of an AhR modulator, such as an AhR antagonist of formula (I) as described herein. In some embodiments of these aspects and all such aspects described herein, the method further includes the step of selecting a subject having constitutive AhR activity.

[0024] The compounds of formula (I) of the present invention exhibit a valuable spectrum of pharmacological actions, which could not have been predicted. It was surprisingly found that the compounds of the present invention effectively inhibit AhR, and therefore the compounds are potentially useful for treating or preventing diseases or conditions mediated by the aryl hydrocarbon receptor (AhR), preferably cancer, cancerous conditions, tumors, fibrotic conditions or conditions with dysregulated immune responses or other disorders associated with abnormal AhR signaling in humans and animals.

[0025] Examples of such diseases involving dysregulated immune responses associated with AhR signaling are sepsis (SIRS), multiple organ failure (MODS, MOF), inflammatory kidney diseases, chronic intestinal inflammation (IBD, Crohn's disease, UC), pancreatitis, peritonitis, inflammatory skin diseases and inflammatory eye diseases, autoimmune diseases such as rheumatoid diseases including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), multiple sclerosis (MS), etc.

[0026] Examples of such fibrotic disorders are fibrotic disorders of internal organs, such as fibrotic disorders of the lungs, heart, kidneys, bone marrow, in particular of the liver, as well as dermatological fibrosis and fibrotic eye diseases. In the context of the present invention, the term fibrotic disease includes in particular the following terms: liver fibrosis, cirrhosis, pulmonary fibrosis, endomyocardial fibrosis, nephropathy, glomerulonephritis, interstitial renal fibrosis, fibrotic lesions caused by diabetes, myelofibrosis and similar fibrotic diseases, scleroderma, morphea, keloids, hypertrophic scars (also after surgery), nevi, diabetic retinopathy, proliferative vitreoretinopathy and connective tissue diseases (e.g. sarcoidosis).

[0027] In other aspects, described herein are methods of treating cancer or cancerous conditions by modulating AhR activity. Such methods include administering to a subject having cancer or a cancerous condition a therapeutically effective amount of any pharmaceutical composition including an AhR modulator, such as an AhR antagonist of formula (I) described herein.

[0028] In certain aspects, described herein are methods of inhibiting tumor cell invasiveness in a subject having cancer, a cancerous condition, or a tumor. Such methods include administering to a subject having cancer or a tumor a therapeutically effective amount of any pharmaceutical composition, including an AhR modulator, such as an antagonist of AhR of formula (I) described herein.

[0029] In some embodiments of these aspects and all such aspects described herein, the method further comprises the step of selecting a subject having cancer, a cancerous condition, or a tumor.

[0030] The cancers, cancerous conditions or tumors that are particularly suitable for treatment with the AHR inhibitors of the present invention are liquid tumors and solid tumors, such as cancers of the breast, respiratory tract, brain, reproductive organs, digestive tract, urinary tract, eye, liver, skin, head and neck, thyroid, parathyroid glands and distant metastases thereof. These diseases also include lymphomas, sarcomas and leukemias.

[0031] 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.

[0032] Examples of respiratory tract cancers include, but are not limited to, small cell and non-small cell lung cancer, as well as bronchial adenoma and pleuropulmonary blastoma.

[0033] Examples of brain cancers include, but are not limited to, brainstem and hypothalamic gliomas, cerebellar and cerebral astrocytomas, glioblastomas, medulloblastomas, ependymomas, and neuroectodermal and pineal tumors.

[0034] Tumors of the male reproductive organs include, but are not limited to, prostate cancer and testicular cancer.

[0035] Tumors of the female reproductive organs include, but are not limited to, endometrial, cervical, ovarian, vaginal and vulvar cancers, and uterine sarcomas.

[0036] Examples of ovarian cancer include, but are not limited to, serous tumors, endometrioid tumors, mucinous cystadenocarcinomas, granulosa cell tumors, Sertoli-Leydig cell tumors, and ovarian male cell tumors.

[0037] Examples of cervical cancer include, but are not limited to, squamous cell carcinoma, adenocarcinoma, adenosquamous carcinoma, small cell carcinoma, neuroendocrine tumors, glassy cell carcinoma, and villoglandular adenocarcinoma.

[0038] Digestive tract tumors include, but are not limited to, anal cancer, colon cancer, colorectal cancer, esophageal cancer, gallbladder cancer, stomach cancer, pancreatic cancer, rectal cancer, small intestine cancer, and salivary gland cancer.

[0039] Examples of esophageal cancer include, but are not limited to, esophageal cell carcinoma and adenocarcinoma, as well as squamous cell carcinoma, leiomyosarcoma, malignant melanoma, rhabdomyosarcoma, and lymphoma.

[0040] Examples of gastric cancer include, but are not limited to, intestinal-type and diffuse-type gastric adenocarcinoma.

[0041] Examples of pancreatic cancer include, but are not limited to, ductal adenocarcinoma, adenosquamous carcinoma, and pancreatic endocrine tumors.

[0042] 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 carcinoma.

[0043] Examples of renal cancer include, but are not limited to, renal cell carcinoma, urothelial cell carcinoma, juxtaglomerular cell tumor (reninoma), angiomyolipoma, renal oncocytoma, Bellini duct carcinoma, clear cell sarcoma of the kidney, mesoblastic nephroma, and Wilms' tumor.

[0044] Examples of bladder cancer include, but are not limited to, transitional cell carcinoma, squamous cell carcinoma, adenocarcinoma, sarcoma, and small cell carcinoma.

[0045] Eye cancers include, but are not limited to, intraocular melanoma and retinoblastoma.

[0046] Examples of liver cancer include, but are not limited to, hepatocellular carcinoma (hepatocellular carcinoma with or without fibrolamellar variant), cholangiocarcinoma (intrahepatic bile duct carcinoma), and mixed hepatocellular cholangiocarcinoma.

[0047] Skin cancers include, but are not limited to, squamous cell carcinoma, Kaposi's sarcoma, malignant melanoma, Merkel cell skin cancer, and non-melanoma skin cancer.

[0048] 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 cancer and oral cavity cancer, and squamous cell carcinoma.

[0049] Lymphomas include, but are not limited to, AIDS-related lymphoma, non-Hodgkin's lymphoma, cutaneous T-cell lymphoma, Burkitt's lymphoma, Hodgkin's disease, and central nervous system lymphoma.

[0050] Sarcomas include, but are not limited to, soft tissue sarcomas, osteosarcomas, malignant fibrous histiocytomas, lymphosarcoma, and rhabdomyosarcomas.

[0051] Leukemias include, but are not limited to, acute myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, and hairy cell leukemia.

[0052]

[00136] The terms "treating" or "treatment" as described throughout this document are used conventionally, eg, to manage or care for a subject in order to combat, alleviate, reduce, relieve, or ameliorate the symptoms of a disease or disorder (eg, cancer).

[0053] The compounds of the invention are particularly useful for treatment and prevention, i.e. prevention of tumor growth and metastasis, particularly in solid tumors of all indications and stages, whether or not pre-treated for tumor growth, the cancer being 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 or uterine cancer, salivary gland cancer, kidney cancer or cancer of the kidney, 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.

[0054] Some embodiments of these methods may further include the administration or treatment of 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.

[0055] Some embodiments of these methods can further comprise the administration or treatment of one or more anti-cancer therapeutic agents. In some such embodiments, the anti-cancer therapeutic agent is a chemotherapeutic agent, a growth inhibitory agent, an anti-angiogenic agent, a cytotoxic agent, an anti-hormone agent, a prodrug, or a cytokine.

[0056] In a further embodiment of the present invention, the compound of formula (I) of the present invention can be used to sensitize cells to radiation, that is, before cell radiotherapy, cells are treated with the compound of the present invention, making the cells more susceptible to DNA damage and cell death than cells not treated with any compound of the present invention. In one aspect, the cells are treated with at least one compound of general formula (I) of the present invention.

[0057] Thus, the present invention also provides a method of killing cells wherein one or more compounds of the present invention are administered to the cells in combination with conventional radiation therapy.

[0058] The present invention also provides a method for making cells more sensitive to cell death, wherein the cells are treated with one or more compounds of formula (I) of the present invention before treating the cells to cause or induce cell death. On the one hand, after treating the cells with one or more compounds of formula (I) of the present invention, the cells are treated with at least one compound or at least one method or a combination thereof to cause DNA damage to achieve the purpose of inhibiting normal cell function or killing cells.

[0059] In other embodiments of the present invention, cells are killed by treating cells with at least one DNA damaging agent, i.e., after treating cells with one or more compounds of formula (I) of the present invention to sensitize cells to cell death, cells are treated with at least one DNA damaging agent to kill cells. DNA damaging agents that can be used in the present invention include, but are not limited to, chemotherapeutic agents (e.g., cisplatin), ionizing radiation (X-rays, ultraviolet radiation), carcinogens, and mutagens.

[0060] In other embodiments, the cells are killed by treating the cells with at least one method to cause or induce DNA damage. Such methods include, but are not limited to, activating a cell signaling pathway that, when activated, causes DNA damage; inhibiting a cell signaling pathway that, when inhibited, causes DNA damage; inducing biochemical changes in the cell, wherein the changes cause DNA damage. As a non-limiting example, a DNA repair pathway in the cell can be inhibited, thereby preventing the repair of DNA damage and causing abnormal accumulation of DNA damage in the cell.

[0061] In one aspect of the invention, the compound of formula (I) of the present invention is applied to the cell before the radiation or other induction of DNA damage in the cell. In another aspect of the invention, the compound of general formula (I) of the present invention is applied to the cell simultaneously with the radiation or other induction of DNA damage in the cell. In another aspect of the invention, the compound of formula (I) of the present invention is applied to the cell immediately after the radiation or other induction of DNA damage in the cell begins.

[0062] In another aspect, the cell is in vitro. In another embodiment, the cell is in vivo. The compounds of the invention may be administered as a single agent or in combination with one or more other pharmaceutically active ingredients, where the combination does not cause unacceptable side effects.

[0063] The present invention also encompasses combinations of such drugs. For example, the compounds of the present invention can be combined with 131 1-chTNT, abarelix, abiraterone, aclarubicin, adalimumab, ado-trastuzumab emtansine, afatinib, aflibercept, aldesleukin, alectinib, alemtuzumab, alendronic acid, alitretinoin, altretamine, amifostine, aminoglutethimide, hexyl aminolevulinate, aminolevulinate, amrubicin, amsacrine, anastrozole, ancestim, anethole dithiolethione, anetumab ravtansine, angiotensin II, antithrombin III, aprepitant, arcitumomab, arglabin, arsenic trioxide trioxide), asparaginase, atezolizumab, axitinib, azacitidine, basiliximab, belotecan, bendamustine, besilesomab, belinostat, bevacizumab, bexarotene, bicalutamide, bisantrene, bleomycin, blinatumomab, bortezomib, buserelin, bosutinib, brentuximabvedotin, busulfan, cabazitaxel, cabozantinib, calcitonine, calcium folinate, calcium levofolinate, capecitabine, capromab, carbamazepine, carboplatin carboplatin, carboquone, carfilzomib, carmofur, carmustine, catumaxomab, celecoxib, celmoleukin, ceritinib, cetuximab, chlorambucil, chlormadinone, chlormethine, cidofovir, cinacalcet, cisplatin, cladribine, clodronic acid 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, dibrospidium chloridechloride), dianhydrogalactitol, diclofenac, dinutuximab, docetaxel, dolasetron, doxifluridine, doxorubicin, doxorubicin+estrone, dronabinol, eculizumab, edrecolomab, elliptinium acetate, elotuzumab, eltrombopag, endostatin, enocitabine, enzalutamide, epirubicin, epitiostanol, epoetinalfa, epoetin beta beta), epoetin zeta, eptaplatin, eribulin, erlotinib, esomeprazole, estradiol, estramustine, ethinylestradiol, etoposide, everolimus, exemestane, fadrozole, fentanyl, filgrastim, fluoxymesterone, floxuridine, fludarabine, fluorouracil, flutamide, folinic acid acid, formestane, fosaprepitant, fotemustine, fulvestrant, gadobutrol, gadoteridol, gadoteric acid, meglumine, gadooversetamide, gadoxetic acid, gallium nitratenitrate), ganirelix, gefitinib, gemcitabine, gemtuzumab, Glucarpidase, glutoxim, GM-CSF, goserelin, granisetron, granulocyte colony stimulating factor, histamine dihydrochloride, histrelin, hydroxycarbamide, iodine-125 sealed seed source, lansoprazole, ibandronic acid, ibritumomab tiuxetan), ibrutinib, idarubicin, ifosfamide, imatinib, imiquimod, improsulfan, indisetron, incadronic acid, ingenol mebutate, interferon alfa, interferon beta, interferon gamma gamma), iobitridol, iobenguane (1231), iomeprol, ipilimumab, irinotecan, itraconazole, ixabepilone, ixazomib, lanreotide, lansoprazole, lapatinib, lasocholine, lenalidomide, lenvatinib, lenograstim, lentinan, letrozole, leuprorelin, levamisole, levonorgestrel, levothyroxinesodium), lisuride, lobaplatin, lomustine, lonidamine, masoprocol, medroxyprogesterone, megestrol, melarsoprol, melphalan, mepitiostane, mercaptopurine, mesna, methadone, methotrexate, methoxsalen, methylaminolevulinate, methylprednisolone, methyltestosterone, metirosine, 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 acidacid, netupitant / palonosetron, nivolumab, pentetreotide, nilotinib, nilutamide, nimorazole, nimotuzumab, nimustine, nintedanib, nitracrine, nivolumab, obinutuzumab, octreotide, ofatumumab, olaparib, olaratumab, omacetaxine mepesuccinate, omeprazole, ondansetron, oprelvekin, orgotein, orilotimod, osimertinib, oxaliplatin, oxycodone, oxymetholone, ozogamicine, p53 gene therapy, paclitaxel, palbociclib, palifermin ifermin), 103 palladium seed, palonosetron, pamidronate, panitumumab, panobinostat, pantoprazole, pazopanib, pegaspargase, PEG-epoetin beta (methoxy PEG-erythropoietin beta), pembrolizumab, pegfilgrastim, peginterferon α-2b (peginterferonalfa-2b), pembrolizumab, pemetrexed, pentazocine, pentostatin, peplomycin, perflubutane, perfosfamide, pertuzumab, picibanil, pilocarpine, pirarubicin, pixantrone, plerixafor, plicamycin, poliglusam, polyestradiol phosphate, polyvinylpyrrolidone+sodium hyaluronate hyaluronate), polysaccharide-K, pomalidomide, ponatinib, porfimer sodium sodium), pralatrexate, prednimustine, prednisone, procarbazine, procodazole, propranolol, quinagolide, rabeprazole, racotumomab, radium-223 chloride, radotinib, raloxifene, raltitrexed, ramosetron, ramucirumab, ranimustine, rasburicase, razoxane, refametinib, regorafenib, risedronic acid,acid), rhenium-186 etidronate, rituximab, rolapitant, romidepsin, romiplostim, romurtide, roniciclib, samarium (153Sm), samarium lexidronan, sargramostim, satumomab, secretin, siltuximab, sipuleucel-T, sizofiran, sobuzoxane, sodium glycididazole, sonidegib, sorafenib, stanozolol, streptozotocin, sunitinib, talaporfin, oncolytic virus (Talimogene laherparepvec), tamibarotene, tamoxifen, tapentadol, tasonermin, teceleukin, technetium (99mTc) nofetumomab merpentan, 99mTc-HYNIC-[Tyr3]-octreotide, tegafur, tegafur+gimeracil+oteracil, temoporfin, temozolomide, temsirolimus, teniposide, testosterone, tetrofosmin tetrofosmin, thalidomide, thiotepa, thymalfasin, thyrotropin alfa, thioguanine, tocilizumab, topotecan, toremifene, tositumomab, trabectedin, trametinib, tramadol, trastuzumab, trastuzumab enmetinibemtansine), 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 acid), zorubicin.

[0064] The compounds of the invention may further be combined with other agents targeting the immune system, such as immune checkpoint inhibitors, for example, aPD-1 / -L1 axis antagonists.

[0065] PD-1, together with its ligands PD-L1 and PD-L2, acts as a negative regulator of T cell activation. AHR inhibits immune cell function while increasing the proliferation and motility of cancer cells. PD-L1 is overexpressed in many cancers, and overexpression of PD-1 usually occurs simultaneously in tumor-infiltrating T cells. Therefore, it leads to weakening of T cell activation and escape of immune surveillance, thereby contributing to impaired anti-tumor immune response (Keir ME et al., (2008) Annu. Rev. Immunol. 26: 677).

[0066] Simultaneous targeting of the PD-1 / -L1 axis and AHR enhanced the anti-tumor immune response more than additively, leading to an unexpected reduction in tumor growth.

[0067] Therefore, the composition comprising a PD-1 / -L1 axis antagonist and an AHR antagonist has unexpected effects in enhancing immune response and treating cancer.

[0068] In addition, the compounds of the present invention are also useful as therapeutic agents for various other diseases involving AHR.

[0069] Examples of other diseases associated with aberrant AhR signaling inflammation include vaccination with infection and cancer, viral infections, obesity and diet-induced obesity, excessive obesity, metabolic disorders, hepatic steatosis and uterine fibroids (leiomyomas or uterine myomas) in women, chronic kidney disease, acute and chronic renal insufficiency, diabetes, inflammatory or hypertensive kidney disease, cardiac insufficiency, angina, hypertension, pulmonary hypertension, ischemia, vascular disease, thromboembolic disease, atherosclerosis, sickle cell anemia, erectile dysfunction, benign prostatic hyperplasia, dysuria associated with benign prostatic hyperplasia, Huntington's disease, dementia, Alzheimer's disease, and Creutzfeld-Jakob disease.

[0070] In other aspects, provided herein are pharmaceutical compositions comprising an AhR modulator, such as an AhR antagonist of formula (I), and a pharmaceutically acceptable excipient.

[0071] In some aspects, pharmaceutical compositions comprising an AhR modulator, such as an AhR antagonist of Formula (I), are provided for use in modulating constitutive AhR activity in a subject in need thereof.

[0072] In some aspects, pharmaceutical compositions comprising AhR modulators, such as AhR antagonists of Formula (I), are provided for use in treating cancer or a cancerous condition by modulating AhR activity.

[0073] In some aspects, pharmaceutical compositions comprising AhR modulators, such as AhR antagonists of Formula (I), are provided for use in inhibiting proliferation, tissue invasion, metastasis, and angiogenesis of cancer cells in a subject having cancer, a cancerous condition, or a tumor.

[0074] In some embodiments of these aspects and all such aspects described herein, the use further comprises the step of selecting a subject having a cancer, a cancerous condition, or a 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 or uterine cancer, salivary gland cancer, kidney cancer or cancer of the kidney, 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.

[0075] In some embodiments of these aspects and all such aspects described herein, the use further comprises one or more additional anti-cancer therapies. In some such embodiments, the additional anti-cancer therapies comprise surgery, radiotherapy, biological therapy, immunotherapy, or chemotherapy.

[0076] In some embodiments of these aspects and all 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, a growth inhibitory agent, an anti-angiogenic agent, a cytotoxic agent, an anti-hormone agent, a prodrug or a cytokine.

[0077] Advantageous Effects of the Invention

[0078] The novel compounds of formula (I) according to the present invention can effectively regulate AhR activity, so they can be used as therapeutic or preventive drugs for various diseases, disorders or conditions related to AhR activity, such as cancer, cancerous conditions, tumors, fibrotic diseases, conditions of dysregulated immune responses, including autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus (SLE), multiple sclerosis (MS), or other diseases related to abnormal AhR signaling, etc. DETAILED DESCRIPTION

[0079] Hereinafter, the present invention will be described in more detail.

[0080] Unless otherwise defined, all technical terms used herein have the same meaning as those generally understood by those of ordinary skill in the art to which the present invention belongs. In addition, although the present invention has been described in conjunction with specific methods and samples, their analogs or equivalents should also be within the scope of the present invention. In addition, unless explicitly stated, the numerical values ​​listed herein are considered to include the meaning of "about". All publications and other references mentioned herein are hereby incorporated by reference in their entirety.

[0081] The definitions of the residues used are described in detail herein. Unless otherwise indicated, each residue has the following definition and is used as commonly understood by those of ordinary skill in the art.

[0082] As used herein, the terms "halo" or "halogen" or "halide" include fluorine, chlorine, bromine and iodine.

[0083] As used herein, "alkyl" refers to aliphatic hydrocarbon groups, including straight chain and branched chain hydrocarbon groups. 1-6 Alkyl is an aliphatic hydrocarbon having 1 to 6 carbon atoms, including 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 defined, alkyl refers to C 1-6 Alkyl, preferably C 1-4 Alkyl, more preferably C 1-3 alkyl.

[0084] As used herein, "alkenyl" refers to an aliphatic hydrocarbon group containing at least one carbon-carbon double bond, and includes straight chain and branched hydrocarbon groups. Non-limiting examples of "alkenyl" are vinyl, allyl, but-1-enyl or but-2-enyl.

[0085] As used herein, "alkynyl" refers to an aliphatic hydrocarbon group containing at least one carbon-carbon triple bond, and includes straight and branched hydrocarbon groups. Non-limiting examples of "alkynyl" are ethynyl, propargyl, but-1-ynyl or but-2-ynyl.

[0086] As used herein, "haloalkyl" refers to an alkyl group substituted with one or more halogen atoms, alkyl being as defined above. "Halo" refers to F, Cl, Br or I, and is used compatible with the term "halogen". Unless otherwise defined, haloalkyl refers to fluoromethyl, difluoromethyl, chloromethyl, trifluoromethyl or 2,2,2-trifluoromethyl.

[0087] As used herein, the term "alkoxy" refers to an -O-alkyl or alkyl-O- group, and the definition of alkyl is as shown above. For example, it includes methoxy, ethoxy, n-propoxy, n-butoxy and tert-butoxy.

[0088] As used herein, "alkoxyalkyl" refers to alkyl-O-alkyl, and alkyl is as defined above. Non-limiting examples are methoxymethyl, ethoxymethyl, methoxyethyl or isopropoxymethyl.

[0089] As used herein, the terms "hydroxy" or "hydroxyl," employed alone or in combination with other terms, refer to -OH.

[0090] As used herein, "cyano" refers to -CN and "cyanoalkyl" refers to an alkyl group substituted with -CN, wherein alkyl is as defined above.

[0091] As used herein, "amino" refers to -NH 2 ; "Nitro" refers to -NO 2 .

[0092] As used herein, "carboxy" refers to a -C(O)-OH group.

[0093] As used herein, "ester" refers to a -C(O)-OR group, where R is an alkyl group, which can be C 1-10 , preferably C 1-8 , C 1-6 or C 1-4 Such ester groups may or may not be substituted with one or more suitable substituents.

[0094] As used herein, the term "cycloalkyl" refers to a cyclic alkyl group which may be substituted or unsubstituted, for example, C 3-20 Cycloalkyl represents 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, etc. Preferably, unless otherwise defined, cycloalkyl can be C 3-8 Cycloalkyl or C 3-6 Cycloalkyl.

[0095] As used herein, the term "aryl" refers to a group having, for example, 6 to 20 carbon atoms (C 6-20 ) is a monovalent aromatic hydrocarbon derived by removing a hydrogen atom from a single carbon atom of a parent aromatic ring system. Aryl groups may include bicyclic groups containing an aromatic ring fused to a saturated or partially unsaturated ring. Exemplary aryl groups may include, derived from benzene (phenyl), substituted phenyl, biphenyl, naphthyl, toluoyl, naphthyl (naphthalenyl), anthracenyl, indenyl, dihydroindenyl, and the like. Unless otherwise defined, aryl refers to C 6-12 Aryl, preferably C 6-10 Aryl.

[0096] As used herein, "heteroaryl" refers to a monovalent or divalent substituent derived from a monocyclic or polycyclic heterocyclic aromatic hydrocarbon having 1 to 10 carbon ring members, which contains one or more, preferably 1 to 3, heteroatoms selected from N, O and S. Examples of heteroaryl include, but are not limited to, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, Azolyl, iso Azolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, 1,2,4- Oxazolyl, 1,3,4- oxadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, triazolyl, tetrazolyl, triazinyl, indolyl, etc. Examples of bicyclic heteroaryl groups include indolyl, benzothiophenyl, benzofuranyl, benzimidazolyl, benzo Azolyl, benzyl oxazolyl, benzothiazolyl, benzothiadiazolyl, quinolyl, isoquinolyl, furanyl, furanyl, octahydropyranopyridine, benzodioxole and the like, but are not limited thereto. Unless otherwise defined, heteroaryl is C 3-10 Heteroaryl, preferably C 3-7 Heteroaryl, more preferably C 3-5 Heteroaryl.

[0097] As used herein, "heterocycloalkyl" refers to a monocyclic, bicyclic, tricyclic or higher cyclic alkyl group having 3 to 10 carbon ring members, which contains one or more, for example, 1 to 4 heteroatoms selected from N, O and S. In addition, the heterocycle according to the present invention can also be a fused or bridged heterocycloalkyl group. Examples of non-aromatic rings include azetidinyl, oxetanyl, tetrahydrothienyl, tetrahydrofuranyl, pyrrolinyl, pyrrolidinyl, imidazolinyl, imidazolidinyl, Oxazoline, Oxazolidinyl, Piperazine, piperidinyl, pyrazolyl, pyrazolidinyl, thiazolinyl, thiazolidinyl, tetrahydrofuranyl, tetrahydrofuryl, tetrahydroisothiazolyl, tetrahydro Azolyl, tetrahydroisoxazine 1-Hydroxy-1-oxazolyl, ... 3-7 The heterocycloalkyl group is more preferably a heterocycloalkyl group having 3 to 5 carbon ring atoms.

[0098] Unless otherwise specified herein, the term "substituted" means that at least one hydrogen atom is replaced by one to three substituents selected from the group consisting of 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 azido group, an amidine group, a hydrazine group, a hydrazone group, an oxo group, a carbonyl group, a carbamoyl 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, halogenated C 1-6 Alkyl, C 2-6 Alkenyl, halogenated C 2-6 Alkenyl, C 2-6 Alkynyl, halo C 2-6 Alkynyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-20 Alkylthio, C 3-20 Carbocyclic groups (e.g., C3-9 Cycloalkyl, halogenated C 3-9 Cycloalkyl, C 3-9 Cycloalkenyl, halogenated C 3-9 Cycloalkenyl, C 1-9 Heterocycloalkyl, halogenated C 1-9 Heterocycloalkyl, C 2-9 Heterocycloalkenyl, halogenated C 2-9 Heterocycloalkenyl) and C 1-20 Heterocyclic groups (e.g., C 6-20 Aryl, C 6-20 Aryloxy, C 6-20 Arylthio, C 2-20 Heteroaryl, C 2-20 Heteroaryloxy, C 2-20 heteroarylthio).

[0099] Aryl hydrocarbon receptor

[0100] The aryl hydrocarbon receptor ("AhR") is a ligand-dependent member of the basic-helix-loop-helix transcription factor family and has been found to be activated by a variety of structurally diverse synthetic and naturally occurring compounds, such as polycyclic aromatic hydrocarbons, indoles, flavonoids, etc. In the absence of bound ligand, AhR exists in a latent conformation in the cytoplasmic compartment of the cell, associated with two molecules of the molecular chaperone heat shock protein 90 ("hsp90"), the immunophilin-like protein XAP2, and the hsp90-interacting protein p23.

[0101] As used herein, the term "aryl hydrocarbon receptor" or "AhR" refers to the 848 amino acid polypeptide described by, for example, NP_001612, together with any naturally occurring alleles, splice variants, and processed forms thereof. Typically, AhR refers to human AhR. The term AhR is also used to refer to truncated forms or fragments of AhR polypeptides, including, for example, specific AhR domains. References to any such AhR forms can be identified in the application, for example, "AhR (122-224)".

[0102] AhR modulators

[0103] The inventors of the present invention have discovered that novel AhR modulator compounds described herein, such as small molecules of formula (I), modulate constitutive AhR activity by acting as AhR antagonists. In addition, they found that such AhR modulator compounds can inhibit cancer cell growth, as well as tumor invasion, metastasis and angiogenesis. Thus, novel modulators of AhR and constitutive AhR signaling are described herein, therapeutic compositions and methods for treating and inhibiting cancer growth and tumor cell invasion, and immune-related diseases, such as autoimmune diseases.

[0104] The AhR mediates a variety of functional responses, including but not limited to de novo transcription of a target gene or AhR gene set having a DRE or XRE response element 5'-TNGCGTG-3'. Alternative pathways of AhR signaling have also been described, such as binding to retinoblastoma protein, estrogen receptor (ER), transcription factor E2F1, and NFκB pathway subunits RelA and RelB. The AhR may also act as a ubiquitin ligase. Thus, signaling via the AhR includes a variety of pathways, including constitutive and non-constitutive AhR signaling pathways or signaling activities, as those terms are defined herein.

[0105] As used herein, "constitutive AhR signaling" refers to one or more signaling pathways mediated or regulated by AhR, which are activated or driven by one or more endogenous AhR ligands or one or more environmental ligands such as toxins or pollutants, resulting in constitutive or chronic translocation of AhR to the cell nucleus, and activation or regulation of one or more AhR gene sets involved in unregulated cell growth and proliferation, tumor cell invasiveness, or a combination thereof.

[0106] As used herein, "non-constitutive AhR signaling" refers to one or more signaling pathways mediated or induced by AhR that do not result in constitutive or chronic translocation of AhR to the nucleus, and do not activate or modulate one or more AhR gene sets involved in unregulated cell growth, tumor cell invasiveness, or a combination thereof. In some embodiments, non-constitutive AhR signaling does not result in upregulated expression of CYP1A1, CYP1B1, or a combination thereof.

[0107] Thus, as used herein, the term "AhR modulator" refers to an agent, such as a compound of formula (I), that modulates or causes or promotes a qualitative or quantitative change, alteration or modification in one or more processes, mechanisms, effects, responses, functions, activities or pathways mediated by the AhR receptor. Such changes mediated by AhR modulators, such as antagonists of AhR as described herein, may refer to a reduction, inhibition or shift in the constitutive activity of AhR. The term "expression" refers to cellular processes involved in the production of RNA and proteins and, where applicable, secretion of proteins, including (where applicable) but not limited to, for example, transcription, translation, folding, modification and processing. "Expression products" include RNA transcribed from a gene and polypeptides obtained by translation of mRNA transcribed from a gene.

[0108] The term "modulate" with respect to an Ahr modulator is consistent with its use in the art, e.g., it means to cause or promote a qualitative or quantitative change, alteration or modification in 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 or alteration or modification in one or more processes, mechanisms, effects, responses, functions, activities or pathways mediated by the AhR receptor.

[0109] As used herein, the term "agent" with respect to AhR modulators refers to any compound or substance, such as, but not limited to, small molecules, nucleic acids, polypeptides, peptides, drugs, ions, and the like. An "agent" can be any chemical substance, entity, or moiety, including, but not limited to, synthetic and naturally occurring proteins and non-protein entities. 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 carbohydrate, and includes, but is not limited to, proteins, oligonucleotides, ribozymes, deoxyribonucleases, glycoproteins, siRNAs, lipoproteins, aptamers, modifications thereof, and combinations thereof, and the like. In certain embodiments, as described herein, the agent is a small molecule having a chemical moiety. For example, the chemical moiety includes an unsubstituted or substituted alkyl, aromatic, or heterocyclyl moiety. The compound may be known to have a desired activity and / or property, such as modulating AhR activity, or may be selected from a library of a variety of compounds using, for example, a screening method described herein.

[0110] In some embodiments, the AhR modulator selectively binds to AhR. As used herein, "selectively binds" or "specifically binds" refers to the ability of the AhR antagonists described herein to bind to a target, such as K D 10 -5 M (10000nM) or less, for example, 10 -6 M or smaller, 10 -7 M or smaller, 10 -8 M or smaller, 10 -9 M or smaller, 10 -10 M or smaller, 10 -11 M or smaller, or 10 -12 M or less AhR. For example, if the antagonist described herein is -5 M or smaller K D An agent is said to specifically bind to AhR if it binds to AhR but not to other molecules or related homologs. Specific binding can be affected by, for example, the affinity and activity of the antagonist, as well as the concentration of the antagonist used. One of ordinary skill in the art can determine suitable conditions for selective binding of the antagonists described herein using any suitable method, such as titrating the AhR antagonist in a suitable cell binding assay, such as those described herein.

[0111] In some aspects of the compositions and methods described herein, the AhR modulator is an AhR antagonist having the chemical structure of Formula (I) described herein.

[0112] As used herein, AhR is an "AhR antagonist". An AhR antagonist refers to an AhR inhibitor that does not itself elicit a biological response when specifically binding to AhR, but blocks or inhibits an agonist-mediated or ligand-mediated response, i.e., an AhR antagonist can bind to but not activate AhR, and the binding disrupts the interaction, displaces an AhR agonist, and / or inhibits the function of an AhR agonist. Thus, as used herein, AhR antagonists do not act as inducers of AhR activity when binding to AhR, i.e., they act as pure AhR inhibitors. In some embodiments, an AhR antagonist selectively binds to AhR.

[0113] In some embodiments of these aspects, the AhR antagonists described herein, such as compounds of Formula (I), block constitutive AhR effector functions that mediate the growth and progression of established tumors. In other embodiments, the small molecule AhR antagonists of Formula (I) described herein act as chemopreventive agents by blocking AhR-mediated CYP1A1 induction and mutagen production upon exposure to environmental ligands.

[0114] In some embodiments of these aspects, the AhR antagonists of Formula (I) described herein inhibit the early contribution of constitutively active AhR in driving malignant transformation. In some embodiments, the compounds of Formula (I) described herein inhibit cancer or tumor cell growth mediated by constitutive AhR signaling. In some embodiments, the compounds of Formula (I) described herein inhibit tumor invasion mediated by constitutive AhR signaling in driving malignant transformation.

[0115] Thus, provided for use in the various aspects described herein are AhR antagonists of formula (I):

[0116] One aspect of the present invention relates to novel compounds that can modulate the human aryl hydrocarbon receptor (AhR).These compounds bind specifically to AhR.

[0117] In some embodiments, the compound has the structure of Formula (I), or an enantiomer, diastereomer, racemate, solvate, hydrate or pharmaceutically acceptable salt thereof:

[0118]

[0119] in:

[0120] Ar 1 and Ar 2are independently selected from the group consisting of halogen, 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;

[0121] L is absent (direct bond), H, halogen, cyano, hydroxyl, amino, nitro, ether (-O-), thioether (-S-), sulfinyl (-SO-), sulfonyl (-SO 2 -), sulfonylamino (-SO 2 NR 2 -), aminosulfonyl (-NR 2 SO 2 -), 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 and substituted or unsubstituted monocyclic or bicyclic C 5-10 heteroaryl;

[0122] R 1 Is not present (direct bonding), H, halogen, cyano, hydroxyl, 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 (-SO 2 -H), sulfonamide (-SO 2 NR 2 2 ), aminosulfonic acid (-NR 2 SO 2 -H), carboxylic acid (-(CO)-H), carbonyl (-(CO)R 2 ), amide (-(CO)NR 2 2 ), trans-alkylamide (-NH(CO)-R 2 ), alkyl esters (-(CO)OR 2 ), sulfonate (-SO 2 -R 2 ), C 3-10 Cycloalkyl, C 1-5 Alkyl hydroxyl, C1-5 Alkenyl hydroxyl, C 1-5 Alkynyl hydroxyl, C 1-5 Alkylamine, C 1-5 Alkenylamine, C 1-5 Alkynylamine, substituted or unsubstituted monocyclic or bicyclic C 3-10 Heterocycloalkyl and substituted or unsubstituted monocyclic or bicyclic C 5-10 heteroaryl;

[0123] R 2 is H, halogen, hydroxy, amino, substituted or unsubstituted C 1-5 Alkyl, substituted or unsubstituted C 1-5 Alkoxy, substituted or unsubstituted C 3-8 Cycloalkyl and substituted or unsubstituted C 1-5 Alkyl carboxylic acids;

[0124] R 3 is H, substituted or unsubstituted C 1-5 Alkyl, C 1-5 Alkyl acetyl (alkyl-CO-), C 1-5 Sulfonylalkyl (alkyl-SO 2 -), C 1-5 Sulfonylaminoalkyl (alkyl-SO 2 NR 2 2 ), C 1-5 Amide alkyl (alkyl-(CO)NR 2 2 ), C 1-5 Reverse amide alkyl (alkyl-NR 2 (CO)-), substituted or unsubstituted C 1-5 Alkoxy and substituted or unsubstituted C 1-5 Alkyl carboxylic acid.

[0125] In a preferred embodiment, Ar 1 and Ar 2 can be independently halogen, substituted or unsubstituted monocyclic or bicyclic C 6-10 Aryl, substituted or unsubstituted monocyclic C containing one or more heteroatoms selected from the group consisting of N, O and S 5-7 heteroaryl, or a 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 may be each independently phenyl, a monocyclic C containing one or two heteroatoms selected from the group consisting of N, O and S 5-6 heteroaryl, or a monocyclic C containing one or two heteroatoms selected from the group consisting of N, O and S5-6 Heterocycloalkyl, the monocyclic C 5-6 The heterocycloalkyl group may be unsubstituted or substituted by halogen, hydroxy, amino, C 1-3 Alkyl or C 1-3 Alkoxy substituted, where C 1-3 Alkyl or C 1-3 The alkoxy group may be unsubstituted or substituted with 1 to 3 halogens.

[0126] More preferably, Ar 1 and Ar 2 can each independently be phenyl, imidazole, pyridine, pyrimidine, piperidine or morpholine. More preferably, Ar 1 and Ar 2 Can be unsubstituted or substituted with Cl, CH 3 or CF 3 replace.

[0127] In a preferred embodiment, L is absent (direct bond), H, halogen, cyano, hydroxyl, amino, nitro, ether (-O-), thioether (-S-), sulfinyl (-SO-), sulfonyl (-SO 2 -), sulfonylamino (-SO 2 NR 2 -), aminosulfonyl (-NR 2 SO 2 -), carbonyl (-(CO)-), amide (-(CO)NR 2 -), reverse amide (-NR 2 (CO)-), esters (-(CO)O-), substituted or unsubstituted monocyclic or bicyclic C 3-8 Cycloalkyl, substituted or unsubstituted monocyclic or bicyclic C 3-8 Heterocycloalkyl, substituted or unsubstituted monocyclic or bicyclic C 6-10 Aryl and substituted or unsubstituted monocyclic or bicyclic C 5-8 Heteroaryl; wherein the monocyclic or bicyclic C 3-8 Heterocycloalkyl and monocyclic or bicyclic C 5-8 The heteroaryl group contains one or more, preferably one or two, heteroatoms selected from the group consisting of N, O and S.

[0128] More preferably, L is absent (direct bond), H, substituted or unsubstituted C 1-5 Alkyl, 1,1-dioxytetrahydrothiopyran, piperidine, substituted or unsubstituted monocyclic or bicyclic C 3-6 Cycloalkyl, wherein C 1-5 Alkyl, substituted or unsubstituted monocyclic or bicyclic C 3-6 The cycloalkyl group may be one or more (preferably one to three) selected from hydroxy, halogen, halogenated C 1-3 Alkyl and C1-3 The substituent in the group consisting of the alkyl group is substituted.

[0129] In a preferred embodiment, R 1 is absent, H, halogen, cyano, hydroxyl, 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 hydroxyl, C 1-4 Alkenyl hydroxyl, C 1-4 Alkynyl hydroxyl, C 1-4 Alkylamine, C 1-4 Alkenylamine, C 1-4 Alkynylamine, substituted or unsubstituted monocyclic or bicyclic C 3-8 Heterocycloalkyl and substituted or unsubstituted monocyclic or bicyclic C 5-8 Heteroaryl, wherein the monocyclic or bicyclic C 3-8 Heterocycloalkyl and monocyclic or bicyclic C 5-8 The heteroaryl group includes one or more, preferably 1 or 2, heteroatoms selected from the group consisting of N, O and S. More preferably, R 1 is not present, H, 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 、-C(O)CH 3 or hydroxyl.

[0130] Further, in a more specific embodiment, the compound of formula I can be one selected from compounds 1 to 96, as shown below:

[0131] 1. 3-(3-hydroxycyclohexyl)-8-(1-methyl-1H-pyrazol-4-yl)-6-(4-trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one;

[0132] 2. 3-(3-hydroxycyclohexyl)-6,8-bis(1-methyl-1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one;

[0133] 3. 3-(1-hydroxypropan-2-yl)-6,8-bis(1-methyl-1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one;

[0134] 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;

[0135] 5. 8-(4-chlorophenyl)-3-(1-hydroxypropan-2-yl)-6-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one;

[0136] 6. 3-(1-hydroxypropan-2-yl)-6,8-bis(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one;

[0137] 7. 2-(6-chloro-8-(4-chlorophenyl)-4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)propyl acetate;

[0138] 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;

[0139] 9. 3-((1r,4r)-4-hydroxycyclohexyl)-6,8-bis(1-methyl-1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one;

[0140] 10. 6-(4-chlorophenyl)-3-((1r,4r)-4-hydroxycyclohexyl)-8-(1-methyl-1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one;

[0141] 11. 3-(2-Hydroxypropyl)-6,8-bis(1-methyl-1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one;

[0142] 12. 3-(2-Hydroxypropyl)-8-(1-methyl-1H-pyrazol-4-yl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one;

[0143] 13. 6-(4-chlorophenyl)-3-(2-hydroxypropyl)-8-(1-methyl-1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one;

[0144] 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;

[0145] 15. 3-((1S,2R)-2-hydroxycyclohexyl)-8-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one;

[0146] 16. 3-((1R,2S)-2-hydroxycyclohexyl)-8-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one;

[0147] 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;

[0148] 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;

[0149] 19. 6-(4-chlorophenyl)-3-((1R,2S)-2-hydroxycyclohexyl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one;

[0150] 20. 6-(4-chlorophenyl)-3-((1S,2R)-2-hydroxycyclohexyl)-8-(1-methyl-1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one;

[0151] 21. 6-(4-chlorophenyl)-3-((1S,2R)-2-hydroxycyclohexyl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one;

[0152] 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;

[0153] 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;

[0154] 24. 6-(4-chlorophenyl)-8-(pyridin-3-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)pyrido[3,4-d]pyrimidin-4(3H)-one;

[0155] 25. 8-(Pyridin-3-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one;

[0156] 26. 6-(4-chlorophenyl)-3-(3-hydroxyphenyl)-8-(1-methyl-1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one;

[0157] 27. 3-(3-Hydroxyphenyl)-8-(1-methyl-1H-pyrazol-4-yl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one;

[0158] 28. 6-(4-chlorophenyl)-3-((1R,3S)-3-hydroxycyclopentyl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one;

[0159] 29. 3-((1R,3S)-3-hydroxycyclopentyl)-8-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one;

[0160] 30. 6-(4-chlorophenyl)-3-((1R,3S)-3-hydroxycyclopentyl)-8-(1-methyl-1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one;

[0161] 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;

[0162] 32. 6-(4-chlorophenyl)-3-((1S,3R)-3-hydroxycyclopentyl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one;

[0163] 33. 3-((1S,3R)-3-hydroxycyclopentyl)-8-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one;

[0164] 34. 6-(4-chlorophenyl)-3-((1S,3R)-3-hydroxycyclopentyl)-8-(1-methyl-1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one;

[0165] 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;

[0166] 36. 1-(6-(4-chlorophenyl)-4-oxo-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-3(4H)-yl)-2-methylpropan-2-yl acetate;

[0167] 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;

[0168] 38. 6-(4-chlorophenyl)-3-(2-hydroxy-2-methylpropyl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one;

[0169] 39. 3-(2-Hydroxy-2-methylpropyl)-8-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one;

[0170] 40. 3-(2-Hydroxy-2-methylpropyl)-8-(pyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one;

[0171] 41. 6-(4-chlorophenyl)-3-(1-hydroxy-3-methylbutan-2-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one;

[0172] 42. 3-(1-Hydroxy-3-methylbutan-2-yl)-8-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one;

[0173] 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;

[0174] 44. (S)-2-((6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)amino)propan-1-ol;

[0175] 44. 3-(1-Hydroxypropan-2-yl)-8-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one;

[0176] 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;

[0177] 46. ​​6-(4-chlorophenyl)-3-(1-hydroxypropan-2-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one;

[0178] 47. 2-(6-(4-chlorophenyl)-4-oxo-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-3(4H)-yl)propyl diethyl phosphate;

[0179] 48. 6-(4-chlorophenyl)-3-(1-hydroxypropan-2-yl)-8-(1-methyl-1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one;

[0180] 49. 3-(1-Hydroxypropan-2-yl)-8-(pyridin-3-yl)-6-(4-(trifluoromethoxy)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one;

[0181] 50. 3-(1-Hydroxypropan-2-yl)-8-(pyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one;

[0182] 51. 6-(4-chlorophenyl)-3-(1-hydroxybutan-2-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one;

[0183] 52. 6-(4-chlorophenyl)-3-(1-hydroxybutan-2-yl)-8-(1-methyl-1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one;

[0184] 53. 3-(1-Hydroxybutan-2-yl)-8-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one;

[0185] 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;

[0186] 55.6-(4-chlorophenyl)-8-(3-fluorophenyl)-3-(1-hydroxybutan-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one;

[0187] 56. 6-(4-chlorophenyl)-3-((1r,4r)-4-hydroxycyclohexyl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one;

[0188] 57. 3-((1r,4r)-4-hydroxycyclohexyl)-8-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one;

[0189] 58. 6-(4-chlorophenyl)-3-((1s,4s)-4-hydroxycyclohexyl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one;

[0190] 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;

[0191] 60. 6-(4-chlorophenyl)-3-(1-hydroxypropan-2-yl)-8-(pyridin-3-yl)-2,3-dihydropyrido[3,4-d]pyrimidin-4(1H)-one;

[0192] 61. 6-(4-chlorophenyl)-3-(3-hydroxyphenyl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one;

[0193] 62. 3-(3-Hydroxyphenyl)-8-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one;

[0194] 63. 6-(4-chlorophenyl)-3-(3-hydroxycyclohexyl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one;

[0195] 64. 6-(4-chlorophenyl)-3-(3-hydroxycyclohexyl)-8-(1-methyl-1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one;

[0196] 65. 3-((1R,3S)-3-hydroxycyclopentyl)-8-(pyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one;

[0197] 65. 3-((1R,3S)-3-hydroxycyclopentyl)-8-(pyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one;

[0198] 66. 3-(2,3-dihydroxypropyl)-8-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one;

[0199] 67. 6-(4-chlorophenyl)-3-(2,3-dihydroxypropyl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one;

[0200] 68. 3-(2,3-dihydroxypropyl)-6-(4-(4-methylpiperazin-1-yl)phenyl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one;

[0201] 69. 3-(1,3-dihydroxypropan-2-yl)-8-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one;

[0202] 70. 6-(4-chlorophenyl)-3-(1,3-dihydroxypropan-2-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one;

[0203] 71. 6-(6-chloropyridin-3-yl)-3-((1R,3S)-3-hydroxycyclopentyl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one;

[0204] 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;

[0205] 73. 3-((1R,3S)-3-hydroxycyclopentyl)-6-(4-morpholinophenyl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one;

[0206] 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;

[0207] 75. 3-(1-Hydroxypropan-2-yl)-6-(4-morpholinophenyl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one;

[0208] 76. 3-(2-(Methylsulfonyl)ethyl)-8-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one;

[0209] 76. 3-(2-(Methylsulfonyl)ethyl)-8-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one;

[0210] 77. 6-(4-chlorophenyl)-3-(2-(methylsulfonyl)ethyl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one;

[0211] 78. 3-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-6-(4-morpholinophenyl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one;

[0212] 79. 3-(2-(Methylsulfonyl)ethyl)-6-(4-morpholinophenyl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one;

[0213] 80. 3-(1,3-dihydroxypropan-2-yl)-6-(4-morpholinophenyl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one;

[0214] 80. 3-(1,3-dihydroxypropan-2-yl)-6-(4-morpholinophenyl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one;

[0215] 81. (R)-3-(2,3-dihydroxypropyl)-8-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one;

[0216] 82. 3-(2,3-dihydroxypropyl)-6-(4-morpholinophenyl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one;

[0217] 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;

[0218] 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;

[0219] 86. N-(2-(4-oxo-8-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidin-3(4H)-yl)propyl)acetamide;

[0220] 85. 3-(1-aminopropan-2-yl)-8-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one;

[0221] 86. N-(2-(4-oxo-8-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidin-3(4H)-yl)propyl)acetamide;

[0222] 87. 3-(1-aminopropan-2-yl)-6-(4-chlorophenyl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one;

[0223] 88. N-(2-(6-(4-chlorophenyl)-4-oxo-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-3(4H)-yl)propyl)acetamide;

[0224] 89. N-(2-(6-(4-chlorophenyl)-4-oxo-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-3(4H)-yl)propyl)methanesulfonamide;

[0225] 90. 3-(1-aminopropan-2-yl)-6-(4-morpholinophenyl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one;

[0226] 91. N-(2-(6-(4-morpholinophenyl)-4-oxo-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-3(4H)-yl)propyl)methanesulfonamide;

[0227] 92. N-(2-(6-(4-morpholinophenyl)-4-oxo-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-3(4H)-yl)propyl)acetamide;

[0228] 93. 3-(Piperidin-4-yl)-8-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one;

[0229] 94. 6-(4-chlorophenyl)-3-(1-(methylsulfonyl)piperidin-4-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one;

[0230] 95. 6-(4-chlorophenyl)-3-(1-(cyclopropylsulfonyl)piperidin-4-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; and

[0231] 96. 3-(1-Acetylpiperidin-4-yl)-6-(4-chlorophenyl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one.

[0232] The compounds of the present invention can be synthesized by methods known in the art or by the methods shown in Examples 1-96 below.

[0233] Pharmaceutical compositions, methods and uses

[0234] In specific embodiments, the pharmaceutical compositions and methods provided herein comprise a compound of Formula (I) or an enantiomer, diastereomer, racemate, solvate, hydrate or pharmaceutically acceptable salt thereof.

[0235] The subject can be a mammal, including a human, or a mammalian cell; for example, a mammal (eg, a human) having a disease, disorder, or condition associated with AhR activity as described above, or a mammalian cell isolated therefrom.

[0236] The compound can be administered orally or parenterally as an active ingredient or pharmaceutical composition. For example, parenteral administration can be carried out by any of intravenous injection, subcutaneous injection, intramuscular injection, intraperitoneal injection, endothelial administration, topical administration, intranasal administration, intrapulmonary administration, rectal administration, etc.

[0237] The effective amount may refer to a pharmaceutically and / or therapeutically effective amount, and may be specified according to factors such as the type of preparation (formulation), route of administration, age, weight, sex, and / or pathological condition of the patient.

[0238] Pharmaceutically acceptable salts of the compounds of formula (I) may include addition salts formed from inorganic acids, such as hydrochlorides, sulfates, phosphates, hydrobromides, hydroiodides, nitrates, pyrosulfates or metaphosphates; addition salts formed from organic acids, such as citrates, oxalates, benzoates, acetates, trifluoroacetates, propionates, succinates, fumarates, lactates, maleates, tartrates, valerates or sulfonates, or metal salts such as lithium salts, sodium salts, potassium salts, magnesium salts and calcium salts, but are not limited thereto.

[0239] Pharmaceutical composition according to the present invention can be formulated into suitable form together with conventional pharmaceutically acceptable carriers. "Pharmaceutically acceptable" refers to physiologically acceptable, and does not usually cause allergic reactions or similar reactions when applied to humans, such as gastrointestinal diseases and dizziness. In addition, pharmaceutical composition of the present invention can be used after being formulated into oral preparations, such as powders, granules, tablets, capsules, suspensions, emulsions, syrups and aerosols, and parenteral preparations carried out according to conventional methods, such as epidermal preparations, suppositories or sterile injections.

[0240] The examples of carriers, excipients and diluents that can be included in the composition can include lactose, glucose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gum arabic, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methylcellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoic acid methyl ester, hydroxybenzoic acid propyl ester, talcum powder, magnesium stearate and mineral oil, but are not limited thereto. When formulated into preparations, diluents or excipients can be used, such as commonly used fillers, stabilizers, bonding agents, disintegrants and surfactants. Solid preparations for oral administration include tablets, pills, powders, granules, capsules, etc., and these solid preparations can be prepared by mixing the compound of the present invention with at least one excipient, such as starch, microcrystalline cellulose, sucrose, lactose, low-substituted hydroxypropyl cellulose, hydroxypropyl methylcellulose, etc. In addition to simple excipients, lubricants such as magnesium stearate and talcum powder are also used. Liquid preparations for oral administration include suspensions, liquids for internal use, emulsions, syrups, etc. In addition to commonly used simple diluents, such as water and liquid paraffin, various excipients may also be contained, such as humectants, sweeteners, aromatics, preservatives, etc. Preparations for parenteral administration include sterile aqueous solutions, non-aqueous solutions, suspensions, emulsions, lyophilized preparations, and suppositories. The 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 the basis of suppositories, semi-synthetic fatty acid esters (witepsol), polyethylene glycol, Tween 61, cocoa butter, laurel oil, glycerol tetralin, etc. may be used. In order to prepare a preparation for parenteral administration, the compound of formula I or a pharmaceutically acceptable salt thereof can be mixed in water with sterilized and / or containing adjuvants such as preservatives, stabilizers, auxiliary agents such as wettable powders or emulsifying promoters, salts and / or buffers for controlling osmotic pressure, and other therapeutically useful substances to prepare a solution or suspension, and then manufactured in the form of an ampoule or vial unit for administration.

[0241] Pharmaceutical compositions including the compounds of Formula I disclosed herein as active ingredients can be administered to mammals such as mice, livestock and humans through various routes for modulating AhR activity, or preventing or treating diseases, disorders or conditions associated with AhR activity.

[0242] In some embodiments, the disease, disorder or condition is associated with AhR activity, and may be cancer, a cancerous condition, a tumor, a fibrotic condition, an immune-related disease, or other disease associated with AhR signaling.

[0243] In some embodiments, the disease involving dysregulated immune response associated with AhR signaling is selected from the group consisting of sepsis (SIRS), multiple organ failure (MODS, MOF), inflammatory kidney disease, chronic intestinal inflammation (IBD, Crohn's disease, UC), pancreatitis, peritonitis, inflammatory skin disease and inflammatory eye disease, autoimmune disease, such as rheumatoid disease, including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE) and multiple sclerosis (MS).

[0244] In some embodiments, the fibrotic disorder is selected from the group consisting of: fibrotic disorders of internal organs, such as the lungs, heart, kidneys, bone marrow, in particular the liver, as well as dermatological fibrosis and fibrotic eye diseases. In the context of the present invention, the term fibrotic disease includes in particular the following terms: liver fibrosis, cirrhosis, pulmonary fibrosis, endomyocardial fibrosis, nephropathy, glomerulonephritis, interstitial renal fibrosis, fibrotic lesions caused by diabetes, myelofibrosis and similar fibrotic diseases, scleroderma, morphea, keloids, hypertrophic scars (also after surgery), nevi, diabetic retinopathy, proliferative vitreoretinopathy and connective tissue diseases (e.g. sarcoidosis).

[0245] In some embodiments, cancers, cancerous conditions or tumors that are particularly suitable for treatment with the AHR antagonists of the present invention are liquid tumors 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, liver cancer, colon cancer, colorectal cancer, endometrial or uterine cancer, salivary gland cancer, kidney cancer or cancer of the kidney, 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.

[0246] In some embodiments, the pharmaceutical compositions of the present invention can be used together with one or more additional anti-cancer therapies. In some such embodiments, the additional anti-cancer therapies include surgery, radiotherapy, biological therapy, immunotherapy, chemotherapy, or any combination thereof.

[0247] In some embodiments, the pharmaceutical compositions of the present invention can be used together with an anti-cancer therapeutic agent. In some such embodiments, the anti-cancer therapeutic agent is a chemotherapeutic agent, a growth inhibitory agent, an anti-angiogenic agent, a cytotoxic agent, an anti-hormone agent, a prodrug or a cytokine.

[0248] Examples of other diseases associated with aberrant AhR signaling inflammation include vaccination with infections and cancer, viral infections, obesity and diet-induced obesity, excessive obesity, metabolic disorders, hepatic steatosis and uterine fibroids (leiomyomas or uterine myomas) in women, chronic kidney disease, acute and chronic renal insufficiency, diabetes, inflammatory or hypertensive kidney disease, cardiac insufficiency, angina, hypertension, pulmonary hypertension, ischemia, vascular disease, thromboembolic disease, atherosclerosis, sickle cell anemia, erectile dysfunction, benign prostatic hyperplasia, dysuria associated with benign prostatic hyperplasia, Huntington's disease, dementia, Alzheimer's disease, and Creutzfeldt-Jakob disease.

[0249] In other aspects, provided herein are pharmaceutical compositions comprising an AhR modulator, such as an AhR antagonist of formula (I) or an enantiomer, diastereomer, racemate, solvate, hydrate or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0250] In some aspects, pharmaceutical compositions comprising an AhR modulator, such as an AhR antagonist of Formula (I) or an enantiomer, diastereomer, racemate, solvate, hydrate or pharmaceutically acceptable salt thereof, are provided for modulating constitutive AhR activity in a subject in need thereof.

[0251] In some aspects, pharmaceutical compositions comprising AhR modulators, such as AhR antagonists of Formula (I) or enantiomers, diastereomers, racemates, solvates, hydrates or pharmaceutically acceptable salts thereof, are provided for treating cancer or cancerous conditions by modulating AhR activity.

[0252] In some aspects, pharmaceutical compositions comprising AhR modulators, such as AhR antagonists of Formula (I) or enantiomers, diastereomers, racemates, solvates, hydrates or pharmaceutically acceptable salts thereof, are provided for inhibiting proliferation, tissue invasion, metastasis and angiogenesis of cancer cells in a subject suffering from cancer, a cancerous condition or a tumor.

[0253] In some embodiments, the pharmaceutical compositions of the present invention can be used to inhibit proliferation, tissue invasion, metastasis, and angiogenesis of cancer cells in a subject suffering from cancer, a cancerous condition, or a tumor.

[0254] The pharmaceutical formulations described herein can be administered to a subject by a variety of routes of administration, including, but not limited to, oral, parenteral (e.g., intravenous, subcutaneous, intramuscular, rectal, intrauterine, or intracerebrovascular), intranasal, buccal, topical, or transdermal routes of administration.

[0255] In some embodiments, the compound of formula (I), or an enantiomer, diastereomer, racemate, solvate, hydrate or pharmaceutically acceptable salt thereof is administered orally.

[0256] Another aspect of the present invention relates to a method for stimulating the immune system in a patient in need, for example, in a patient suffering from cancer or infection (e.g., viral, bacterial or parasitic infection). The method includes administering to the patient one or a combination of a therapeutically effective amount of a compound as described herein. In some embodiments, the patient increases the count of white blood cells, T and / or B lymphocytes, macrophages, dendritic cells, neutrophils, natural killer (NK) cells and / or platelets after the administration step. In some embodiments, the compound reduces the IL-21 level in the patient. The patient may suffer from cancer, or be immunocompromised.

[0257] "Treat," "treating," or "treatment" refers to a method of alleviating or eliminating a biological disease and / or at least one of its associated symptoms. As used herein, "alleviating" a disease, disorder, or condition means reducing the severity and / or frequency of the symptoms of the disease, disorder, or condition. In addition, references to "treatment" herein include references to curative, palliative, and preventive treatments. Treatment of cancer includes inhibiting cancer growth (including causing partial or complete cancer regression), inhibiting cancer progression or metastasis, preventing cancer recurrence or residual disease, and / or prolonging patient survival. A "therapeutically effective amount" is the amount of a drug that can achieve the desired curative, palliative, or preventive effect for the condition being treated.

[0258] In some embodiments, the effective dosage range of the compound is determined by measuring the concentration of the compound in the patient's blood under a specified dosing regimen to establish a concentration-time curve, a correlation between the concentration-time curve obtained during the trial and the effect of cancer inhibition or eradication, and balancing the achievable therapeutic effect with possible toxicity to the patient, further considering the patient's health status or physical durability. The frequency of dosing of the compound can be determined similarly. Dosing can be continued until the patient is free of cancer.

[0259] In some embodiments, the effective amount for tumor treatment can be measured by its ability to stabilize the patient's disease progression and / or improve symptoms, and preferably reverse disease progression, for example, by reducing tumor size. In some embodiments, a maintenance dose can be provided after the patient is free of cancer to ensure its complete elimination or eradication, or to prevent residual disease. The duration of maintenance administration can be determined based on clinical trial data.

[0260] In some embodiments, the compound can be administered in combination with one or more other cancer therapeutics that also target AhR, or target molecules other than AhR. The compound can be formulated separately from other cancer therapeutics or formulated together with other cancer therapeutics. The compound can be administered on the same schedule as other cancer therapeutics or on a different schedule. The ratio of the compound relative to other cancer therapeutics can be determined by clinical trials. Combining these compounds with other cancer therapeutics can further enhance the efficacy of each other. For example, the compounds of the present invention can be administered with immune checkpoint inhibitors, such as inhibitors of PD-1, PD-L1 or PD-L2 (e.g., pembrolizumab, nivolumab or atezolizumab), or with CAR-T therapeutics (e.g., axicabtageneciloleucel) to achieve additive or synergistic anti-cancer effects.

[0261] Dosage regimens may be adjusted to provide the optimum desired response. Dosage unit form as used herein refers to physically discrete units suited as unitary dosages for the patients / subjects to be treated; each unit contains a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier.

[0262] It should be noted that dosage values ​​may vary with the type and severity of the disease to be alleviated, and may include single or multiple doses. It should be further understood that for any particular subject, a specific dosage regimen should be adjusted over time according to individual needs and the professional judgment of the personnel administering or supervising the administration of the composition, and the dosage ranges specified herein are exemplary only and are not intended to limit the scope or practice of the embodied composition. In addition, the dosage regimen using the composition of the present invention can be based on a variety of factors, including the type of disease, the patient's age, weight, sex, medical condition, severity of the disease, route of administration, and the specific antibody used. Therefore, the dosage regimen can vary greatly, but can be routinely determined using standard methods. For example, the dosage can be adjusted according to pharmacokinetic or pharmacodynamic parameters, which can include clinical effects, such as toxic effects and / or laboratory values.

[0263] It is expected that the suitable dosage of the compounds of the present invention can be within the range of 0.001-200mg / kg per day, and preferably about 0.01mg / kg to about 20mg / kg body weight per day, for example, about 0.5-50mg / kg, for example, about 1-20mg / kg. The compound can be administered, for example, with a dosage of at least 0.25mg / kg, for example, at least 0.5mg / kg, for example, at least 1mg / kg, for example, at least 1.5mg / kg, for example, at least 2mg / kg, for example, at least 3mg / kg, for example, at least 4mg / kg, for example, at least 5mg / kg; For example, up to 50mg / kg, such as up to 30mg / kg, for example, up to 20mg / kg, such as up to 15mg / kg. 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, and as long as the responsible doctor deems it appropriate, they can optionally increase or decrease the dosage as needed.

[0264] General Synthesis Methods

[0265] The compounds of the present invention can be prepared according to one or more of the schemes discussed below.

[0266] These methods can be used directly, or with obvious modifications by a trained chemist, to prepare the key intermediates and certain compounds of the present invention.

[0267] The selection of an appropriate synthetic sequence is readily accomplished according to the specific structure of the invention, but is within the skill of individuals engaged in organic synthesis, such as methods summarized in available chemical databases, such as CAS Scifinder and Elesevier Reaxys. Based on these general methods, it is possible to make the compounds of the invention directly and can be practiced within the scope of ordinary expertise. Some general synthetic methods for preparing the compounds of the invention are illustrated in the following Schemes 1-3 (General Procedures A to C).

[0268] A general method for preparing compounds of the invention is illustrated in General Scheme 1.

[0269]

[0270] Scheme 1. General procedure A.

[0271] a) N-iodosuccinimide, DMF; b) NH 2 -R 1 , EDC, HOBt, TEA, DMF; c) (EtO) 3 CH, acetic acid; d) Pd 2 (dba) 3 .CHCl3 , K 2 CO 3 , phosphating agent (Sphos), 1,4-di Alkane / H 2 O(4 / 1);e)Pd(dppf)Cl 2 .CH 2 Cl 2 , K 2 CO 3 , 1,4-di Alkane / H 2 O(4 / 1), heating, microwave.

[0272] Another general method for preparing compounds of the invention is illustrated in General Scheme 2.

[0273]

[0274] Scheme 2. General procedure B.

[0275] a) NH 2 -R 2 -OTBDPS, EDC, HOBt, TEA, DMF; b) Pd(dppf)Cl 2 .CH 2 Cl 2 , K 2 CO 3 , 1,4-di Alkane / H 2 O (4 / 1), heating, microwave; c) N-bromosuccinimide, DMF; d) (EtO) 3 CH, acetic acid; e) Pd 2 (dba) 3 .CHCl 3 , K 2 CO 3 , phosphating agent (Sphos), 1,4-di Alkane / H 2 O(4 / 1); f)TBAF, THF.

[0276] Another general method for preparing compounds of the invention is illustrated in General Scheme 3.

[0277]

[0278] Scheme 3. General procedure C.

[0279] a) NH 2 -R 2 -OTBDPS, EDC, HOBt, TEA, DMF; b) Pd(dppf)Cl 2 .CH2 Cl 2 , K 2 CO 3 , 1,4-di Alkane / H 2 O (4 / 1), heating, microwave; c) N-bromosuccinimide, DMF; d) (EtO) 3 CH, acetic acid; e) Pd 2 (dba) 3 .CHCl 3 , K 2 CO 3 , phosphating agent (Sphos), 1,4-di Alkane / H 2 O(4 / 1); f)NaBH 4 ; THF; g) TBAF, THF.

[0280] Another general method for preparing compounds of the invention is illustrated in General Scheme 4.

[0281]

[0282] Scheme 4. General procedure D.

[0283] a) N-iodosuccinimide, DMF; b) NH 2 -R 1 , EDC, HOBt, TEA, DMF; c) (EtO) 3 CH, acetic acid; d) Pd(dppf)Cl 2 .CH 2 Cl 2 , K 2 CO 3 , 1,4-di Alkane / H 2 O, heating; e) Pd(dppf)Cl 2 .CH 2 Cl 2 , K 2 CO 3 , 1,4-di Alkane / H 2 O(4 / 1), heating, microwave.

[0284] Another general method for preparing compounds of the invention is illustrated in General Scheme 5.

[0285]

[0286] Scheme 5. General Procedure E.

[0287] a) K 2 CO3 , MeI, DMF; b) PdCl 2 (dtbpf), K 2 CO 3 , 1,4-di Alkane / H 2 O(4 / 1), heating, microwave or Pd(dppf)Cl 2 .CH 2 Cl 2 , K 2 CO 3 , 1,4-di Alkane / H2O (4 / 1), heating, microwave; c) NH 2 -R 1 , EDC, HOBt, TEA, DMF; d) (EtO) 3 CH, acetic acid.

[0288] Another general method for preparing compounds of the invention is illustrated in General Scheme 6.

[0289]

[0290] Scheme 6. General Procedure F.

[0291] a) NH 2 -R 1 , EDC, HOBt, TEA, DMF; b) (EtO) 3 CH, acetic acid; c) Pd(dppf)Cl 2 .CH 2 Cl 2 , K 2 CO 3 , 1,4-di Alkane / H 2 O(4 / 1), heating, microwave.

[0292] Another general method for preparing compounds of the invention is illustrated in General Scheme 7.

[0293]

[0294] Scheme 7. General Procedure G.

[0295] a) N-iodosuccinimide, DMF; b) NH 2 -R 1 -NH-Boc, EDC, HOBt, TEA, DMF; c) (EtO) 3 CH, acetic acid; d) Pd(dppf)Cl 2 .CH 2 Cl 2 , K2 CO 3 , 1,4-di Alkane / H 2 O(4 / 1), heating, microwave; e) Pd(dppf)Cl 2 .CH 2 Cl 2 , K 2 CO 3 , 1,4-di Alkane / H 2 O (4 / 1), heating, microwave; f) 4M HCl in 1,4-dihydrochloric acid In alkane; g) R 2 -Cl, TEA, DCM.

[0296] Implementation

[0297] Example

[0298] Embodiments of the present invention are described in the following examples, which are intended to illustrate but not to limit the scope of the invention. Common abbreviations well known to those of ordinary skill in the synthetic arts are used throughout.

[0299] All chemical reagents are commercially available. Unless otherwise indicated, flash column chromatography refers to silica gel chromatography, performed on a Teledyne Combiflash-RF200 system. 1H NMR spectra (δ, ppm) were recorded on 400MHz or 600MHz instruments. Mass spectral data for positive ionization methods are provided. Preparative HPLC was performed on Agilent Technology G1361A and Gilson Preparative HPLC systems.

[0300] Examples 1 and 2.

[0301] 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

[0302] Preparation scheme of the compound of Example 1:

[0303]

[0304] Intermediate 1.3-Amino-6-chloro-2-iodoisonicotinic acid

[0305]

[0306] 5-Amino-2-chloroisonicotinic acid (1) (2 g, 14.5 mmol, 1 eq.) and N-iodosuccinimide (4.9 g, 21.7 mmol, 1.5 eq.) 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×3), washed with brine (20 mL×3), and washed with Na 2 SO 4 Dry and filter glass. The filtrate was evaporated in vacuo to give 6.89 g (80% yield) of 3-amino-6-chloro-2-iodoisonicotinic acid (Intermediate 1), which was used without further purification.

[0307] 1H NMR (400MHz, CDCl 3 )δ[ppm]=7.69(s,1H); MS(ESI,m / z):298.90[M+H] +

[0308] Intermediate 2.3-Amino-6-chloro-N-(3-hydroxycyclohexyl)-2-iodoisonicotinamide

[0309]

[0310] A mixture of 3-amino-6-chloro-2-iodoisonicotinic acid (intermediate 1) (1.24 g, 4.15 mmol, 1 eq.), EDC (0.96 g, 4.99 mmol, 1.2 eq.), HOBT (0.76 g, 4.99 mmol, 1.2 eq.) and TEA (0.87 mL, 6.23 mmol, 1.5 eq.) was dissolved in DMF (10 mL, 0.4 M) and stirred for 5 minutes. Then, 3-aminocyclohexanol (0.53 g, 4.57 mmol, 1.1 eq.) was added to the reaction mixture and stirred at 60 ° C for 12 h. The reaction mixture was diluted with water (50 mL), extracted with EtOAc (20 mL×3), washed with brine (20 mL×3), and purified by Na 2 SO 4 Dry and filter through a glass filter. The filtrate was evaporated in vacuo and purified by MPLC (silica gel, 0-50% EtOAc / hexanes) to give 0.75 g (46% yield) of 3-amino-6-chloro-N-(3-hydroxycyclohexyl)-2-iodoisonicotinamide (Intermediate 2).

[0311] 1H NMR (400MHz, MeOD) δ [ppm] = 7.40 (s, 1H), 3.91 (tt, J = 11.5, 3.7Hz, 1H), 3.66 (tt, J = 10.6, 4.1Hz, 1H), 2.19 (d, J = 11.7Hz, 1H), 1.95 (d, J = 12.8Hz, 1H),1.87-1.81(m,2H),1.69-1.61(m,1H),1.55-1.50(m,1H),1.40(ddd ,J=12.9,6.3,3.2Hz,1H).1.25-1.16(m,1H); MS(ESI,m / z):395.90[M+H] +

[0312] Intermediate 3. 6-Chloro-3-(3-hydroxycyclohexyl)-8-iodopyrido[3,4-d]pyrimidin-4(3H)-one

[0313]

[0314] 3-Amino-6-chloro-N-(3-hydroxycyclohexyl)-2-iodoisonicotinamide (Intermediate 2) (0.75 g, 1.90 mmol, 1 eq.) was dissolved in (EtO) 3 CH (2.9 mL, 17.1 mmol, 9 equiv) and CH 3 CO 2 The reaction mixture was stirred and heated at 150 °C in a Biotage microwave initiator for 1 hour. The reaction mixture was diluted with water (20 mL), extracted with EtOAc (20 mL×3), washed with brine (20 mL×3), and purified by Na 2 SO 4 The filtrate was evaporated in vacuo and purified by MPLC (silica gel, 0-50% EtOAc / hexanes) to give 0.28 g (36% yield) of 6-chloro-3-(3-hydroxycyclohexyl)-8-iodopyrido[3,4-d]pyrimidin-4(3H)-one (Intermediate 3).

[0315] 1H NMR (400MHz, CDCl 3)δ[ppm]=8.26(s,1H),8.03(s,1H),4.77(tt,J=12.1,3.6Hz,1H),3.90-3.80(m,1H),2.29(d,J=11.2Hz,1H),2.11(d,J=11.7Hz,1H),2.0 4-1.92(m,2H),1.70-1.65(m,1H),1.65-1.58(m,1H),1.53-1.49(m,1H),1.33(ddd,J=23.8,12.5,3.9Hz,1H);MS(ESI,m / z):405.83[M+H] +

[0316] Intermediate 4 and Example 2.

[0317] 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

[0318]

[0319] 6-chloro-3-(3-hydroxycyclohexyl)-8-iodopyrido[3,4-d]pyrimidin-4(3H)-one (Intermediate 3) (68 mg, 0.168 mmol, 1 eq), (1-methyl-1H-pyrazol-4-yl)boronic acid (23.2 mg, 0.184 mmol, 1.1 eq), K 2 CO 3 (93 mg, 0.671 mmol, 4 eq), phosphating agent (Sphos) (6.9 mg, 0.017 mmol, 0.1 eq) and Pd 2 (dba) 3 ·CHCl 3 (8.68 mg, 8.38 μmol, 0.05 eq.) dissolved in 1,4-dihydrochloric acid The mixture was added with 1% oxane / water (4 mL / 1 mL, 0.3 M) and stirred at 50° C. for 12 hours. The reaction mixture was concentrated under reduced pressure and purified directly by MPLC (silica gel, 0-10% MeOH / DCM) to give 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 of 3-(3-hydroxycyclohexyl)-6,8-bis(1-methyl-1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (Example 2), with a yield of 19%.

[0320] Intermediate 4

[0321] 1H NMR (400MHz, CDCl 3 )δ[ppm]=8.53(s,1H),8.50(s,1H),8.19(s,1H),7.88(s,1H),4.82(t,J=12.3H z,1H),3.99(s,3H),3.87(t,J=10.5Hz,1H),2.31(d,J=11.0Hz,1H),2.12(d,J= 11.6Hz,1H),2.05-1.94(m,2H),1.79(s,1H),1.74-1.66(m,1H),1.51(dd,J=18 .2,8.3Hz,1H),1.33(ddd,J=24.3,12.7,3.4Hz,1H);MS(ESI,m / z):360.00[M+H] +

[0322] Example 2

[0323] 1H-NMR (400MHz, CDCl 3 ): 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=11.3Hz,1H),2.13(d,J=11.5Hz,1H),2.01(d,J=10.2Hz,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] +

[0324] Example 1.

[0325] 3-(3-Hydroxycyclohexyl)-8-(1-methyl-1H-pyrazol-4-yl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one

[0326]

[0327] 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 eq), (4-(trifluoromethyl)phenyl)boronic acid (32 mg, 0.17 mmol, 2 eq), K 2 CO 3 (35 mg, 0.25 mmol, 3 equiv) and Pd(dppf)Cl 2 ·CH 2 Cl 2 (6.8 mg, 8.34 μmol, 0.1 eq.) dissolved in 1,4-dihydrochloric acid The reaction mixture was stirred and heated at 130°C in a Biotage microwave initiator for 30 minutes. The reaction mixture was concentrated under reduced pressure and directly analyzed by MPLC (Silica gel Chromatorex NH-DM1020 (NH-SiO 2 ), 0-70% EtOAc / hexanes) to afford 16 mg (40% yield) 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).

[0328] 1H-NMR (400MHz, CDCl 3 ): δ[ppm]=8.62(s,1H),8.59(s,1H),8.38(s,1H),8.33(d,J=8.3Hz,2H),8.24( s,1H),7.78(d,J=8.3Hz,2H),4.92-4.86(m,1H),4.03(s,3H),3.93-3.86(m,1H ),2.35(d,J=11.6Hz,1H),2.14(d,J=11.2Hz,1H),2.03(d,J=10.6Hz,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] +

[0329] Example 3.

[0330] 3-(1-Hydroxypropan-2-yl)-6,8-bis(1-methyl-1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one

[0331]

[0332] The title compound was obtained as described in Example 2 using 2-aminopropan-1-ol (Scheme 1. General Procedure A.).

[0333] 1H-NMR (400MHz, CD 3 OD): 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,1H),3.90(d ,J=6.9Hz,6H),3.87(d,J=6.9Hz,1H),3.77(dd,J=11.8,4.3Hz,1H),1.47(d,J=7.1Hz,3H); MS(ESI,m / z):366.06[M+H] +

[0334] Example 4.

[0335] 3-(1-Hydroxypropan-2-yl)-6-(1-methyl-1H-pyrazol-4-yl)-8-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one

[0336]

[0337] The title compound was obtained as described in Example 1 using 2-aminopropan-1-ol (Scheme 1. General Procedure A.).

[0338] 1H-NMR (400MHz, CDCl 3 ): δ [ppm] = 8.26-8.16 (m, 2H), 8.04 (dd, J = 20.2, 13.9Hz, 2H), 7.77 (d, J = 8.2Hz, 1H), 7.53 (s, 1H), 7.42 (s, 1H) ),5.10-4.99(m,1H),3.96(d,J=7.4Hz,2H),3.91(s,3H),1.59(d,J=7.2Hz,3H); MS(ESI,m / z):430.00[M+H] +

[0339] Example 5.

[0340] 8-(4-Chlorophenyl)-3-(1-hydroxypropan-2-yl)-6-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one

[0341]

[0342] The title compound was obtained as described in Example 1 using 2-aminopropan-1-ol, (4-chlorophenyl)boronic acid and pyridin-3-ylboronic acid (Scheme 1. General Procedure A.).

[0343] 1H-NMR (400MHz, CDCl 3 ): δ [ppm] = 9.41 (s, 1H), 8.67 (d, J = 3.7Hz, 1H), 8.56 (s, 1H), 8.50 (d, J = 8.1Hz, 1H), 8.31 (s, 1H), 8.19 (d, J = 8.6Hz, 2H), 7.51 (d, J = 8. 6Hz,2H),7.47-7.41(m,2H),5.10(dd,J=11.9,4.9Hz,1H),4.00(d,J=4.5Hz,1H),1.60(d,J=7.3Hz,3H); MS(ESI,m / z):393.02[M+H] +

[0344] Example 6.

[0345] 3-(1-Hydroxypropan-2-yl)-6,8-bis(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one

[0346]

[0347] The title compound was obtained as described in Example 2 using 2-aminopropan-1-ol and (4-(trifluoromethyl)phenyl)boronic acid (Scheme 1. General Procedure A.).

[0348] 1H-NMR (400MHz, CD 3 OD): δ [ppm] = 8.46 (s, 1H), 8.31 (s, 1H), 8.27 (dd, J = 7.8, 5.1Hz, 4H), 7.68 (d, J = 8.3Hz, 4H), 4.94-4.83 (m, 1H), 3.85 (dd, J=11.9, 6.8Hz, 1H), 3.75 (dd, J=11.9, 4.3Hz, 1H), 1.44 (d, J=7.1Hz, 3H); MS (ESI, m / z): 494.04[M+H] +

[0349] Example 7.

[0350] 2-(6-Chloro-8-(4-chlorophenyl)-4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)propyl acetate

[0351]

[0352] The title compound was obtained as described for intermediate 4 of Example 1 using 2-aminopropyl acetate and (4-chlorophenyl)boronic acid (Scheme 1. General Procedure A.).

[0353] 1H-NMR (400MHz, CDCl 3 ): δ[ppm]=8.15(s,1H),8.09(d,J=8.2Hz,2H),7.48(d,J=8.5Hz,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=7.2Hz,3H); MS(ESI,m / z):391.95[M+H] +

[0354] Example 8.

[0355] 3-((1r,4r)-4-hydroxycyclohexyl)-8-(1-methyl-1H-pyrazol-4-yl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one

[0356]

[0357] The title compound was obtained as described in Example 1 using (1r,4r)-4-aminocyclohexan-1-ol (Scheme 1. General Procedure A.).

[0358] 1H-NMR (400MHz, CDCl 3 ): δ[ppm]=8.60(s,1H),8.59(s,1H),8.37(s,1H),8.32(d,J=8.2Hz,1H),8.20(s,1H),7.77(d,J=8.3Hz,1H),4.88-4.78(m,1H),4.0 3(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] +

[0359] Example 9.

[0360] 3-((1r,4r)-4-hydroxycyclohexyl)-6,8-bis(1-methyl-1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one

[0361]

[0362] The title compound was obtained as described in Example 2 using (1r,4r)-4-aminocyclohexan-1-ol (Scheme 1. General Procedure A.).

[0363] 1H-NMR (400MHz, CDCl 3 ): 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] +

[0364] Example 10.

[0365] 6-(4-Chlorophenyl)-3-((1r,4r)-4-hydroxycyclohexyl)-8-(1-methyl-1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one

[0366]

[0367] The title compound was obtained as described in Example 1 using (1r,4r)-4-aminocyclohexan-1-ol and (4-chlorophenyl)boronic acid (Scheme 1. General Procedure A.).

[0368] 1H-NMR (400MHz, CDCl 3 ): δ[ppm]=8.59(s,1H),8.58(s,1H),8.31(s,1H),8.18(s,1H),8.16(d,J=8.8Hz,2H),7.49(d,J=8.6Hz,2H),4.88-4.78(m,1H),4.0 2(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] +

[0369] Example 11.

[0370] 3-(2-Hydroxypropyl)-6,8-bis(1-methyl-1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one

[0371]

[0372] The title compound was obtained as described in Example 2 using 1-aminopropan-2-ol (Scheme 1. General Procedure A.).

[0373] 1H-NMR (400MHz, CD 3 OD): 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=13.6,3.0Hz,1H),4 .19-4.11(m,1H),4.00(s,3H),3.99(s,3H),3.74(dd,J=13.6,8.8Hz,1H),1.30(d,J=6.3Hz,3H); MS(ESI,m / z):366.01[M+H] +

[0374] Example 12.

[0375] 3-(2-Hydroxypropyl)-8-(1-methyl-1H-pyrazol-4-yl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one

[0376]

[0377] The title compound was obtained as described in Example 1 using 1-aminopropan-2-ol (Scheme 1. General Procedure A.).

[0378] 1H-NMR (400MHz, CDCl 3 ): δ [ppm] = 8.50 (s, 1H), 8.49 (s, 1H), 8.32 (s, 1H), 8.24 (d, J = 8.2Hz, 2H), 8.18 (s, 1H), 7.72 (d, J = 8.3Hz, 2H), 4.38 (dd, J = 13.6, 2.5Hz, 1H),4.30(br,1H),3.99(s,3H),3.70(dd,J=13.6,8.5Hz,1H),2.78(d,J=4.4Hz,1H),1.38(d,J=6.3Hz,3H); MS(ESI,m / z):430.00[M+H] +

[0379] Example 13.

[0380] 6-(4-Chlorophenyl)-3-(2-hydroxypropyl)-8-(1-methyl-1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one

[0381]

[0382] The title compound was obtained as described in Example 1 using 1-aminopropan-2-ol and (4-chlorophenyl)boronic acid (Scheme 1. General Procedure A.).

[0383] 1H-NMR (400MHz, CDCl 3 ): δ [ppm] = 8.55 (s, 1H), 8.53 (s, 1H), 8.28 (s, 1H), 8.17 (s, 1H), 8.12 (d, J = 8.6Hz, 2H), 7.47 (d, J = 8.5Hz, 2H), 4.36 (dd, J = 13.7, 2.6Hz, 1H),4.28(br,1H),4.00(s,3H),3.73(dd,J=13.6,8.3Hz,1H),2.43(d,J=4.5Hz,1H),1.37(d,J=6.3Hz,3H); MS(ESI,m / z):396.00[M+H] +

[0384] Example 14.

[0385] 3-(2-Hydroxypropyl)-8-(1-methyl-1H-pyrazol-4-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one

[0386]

[0387] The title compound was obtained as described in Example 1 using 1-aminopropan-2-ol and (6-(trifluoromethyl)pyridin-3-yl)boronic acid (Scheme 1. General Procedure A.).

[0388] 1H-NMR (400MHz, CDCl 3 ): 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=8.2Hz,1H),4.39(dd,J=13.5,2.5Hz ,1H),4.30(br,1H),4.01(s,3H),3.73(dd,J=13.6,8.4Hz,1H),2.41(d,J=4.2Hz,1H),1.39(d,J=6.3Hz,3H); MS(ESI,m / z):431.00[M+H] +

[0389] Example 15.

[0390] 3-((1S,2R)-2-Hydroxycyclohexyl)-8-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one

[0391]

[0392] The title compound was obtained as described in Example 1 using (1R,2S)-2-aminocyclohexanol, pyridin-3-ylboronic acid and (4-(trifluoromethyl)phenyl)boronic acid (Scheme 1. General Procedure A.).

[0393] 1H-NMR (400MHz, MeOD): δ [ppm] = 9.42 (s, 1H), 8.73 (d, J = 8.0Hz, 1H), 8.64 (d, J = 4.8Hz, 1H ),8.62(s,1H),8.51(s,1H),8.41(d,J=8.2Hz,2H),7.83(d,J=8.3Hz,2H),7.61(dd,J=7.9 ,4.9Hz,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=9.3Hz,2H),1.71(s,1H),1.59(dt,J=17.5,8.6Hz,2H); MS(ESI,m / z):467.15[M+H]+

[0394] Example 16.

[0395] 3-((1R,2S)-2-Hydroxycyclohexyl)-8-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one

[0396]

[0397] The title compound was obtained as described in Example 1 using (1S,2R)-2-aminocyclohexanol hydrochloride, pyridin-3-ylboronic acid and (4-(trifluoromethyl)phenyl)boronic acid (Scheme 1. General Procedure A.).

[0398] 1H-NMR (400MHz, MeOD): δ [ppm] = 9.41 (s, 1H), 8.75-8.66 (m, 1H), 8.63 (d, J = 4.7Hz, 1H), 8.58 (d, J = 6.5H z,1H),8.49(d,J=1.9Hz,1H),8.38(dd,J=8.1,3.9Hz,2H),7.81(d,J=6.8Hz,2H),7.63(d,J=8.9Hz,1H) ,7.61-7.57(m,1H),4.86(dd,J=13.3,2.6Hz,1H),4.08(s,1H),2.34(dd,J=22.2,12.3Hz,1H),2.04-1. 93(m,2H),1.77(t,J=9.3Hz,2H),1.71(d,J=10.1Hz,1H),1.64-1.51(m,2H); MS(ESI,m / z):467.13[M+H] +

[0399] Example 17.

[0400] 3-((1S,2R)-2-Hydroxycyclohexyl)-8-(1-methyl-1H-pyrazol-4-yl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one

[0401]

[0402] The title compound was obtained as described in Example 1 using (1R,2S)-2-aminocyclohexanol, (1-methyl-1H-pyrazol-4-yl)boronic acid and (4-(trifluoromethyl)phenyl)boronic acid (Scheme 1. General Procedure A.).

[0403] 1H-NMR (400MHz, CDCl3): δ[ppm]=8.48(s,1H),8.37(s,1H),8.33(s,1H),8.27(s ,1H),8.14(d,J=8.1Hz,2H),7.67(d,J=8.3Hz,2H),4.95(dd,J=10.2,2.4Hz,1H) ,4.30(s,1H),3.99(s,3H),3.23(s,1H),2.39-2.27(m,1H),2.03(d,J=12.2Hz,2 H),1.89-1.74(m,2H),1.68(dd,J=24.7,13.2Hz,3H); MS(ESI,m / z):470.18[M+H] +

[0404] Example 18.

[0405] 3-((1R,2S)-2-Hydroxycyclohexyl)-8-(1-methyl-1H-pyrazol-4-yl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one

[0406]

[0407] The title compound was obtained as described in Example 1 using (1S,2R)-2-aminocyclohexanol hydrochloride, (1-methyl-1H-pyrazol-4-yl)boronic acid and (4-(trifluoromethyl)phenyl)boronic acid (Scheme 1. General Procedure A.).

[0408] 1H-NMR (400MHz, CDCl3): δ [ppm] = 8.50 (s, 1H), 8.37 (d, J = 9.4Hz, 2H), 8.28 (s ,1H),8.17(d,J=8.2Hz,2H),7.69(d,J=8.2Hz,2H),4.96(d,J=13.3Hz,1H),4 .29(s,1H),3.99(s,3H),3.06(s,1H),2.34(dd,J=22.1,12.5Hz,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] +

[0409] Example 19.

[0410] 6-(4-Chlorophenyl)-3-((1R,2S)-2-hydroxycyclohexyl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one

[0411]

[0412] The title compound was obtained as described in Example 1 using (1S,2R)-2-aminocyclohexanol hydrochloride, pyridin-3-ylboronic acid and (4-chlorophenyl)boronic acid (Scheme 1. General Procedure A.).

[0413] 1H-NMR (400MHz, CDCl3): δ [ppm] = 9.34 (d, J = 1.6Hz, 1H), 8.60 (dd, J = 4.9, 1.5Hz, 1H), 8.48-8.43 (m, 1H), 8.43(s,1H),8.40(s,1H),8.07(d,J=8.6Hz,2H),7.45(d,J=8.6Hz,2H),7.38(dd,J=7.7,4.9Hz,1H),4.9 3(d,J=12.8Hz,1H),4.19(s,1H),3.09(s,1H),2.32(ddd,J=25.3,12.6,3.5Hz,1H),2.06-1.96(m,2H),1 .81(dd,J=25.2,12.1Hz,2H),1.71(d,J=11.0Hz,2H),1.63(d,J=17.4Hz,1H); MS(ESI,m / z):433.14[M+H] +

[0414] Example 20.

[0415] 6-(4-Chlorophenyl)-3-((1S,2R)-2-hydroxycyclohexyl)-8-(1-methyl-1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one

[0416]

[0417] The title compound was obtained as described in Example 1 using (1R,2S)-2-aminocyclohexanol, (1-methyl-1H-pyrazol-4-yl)boronic acid and (4-chlorophenyl)boronic acid (Scheme 1. General Procedure A.).

[0418] 1H-NMR (400MHz, CDCl3): δ [ppm] = 8.48 (s, 1H), 8.37 (d, J = 9.2Hz, 2H), 8.21 (s, 1H) ,8.03(d,J=8.6Hz,2H),7.42(d,J=8.6Hz,2H),4.94(d,J=13.0Hz,1H),4.27(s,1H) ,2.85(d,J=4.2Hz,1H),2.33(dt,J=21.6,10.7Hz,1H),2.06-1.94(m,2H),1.89-1 .75(m,2H),1.75-1.66(m,2H),1.63(d,J=16.2Hz,1H); MS(ESI,m / z):436.15[M+H] +

[0419] Example 21.

[0420] 6-(4-Chlorophenyl)-3-((1S,2R)-2-hydroxycyclohexyl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one

[0421]

[0422] The title compound was obtained as described in Example 1 using (1R,2S)-2-aminocyclohexanol, pyridin-3-ylboronic acid and (4-chlorophenyl)boronic acid (Scheme 1. General Procedure A.).

[0423] 1H-NMR (400MHz, CDCl3): δ [ppm] = 9.33 (d, J = 1.8Hz, 1H), 8.59 (dd, J = 4.8, 1.6Hz, 1H), 8.4 7-8.43(m,1H),8.42(s,1H),8.38(s,1H),8.05(d,J=8.6Hz,2H),7.44(d,J=8.6Hz,2H),4 .93(d,J=12.7Hz,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=13.8Hz,1H); MS(ESI,m / z):433.17[M+H] +

[0424] Example 22.

[0425] 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

[0426]

[0427] The title compound was obtained as described in Example 1 using 3-amino-1,1,1-trifluoropropan-2-ol, (1-methyl-1H-pyrazol-4-yl)boronic acid and (4-(trifluoromethyl)phenyl)boronic acid (Scheme 1. General Procedure A.).

[0428] 1H-NMR (400MHz, 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 = 8.3Hz, 2H), 5.44 (s,1H),4.71(dd,J=13.7,2.3Hz,1H),4.67-4.56(m,1H),3.95(s,3H),3.83(dd,J=13.7,9.5Hz,1H); MS(ESI,m / z):484.14[M+H] +

[0429] Example 23.

[0430] 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

[0431]

[0432] The title compound was obtained as described in Example 1 using 3-amino-1,1,1-trifluoropropan-2-ol, (1-methyl-1H-pyrazol-4-yl)boronic acid and (4-chlorophenyl)boronic acid (Scheme 1. General Procedure A.).

[0433] 1H-NMR (400MHz, CDCl3): δ [ppm] = 8.31 (s, 1H), 8.17 (s, 1H), 8.13 (s, 1H), 8.04 (s, 1H), 7.91 (d, J = 8.5Hz, 2H), 7.37 (d, J = 8.4Hz, 2H ),5.63(s,1H),4.68(d,J=13.6Hz,1H),4.66-4.56(m,1H),3.92(s,2H),3.79(dd,J=13.5,9.4Hz,1H); MS(ESI,m / z):450.10[M+H] +

[0434] Example 24.

[0435] 6-(4-Chlorophenyl)-8-(pyridin-3-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)pyrido[3,4-d]pyrimidin-4(3H)-one

[0436]

[0437] The title compound was obtained as described in Example 1 using 3-amino-1,1,1-trifluoropropan-2-ol, pyridin-3-ylboronic acid and (4-chlorophenyl)boronic acid (Scheme 1. General Procedure A.).

[0438] 1H-NMR (400MHz, CDCl3): δ[ppm]=δ9.21(d,J=1.5Hz,1H),8.42(dd,J=4.9,1.4Hz,1H),8.40-8.35(m,1H),8.18(d,J=8.1Hz,2H),7.87(d,J=8.6Hz,2 H),7.38(d,J=8.6Hz,2H),7.36-7.32(m,1H),4.76(d,J=13.5Hz,1H),4.7 0-4.55(m,1H),3.75(dd,J=13.5,10.1Hz,1H); MS(ESI,m / z):447.09[M+H] +

[0439] Example 25.

[0440] 8-(Pyridin-3-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one

[0441]

[0442] The title compound was obtained as described in Example 1 using 3-amino-1,1,1-trifluoropropan-2-ol, pyridin-3-ylboronic acid and (4-(trifluoromethyl)phenyl)boronic acid (Scheme 1. General Procedure A.).

[0443] 1H-NMR (400MHz, CDCl3): δ [ppm] = 9.29 (d, J = 1.6Hz, 1H), 8.48 (dd, J = 4.9, 1.5H z,1H),8.45-8.39(m,1H),8.29(s,1H),8.23(s,1H),8.08(d,J=8.2Hz,2H),7. 67(d,J=8.3Hz,2H),7.39(dd,J=8.0,4.9Hz,1H),4.77(dd,J=13.6,2.5Hz,1H) ,4.71-4.62(m,1H),3.81(dd,J=13.5,9.9Hz,1H);MS(ESI,m / z):480.90[M+H] +

[0444] Example 26.

[0445] 6-(4-Chlorophenyl)-3-(3-hydroxyphenyl)-8-(1-methyl-1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one

[0446]

[0447] The title compound was obtained as described in Example 1 using 3-aminophenol, (1-methyl-1H-pyrazol-4-yl)boronic acid and (4-chlorophenyl)boronic acid (Scheme 1. General Procedure A.).

[0448] 1H NMR (400MHz, CDCl3): δ [ppm] = 8.62 (s, 1H), 8.62 (s, 1H), 8.35 (s, 1H), 8.19 (s, 1H), 8.17 (d, J = 8.5Hz, 2H), 7.49 (d,J=8.5Hz,2H),7.47-7.42(m,1H),7.04-6.93(m,3H),5.83(br,1H),4.04(s,3H); MS(ESI,m / z):430.08[M+H] +

[0449] Example 27.

[0450] 3-(3-Hydroxyphenyl)-8-(1-methyl-1H-pyrazol-4-yl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one

[0451]

[0452] The title compound was obtained as described in Example 1 using 3-aminophenol, (1-methyl-1H-pyrazol-4-yl)boronic acid and (4-(trifluoromethyl)phenyl)boronic acid (Scheme 1. General Procedure A.).

[0453] 1H NMR (400MHz, MeOD): δ [ppm] = 8.80 (s, 1H), 8.58 (s, 1H), 8.47-8.33 (m, 4H), 7.82 (d, J = 8. 3Hz,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] +

[0454] Example 28.

[0455] 6-(4-Chlorophenyl)-3-((1R,3S)-3-hydroxycyclopentyl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one

[0456]

[0457] The title compound was obtained as described in Example 1 using (1S,3R)-3-aminocyclopentanol, pyridin-3-ylboronic acid and (4-chlorophenyl)boronic acid (Scheme 1. General Procedure A.).

[0458] 1H NMR (400MHz, CDCl3): δ [ppm] = 9.46 (d, J = 1.8Hz, 1H), 8.71 (dd, J = 4.8, 1.6Hz, 1H), 8.60 (s, 1H) ,8.56(dd,J=1.9,1.9Hz,1H),8.54(s,1H),8.19(d,J=8.6Hz,2H),7.49(d,J=8.5Hz,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] +

[0459] Example 29.

[0460] 3-((1R,3S)-3-Hydroxycyclopentyl)-8-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one

[0461]

[0462] The title compound was obtained as described in Example 1 using (1S,3R)-3-aminocyclopentanol, pyridin-3-ylboronic acid and (4-(trifluoromethyl)phenyl)boronic acid (Scheme 1. General Procedure A.).

[0463] 1H NMR (400MHz, CDCl3): δ [ppm] = 9.48 (s, 1H), 8.74 (d, J = 3.9Hz, 1H), 8.64 (s, 1H), 8.62 (s, 1 H),8.58(d,J=8.1Hz,1H),8.36(d,J=8.2Hz,2H),7.78(d,J=8.3Hz,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] +

[0464] Example 30.

[0465] 6-(4-Chlorophenyl)-3-((1R,3S)-3-hydroxycyclopentyl)-8-(1-methyl-1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one

[0466]

[0467] The title compound was obtained as described in Example 1 using (1S,3R)-3-aminocyclopentanol, (1-methyl-1H-pyrazol-4-yl)boronic acid and (4-chlorophenyl)boronic acid (Scheme 1. General Procedure A.).

[0468] 1H NMR (400MHz, CDCl3): δ [ppm] = 8.64 (s, 1H), 8.60 (s, 1H), 8.57 (s, 1H), 8.33 (s, 1H), 8.18 (d, J = 8.5Hz, 2H), 7.50 (d, J = 8.5Hz, 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] +

[0469] Example 31.

[0470] 3-((1R,3S)-3-Hydroxycyclopentyl)-8-(1-methyl-1H-pyrazol-4-yl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one

[0471]

[0472] The title compound was obtained as described in Example 1 using (1S,3R)-3-aminocyclopentanol, (1-methyl-1H-pyrazol-4-yl)boronic acid and (4-(trifluoromethyl)phenyl)boronic acid (Scheme 1. General Procedure A.).

[0473] 1H NMR (400MHz, CDCl3): δ [ppm] = 8.66 (s, 1H), 8.62 (s, 1H), 8.61 (s, 1H), 8.40 (s, 1H) ),8.35(d,J=8.1Hz,2H),7.79(d,J=8.2Hz,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),2.3 1-2.22(m,1H),2.11-2.02(m,1H),1.91-1.81(m,1H); MS(ESI,m / z):456.18[M+H] +

[0474] Example 32.

[0475] 6-(4-Chlorophenyl)-3-((1S,3R)-3-hydroxycyclopentyl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one

[0476]

[0477] The title compound was obtained as described in Example 1 using (1R,3S)-3-aminocyclopentanol hydrochloride, pyridin-3-ylboronic acid and (4-chlorophenyl)boronic acid (Scheme 1. General Procedure A.).

[0478] 1H NMR (400MHz, CDCl3): δ [ppm] = 9.46 (s, 1H), 8.71 (d, J = 4.1Hz, 1H), 8.61 (s, 1 H),8.58-8.48(m,2H),8.18(d,J=8.5Hz,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),2.29-2.1 7(m,1H),2.10-1.94(m,2H),1.89-1.77(m,1H); MS(ESI,m / z):419.13[M+H] +

[0479] Example 33.

[0480] 3-((1S,3R)-3-Hydroxycyclopentyl)-8-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one

[0481]

[0482] The title compound was obtained as described in Example 1 using (1R,3S)-3-aminocyclopentanol hydrochloride, pyridin-3-ylboronic acid and (4-(trifluoromethyl)phenyl)boronic acid (Scheme 1. General Procedure A.).

[0483] 1H NMR (400MHz, CDCl3): δ [ppm] = 9.47 (d, J = 1.6Hz, 1H), 8.73 (dd, J = 4.8, 1.2Hz, 1H), 8.63 (s, 1H), 8.62 (s,1H),8.60-8.52(m,1H),8.36(d,J=8.2Hz,2H),7.78(d,J=8.3Hz,2H),7.48(dd,J=7.9,4.9Hz,1H) ,5.35-5.24(m,1H),4.57-4.48(m,1H),2.67(d,J=4.4Hz,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=12.6,6.2Hz,1H); MS(ESI,m / z):453.16[M+H] +

[0484] Example 34.

[0485] 6-(4-Chlorophenyl)-3-((1S,3R)-3-hydroxycyclopentyl)-8-(1-methyl-1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one

[0486]

[0487] The title compound was obtained as described in Example 1 using (1R,3S)-3-aminocyclopentanol hydrochloride, (1-methyl-1H-pyrazol-4-yl)boronic acid and (4-chlorophenyl)boronic acid (Scheme 1. General Procedure A.).

[0488] 1H NMR (400MHz, CDCl3): δ[ppm]=8.63(s,1H),8.58(s,1H),8.56(s,1H),8.32(s ,1H),8.17(d,J=8.6Hz,2H),7.49(d,J=8.7Hz,2H),5.27-5.21(m,1H),4.56- 4.51(m,1H),4.02(s,3H),2.78(d,J=5.0Hz,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] +

[0489] Example 35.

[0490] 3-((1S,3R)-3-Hydroxycyclopentyl)-8-(1-methyl-1H-pyrazol-4-yl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one

[0491]

[0492] The title compound was obtained as described in Example 1 using (1R,3S)-3-aminocyclopentanol hydrochloride, (1-methyl-1H-pyrazol-4-yl)boronic acid and (4-(trifluoromethyl)phenyl)boronic acid (Scheme 1. General Procedure A.).

[0493] 1H NMR (400MHz, CDCl3): δ [ppm] = 8.64 (s, 1H), 8.60 (s, 1H), 8.59 (s, 1H), 8.38 (s, 1H) ,8.33(d,J=8.2Hz,2H),7.77(d,J=8.3Hz,2H),5.30-5.22(m,1H),4.58-4.49(m,1 H),4.03(s,3H),2.77(d,J=4.8Hz,1H),2.60-2.52(m,1H),2.39-2.31(m,1H),2.3 0-2.21(m,1H),2.09-1.98(m,2H),1.90-1.80(m,1H); MS(ESI,m / z):456.20[M+H] +

[0494] Example 36.

[0495] 1-(6-(4-chlorophenyl)-4-oxo-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-3(4H)-yl)-2-methylpropan-2-yl acetate

[0496]

[0497] General Procedure A (Scheme 1) was followed using 1-amino-2-methylpropan-2-ol, pyridin-3-ylboronic acid and (4-chlorophenyl)boronic acid. During cyclization step c, the 1 H NMR analysis observed additional acetylation on the hydroxyl group.The title compound was obtained as described in Example 1 (Scheme 1. General Procedure A.).

[0498] 1H NMR (400MHz, CDCl3): δ [ppm] = 9.47 (s, 1H), 8.73 (d, J = 4.1Hz, 1H), 8.59-8.51 (m, 2H), 8.19 (d, J = 8.6Hz, 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] +

[0499] Example 37.

[0500] 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

[0501]

[0502] General Procedure A (Scheme 1) was followed using 1-amino-2-methylpropan-2-ol, pyridin-3-ylboronic acid and (4-(trifluoromethyl)phenyl)boronic acid. During cyclization step c, the 1 H NMR analysis observed additional acetylation on the hydroxyl group.The title compound was obtained as described in Example 1 (Scheme 1. General Procedure A.).

[0503] 1H NMR (400MHz, CDCl3): δ [ppm] = 9.49 (s, 1H), 8.74 (d, J = 4.0Hz, 1H), 8.62 (s, 1H), 8.56 (ddd, J = 7.9, 1.8, 1.8Hz, 1H), 8.35 (d, J = 8.2H z,2H),8.17(s,1H),7.78(d,J=8.3Hz,2H),7.53-7.46(m,1H),4.37(s,2H),2.06(s,3H),1.59(s,6H); MS(ESI,m / z):483.12[M+H] +

[0504] Example 38.

[0505] 6-(4-Chlorophenyl)-3-(2-hydroxy-2-methylpropyl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one

[0506]

[0507] General Procedure A (Scheme 1) was followed using 1-amino-2-methylpropan-2-ol, pyridin-3-ylboronic acid and (4-chlorophenyl)boronic acid. During cyclization step c, the 1 H NMR analysis observed additional acetylation on the hydroxyl group. The acetylated intermediate was further reacted with K 2 CO 3 Deprotection under conditions of solution in MeOH: water (5:1) at room temperature provided the title compound of Example 1 (Scheme 1. General Procedure A.).

[0508] 1H NMR (400MHz, CDCl3): δ [ppm] = 9.43 (s, 1H), 8.69 (d, J = 3.8Hz, 1H), 8.55 (d, J = 8.0Hz, 1H), 8.52 (s, 1H), 8.27 (s, 1H), 8 .16(d,J=8.6Hz,2H),7.49(d,J=8.6Hz,2H),7.46-7.38(m,1H),4.14(s,2H),1.37(s,6H); MS(ESI,m / z):407.24[M+H] +

[0509] Example 39.

[0510] 3-(2-Hydroxy-2-methylpropyl)-8-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one

[0511]

[0512] General Procedure A (Scheme 1) was followed using 1-amino-2-methylpropan-2-ol, pyridin-3-ylboronic acid, and (4-(trifluoromethyl)phenyl)boronic acid. During the cyclization step c, additional acetylation on the hydroxyl group was observed based on LC-MS and 1H NMR analysis. The acetylated intermediate was further reacted with K 2 CO 3 Deprotection under conditions of solution in MeOH: water (5:1) at room temperature provided the title compound of Example 1 (Scheme 1. General Procedure A.).

[0513] 1H NMR (400MHz, CDCl3): δ [ppm] = 9.47 (s, 1H), 8.73 (d, J = 3.2Hz, 1H), 8.62 (s, 1H), 8.58 (d, J = 8.0Hz, 1H), 8.35 (d, J = 8.2 Hz,2H),8.30(s,1H),7.78(d,J=8.3Hz,2H),7.51-7.44(m,1H),4.15(s,2H),1.37(s,6H); MS(ESI,m / z):441.31[M+H] +

[0514] Example 40.

[0515] 3-(2-Hydroxy-2-methylpropyl)-8-(pyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one

[0516]

[0517] General Procedure A (Scheme 1) was followed using 1-amino-2-methylpropan-2-ol, pyridin-3-ylboronic acid and (6-(trifluoromethyl)pyridin-3-yl)boronic acid. During the cyclization step c, additional acetylation on the hydroxyl group was observed by LC-MS analysis. The acetylated intermediate was further reacted with K 2 CO 3 Deprotection under conditions of solution in MeOH: water (5:1) at room temperature provided the title compound of Example 1 (Scheme 1. General Procedure A.).

[0518] 1H NMR (400MHz, CDCl3): δ [ppm] = 9.52 (d, J = 1.9Hz, 1H), 9.48 (d, J = 1.8Hz, 1H), 8.76-8.67 (m, 2H), 8.65 (s, 1H), 8.60-8.55 (m, 1H),8.35(s,1H),7.84(d,J=8.2Hz,1H),7.48(dd,J=8.0,4.8Hz,1H),4.16(s,2H),1.37(s,6H); MS(ESI,m / z):442.17[M+H] +

[0519] Example 41.

[0520] 6-(4-Chlorophenyl)-3-(1-hydroxy-3-methylbutan-2-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one

[0521]

[0522] The title compound was obtained as described in Example 1 using 2-amino-3-methylbutan-1-ol, pyridin-3-ylboronic acid and (4-chlorophenyl)boronic acid (Scheme 1. General Procedure A.).

[0523] 1H-NMR (400MHz, CDCl 3 ): δ [ppm] = 9.43 (d, J = 1.8Hz, 1H), 8.68 (dd, J = 4.8, 1.5Hz, 1H), 8.54 (dt, J = 7.8, 1.9Hz, 1H),8.50(s,1H),8.30(s,1H),8.15(d,J=8.6Hz,2H),7.48(d,J=8.6Hz,2H),7.45(dd,J =8.2,5.2Hz,1H),4.51(br,1H),4.25-4.16(m,1H),4.01(dd,J=11.8,2.2Hz,1H),2.57 -2.43(m,2H),1.20(d,J=6.5Hz,3H),0.89(d,J=6.6Hz,3H); MS(ESI,m / z):421.20[M+H] +

[0524] Example 42.

[0525] 3-(1-Hydroxy-3-methylbutan-2-yl)-8-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one

[0526]

[0527] The title compound was obtained as described in Example 1 using 2-amino-3-methylbutan-1-ol, pyridin-3-ylboronic acid and (4-(trifluoromethyl)phenyl)boronic acid (Scheme 1. General Procedure A.).

[0528] 1H-NMR (400MHz, CDCl 3): δ [ppm] = 9.42 (s, 1H), 8.67 (dd, J = 4.8, 1.4Hz, 1H), 8.55-8.52 (m, 1H), 8.54 (s, 1H), 8 .33(s,1H),8.29(d,J=8.2Hz,2H),7.75(d,J=8.3Hz,2H),7.44(dd,J=7.7,5.1Hz,1H),4 .52(br,1H),4.26-4.18(m,1H),4.02(dd,J=11.9,2.2Hz,1H),2.91-2.74(m,1H),2.55 -2.44(m,1H),1.20(d,J=6.5Hz,3H),0.89(d,J=6.7Hz,3H); MS(ESI,m / z):455.21[M+H] +

[0529] Example 43.

[0530] 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

[0531]

[0532] The title compound was obtained as described in Example 1 using 2-amino-3-methylbutan-1-ol, pyridin-3-ylboronic acid and (6-(trifluoromethyl)pyridin-3-yl)boronic acid (Scheme 1. General Procedure A.).

[0533] 1H-NMR (400MHz, CDCl 3 ): δ[ppm]=9.50(d,J=1.5Hz,1H),9.46(d,J=1.6Hz,1H),8.72(dd,J=4.8,1.4Hz,1H),8.68(dd,J=8 .3,1.7Hz,1H),8.62(s,1H),8.56(dt,J=8.0,1.9Hz,1H),8.37(s,1H),7.83(d,J=8.2Hz,1H),7.47( dd,J=7.9,4.9Hz,1H),4.55(br,1H),4.26-4.17(m,1H),4.02(dt,J=11.7,3.1Hz,1H),2.55-2.43( m,1H),2.34-2.24(m,1H),1.21(d,J=6.5Hz,3H),0.90(d,J=6.7Hz,3H); MS(ESI,m / z):456.19[M+H] +

[0534] Example 44.

[0535] (S)-2-((6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)amino)propan-1-ol

[0536] Preparation scheme of Example 44 compound:

[0537]

[0538] Intermediate 5.

[0539] 5-Amino-N-(1-((tert-butylbiphenylsilyl)oxy)propan-2-yl)-2-chloroisonicotinamide

[0540]

[0541] 5-Amino-2-chloroisonicotinic acid (1 g, 5.79 mmol, 1 eq.), EDC (1.33 g, 6.95 mmol, 1.2 eq.), HOBT (1.06 g, 6.95 mmol, 1.2 eq.) and TEA (1.21 mL, 8.69 mmol, 1.5 eq.) were dissolved in DMF (10 mL, 0.6 M) and stirred for 5 minutes. Then, 1-((tert-butylbiphenylsilyl)oxy)propan-2-amine (2.73 g, 8.69 mmol, 1.5 eq.) was added to the reaction mixture and stirred at 60 ° C for 12 hours. The reaction mixture was diluted with water (50 mL), extracted with EtOAc (20 mL×3), washed with brine (20 mL×3), and purified by Na 2 SO 4 The filtrate was evaporated in vacuo and purified by MPLC (silica gel, 0-30% EtOAc / hexanes) to give 0.87 g (32% yield) of 5-amino-N-(1-((tert-butylbiphenylsilyl)oxy)propan-2-yl)-2-chloroisonicotinamide (Intermediate 5).

[0542] MS (ESI, m / z): 468.04 [M+H] +

[0543] Intermediate 6.

[0544] 5-amino-N-(1-((tert-butylbiphenylsilyl)oxy)propan-2-yl)-2-(4-(trifluoromethyl)phenyl)isonicotinamide

[0545]

[0546] 5-amino-N-(1-((tert-butylbiphenylsilyl)oxy)propan-2-yl)-2-chloroisonicotinamide (Intermediate 5) (0.64 g, 1.37 mmol, 1 eq), (4-(trifluoromethyl)phenyl)boronic acid (0.52 g, 2.73 mmol, 2 eq), K 2 CO 3 (0.57 g, 4.10 mmol, 3 equiv) and Pd(dppf)Cl 2 ·CH 2 Cl 2 (0.11 g, 0.14 mmol, 0.1 equivalent) was dissolved in 1,4-dihydrochloric acid The reaction mixture was stirred and heated in a Biotage microwave initiator at 130°C for 1 hour. The reaction mixture was concentrated under reduced pressure and purified directly by MPLC (silica gel, 0-30% EtOAc / hexanes) to give 0.48 g (61% yield) of 5-amino-N-(1-((tert-butylbiphenylsilyl)oxy)propan-2-yl)-2-(4-(trifluoromethyl)phenyl)isonicotinamide (Intermediate 6).

[0547] MS (ESI, m / z): 578.16 [M+H] +

[0548] Intermediate 7.

[0549] 3-Amino-2-bromo-N-(1-((tert-butylbiphenylsilyl)oxy)propan-2-yl)-6-(4-(trifluoromethyl)phenyl)isonicotinamide

[0550]

[0551] 5-amino-N-(1-((tert-butylbiphenylsilyl)oxy)propan-2-yl)-2-(4(trifluoromethyl)phenyl)isonicotinamide (Intermediate 6) (0.1 g, 0.17 mmol, 1 eq) and N-bromosuccinimide (0.046 g, 0.26 mmol, 1.5 eq) were dissolved in DMF (5 mL, 0.035 M) and stirred at room temperature for 1 hour. The reaction mixture was diluted with water (20 mL), extracted with EtOAc (20 mL×3), washed with brine (10 mL×3), and purified by Na 2 SO 4 Dry and filter through a glass filter. The filtrate was evaporated in vacuo to give 0.082 g (72% yield) of 3-amino-2-bromo-N-(1-((tert-butylbiphenylsilyl)oxy)propan-2-yl)-6-(4-(trifluoromethyl)phenyl)isonicotinamide (Intermediate 7).

[0552] MS (ESI, m / z): 656.14 [M+H] +

[0553] Intermediate 8.

[0554] 8-Bromo-3-(1-((tert-butylbiphenylsilyl)oxy)propan-2-yl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one

[0555]

[0556] 3-Amino-2-bromo-N-(1-((tert-butylbiphenylsilyl)oxy)propan-2-yl)-6-(4-(trifluoromethyl)phenyl)isonicotinamide (Intermediate 7) (82 mg, 0.125 mmol, 1 eq.) was dissolved in (EtO) 3 CH (1.5 mL, 9.01 mmol, 9 equiv) and CH 3 CO 2 The reaction mixture was stirred and heated at 150 °C in a Biotage microwave initiator for 1 hour. The reaction mixture was diluted with water (20 mL), extracted with EtOAc (20 mL×3), washed with brine (10 mL×3), and purified by Na 2 SO 4 Dry and filter through a glass filter. The filtrate was evaporated in vacuo and used without further purification to give 0.06 g (72% yield) of 8-bromo-3-(1-((tert-butylbiphenylsilyl)oxy)propan-2-yl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one (Intermediate 8).

[0557] MS (ESI, m / z): 666.09 [M] +

[0558] Intermediate 9.

[0559] 3-(1-((tert-butylbiphenylsilyl)oxy)propan-2-yl)-8-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one

[0560]

[0561] 8-Bromo-3-(1-((tert-butylbiphenylsilyl)oxy)propan-2-yl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one (Intermediate 8) (60 mg, 0.090 mmol, 1 eq), pyridin-3-ylboronic acid (17 mg, 0.13 mmol, 2 eq), K 2 CO 3 (37 mg, 0.27 mmol, 3 eq.), phosphating agent (Sphos) (3.7 mg, 9.00 μmol, 0.1 eq.) and Pd 2 (dba) 3 ·CHCl 3 (9.32 mg, 9 μmol, 0.1 eq.) dissolved in 1,4-dihydrochloric acid In alkane / water (4mL / 1mL, 0.02M). The reaction mixture was stirred and heated in a Biotage microwave initiator at 130°C for 1 hour. The reaction mixture was concentrated under reduced pressure and directly purified by MPLC (silica gel, 0-30% EtOAc / hexane) to give 10mg (17% yield) of 3-(1-((tert-butylbiphenylsilyl)oxy)propan-2-yl)-8-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidine-4(3H)-one (intermediate 9).

[0562] MS (ESI, m / z): 665.15 [M+H] +

[0563] Example 44.

[0564] 3-(1-Hydroxypropan-2-yl)-8-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one

[0565]

[0566] A solution of 3-(1-((tert-butylbiphenylsilyl)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 eq) and TBAF (1.0 M in THF, 15 μL, 0.015 mmol, 1 eq) in THF (2 mL, 0.0075 M) was stirred at 40 °C for 12 hours. The reaction mixture was diluted with water (5 mL), extracted with EtOAc (5 mL×3), washed with brine (5 mL×3), and purified by Na 2 SO 4The filtrate was dried and filtered through a glass filter. The filtrate was evaporated in vacuo and purified by preparative TLC (silica gel, 0-50% EtOAc / hexanes) to give 1.9 mg (30% yield) of 3-(1-hydroxypropan-2-yl)-8-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one (Example 44).

[0567] 1H-NMR (400MHz, CD 3 OD): δ [ppm] = 9.44 (d, J = 1.6Hz, 1H), 8.75 (d, J = 8.0Hz, 1H), 8.69 (s, 1H), 8.66 ( d,J=4.8Hz,1H),8.48(s,1H),8.45(d,J=8.2Hz,2H),7.86(d,J=8.3Hz,2H),7. 63(dd,J=8.0,5.0Hz,1H),5.08-4.99(m,1H),3.99(dd,J=11.9,7.0Hz,1H),3. 88(dd,J=11.9,4.3Hz,1H),1.58(d,J=7.1Hz,3H); MS(ESI,m / z):426.94[M+H] +

[0568] Example 45.

[0569] 3-(1-Hydroxypropan-2-yl)-8-(1-methyl-1H-pyrazol-4-yl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one

[0570]

[0571] The title compound was obtained as described in Example 44 using (1-methyl-1H-pyrazol-4-yl)boronic acid (Scheme 2. General Procedure B.).

[0572] 1H-NMR (400MHz, CD 3 OD): δ [ppm] = 8.69 (s, 1H), 8.46 (s, 1H), 8.38 (s, 1H), 8.31 (s, 1H), 8.29 (d, J = 2.7Hz, 2H), 7.71 (d, J = 8.3Hz, 2H), 4.94-4.86 ( m,1H),3.90(s,3H),3.87(t,J=5.9Hz,1H),3.77(dd,J=11.9,4.3Hz,1H),1.47(d,J=7.1Hz,3H); MS(ESI,m / z):430.02[M+H] +

[0573] Example 46.

[0574] 6-(4-Chlorophenyl)-3-(1-hydroxypropan-2-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one

[0575]

[0576] The title compound was obtained as described in Example 44 using pyridin-3-ylboronic acid (Scheme 2. General Procedure B.).

[0577] 1H-NMR (400MHz, CD 3 OD): δ [ppm] = 9.31 (s, 1H), 8.65-8.59 (m, 1H), 8.53 (d, J = 4.2Hz, 1H), 8.49 ( s,1H),8.34(s,1H),8.14(d,J=8.6Hz,2H),7.51(dd,J=7.9,5.0Hz,1H),7. 44(d,J=8.6Hz,2H),4.95-4.86(m,1H),3.87(dd,J=11.9,7.0Hz,1H),3.76 (dd,J=11.9,4.3Hz,1H),1.46(d,J=7.1Hz,3H); MS(ESI,m / z):392.91[M+H] +

[0578] Example 47.

[0579] 2-(6-(4-chlorophenyl)-4-oxo-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-3(4H)-yl)propyl diethyl phosphate

[0580]

[0581] 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 eq) and sodium hydride (18.33 mg, 0.764 mmol, 3 eq) were dissolved in THF (1273 μl, 0.2 M) and stirred for 10 minutes. Then, a solution of diethyl chlorophosphate (73.8 μl, 0.509 mmol, 2 eq) and N,N-dimethylpyridin-4-amine (15.55 mg, 0.127 mmol, 0.5 eq) in THF (1273 μl, 0.2 M) was added dropwise to the reaction mixture and stirred at room temperature for 12 hours. The reaction mixture was quenched with water (10 mL), extracted with DCM (10 mL×3), washed with brine (10 mL×3), and purified by Na 2SO 4 The filtrate was evaporated in vacuo and used without further purification to give 79 mg (59% yield) of diethyl 2-(6-(4-chlorophenyl)-4-oxo-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-3(4H)-yl)propyl phosphate (Example 47).

[0582] 1H-NMR (400MHz, CDCl 3 ): δ [ppm] = 9.45 (d, J = 1.6Hz, 1H), 8.72 (dd, J = 4.8, 1.4Hz, 1H), 8.55 (dt, J = 8.0, 1.9Hz, 1 H),8.53(s,1H),8.18(d,J=8.5Hz,3H),7.49(d,J=8.7Hz,2H),7.47(dd,J=5.2,3.1,1H), 5.15(dd,J=10.2,6.3Hz,1H),4.45(ddd,J=11.2,7.5,6.2Hz,1H),4.37-4.28(m,1H),4.0 6(p,J=7.3Hz,4H),1.65(d,J=7.2Hz,3H),1.29-1.23(m,6H); MS(ESI,m / z):529.23[M+H] +

[0583] Example 48.

[0584] 6-(4-Chlorophenyl)-3-(1-hydroxypropan-2-yl)-8-(1-methyl-1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one

[0585]

[0586] The title compound was obtained as described in Example 44 using (1-methyl-1H-pyrazol-4-yl)boronic acid and (4-chlorophenyl)boronic acid (Scheme 2. General Procedure B.).

[0587] 1H-NMR (400MHz, CD 3OD): δ [ppm] = 8.79 (s, 1H), 8.56 (s, 1H), 8.46 (s, 1H), 8.33 (s, 1H), 8.22 (d, J = 8.4Hz, 2H), 7.77 (s, 1H), 7.52 (d, J = 8.4Hz, 2H), 5.0 3-4.99(m,1H),4.01(s,3H),3.99-3.93(m,1H),3.86(dd,J=11.8,4.3Hz,1H),1.57(d,J=7.1Hz,3H); MS(ESI,m / z):396.00[M+H] +

[0588] Example 49.

[0589] 3-(1-Hydroxypropan-2-yl)-8-(pyridin-3-yl)-6-(4-(trifluoromethoxy)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one

[0590]

[0591] The title compound was obtained as described in Example 44 using pyridin-3-ylboronic acid and (4-(trifluoromethoxy)phenyl)boronic acid (Scheme 2. General Procedure A.).

[0592] 1H-NMR (400MHz, CD 3 OD): δ [ppm] = 9.43 (s, 1H), 8.74 (dd, J = 6.2, 1.8Hz, 1H), 8.68-8.64 (m, 1H), 8 .62(s,1H),8.46(s,1H),8.37(d,J=8.8Hz,2H),7.63(dd,J=7.9,5.0Hz,1H), 7.46(d,J=8.4Hz,2H),5.08-4.98(m,1H),3.99(dd,J=11.9,7.0Hz,1H),3.8 8(dd,J=11.9,4.3Hz,1H),1.58(d,J=7.1Hz,3H); MS(ESI,m / z):442.93[M+H] +

[0593] Example 50.

[0594] 3-(1-Hydroxypropan-2-yl)-8-(pyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one

[0595]

[0596] The title compound was obtained as described in Example 44 using pyridin-3-ylboronic acid and (6-(trifluoromethyl)pyridin-3-yl)boronic acid (Scheme 2. General Procedure B.).

[0597] 1H-NMR (400MHz, CD 3 OD): δ [ppm] = 9.59 (s, 1H), 9.45 (d, J = 1.9Hz, 1H), 8.89 (d, J = 8.2Hz, 1H), 8.79 (s, 1H),8.76(d,J=8.0Hz,1H),8.70-8.59(m,1H),8.52(s,1H),8.01(d,J=8.3Hz,1H ),7.65(dd,J=8.0,4.9Hz,1H),5.07-5.00(m,1H),4.00(dd,J=11.9,7.0Hz,1H), 3.88(dd,J=11.9,4.3Hz,1H),1.59(d,J=7.1Hz,3H); MS(ESI,m / z):427.96[M+H] +

[0598] Example 51.

[0599] 6-(4-Chlorophenyl)-3-(1-hydroxybutan-2-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one

[0600]

[0601] The title compound was obtained as described in Example 44 using 2-aminobutan-1-ol, pyridin-3-ylboronic acid and (4-chlorophenyl)boronic acid (Scheme 2. General Procedure B.).

[0602] 1H-NMR (400MHz, CD 3 OD): δ [ppm] = 9.43 (d, J = 1.6Hz, 1H), 8.74 (d, J = 8.0Hz, 1H), 8.65 (d, J = 4.8Hz, 1H), 8.61(s,1H),8.44(s,1H),8.26(d,J=8.5Hz,2H),7.63(dd,J=8.0,5.0Hz,1H),7.56 (d,J=8.5Hz,2H),4.84(s,1H),4.04(dd,J=12.0,7.1Hz,1H),3.89(dd,J=12.0,4. 0Hz, 1H), 2.02 (p, J = 7.4Hz, 2H), 1.00 (t, J = 7.4Hz, 3H); MS (ESI, m / z): 406.95 [M+H] +

[0603] Example 52.

[0604] 6-(4-Chlorophenyl)-3-(1-hydroxybutan-2-yl)-8-(1-methyl-1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one

[0605]

[0606] The title compound was obtained as described in Example 44 using 2-aminobutan-1-ol, (1-methyl-1H-pyrazol-4-yl)boronic acid and (4-chlorophenyl)boronic acid (Scheme 2. General Procedure B.).

[0607] 1H-NMR (400MHz, CD 3 OD): δ[ppm]=8.79(s,1H),8.55(s,1H),8.45(s,1H),8.31(s,1H),8.21(d,J=8.5Hz,2H),7.53(d,J=8.5Hz,2H),4.82(s,1H),4.08 -4.03(m,1H),4.02(s,3H),3.89(dd,J=12.0,4.0Hz,1H),2.03(p,J=7.4Hz,2H),1.00(t,J=7.4Hz,3H); MS(ESI,m / z):409.99[M+H] +

[0608] Example 53.

[0609] 3-(1-Hydroxybutan-2-yl)-8-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one

[0610]

[0611] The title compound was obtained as described in Example 44 using 2-aminobutan-1-ol, pyridin-3-ylboronic acid and (4-(trifluoromethyl)phenyl)boronic acid (Scheme 2. General Procedure B.).

[0612] 1H-NMR (400MHz, CD 3OD): δ [ppm] = 9.43 (d, J = 2.0Hz, 1H), 8.74 (dt, J = 8.0, 1.8Hz, 1H), 8.66 (s, 1H), 8.6 6-8.63(m,1H),8.46(s,1H),8.43(d,J=8.3Hz,2H),7.84(d,J=8.4Hz,2H),7.62(d d,J=8.0,5.0Hz,1H),4.84(s,1H),4.04(dd,J=12.0,7.0Hz,1H),3.89(dd,J=12.0 ,4.0Hz,1H),2.07-1.94(m,2H),1.01(t,J=7.4Hz,3H); MS(ESI,m / z):441.00[M+H] +

[0613] Example 54.

[0614] 3-(1-Hydroxybutan-2-yl)-8-(1-methyl-1H-pyrazol-4-yl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one

[0615]

[0616] The title compound was obtained as described in Example 44 using 2-aminobutan-1-ol, (1-methyl-1H-pyrazol-4-yl)boronic acid and (4-(trifluoromethyl)phenyl)boronic acid (Scheme 2. General Procedure B.).

[0617] 1H-NMR (400MHz, CD 3 OD): 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=8.1Hz,2H),4.83(s,1H),4.08-4.0 3(m,1H),4.02(s,3H),3.90(dd,J=12.0,3.9Hz,1H),2.03(t,J=7.5Hz,2H),1.01(t,J=7.4Hz,3H); MS(ESI,m / z):444.01[M+H] +

[0618] Example 55.

[0619] 6-(4-Chlorophenyl)-8-(3-fluorophenyl)-3-(1-hydroxybutan-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one

[0620]

[0621] The title compound was obtained as described in Example 44 using 2-aminobutan-1-ol, (3-fluorophenyl)boronic acid and (4-chlorophenyl)boronic acid (Scheme 2. General Procedure B.).

[0622] 1H-NMR (400MHz, CD 3 OD): δ [ppm] = 8.56 (s, 1H), 8.41 (s, 1H), 8.24 (d, J = 8.6Hz, 2H), 8.12-7.96 (m, 2H), 7.58-7.52 (m, 3H), 7.24 (td, J = 8.5, 2.6Hz, 1H), 4.83 ( s,1H),4.03(dd,J=12.0,7.0Hz,1H),3.88(dd,J=12.0,4.1Hz,1H),2.07-1.95(m,2H),1.00(t,J=7.4Hz,3H); MS(ESI,m / z):423.98[M+H] +

[0623] Example 56.

[0624] 6-(4-Chlorophenyl)-3-((1r,4r)-4-hydroxycyclohexyl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one

[0625]

[0626] The title compound was obtained as described in Example 44 using (1r,4r)-4-aminocyclohexan-1-ol, pyridin-3-ylboronic acid and (4-chlorophenyl)boronic acid (Scheme 2. General Procedure B.).

[0627] 1H-NMR (400MHz, CDCl 3 ): δ[ppm]=9.45(s,1H),8.72(s,1H),8.58-8.46(m,2H),8.19(d,J=8.6Hz,2H),8.17(s,1H),7.54-7.42(m,3H),4.89-4.76(m,9 H),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] +

[0628] Example 57.

[0629] 3-((1r,4r)-4-hydroxycyclohexyl)-8-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one

[0630]

[0631] The title compound was obtained as described in Example 44 using (1r,4r)-4-aminocyclohexan-1-ol, pyridin-3-ylboronic acid and (4-(trifluoromethyl)phenyl)boronic acid (Scheme 2. General Procedure B.).

[0632] 1H-NMR (400MHz, CDCl 3 ): δ [ppm] = 9.46 (d, J = 1.9Hz, 1H), 8.73 (dd, J = 4.8, 1.6Hz, 1H), 8.62 (s, 1H), 8.58 -8.51(m,1H),8.36(d,J=8.3Hz,2H),8.20(s,1H),7.79(d,J=8.4Hz,2H),7.48(dd ,J=7.9,4.9Hz,1H),4.87-4.79(m,1H),3.83-3.75(m,1H),2.28-2.16(m,2H),2.1 4-2.03(m,2H),1.92-1.79(m,2H),1.69-1.60(m,2H); MS(ESI,m / z):466.97[M+H] +

[0633] Example 58.

[0634] 6-(4-Chlorophenyl)-3-((1s,4s)-4-hydroxycyclohexyl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one

[0635]

[0636] General Procedure B (Scheme 2) was followed using methyl (1r,4r)-4-aminocyclohexanol, pyridin-3-ylboronic acid, and (4-chlorophenyl)boronic acid. During the cyclization step c, additional acetylation on the hydroxyl group was observed based on LC-MS analysis. The acetylated intermediate was further reacted with K 2 CO 3 Deprotection under conditions of solution in MeOH: water (5:1) at room temperature provided the title compound of Example 58 (Scheme 2. General Procedure B.).

[0637] 1 H NMR (400 MHz, CDCl 3): δ[ppm]=9.46(s,1H),8.72(s,1H),8.56(d,J=10.0Hz,2H),8.29(s,1H),8.22-8.10(m,2H),7.57-7.36(m,3H),4.90(tt,J =12.7,3.5Hz,1H),4.24-4.17(m,1H),2.28-2.11(m,2H),2.09-1.97(m,2H),1.90-1.72(m,4H); MS(ESI,m / z):433.17[M+H] +

[0638] Example 59.

[0639] 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

[0640] Preparation scheme of Example 59 compound:

[0641]

[0642] Intermediate 10.

[0643] 3-(1-((tert-butylbiphenylsilyl)oxy)propan-2-yl)-8-(1-methyl-1H-pyrazol-4-yl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one

[0644]

[0645] The title compound was obtained as described for intermediate 9 of Example 44 using (1-methyl-1H-pyrazol-4-yl)boronic acid (Scheme 2. General Procedure B.).

[0646] MS (ESI, m / z): 668.31 [M+H] +

[0647] Intermediate 11.

[0648] 3-(1-((tert-butylbiphenylsilyl)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

[0649]

[0650] 3-(1-((tert-butylbiphenylsilyl)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 eq) was dissolved in THF (3 mL, 0.011 M) and cooled at 0°C. Then, NaBH 4 (5.21 mg, 0.14 mmol, 4 equivalents) was added to the reaction mixture and stirred at room temperature for 2 hours. The reaction mixture was quenched with MeOH (3 mL), diluted with water (3 mL), extracted with EtOAc (5 mL×3), washed with brine (5 mL×3), and purified by Na 2 SO 4 The filtrate was dried and filtered through a glass filter. The filtrate was evaporated in vacuo and purified by MPLC (silica gel, 0-30% EtOAc / hexanes) to give 20 mg (87% yield) of 3-(1-((tert-butylbiphenylsilyl)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).

[0651] MS (ESI, m / z): 670.26 [M+H] +

[0652] Example 59.

[0653] 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

[0654]

[0655] To a solution of 3-(1-((tert-butylbiphenylsilyl)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 eq) in THF (2 mL, 0.01 M) was added TBAF (1.0 M in THF, 30 μL, 0.03 mmol, 1 eq) 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), and purified by Na 2 O 4 3-nitropropane. 2 SO 4Dry and filter through a glass filter. The filtrate is evaporated in vacuo and analyzed by preparative TLC (silica gel, Chromatorex KP80805 (NH-SiO 2 ), 0-70% EtOAc / hexanes) to afford 3.9 mg (30% yield) 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).

[0656] 1H-NMR (400MHz, CDCl 3 ): δ[ppm]=8.17(s,1H),8.15(d,J=8.2Hz,2H),8.03(s,1H),7.98(s,1H),7.69(d,J=8.3Hz,2H),4.74(dt,J=11.0,3.8Hz,2H),4.70 -4.62(m,2H),3.86(dd,J=11.6,3.8Hz,1H),3.73(d,J=7.8Hz,1H),1.61(s,2H),1.32(d,J=7.0Hz,3H); MS(ESI,m / z):432.01[M+H] +

[0657] Example 60.

[0658] 6-(4-Chlorophenyl)-3-(1-hydroxypropan-2-yl)-8-(pyridin-3-yl)-2,3-dihydropyrido[3,4-d]pyrimidin-4(1H)-one

[0659]

[0660] 6-(4-Chlorophenyl)-3-(1-hydroxypropan-2-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (Example 46) (50 mg, 0.127 mmol, 1 eq) was dissolved in THF (3 mL, 0.042 M) and cooled at 0°C. Then, NaBH 4 (9.6 mg, 0.255 mmol, 2 equivalents) was added to the reaction mixture and stirred at room temperature for 2 hours. The reaction mixture was quenched with MeOH (3 mL), diluted with water (3 mL), extracted with EtOAc (5 mL×3), washed with brine (5 mL×3), and purified by Na 2 SO 4The mixture was dried and filtered through a glass filter. The filtrate was evaporated in vacuo and purified by preparative TLC (silica gel, 0-10% MeOH / DCM) to give 2.9 mg (5.7% yield) of 6-(4-chlorophenyl)-3-(2,3-dihydroxypropyl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (Example 60).

[0661] 1H-NMR (400MHz, CDCl 3 ): δ[ppm]=9.04(s,1H),8.70(s,1H),8.24(s,1H),8.12(d,J=7.9Hz,1H),7.9 9(d,J=8.6Hz,2H),7.47(dd,J=7.6,5.0Hz,1H),7.41(d,J=8.5Hz,2H),4.85(s ,1H),4.79-4.73(m,1H),4.73-4.61(m,2H),3.85(dd,J=11.6,3.8Hz,1H),3. 70(dd,J=11.5,7.6Hz,1H),1.31(d,J=7.0Hz,3H); MS(ESI,m / z):395.15[M+H] +

[0662] Example 61.

[0663] 6-(4-Chlorophenyl)-3-(3-hydroxyphenyl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one

[0664]

[0665] The title compound was obtained as described in Example 44 using 3-aminophenol, pyridin-3-ylboronic acid and (4-chlorophenyl)boronic acid (Scheme 2. General Procedure B.).

[0666] 1H-NMR (400MHz, CDCl 3 ): δ [ppm] = 9.50 (d, J = 1.7Hz, 1H), 8.72 (dd, J = 4.9, 1.5Hz, 1H), 8.63-8.59 (m, 1H),8.57(s,1H),8.17(d,J=8.6Hz,2H),8.15(s,1H),7.54(dd,J=7.9,4.9Hz ,1H),7.49(d,J=8.6Hz,2H),7.44(dd,J=8.1,8.1Hz,1H),7.04(dd,J=8.2,1. 8Hz,1H),6.96(d,J=7.8Hz,1H),6.93-6.90(m,1H); MS(ESI,m / z):427.0[M+H]+

[0667] Example 62.

[0668] 3-(3-Hydroxyphenyl)-8-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one

[0669]

[0670] The title compound was obtained as described in Example 44 using 3-aminophenol, pyridin-3-ylboronic acid and (4-(trifluoromethyl)phenyl)boronic acid (Scheme 2. General Procedure B.).

[0671] 1H-NMR (400MHz, CDCl 3 ): δ [ppm] = 9.50 (d, J = 2.0Hz, 1H), 8.74 (dd, J = 4.9, 1.6Hz, 1H), 8.66 (s, 1H), 8.62-8.57(m,1H),8.36(d,J=8.1Hz,2H),8.20(s,1H),7.79(d,J=8.3Hz,2H) ,7.53(dd,J=8.4,4.5Hz,1H),7.46(dd,J=8.1,8.1Hz,1H),7.04(dd,J=8.3,2 .3Hz,1H),7.02-6.98(m,1H),6.96-6.92(m,1H); MS(ESI,m / z):461.03[M+H] +

[0672] Example 63.

[0673] 6-(4-Chlorophenyl)-3-(3-hydroxycyclohexyl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one

[0674]

[0675] The title compound was obtained as described in Example 44 using 3-aminocyclohexan-1-ol, pyridin-3-ylboronic acid and (4-chlorophenyl)boronic acid (Scheme 2. General Procedure B.).

[0676] 1H NMR (400MHz, MeOD) δ [ppm] = 9.42 (s, 1H), 8.74 (d, J = 7.9Hz, 1H), 8.65 (d, J = 4.8Hz, 1H), 8.60 (s, 1H),8.50(s,1H),8.26(d,J=7.6Hz,2H),7.63(dd,J=8.0,4.9Hz,1H),7.56(d,J=7.7Hz,2H),4.7 9(t,J=12.5Hz,1H),3.90-3.75(m,1H),2.28(d,J=12.1Hz,1H),2.07-1.98(m,3H),1.91-1.80( m,2H),1.56(dd,J=25.7,13.1Hz,1H),1.38(dd,J=18.1,8.6Hz,1H); MS(ESI,m / z):433.11[M+H] +

[0677] Example 64.

[0678] 6-(4-Chlorophenyl)-3-(3-hydroxycyclohexyl)-8-(1-methyl-1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one

[0679]

[0680] The title compound was obtained as described in Example 44 using 3-aminocyclohexan-1-ol, (1-methyl-1H-pyrazol-4-yl)boronic acid and (4-chlorophenyl)boronic acid (Scheme 2. General Procedure B.).

[0681] 1H NMR (400MHz, MeOD) δ [ppm] = 8.80 (s, 1H), 8.58 (s, 1H), 8.52 (s, 1H), 8.34 (s, 1H), 8. 23(d,J=8.6Hz,2H),7.54(d,J=8.6Hz,2H),4.79(t,J=12.4Hz,1H),4.02(s,3H),3.8 4-3.73(m,1H),2.28(d,J=11.1Hz,1H),2.11-2.01(m,2H),1.91-1.83(d,J=12.0Hz, 2H),1.56(dd,J=26.7,13.4Hz,1H),1.42-1.33(m,1H).;MS(ESI,m / z):436.10[M+H] +

[0682] Example 65.

[0683] 3-((1R,3S)-3-Hydroxycyclopentyl)-8-(pyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one

[0684] Preparation scheme of Example 65 compound:

[0685]

[0686] Intermediate 12.

[0687] 3-Amino-6-chloro-N-((1R,3S)-3-hydroxycyclopentyl)-2-iodoisonicotinamide

[0688]

[0689] A mixture of 3-amino-6-chloro-2-iodoisonicotinic acid (2 g, 6.70 mmol, 1 eq.), EDC (1.541 g, 8.04 mmol, 1.2 eq.), HOBT (1.231 g, 8.04 mmol, 1.2 eq.) and TEA (1.401 mL, 10.05 mmol, 1.5 eq.) 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 eq.) was added to the reaction mixture and stirred at 50 °C for 12 h. The reaction mixture was diluted with water (50 mL), extracted with EtOAc (20 mL×3), washed with brine (20 mL×3), and purified by Na 2 SO 4 The filtrate was evaporated in vacuo and purified by MPLC (silica gel, 0-5% MeOH / DCM) to give 2 g (78% yield) of 3-amino-6-chloro-N-((1R,3S)-3-hydroxycyclopentyl)-2-iodoisonicotinamide (Intermediate 12).

[0690] MS (ESI, m / z): 381.85 [M+H] +

[0691] Intermediate 13.

[0692] 6-Chloro-3-((1R,3S)-3-hydroxycyclopentyl)-8-iodopyrido[3,4-d]pyrimidin-4(3H)-one

[0693]

[0694] 3-Amino-6-chloro-N-((1R,3S)-3-hydroxycyclopentyl)-2-iodoisonicotinamide (Intermediate 12) (1.5 g, 3.93 mmol, 1 eq.) was dissolved in (EtO)3 CH (15 mL, 90 mmol, 23 equiv) and CH 3 CO 2 H (15 mL, 262 mmol, 67 equiv). The reaction mixture was stirred and heated at 150 ° C in a Biotage microwave initiator for 1 hour. 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 evaporated in vacuo 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 without further purification.

[0695] 1H NMR (400MHz, 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, 5.1Hz, 1 H),2.42-2.33(m,1H),2.18-2.07(m,1H),2.07-1.96(m,1H),1.93-1.86(m,1H),1.86-1.76(m,1H); MS(ESI,m / z):391.89[M+H]+

[0696] Intermediate 14.

[0697] 6-Chloro-3-((1R,3S)-3-hydroxycyclopentyl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one

[0698]

[0699] 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 eq), pyridin-3-ylboronic acid (0.125 g, 1.018 mmol, 1.1 eq), K 2 CO 3 (0.384 g, 2.78 mmol, 3 equiv) and Pd(dppf)Cl 2 ·CH 2 Cl 2 (0.076 g, 9.3 μmol, 0.1 eq.) dissolved in 1,4-dihydrochloric acid The reaction mixture was stirred and heated in a Biotage microwave initiator at 130 ° C for 30 minutes. The reaction mixture was concentrated under reduced pressure and directly purified by MPLC (silica gel, 0-10% MeOH / DCM) to give 0.186 g (60% yield) of 6-chloro-3-((1R, 3S)-3-hydroxycyclopentyl-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (intermediate 14).

[0700] MS (ESI, m / z): 343.05 [M+H] +

[0701] Example 65.

[0702] 3-((1R,3S)-3-Hydroxycyclopentyl)-8-(pyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one

[0703]

[0704] 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 eq), (6-(trifluoromethyl)pyridin-3-yl)boronic acid (25 mg, 0.131 mmol, 1.5 eq), K 2 CO 3 (36.6 mg, 0.263 mmol, 3 equiv) and Pd(dppf)Cl 2 ·CH 2 Cl 2 (7.2 mg, 8.75 μmol, 0.1 eq.) dissolved in 1,4-dihydrochloric acid The reaction mixture was stirred and heated in a Biotage microwave initiator at 130 ° C for 30 minutes. The reaction mixture was concentrated under reduced pressure and directly purified by MPLC (silica gel, 0-10% MeOH / DCM) to give 0.027 g (69% yield) 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).

[0705] 1H NMR (400MHz, CDCl3): δ [ppm] = 9.55 (d, J = 0.9Hz, 1H), 9.50 (d, J = 1.6Hz, 1H), 8.82-8.70 (m ,3H),8.67(s,1H),8.62-8.55(m,1H),7.86(d,J=8.2Hz,1H),7.50(dd,J=7.8,4.8Hz,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,1 H),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] +

[0706] Example 66.

[0707] 3-(2,3-Dihydroxypropyl)-8-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one

[0708]

[0709] The title compound was obtained as described in Example 65 using 3-aminopropane-1,2-diol, pyridin-3-ylboronic acid and (4-(trifluoromethyl)phenyl)boronic acid (Scheme 4. General Procedure D.).

[0710] 1H-NMR (400MHz, CDCl 3 ): δ[ppm]=9.44(d,J=1.7Hz,1H),8.78-8.74(m,1H),8.73(s,1H),8.67(dd,J= 4.9,1.5Hz,1H),8.48(d,J=8.2Hz,2H),8.39(s,1H),7.87(d,J=8.4Hz,2H),7. 64(dd,J=8.1,4.9Hz,1H),4.49(dd,J=13.6,3.2Hz,1H),4.10-4.02(m,1H),3. 91(dd,J=13.6,8.8Hz,1H),3.66(d,J=5.2Hz,2H); MS(ESI,m / z):443.19[M+H] +

[0711] Example 67.

[0712] 6-(4-Chlorophenyl)-3-(2,3-dihydroxypropyl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one

[0713]

[0714] General Procedure D (Scheme 4) was followed using 3-aminopropane-1,2-diol, pyridin-3-ylboronic acid and (4-chlorophenyl)boronic acid. During the cyclization step c, additional acetylation on one of the two hydroxyl groups was observed by LC-MS analysis. The formylated intermediate was deprotected under conditions of 2M HCl in MeOH at 40°C for 3 hours to afford the title compound of Example 67.

[0715] 1H-NMR (400MHz, CDCl 3 ): δ [ppm] = 9.42 (s, 1H), 8.65 (d, J = 3.8Hz, 1H), 8.52 (d, J = 7.9Hz, 1H), 8.45 (s, 1H),8.20(s,1H),8.12(d,J=8.5Hz,2H),7.47(d,J=8.5Hz,2H),7.43(dd,J=7.8 ,4.9Hz,1H),4.33(dd,J=13.7,2.8Hz,1H),4.22-4.15(m,1H),4.09(dd,J=13. 6,6.8Hz,1H),3.72(ddd,J=16.4,11.5,3.9Hz,2H); MS(ESI,m / z):409.27[M+H] +

[0716] Example 68.

[0717] 3-(2,3-Dihydroxypropyl)-6-(4-(4-methylpiperazin-1-yl)phenyl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one

[0718]

[0719] General Procedure D (Scheme 4) was followed using 3-aminopropane-1,2-diol, pyridin-3-ylboronic acid and (4-(4-methylpiperazin-1-yl)phenyl)boronic acid. During the cyclization step c, additional acetylation on one of the two hydroxyl groups was observed by LC-MS analysis. The formylated intermediate was deprotected under conditions of 2M HCl in MeOH at 40 °C for 3 hours to afford the title compound of Example 68.

[0720] 1H-NMR (400MHz, CDCl 3): δ [ppm] = 9.38 (d, J = 1.5Hz, 1H), 8.70 (dt, J = 8.0, 1.9Hz, 1H), 8.62 (dd, J = 4.9, 1.6Hz, 1H), 8.4 5(s,1H),8.26(s,1H),8.13(d,J=8.9Hz,2H),7.60(dd,J=7.9,5.0Hz,1H),7.10(d,J=9.0Hz,2H) ,4.44(dd,J=13.6,3.2Hz,2H),4.08-4.01(m,1H),3.86(dd,J=13.7,8.8Hz,1H),3.65(d,J=5.2 Hz,2H),3.36(t,J=10.0Hz,4H),2.66(t,J=9.9Hz,4H),2.39(s,3H); MS(ESI,m / z):473.17[M+H] +

[0721] Example 69.

[0722] 3-(1,3-Dihydroxypropan-2-yl)-8-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one

[0723]

[0724] Use 2,2-dimethyl-1,3-dimethoxy Alkyl-5-amine, pyridin-3-ylboronic acid and (4-(trifluoromethyl)phenyl)boronic acid followed General Procedure D (Scheme 4). The intermediate was deprotected with 2M HCl in MeOH at 40°C for 3 hours to afford the title compound of Example 69.

[0725] 1H-NMR (400MHz, CDCl 3 ): δ[ppm]=9.45(s,1H),8.78-8.74(m,1H),8.71(s,1H),8.66(dd,J=4.9,1.6Hz,1H),8.49(s,1H),8.47(d,J=8.2Hz,2H),7.86(d,J=8.3Hz,2H) ,7.64(ddd,J=8.0,5.0,0.8Hz,1H),4.99-4.92(m,1H),4.13(dd,J=11.9,7.2Hz,2H),4.00(dd,J=11.9,4.9Hz,2H); MS(ESI,m / z):443.17[M+H] +

[0726] Example 70.

[0727] 6-(4-Chlorophenyl)-3-(1,3-dihydroxypropan-2-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one

[0728]

[0729] Use 2,2-dimethyl-1,3-dimethoxy Alkyl-5-amine, pyridin-3-ylboronic acid and (4-chlorophenyl)boronic acid followed General Procedure D (Scheme 4). The intermediate was deprotected under conditions of 2M HCl in MeOH at 40°C for 3 hours to give the title compound of Example 70.

[0730] 1H-NMR (400MHz, CDCl 3 ): δ[ppm]=9.45(s,1H),8.75-8.72(m,1H),8.65(dd,J=5.0,1.6Hz,1H),8.61(s,1H),8.45(s,1H),8.26(dd,J=6.7,1.9Hz,2H),7.64-7.61(m ,1H),7.56(dd,J=6.7,1.9Hz,1H),4.96-4.94(m,1H),4.11(dd,J=11.9,7.2Hz,2H),3.99(dd,J=11.9,4.9Hz,2H); MS(ESI,m / z):409.13[M+H] +

[0731] Example 71.

[0732] 6-(6-chloropyridin-3-yl)-3-((1R,3S)-3-hydroxycyclopentyl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one

[0733]

[0734] The title compound was obtained as described in Example 65 using (1S,3R)-3-aminocyclopentanol, pyridin-3-ylboronic acid and (6-chloropyridin-3-yl)boronic acid (Scheme 4. General Procedure D.).

[0735] 1H NMR (400MHz, CDCl3): δ [ppm] = 9.46 (s, 1H), 9.19 (d, J = 2.3Hz, 1H), 8.72 (s, 1H), 8.67 (s,1H),8.59-8.52(m,2H),8.50(dd,J=8.4,2.5Hz,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] +

[0736] Example 72.

[0737] 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

[0738]

[0739] The title compound was obtained as described in Example 65 using (1S,3R)-3-aminocyclopentanol, pyridin-3-ylboronic acid and (2-(trifluoromethyl)pyrimidin-5-yl)boronic acid (Scheme 4. General Procedure D.).

[0740] 1H NMR (400MHz, MeOD): δ [ppm] = 9.98-9.72 (m, 3H), 9.46 (d, J = 8.2Hz, 1H), 9.01-8.83 (m, 3H), 8.13 (dd, J = 8.0, 5.8Hz, 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] +

[0741] Example 73.

[0742] 3-((1R,3S)-3-Hydroxycyclopentyl)-6-(4-morpholinophenyl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one

[0743]

[0744] The title compound was obtained as described in Example 65 using (1S,3R)-3-aminocyclopentanol, pyridin-3-ylboronic acid and (4-morpholinophenyl)boronic acid (Scheme 4. General Procedure D.).

[0745] 1H NMR (400MHz, CDCl3): δ [ppm] = 9.46 (d, J = 1.6Hz, 1H), 8.69 (dd, J = 4.8, 1.3Hz, 1H), 8.59-8.52 (m, 1H), 8.49(s,1H),8.48(s,1H),8.19(d,J=8.9Hz,2H),7.45(dd,J=7.8,4.9Hz,1H),7.02(d,J=8.9Hz,2H),5 .26-5.17(m,1H),4.55-4.47(m,1H),3.96-3.79(m,4H),3.36-3.18(m,4H),2.88(d,J=3.3Hz,1H),2. 59-2.49(m,1H),2.38-2.23(m,2H),2.07-1.95(m,2H),1.88-1.78(m,1H); MS(ESI,m / z):470.29[M+H] +

[0746] Example 74.

[0747] 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

[0748]

[0749] General Procedure D (Scheme 4) was followed using 2-aminopropan-1-ol, pyridin-3-ylboronic acid and (4-chlorophenyl)boronic acid. In step e of the Suzuki coupling procedure, the title biphenyl product was obtained as a byproduct and purified by preparative HPLC eluting with 20-50-80 0.1% TFA in acetonitrile / water.

[0750] 1H-NMR (400MHz, CDCl3): δ [ppm] = 9.46 (d, J = 1.7Hz, 1H), 8.78-8.76 (m, 1H), 8.66 (d, J = 4.7 Hz,2H),8.46(s,1H),8.38(d,J=8.5Hz,2H),7.84(d,J=8.4Hz,2H),7.74(d,J=8.6Hz,2H), 7.64(dd,J=8.2,5.4Hz,1H),7.51(d,J=8.6Hz,2H),5.06-5.01(m,1H),4.00(dd,J=12.8,7 .1Hz, 1H), 3.88 (dd, J=11.8, 4.2Hz, 1H), 1.58 (d, J=7.1Hz, 3H); MS (ESI, m / z): 469.21[M+H] +

[0751] Example 75.

[0752] 3-(1-Hydroxypropan-2-yl)-6-(4-morpholinophenyl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one

[0753]

[0754] The title compound was obtained as described in Example 65 using 2-aminopropan-1-ol, pyridin-3-ylboronic acid and (4-morpholinophenyl)boronic acid (Scheme 4. General Procedure D.).

[0755] 1H-NMR (400MHz, CDCl 3 ): δ [ppm] = 9.42 (d, J = 1.5Hz, 1H), 8.75-8.70 (m, 1H), 8.64 (dd, J = 4.9, 1.6Hz, 1H), 8.5 0(s,1H),8.39(s,11H),8.18(d,J=9.0Hz,2H),7.62(dd,J=7.6,4.6Hz,1H),7.13(d,J= 9.0Hz,2H),5.05-4.99(m,1H),3.99(dd,J=11.8,7.0Hz,1H),3.91-3.87(m,4H),3.86( d,J=4.3Hz,1H),3.31-3.27(m,4H),1.57(d,J=7.1Hz,3H); MS(ESI,m / z):444.21[M+H] +

[0756] Example 76.

[0757] 3-(2-(Methylsulfonyl)ethyl)-8-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one

[0758] Preparation scheme of Example 76 compound:

[0759]

[0760] Intermediate 15. 3-Amino-6-chloro-[2,3'-bipyridine]-4-carboxylic acid methyl ester

[0761]

[0762] Stir 3-amino-6-chloro-[2,3'-bipyridine]-4-carboxylic acid (0.5 g, 2.003 mmol, 1 eq), K 2 CO 3 (0.415 g, 3.00 mmol, 1.5 eq) in DMF (20 mL, 0.1 M) for 5 minutes. Then MeI (0.426 g, 3.00 mmol, 1.5 eq) was added to the reaction mixture and stirred at room temperature for 3 hours. The reaction mixture was diluted with water (50 mL), extracted with EtOAc (20 mL × 3), washed with brine (20 mL × 3), and purified by Na 2 SO 4 Dry and filter through a glass filter. The filtrate was evaporated in vacuo and purified by MPLC (silica gel, 0-30% EtOAc / hexane) to give 0.155 g (29% yield) of 3-amino-6-chloro-[2,3'-bipyridine]-4-carboxylic acid methyl ester (Intermediate 15). MS (ESI, m / z): 264.01 [M+H] +

[0763] Intermediate 16. 3-Amino-6-(4-(trifluoromethyl)phenyl)-[2,3'-bipyridine]-4-carboxylic acid

[0764]

[0765] 3-Amino-6-chloro-[2,3'-bipyridine]-4-carboxylic acid methyl ester (Intermediate 15) (80 mg, 0.303 mmol, 1 eq.), (4-(trifluoromethyl)phenyl)boronic acid (86 mg, 0.455 mmol, 1.5 eq.), K 2 CO 3 (126 mg, 0.910 mmol, 3 eq.) and PdCl 2 (dtbpf) (20 mg, 3 μmol, 0.1 eq) was dissolved in 1,4-dihydrochloric acid The reaction mixture was stirred and heated in a Biotage microwave initiator at 130°C for 30 minutes. The reaction mixture was concentrated under reduced pressure and purified directly by MPLC (silica gel, 0-10% MeOH / DCM) to give 76 mg (70% yield) of 3-amino-6-(4-(trifluoromethyl)phenyl)-[2,3'-bipyridine]-4-carboxylic acid (Intermediate 16).

[0766] MS (ESI, m / z): 360.02 [M+H] +

[0767] Intermediate 17.

[0768] 3-Amino-N-(2-(methylsulfonyl)ethyl)-6-(4-(trifluoromethyl)phenyl)-[2,3'-bipyridine]-4-carboxamide

[0769]

[0770] A mixture of 3-amino-6-(4-(trifluoromethyl)phenyl)-[2,3'-bipyridine]-4-carboxylic acid (Intermediate 16) (65 mg, 0.181 mmol, 1 eq.), EDC (42 mg, 0.217 mmol, 1.2 eq.), HOBT (33 mg, 0.217 mmol, 1.2 eq.) and TEA (0.038 mL, 0.271 mmol, 1.5 eq.) was stirred in DMF (10 mL, 0.4 M) for 5 minutes. Then 2-(methylsulfonyl)ethylamine (27 mg, 0.217 mmol, 1.2 eq.) was added to the reaction mixture and stirred at 50 °C for 12 h. The reaction mixture was diluted with water (50 mL), extracted with EtOAc (20 mL×3), washed with brine (20 mL×3), and purified by Na 2 SO 4 The filtrate was evaporated in vacuo and purified by MPLC (silica gel, 0-5% MeOH / DCM) to give 0.07 g (83% yield) of 3-amino-N-(2-(methylsulfonyl)ethyl)-6-(4-(trifluoromethyl)phenyl)-[2,3'-bipyridine]-4-carboxamide (Intermediate 17).

[0771] MS (ESI, m / z): 465.09 [M+H] +

[0772] Example 76.

[0773] 3-(2-(Methylsulfonyl)ethyl)-8-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one

[0774]

[0775] 3-Amino-N-(2-(methylsulfonyl)ethyl)-6-(4-(trifluoromethyl)phenyl)-[2,3'-bipyridine]-4-carboxamide (Intermediate 17) (70 mg, 0.151 mmol, 1 eq.) was dissolved in (EtO) 3 CH (1.5 mL, 9.04 mmol, 60 equiv) and CH 3 CO 2 The reaction mixture was stirred and heated at 150 °C in a Biotage microwave initiator for 1 hour. The reaction mixture was diluted with water (20 mL), extracted with EtOAc (20 mL×3), washed with brine (10 mL×3), and purified by Na 2 SO 4 The mixture was dried and filtered through a glass filter. The filtrate was evaporated in vacuo and purified by MPLC (silica gel, 0-5% MeOH / DCM) to give 29 mg (40.6% yield) of 3-(2-(methylsulfonyl)ethyl)-8-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one (Example 76).

[0776] 1H-NMR (400MHz, CDCl 3 ): δ [ppm] = 9.40 (d, J = 1.5Hz, 1H), 8.74-8.70 (m, 1H), 8.68 (s, 1H), 8.64 (dd, J = 4.9, 1.5Hz, 1H), 8.44 (t, J = 4.1Hz, 3H), 7.84 (d, J=8.3Hz,2H),7.61(dd,J=8.0,4.9Hz,1H),4.58(t,J=6.5Hz,2H),3.74(t,J=6.5Hz,2H),3.10(s,3H).MS(ESI,m / z):475.00[M] +

[0777] Example 77.

[0778] 6-(4-Chlorophenyl)-3-(2-(methylsulfonyl)ethyl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one

[0779]

[0780] The title compound was obtained as described in Example 76 using 2-(methylsulfonyl)ethylamine and (4-chlorophenyl)boronic acid (Scheme 5. General Procedure E.).

[0781] 1H-NMR (400MHz, CDCl3): δ = 9.39 (s, 1H), 8.70 (d, J = 8.0Hz, 1H), 8.64 (d, J = 4.6Hz, 1H), 8.60 (s, 1H), 8.42 (s, 1H), 8.25 (d, J = 8.6Hz, 2H) ,7.61(dd,J=8.0,5.0Hz,1H),7.55(d,J=8.6Hz,2H),4.60-4.50(m,2H),3.73(t,J=6.5Hz,2H),3.10(s,3H); MS(ESI,m / z):441.07[M+H] +

[0782] Example 78.

[0783] 3-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-6-(4-morpholinophenyl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one

[0784]

[0785] The title compound was obtained as described in Example 76 using 4-aminotetrahydro-2H-thiopyran 1,1-dioxide and (4-morpholinophenyl)boronic acid (Scheme 5. General Procedure E.).

[0786] 1H-NMR (400MHz, CDCl3): δ [ppm] = 9.44 (d, J = 1.8Hz, 1H), 8.71 (dd, J = 4.8, 1.5Hz, 1H), 8 .57-8.49(m,1H),8.45(s,1H),8.19(d,J=8.9Hz,2H),8.14(s,1H),7.46(dd,J=7.9,5. 1Hz,1H),7.03(d,J=9.0Hz,2H),5.19-5.08(m,1H),3.92-3.86(m,4H),3.39-3.20(m,8 H),2.70(dd,J=26.1,13.0Hz,2H),2.37(d,J=12.6Hz,2H); MS(ESI,m / z):518.22[M+H] +

[0787] Example 79.

[0788] 3-(2-(Methylsulfonyl)ethyl)-6-(4-morpholinophenyl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one

[0789]

[0790] The title compound was obtained as described in Example 76 using 2-(methylsulfonyl)ethylamine and (4-morpholinophenyl)boronic acid (Scheme 5. General Procedure E.).

[0791] 1H-NMR (400MHz, CDCl3): δ [ppm] = 9.45 (d, J = 1.6Hz, 1H), 8.70 (dd, J = 4.8, 1.4Hz, 1 H),8.56(dt,J=7.9,1.9Hz,1H),8.43(s,1H),8.17(d,J=10.2Hz,2H),7.45(dd,J= 7.8,4.9Hz,1H),7.02(d,J=8.9Hz,2H),4.51(t,J=6.2Hz,2H),3.92-3.81(m,4H), 3.61(t,J=6.2Hz,2H),3.34-3.21(m,4H),2.98(s,3H); MS(ESI,m / z):492.21[M+H] +

[0792] Example 80.

[0793] 3-(1,3-Dihydroxypropan-2-yl)-6-(4-morpholinophenyl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one

[0794] Preparation scheme of Example 80 compound:

[0795]

[0796] Intermediate 20.

[0797] 3-(2,2-dimethyl-1,3- alkyl-5-yl)-6-(4-morpholinophenyl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one

[0798]

[0799] Use 2-dimethyl-1,3-di Alkane-5-amine and (4-morpholinophenyl)boronic acid to obtain the title compound as described for Intermediate 20 (Scheme 6. General Procedure F.).

[0800] Example 80.

[0801] 3-(1,3-Dihydroxypropan-2-yl)-6-(4-morpholinophenyl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one

[0802]

[0803] Use 2,2-dimethyl-1,3-dimethoxy Alkane-5-amine and (4-morpholinophenyl)boronic acid, the intermediate was deprotected under conditions of 2M HCl in MeOH at 40 °C for 3 hours to afford the title compound of Example 80 (Scheme 6. General Procedure F.).

[0804] 1H NMR (400MHz, DMSO): δ [ppm] = 9.33 (d, J = 1.7Hz, 1H), 8.68 (dd, J = 4.8, 1.5Hz, 1 H),8.54(dt,J=8.0,1.8Hz,1H),8.40(d,J=4.5Hz,2H),8.15(d,J=8.9Hz,2H), 7.58(dd,J=7.9,4.8Hz,1H),7.10(d,J=8.9Hz,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] +

[0805] Example 81.

[0806] (R)-3-(2,3-dihydroxypropyl)-8-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one

[0807]

[0808] General Procedure F (Scheme 6) was followed using (R)-3-aminopropane-1,2-diol, pyridin-3-ylboronic acid and (4-(trifluoromethyl)phenyl)boronic acid. During the cyclization step c, additional acetylation on one of the two hydroxyl groups was observed by LC-MS analysis. The formylated intermediate was deprotected under conditions of 2M HCl in MeOH at 40 °C for 3 hours to give the title compound of Example 81 (Scheme 6. General Procedure F.).

[0809] 1H-NMR (400MHz, CDCl3): δ [ppm] = 9.44 (s, 1H), 8.77-8.71 (m, 1H), 8.71 (s, 1H), 8.66(d,J=3.8Hz,1H),8.46(d,J=8.2Hz,2H),8.38(s,1H),7.86(d,J=8.3Hz,2H) ,7.63(dd,J=7.9,5.0Hz,1H),4.49(dd,J=13.6,3.2Hz,1H),4.10-3.99(m,1H), 3.91(dd,J=13.6,8.8Hz,1H),3.66(d,J=5.2Hz,2H); MS(ESI,m / z):443.45[M+H] +

[0810] Example 82.

[0811] 3-(2,3-Dihydroxypropyl)-6-(4-morpholinophenyl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one

[0812]

[0813] General Procedure F (Scheme 6) was followed using 3-aminopropane-1,2-diol and (4-morpholinophenyl)boronic acid. During the cyclization step c, additional acetylation on one of the two hydroxyl groups was observed by LC-MS analysis. The formylated intermediate was deprotected under conditions of 2M HCl in MeOH at 40 °C for 3 hours to give the title compound of Example 82 (Scheme 6. General Procedure F.).

[0814] 1H-NMR (400MHz, CDCl3): δ [ppm] = 9.45 (d, J = 1.8Hz, 1H), 8.67 (d, J = 3.5Hz, 1H), 8.5 5(d,J=7.9Hz,1H),8.44(s,1H),8.17(d,J=8.8Hz,2H),8.14(s,1H),7.43(dd,J=7. 8,5.0Hz,1H),7.02(d,J=8.9Hz,2H),4.30(d,J=10.2Hz,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] +

[0815] Example 83.

[0816] 2-(6-(4-chlorophenyl)-4-oxo-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-3(4H)-yl)propanoic acid, 2,2,2-trifluoroacetate

[0817]

[0818] The title compound was obtained as described in Example 80 using methyl 2-aminopropanoate hydrochloride, pyridin-3-ylboronic acid and (4-chlorophenyl)boronic acid (Scheme 6. General Procedure F.).

[0819] 1H NMR (400MHz, DMSO): δ [ppm] = 9.38 (s, 1H), 8.75 (d, J = 3.6Hz, 1H), 8.64 (d, J = 8.0Hz, 1H), 8.62 (s, 1H), 8.56 (s, 1H), 8.33 (d, J = 8.6Hz ,2H),7.67(dd,J=7.8,4.9Hz,1H),7.61(d,J=8.6Hz,2H),5.34(q,J=7.2Hz,1H),1.72(d,J=7.3Hz,3H); MS(ESI,m / z):407.04[M+H] +

[0820] Example 84.

[0821] 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

[0822]

[0823] The title compound was obtained as described in Example 80 using methyl 2-aminopropanoate hydrochloride, pyridin-3-ylboronic acid and (4-(trifluoromethyl)phenyl)boronic acid (Scheme 6. General Procedure F.).

[0824] 1H NMR (400MHz, DMSO): δ [ppm] = 9.38 (br, 1H), 8.73 (br, 1H), 8.64 (s, 2H), 8.56 (d, J = 7.9Hz, 1H), 8.52 (d, J = 8.2Hz, 2H) ,7.91(d,J=8.4Hz,2H),7.67-7.58(m,1H),5.35(q,J=7.2Hz,1H),1.72(d,J=7.3Hz,3H); MS(ESI,m / z):441.07[M+H] +

[0825] Example 86.

[0826] N-(2-(4-oxo-8-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidin-3(4H)-yl)propyl)acetamide

[0827] Preparation scheme of Example 86 compound:

[0828]

[0829] Intermediate 21. tert-Butyl (2-(3-amino-6-chloro-2-iodoisonicotinamido)propyl)carbamate

[0830]

[0831] A mixture of 3-amino-6-chloro-2-iodoisonicotinic acid (intermediate 1) (0.8 g, 2.68 mmol, 1 eq.), EDC (0.617 g, 3.22 mmol, 1.2 eq.), HOBT (0.493 g, 3.22 mmol, 1.2 eq.) and TEA (0.560 mL, 4.02 mmol, 1.5 eq.) was dissolved in DMF (13.4 mL, 0.2 M) and stirred for 10 minutes. Then, tert-butyl (2-aminopropyl)carbamate (0.475 mL, 2.68 mmol, 1 eq.) was added to the reaction mixture and stirred at 50 ° C for 12 h. The reaction mixture was diluted with water (50 mL), extracted with EtOAc (20 mL×3), washed with brine (20 mL×3), and purified by Na 2 SO 4 The filtrate was evaporated in vacuo and purified by MPLC (silica gel, 0-50% EtOAc / hexanes) to give 0.372 g (31% yield) of tert-butyl (2-(3-amino-6-chloro-2-iodoisonicotinamido)propyl)carbamate (Intermediate 21).

[0832] 1H NMR (400MHz, CDCl 3 ): δ=7.71(d,J=5.1Hz,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=6.5Hz,3H);MS(ESI,m / z):455.08[M+H] +

[0833] Intermediate 22.

[0834] 6-Chloro-3-((1R,3S)-3-hydroxycyclopentyl)-8-iodopyrido[3,4-d]pyrimidin-4(3H)-one

[0835]

[0836] Tert-butyl (2-(3-amino-6-chloro-2-iodoisonicotinamido)propyl)carbamate (Intermediate 21) (0.372 mg, 0.818 mmol, 1 eq.) was dissolved in (EtO) 3 CH (1.226 mL, 7.36 mmol, 9 equiv) and CH 3 CO 2 The reaction mixture was stirred and heated at 150 °C in a Biotage microwave initiator for 1 hour. The reaction mixture was diluted with water (20 mL), extracted with EtOAc (20 mL×3), washed with brine (10 mL×3), and purified by Na 2 SO 4 The filtrate was evaporated in vacuo and purified by MPLC (silica gel, 0-50% EtOAc / hexanes) to give 0.135 g (36% yield) of tert-butyl (2-(6-chloro-8-iodo-4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)propyl)carbamate (Intermediate 22), which was used without further purification.

[0837] 1H NMR (400MHz, CDCl 3 ): 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=6.2Hz, 2H), 1.54 (d, J=7.2Hz, 3H), 1.32 (s, 9H); MS (ESI, m / z): 465.07[M+H] +

[0838] Intermediate 23.

[0839] Tert-butyl 2-(6-chloro-4-oxo-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-3(4H)-yl)propyl)carbamate

[0840]

[0841] 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 eq), pyridin-3-ylboronic acid (0.036 g, 0.291 mmol, 1.1 eq), K 2 CO 3(0.110 g, 0.794 mmol, 3 equiv) and Pd(dppf)Cl 2 ·CH 2 Cl 2 (0.022 g, 0.026 mmol, 0.1 eq.) was dissolved in 1,4-dihydrochloric acid. The reaction mixture was stirred and heated at 130°C in a Biotage microwave initiator for 30 minutes. The reaction mixture was diluted with water (10 mL), extracted with EtOAc (10 mL×3), washed with brine (10 mL×3), and purified by Na 2 SO 4 The filtrate was evaporated in vacuo and purified by MPLC (silica gel, 0-5% MeOH / DCM) to give 0.093 g (84% yield) of tert-butyl (2-(6-chloro-4-oxo-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-3(4H)-yl)propyl)carbamate (Intermediate 23).

[0842] 1H NMR (400MHz, CDCl 3 ): δ=9.37(d,J=1.8Hz,1H),8.70(dd,J=4.8,1.5Hz,1H),8.44(dt,J=8.0,1.8Hz,1H),8.13(s,1H),8.09(s,1H),7.44(dd,J=7.9,4. 8Hz,1H),5.02-4.91(m,1H),4.81-4.72(m,1H),3.66-3.47(m,2H),1.56(d,J=7.1Hz,3H),1.29(s,9H);MS(ESI,m / z):416.18[M+H] +

[0843] Intermediate 24.

[0844] tert-Butyl (2-(4-oxo-8-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidin-3(4H)-yl)propyl)carbamate

[0845]

[0846] 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 eq), (4-(trifluoromethyl)phenyl)boronic acid (15.1 mg, 0.079 mmol, 1.1 eq), K 2 CO3 (29.9 mg, 0.216 mmol, 3 equiv) and Pd(dppf)Cl 2 ·CH 2 Cl 2 (5.9 mg, 7.21 μmol, 0.1 eq.) dissolved in 1,4-dihydrochloric acid The reaction mixture was stirred and heated at 130°C in a Biotage microwave initiator for 30 minutes. The reaction mixture was diluted with water (10 mL), extracted with EtOAc (10 mL×3), washed with brine (5 mL×3), and purified by Na 2 SO 4 The filtrate was dried and filtered through a glass filter. The filtrate was evaporated in vacuo and purified by MPLC (silica gel, 0-10% MeOH / DCM) to give 29 mg (76% yield) of 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).

[0847] 1H-NMR (400MHz, CDCl 3 ): δ=9.53(s,1H),8.75(d,J=3.8Hz,1H),8.63-8.57(m,2H),8.34(d,J=8.2Hz,2H),8.11(s,1H),7.78(d,J=8.3Hz,2H),7.50(dd,J=7.6 ,5.0Hz,1H),5.05-4.95(m,1H),4.82-4.74(m,1H),3.69-3.51(m,2H),1.58(d,J=8.0Hz,3H),1.29(s,9H);MS(ESI,m / z):526.22[M+H] +

[0848] Example 85.

[0849] 3-(1-aminopropan-2-yl)-8-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one

[0850]

[0851] 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 eq) was dissolved in 4 M HCl in 1,4-dihydrochloric acid. The reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure and diluted with DCM (10 mL). The solution was carefully basified with 1 M NaOH solution until the pH value of the aqueous layer reached 7. The aqueous layer was further extracted with DCM (10 mL × 2), and the combined organic layers were washed with Na 2 SO 4 The filtrate was evaporated in vacuo and purified by MPLC (0-10% MeOH / DCM) to give 12.2 mg (51% yield) of 3-(1-aminopropan-2-yl)-8-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl[3,4-d]pyrimidin-4(3H)-one (Example 85).

[0852] 1H-NMR (400MHz, CDCl 3 ): δ[ppm]=9.47(d,J=1.7Hz,1H),8.72(dd,J=4.8,1.6Hz,1H),8.61(d,J=2.7Hz,1H),8.57(dt,J=7.9,1.9Hz,1H),8.35(d,J=8.2Hz,2H),8.31(s, 1H),7.78(d,J=8.3Hz,2H),7.47(dd,J=7.8,4.9Hz,1H),5.09-4.98(m,1H),3.20-3.08(m,2H),1.55(d,J=7.1Hz,3H); MS(ESI,m / z):426.15[M+H] +

[0853] Example 86.

[0854] N-(2-(4-oxo-8-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidin-3(4H)-yl)propyl)acetamide

[0855]

[0856] 3-(1-aminopropan-2-yl)-8-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl[3,4-d]pyrimidin-4(3H)-one (Example 85) (9.8 g, 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. Then, acetyl chloride (1.97 μl, 0.028 mmol, 1.2 eq) was added to the reaction mixture and stirred at room temperature for 30 minutes. The reaction mixture was diluted with water (5 mL), extracted with DCM (5 mL×3), washed with brine (5 mL×3), and purified by Na 2 SO 4 The mixture was dried and filtered through a glass filter. The filtrate was evaporated in vacuo and purified by MPLC (silica gel, 0-10% MeOH / DCM) to give 4.2 mg (38% yield) 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).

[0857] 1H NMR (400MHz, CDCl 3 ): δ [ppm] = 9.46 (d, J = 1.7Hz, 1H), 8.71 (dd, J = 4.8, 1.5Hz, 1H), 8.59-8.54 (m, 2 H),8.33(d,J=8.2Hz,2H),8.14(s,1H),7.77(d,J=8.3Hz,2H),7.46(dd,J=7.8 ,4.7Hz,1H),5.94(t,J=5.9Hz,1H),5.06-4.96(m,1H),3.89-3.77(m,1H),3.7 1-3.61(m,1H),1.92(s,3H),1.60(d,J=7.1Hz,3H); MS(ESI,m / z):468.20[M+H] +

[0858] Example 87.

[0859] 3-(1-aminopropan-2-yl)-6-(4-chlorophenyl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one

[0860]

[0861] The title compound was obtained as described in Example 85 using tert-butyl (2-aminopropyl)carbamate, pyridin-3-ylboronic acid and (4-chlorophenyl)boronic acid (Scheme 7. General Procedure G.).

[0862] 1H NMR (400MHz, MeOD): δ [ppm] = 9.41 (d, J = 1.7Hz, 1H), 8.72 (dt, J = 8.0, 1.9Hz, 1H) ,8.63(dd,J=4.9,1.5Hz,1H),8.58(s,1H),8.39(s,1H),8.23(d,J=8.6Hz,2H), 7.61(dd,J=8.2,4.7Hz,1H),7.53(d,J=8.6Hz,2H),5.00-4.91(m,1H),2.36-2. 28(m,1H),2.23-2.13(m,1H),1.58(d,J=7.0Hz,3H); MS(ESI,m / z):392.14[M+H] +

[0863] Example 88.

[0864] N-(2-(6-(4-chlorophenyl)-4-oxo-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-3(4H)-yl)propyl)acetamide

[0865]

[0866] The title compound was obtained as described in Example 86 using tert-butyl (2-aminopropyl)carbamate, pyridin-3-ylboronic acid, (4-chlorophenyl)boronic acid and acetyl chloride (Scheme 7. General Procedure G.).

[0867] 1H NMR (400MHz, MeOD): δ [ppm] = 9.41 (s, 1H), 8.71 (dt, J = 8.0, 1.8Hz, 1H), 8.63 (d, J = 3.5Hz, 1H), 8.57 (s, 1H), 8.35 (s, 1H), 8.23 ​​(d, J = 8.6Hz, 2H), 7.61 (dd,J=7.9,4.9Hz,1H),7.54(d,J=8.6Hz,2H),5.08-4.98(m,1H),3.70-3. 63(m,2H),1.84(s,3H),1.59(d,J=7.1Hz,3H); MS(ESI,m / z):434.16[M+H] +

[0868] Example 89.

[0869] N-(2-(6-(4-chlorophenyl)-4-oxo-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-3(4H)-yl)propyl)methanesulfonamide

[0870]

[0871] The title compound was obtained as described in Example 86 using tert-butyl (2-aminopropyl)carbamate, pyridin-3-ylboronic acid, (4-chlorophenyl)boronic acid and methanesulfonyl chloride (Scheme 7. General Procedure G.).

[0872] 1H NMR (400MHz, CDCl 3 ): δ [ppm] = 9.35 (d, J = 1.5Hz, 1H), 8.64 (dd, J = 4.7, 1.3Hz, 1H), 8.46 (dt, J = 8.0, 1.9Hz,1H),8.30(s,1H),8.14(s,1H),8.03(d,J=8.7Hz,2H),7.42(d,J=8.7Hz, 2H),7.41-7.37(m,1H),6.07(t,J=6.5Hz,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] +

[0873] Example 90.

[0874] 3-(1-aminopropan-2-yl)-6-(4-morpholinophenyl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one

[0875]

[0876] The title compound was obtained as described in Example 85 using tert-butyl (2-aminopropyl)carbamate, pyridin-3-ylboronic acid and (4-morpholinophenyl)boronic acid (Scheme 7. General Procedure G.).

[0877] 1H NMR (400MHz, 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 .9,1.6Hz,1H),8.46(s,1H),8.31(s,1H),8.14(d,J=8.9Hz,2H),7.59(dd,J=8.0,4.9Hz,1H), 7.09(d,J=9.0Hz,2H),4.96-4.88(m,1H),3.86(t,J=4.8Hz,4H),3.27(t,J=4.8Hz,4H),3.23- 3.19(m,1H),3.10(dd,J=13.6,5.1Hz,1H),1.56(d,J=7.0Hz,3H); MS(ESI,m / z):443.23[M+H]+

[0878] Example 91.

[0879] N-(2-(6-(4-morpholinophenyl)-4-oxo-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-3(4H)-yl)propyl)methanesulfonamide

[0880]

[0881] The title compound was obtained as described in Example 86 using tert-butyl (2-aminopropyl)carbamate, pyridin-3-ylboronic acid, (4-morpholinophenyl)boronic acid and methanesulfonyl chloride (Scheme 7. General Procedure G.).

[0882] 1H NMR (400MHz, MeOD): δ [ppm] = 9.37 (s, 1H), 8.68 (dt, J = 8.0, 1.8Hz, 1H), 8.61 (d, J = 4.6Hz, 1H), 8.42(s,1H),8.27(s,1H),8.11(d,J=8.9Hz,2H),7.58(dd,J=7.9,5.0Hz,1H),7.07(d,J=8.9Hz ,2H),4.96-4.90(m,1H),3.86(t,J=4.8,4H),3.63(dd,J=14.4,7.9Hz,1H),3.50(dd,J=14.3,4 .7Hz,1H),3.26(t,J=4.8,4H),2.92(s,3H),1.60(d,J=7.1Hz,3H); MS(ESI,m / z):521.21[M+H] +

[0883] Example 92.

[0884] N-(2-(6-(4-morpholinophenyl)-4-oxo-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-3(4H)-yl)propyl)acetamide

[0885]

[0886] The title compound was obtained as described in Example 86 using tert-butyl (2-aminopropyl)carbamate, pyridin-3-ylboronic acid, (4-morpholinophenyl)boronic acid and acetyl chloride (Scheme 7. General Procedure G.).

[0887] 1H NMR (400MHz, MeOD): δ [ppm] = 9.40 (s, 1H), 8.74-8.69 (m, 1H), 8.62 (d, J = 4.8Hz, 1H), 8.44(s,1H),8.28(s,1H),8.13(d,J=8.9Hz,2H),7.60(dd,J=7.9,4.9Hz,1H),7.09( d,J=8.9Hz,2H),5.06-4.98(m,1H),3.86(t,J=4.8Hz,4H),3.66(t,J=5.8Hz,2H),3. 27(t,J=4.8Hz,4H),1.84(s,3H),1.58(d,J=7.1Hz,3H); MS(ESI,m / z):485.16[M+H] +

[0888] Example 93.

[0889] 3-(Piperidin-4-yl)-8-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one

[0890]

[0891] The title compound was obtained as described in Example 85 using tert-butyl 4-aminopiperidine-1-carboxylate, pyridin-3-ylboronic acid and (4-(trifluoromethyl)phenyl)boronic acid (Scheme 7. General Procedure G.).

[0892] 1H NMR (400MHz, 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=5.0,1.5Hz,1H),8.62(s,1H),8.44(s,1H),8.41(d,J=8.2Hz,2H),7.82( d,J=8.3Hz,2H),7.61(dd,J=8.0,4.9Hz,1H),4.85-4.78(m,1H),3.26(d,J=12.9Hz ,2H),2.82(td,J=13.0,2.8Hz,2H),2.12-2.01(m,4H);MS(ESI,m / z):452.19[M+H] +

[0893] Example 94.

[0894] 6-(4-Chlorophenyl)-3-(1-(methylsulfonyl)piperidin-4-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one

[0895]

[0896] The title compound was obtained as described in Example 86 using tert-butyl 4-aminopiperidine-1-carboxylate, pyridin-3-ylboronic acid, (4-chlorophenyl)boronic acid and methanesulfonyl chloride (Scheme 7. General Procedure G.).

[0897] 1H NMR (400MHz, CDCl 3 ): δ[ppm]=9.44(d,J=1.6Hz,1H),8.72(dd,J=4.8,1.6Hz,1H),8.56-8.53(m,2H),8.19(d,J=8.7Hz,2H),8.17(s,1H),7.50(d,J=8.7Hz,2H), 7.49-7.44(m,1H),5.03-4.93(m,1H),4.09(d,J=12.4Hz,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] +

[0898] Example 95.

[0899] 6-(4-Chlorophenyl)-3-(1-(cyclopropylsulfonyl)piperidin-4-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one

[0900]

[0901] The title compound was obtained as described in Example 86 using tert-butyl 4-aminopiperidine-1-carboxylate, pyridin-3-ylboronic acid, (4-chlorophenyl)boronic acid and methanesulfonyl chloride (Scheme 7. General Procedure G.).

[0902] 1H NMR (400MHz, CDCl 3 ): δ[ppm]=9.48(s,1H),8.74(s,1H),8.59(d,J=7.9Hz,1H),8.53(s,1H), 8.18(d,J=9.6Hz,3H),7.50(d,J=8.6Hz,3H),5.04-4.93(m,1H),4.08(d, J=12.8Hz,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=5.4,0.6Hz,2H); MS(ESI,m / z):522.16[M] +

[0903] Example 96.

[0904] 3-(1-acetylpiperidin-4-yl)-6-(4-chlorophenyl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one

[0905]

[0906] The title compound was obtained as described in Example 86 using tert-butyl 4-aminopiperidine-1-carboxylate, pyridin-3-ylboronic acid, (4-chlorophenyl)boronic acid and acetyl chloride (Scheme 7. General Procedure G.).

[0907] 1H NMR (400MHz, CDCl 3 ): δ[ppm]=9.43(d,J=2.0Hz,1H),8.72(dd,J=4.9,1.6Hz,1H),8.55-8.51(m,2H),8.19(d,J=8.6H z,2H),8.13(s,1H),7.50(d,J=8.7Hz,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=13.9Hz,1H),3.33(t,J=11.8Hz,1H),2.75(td,J=13.2,2.1Hz,1H),2.18(s,3H ),2.13(d,J=10.8Hz,1H),2.06(d,J=10.9Hz,1H),1.98-1.82(m,2H); MS(ESI,m / z):460.19[M+H] +

[0908] XRE-luciferase reporter gene in vitro assay (in vitro assays 1, 2, 3)

[0909] AhR activation induces target gene expression, such as CYP1A1 and CYP1B1, by binding of AhR to AhR-responsive DNA elements, also known as xenobiotic-responsive elements (XREs). The assay used herein to measure AhR activity is a luciferase assay using a cell line transfected with a luciferase reporter plasmid containing an XRE upstream of the reporter gene. Cells transfected with the XRE-luciferase reporter (XRE-Luc) plasmid drive luciferase activity that reflects activation and inhibition of AhR in the cell. In addition to transfection with the XRE reporter vector, cells were co-transfected with a nanoluciferase reporter construct (Nano-Luc) containing a constitutively active promoter as an internal control. Kynurenine, an endogenous AhR agonist, was used to stimulate cells to test the antagonistic properties of the compounds. The half-maximal inhibitory concentration (IC) was calculated using nonlinear regression (four parameters) and Prism 8.0 software (GraphPad). 50 ) or half maximal effective concentration (EC 50 )value.

[0910] In vitro assay 1: antagonism in human cell lines

[0911] HepG2 (human hepatoma cell line) cells transiently or stably transfected with XRE-luciferase reporter gene (Invivogen) were plated in complete medium and incubated at 37°C in CO. 2 Incubate in an incubator. After 24 hours, treat cells with kynurenine (50* or 200 μM) alone (negative control) or with test compounds for 6 hours. Luciferase activity is measured using a commercial kit, such as the Promega luciferase kit or other reagents that measure luciferase activity. Calculate IC using relative luciferase activity (Firefly / Nano-Luc) 50 The relative luciferase activity was further normalized by taking the kynurenine group alone as the maximum control and the vehicle group as the minimum control. The AhR antagonistic potency of the example compounds is listed in the following Table 1. (IC 50 The values ​​are grouped into A, B, C, and D, where A: IC 50 <0.01μM; B: 0.01 <IC 50 <0.1μM; C: 0.1 <IC 50 <1.0μM; D:IC 50 >1.0μM)

[0912] In vitro assay 2: antagonism in mouse cell lines

[0913] Hepa1c1c7 (murine hepatoma cell line) cells co-transfected with XRE-Luc and Nano-Luc plasmids were placed in complete medium and incubated at 37°C in a CO atmosphere. 2Incubate overnight in an incubator. After incubation, treat cells with AhR activating ligands such as kynurenic acid, kynurenine (#) in the presence or absence of test compounds for 6 hours. Firefly luciferase and nano-luciferase activities were measured using the Nano-glo luciferase kit (Promega), and the relative luciferase activity (Firefly / Nano-Luc) was used to calculate the IC 50 The relative luciferase activity was further normalized by taking the agonist group alone as the maximum control and the vehicle group as the minimum control. The AhR antagonistic potency of the example compounds is listed in Table 1 below. (IC 50 The values ​​are grouped into A, B, C, and D, where A: IC 50 <0.01μM; B: 0.01 <IC 50 <0.1μM; C: 0.1 <IC 50 <1.0μM; D:IC 50 >1.0μM)

[0914] In vitro assay 3: agonism in human cell lines

[0915] HepG2 (human hepatoma cell line) cells co-transfected with XRE-Luc and Nano-Luc plasmids were seeded in tryptophan-free medium containing 1% dialyzed fetal bovine serum and incubated at 37°C in a CO atmosphere. 2 Incubate overnight in an incubator. After 24 h, cells were treated with or without test compounds for 6 h. Firefly luciferase and nano-luciferase activities were measured using the Nano-glo luciferase kit (Promega), and the EC was calculated using the relative luciferase activity (Firefly / Nano-Luc). 50 As a positive control, cells were incubated with TCDD.

[0916] (EC 50 The values ​​are divided into A, B, C and D, where A:EC 50 <0.1μM; B: 0.1 <EC 50 <1.0μM; C: 1.0 <EC 50 <10μM; D:EC 50 >10μM)

[0917] Table 1

[0918]

[0919]

[0920]

[0921] (*: cells treated with kynurenine 50uM#: cells treated with kynurenine)

[0922] In vitro assay 4: endogenous AhR activity assay

[0923] HepG2 cells were seeded in 12-well plates (3 × 10 5 cells / well). One day after seeding, cells were treated with TCDD (10 nM) alone or with compounds (123 nM) for 4 h. Total RNA was extracted using Trizol (Thermo Fisher Scientific). PrimeScript TM RT Master Mix(TAKARA) and TB Green TM PremixEx Taq TM cDNA synthesis and quantitative RT-PCR (qRT-PCR) assays were performed by TAKARA II. For the measurement of endogenous AhR activity, the relative mRNA levels of CYP1A1 and CYP1B1 were quantified relative to β(beta)-actin mRNA by the comparative Ct (ΔΔCt) method. The inhibition percentage was calculated according to the following formula:

[0924]

[0925] The endogenous AhR antagonistic potency of the example compounds is listed in Table 2 below.

[0926] Table 2

[0927]

Claims

1. A compound of formula (I) or an enantiomer, diastereomer, racemate or pharmaceutically acceptable salt thereof: in: Ar 1 and Ar 2 are independently selected from the group consisting of: 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, wherein Ar 1 and Ar 2 are independently unsubstituted or substituted with halogen, hydroxy, amino, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, phenyl, halogenated phenyl, piperazine, C 1-6 Alkylpiperazine or morpholine substitution; L is a monocyclic or bicyclic C 3-10 Cycloalkyl, monocyclic or bicyclic C 6-10 Aryl or monocyclic or bicyclic C 5-10 heteroaryl; R 1 is halogen, cyano, hydroxyl, amino, N(R 3 2. NHR 3 , OR 3 , phosphate, C 1-3 Alkyl phosphate, C 1-5 Alkyl, -S(=O)-OH, -S(=O)2-OH, -SO2NR 2 2. -NR 2 SO2-H, -(CO)-OH, (-(CO)R 2 、-(CO)NR 2 2. -NH(CO)-R 2 、-(CO)OR 2 、-SO2-R 2 , C 3-10 Cycloalkyl, C 1-5 Alkyl hydroxyl, C 1-5 Alkenyl hydroxyl, C 1-5 Alkynyl hydroxyl, C 1-5 Alkylamine, C 1-5 Alkenylamine, C 1-5 Alkynylamine, monocyclic or bicyclic C 3-10 Heterocycloalkyl or monocyclic or bicyclic C 5-10 heteroaryl; R 2 H, halogen, hydroxyl, amino, C 1-5 Alkyl, C 1-5 Alkoxy, C 3-8 Cycloalkyl or C 1-5 Alkyl carboxylic acids; R 3 It is H, C 1-5 Alkyl, C 1-5 Alkyl-CO-, C 1-5 Alkyl-SO2-, C 1-5 Alkyl-SO2NR 2 2. C 1-5 Alkyl-(CO)NR 2 2. C 1-5 Alkyl-NR 2 (CO)-、C 1-5 Alkoxy or C 1-5 Alkyl carboxylic acid.

2. The compound according to claim 1 or its enantiomer, diastereomer, racemate or pharmaceutically acceptable salt, in, Ar 1 and Ar 2 Each is independently a substituted or unsubstituted monocyclic or bicyclic C 6-10 Aryl, substituted or unsubstituted monocyclic C containing one or more heteroatoms selected from the group consisting of N, O and S 5-7 heteroaryl, or a substituted or unsubstituted monocyclic C containing one or more heteroatoms selected from the group consisting of N, O and S 5-7 Heterocycloalkyl, wherein Ar 1 and Ar 2 are independently unsubstituted or substituted with halogen, hydroxy, amino, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, phenyl, halogenated phenyl, piperazine, C 1-6 Alkylpiperazine or morpholine substitution.

3. The compound according to claim 1 or its enantiomer, diastereomer, racemate or pharmaceutically acceptable salt, in, Ar 1 and Ar 2 are each independently phenyl, a monocyclic C 5-6 heteroaryl, or a monocyclic C containing one or two heteroatoms selected from the group consisting of N, O and S 5-6 Heterocycloalkyl, which is unsubstituted or substituted by halogen, hydroxy, amino, phenyl, C 1-3 Alkyl or C 1-3 Alkoxy substituted, wherein phenyl, C 1-3 Alkyl or C 1-3 The alkoxy group is unsubstituted or substituted with 1 to 3 halogens.

4. The compound according to claim 1 or its enantiomer, diastereomer, racemate or pharmaceutically acceptable salt, in, L is a monocyclic or bicyclic C 3-8 Cycloalkyl, monocyclic or bicyclic C 6-10 Aryl or monocyclic or bicyclic C 5-8 Heteroaryl; wherein the monocyclic or bicyclic C 5-8 The heteroaryl group contains one or more heteroatoms selected from the group consisting of N, O and S.

5. The compound according to claim 1 or its enantiomer, diastereomer, racemate or pharmaceutically acceptable salt, in, L is a monocyclic or bicyclic C 3-6 Cycloalkyl.

6. The compound according to claim 1 or its enantiomer, diastereomer, racemate or pharmaceutically acceptable salt, in, R 1 is halogen, cyano, hydroxyl, amino, N(R 3 2. NHR 3 , OR 3 , C 1-4 Alkyl, -(CO)R 2 , C 3-8 Cycloalkyl, C 1-4 Alkyl hydroxyl, C 1-4 Alkenyl hydroxyl, C 1-4 Alkynyl hydroxyl, C 1-4 Alkylamine, C 1-4 Alkenylamine, C 1-4 Alkynylamine, monocyclic or bicyclic C 3-8 Heterocycloalkyl or monocyclic or bicyclic C 5-8 Heteroaryl, wherein the monocyclic or bicyclic C 3-8 Heterocycloalkyl and monocyclic or bicyclic C 5-8 The heteroaryl group contains one or more heteroatoms selected from the group consisting of N, O and S.

7. The compound according to claim 1 or its enantiomer, diastereomer, racemate or pharmaceutically acceptable salt, in, R 1 It is hydroxy, -NH2, -NH-C(O)CH3, -NH-SO2-CH3, -C(O)OH, -SO2-CH3, -OC(O)-CH3, -OP(=O)(OCH2CH3)2 or -C(O)CH3.

8. A compound selected from compounds (1) to (22), (25) to (37) and (41) to (96), or an enantiomer, diastereomer, racemate or pharmaceutically acceptable salt thereof: (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; (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) 2-(6-(4-chlorophenyl)-4-oxo-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-3(4H)-yl)propyl diethyl 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-(1-hydroxypropan-2-yl)-8-(pyridin-3-yl)-2,3-dihydropyrido[3,4-d]pyrimidin-4(1H)-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-dioxidotetrahydro-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.

9. A pharmaceutical composition comprising the compound according to claim 1 or 8 or its enantiomer, diastereomer, racemate or pharmaceutically acceptable salt and a pharmaceutically acceptable carrier.

10. The pharmaceutical composition according to claim 9, for use in preventing and / or treating diseases or disorders mediated by the aryl hydrocarbon receptor (AhR).

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

12. The pharmaceutical composition according to claim 9, for inhibiting proliferation, tissue invasion, metastasis and angiogenesis of cancer cells in a subject suffering from cancer.

13. The pharmaceutical composition according to claim 12, wherein The cancer is selected from the group consisting of breast cancer, squamous cell carcinoma, lung cancer, peritoneal cancer, gastric cancer, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, colon cancer, colorectal cancer, endometrial or 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. The pharmaceutical composition according to claim 12, wherein The cancer is hepatocellular carcinoma.

15. The pharmaceutical composition according to claim 11, wherein The fibrotic disorder is selected from the group consisting of liver fibrosis, liver cirrhosis, pulmonary fibrosis, endomyocardial fibrosis, nephropathy, interstitial renal fibrosis, fibrotic lesions caused by diabetes, myelofibrosis, scleroderma, morphea, keloids, hypertrophic scars, nevi, diabetic retinopathy, proliferative vitreoretinopathy and sarcoidosis.

16. The pharmaceutical composition according to claim 11, wherein The fibrotic disorder is glomerulonephritis.

17. The pharmaceutical composition according to claim 11, wherein The disorder of the dysregulated immune response is selected from the group consisting of sepsis, multiple organ failure, inflammatory kidney disease, chronic intestinal inflammation, pancreatitis, peritonitis, inflammatory skin disease and inflammatory eye disease, rheumatoid disease, systemic lupus erythematosus and multiple sclerosis.

18. Use of the compound according to claim 1 or 8 or its enantiomer, diastereomer, racemate or pharmaceutically acceptable salt in the preparation of an AhR activity modulator.

19. Use of the compound according to claim 1 or 8 or its enantiomer, diastereomer, racemate or pharmaceutically acceptable salt in the preparation of a medicament for preventing or treating a disease or condition mediated by the aryl hydrocarbon receptor (AhR).

20. The use according to claim 19, wherein The disease or condition mediated by the aryl hydrocarbon receptor (AhR) is cancer, a fibrotic disorder, or a disorder of a dysregulated immune response or other disorder associated with aberrant AhR signaling.

21. The use according to claim 20, wherein The cancer is selected from the group consisting of breast cancer, squamous cell carcinoma, lung cancer, peritoneal cancer, gastric cancer, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, colon cancer, colorectal cancer, endometrial or 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.

22. The use according to claim 20, wherein The cancer is hepatocellular carcinoma.

23. The use according to claim 20, wherein The fibrotic disorder is selected from the group consisting of liver fibrosis, liver cirrhosis, pulmonary fibrosis, endomyocardial fibrosis, nephropathy, interstitial renal fibrosis, fibrotic lesions caused by diabetes, myelofibrosis, scleroderma, morphea, keloids, hypertrophic scars, nevi, diabetic retinopathy, proliferative vitreoretinopathy and sarcoidosis.

24. The use according to claim 20, wherein The fibrotic disorder is glomerulonephritis.

25. The use according to claim 20, wherein The disorder of the dysregulated immune response is selected from the group consisting of sepsis, multiple organ failure, inflammatory kidney disease, chronic intestinal inflammation, pancreatitis, peritonitis, inflammatory skin disease and inflammatory eye disease, rheumatoid disease, systemic lupus erythematosus and multiple sclerosis.

26. Use of the compound according to claim 1 or 8 or its enantiomer, diastereomer, racemate or pharmaceutically acceptable salt in the preparation of an inhibitor of cancer cell proliferation, tissue invasion, metastasis or angiogenesis.

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