RU2818954C1 - Pyridopyrimidinone derivatives and use thereof as aromatic hydrocarbon receptor modulators - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (I), where Ar¹, Ar², L, R¹ are defined in the claims, effective as modulators of the aromatic hydrocarbon receptor (AhR), a pharmaceutical composition containing compounds for modulating AhR or preventing or treating a disease, disorder or condition associated with AhR activity, as an active ingredient.

EFFECT: invention can be used as a drug for preventing or treating a disease, disorder or condition associated with the activity of AhR, in particular, a malignant tumour, a cancer condition, a tumour, a fibrous disease, a condition with uncontrolled immune responses.

21 cl, 2 tbl, 96 ex

Description

[Technical field]

The present invention relates to novel pyridopyrimidinone derivatives that can modulate the activity of the aromatic hydrocarbon receptor (AhR). The compounds of formula (I) of the present invention can also be used for the inhibition of cancer cell growth, metastasis and invasion of tumor cells, as well as for the treatment of diseases associated with uncontrolled immune responses associated with AhR signaling (single agent or in combination with other active substances ).

[Prior Art]

The aromatic hydrocarbon receptor (AhR) is a ligand-activating transcription factor and is well known as an important intracellular chemosensor that responds to both natural and synthetic environmental compounds. As is well known, AhR is a member of the circadian rhythm protein (PER)-AhR nuclear translocator (ARNT)-targeted homologue (SIM) superfamily of transcription factors, in which the PER-ARNT-SIM(PAS) domain responds to ligands (Burbach et al., PNAS September 1, 1992 89 (17) 8185-8189). AhR, activated by multiple binding ligands, translocates to the nucleus and dimerizes with its protein partner ARNT. This heterodimeric complex interacts with xenobiotic response elements (XREs) and it directly or indirectly controls the expression of AhR-related genes. One well-studied endogenous ligand is kynurenine, produced by tryptophan 2,3-dioxygenase (Opitz et al., Nature, Nature. 2011 Oct 5;478(7368): 197-203) orlDO (Meznch, J Immunol. 2010 Sep 15; 185(6):3190-8.) or indoleamine 2,3-dioxygenase (Mezrich, J Immunol. 2010 Sep 15; 185(6):3190-8.).

Recent studies have found that high concentrations of kynurenine in the plasma of various cancer patients and a high plasma kynurenine/tryptophan ratio correlate with poor prognosis after blockade of PD-1 (programmed cell death protein 1) in several types of malignancies, including lung cancer, melanoma and renal cell carcinoma (Haoxin Li et al., Nat Commun. 2019 Sep 25;10(1):4346).

It has long been well known that AhR regulates the functions of numerous cells of both the innate and adaptive immune systems. Activated AhR attenuates the induction of cytokines that stimulate the polarization of pathogenic T-lymphocyte subsets and reduces the expression of major histocompatibility complex (MHC) class II. In addition, activation of the AhR by an agonist or modulator inhibits Th17 helper cell differentiation and stabilizes T suppressor cells. Activated AhR also induces the production of its ligands through a positive feedback loop involving indoleamine 2,3-dioxygenase 1 (IDO1) (Nguyen et al., PNAS, 2010, 107(46): 19961-19966, Mascanfroni, I. D. et al. Nat. Med., 2015, 21:638-646). As an immune evasion mechanism, tumor repopulating cells (TRCs) stimulate increased PD-1 expression in CD8+ T cells through the Kyn-AhR pathway (Yuying Liu et al., Cancer cell, 2018).

Moreover, several studies have shown that AhR signaling plays an important role in various diseases such as autoimmune diseases, infections and malignancy. AhR signaling may be associated with autoimmune diseases, including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), multiple sclerosis (MS) (Xiao-Song Wang et al., Inflammopharmacology, 2020 Feb;28(l): 63-81). Constitutive activation of the AhR reduces the antiviral type I interferon (IF-1) response (Yamada et al., Nat Immunol, 2016 Jun;17(6):687-94). AhR activation is induced by various viruses to evade the host immune response, a technique developed in mouse models to limit the replication of Zika virus, severe acute respiratory syndrome coronavirus 2 (SARS-COV-2) infection (Federico Giovannoni et al., Cell Research, 2021 Dec. 31:1-2). AhR can influence proliferation, tissue invasion, metastasis and angiogenesis of malignant tumor cells (Jae Eun Cheong et al., Trends in Pharmacological Sciences, 2018 Mar;39(3):307-325). In addition, many types of malignant tumors can evade immune recognition through the AhR signaling pathway. The development of therapeutics targeting the AhR may be a potential opportunity to combat immune system-related diseases.

[Description of the invention]

[Technical Objective] It is therefore an object of the present invention to provide novel compounds or their enantiomers, diastereoisomers, racemates, solvates, hydrates or pharmaceutically acceptable salts as AhR modulators.

An object of the present invention is to provide a pharmaceutical composition for modulating AhR activity, containing the specified compounds as AhR modulators

An object of the present invention is to provide a pharmaceutical composition for the prevention or treatment of a disease, disorder or condition associated with AhR activity, such as cancer or an autoimmune disease, comprising said compounds as AhR modulators.

An object of the present invention is to provide a method for modulating AhR activity by administering said compounds as AhR modulators.

An object of the present invention is to provide a method for preventing or treating prostaglandin-related diseases by administering said compounds as AhR modulators.

An object of the present invention is to provide the use of a prostaglandin analog for modulating AhR activity or preventing or treating a disease, disorder or condition associated with the AhR.

[Technical solution]

SUMMARY OF THE INVENTION

The present invention provides new compounds and pharmaceutically acceptable compositions that are effective as AhR modulators or inhibitors. The compounds are represented by formula (I)

wherein:

Ar ¹ and Ar ² are independently selected from the group consisting of halogen, substituted or unsubstituted mono- or bicyclic C _6-10 -aryl, substituted or unsubstituted mono- or bicyclic C _5-10 -heteroaryl and substituted or unsubstituted mono- or bicyclic C _3-10 -heterocycloalkyl;

L is absent (direct connection), H, halogen, cyano, hydroxy, amino, nitro, ether (-O-), thioether (-S-), sulfinyl (-SO-)-, sulfonyl (-SO ₂ - ), sulfonylamido (-SO ₂ NR ² -), aminosulfonyl (-NR ² SO ₂ -), carbonyl (-(CO)-), amido (-(CO)NR ² -), reverse amido (-NR ² (CO )-), ester (-(CO)O-), substituted or unsubstituted C _1-5 -alkyl, substituted or unsubstituted mono- or bicyclic C _3-10 -cycloalkyl, substituted or unsubstituted mono- or bicyclic C _4-10 -heterocycloalkyl, substituted or unsubstituted mono- or bicyclic C _6-10 -aryl and substituted or unsubstituted mono- or bicyclic C _5-10 -heteroaryl;

R ¹ is absent (direct bond), H, halogen, cyano, hydroxy, amino, NHR ³ , OR ³ , phosphate, substituted or unsubstituted C _1-3 alkyl phosphate, 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 ), reverse alkyl amide (-NH(CO)-R ² ), alkyl ester (-(CO)OR ² ), sulfonate (-SO ₂ -R ² ), C _3-10 -cycloalkyl, C _1-5 -alkylhydroxy, C _1-5 -alkenylhydroxy, C _1-5 -alkynylhydroxy, C _1-5 -alkylamine, C _1-5 -alkenylamine, C _{1 -5} -alkynylamine, substituted or unsubstituted mono- or bicyclic C _3-10 -heterocycloalkyl and substituted or unsubstituted mono- or bicyclic C _1-5 -heteroaryl;

R ² represents H, halogeno, 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 - alkylcarboxylic acid;

R ³ represents H, substituted or unsubstituted C _1-5 -alkyl, C _1-5 -alkylacetyl (alkyl-CO-), C _1-5 -sulfonylalkyl (alkyl-SO ₂ -), C _1-5 -sulfonylamidoalkyl ( alkyl-SO ₂ NR ² ₂ ), C _1-5 -amidoalkyl (alkyl-(CO)NR ² ₂ ), reverse C _1-5 -amidoalkyl (alkyl-NR ² (CO)-), substituted or unsubstituted C _{1- 5} -alkoxy and substituted or unsubstituted C _1-5 -alkylcarboxylic acid.

In some embodiments of these aspects and any similar aspects described herein, the AhR modulator of formula (I) is an AhR modulator or an AhR antagonist.

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

The compounds of formula (I) according to the present invention exhibit a valuable pharmacological spectrum of action that was impossible to predict. Surprisingly, it has been found that the compounds of the present invention effectively inhibit the AhR, and it is therefore possible for the compounds to be used for the treatment or prevention of aromatic hydrocarbon receptor (AhR) mediated disease or condition, preferably cancer, cancerous conditions, tumor, fibrosing disorders or conditions with dysregulated immune responses, or other disorders associated with aberrant AhR signaling in humans and animals.

Examples of these diseases associated with an uncontrolled immune response associated with AhR signaling are sepsis (systemic inflammatory response syndrome (SIRS)), multiple organ failure (MODS, MOF), inflammatory kidney disorders, chronic intestinal inflammation (inflammatory bowel disease, Crohn's disease , ulcerative colitis), pancreatitis, peritonitis, inflammatory skin disorders and inflammatory eye disorders, autoimmune diseases such as rheumatoid diseases, including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), multiple sclerosis (MS), etc.

Examples of these fibrosing disorders are fibrosing disorders of internal organs, for example the lungs, heart, kidneys, bone marrow and in particular the liver, as well as dermatological fibroses and fibrosing disorders of the eyes. As used herein, the term fibrosing disorders includes, but is not limited to, the following terms: liver fibrosis, liver cirrhosis, pulmonary fibrosis, endomyocardial fibrosis, nephropathy, glomerulonephritis, interstitial renal fibrosis, fibrotic damage due to diabetes, fibrous marrow and similar fibrosing disorders, scleroderma, annular scleroderma, keloids, hypertrophied scars (including after surgery), nevus, diabetic retinopathy, proliferative vitreoretinopathy and connective tissue diseases (for example, sarcoidosis).

In other aspects, methods are described herein for treating a cancer or cancerous condition by modulating AhR activity. Such methods include administering to a subject with a malignant tumor or cancerous condition a therapeutically effective amount of any of the pharmaceutical compositions containing an AhR modulator, such as an AhR antagonist of formula (I) described herein.

In some aspects, methods are described herein for inhibiting the invasiveness of tumor cells in a subject with a cancer, cancerous condition, or tumor. Such methods include administering to a subject with a cancer or tumor a therapeutically effective amount of any of the pharmaceutical compositions containing an AhR modulator, such as the AhR antagonist of formula (I) described herein.

In some embodiments of these aspects and any similar aspects described herein, the methods further include the step of selecting a subject with a cancer, cancerous condition, or tumor.

Specified malignancies, cancerous conditions or tumors particularly suitable for treatment with an AHR inhibitor according to the present invention are hematological malignancies and solid tumors such as breast, respiratory tract, brain, reproductive organs, digestive tract, urinary tract, eyes, liver, skin, head and neck, thyroid gland, parathyroid gland, and their distant metastases. Such disorders also include lymphomas, sarcomas and leukemias.

Examples of malignant breast tumors 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.

Examples of malignant tumors of the respiratory tract include, but are not limited to, small cell and non-small cell lung carcinoma, as well as bronchial adenoma and pleuropulmonary blastoma.

Examples of malignant brain tumors include, but are not limited to, brainstem and hypophthalmic glioma, cerebellar and medullary astrocytoma, glioblastoma, medulloblastoma, ependymoma, and neuroectodermal tumor and pineal tumor.

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

Tumors of the female reproductive organs include, but are not limited to, cancers of the endometrium, cervix, ovary, vagina and vulva, and sarcoma of the uterus.

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

Examples of cervical cancer include, but are not limited to, squamous cell carcinoma, adenocarcinoma, adenosquamous carcinoma, small cell carcinoma, neuroendocrine tumor, vitreous cell carcinoma, and villoglandular adenocarcinoma.

Tumors of the digestive tract include, but are not limited to, malignant tumors of the anal canal, colon, colorectum, esophagus, gallbladder, stomach, pancreas, rectum, small intestine, and salivary gland.

Examples of esophageal malignancy include, but are not limited to, cell carcinoma and adenocarcinoma of the esophagus, as well as squamous cell carcinoma, leiomyosarcoma, malignant melanoma, rhabdomyosarcoma and lymphoma.

Examples of gastric malignancy include, but are not limited to, gastric adenocarcinoma of the intestinal and diffuse type.

Examples of pancreatic malignancy include, but are not limited to, ductal adenocarcinoma, adenosquamous carcinoma, and endocrine pancreatic tumors.

Urinary tract tumors include, but are not limited to, malignant tumors of the bladder, penis, kidney, renal pelvis, ureter, urethra, and human papillary renal cancer.

Examples of malignant kidney tumor include, but are not limited to, renal cell carcinoma, urothelial cell carcinoma, juxtaglomerular cell tumor (reninoma), angiomyolipoma, renal oncocytoma, Bellini tubular carcinoma, clear cell sarcoma of the kidney, mesoblastic nephroma, and Wilms tumor.

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

Malignant ocular tumors include, but are not limited to, intraocular melanoma and retinoblastoma.

Examples of malignant liver tumors include, but are not limited to, hepatocellular carcinoma (hepatocellular carcinoma, whether fibrolamellar or not), cholangiocarcinoma (intrahepatic bile duct carcinoma), and mixed hepatocellular cholangiocarcinoma.

Malignant skin tumors include, but are not limited to, squamous cell carcinoma, Kaposi's sarcoma, malignant melanoma, Merkel cell skin cancer and non-melanoma skin cancer.

Malignant tumors of the head and neck include, but are not limited to, squamous cell carcinoma of the head and neck, laryngeal cancer, hypopharyngeal, nasopharyngeal, oropharyngeal cancer, salivary gland cancer, lip and oral cavity cancer, and squamous cell carcinoma.

Lymphoma includes, but is not limited to, AIDS-associated lymphoma, non-Hodgkin's lymphoma, cutaneous T-cell lymphoma, Burkitt's lymphoma, Hodgkin's disease, and central nervous system lymphoma.

Sarcoma includes, but is not limited to, soft tissue sarcoma, osteosarcoma, malignant fibrous histiocytoma, lymphosarcoma and rhabdomyosarcoma.

Leukemia includes, but is not limited to, acute myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, and hairy cell leukemia.

The term “treatment” or “method of treatment” as defined throughout this document is used generally, for example, the management or care of a subject for the purpose of controlling, alleviating, reducing, mitigating, ameliorating a disease or disorder, such as a cancer.

The compounds according to the present invention can be used, in particular, in therapy and prophylaxis, i.e. preventing tumor growth and metastases, especially in solid tumors with any signs and stages, with or without prior treatment of tumor growth; malignant tumor is breast cancer, squamous cell carcinoma, lung cancer, peritoneal cancer, hepatocellular cancer, stomach cancer, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, hepatoma, colon cancer, cancer colorectal, endometrial or uterine carcinoma, salivary gland carcinoma, renal or renal cell carcinoma, prostate cancer, vulvar cancer, thyroid cancer, head and neck malignancy, 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.

Some embodiments of these methods may further include administering or treating one or more additional anticancer treatments. In some such embodiments, the additional anticancer treatment includes surgery, radiation therapy, biotherapy, immunotherapy, chemotherapy, or any combination thereof.

Some embodiments of these methods may further include administration or treatment of one or more anticancer drugs. In some such embodiments, the antitumor drug is a chemotherapeutic agent, a growth inhibitory agent, an antiangiogenesis agent, a cytotoxic agent, an antihormonal agent, a prodrug, or a cytokine.

In a further embodiment of the present invention, the compounds of formula (I) according to the present invention can be used to sensitize cells to radiation, i.e. treating a cell with a compound of the present invention prior to radiation treatment of the cell makes the cell more susceptible to DNA damage and cell death than the cell would be in the absence of any treatment with a compound of the present invention. In one aspect, the cell is treated with one or more compounds of general formula (I) according to the present invention.

Thus, the present invention also provides a cell killing method in which one or more compounds of the present invention are administered to a cell in combination with conventional radiation therapy.

The present invention also provides a method of making cells more sensitive to cell death, wherein the cell is treated with one or more compounds of formula (I) according to the present invention before treating the cell to cause or induce cell death. In one aspect, after a cell has been treated with one or more compounds of formula (I) according to the present invention, the cell is treated with at least one compound or at least one method, or a combination thereof, to cause DNA damage to inhibit the functioning of a normal cell or cell destruction. In other embodiments of the present invention, the cell is killed by treating the cell with one or more DNA damaging agents, i.e. after treating a cell with one or more compounds of formula (I) according to the present invention to sensitize the cell to cell death, the cell is treated with at least one DNA damaging agent to kill the cell. DNA damaging agents useful in the present invention include, but are not limited to, chemotherapeutic drugs (eg, cisplatin), ionizing radiation (x-rays, ultraviolet radiation), carcinogens, and mutagenic agents.

In other embodiments, the cell is killed by treating the cell 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 results in DNA damage when the pathway is activated, inhibiting a cell signaling pathway that results in DNA damage when the pathway is inhibited, and inducing a biochemical change in the cell whereby the change leads to DNA damage. By way of non-limiting example, a DNA repair signaling pathway in a cell can be inhibited, thereby preventing DNA damage repair and leading to abnormal accumulation of DNA damage in the cell.

In one aspect of the invention, a compound of formula (I) of the present invention is administered to a cell prior to irradiation or other induction of DNA damage in the cell. In another aspect of the invention, a compound of general formula (I) according to the present invention is introduced into a cell simultaneously with irradiation or other induction of DNA damage in the cell. In yet another aspect of the invention, a compound of formula (I) according to the present invention is introduced into a cell immediately after irradiation or other induction of DNA damage in the cell has begun.

In another aspect, the cell is in vitro. In another embodiment of the invention, the cell is in vivo. The compounds of the present invention may be administered as a single pharmaceutical agent or in combination with one or more other pharmaceutically active ingredients, as long as such combination does not cause undesirable negative effects.

The present invention also covers such pharmaceutical combinations. For example, the following may be combined with the compound of the present invention: monoclonal antibody iodine 131 1-chTNT, abarelix, abiraterone, aclarubicin, adalimumab, ado-trastuzumab emtansine, afatinib, aflibercept, aldesleukin, alectinib, alemtuzumab, alendronic acid, alitretinoin, altretamine, amifostine , aminoglutethimide, hexylaminolevulinate, amrubicin, amsacrine, anastrozole, ancestim, anetoldithiolthione, anetumab ravtansin, angiotensin II, antithrombin III, aprepitant, arcitumomab, arglabin, arsenic trioxide, asparaginase, atezolizumab, axitinib, azacitidine, mab, belotecan, bendamustine, besilezomab, belinostat , bevacizumab, bexarotene, bicalutamide, bisantrene, bleomycin, blinatumomab, bortezomib, buserelin, bosutinib, brentuximab vedotin, busulfan, cabazitaxel, cabozantinib, calcitonin, calcium folinate, calcium levofolinate, capecitabine, capromab, carbamazepine carboplatin, Vaughn, carfilzomib, carmofur, carmustine, catumaxomab, celecoxib, celmoleuquin, ceritinib, cetuximab, chlorambucil, chlormadinone, chlormethine, cidofovir, cinacalcet, cisplatin, cladribine, clodronic acid, clofarabine, cobimetinib, copanlisib, crizantaspase, crizotinib, cyclophosphamide, cyproterone, , dacarbazine, dactinomycin, daratumumab, darbepoetin alpha, dabrafenib, dasatinib, daunorubicin, decitabine, degarelix, denileukin diftitox, denosumab, depreotide, deslorelin, dihydrogalactitol, dexrazoxane, dibrospidium chloride, dihydrogalactitol, diclofenac, dinutuximab, docetaxel, dolasetron, doxifluridine, doxorubicin, cin+estrone, dronabinol, eculizumab, edrecolomab, elliptinium acetate, elotuzumab, eltrombopag, endostatin, enocitabine, enzalutamide, epirubicin, epithiostanol, epoetin alfa, epoetin beta, epoetin zeta, eptaplatin, eribulin, erlotinib, esomeprazole, estradiol, estramustine, ethinyl estradiol, etoposide, verolimus, exemestane, fadrozole, fentanyl, filgrastim, fluoxymesterone, floxuridine, fludarabine, fluorouracil, flutamide, folinic acid, formestane, fosaprepitant, fotemustine, fulvestrant, gadobutrol, gadoteridol, gadoteric acid meglumine, gadoversetamide, gadoxetic acid, gallium nitrate, ganirelix, gefitinib, emcitabine, gemtuzumab, glucarpidase , glutoxim, granulocyte-macrophage-colony-stimulating factor (GM-CSF), goserelin, granisetron, granulocyte colony-stimulating factor, histamine dihydrochloride, histrelin, hydroxyurea, grains 1-125, lansoprazole, ibandronic acid, ibritumomab tiuxetan, ibrutinib, idarubicin, and phosphamide, imatinib , imiquimod, improsulfan, indisetron, incadronic acid, ingenol mebutate, interferon alpha, interferon beta, interferon gamma, iobitridol, yobenguane (1231), iomeprol, ipilimumab, irinotecan, itraconazole, ixabepilone, ixazomib, lanreotide, lansoprazole, lapatinib, lazocholine, lenalidomide, lenvatinib, lenograstim, lentinan, letrozole, leuprorelin, levamisole, levonorgestrel, levothyroxine sodium, lisuride, lobaplatin, lomustine, lonidamine, masoprocol, medroxyprogesterone, megestrol, melarsoprol, melphalan, mepithiostane, mercaptopurine, mesna, methadone, methotrexate, oxalene, methylaminolevulinate, methylprednisolone , methyltestosterone, metyrosine, mifamurtide, miltefosine, miriplatin, mitobronitol, mitoguazone, mitolactol, mitomycin, mitotane, mitoxantrone, mogamulizumab, molgramostim, mopidamol, morphine hydrochloride, morphine sulfate, nabilone, nabiximols, naloxone+pentazo, cin, naltrexone, nartograstim, necitumumab , nedaplatin, nelarabine, neridronic acid, netupitant/palonosetron, nivolumab, pentetreotide, nilotinib, nilutamide, nimorazole, nimotuzumab, nimustine, nintedanib, nitracrine, nivolumab, obinutuzumab, octreotide, ofatumumab, olaparib, olaratumab, omacetaxine mepe succinate, omeprazole, ondansetron, oprelvekin , orgotein, orilotimod, osimertinib, oxaliplatin, oxycodone, oxymetholone, ozogamicin, p53 gene therapy, paclitaxel, palbociclib, palifermin, Pd-103 grain, palonosetron, pamidronic acid, panitumumab, panobinostat, pantoprazole, pazopanib, pegaspargase, PEG-epoetin ( methoxypolyethylene glycol-epoetin beta), pembrolizumab, pegfilgrastim, peginterferon alfa-2b, pembrolizumab, pemetrexed, pentazocine, pentostatin, peplomycin, perflubutan, perfosfamide, pertuzumab, picibanil, pilocarpine, pirarubicin, pixantrone, plerixafor, plicamycin, deputy, polyestradiol phosphate, polyvinylpyrrolidone+ sodium hyaluronate, polysaccharide-K, pomalidomide, ponatinib, sodium porfimer, pralatrexate, prednimustine, prednisone, procarbazine, procodazole, propranolol, quinagolide, rabeprazole, racotumomab, radium chloride [223Ra], radotinib, raloxifene, raltitrexed, ramosetron, ramucirumab, steen, rasburicase, razoxane, refametinib, regorafenib, risedronic acid, rhenium-186 etidronate, rituximab, rolapitant, romidepsin, romiplostim, romurtide, roniciclib, samarium (153Sm) lexidronam, sargramostim, satumomab, secretin, sipuleucel-T, sisofiran, sobuzoxan, glycididazole sodium, sonidegib, sorafenib, stanozolol, streptozocin, sunitinib, talaporfin, talimogen laherparepvec, tamibarotene, tamoxifen, tapentadol, tazonermine, teceleukin, technetium ( ^99m Tc) nofetumomab merpentane, ^99m Tc-HYNIC-[Tyr3]-octreotide, tegafur +gimeracil+oteracil, temoporfin, temozolomide, temsirolimus, teniposide, testosterone, tetrofosmin, thalidomide, thiotepa, thymalfasin, thyrotropin-alpha, thioguanine, tocilizumab, topotecan, toremifene, tositumomab, trabecdecin, trametinib, tramadol, trastuzumab, emtansine, treosulfan, tretinoin, trifluridine+tipiracil, trilostane, triptorelin, trametinib, trofosfamide, thrombopoietin, tryptophan, ubenimex, valatinib, valrubicin, vandetanib, vapreotide, vemurafenib, vinblastine, vincristine, vindesine, vinflunine, vinorelbine, vismodegib, vorinostat, vorozol, glass micro yttrium spheres- 90, cinostatin, cinostatin stimalamer, zoledronic acid, zorubicin.

The compounds of the invention can also be combined with other reagents targeting the immune system, such as immune checkpoint inhibitors, for example aPD-1/-L1 axis antagonists.

PD-1, together with its ligands PD-L1 and PD-L2, function as negative regulators of T cell activation. AhR inhibits the function of immune cells while increasing the proliferation and motility of malignant tumor cells. PD-L1 is overexpressed in many malignancies, and PD-1 overexpression often occurs simultaneously in tumor-infiltrating T cells. This results in decreased T cell activation and evasion of immune surveillance, resulting in weakened antitumor immune responses (Keir ME et al. (2008) Annu. Rev. Immunol. 26:677).

Simultaneous targeting of both the PD-1/-L1 axis and the AhR enhances antitumor immune responses more than an additive mode of action, resulting in an unexpected reduction in tumor growth.

Thus, compositions containing a PD-1/-L1 axis antagonist and an AhR antagonist are surprisingly effective for enhancing the immune response and for treating cancer.

In addition, the developed compounds can also be used as therapeutic agents for a number of other diseases in which the AhR is involved.

Examples of other disorders associated with inflammation due to aberrant AhR signaling are vaccination against infection and cancer, viral infections, obesity and diet-induced obesity, fat deposition, metabolic disorders, hepatic steatosis and uterine fibroids (uterine leiomyoma or uterine fibroids). in women, chronic kidney disorders, acute and chronic renal failure, diabetic, inflammatory or hypertensive nephropathies, heart failure, angina pectoris, hypertension, pulmonary hypertension, coronary artery disease, vascular disorders, thromboembolic disorders, arteriosclerosis, 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.

Also provided herein in some aspects are pharmaceutical compositions containing an AhR modulator, such as an AhR antagonist of formula (I) and pharmaceutically acceptable excipients.

In some aspects, pharmaceutical compositions containing 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.

In some aspects, pharmaceutical compositions containing an AhR modulator, such as an AhR antagonist of formula (I), are provided for use in treating a malignant tumor or cancerous condition by modulating AhR activity.

In some aspects, pharmaceutical compositions containing an AhR modulator, such as an AhR antagonist of formula (I), are provided for use in inhibiting the proliferation, tissue invasion, metastasis, and angiogenesis of cancer cells in a subject with a cancer, cancerous condition, or tumor.

In some embodiments of these aspects and any similar aspects described herein, use further includes the step of selecting a subject with cancer, a cancerous condition, or a tumor. In some such embodiments, the cancer is breast cancer, squamous cell cancer, lung cancer, peritoneal cancer, hepatocellular cancer, gastric cancer, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, hepatoma , colon cancer, colorectal cancer, endometrial or uterine carcinoma, salivary gland carcinoma, kidney malignancy or renal cell carcinoma, prostate cancer, vulvar cancer, thyroid cancer, head and neck malignancy, 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.

In some embodiments of these and any similar aspects described herein, the use further includes one or more additional anticancer therapies. In some such embodiments, the additional anticancer treatment includes surgery, radiation therapy, biotherapy, immunotherapy, or chemotherapy.

In some embodiments of these and any similar aspects described herein, the use further includes one or more antineoplastic drugs. In some such embodiments, the antitumor drug is a chemotherapeutic agent, a growth inhibitor, an antiangiogenesis agent, a cytotoxic agent, an antihormonal agent, a prodrug, or a cytokine.

[USEFUL EFFECTS OF THE INVENTION]

The new compounds of formula (I) according to the present invention effectively modulate the activity of the AhR and are therefore useful as a therapeutic or prophylactic drug for various diseases, disorders or conditions associated with the activity of the AhR, such as malignancy, cancerous condition, tumor, fibrosing disease , conditions with dysregulated immune responses, including autoimmune disease such as rheumatoid arthritis, systemic lupus erythematosus (8EE), multiple sclerosis (MS), or other disorders associated with aberrant AhR signaling, etc.

[Best Mode for Carrying Out the Invention]

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

Unless otherwise specified, all technical terms used herein have the same meaning as commonly understood by one skilled in the art to which the present invention relates. In addition, although the invention is described in conjunction with specific methods and samples, their analogues or equivalents must be within the scope of the present invention. In addition, numerical values set forth herein are deemed to include the value “about” unless clearly indicated. All publications and other references mentioned herein are incorporated herein by reference in their entirety.

The definition of the structural units used in this document is described in detail. Unless otherwise indicated, each structural unit is defined as follows and is used in the sense generally understood by one skilled in the art.

As used herein, the terms "halogen", "halogen", "halogenide(s)" include fluoro-, chloro-, bromo- and iodo-.

As used herein, “alkyl” means an aliphatic hydrocarbon radical and includes both linear and branched hydrocarbon radicals. For example, C _1-6 -alkyl is an aliphatic hydrocarbon with 1-6 carbon atoms and includes methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl and 2-ethylbutyl. Unless otherwise specified, alkyl means C _1-6 alkyl, preferably C _1-4 alkyl, more preferably C _1-3 alkyl.

As used herein, "alkenyl" means an aliphatic hydrocarbon radical containing one or more carbon-carbon double bonds and includes both linear and branched hydrocarbon radicals. A non-limiting example of "alkenyl" is vinyl, allyl, but-1-enyl or but-2-enyl.

As used herein, "alkynyl" means an aliphatic hydrocarbon radical containing one or more carbon-carbon triple bonds and includes both linear and branched hydrocarbon radicals. A non-limiting example of "alkynyl" is ethynyl, propargyl, but-1-ynyl or but-2-ynyl.

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

As used herein, “alkoxy” means O-alkyl or an alkyl-O- group, and an alkyl group is defined as above. For example, it includes methoxy, ethoxy, n-propoxy, n-butoxy and t-butoxy.

As used herein, “alkoxyalkyl” means an alkyl-O-alkyl group, and an alkyl group is defined as above. A non-limiting example is methoxymethyl, ethoxymethyl, methoxyethyl or isopropoxymethyl.

As used herein, the term "hydroxy" or "hydroxyl", alone or in combination with other terms, means -OH.

As used herein, "cyano" means -CN, "cyanoalkyl" means alkyl substituted -CN, in which the alkyl group is the same as defined above.

As used herein, "amino" means -NH2; and "nitro" means -NO ₂ .

As used herein, "carboxy" means a -C(O)-OH group.

As used herein, "ester" means a -C(O)-OR group in which R is alkyl, may be _C1-10 , preferably _C1-8- , _C1-6- or _{C1- 4} -alkyl. Such ester groups may or may not be substituted with one or more suitable substituents.

As used herein, the term “cycloalkyl” means cyclic alkyl, which may be substituted or unsubstituted, and, for example, C _3-20 -cycloalkyl is a monovalent saturated hydrocarbon ring system having from 3 to 20 carbon atoms. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like. Preferably, unless otherwise specified, the cycloalkyl may be C _3-8 cycloalkyl or C _3-6 cycloalkyl.

As used herein, the term “aryl” means a monovalent aromatic hydrocarbon having, for example, 6 to 20 carbon atoms (Ce-20), which is obtained by abstraction of one hydrogen atom from one carbon atom from a basic aromatic ring system. Aryl may include a bicyclic radical containing an aromatic ring fused to a saturated or partially unsaturated ring. Typical aryl groups may include radicals derived from benzene (phenyl), substituted phenyl, biphenyl, naphthyl, toluyl, naphthalenyl, anthracenyl, indenyl, indanyl, and the like. Unless otherwise specified, aryl means C _6-12 -aryl, preferably C _6-10 -aryl.

As used herein, “heteroaryl” means a monovalent or divalent substituent derived from a monoheterocyclic or polyheterocyclic aromatic hydrocarbon having from 1 to 10 carbon ring members containing one or more, preferably one to three, heteroatoms selected from N, O or S. Examples of heteroaryl include thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,4 -thiadiazolyl, 1,3,4-thiadiazolyl, triazolyl, tetrazolyl, triazinyl, indolyl, and the like, but are not limited to. Examples of bicyclic heteroaryl include, but are not limited to, indolyl, benzothiophenyl, benzofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzothiadiazolyl, quinolinyl, isoquinolinyl, furynyl, furopyridinyl, octahydropyranopyridine, benzodioxolyl and the like. Unless otherwise specified, heteroaryl is C _3-10 heteroaryl, preferably C _3-7 heteroaryl, more preferably C _3-5 heteroaryl.

As used herein, “heterocycloalkyl” means a monocyclic, bicyclic, tricyclic or higher cyclic alkyl having from 3 to 10 carbon ring members containing one or more, for example, from one to four heteroatoms selected from N, O or S. Additionally , the heterocycle according to the present invention may also be a fused or bridged heterocycloalkyl. Examples of non-aromatic rings include azetidinyl, oxetanyl, tetrahydrothienyl, tetrahydrofuranyl, pyrrolinyl, pyrrolidinyl, imidazolinyl, imidazolidinyl, oxazolinyl, oxazolidinyl, oxapiperazinyl, oxapiperidinyl, pyrazolinyl, pyrazolidinyl, thiazolinyl, thiazolidinyl, yl, tetrahydrofuryl, tetrahydroisothiazolyl, tetrahydrooxazolyl, tetrahydroisoxazolyl, piperidinyl, piperazinyl, tetrahydropyranyl, dihydropyranyl, tetrahydropyridinyl, dihydropyridinyl, dihydrothiopyranyl, tetrahydropyrimidinyl, tetrahydropyridazinyl, dihydropyranyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, indolinyl, indolinylmethyl, thiomorpholinyl, azepanil, diazepanil, , azaadamantanil, diazamantanil, and the like, but are not limited to these. The addition of a heterocycloalkyl substituent can occur via a carbon atom or a heteroatom. The heterocycloalkyl group may be optionally substituted by one or more suitable groups through one or more of the above groups. Unless otherwise specified, heterocycloalkyl means heterocycloalkyl having from 3 to 10 carbon ring members, preferably C _3-7 heterocycloalkyl, more preferably heterocycloalkyl having from 3 to 5 carbon ring atoms.

Unless otherwise specified herein, the term “substituted” means that one or more hydrogen atoms are replaced by one to three substituents selected from the group consisting of a halogen atom (for example, F, Cl, Br or I), a cyano group, a hydroxyl group , thiol group, nitro group, amino group, imino group, azido group, amidino group, hydrazino group, hydrazone group, oxo group, carbonyl group, carbamyl group, ester group, ether group, carboxyl group or salt thereof, sulfonic acid group or salt thereof, phosphoric acid or salt thereof , C _1-6 -alkyl group, halogen-C _1-6 -alkyl group, C _1-6 -alkenyl group, halogen-C _1-6 -alkenyl group, C _2-6 -alkynyl group, halogen-C _{2- 6} -alkynyl group, C _1-6 -alkoxy group, halo-C _1-6 -alkoxy group, C _1-20 -alkylthio group, C _3-20 -carbocyclic group (for example, C _3-9 -cycloalkyl group, halo-C _{3 -9} -cycloalkyl group, C _3-9 -cycloalkenyl group, halo-C _3-9 -cycloalkenyl group, Ci-9-heterocycloalkyl group, halo-C _3-9 - heterocycloalkyl group, C _2-9 -heterocycloalkenyl group, halogen -C _2-9 -heterocycloalkenyl group and C _1-20 -heterocyclic group (for example, C _6-20 -aryl group, C _6-20 -aryloxy group, C _6-20 -arylthio group, C _2-20 -heteroaryl group, C _2-20 -heteroaryloxy groups, C _2-20 -heteroarylthio groups).

Receptor of aromatic hydrocarbons

The aromatic hydrocarbon receptor ("AhR") is a ligand-dependent member of a family of basic helix-loop-helix transcription factors that have been found to be activated by numerous structurally diverse synthetic and natural compounds, such as polycyclic aromatic hydrocarbons, indoles, and flavonoids. In the absence of bound ligand, AhR is present in a cryptic conformation in the cytoplasmic compartment of the cell, bound to two molecules of the molecular chaperone heat shock protein 90 (“hsp90”), the immunophilin-like protein XAP2 and the hsp90-interacting protein p23.

As used herein, the term “aromatic hydrocarbon receptor” or “AhR” means an 848 amino acid polypeptide as characterized, for example, NP_001612, together with any naturally occurring allelic, splice variant and processed forms thereof. Generally, AhR means the human AhR. The term AhR is also used to refer to truncated forms or fragments of the AhR polypeptide, including, for example, specific AhR domains. A reference to any such AhR forms may be provided in the application, for example by “AhR (122-224)”.

AhR modulators

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

The AhR mediates a number of functional responses, including, but not limited to, de novo transcription of target genes or AhR battery genes having a 5'-TNCGTG-3' DRE (dioxin response element) or XRE (xenobiotic response element) response element. Alternative AhR signaling pathways have also been described, such as binding to retinoblastoma protein, estrogen receptor (ER), transcription factor E2F1, and NFκB pathway subunits Re1A and Re1B. AhR can also act as a ubiquitin ligase. Accordingly, signal transduction through the AhR involves a variety of pathways, including constitutive and non-constitutive AhR signaling pathways or signaling activity as those terms are defined herein.

As used herein, “constitutive AhR signaling” means one or more signaling pathways mediated or regulated by the AhR that are activated or driven by one or more endogenous AhR ligands or one or more environmental ligands, such as toxins or pollutants, that cause constitutive or long-term nuclear translocation of the AhR, and activation or modulation of one or more AhR battery genes involved in unregulated cell growth and proliferation, tumor cell invasiveness, or a combination thereof.

As used herein, “non-constitutive AhR signaling” means one or more signal transduction pathways mediated or induced by the AhR that do not cause constitutive or sustained nuclear translocation of the AhR or activation or modulation of one or more AhR battery genes involved in unregulated growth cells, tumor cell invasiveness, or a combination thereof. In some embodiments, nonconstitutive AhR signaling does not cause increased expression of CYP1A1, CYP1B1, or a combination thereof.

Accordingly, as used herein, “AhR modulator” means an agent, such as a compound of formula (I), that modulates or causes, or facilitates a qualitative or quantitative change, rearrangement or modification in one or more processes, mechanisms, effects, responses, functions, activities or pathways mediated by the AhR receptor. Such changes, mediated by an AhR modulator, such as an AhR antagonist described herein, may reduce, inhibit, or redirect constitutive AhR activity. The term "expression" means cellular processes involved in the production of RNA and proteins and, where appropriate, secretory 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 produced by translation of mRNA transcribed from the gene.

The term “modulate” in relation to an AhR modulator is used consistent with its use in the art, for example, to cause or facilitate a qualitative or quantitative change, rearrangement or modification in one or more biological processes, mechanisms, effects, responses, functions, activities, pathways or other phenomena of interest. Accordingly, as used herein, modulate means a qualitative or quantitative change, rearrangement, or modification in one or more AhR receptor-mediated processes, mechanisms, effects, responses, functions, activities, or pathways.

The term “agent” as used herein in relation to an AhR modulator means, but is not limited to, any compound or substance such as, but is not limited to, a small molecule, nucleic acid, polypeptide, peptide, drug, ion, etc. "Agent" may be any chemical entity, entity or fragment, including, but not limited to, synthetic and natural protein and non-protein entities. In some embodiments, the agent is a nucleic acid, nucleic acid analog, protein, antibody, peptide, aptamer, nucleic acid oligomer, amino acid, or carbohydrate and includes proteins, oligonucleotides, ribozymes, DNAzymes, glycoproteins, siRNA, lipoproteins, aptamers, and modifications thereof and combinations, etc., but not limited to these. In some embodiments, as described herein, the agents are small molecules having a chemical moiety. For example, the chemical moieties include unsubstituted or substituted alkyl, aromatic, or heterocyclic moieties. The compounds may be known, have the desired activity and/or property, eg, modulate AhR activity, or may be selected from a library of various compounds using, for example, the screening methods described herein.

In some embodiments, the AhR modulator selectively binds to the AhR. As used herein, “selectively binds” or “specifically binds” means the ability of an AhR antagonist described herein to bind to a target, such as AhR, with a dissociation constant ( _KD ) of 10 ^-5 M (10,000 nM) or less, e.g. 10 ^-6 M or less, 10 ^-7 M or less, 10 ^-8 M or less, 10 ^-9 M or less, 10 ^-10 M or less, 10 ^-11 M or less, or 10 ^-12 M or less. For example, if an antagonist described herein binds to the AhR with a K _{D of} 10 ^-5 M or lower, but not to other molecules or a related homologue, then the agent is considered to specifically bind to the AhR. Specific binding can be influenced, for example, by the affinity and avidity of the antagonist, as well as the concentration of the antagonist used. One skilled in the art can determine the appropriate conditions under which the antagonists described herein selectively bind using any suitable methods, such as titrating the AhR antagonist in a suitable cell binding assay such as those described herein.

In some aspects of the compositions and methods described herein, AhR modulators are AhR antagonists having the chemical structures of formula (I) described herein.

As used herein, an AhR inhibitor is an “AhR antagonist”. An AhR antagonist means an AhR inhibitor that, as such, does not produce a biological response when specifically bound to the AhR, but blocks or attenuates agonist-mediated or ligand-mediated responses, i.e. an AhR antagonist can bind but does not activate the AhR, and binding disrupts the interaction, displaces the AhR agonist, and/or inhibits the function of the AhR agonist. Thus, as used herein, an AhR antagonist does not function as, for example, an inducer of AhR activity upon binding to the AhR, i.e. they function as pure AhR inhibitors. In some embodiments, the AhR antagonist selectively binds to the AhR.

In some embodiments of these aspects, 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 of the invention, the small molecule AhR antagonists of formula (I) described herein act as chemopreservative agents by blocking AhR-mediated induction of CYP1A1 and the production of mutagens upon exposure to environmental ligands.

In some embodiments of these aspects, the AhR antagonists of formula (I) described herein inhibit the early contributions of constitutively active AhR in driving malignant transformation. In some embodiments, the compounds of formula (I) described herein inhibit the growth of a malignant tumor or tumor cells mediated by constitutive AhR signaling. In some embodiments, the compounds of formula (I) described herein inhibit constitutive AhR signaling-mediated tumor invasion in driving malignant transformation.

Accordingly, an AhR antagonist of formula (I) is provided for use in the various aspects described herein:

An aspect of the present invention relates to new compounds that can modulate the human aromatic hydrocarbon receptor (AhR). These compounds specifically bind to the AhR.

In some embodiments, the compound has the structure of formula (I) or the corresponding enantiomer, diastereomer, racemate, solvate, hydrate, or pharmaceutically acceptable salt:

wherein:

Ar ¹ and Ar ² are independently selected from the group consisting of halogen, substituted or unsubstituted mono- or bicyclic C _6-10 -aryl, substituted or unsubstituted mono- or bicyclic C _5-10 -heteroaryl and substituted or unsubstituted mono- or bicyclic C _3-10 -heterocycloalkyl;

L is absent (direct bond), represents H, halogen, cyano, hydroxy, amino, nitro, ether (-O-), thioether (-S-), sulfinyl (-SO-)-, sulfonyl (-SO ₂ -), sulfonylamido (-SO2NR ₂ -), aminosulfonyl (-(-NR ² SO ₂ -), carbonyl (-(CO)-), amido (-(CO)NR ² -), reverse amido (-NR ² ( CO)-), ester (-(CO)O-), substituted or unsubstituted C _1-5 -alkyl, substituted or unsubstituted mono- or bicyclic C _3-10 -cycloalkyl, substituted or unsubstituted mono- or bicyclic C _{4- 10} -heterocycloalkyl, substituted or unsubstituted mono- or bicyclic C _6-10 -aryl and substituted or unsubstituted mono- or bicyclic C _5-10 -heteroaryl;

R ¹ absent (direct bond), represents H, halogen, cyano, hydroxy, amino, NHR ³ , OR ³ , phosphate, substituted or unsubstituted C _1-3 alkyl phosphate, 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 ), reverse alkylamide (-NH(CO)-R ² ), alkyl ester (-(CO)OR ² ), sulfonate (- SO ₂ -R ² ), C _3-10 -cycloalkyl, C _1-5 -alkylhydroxy, C _1-5 -alkenylhydroxy, C _1-5 -alkynylhydroxy, C _1-5 -alkylamine, C _1-5 -alkenylamine, C _1-5 -alkynylamine, substituted or unsubstituted mono- or bicyclic C _3-10 -heterocycloalkyl and substituted or unsubstituted mono- or bicyclic C _5-10 -heteroaryl;

R ² represents 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 -alkylcarboxylic acid;

R ³ represents H, substituted or unsubstituted C _1-5 -alkyl, C _1-5 -alkylacetyl (alkyl-CO-), C _1-5 -sulfonylalkyl (alkyl-SO ₂ -), C _1-5 -sulfonylamidoalkyl ( alkyl-SO ₂ NR ² ₂ ), C _1-5 -amidoalkyl (alkyl-(CO)NR ² ₂ ), reverse C _1-5 -amidoalkyl (alkyl-NR ² (CO)-), substituted or unsubstituted C _{1- 5} -alkoxy and substituted or unsubstituted C _1-5 -alkylcarboxylic acid.

In a preferred embodiment of the invention, Ar ¹ and Ar ² may independently be halogen, substituted or unsubstituted mono- or bicyclic C _6-10 -aryl, substituted or unsubstituted monocyclic C _5-7 -heteroaryl containing one or more heteroatoms selected from the group consisting of N, O and S, or a substituted or unsubstituted monocyclic C _5-7 -heterocycloalkyl containing one or more heteroatoms selected from the group consisting of N, O and S. More preferably, Ar ¹ and Ar ² can each independently represent is phenyl, monocyclic C _5-6 -heteroaryl containing one or two heteroatoms selected from the group consisting of N, O and S, or monocyclic C _5-6 -heterocycloalkyl containing one or two heteroatoms selected from the group consisting of N, O and S, which may be unsubstituted or substituted with halogen, hydroxyl, amino, C _1-3 -alkyl or C _1-3 -alkoxy, where C _1-3 -alkyl or C _1-3 -alkoxy may be unsubstituted or substituted with one to three halogens.

Much more preferably, Ar ¹ and Ar ² may each independently be phenyl, imidazole, pyridine, pyrimidine, piperidine or morpholine. Much more preferably, Ar ¹ and Ar ² may be unsubstituted or substituted with Cl, CH ₃ or CF ₃ .

In a preferred embodiment of the invention, L is absent (direct bond), represents H, halogen, cyano, hydroxy, amino, nitro, ether (-O-), thioether (-S-), sulfinyl (-SO-)-, sulfonyl (-SO ₂ -), sulfonylamido (-SO ₂ NR ² -), aminosulfonyl (-NR ² SO ₂ -), carbonyl (-(CO)-), amido (-(CO)NR ² -), reverse amido (-NR ² (CO)-), ester (-(CO)O-), substituted or unsubstituted mono- or bicyclic C _3-8 -cycloalkyl, substituted or unsubstituted mono- or bicyclic C _3-8 -heterocycloalkyl, substituted or unsubstituted mono- or bicyclic C _6-10 -aryl and substituted or unsubstituted mono- or bicyclic C _5-8 -heteroaryl, where the mono- or bicyclic C _3-8 -heterocycloalkyl and mono- or bicyclic C _5-8 -heteroaryl contains one or more, preferably one or two heteroatoms selected from the group consisting of N, O or S.

More preferably, L is absent (direct bond), is H, substituted or unsubstituted C _1-5 -alkyl, 1,1-dioxidotetrahydrothiopyran, piperidine, substituted or unsubstituted mono- or bicyclic C _3-6 -cycloalkyl, where C _{1- 5} -alkyl, substituted or unsubstituted mono- or bicyclic C _3-6 -cycloalkyl may be substituted with one or more (preferably one to three) substituents selected from the group consisting of hydroxyl, halo, halo-C _1-3 -alkyl and C _1-3 alkyl.

In a preferred embodiment of the invention, R ¹ is absent, represents H, halogen, cyano, hydroxy, amino, N(R ³ ) ₂ , OR ³ , substituted or unsubstituted C _1-4 -alkyl, carbonyl (-(CO)R ² ) , C _3-8 -cycloalkyl, C _1-4 -alkylhydroxy, C _1-4 -alkenylhydroxy, Ci-4-alkynylhydroxy, C _1-4 -alkylamine, C _1-4 -alkenylamine, C _1-4 -alkynylamine, substituted or unsubstituted mono- or bicyclic C _3-8 -heterocycloalkyl and substituted or unsubstituted mono- or bicyclic C _5-8 -heteroaryl, where the mono- or bicyclic C _3-8 -heterocycloalkyl and mono- or bicyclic C _5-8 - heteroaryl contains one or more, preferably one or two heteroatoms selected from the group consisting of N, O and S. More preferably, R ¹ is absent, represents H, hydroxyl, -NH ₂ , -NH-C(O)CH ₃ , - NH-SO ₂ -CH ₃ , -C(O)OH, -SO ₂ -CH ₃ , -OS(O)-CH ₃ , -O-P(=O)(OSH ₂ CH ₃ ) ₂ , -C( O)CH ₃ or hydroxyl.

Further, in a more specific embodiment of the invention, the compound of formula I may be one selected from the group consisting of compounds 1-96, as follows:

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

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

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

4. 3-(1-hydroxypropan-2-yl)-6-(1-methyl-1H-pyrazol-4-yl)-8-(4-(trifluoromethyl)phenyl)pyrido[3,4-(1]pyrimidine -4(3H)-on;

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

6. 3-(1-hydroxypropan-2-yl)-6,8-bis(4-(trifluoromethyl)phenyl)pyrido[3,4-c1]pyrimidin-4(3H)-one;

7. 2-(6-chloro-8-(4-chlorophenyl)-4-oxopyrido[3,4-(1]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-(1 ]pyrimidin-4(3H)-one;

9. 3-((1R,4R)-4-hydroxycyclohexyl)-6,8-bis(1-methyl-1H-pyrazol-4-yl)pyrido[3,4-(1]pyrimidin-4(3H)- He;

10. 6-(4-chlorophenyl)-3-((1R,4R)-4-hydroxycyclohexyl)-8-(1-methyl-1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidine-4 (3H)-on;

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) -He;

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

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

17. 3-((1S,2R)-2-hydroxycyclohexyl)-8-(1-methyl-1H-pyrazol-4-yl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-(1 ]pyrimidin-4(3H)-one;

18. 3-((1R,2S)-2-hydroxycyclohexyl)-8-(1-methyl-1H-pyrazol-4-yl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-(1 ]pyrimidin-4(3H)-one;

19. 3-((1R,2S)-2-hydroxycyclohexyl)-8-(1-methyl-1H-pyrazol-4-yl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-(1 ]pyrimidin-4(3H)-one;

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

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- (1]pyrimidin-4(3H)-one;

23. 6-(4-chlorophenyl)-8-(1-methyl-1H-pyrazol-4-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)pyrido[3,4-d]pyrimidine -4(3H)-on;

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

25. 8-(pyridin-3-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-(1]pyrimidine-4 (3H)-on;

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) -He;

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) -He;

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

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) -He;

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

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- silt acetate;

37. 2-methyl-1-(4-oxo-8-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidin-3(4H)-yl) propan-2-yl acetate;

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

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

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

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

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

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-(1]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 )-He;

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)-on;

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 )-He;

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) -He;

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

59. 3-(1-hydroxypropan-2-yl)-8-(1-methyl-1H-pyrazol-4-yl)-6 -(4-(trifluoromethyl)phenyl)-2,3-dihydropyrido[3,4 -d]pyrimidin-4(1H)-one;

60. 6-(4-chlorophenyl)-3-(2,3-dihydroxypropyl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one;

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

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

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

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

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

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

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

68. 3-(2,3-Dihydroxypropyl)-6-(4-(4-methylpiperazin-1-yl)phenyl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4( 3H)-on

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

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-((1K,38)-3-hydroxycyclopentyl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H )-He

72. 3-((1R,3S)-3-hydroxycyclopentyl)-8-(pyridin-3-yl)-6-(2-(trifluoromethyl)pyrimidin-5-yl)pyrido[3,4-d]pyrimidin- 4(3H)-one, trifluoroacetic acid salt (TFA);

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 )-He;

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) -He;

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)propane acid, salt 2.2 ,2-trifluoroacetic acid;

84. 2-(4-oxo-8-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidin-3(4H)-yl)propanoic acid, salt 2,2,2-trifluoroacetic acid;

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

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

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

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

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

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

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

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

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

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

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

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

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

Pharmaceutical compositions, methods and uses

In particular embodiments, the pharmaceutical composition and method provided herein comprises a compound of formula (I) or an enantiomer, diastereomer, racemate, solvate, hydrate or pharmaceutically acceptable salt thereof.

The subject may be a mammal, including a human, or a mammalian cell; for example, a mammal (eg, human) suffering from a disease, disorder or condition associated with AhR activity as described above, or a mammalian cell isolated therefrom.

The active ingredient compound or pharmaceutical composition may be administered orally or parenterally. For example, parenteral administration can be accomplished by any of intravenous injection, subcutaneous injection, intramuscular injection, intraperitoneal injection, endothelial injection, topical administration, intranasal administration, intrapulmonary administration, rectal administration, and the like.

An effective amount may mean a pharmaceutically and/or therapeutically effective amount and may be prescribed depending on factors such as the type of drug (formulation and dosage form), route of administration of the drug, age, weight and sex of the patient and/or pathological conditions, etc. .P.

A pharmaceutically acceptable salt of a compound of formula (I) may include addition salts formed with inorganic acids such as hydrochloride, sulfate, phosphate, hydrobromide, hydroiodide, nitrate, pyrosulfate or metaphosphate, addition salts formed with organic acids such as citrate, oxalate, benzoate, acetate, trifluoroacetate, propionate, succinate, fumarate, lactate, maleate, tartrate, glutarate or sulfonate, or metal salts such as, but not limited to, lithium salt, sodium salt, potassium salt, magnesium salt and calcium salt.

The pharmaceutical composition of the present invention may be formulated in a suitable form together with a commonly used pharmaceutically acceptable carrier. "Pharmaceutically acceptable" means being physiologically acceptable and not typically causing an allergic reaction or the like, such as gastrointestinal upset and dizziness, when administered to a human. Moreover, the pharmaceutical composition according to the present invention can be used after processing to an oral drug such as powders, granules, tablets, capsules, suspensions, emulsions, syrups and aerosols, etc., and a parenteral drug. application, such as epidermal preparations, suppositories or sterile injection solutions, in accordance with a conventional method.

Examples of carriers, auxiliaries and diluents that may be contained in the composition may include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gum acacia, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methylcellulose , microcrystalline cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil. In pre-formulation processing, a diluent or excipient may be used, such as commonly used fillers, stabilizers, binders, disintegrants and surfactants. Solid preparations for oral administration include tablets, pills, powders, granules, capsules and the like, and these solid preparations can be prepared by mixing the compound of the present invention with at least one excipient, for example, starch, microcrystalline cellulose , sucrose, lactose, low-substituted hydroxypropylcellulose, hypromellose or the like. In addition to the simple excipient, a lubricant such as magnesium stearate and talc is also used. Oral liquid preparations include suspension, oral liquid, emulsion, syrup, etc. In addition to the commonly used simple diluents such as water and petroleum jelly, various excipients such as humectants, sweeteners, flavorings, preservatives, etc. may also be contained. Dosage forms for parenteral administration include sterilized aqueous solution, non-aqueous solution, suspension, emulsion, lyophilized formulation and suppository. The non-aqueous solution or suspension may include propylene glycol, polyethylene glycol, a vegetable oil such as olive oil, an injectable ester such as ethyl oleate, and the like. Witepsol, macrogol, Tween 61, cocoa butter, lauric oil, glycerogelatin, etc. can be used as a suppository base. In order to prepare a dosage form for parenteral administration, a compound of formula I or a pharmaceutically acceptable salt thereof can be mixed in water together with sterilized and/or contained excipients such as preservatives, stabilizers, excipients such as wettable powder or emulsification accelerators, salt to regulate osmotic pressure and/or buffers, etc., as well as other therapeutically useful substances for the preparation of a solution or suspension, which is then released in the form of an ampoule or a set of bottles for administration.

A pharmaceutical composition containing a compound of Formula I disclosed herein as an active ingredient can be administered to mammals, such as mice, livestock, and humans, in various ways to modulate AhR activity or prevent, or treat, a disease, disorder, or condition associated with AhR activity.

In some embodiments, the disease, disorder, or condition associated with AhR activity may be a malignancy, cancerous condition, tumor, fibrosing disorder, immune-related disease, or other disease associated with AhR signaling.

In one embodiment of the invention, diseases associated with a dysregulated immune response associated with AhR signaling are selected from the group consisting of sepsis (SIRS), multiple organ failure (MODS, MOF), inflammatory kidney disorders, chronic intestinal inflammation (inflammatory bowel disease). IBD), Crohn's disease, ulcerative colitis (UC)), pancreatitis, peritonitis, inflammatory skin disorders and inflammatory eye disorders, autoimmune diseases such as rheumatoid diseases including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE) and multiple sclerosis ( MS).

In one embodiment of the invention, the fibrosing conditions are selected from the group consisting of fibrosing conditions of internal organs, for example, lungs, heart, kidneys, bone marrow and in particular the liver, as well as dermatological fibroses and fibrosing conditions of the eyes. As used herein, the term fibrosing disorders includes, but is not limited to, the following terms: liver fibrosis, liver cirrhosis, pulmonary fibrosis, endomyocardial fibrosis, nephropathy, glomerulonephritis, interstitial renal fibrosis, fibrotic damage due to diabetes, bone marrow fibrosis and similar fibrosing disorders, scleroderma , annular scleroderma, keloids, hypertrophied scars (including as a result of surgical operations), nevus, diabetic retinopathy, proliferative vitreoretinopathy and connective tissue diseases (for example, sarcoidosis). In some embodiments, the malignancy, cancerous condition or tumor particularly suitable for treatment with an AhR antagonist of the present invention are liquid tissue tumors and solid tumors such as breast cancer, squamous cell carcinoma, lung cancer, peritoneal cancer, hepatocellular cancer, stomach cancer, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, hepatoma, colon cancer, colorectal cancer, endometrial or uterine carcinoma, salivary gland carcinoma, renal malignancy or renal cell cancer, prostate cancer, vulvar cancer, thyroid cancer, head and neck malignancy, B-cell lymphoma, chronic lymphocytic leukemia (CLL); acute lymphoblastic leukemia (ALL), hairy cell leukemia, or chronic myeloblastic leukemia.

In some embodiments, the pharmaceutical composition of the present invention may be used in conjunction with one or more additional anticancer treatments. In some such embodiments, the additional anticancer treatment includes surgery, radiation therapy, biotherapy, immunotherapy, chemotherapy, or any combination thereof.

In some embodiments, the pharmaceutical composition of the present invention can be used in conjunction with anticancer drugs. In some such embodiments, the anticancer drug is a chemotherapeutic agent, a growth inhibitor, an antiangiogenesis agent, a cytotoxic agent, an antihormonal agent, a prodrug, or a cytokine.

Examples of other disorders associated with inflammation due to aberrant AhR signaling are vaccination against infections and cancer, viral infections, obesity and diet-induced obesity, fat deposition, metabolic disorders, hepatic steatosis and uterine fibroids (uterine leiomyoma or uterine fibroids). in women, chronic kidney disorders, acute and chronic renal failure, diabetic, inflammatory or hypertensive nephropathies, heart failure, angina pectoris, hypertension, pulmonary hypertension, coronary artery disease, vascular disorders, thromboembolic disorders, arteriosclerosis, 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.

Also provided herein in other aspects are pharmaceutical compositions containing an AhR modulator, such as an AhR antagonist of formula (I) or an enantiomer, diastereomer, racemate, solvate, hydrate or pharmaceutically acceptable salt thereof, and pharmaceutically acceptable excipients.

In some aspects, pharmaceutical compositions containing 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 use in modulating constitutive AhR activity in a subject in need thereof.

In some aspects, pharmaceutical compositions containing 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 use in the treatment of a malignant tumor or cancerous condition by modulating AhR activity.

In some aspects, pharmaceutical compositions containing 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 use in inhibiting the proliferation, tissue invasion, metastasis, and angiogenesis of cancer cells in a subject with a malignancy, cancerous condition or tumor.

In some embodiments, the pharmaceutical composition of the present invention may be used to inhibit the proliferation, tissue invasion, metastasis, and angiogenesis of cancer cells in a subject with a cancer, cancerous condition, or tumor.

The pharmaceutical compositions described herein can be administered to a subject through a variety of multiple routes of administration, including oral, parenteral (e.g., intravenous, subcutaneous, intramuscular, rectal, intrauterine, or cerebrovascular injection), intranasal, buccal, topical, or transdermal routes of administration, but not limited to this.

In some embodiments, compounds of chemical formula (I), or an enantiomer, diastereomer, racemate, solvate, hydrate, or pharmaceutically acceptable salt thereof, are administered orally.

Another aspect of the present invention relates to a method of stimulating the immune system in a patient in need thereof, for example, a patient suffering from a cancer or infection (eg, a viral, bacterial or parasitic infection). The method includes administering to a patient a therapeutically effective amount of one or a combination of compounds described herein. In some embodiments, after the drug administration step, the patient has an increased number of white blood cells, T and/or B lymphocytes, macrophages, dendritic cells, neutrophils, natural killer (NK) cells, and/or platelets. In some embodiments, the compound reduces IL-21 levels in a patient. The patient may have a malignant tumor or may be immunocompromised.

“Treat,” “treatment,” and “treatment method” mean a method of alleviating or stopping a biological disorder and/or its accompanying symptoms. As used herein, “alleviate” a disease, disorder or condition means reducing the severity of the disease and/or the frequency of symptoms of the disease, disorder or condition. In addition, references herein to “treatment” include references to therapeutic, palliative, and prophylactic treatment. A method of treating a cancer includes inhibiting the growth of a cancer (including inducing partial or complete regression of a cancer), inhibiting the progression of a cancer or metastasis, preventing recurrence of a cancer or residual disease, and/or prolonging the life of a patient. “Therapeutically effective amount” means an amount of a drug that achieves the desired therapeutic, palliative, or prophylactic effect for the condition being treated.

In some embodiments, the effective dose range of a compound is determined by measuring the concentration of the compound in the patient's blood at a particular dosage regimen to establish a concentration-time profile, compared with the established correlation between the concentration-time profile and the tumor inhibition or tumor killing effects achieved in the trial. , and balancing the achievable therapeutic effects against possible toxicity to the patient, with further consideration of the patient's health or physical endurance. The frequency of dosing of a compound can be determined in a similar manner. Dosing can be continued until the patient gets rid of the malignant tumor.

In some embodiments, an effective amount for treating a tumor may be measured by its ability to stabilize disease progression and/or alleviate symptoms in a patient, and preferably help eliminate disease progression, for example, by reducing tumor size. In some embodiments of the invention, administration of a maintenance dose may be provided after the patient has become cancer-free to ensure complete elimination or destruction of the cancer, or to prevent residual effects of the disease. The duration of administration of the maintenance dose may be determined based on clinical trial data.

In some embodiments, the compound may be administered in combination with one or more other cancer treatments that also target the AhR or target molecules other than the AhR. The compounds may be formulated either alone or together with other agents for the treatment of malignant tumors. The compounds may be administered either on the same schedule or on a schedule different from other cancer treatments. The proportion of the compound related to other cancer treatments can be determined in clinical trials. Combining the compounds with other cancer treatments may further enhance each other's effectiveness. For example, a compound of the present invention may be administered with an immune checkpoint inhibitor, such as a PD-1, PD-L1, or PD-L2 inhibitor (eg, pembrolizumab, nivolumab, or atezolizumab), or administered in CAR-T cell therapy (CAR-T therapy) (eg, axicabtagene ciloleucel) to achieve an additive or synergistic antitumor effect.

Dosing regimens may be adjusted to provide the optimal desired response. As used herein, unit dosage form means physically discrete units suitable as unitary dosages for patients/subjects being treated; each unit containing a predetermined amount of the active compound to obtain the desired therapeutic effect in combination with the required pharmaceutical carrier.

It should be noted that dosage amounts may vary depending on the type and severity of the condition sought to be alleviated, and may include single or multiple doses. It should also be understood that for each individual subject, specific dosage regimens should be adjusted over time in accordance with the individual needs and professional judgment of the person administering or supervising the administration of the compositions, and that the dosage ranges set forth herein are provided as examples only and not are intended to limit the scope or practice of implementing a realized composition. In addition, the dosage regimen for the compositions of the present invention may be based on a number of factors, including the type of disease, age, weight, sex, medical condition of the patient, severity of the condition, route of administration, and the specific antibody used. Thus, the dosage regimen may vary widely, but can be determined in daily practice using standard methods. For example, dosages may be adjusted based on pharmacokinetic or pharmacodynamic parameters, which may include clinical effects, such as toxic effects, and/or laboratory test data.

It is contemplated that a suitable dose of a compound of the present invention may be in the range of 0.001-200 mg/kg per day and preferably from about 0.01 mg/kg to 20 mg/kg body weight per day, in particular about 0.5 -50 mg/kg, for example about 1-20 mg/kg. The compound can be administered, for example, at a dose of at least 0.25 mg/kg, for example at least 0.5 mg/kg, in particular at least 1 mg/kg, for example at least 1.5 mg /kg, in particular at least 2 mg/kg, for example at least 3 mg/kg, in particular at least 4 mg/kg, for example at least 5 mg/kg; and, for example, up to a maximum of 50 mg/kg, in particular, up to a maximum of 30 mg/kg, for example, up to a maximum of 20 mg/kg, in particular, up to a maximum , 15 mg/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 for as long as deemed appropriate. responsible physician who can further increase or decrease the dosage as needed.

General synthesis methods

The compounds of the present invention can be prepared in accordance with one or more of the following schemes.

These methods can be used either directly or with obvious modifications by skilled chemists to obtain key intermediates and some of the compounds of the present invention.

Suitable synthetic sequences are readily selected to suit the specific structures of the present invention only within the scope of the art known to those skilled in organic synthesis, such as methods summarized in available chemistry databases such as CAS Scifinder and Elesevier Reaxys. Based on these general methods, the implementation of the possibilities for producing the compound according to the present invention is straightforward and can be practiced within the scope of general professional knowledge. Some general synthetic methods for preparing the compounds of the present invention are shown below in Schemes 1-3 (General Procedure A~C).

One general approach to the compounds of the present invention is shown in General Scheme 1.

a) N-iodosuccinimide (NIS), dimethylformamide (DMF); b) NH ₂ -R ¹ , 1 -ethyl-3-(3-dimethylaminopropyl)-carbodiimide (EDC), hydroxybenzotriazole (HOBt) triethylamine (TEA), DMF; c) (EtO) ₃ CH, acetic acid; d) tris(dibenzylideneacetone) dipalladium-chloroform adduct (Pd ₂ (dba) ₃ ⋅CHCl ₃ ), K ₂ CO ₃ , 2-dicyclohexylphosphino-2',6',-dimethoxybiphenyl (Sphos), 1,4-dioxane/H ₂ O (4/1); e) 1,1'-bis(diphenylphosphino)ferrocene palladium (II) dichloride dichloromethane complex (Pd(dppf)Cl ₂ ⋅CH ₂ Cl ₂ ), K ₂ CO ₃ , 1,4-dioxane/H ₂ O (4/1 ), heating, microwaves

Another general approach to the compounds of the present invention is shown in General Scheme 2.

a) NH ₂ -R ² -OTBDPS (NH ₂ -R ₂ -O-tert-butyldiphenylsilyl), EDC, HOBt, TEA, DMF; b) Pd(dppf)Cl ₂ ⋅CH ₂ Cl ₂ , K ₂ CO ₃ , 1,4-dioxane/H ₂ O (4/1), heating, microwaves; c) N-bromosuccinimide (NBS), DMF; d) (EtO) ₃ CH, acetic acid; e) Pd ₂ (dba) ₃ ⋅CHCl ₃ , K ₂ CO ₃ , Sphos, 1,4-dioxane/H ₂ O (4/1); f) tetrabutylammonium fluoride (TBAF), tetrahydrofuran (THF).

Another general approach to the compounds of the present invention is shown in General Scheme 3.

a) NH ₂ -R ² -OTBDPS, 1 EDC, HOBt, TEA, DMF; b) Pd(dppf)Cl ₂ ⋅CH ₂ Cl ₂ , K ₂ CO ₃ , 1,4-dioxane/H ₂ O (4/1), heating, microwaves; c) N-bromosuccinimide, DMF; d) (EtO) ₃ CH, acetic acid; e) Pd ₂ (dba) ₃ ⋅CHCl ₃ , K ₂ CO ₃ , Sphos, 1,4-dioxane/H ₂ O (4/1); f)NaBH ₄ , THF; d) TBAF, THF

Another general approach to the compounds of the present invention is shown in General Scheme 4.

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-dioxane/H ₂ O, heating; e) Pd(dppf)Cl ₂ ⋅CH ₂ Cl ₂ , K ₂ CO ₃ , 1,4-dioxane/H ₂ O (4/1), heating, microwaves.

Another general approach to the compounds of the present invention is shown in General Scheme 5.

a) K ₂ CO ₃ , MeI, DMF; b) [1,1'-bis(di-tert-butylphosphino)ferrocene] dichloropalladium (II) (PdCl ₂ (dtbpf)), K ₂ CO ₃ , 1,4-dioxane/H ₂ O (4/1), heating, microwaves or Pd(dppf)Cl ₂ ⋅CH ₂ Cl ₂ , K ₂ CO ₃ , 1,4-dioxane/H ₂ O (4/1), heating, microwaves; c) NH ₂ '-R ¹ , EDC, HOBt, TEA, DMF; d) (EtO) ₃ CH, acetic acid;

Another general approach to the compounds of the present invention is shown in General Scheme 6.

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-dioxane/H ₂ O (4/1), heating, microwaves

Another general approach to the compounds of the present invention is shown in General Scheme 7.

a) N-iodosuccinimide (NIS), 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 , K ₂ CO ₃ , 1,4-dioxane/H ₂ O (4/1), heating, microwave; e) Pd(dppf)Cl ₂ ⋅CH ₂ Cl ₂ , K ₂ CO ₃ , 1,4-dioxane/H ₂ O (4/1), heating, microwaves; f) 4M HCl in 1,4-dioxane; d) R ² -Cl, TEA, dichloromethane (DCM).

[Principle of invention]

Examples

Embodiments of the present invention are described in the following examples, which are provided for illustration and do not limit the scope of the present invention. Conventional abbreviations well known to average synthesis specialists are used throughout.

All chemical reagents are available in the market. Unless otherwise noted, flash column chromatography refers to silica gel chromatography performed on a Teledyne Combiflash-RF200. Proton magnetic resonance spectra ( ^1H NMR spectra) (δ, ppm) were recorded with a 400 MHz or 600 MHz instrument. Mass spectroscopy data for the positive ionization mode are presented. Preparative high-performance liquid chromatography (HPLC) was performed on an Agilent technologies G1361A and Gilson Preparative HPLC unit.

Example 1 and 2. 3-(3-hydroxycyclohexyl)-8-(1-methyl-1H-pyrazol-4-yl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidin-4 (3H)-one and 3-(3-hydroxycyclohexyl)-6,8-bis(1-methyl-1H-pyrazol-4-yl)pyrido[3,4-c1]pyrimidin-4(3H)-one

Scheme for obtaining a connection according to example 1:

Intermediate 1,3-amino-6-chloro-2-iodoisonicotinic acid

5-Amino-2-chloroisonicotinic acid (1) (2 g, 14.5 mmol, 1 equiv.) and N-iodosuccinimide (4.9 g, 21.7 mmol, 1.5 equiv.) were dissolved in DMF (50 ml, 0.3 M) and stirred for 12 hours at 100°C. The reaction mixture was diluted with water (50 ml), extracted with ethyl acetate (50 ml×3), washed with brine (20 ml×3), dried over Na ₂ SO ₄ and filtered on a glass filter. The filtrate was evaporated in vacuo to give 6.89 g (80% yield) of 3-amino-6-chloro-2-iodoisonicotinic acid (intermediate 1) and

used without further purification.

¹ H NMR (400 MHz, CDCl ₃ ) δ [ppm]=7.69 (s, 1H); mass spectrum (MS) (electrospray ionization (ESI), mass/charge (m/z)): 298.90 [M+H] ⁺ .

Intermediate 2,3-amino-6-chloro-N(3-hydroxycyclohexyl)-2-iodoisonicotinamide

3-Amino-6-chloro-2-iodoisonicotinic acid mixture (intermediate 1) (1.24 g, 4.15 mmol, 1 equiv), EDC (0.96 g, 4.99 mmol, 1.2 equiv .), HOBT (0.76 g, 4.99 mmol, 1.2 equiv.) and TEA (0.87 ml, 6.23 mmol, 1.5 equiv.) were dissolved in DMF (10 ml, 0.4 equiv.) M) and stirred for 5 minutes. 3-Aminocyclohexanol (0.53 g, 4.57 mmol, 1.1 equiv) was then added to the reaction mixture and stirred for 12 hours at 60°C. The reaction mixture was diluted with water (50 ml), extracted with ethyl acetate (20 ml×3), washed with brine (20 ml×3), dried over Na ₂ SO ₄ and filtered on a glass filter. The filtrate was evaporated in vacuo and purified by medium pressure liquid chromatography (MPLC) (silica gel, 0~50% ethyl acetate/hexane) to give 0.75 g (46% yield) 3-amino-6-chloro-N-(3-hydroxycyclohexyl )-2-iodoisonicotinamide (intermediate 2).

¹ H NMR (400 MHz, MeOD) δ [ppm]=7.40 (s, 1H), 3.91 (tt, J=11.5, 3.7 Hz, 1H), 3.66 ( tt, J=10.6, 4.1 Hz, W), 2.19 (d, J=11.7 Hz, 1H), 1.95 (d, J=12.8 Hz, 1H), 1, 87-1.81 (m, 2H), 1.69-1.61 (m, 1H), 1.55-1.50 (m, 1H), 1.40 (ddd, J=12.9, 6 ,3, 3.2 Hz, 1H). 1.25-1.16 (m, 1H); MS (ESI, m/z): 395.90 [M+H] ⁺ .

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

3-Amino-6-chloro-N-(3-hydroxycyclohexyl)-2-iodoisonicotinamide (intermediate 2) (0.75 g, 1.90 mmol, 1 equiv.) was dissolved in a solution of (EtO) ₃ CH (2, 9 ml, 17.1 mmol, 9 equiv.) and CH ₃ CO ₂ H (2.9 ml, 49.8 mmol, 26.2 equiv.). The reaction mixture was stirred and heated in a Biotage microwave initiator at 150°C for 1 hour. The reaction mixture was diluted with water (20 ml), extracted with ethyl acetate (20 ml×3), washed with brine (20 ml×3), dried over Na ₂ SO ₄ and filtered on a glass filter.

The filtrate was evaporated in vacuo and purified by MPLC (silica gel, 0~50% ethyl acetate/hexane) to give 0.28 g (36% yield) 6-chloro-3-(3-hydroxycyclohexyl)-8-iodopyrido[3,4- d]pyrimidin-4(3H)-one (intermediate 3).

1H NMR (400 MHz, CDCl ₃ ) δ [ppm]=8.26 (s, 1H), 8.03 (s, 1H), 4.77 (tt, J=12.1,3.6 Hz, 1H), 3.90-3.80 (m, 1H), 2.29 (d, J=11.2 Hz, 1H), 2.11 (d, J=11.7 Hz, 1H), 2.04-1.92 (m, 2H), 1.70-1.65 (m, 1H), 1.65-1.58 (m, 1H), 1.53-1.49 (m, 1H ), 1.33 (ddd, J=23.8, 12.5, 3.9 Hz, 1H); MS (ESI, m/z): 405.83 [M+H] ⁺ .

Intermediate 4 and Example 2 6-chloro-3-(3-hydroxycyclohexyl)-8-(1-methyl-1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one and 3-(3-hydroxycyclohexyl)-6,8-bis(1-methyl-1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one

6-Chloro-3-(3-hydroxycyclohexyl)-8-iodopyrido[3,4-d]pyrimidin-4(3H)-one (intermediate 3) (68 mg, 0.168 mmol, 1 equiv.), (1- methyl-1H-pyrazol-4-yl)boronic acid (23.2 mg, 0.184 mmol, 1.1 equiv.), K ₂ CO ₃ (93 mg, 0.671 mmol, 4 equiv.), Sphos (6.9 mg , 0.017 mmol, 0.1 equiv.) and Pd ₂ (dba) ₃ ⋅CHCl ₃ (8.68 mg, 8.38 µmol, 0.05 equiv.) were dissolved in 1,4-dioxane/water (4 ml/ 1 ml, 0.3 M) and stirred for 12 hours at 50°C. The reaction mixture was concentrated under reduced pressure and immediately purified by MPLC (silica gel, 0~10% MeOH/DCM) to obtain 30 mg (50% yield) of 6-chloro-3-(3-hydroxycyclohexyl)-8-(1-methyl -1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (intermediate 4) with 13 mg 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%, intermediate 4

¹ H NMR (400 MHz, CDCl ₃ ) δ [ppm]=8.53 (s, 1H), 8.50 (s, 1H), 8.19 (s, 1H), 7.88 (s , 1H), 4.82 (t, J=12.3 Hz, 1H), 3.99 (s, 3H), 3.87 (t, J=10.5 Hz, 1H), 2.31 (d , J=11.0 Hz, 1H), 2.12 (d, J=11.6 Hz, 1H), 2.05-1.94 (m, 2H), 1.79 (s, 1H), 1 .74-1.66 (m, 1H), 1.51 (dd, J=18.2, 8.3 Hz, 1H), 1.33 (ddd, J=24.3, 12.7, 3, 4 Hz, 1H); MS (ESI, m/z):360.00 [M+H] ⁺ ,

example 2

¹ H-NMR (400 MHz, 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=11.3 Hz, 1H), 2.13 (d, J=11.5 Hz, 1H), 2.01 (d, J=10.2 Hz, 2H), 1.76 - 1.67 (m, 2H), 1.64 - 1.53 (m, 1H), 1.39 - 1.30 ( m, 1H); MS (ESI, m/z):406.07 [M+H] ₊ .

Example 1. 3-(3-hydroxycyclohexyl)-8-(1-methyl-1H-pyrazol-4-yl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-a]pyrimidin-4(3H )-He

6-chloro-3-(3-hydroxycyclohexyl)-8-(1-methyl-1H-pyrazol-4-yl)pyrido[3,4-e]pyrimidin-4(3H)-one (intermediate 4) (30 mg, 0.083 mmol, 1 equiv.), (4-(trifluoromethyl)phenyl)boronic acid (32 mg, 0.17 mmol, 2 equiv.), 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 equiv.) were dissolved in 1,4-dioxane/water (4 ml/1 ml, 0.02 M ). The reaction mixture was stirred and heated in a Biotage microwave initiator at 130°C for 30 min. The reaction mixture was concentrated under reduced pressure and immediately purified by MPLC (Chromatorex NH-DM1020 (NH- _SiO2 ) silica gel, 0~70% ethyl acetate/hexane) to obtain 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).

¹ H-NMR (400 MHz, CDCl ₃ ): δ [ppm]=8.62 (s, 1H), 8.59 (s, 1H), 8.38 (s, 1H), 8.33 (d, J=8.3 Hz, 2H), 8.24 (s, 1H), 7.78 (d, J=8.3 Hz, 2H), 4.92 - 4.86 (m, 1H) , 4.03 (s, 3H), 3.93-3.86 (m, 1H), 2.35 (d, J=11.6 Hz, 1H), 2.14 (d, J=11.2 Hz, 1H), 2.03 (d, J=10.6 Hz, 2H), 1.78-1.69 (m, 2H), 1.65-1.56 (m, 1H), 1.41 -1.31 (m, 1H); MS (ESI, m/z):470.06 [M+H] ⁺ .

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

Using 2-aminopropan-1-ol, the title compound was prepared as described for Example 2 (Scheme 1 General Procedure A).

¹ H-NMR (400 MHz, 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=6.9 Hz , 6H), 3.87 (d, J - 6.9 Hz, 1H), 3.77 (dd, J=11.8, 4.3 Hz, 1H), 1.47 (d, J=7, 1 Hz, 3H); MS (ESI, m/z):366.06 [M+H] ⁺ .

Example 4 3-(1-hydroxypropan-2-yl)-6-(1-methyl-1H-pyrazol-4-yl)-8-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidine -4(3H)-on

Using 2-aminopropan-1-ol, the title compound was prepared as described for Example 1 (Scheme 1 General Procedure A).

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

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

Using 2-aminopropan-1-ol, (4-chlorophenyl)boronic acid and pyridin-3-yl-boronic acid, the title compound was prepared as described for Example 1 (Scheme 1: General Procedure A).

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

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

Using 2-aminopropan-1-ol and (4-(trifluoromethyl)phenyl)boronic acid, the title compound was prepared as described for Example 2 (Scheme 1: General Procedure A).

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

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

Using 2-aminopropyl acetate and (4-chlorophenyl)boronic acid, the title compound was prepared as described for Intermediate 4 of Example 1 (Scheme 1. General Procedure A).

¹ H-NMR (400 MHz, CDCl ₃ ): δ [ppm]=8.15 (s, 1H), 8.09 (d, J=8.2 Hz, 2H), 7.48 (d , J=8.5 Hz, 2H), 5.18 (dd, J=11.1, 6.9 Hz, 1H), 4.47-4.32 (m, 2H), 2.04 (s, 3H), 1.59 (d, J=7.2 Hz, 3H); MS (ESI, m/z): 391.95 [M+H] ⁺ .

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

Using (1R,4R)-4-aminocyclohexan-1-ol, the title compound was prepared as described for Example 1 (Scheme 1 General Procedure A).

¹ H-NMR (400 MHz, CDCl ₃ ): δ [ppm]=8.60 (s, 1H), 8.59 (s, 1H), 8.37 (s, 1H), 8.32 (d, J=8.2 Hz, 1H), 8.20 (s, 1H), 7.77 (d, J=8.3 Hz, 1H), 4.88-4.78 (m, 1H) , 4.03 (s, 3H), 3.85-3.74 (m, 1H), 2.27-2.19 (m, 2H), 2.15-2.06 (m, 2H), 1 .94-1.81 (m, 2H), 1.70 - 1.57 (m, 2H); MS (ESI, m/z):470.02 [M+H] ⁺ .

Example 9 He

Using (1R,4R)-4-aminocyclohexan-1-ol, the title compound was prepared as described for Example 2 (Scheme 1 General Procedure A).

¹ H-NMR (400 MHz, CDCl ₃ ): 8 [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, ZH), 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] ⁺ .

Example 10 4(3H)-on

Using (1R,4R)-4-aminocyclohexan-1-ol and (4-chlorophenyl)boronic acid, the title compound was prepared as described for Example 1 (Scheme 1 General Procedure A).

¹ H-NMR (400 MHz, CDCl ₃ ): δ [ppm]=8.59 (s, 1H), 8.58 (s, 1H), 8.31 (s, 1H), 8.18 (s, 1H), 8.16 (d, J=8.8 Hz, 2H), 7.49 (d, J=8.6 Hz, 2H), 4.88-4.78 (m, 1H) , 4.02 (s, 3H), 3.84-3.74 (m, 1H), 2.26 -2.18 (m, 2H), 2.14-2.02 (m, 2H), 1 .93-1.80 (m, 2H), 1.70-1.61 (m, 2H); MS (ESI, m/z):436.01 [M+H] ⁺ .

Example 11 3-(2-hydroxypropyl)-6,8-bis(1-methyl-1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one

Using 1-aminopropan-2-ol, the title compound was prepared as described for Example 2 (Scheme 1 General Procedure A).

¹ H-NMR (400 MHz, 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, 3.0 Hz, 1H), 4.19-4 .11 (m, 1H), 4.00 (s, 3H), 3.99 (s, 3H), 3.74 (dd, J=13.6, 8.8 Hz, 1H), 1.30 ( d, J=6.3 Hz, 3H); MS (ESI, m/z): 366.01 [M+H]+.

Example 12 )-He

Using 1-aminopropan-2-ol, the title compound was prepared as described for Example 1 (Scheme 1 General Procedure A).

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

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

Using 1-aminopropan-2-ol and (4-chlorophenyl)boronic acid, the title compound was prepared as described for Example 1 (Scheme 1. General Procedure A).

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

Example 14 3-(2-hydroxypropyl)-8-(1-methyl-1H-pyrazol-4-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimide in-4 (3H)-on

Using 1-aminopropan-2-ol and (6-(trifluoromethyl)pyridin-3-yl)boronic acid, the title compound was prepared as described for Example 1 (Scheme 1 General Procedure A).

¹ H-NMR (400 MHz, 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 - 8.2 Hz, 1H), 4.39 (dd, J=13, 5, 2.5 Hz, 1H), 4.30 (ush, 1H), 4.01 (s, 3H), 3.73 (dd, J=13.6, 8.4 Hz, 1H), 2, 41 (d, J=4.2 Hz, 1H), 1.39 (d, J=6.3 Hz, ZN); MS (ESI, m/z):431.00 [M+H] ⁺ .

Example 15 )-He

Using (1R,2S)-2-aminocyclohexanol, pyridin-3-yl-boronic acid and (4-(trifluoromethyl)phenyl)boronic acid, the title compound was prepared as described for Example 1 (Scheme 1: General Procedure A).

1H-NMR (400 MHz, MeOD): δ [ppm]=9.42 (s, 1H), 8.73 (d, J=8.0 Hz, 1H), 8.64 (d, J =4.8 Hz, 1H), 8.62 (s, 1H), 8.51 (s, 1H), 8.41 (d, J=8.2 Hz, 2H), 7.83 (d, J =8.3 Hz, 2H), 7.61 (dd, J=7.9, 4.9 Hz, 1H), 4.90-4.85 (m, 1H), 4.09 (s, 1H) , 2.41-2.27 (m, 1H), 2.06 - 1.93 (m, 2H), 1.76 (d, J=9.3 Hz, 2H), 1.71 (s, 1H ), 1.59 (dt, J=17.5, 8.6 Hz, 2H); MS (ESI, m/z):467.15 [M+H] ⁺ .

Example 16 )-He

Using (1S,2R)-2-aminocyclohexanol hydrochloride, pyridin-3-yl-boronic acid and (4-(trifluoromethyl)phenyl)boronic acid, the title compound was prepared as described for Example 1 (Scheme 1 General Procedure A).

1H-NMR (400 MHz, MeOD): δ [ppm]=9.41 (s, 1H), 8.75-8.66 (m, 1H), 8.63 (d, J=4, 7 Hz, 1H), 8.58 (d, J=6.5 Hz, 1H), 8.49 (d, J=1.9 Hz, 1H), 8.38 (dd, J=8.1, 3.9 Hz, 2H), 7.81 (d, J=6.8 Hz, 2H), 7.63 (d, J=8.9 Hz, 1H), 7.61-7.57 (m, 1H), 4.86 (dd, J=13.3, 2.6 Hz, 1H), 4.08 (s, 1H), 2.34 (dd, J=22.2, 12.3 Hz, 1H ), 2.04-1.93 (m, 2H), 1.77 (t, J=9.3 Hz, 2H), 1.71 (d, J=10.1 Hz, 1H), 1.64 -1.51 (m, 2H); MS (ESI, m/z):467.13 [M+H] ⁺ .

Example 17 3-((1S,2R)-2-hydroxycyclohexyl)-8-(1-methyl-1H-pyrazol-4-yl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-( 1]pyrimidin-4(3H)-one

Using (1R,2S)-2-aminocyclohexanol, (1-methyl-1H-pyrazol-4-yl)boronic acid and (4-(trifluoromethyl)phenyl)boronic acid, the title compound was prepared as described for Example 1 (Scheme 1 General method A).

¹ H-NMR (400 MHz, CDCl ₃ ): δ [ppm]=8.48 (s, 1H), 8.37 (s, 1H), 8.33 (s, 1H), 8.27 (s, 1H), 8.14 (d, J=8.1 Hz, 2H), 7.67 (d, J=8.3 Hz, 2H), 4.95 (dd, J=10.2, 2.4 Hz, 1H), 4.30 (s, 1H), 3.99 (s, 3H), 3.23 (s, 1H), 2.39 - 2.27 (m, 1H), 2, 03 (d, J=12.2 Hz, 2H), 1.89-1.74 (m, 2H), 1.68 (dd, J=24.7, 13.2 Hz, 3H); MS (ESI, m/z): 470.18 [M+H] ⁺ .

Example 18 3-((1R,2S)-2-hydroxycyclohexyl)-8-(1-methyl-1H-pyrazol-4-yl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-d ]pyrimidin-4(3H)-one

Using (1S,2R)-2-aminocyclohexanol hydrochloride, (1-methyl-1H-pyrazol-4-yl)boronic acid and (4-(trifluoromethyl)phenyl)boronic acid, the title compound was prepared as described for Example 1 (Scheme 1. General technique A).

¹ H-NMR (400 MHz, CDCl ₃ ): δ [ppm]=8.50 (s, 1H), 8.37 (d, J=9.4 Hz, 2H), 8.28 (s , 1H), 8.17 (d, J - 8.2 Hz, 2H), 7.69 (d, J - 8.2 Hz, 2H), 4.96 (d, J - 13.3 Hz, 1H ), 4.29 (s, 1H), 3.99 (s, ZN), 3.06 (s, 1H), 2.34 (dd, J=22.1, 12.5 Hz, 1H), 2 .06-1.98 (m, 2H), 1.90-1.78 (m, 2H), 1.75-1.63 (m, 3H); MS (ESI, m/z):470.18 [M+H] ⁺ .

Example 19 1]pyrimidin-4(3N)-one

Using (1S,2R)-2-aminocyclohexanol hydrochloride, pyridin-3-yl-boronic acid and (4-chlorophenyl)boronic acid, the title compound was prepared as described for Example 1 (Scheme 1 General Procedure A).

¹ H-NMR (400 MHz, CDCl ₃ ): δ [ppm]=9.34 (d, J=1.6 Hz, 1H), 8.60 (dd, J=4.9, 1, 5 Hz, 1H), 8.48 - 8.43 (m, 1H), 8.43 (s, 1H), 8.40 (s, 1H), 8.07 (d, J=8.6 Hz, 2H), 7.45 (d, J=8.6 Hz, 2H), 7.38 (dd, J=7.7, 4.9 Hz, 1H), 4.93 (d, J=12.8 Hz, 1H), 4.19 (s, 1H), 3.09 (s, 1H), 2.32 (ddd, J=25.3, 12.6, 3.5 Hz, 1H), 2.06 - 1.96 (m, 2H), 1.81 (dd, J=25.2, 12.1 Hz, 2H), 1.71 (d, J=11.0 Hz, 2H), 1.63 ( d, J=17.4 Hz, 1H); MS (ESI, m/z):433.14 [M+H] ⁺ .

Example 20 4(3H)-on

Using (1R,2S)-2-aminocyclohexanol, (1-methyl-1H-pyrazol-4-yl)boronic acid and (4-chlorophenyl)boronic acid, the title compound was prepared as described for Example 1 (Scheme 1. General Procedure A).

¹ H-NMR (400 MHz, CDCl ₃ ): δ [ppm]=8.48 (s, 1H), 8.37 (d, J=9.2 Hz, 2H), 8.21 (s , 1H), 8.03 (d, J - 8.6 Hz, 2H), 7.42 (d, J - 8.6 Hz, 2H), 4.94 (d, J=13.0 Hz, 1H ),4.27 (s, 1H),2.85 (d,J=4.2 Hz, 1H), 2.33 (dt, J=21.6, 10.7 Hz, 1H), 2.06 -1.94 (m, 2H), 1.89-1.75 (m, 2H), 1.75-1.66 (m, 2H), 1.63 (d, J=16.2 Hz, 1H ); MS (ESI, m/z): 436.15 [M+H]+.

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

Using (1R,2S)-2-aminocyclohexanol, pyridin-3-yl-boronic acid and (4-chlorophenyl)boronic acid, the title compound was prepared as described for Example 1 (Scheme 1 General Procedure A).

¹ H-NMR (400 MHz, CDCl ₃ ): δ [ppm]=9.33 (d, J=1.8 Hz, 1H), 8.59 (dd, J=4.8, 1, 6 Hz, 1H), 8.47 - 8.43 (m, 1H), 8.42 (s, 1H), 8.38 (s, 1H), 8.05 (d, J=8.6 Hz, 2H), 7.44 (d, J=8.6 Hz, 2H), 4.93 (d, J=12.7 Hz, 1H), 4.18 (s, 1H), 3.31 (s, 1H), 2.38 - 2.26 (m, 1H), 2.06-1.95 (m, 2H), 1.87-1.75 (m, 2H), 1.75-1.67 ( m, 2H), 1.63 (d, J=13.8 Hz, 1H); MS (ESI, m/z):433.17 [M+H] ⁺ .

Example 22 8-(1-methyl-1H-pyrazol-4-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4 -d]pyrimidin-4(3H)-one

Using 3-amino-1,1,1-trifluoropropan-2-ol, (1-methyl-1H-pyrazol-4-yl)boronic acid and (4-(trifluoromethyl)phenyl)boronic acid, the title compound was prepared as described for example 1 (Scheme 1. General procedure A).

¹ H-NMR (400 MHz, CDCl ₃ ): S [ppm]=8.34 (s, 1H), 8.25 (s, 1H), 8.24 (s, 1H), 8.10 (s, 1H), 8.09 (s, 2H), 7.65 (d,7=8.3 Hz, 2H), 5.44 (s, 1H), 4.71 (dd, J=13, 7, 2.3 Hz, 1H), 4.67 - 4.56 (m, 1H), 3.95 (s, 3H), 3.83 (dd,7=13.7, 9.5 Hz, 1H ); MS (ESI, m/z):484.14 [M+H] ⁺ .

Example 23 6-(4-chlorophenyl)-8-(1-methyl-1H-pyrazol-4-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)pyrido[3,4-a] pyrimidin-4(3H)-one

Using 3-amino-1,1,1-trifluoropropan-2-ol, (1-methyl-1H-pyrazol-4-yl)boronic acid and (4-chlorophenyl)boronic acid, the title compound was prepared as described for Example 1 (Scheme 1. General technique A).

¹ H-NMR (400 MHz, CDCl ₃ ): S [ppm]=8.31 (s, 1H), 8.17 (s, 1H), 8.13 (s, 1H), 8.04 (s, 1H), 7.91 (d, J=8.5 Hz, 2H), 7.37 (d, J=8.4 Hz, 2H), 5.63 (s, 1H), 4.68 (d, J=13.6 Hz, 1H), 4.66-4.56 (m, 1H), 3.92 (s, 2H), 3.79 (dd, J=13.5, 9.4 Hz, 1H); MS (ESI, m/z):450.10 [M+H] ⁺ .

Example 24 -He

Using 3-amino-1,1,1-trifluoropropan-2-ol, pyridin-3-yl-boronic acid and (4-chlorophenyl)boronic acid, the title compound was prepared as described for Example 1 (Scheme 1. General Procedure A ).

¹ H-NMR (400 MHz, CDCl ₃ ): 5 [ppm]=δ 9.21 (d.7=1.5 Hz, 1H), 8.42 (dd.7=4.9, 1 .4 Hz, 1H), 8.40 - 8.35 (m, 1H), 8.18 (d, J=8.1 Hz, 2H), 7.87 (d, J=8.6 Hz, 2H ), 7.38 (d, J=8.6 Hz, 2H), 7.36-7.32 (m, 1H), 4.76 (d, J=13.5 Hz, 1H), 4.70 -4.55 (m, 1H), 3.75 (d, J=13.5, 10.1 Hz, 1H); MS (ESI, m/z): 447.09 [M+H] ⁺ .

Example 25 8-(pyridin-3-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidine-4 (3H)-on

Using 3-amino-1,1,1-trifluoropropan-2-ol, pyridin-3-yl-boronic acid and (4-(trifluoromethyl)phenyl)boronic acid, the title compound was prepared as described for Example 1 (Scheme 1. General technique A).

¹ H-NMR (400 MHz, CDCl ₃ ): 8 [ppm]=9.29 (d, J=1.6 Hz, 1H), 8.48 (dd, J=4.9, 1, 5 Hz, 1H), 8.45 - 8.39 (m, 1H), 8.29 (s, 1H), 8.23 (s, 1H), 8.08 (d, J=8.2 Hz, 2H), 7.67 (d, J=8.3 Hz, 2H), 7.39 (dd, J=8.0, 4.9 Hz, W), 4.77 (dd, J=13.6 , 2.5 Hz, 1H), 4.71-4.62 (m, 1H), 3.81 (dd, J=13.5, 9.9 Hz, 1H); MS (ESI, m/z): 480.90 [M+H] ⁺ .

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

Using 3-aminophenol, (1-methyl-1H-pyrazol-4-yl)boronic acid and (4-chlorophenyl)boronic acid, the title compound was prepared as described for Example 1 (Scheme 1 General Procedure A). ¹ H-NMR (400 MHz, CDCl ₃ ): 8 [ppm]=8.62 (s, 1H), 8.62 (s, 1H), 8.35 (s, 1H), 8.19 (s, 1H), 8.17 (d, J=8.5 Hz, 2H), 7.49 (d, J=8.5 Hz, 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] ⁺ .

Example 27 He

Using 3-aminophenol, (1-methyl-1H-pyrazol-4-yl)boronic acid and (4-(trifluoromethyl)phenyl)boronic acid, the title compound was prepared as described for Example 1 (Scheme 1 General Procedure A).

^1H NMR (400 MHz, MeOD): δ [ppm]=8.80 (s, 1H), 8.58 (s, 1H), 8.47-8.33 (m, 4H), 7 .82 (d, J=8.3 Hz, 2H), 7.45 - 7.38 (m, 1H), 7.05-6.92 (m, 3H), 4.00 (s, 3H); MS (ESI, m/z): 464.1 [M+H] ⁺ .

Example 28

Using (1S,3R)-3-aminocyclopentanol, pyridin-3-yl-boronic acid and (4-chlorophenyl)boronic acid, the title compound was prepared as described for Example 1 (Scheme 1 General Procedure A).

^1H NMR (400 MHz, CDCl ₃ ): δ [ppm]=9.46 (d, J=1.8 Hz, 1H), 8.71 (dd, J=4.8, 1.6 Hz, 1H), 8.60 (s, 1H), 8.56 (dd, J=1.9, 1.9 Hz, 1H), 8.54 (s, 1H), 8.19 (d, J =8.6 Hz, 2H), 7.49 (d, J=8.5 Hz, 2H), 7.48-7.44 (m, 1H), 5.33-5.23 (m, 1H) , 4.58-4.48 (m, 1H), 2.84 (br, 1H), 2.59-2.49 (m, 1H), 2.40-2.31 (m, 1H), 2 .29 - 2.18 (m, 1H), 2.07-1.95 (m, 2H), 1.88-1.78 (m, 1H); MS (ESI, m/z): 419.1 [M+H] ⁺ .

Example 29 )-He

Using (1S,3R)-3-aminocyclopentanol, pyridin-3-yl-boronic acid and (4-(trifluoromethyl)phenyl)boronic acid, the title compound was prepared as described for Example 1 (Scheme 1 General Procedure A).

¹ H NMR (400 MHz, CDCl ₃ ): δ [ppm]=9.48 (s, 1H), 8.74 (d, J=3.9 Hz, 1H), 8.64 (s, 1H), 8.62 (s, 1H), 8.58 (d, J=8.1 Hz, 1H), 8.36 (d, J=8.2 Hz, 2H), 7.78 (d, J=8.3 Hz, 2H), 7.53-7.46 (m, 1H), 5.35-5.26 (m, 1H), 4.57-4.51 (m, 1H), 2 .72 (ush, 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] ⁺ .

Example 30 4(3H)-on

Using (1S,3R)-3-aminocyclopentanol, (1-methyl-1H-pyrazol-4-yl)boronic acid and (4-chlorophenyl)boronic acid, the title compound was prepared as described for Example 1 (Scheme 1. General Procedure A).

^1H NMR (400 MHz, CDCl ₃ ): δ [ppm]=8.64 (s, 1H), 8.60 (s, 1H), 8.57 (s, 1H), 8.33 ( s, 1H), 8.18 (d, J=8.5 Hz, 2H), 7.50 (d, J=8.5 Hz, 2H), 5.29-5.20 (m, 1H), 4.58-4.51 (m, 1H), 4.04 (s, 3H), 2.61-2.51 (m, 1H), 2.39-2.22 (m, 2H), 2. 10-1.97 (m, 2H), 1.90-1.79 (m, 1H); MS (ESI, m/z): 422.15 [M+H] ⁺ .

Example 31 1]pyrimidin-4(3H)-one

Using (1R,3S)-3-aminocyclopentanol, (1-methyl-1H-pyrazol-4-yl)boronic acid and (4-(trifluoromethyl)phenyl)boronic acid, the title compound was prepared as described for Example 1 (Scheme 1 General method A).

¹ H NMR (400 MHz, CDCl ₃ ): S [ppm]=8.66 (s, 1H), 8.62 (s, 1H), 8.61 (s, 1H), 8.40 ( s, 1H), 8.35 (d, J=8.1 Hz, 2H), 7.79 (d, J=8.2 Hz, 2H), 5.33-5.24 (m, 1H), 4.58-4.52 (m, 1H), 4.05 (s, 3H), 2.83-2.75 (m, 1H), 2.63-2.53 (m, 1H), 2. 41-2.33 (m, 1H), 2.31-2.22 (m, 1H), 2.11-2.02 (m, 1H), 1.91-1.81 (m, 1H); MS (ESI, m/z): 456.18 [M+H] ⁺ .

Example 32

Using (1R,3S)-3-aminocyclopentanol hydrochloride salt, pyridin-3-yl-boronic acid and (4-chlorophenyl)boronic acid, the title compound was prepared as described for Example 1 (Scheme 1. General Procedure A).

¹ H NMR (400 MHz, CDCl ₃ ): δ [ppm]=9.46 (s, 1H), 8.71 (d, J=4.1 Hz, 1H), 8.61 (s, 1H), 8.58-8.48 (m, 2H), 8.18 (d, J=8.5 Hz, 2H), 7.53-7.42 (m, 3H), 5.35-5 .24 (m, 1H), 4.57-4.48 (m, 1H), 2.60-2.48 (m, 1H), 2.41-2.31 (m, 1H), 2.29 -2.17 (m, 1H), 2.10-1.94 (m, 2H), 1.89-1.77 (m, 1H); MS (ESI, m/z): 419.13 [M+H] ⁺ .

Example 33 3H)-on

Using (1R,3S)-3-aminocyclopentanol hydrochloride salt, pyridin-3-yl-boronic acid and (4-(trifluoromethyl)phenyl)boronic acid, the title compound was prepared as described for Example 1 (Scheme 1. General Procedure A) .

¹ H NMR (400 MHz, CDCl ₃ ): δ [ppm]=9.47 (d, J=1.6 Hz, 1H), 8.73 (dd, J=4.8, 1.2 Hz, 1H), 8.63 (s, 1H), 8.62 (s, 1H), 8.60-8.52 (m, 1H), 8.36 (d, J=8.2 Hz, 2H ), 7.78 (d, J=8.3 Hz, 2H), 7.48 (dd, J=7.9, 4.9 Hz, 1H), 5.35-5.24 (m, 1H) , 4.57-4.48 (m, 1H), 2.67 (d, J=4.4 Hz, 1H), 2.61-2.47 (m, 1H), 2.44-2.32 (m, 1H), 2.30-2.16 (m, 1H), 2.09-1.92 (m, 2H), 1.91-1.77 (m, J=12.6, 6, 2 Hz, 1H); MS (ESI, m/z): 453.16 [M+H] ⁺ .

Example 34 in-4(3H)-on

Using (1R,3S)-3-aminocyclopentanol hydrochloride salt, (1-methyl-1H-pyrazol-4-yl)boronic acid and (4-chlorophenyl)boronic acid, the title compound was prepared as described for Example 1 (Scheme 1. General technique A).

¹ H NMR (400 MHz, CDCl ₃ ): δ [ppm]=8.63 (s, 1H), 8.58 (s, 1H), 8.56 (s, 1H), 8.32 ( s, 1H), 8.17 (d, J=8.6 Hz, 2H), 7.49 (d, J=8.7 Hz, 2H), 5.27-5.21 (m, 1H), 4.56-4.51 (m, 1H), 4.02 (s, 3H), 2.78 (d, J=5.0 Hz, 1H), 2.58-2.52 (m, 1H) , 2.34-2.19 (m, 2H), 2.07-1.97 (m, 2H), 1.88-1.81 (m, 1H); MS (ESI, m/z): 422.15 [M+H] ⁺ .

Example 35 ]pyrimidin-4(3H)-one

Using (1R,3S)-3-aminocyclopentanol hydrochloride salt, (1-methyl-1H-pyrazol-4-yl)boronic acid and (4-(trifluoromethyl)phenyl)boronic acid, the title compound was prepared as described for Example 1 ( Scheme 1. General methodology A).

^1H NMR (400 MHz, CDCl ₃ ): δ [ppm]=8.64 (s, 1H), 8.60 (s, 1H), 8.59 (s, 1H), 8.38 ( s, 1H), 8.33 (d, J=8.2 Hz, 2H), 7.77 (d, J=8.3 Hz, 2H), 5.30-5.22 (m, 1H), 4.58-4.49 (m, W), 4.03 (s, 3H), 2.77 (d, J=4.8 Hz, 1H), 2.60-2.52 (m, 1H) , 2.39 -2.31 (m, 1H), 2.30 - 2.21 (m, 1H), 2.09-1.98 (m, 2H), 1.90-1.80 (m, Sh); MS (ESI, m/z): 456.20 [M+H] ⁺ .

Example 36 -yl acetate

Using 1-amino-2-methylpropan-2-ol, pyridin-3-yl-boronic acid and (4-chlorophenyl)boronic acid, general procedure A (Scheme 1) was followed. During cyclization step c, additional acetylation of the hydroxyl group was observed by liquid chromatography-mass spectrometry (LC-MS) and ¹ H NMR analysis.

The title compound was prepared as described for Example 1 (Scheme 1. General Procedure A).

¹ H NMR (400 MHz, CDCl ₃ ): δ [ppm]=9.47 (s, 1H), 8.73 (d, J=4.1 Hz, 1H), 8.59 - 8, 51 (m, 2H), 8.19 (d, J=8.6 Hz, 2H), 8.15 (s, 1H), 7.54-7.44 (m, 3H), 4.36 (s , 2H), 2.06 (s, 3H), 1.57 (s, 6H); MS (ESI, m/z): 449.20 [M+H] ⁺ .

Example 37 2-methyl-1-(4-oxo-8-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidin-3(4H)-yl )propan-2-yl acetate

Using 1-amino-2-methylpropan-2-ol, pyridin-3-yl-boronic acid and (4-(trifluoromethyl)phenyl)boronic acid, General Procedure A (Scheme 1) was followed. During cyclization step c, additional acetylation of the hydroxyl group was observed based on LC-MS and ¹ H NMR analysis. The title compound was prepared as described for Example 1 (Scheme 1. General Procedure A).

^1H NMR (400 MHz, CDCl ₃ ): δ [ppm]=9.49 (s, 1H), 8.74 (d, J=4.0 Hz, 1H), 8.62 (s, 1H), 8.56 (ddd, J=7.9, 1.8, 1.8 Hz, 1H), 8.35 (d, J=8.2 Hz, 2H), 8.17 (s, 1H ), 7.78 (d, J=8.3 Hz, 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] ⁺ .

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

Using 1-amino-2-methylpropan-2-ol, pyridin-3-yl-boronic acid and (4-chlorophenyl)boronic acid, general procedure A (Scheme 1) was followed. During cyclization step c, additional acetylation of the hydroxyl group was observed based on LC-MS and ¹ H NMR analysis. The acetylation intermediate was deprotected after a second Suzuki coupling reaction under K ₂ CO ₃ in methanol:water (5:1) at room temperature to give the title compound according to Example 1 (Scheme 1 General Procedure A).

¹ H NMR (400 MHz, CDCl ₃ ): δ [ppm]=9.43 (s, 1H), 8.69 (d, J=3.8 Hz, 1H), 8.55 (d, J=8.0 Hz, 1H), 8.52 (s, 1H), 8.27 (s, 1H), 8.16 (d, J=8.6 Hz, 2H), 7.49 (d, J=8.6 Hz, 2H), 7.46-7.38 (m, 1H), 4.14 (s, 2H), 1.37 (s, 6H); MS (ESI, m/z): 407.24 [M+H] ⁺ .

Example 39 -He

Using 1-amino-2-methylpropan-2-ol, pyridin-3-yl-boronic acid and (4-(trifluoromethyl)phenyl)boronic acid, General Procedure A (Scheme 1) was followed. During cyclization step c, additional acetylation of hydroxyl groups was observed based on LC-MS and ¹ H NMR analysis. The acetylation intermediate was deprotected after a second Suzuki coupling reaction under K ₂ CO ₃ in methanol:water (5:1) at room temperature to obtain the compound of Example 1 (Scheme 1 General Procedure A).

^1H NMR (400 MHz, CDCl ₃ ): δ [ppm] = 9.47 (s, 1H), 8.73 (d, J=3.2 Hz, 1H), 8.62 (s, 1H), 8.58 (d, J=8.0 Hz, 1H), 8.35 (d, J=8.2 Hz, 2H), 8.30 (s, 1H), 7.78 (d, J=8.3 Hz, 2H), 7.51-7.44 (m, 1H), 4.15 (s, 2H), 1.37 (s, 6H); MS (ESI, m/z): 441.31 [M+H] ⁺ .

Example 40 (3H)-on

Using 1-amino-2-methylpropan-2-ol, pyridin-3-yl-boronic acid and (6-(trifluoromethyl)pyridin-3-yl)boronic acid, General Procedure A (Scheme 1) was followed. During cyclization step c, according to LC-MS analysis, additional acetylation of hydroxyl groups was observed. The acetylation intermediate was deprotected after a second reaction of the Suzuki compound under K ₂ CO ₃ in methanol:water (5:1) at room temperature to give the compound of Example 1 (Scheme 1 General Procedure A).

^1H NMR (400 MHz, CDCl ₃ ): δ [ppm] = 9.52 (d, J=1.9 Hz, 1H), 9.48 (d, J=1.8 Hz, 1H) , 8.76-8.67 (m, 2H), 8.65 (s, 1H), 8.60-8.55 (m, 1H), 8.35 (s, 1H), 7.84 (d , J=8.2 Hz, 1H), 7.48 (dd, J=8.0, 4.8 Hz, 1H), 4.16 (s, 2H), 1.37 (s, 6H); MS (ESI, m/z): 442.17 [M+H] ⁺ .

Example 41 6-(4-chlorophenyl)-3-(1-hydroxy-3-methylbutan-2-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H) -He

Using 2-amino-3-methylbutan-1-ol, pyridin-3-yl-boronic acid and (4-chlorophenyl)boronic acid, the title compound was prepared as described for Example 1 (Scheme 1 General Procedure A).

¹ H-NMR (400 MHz, CDCl ₃ ): δ [ppm] = 9.43 (d, J=1.8 Hz, 1H), 8.68 (dd, J=4.8, 1, 5 Hz, 1H), 8.54 (dt, J=7.8, 1.9 Hz, 1H), 8.50 (e, 1H), 8.30 (s, 1H), 8.15 (d, J=8.6 Hz, 2H), 7.48 (d, J=8.6 Hz, 2H), 7.45 (dd, J=8.2, 5.2 Hz, 1H), 4.51 ( ush, 1H), 4.25-4.16 (m, 1H), 4.01 (dd, J=11.8, 2.2 Hz, 1H), 2.57-2.43 (m, 2H) , 1.20 (d, J=6.5 Hz, 3H), 0.89 (d, J=6.6 Hz, 3H); MS (ESI, m/z): 421.20 [M+H] ⁺ .

Example 42 (3H)-on

Using 2-amino-3-methylbutan-1-ol, pyridin-3-yl-boronic acid and (4-(trifluoromethyl)phenyl)boronic acid, the title compound was prepared as described for Example 1 (Scheme 1 General Procedure A) .

¹ H-NMR (400 MHz, CDCl ₃ ): δ [ppm] = 9.42 (s, 1H), 8.67 (dd, J=4.8, 1.4 Hz, 1H), 8 .55-8.52 (m, 1H), 8.54 (s, 1H), 8.33 (s, 1H), 8.29 (d, J=8.2 Hz, 2H), 7.75 ( d, J=83 Hz, 2H), 7.44 (dd, J=7.7, 5.1 Hz, 1H), 4.52 (ush, 1H), 4.26-4.18 (m, 1H ), 4.02 (dd, J=11.9, 2.2 Hz, 1H), 2.91-2.74 (m, 1H), 2.55-2.44 (m, 1H), 1, 20 (d, J=6.5 Hz, 3H), 0.89 (d, J=6.7 Hz, 3H); MS (ESI, m/z): 455.21 [M+H] ⁺ .

Example 43 ]pyrimidin-4(3H)-one

Using 2-amino-3-methylbutan-1-ol, pyridin-3-yl-boronic acid and (6-(trifluoromethyl)pyridin-3-yl)boronic acid, the title compound was prepared as described for Example 1 (Scheme 1. General technique A).

¹ H-NMR (400 MHz, CDCl ₃ ): δ [ppm] = 9.50 (d, J=1.5 Hz, 1H), 9.46 (d, J=1.6 Hz, 1H ), 8.72 (dd, J=4.8, 1.4 Hz, 1H), 8.68 (dd, J=8.3, 1.7 Hz, 1H), 8.62 (s, 1H) , 8.56 (dt, J=8.0, 1.9 Hz, 1H), 8.37 (s, 1H), 7.83 (d, J=8.2 Hz, 1H), 7.47 ( dd, J=7.9, 4.9 Hz, 1H), 4.55 (ush, 1H), 4.26-4.17 (m, 1H), 4.02 (dt, J=11.7, 3.1 Hz, 1H), 2.55 -2.43 (m, 1H), 2.34-2.24 (m, 1H), 1.21 (d, J=6.5 Hz, 3H), 0.90 (d, J=6.7 Hz, 3H); MS (ESI, m/z): 456.19 [M+H] ⁺ .

Example 44 He

Scheme for obtaining a connection according to example 44:

Intermediate 5. 5-amino-N-(1-((tert-butyldiphenylsilyl)oxy)propan-2-yl)-2-chloroisonicotinamide

5-amino-2-chloroisonicotinic acid (1 g, 5.79 mmol, 1 equiv.), EDC (1.33 g, 6.95 mmol, 1.2 equiv.), HOBT (1.06 g, 6.95 mmol , 1.2 equiv.) and TEA (1.21 ml, 8.69 mmol, 1.5 equiv.) were dissolved in DMF (10 ml, 0.6 M) and stirred for 5 min. 1-((tert-Butyldiphenylsilyl)oxy)propan-2-amine (2.73 g, 8.69 mmol, 1.5 equiv) was then added to the reaction mixture and stirred for 12 hours at 60°C. The reaction mixture was diluted with water (50 ml), extracted with ethyl acetate (20 ml x 3), washed with brine (20 ml x 3), dried over Na ₂ SO ₄ and filtered on a glass filter. The filtrate was evaporated in vacuo and purified by MPLC (silica gel, 0~30% ethyl acetate/hexane) to give 0.87 g (32% yield) 5-amino-N-(1-((tert-butyldiphenylsilyl)oxy)propane-2 -yl)-2-chloroisonicotinamide (intermediate 5).

MS (ESI, m/z): 468.04 [M+H] ⁺ .

Intermediate 6. 5-amino-N-(1-((tert-butyldiphenylsilyl)oxy)propan-2-yl)-2-(4-(trifluoromethyl)phenyl)isonicotinamide

5-Amino-N-(1-((tert-butyldiphenylsilyl)oxy)propan-2-yl)-2-chloroisonicotinamide (intermediate 5) (0.64 g, 1.37 mmol, 1 equiv.), (4 -(trifluoromethyl)phenyl)boronic acid (0.52 g, 2.73 mmol, 2 equiv.), 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 equiv.) was dissolved in 1,4-dioxane/water (4 ml/1 ml, 0.4 M). 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 immediately purified by MPLC (silica gel, 0~30% ethyl acetate/hexane) to obtain 0.48 g (yield 61 %) 5-amino-N-(1-((tert-butyldiphenylsilyl)oxy)propan-2-yl)-2-(4-(trifluoromethyl)phenyl)isonicotinamide (intermediate 6). MS (ESI, m/z): 578.16 [M+H] ⁺ .

Intermediate 7. 3-Amino-2-bromo-N-(1-((tert-butyldiphenylsilyl)oxy)propan-2-yl)-6-(4-(trifluoromethyl)phenyl)isonicotinamide

5-amino-N-(1-((tert-butyldiphenylsilyl)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 for 1 h at room temperature. The reaction mixture was diluted with water (20 ml), extracted with ethyl acetate (20 ml x 3), washed with brine (10 ml x 3), dried over Na ₂ SO ₄ and filtered on a glass filter. The filtrate was evaporated in vacuo to give 0.082 g (72% yield) 3-amino-2-bromo-N-(1-((tert-butyldiphenylsilyl)oxy)propan-2-yl)-6-(4-(trifluoromethyl)phenyl )isonicotinamide (intermediate 7). MS (ESI, m/z): 656.14 [M+H] ⁺ .

Intermediate 8. 8-bromo-3-(1-((tert-butyldiphenylsilyl)oxy)propan-2-yl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidin-4( 3H)-on

3-Amino-2-bromo-N-(1-((tert-butyldiphenylsilyl)oxy)propan-2-yl)-6-(4-(trifluoromethyl)phenyl)isonicotinamide (intermediate 7) (82 mg, 0.125 mmol , 1 equiv.) was dissolved in a solution of (EtO) ₃ CH (1.5 ml, 9.01 mmol, 9 equiv.) and CH ₃ CO ₂ H (1.5 ml, 26.2 mmol, 210 equiv.). The reaction mixture was stirred and heated in a Biotage microwave initiator at 150°C for 2 hours. The reaction mixture was diluted with water (20 ml), extracted with ethyl acetate (20 ml × 3), washed with brine (10 ml × 3), dried over Na ₂ SO ₄ and filtered on a glass filter. The filtrate was evaporated under vacuum and used without further purification to obtain 0.06 g (yield 72%) 8-bromo-3-(1-((tert-butyldiphenylsilyl)oxy)propan-2-yl)-6-(4-( trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one

(intermediate 8).

MS (ESI, m/z): 666.09 [M] ⁺ .

Intermediate 9. 3-(1-((tert-butyldiphenylsilyl)oxy)propan-2-yl)-8-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4- d]pyrimidin-4(3H)-one

8-bromo-3-(1-((tert-butyldiphenylsilyl)oxy)propan-2-yl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one (intermediate 8) (60 mg, 0.090 mmol, 1 equiv.), pyridin-3-yl-boronic acid (17 mg, 0.13 mmol, 1.5 equiv.), K ₂ CO ₃ (37 mg, 0 .27 mmol, 3 equiv.), Sphos (3.7 mg, 9.00 µmol, 0.1 equiv.) and Pd ₂ (dba) ₃ ⋅CHCl ₃ (9.32 mg, 9.00 µmol, 0. 1 equiv.) was dissolved in 1,4-dioxane/water (4 ml/1 ml, 0.2 M). 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 immediately purified by MPLC (silica gel, 0~30% ethyl acetate/hexane) to obtain 10 mg (yield 17%) 3-(1-((tert-butyldiphenylsilyl)oxy)propan-2-yl)-8-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidin- 4(3H)-she

(intermediate 9).

MS (ESI, m/z): 665.15[M+H] ⁺ .

Example 44 He

Solution of 3-(1-((tert-butyldiphenylsilyl)oxy)propan-2-yl)-8-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidine -4(3H)-one (intermediate 9) (10 mg, 0.015 mmol, 1 equiv.) and TBAF (1.0 M in THF, 15 μL, 0.015 mmol, 1 equiv.) in THF (2 mL, 0 .0075 M) was stirred for 12 hours at 40°C. The reaction mixture was diluted with water (5 ml), extracted with ethyl acetate (5 ml x 3), washed with brine (5 ml x 3), dried over Na ₂ SO ₄ and filtered on a glass filter. The filtrate was evaporated in vacuo and purified by preparative thin layer chromatography (Prep TLC) (silica gel, 0~50% ethyl acetate/hexane) to give 1.9 g (30% yield) 3-(1-hydroxypropan-2-yl)-8-(pyridine -3-yl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one (Example 44).

¹ H-NMR (400 MHz, CD ₃ OD): δ [ppm] = 9.44 (d, J=1.6 Hz, 1H), 8.75 (d, J=8.0 Hz, 1H), 8.69 (s, 1H), 8.66 (d, J=4.8 Hz, 1H), 8.48 (s, 1H), 8.45 (d, J=8.2 Hz, 2H), 7.86 (d, J=8.3 Hz, 2H), 7.63 (dd, J=8.0, 5.0 Hz, 1H), 5.08-4.99 (m, 1H ), 3.99 (dd, J=11.9, 7.0 Hz, 1H), 3.88 (dd, J=11.9,4.3 Hz, 1H), 1.58 (d, J= 7.1 Hz, 3H); MS (ESI, m/z): 426.94 [M+H] ⁺ .

Example 45 3-(1-hydroxypropan-2-yl)-8-(1-methyl-1H-pyrazol-4-yl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidine -4(3H)-on

Using (1-methyl-1H-pyrazol-4-yl)boronic acid, the title compound was prepared as described for Example 44 (Scheme 2 General Procedure B).

¹ H-NMR (400 MHz, 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=2.7 Hz, 2H), 7.71 (d, J=8.3 Hz, 2H), 4.94-4.86 (m, 1H ), 3.90 (s, 3H), 3.87 (t, J=5.9 Hz, 1H), 3.77 (dd, J=11.9, 4.3 Hz, 1H), 1.47 (d, J=7.1 Hz, 3H); MS (ESI, m/z): 430.02 [M+H] ⁺ .

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

Using pyridin-3-yl-boronic acid, the title compound was prepared as described for Example 44 (Scheme 2 General Procedure B).

¹ H-NMR (400 MHz, CD ₃ OD): δ [ppm] = 9.31 (s, 1H), 8.65-8.59 (m, 1H), 8.53 (d, J =4.2 Hz, 1H), 8.49 (s, 1H), 8.34 (s, 1H), 8.14 (d, J=8.6 Hz, 2H), 7.51 (dd, J =7.9, 5.0 Hz, 1H), 7.44 (d, J=8.6 Hz, 2H), 4.95-4.86 (m, 1H), 3.87 (dd, J= 11.9, 7.0 Hz, 1H), 3.76 (dd, J=11.9, 4.3 Hz, 1H), 1.46 (d, J=7.1 Hz, 3H); MS (ESI, m/z): 392.91 [M+H] ⁺ .

Example 47

b-(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 equiv.) and sodium hydride (18.33 mg, 0.764 mmol, 3 equiv.) were dissolved in THF (1273 μL, 0.2 M) and stirred for 10 min. Then a solution of diethyl chlorophosphate (73.8 µl, 0.509 mmol, 2 equiv.) and N,N-dimethylpyridin-4-amine (15.55 mg, 0.127 mmol, 0.5 equiv.) in THF (1273 µl, 0.2 equiv. M) was added dropwise to the reaction mixture and stirred for 12 hours at room temperature. The reaction mixture was quenched with water (10 ml), extracted with DCM (10 ml x 3), washed with brine (10 ml x 3), dried over Na ₂ SO ₄ and filtered on a glass filter. The filtrate was evaporated in vacuo and used without further purification to obtain 79 mg (59% yield) of 2-(6-(4-chlorophenyl)-4-oxo-8-(pyridin-3-yl)pyrido[3,4-d] pyrimidin-3(4H)-yl)propyl diethyl phosphate (example 47).

¹ H-NMR (400 MHz, CDCl ₃ ): δ [ppm] = 9.45 (d, J=1.6 Hz, 1H), 8.72 (dd, J=4.8, 1, 4 Hz, 1H), 8.55 (dt, J=8.0, 1.9 Hz, 1H), 8.53 (s, 1H), 8.18 (d, J=8.5 Hz, 3H) , 7.49 (d, J=8.7 Hz, 2H), 7.47 (dd, J=5.2, 3.1, 1H), 5.15 (dd, J=10.2, 6, 3 Hz, 1H), 4.45 (ddd, J=11.2, 7.5, 6.2 Hz, 1H), 4.37-4.28 (m, 1H), 4.06 (p, J =7.3 Hz, 4H), 1.65 (d, J=7.2 Hz, 3H), 1.29-1.23 (m, 6H); MS (ESI, m/z): 529.23 [M+H] ⁺ .

Example 48 3H)-on

Using (1-methyl-1H-pyrazol-4-yl)boronic acid and (4-chlorophenyl)boronic acid, the title compound was prepared as described for Example 44 (Scheme 2 General Procedure B).

¹ H-NMR (400 MHz, CD ₃ OD): δ [ppm] = 8.79 (s, 1H), 8.56 (s, 1H), 8.46 (s, 1H), 8. 33 (s, 1H), 8.22 (d, J=8.4 Hz, 2H), 7.77 (s, 1H), 7.52 (d, J=8.4 Hz, 2H), 5, 03-4.99 (m, 1H), 4.01 (s, 3H), 3.99-3.93 (m, 1H), 3.86 (dd, J=11.8, 4.3 Hz, 1H), 1.57 (d, J=7.1 Hz, 3H); MS (ESI, m/z): 396.00 [M+H] ⁺ .

Example 49 He

Using pyridin-3-ylboronic acid and (4-(trifluoromethoxy)phenyl)boronic acid, the title compound was prepared as described for Example 44 (Scheme 2 General Procedure B).

¹ H-NMR (400 MHz, CD ₃ OD): δ [ppm] = 9.43 (s, 1H), 8.74 (dd, J=6.2, 1.8 Hz, 1H), 8.68-8.64 (m, 1H), 8.62 (s, 1H), 8.46 (s, 1H), 8.37 (d, J=8.8 Hz, 2H), 7.63 (dd, J=7.9, 5.0 Hz, 1H), 7.46 (d, J=8.4 Hz, 2H), 5.08-4.98 (m, 1H), 3.99 ( dd, J=11.9, 7.0 Hz, 1H), 3.88 (dd, J=11.9, 4.3 Hz, 1H), 1.58 (d, J=7.1 Hz, 3H ); MS (ESI, m/z): 442.93 [M+H] ⁺ .

Example 50 (3H)-on

Using pyridin-3-yl-boronic acid and (6-(trifluoromethyl)pyridin-3-yl)boronic acid, the title compound was prepared as described for Example 44 (Scheme 2 General Procedure B).

¹ H-NMR (400 MHz, CD ₃ OD): δ [ppm] = 9.59 (s, 1H), 9.45 (d, J=1.9 Hz, 1H), 8.89 ( d, J=8.2 Hz, 1H), 8.79 (s, 1H), 8.76 (d, J=8.0 Hz, 1H), 8.70-8.59 (m, 1H), 8.52 (s, 1H), 8.01 (d, J=8.3 Hz, 1H), 7.65 (dd, J=8.0, 4.9 Hz, 1H), 5.07-5 .00 (m, 1H), 4.00 (dd, J=11.9, 7.0 Hz, 1H), 3.88 (dd, J=11.9, 4.3 Hz, 1H), 1, 59 (d, J=7.1 Hz, 3H); MS (ESI, m/z): 427.96 [M+H] ⁺ .

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

Using 2-aminobutan-1-ol, pyridin-3-yl-boronic acid and (4-chlorophenyl)boronic acid, the title compound was prepared as described for Example 44 (Scheme 2 General Procedure B).

¹ H-NMR (400 MHz, CD ₃ OD): δ [ppm] = 9.43 (d, J=1.6 Hz, 1H), 8.74 (d, J=8.0 Hz, 1H), 8.65 (d, J=4.8 Hz, 1H), 8.61 (s, 1H), 8.44 (s, 1H), 8.26 (d, J=8.5 Hz, 2H), 7.63 (dd, J=8.0, 5.0 Hz, 1H), 7.56 (d, J=8.5 Hz, 2H), 4.84 (s, 1H), 4, 04 (dd, J=12.0, 7.1 Hz, 1H), 3.89 (dd, J=12.0, 4.0 Hz, 1H), 2.02 (p, J=7.4 Hz , 2H), 1.00 (t, J=7.4 Hz, 3H); MS (ESI, m/z): 406.95 [M+H] ⁺ .

Example 52 3H)-on

Using 2-aminobutan-1-ol, (1-methyl-1H-pyrazol-4-yl)boronic acid and (4-chlorophenyl)boronic acid, the title compound was prepared as described for Example 44 (Scheme 2 General Procedure B) .

¹ H-NMR (400 MHz, 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=8.5 Hz, 2H), 7.53 (d, J=8.5 Hz, 2H), 4.82 (s, 1H), 4, 08-4.03 (m, 1H), 4.02 (s, 3H), 3.89 (dd, J=12.0, 4.0 Hz, 1H), 2.03 (p, J=7, 4 Hz, 2H), 1.00 (t, J=7.4 Hz, 3H); MS (ESI, m/z): 409.99 [M+H] ⁺ .

Using 2-aminobutan-1-ol, pyridin-3-yl-boronic acid and (4-(trifluoromethyl)phenyl)boronic acid, the title compound was prepared as described for Example 44 (Scheme 2 General Procedure B).

¹ H-NMR (400 MHz, CD ₃ OD): δ [ppm] = 9.43 (d, J=2.0 Hz, 1H), 8.74 (dt, J=8.0, 1 ,8 Hz, 1H), 8.66 (s, 1H), 8.66-8.63 (m, 1H), 8.46 (s, 1H), 8.43 (d, J=8.3 Hz , 2H), 7.84 (d, J=8.4 Hz, 2H), 7.62 (dd, J=8.0, 5.0 Hz, 1H), 4.84 (s, 1H), 4 .04 (dd, J=12.0, 7.0 Hz, 1H), 3.89 (dd, J=12.0, 4.0 Hz, 1H), 2.07-1.94 (m, 2H ), 1.01 (t, J=7.4 Hz, 3H); MS (ESI, m/z): 441.00 [M+H] ⁺ .

Example 54 3-(1-Hydroxybutan-2-yl)-8-(1-methyl-1H-pyrazol-4-yl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidine -4(3H)-on

Using 2-aminobutan-1-ol, (1-methyl-1H-pyrazol-4-yl)boronic acid and (4-(trifluoromethyl)phenyl)boronic acid, the title compound was prepared as described for Example 44 (Scheme 2 General method B).

¹ H-NMR (400 MHz, 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=8.1 Hz, 2H), 4.83 (s, 1H), 4.08-4.03 (m , 1H), 4.02 (s, 3H), 3.90 (dd, J=12.0, 3.9 Hz, 1H), 2.03 (t, J=7.5 Hz, 2H), 1 .01 (t, J=7.4 Hz, 3H); MS (ESI, m/z): 444.01 [M+H] ⁺ .

Example 55 6-(4-chlorophenyl)-8-(3-fluorophenyl)-3-(1-hydroxybutan-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one

Using 2-aminobutan-1-ol, (3-fluorophenyl)boronic acid and (4-chlorophenyl)boronic acid, the title compound was prepared as described for Example 44 (Scheme 2 General Procedure B).

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

Example 56

Using (1R,4R)-4-aminocyclohexan-1-ol, pyridin-3-yl-boronic acid and (4-chlorophenyl)boronic acid, the title compound was prepared as described for Example 44 (Scheme 2 General Procedure B).

¹ H-NMR (400 MHz, CDCl ₃ ): δ [ppm] = 9.45 (s, 1H), 8.72 (s, 1H), 8.58-8.46 (m, 2H) , 8.19 (d, J=8.6 Hz, 2H), 8.17 (s, 1H), 7.54-7.42 (m, 3H), 4.89-4.76 (m, 9H ), 3.83-3.74 (m, 1H), 2.32-2.16 (m, 2H), 2.14-2.03 (m, 2H), 1.92-1.76 (m , 2H), 1.69-1.59 (m, 2H); MS (ESI, m/z): 433.01 [M+H] ⁺ .

Example 57 )-He

Using (1R,4R)-4-aminocyclohexan-1-ol, pyridin-3-yl-boronic acid and (4-(trifluoromethyl)phenyl)boronic acid, the title compound was prepared as described for Example 44 (Scheme 2. General Procedure IN).

¹ H-NMR (400 MHz, CDCl ₃ ): δ [ppm] = 9.46 (d, J=1.9 Hz, 1H), 8.73 (dd, J=4.8, 1, 6 Hz, 1H), 8.62 (s, 1H), 8.58-8.51 (m, 1H), 8.36 (d, J=8.3 Hz, 2H), 8.20 (s, 1H), 7.79 (d, J=8.4 Hz, 2H), 7.48 (dd, J=7.9, 4.9 Hz, 1H), 4.87-4.79 (m, 1H ), 3.83-3.75 (m, 1H), 2.28-2.16 (m, 2H), 2.14-2.03 (m, 2H), 1.92-1.79 (m , 2H), 1.69-1.60 (m, 2H); MS (ESI, m/z): 466.97 [M+H] ⁺ .

Example 58

Using methyl (1R,4R)-4-aminocyclohexanol, pyridin-3-yl-boronic acid and (4-chlorophenyl)boronic acid, general procedure B (Scheme 2) was followed. During cyclization step c, additional acetylation of hydroxyl groups was observed according to the results of LC-MS analysis. The acetylation intermediate was deprotected after a second Suzuki coupling reaction under K ₂ CO ₃ in methanol:water (5:1) at room temperature to give the title compound according to Example 58 (Scheme 2 General Procedure B).

¹ H NMR (400 MHz, CDCl ₃ ): δ [ppm] = 9.46 (s, 1H), 8.72 (s, 1H), 8.56 (d, J=10.0 Hz, 2H), 8.29 (s, 1H), 8.22-8.10 (m, 2H), 7.57-7.36 (m, 3H), 4.90 (tt, J=12.7, 3.5 Hz, 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] ⁺ .

Example 59 4-d]pyrimidin-4(1H)-one

Scheme for obtaining a connection according to example 59:

Intermediate 10. 3-(1-((tert-butyldiphenylsilyl)oxy)propan-2-yl)-8-(1-methyl-1H-pyrazol-4-yl)-6-(4-(trifluoromethyl)phenyl) pyrido[3,4-d]pyrimidin-4(3H)-one

Using (1-methyl-1H-pyrazol-4-yl)boronic acid, the title compound was prepared as described for Intermediate 9 of Example 44 (Scheme 2 General Procedure B).

MS (ESI, m/z): 668.31 [M+M] ⁺ .

Intermediate 11. 3-(1-((tert-butyldiphenylsilyl)oxy)propan-2-yl)-8-(1-methyl-1H-pyrazol-4-yl)-6-(4-(trifluoromethyl)phenyl) -2,3-dihydropyrido[3,4-d]pyrimidin-4(1H)-one

3-(1-((tert-butyldiphenylsilyl)oxy)propan-2-yl)-8-(1-methyl-1H-pyrazol-4-yl)-6-(4-(trifluoromethyl)phenyl)pyrido[3, 4-d]pyrimidin-4(3H)-one (intermediate 10) (23 mg, 0.034 mmol, 1 equiv.) was dissolved in THF (3 mL, 0.011 M) and cooled at 0°C. NaBH ₄ (5.21 mg, 0.14 mmol, 4 equiv) was then added to the reaction mixture and stirred for 2 hours at room temperature. The reaction mixture was quenched with MeOH (3 ml), diluted with water (3 ml), extracted with ethyl acetate (5 ml x 3), washed with brine (5 ml x 3), dried over Na ₂ SO ₄ and filtered on a glass filter. The filtrate was evaporated in vacuo and purified by MPLC (silica gel, 0~30% ethyl acetate/hexane) to give 20 mg (yield 87%) 3-(1-((tert-butyldiphenylsilyl)oxy)propan-2-yl)-8- (1-methyl-1H-pyrazol-4-yl)-6-(4-(trifluoromethyl)phenyl)-2,3-dihydropyrido[3,4-d]pyrimidin-4(1H)-one (intermediate 11) .

MS (ESI, m/z): 670.26 [M+H] ⁺ .

Example 59 4-d]pyrimidin-4(1H)-one

To a solution of 3-(1-((tert-butyldiphenylsilyl)oxy)propan-2-yl)-8-(1-methyl-1H-pyrazol-4-yl)-6-(4-(trifluoromethyl)phenyl)-2 ,3-dihydropyrido[3,4-d]pyrimidin-4(1H)-one (intermediate 11) (20 mg, 0.03 mmol, 1 equiv) in THF (2 mL, 0.01 M) added TBAF (1.0 M in THF, 30 µl, 0.03 mmol, 1 equiv.) and stirred for 3 hours at 40°C. The reaction mixture was diluted with water (5 ml) and extracted with ethyl acetate (5 ml x 3), washed with brine (5 ml x 3), dried over Na ₂ SO ₄ and filtered on a glass filter. The filtrate was evaporated in vacuo and purified by Prep TLC (Chromatorex KP80805 (NH- _SiO2 ) silica gel, 0~70% ethyl acetate/hexane) to give 3.9 mg (30% yield) 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).

¹ H-NMR (400 MHz, CDCl ₃ ): δ [ppm] = 8.17 (s, 1H), 8.15 (d, J=8.2 Hz, 2H), 8.03 (s , 1H), 7.98 (s, 1H), 7.69 (d, J=8.3 Hz, 2H), 4.74 (dt, J=11.0, 3.8 Hz, 2H), 4 ,70-4.62 (m, 2H), 3.86 (dd, J=11.6, 3.8 Hz, 1H), 3.73 (d, J=7.8 Hz, 1H), 1, 61 (s, 2H), 1.32 (d, J=7.0 Hz, 3H); MS (ESI, m/z):432.01 [M+H] ⁺ .

Example 60 6-(4-chlorophenyl)-3-(2,3-dihydroxypropyl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one

6-(4-chlorophenyl)-3-(1-hydroxypropan-2-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (Example 48) ( 50 mg, 0.127 mmol, 1 equiv.) was dissolved in THF (3 ml, 0.042 M) and cooled at 0°C. NaBH ₄ (9.6 mg, 0.255 mmol, 2 equiv.) was then added to the reaction mixture and stirred for 2 hours at room temperature. The reaction mixture was quenched with methanol (3 ml), diluted with water (3 ml), extracted with ethyl acetate (5 ml x 3), washed with brine (5 ml x 3), dried over Na ₂ SO ₄ and filtered on a glass filter. The filtrate was evaporated in vacuo and purified by Prep TLC (silica gel, 0~10% MeOH/DCM) to give 2.9 mg (5.7% yield) 6-(4-chlorophenyl)-3-(2,3-dihydroxypropyl) -8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (Example 60).

¹ H-NMR (400 MHz, CDCl ₃ ): δ [ppm] = 9.04 (s, 1H), 8.70 (s, 1H), 8.24 (s, 1H), 8.12 (d, J=7.9 Hz, 1H), 7.99 (d, J=8.6 Hz, 2H), 7.47 (dd, J=7.6, 5.0 Hz, 1H), 7 .41 (d, J=8.5 Hz, 2H), 4.85 (s, 1H), 4.79-4.73 (m, 1H), 4.73-4.61 (m, 2H), 3.85 (dd, J=11.6, 3.8 Hz, 1H), 3.70 (dd, J=11.5, 7.6 Hz, 1H), 1.31 (d, J=7, 0 Hz, 3H); MS (ESI, m/z):395.15 [M+H] ⁺ .

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

Using 3-aminophenol, pyridin-3-yl-boronic acid and (4-chlorophenyl)boronic acid, the title compound was prepared as described for Example 44 (Scheme 2 General Procedure B).

¹ H-NMR (400 MHz, CDCl ₃ ): δ [ppm] = 9.50 (d, J=1.7 Hz, 1H), 8.72 (dd, J=4.9, 1, 5 Hz, 1H), 8.63-8.59 (m, 1H), 8.57 (s, 1H), 8.17 (d, J=8.6 Hz, 2H), 8.15 (s, 1H), 7.54 (dd, J=7.9, 4.9 Hz, 1H), 7.49 (d, J=8.6 Hz, 2H), 7.44 (dd, J=8.1 , 8.1 Hz, 1H), 7.04 (dd, J=8.2, 1.8 Hz, 1H), 6.96 (d, J=7.8 Hz, 1H), 6.93-6 .90 (m, 1H); MS (ESI, m/z): 427.0 [M+H] ⁺ .

Example 62

Using 3-aminophenol, pyridin-3-yl-boronic acid and (4-(trifluoromethyl)phenyl)boronic acid, the title compound was prepared as described for Example 44 (Scheme 2 General Procedure B).

¹ H-NMR (400 MHz, CDCl ₃ ): δ [ppm] = 9.50 (d, J=2.0 Hz, 1H), 8.74 (dd, J=4.9, 1, 6 Hz, 1H), 8.66 (s, 1H), 8.62-8.57 (m, 1H), 8.36 (d, J=8.1 Hz, 2H), 8.20 (s, 1H), 7.79 (d, J=8.3 Hz, 2H), 7.53 (dd, J=8.4, 4.5 Hz, 1H), 7.46 (dd, J=8.1 , 8.1 Hz, 1H), 7.04 (dd, J=8.3, 2.3 Hz, 1H), 7.02-6.98 (m, 1H), 6.96-6.92 ( m, 1H); MS (ESI, m/z): 461.03 [M+H] ⁺ .

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

Using 3-aminocyclohexan-1-ol, pyridin-3-yl-boronic acid and (4-chlorophenyl)boronic acid, the title compound was prepared as described for Example 44 (Scheme 2 General Procedure B).

^1H NMR (400 MHz, MeOD) δ [ppm] = 9.42 (s, 1H), 8.74 (d, J=7.9 Hz, 1H), 8.65 (d, J= 4.8 Hz, 1H), 8.60 (s, 1H), 8.50 (s, 1H), 8.26 (d, J=7.6 Hz, 2H), 7.63 (dd, J= 8.0, 4.9 Hz, 1H), 7.56 (d, J=7.7 Hz, 2H), 4.79 (t, J=12.5 Hz, 1H), 3.90-3, 75 (m, 1H), 2.28 (d, J=12.1 Hz, 1H), 2.07-1.98 (m, 3H), 1.91-1.80 (m, 2H), 1 .56 (dd, J=25.7, 13.1 Hz, 1H), 1.38 (dd, J=18.1, 8.6 Hz, 1H); MS (ESI, m/z): 433.11 [M+H] ⁺ .

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

Using 3-aminocyclohexan-1-ol, (1-methyl-1H-pyrazol-4-yl)boronic acid and (4-chlorophenyl)boronic acid, the title compound was prepared as described for Example 44 (Scheme 2 General Procedure B) .

^1H NMR (400 MHz, MeOD) δ [ppm] = 8.80 (s, 1H), 8.58 (s, 1H), 8.52 (s, 1H), 8.34 (s, 1H), 8.23 (d, J=8.6 Hz, 2H), 7.54 (d, J=8.6 Hz, 2H), 4.79 (t, J=12.4 Hz, 1H) , 4.02 (s, 3H), 3.84-3.73 (m, 1H), 2.28 (d, J=11.1 Hz, 1H), 2.11-2.01 (m, 2H ), 1.91-1.83 (d, J=12.0 Hz, 2H), 1.56 (dd, J=26.7, 13.4 Hz, 1H), 1.42-1.33 ( m, 1H).; MS (ESI, m/z): 436.10 [M+H] ⁺ .

Example 65 -4(3H)-on

Scheme for obtaining a connection according to example 65:

Intermediate 12. 3-Amino-6-chloro-N-((1R,3S)-3-hydroxycyclopentyl)-2-iodoisonicotinamide

Blend of 3-amino-6-chloro-2-iodoisonicotinic acid (2 g, 6.70 mmol, 1 equiv), EDC (1.541 g, 8.04 mmol, 1.2 equiv), HOBT (1.231 g, 8 .04 mmol, 1.2 equiv.) and TEA (1.401 ml, 10.05 mmol, 1.5 equiv.) were dissolved in DMF (50 ml, 0.14 M) and stirred for 5 min. (1S,3R)-3-Aminocyclopentanol (0.746 g, 7.37 mmol, 1.1 equiv) was then added to the reaction mixture and stirred for 12 hours at 50°C. The reaction mixture was diluted with water (50 ml), extracted with ethyl acetate (20 ml x 3), washed with brine (20 ml x 3), dried over Na ₂ SO ₄ and filtered on a glass filter. The filtrate was evaporated in vacuo and purified by MPLC (silica gel, 0~5% MeOH/DCM) to give 2 g (78%) 3-amino-6-chloro-N-((1R,3S)-3-hydroxycyclopentyl)- 2-iodoisonicotinamide (intermediate 12). MS (ESI, m/z): 381.85 [M+H] ⁺ .

Intermediate 13. 6-chloro-3-((1R,3S)-3-hydroxycyclopentyl)-8-iodopyrido[3,4-d]pyrimidin-4(3H)-one

3-Amino-6-chloro-N-((1R,3S)-3-hydroxycyclopentyl)-2-iodoisonicotinamide (intermediate 12) (1.5 g, 3.93 mmol, 1 equiv.) was dissolved in solution (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 in a Biotage microwave initiator at 150°C for 1 hour. The reaction mixture was diluted with water (20 ml), extracted with ethyl acetate (20 ml × 3), washed with brine (10 ml × 3), dried over Na ₂ SO ₄ and filtered on a glass filter. The filtrate was evaporated in vacuo to obtain 0.401 g (26%) 6-chloro-3-((1R,3S)-3-hydroxycyclopentyl)-8-iodopyrido[3,4-d]pyrimidin-4(3H)-one ( intermediate 13) and used without further purification.

^1H NMR (400 MHz, CDCl ₃ ): δ [ppm] = 8.78 (s, 1H), 8.04 (s, 1H), 5.39-5.27 (m, 1H), 4.59-4.46 (m, 1H), 2.50 (ddd, J=15.8, 11.1, 5.1 Hz, 1H), 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] ⁺ .

Intermediate 14. 6-chloro-3-((1R,3S)-3-hydroxycyclopentyl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one

6-chloro-3-((1R,3S)-3-hydroxycyclopentyl)-8-iodopyrido[3,4-d]pyrimidin-4(3H)-one (intermediate 13) (0.360 g, 0.925 mmol, 1 equiv .), pyridin-3-yl-boronic acid (0.125 g, 1.018 mmol, 1.1 equiv.), 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 equiv.) was dissolved in 1,4-dioxane/water (4 ml/1 ml, 0.06 M). The reaction mixture was stirred and heated in a Biotage microwave initiator at 130°C for 30 min. The reaction mixture was concentrated under reduced pressure and immediately purified by MPLC (silica gel, 0~10% MeOH/DCM) to obtain 0.186 mg (60% yield) 6-chloro-3-((1R,3S)-3-hydroxycyclopentyl)- 8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (intermediate 14).

MS (ESI, m/z): 343.05 [M+H] ⁺ .

Example 65 -4(3H)-on

6-chloro-3-((1R,3S)-3-hydroxycyclopentyl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (intermediate 14) (30 mg, 0.088 mmol, 1 equiv.), (6-(trifluoromethyl)pyridin-3-yl)boronic acid (25 mg, 0.131 mmol, 1.5 equiv.), 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 equiv.) were dissolved in 1,4-dioxane/water (0.7 ml/0.175 ml, 0.1 M). The reaction mixture was stirred and heated in a Biotage microwave initiator at 130°C for 30 min. The reaction mixture was concentrated under reduced pressure and immediately purified by MPLC (silica gel, 0~10% MeOH/DCM) to obtain 0.027 g (69% yield) of 3-((1R,3S)-3-hydroxycyclopentyl)-8-(pyridine -3-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (Example 65).

^1H NMR (400 MHz, CDCl ₃ ): δ [ppm] = 9.55 (d, J=0.9 Hz, 1H), 9.50 (d, J=1.6 Hz, 1H) , 8.82-8.70 (m, 3H), 8.67 (s, 1H), 8.62-8.55 (m, 1H), 7.86 (d, J=8.2 Hz, 1H ), 7.50 (dd, J=7.8, 4.8 Hz, 1H), 5.44-5.32 (m, 1H), 4.62-4.53 (m, 1H), 2, 70 (ush, 1H), 2.63-2.53 (m, 1H), 2.48-2.37 (m, 1H), 2.31-2.16 (m, 1H), 2.12- 1.96 (m, 2H), 1.94-1.80 (m, 1H); MS (ESI, m/z): 454.18 [M+H] ⁺ .

Example 66

Using 3-aminopropane-1,2-diol, pyridin-3-yl-boronic acid and (4-(trifluoromethyl)phenyl)boronic acid, the title compound was prepared as described for Example 65 (Scheme 4: General Procedure D).

¹ H-NMR (400 MHz, CDCl ₃ ): δ [ppm] = 9.44 (d, J=1.7 Hz, 1H), 8.78-8.74 (m, 1H), 8 .73 (s, 1H), 8.67 (dd, J=4.9, 1.5 Hz, 1H), 8.48 (d, J=8.2 Hz, 2H), 8.39 (s, 1H), 7.87 (d, J=8.4 Hz, 2H), 7.64 (dd, J=8.1, 4.9 Hz, 1H), 4.49 (dd, J=13.6 ,3.2 Hz, 1H), 4.10-4.02 (m, 1H), 3.91 (dd, J=13.6, 8.8 Hz, 1H), 3.66 (d, J= 5.2 Hz, 2H); MS (ESI, m/z):443.19 [M+H] ⁺ .

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

Using 3-aminopropane-1,2-diol, pyridin-3-yl-boronic acid and (4-chlorophenyl)boronic acid, general procedure D was followed (Scheme 4). During cyclization step c, according to the results of LC-M analysis, additional formylation of one of the two hydroxyl groups was observed. The formulated intermediate was deprotected under 2M HCl in methanol for 3 hours at 40°C to give the title compound according to Example 67.

¹ H-NMR (400 MHz, CDCl ₃ ): δ [ppm] = 9.42 (s, 1H), 8.65 (d, J=3.8 Hz, 1H), 8.52 (d , J=7.9 Hz, 1H), 8.45 (s, 1H), 8.20 (s, 1H), 8.12 (d, J=8.5 Hz, 2H), 7.47 (d , J=8.5 Hz, 2H), 7.43 (dd, J=7.8, 4.9 Hz, 1H), 4.33 (dd, J=13.7, 2.8 Hz, 1H) , 4.22-4.15 (m, 1H), 4.09 (dd, J=13.6, 6.8 Hz, 1H), 3.72 (ddd, J=16.4, 11.5, 3.9 Hz, 2H); MS (ESI, m/z):409.27 [M+H] ⁺ .

Example 68 (3H)-on

Using 3-aminopropan-1,2-diol, pyridin-3-yl-boronic acid and (4-(4-methylpiperazin-1-yl)phenyl)boronic acid, general procedure D was followed (Scheme 4). During cyclization step c, additional formylation of one of the two hydroxyl groups was observed based on the results of LC-MS analysis. The formylated intermediate was deprotected under 2M HCl in methanol for 3 hours at 40°C to give the title compound according to Example 68.

¹ H-NMR (400 MHz, CDCl ₃ ): δ [ppm] = 9.38 (d, J=1.5 Hz, 1H), 8.70 (dt, J-8.0.1, 9 Hz, 1H), 8.62 (dd, J=4.9, 1.6 Hz, 1H), 8.45 (s, 1H), 8.26 (s, 1H), 8.13 (d, J=8.9 Hz, 2H), 7.60 (dd, J=7.9, 5.0 Hz, 1H), 7.10 (d, J=9.0 Hz, 2H), 4.44 ( dd, J=13.6, 3.2 Hz, 2H), 4.08-4.01 (m, 1H), 3.86 (dd, J=13.7, 8.8 Hz, 1H), 3 .65 (d, J=5.2 Hz, 2H), 3.36 (t, J=10.0 Hz, 4H), 2.66 (t, J=9.9 Hz, 4H), 2.39 (s, 3H); MS (ESI, m/z):473.17 [M+H] ⁺ .

Example 69 )-He

Using 2,2-dimethyl-1,3-dioxan-5-amine, pyridin-3-yl-boronic acid and (4-(trifluoromethyl)phenyl)boronic acid, general procedure D was followed (Scheme 4). The intermediate was deprotected under 2M HCl in methanol for 3 hours at 40°C to give the title compound according to Example 69.

¹ H-NMR (400 MHz, CDCl ₃ ): δ [ppm] = 9.45 (s, 1H), 8.78-8.74 (m, 1H), 8.71 (s, 1H) , 8.66 (dd, J=4.9, 1.6 Hz, 1H), 8.49 (s, 1H), 8.47 (d, J=8.2 Hz, 2H), 7.86 ( d, J=8.3 Hz, 2H), 7.64 (ddd, J=8.0, 5.0, 0.8 Hz, 1H), 4.99-4.92 (m, 1H), 4 .13 (dd, J=11.9, 7.2 Hz, 2H), 4.00 (dd, J=11.9,4.9 Hz, 2H); MS (ESI, m/z):443.17 [M+H] ⁺ .

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

Using 2,2-dimethyl-1,3-dioxan-5-amine, pyridin-3-yl-boronic acid and (4-chlorophenyl)boronic acid, general procedure D was followed (Scheme 4). The intermediate was deprotected under 2M HCl in methanol for 3 hours at 40°C to give the title compound according to Example 70.

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

Example 71 3H)-on

Using (1S,3R)-3-aminocyclopentanol, pyridin-3-yl-boronic acid and (6-chloropyridin-3-yl)boronic acid, the title compound was prepared as described for Example 65 (Scheme 4. General Procedure D).

^1H NMR (400 MHz, CDCl ₃ ): δ [ppm] = 9.46 (s, 1H), 9.19 (d, J=2.3 Hz, 1H), 8.72 (s, 1H), 8.67 (s, 1H), 8.59-8.52 (m, 2H), 8.50 (dd, J=8.4, 2.5 Hz, 1H), 7.54-7 .40 (m, 2H), 5.40-5.24 (m, 1H), 4.60-4.46 (m, 1H), 2.80 (ush, 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] ⁺ .

Example 72 -4(3H)-one, TFA salt

Using (1S,3R)-3-aminocyclopentanol, pyridin-3-yl-boronic acid and (2-(trifluoromethyl)pyrimidin-5-yl)boronic acid, the title compound was prepared as described for Example 65 (Scheme 4. General Procedure D).

^1H NMR (400 MHz, MeOD): δ [ppm] = 9.98-9.72 (m, 3H), 9.46 (d, J=8.2 Hz, 1H), 9.01 -8.83 (m, 3H), 8.13 (dd, J=8.0, 5.8 Hz, 1H), 5.54-5.42 (m, 1H), 4.50-4.43 (m, 1H), 2.62-2.48 (m, 1H), 2.47-2.35 (m, 1H), 2.29-2.07 (m, 2H), 2.05-1 .91 (m, 2H); MS (ESI, m/z): 455.10 [M+H] ⁺ .

Example 73

Using (1S,3R)-3-aminocyclopentanol, pyridin-3-yl-boronic acid and (4-morpholinophenyl)boronic acid, the title compound was prepared as described for Example 65 (Scheme 4. General Procedure D).

^1H NMR (400 MHz, CDCl ₃ ): δ [ppm] = 9.46 (d, J=1.6 Hz, 1H), 8.69 (dd, J=4.8, 1.3 Hz, 1H), 8.59-8.52 (m, 1H), 8.49 (s, 1H), 8.48 (s, 1H), 8.19 (d, J=8.9 Hz, 2H ), 7.45 (dd, J=7.8, 4.9 Hz, 1H), 7.02 (d, J=8.9 Hz, 2H), 5.26-5.17 (m, 1H) , 4.55 -4.47 (m, 1H), 3.96-3.79 (m, 4H), 3.36-3.18 (m, 4H), 2.88 (d, J=3, 3 Hz, 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] ⁺ .

Example 74 4-d]pyrimidin-4(3H)-one

Using 2-aminopropan-1-ol, pyridin-3-yl-boronic acid and (4-chlorophenyl)boronic acid, general procedure D was followed (Scheme 4). During the Suzuki coupling step, the entitled biphenyl product was obtained as a by-product and purified by HPLC using 20-50-80 0.1% TFA in acetonitrile/water for elution.

¹ H-NMR (400 MHz, CDCl ₃ ): δ [ppm] = 9.46 (d, J=1.7 Hz, 1H), 8.78-8.76 (m, 1H), 8 .66 (d, J=4.7 Hz, 2H), 8.46 (s, 1H), 8.38 (d, J=8.5 Hz, 2H), 7.84 (d, J=8, 4 Hz, 2H), 7.74 (d, J=8.6 Hz, 2H), 7.64 (dd, J=8.2, 5.4 Hz, 1H), 7.51 (d, J= 8.6 Hz, 2H), 5.06-5.01 (m, 1H), 4.00 (dd, J=12.8, 7.1 Hz, 1H), 3.88 (dd, J=11 ,8, 4.2 Hz, 1H), 1.58 (d, J=7.1 Hz, 3H); MS (ESI, m/z): 469.21 [M+H] ⁺ .

Example 75 3-(1-hydroxypropan-2-yl)-6-(4-morpholinophenyl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one

Using 2-aminopropan-1-ol, pyridin-3-yl-boronic acid and (4-morpholinophenyl)boronic acid, the title compound was prepared as described for Example 65 (Scheme 4. General Procedure D).

¹ H-NMR (400 MHz, CDCl ₃ ): δ [ppm] = 9.42 (d, J=1.5 Hz, 1H), 8.75-8.70 (m, 1H), 8 .64 (dd, J=4.9, 1.6 Hz, 1H), 8.50 (s, 1H), 8.39 (s, 11H), 8.18 (d, J=9.0 Hz, 2H), 7.62 (dd, J=7.6, 4.6 Hz, 1H), 7.13 (d, J=9.0 Hz, 2H), 5.05-4.99 (m, 1H ), 3.99 (dd, J=11.8, 7.0 Hz, 1H), 3.91-3.87 (m, 4H), 3.86 (d, J=4.3 Hz, 1H) , 3.31-3.27 (m, 4H), 1.57 (d, J=7.1 Hz, 3H); MS (ESI, m/z):444.21[M+H] ⁺ .

Example 76 3-(2-(methylsulfonyl)ethyl)-8-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one

Scheme for obtaining a connection according to example 76:

Intermediate 15. Methyl 3-amino-6-chloro-[2,3'-bipyridine]-4-carboxylate

A mixture of 3-amino-6-chloro-[2,3'-bipyridine]-4-carboxylic acid (0.5 g, 2.003 mmol, 1 equiv.), K ₂ CO ₃ (0.415 g, 3.00 mmol, 1 .5 equiv.) was dissolved in DMF (20 ml, 0.1 M) and stirred for 5 min. Methyl iodide (0.426 g, 3.00 mmol, 1.5 equiv) was then added to the reaction mixture and stirred for 3 hours at room temperature. The reaction mixture was diluted with water (50 ml), extracted with ethyl acetate (20 ml x 3), washed with brine (20 ml x 3), dried over Na ₂ SO ₄ and filtered on a glass filter. The filtrate was evaporated in vacuo and purified by MPLC (silica gel, 0~30% ethyl acetate/hexane) to give 0.155 g (29%) methyl 3-amino-6-chloro-[2,3'-bipyridine]-4-carboxylate ( intermediate product 15). MS (ESI, m/z): 264.01 [M+H] ⁺ .

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

Methyl 3-amino-6-chloro-[2,3'-bipyridine]-4-carboxylate (intermediate 15) (80 mg, 0.303 mmol, 1 equiv.), (4-(trifluoromethyl)phenyl)boronic acid (86 mg, 0.455 mmol, 1.5 equiv.), K ₃ CO ₂ (126 mg, 0.910 mmol, 3 equiv.) and PdCl ₂ (dtbpf) (20 mg, 3 µmol, 0.1 equiv.) were dissolved in 1, 4-dioxane/water (4 ml/1 ml, 0.06 M). The reaction mixture was stirred and heated in a Biotage microwave initiator at 130°C for 30 min. The reaction mixture was concentrated under reduced pressure and immediately purified by MPLC (silica gel, 0~10% MeOH/DCM) to obtain 76 g (70% yield) of 3-amino-6-(4-(trifluoromethyl)phenyl)-[2, 3'-bipyridine]-4-carboxylic acid (intermediate 16).

MS (ESI, m/z): 360.02 [M+M] ⁺ .

Intermediate 17. 3-Amino-N-(2-(methylsulfonyl)ethyl)-6-(4-(trifluoromethyl)phenyl)-[2,3'-bipyridine]-4-carboxamide

3-Amino-6-(4-(trifluoromethyl)phenyl)-[2,3'-bipyridine]-4-carboxylic acid mixture (intermediate 16) (65 mg, 0.181 mmol, 1 equiv.) EDC (42 mg, 0.217 mmol, 1.2 equiv.), HOBT (33 mg, 0.217 mmol, 1.2 equiv.) and TEA (0.038 ml, 0.271 mmol, 1.5 equiv.) were dissolved in DMF (3 ml, 0.13 M ) and stirred for 5 minutes. 2-(methylsulfonyl)ethanamine (27 mg, 0.217 mmol, 1.2 equiv.) was then added to the reaction mixture and stirred for 12 hours at 50°C. The reaction mixture was diluted with water (50 ml), extracted with ethyl acetate (20 ml x 3), washed with brine (20 ml x 3), dried over Na ₂ SO ₄ and filtered on a glass filter. The filtrate was evaporated in vacuo and purified by MPLC (silica gel, 0~5% MeOH/DCM) to give 0.07 g (83%) 3-amino-N-(2-(methylsulfonyl)ethyl)-6-(4- (trifluoromethyl)phenyl)-[2,3'-bipyridine]-4-carboxamide (intermediate 17).

MS (ESI, m/z): 465.09 [M+H] ⁺ .

Example 76

3-Amino-N-(2-(methylsulfonyl)ethyl)-6-(4-(trifluoromethyl)phenyl)-[2,3'-bipyridine]-4-carboxamide (intermediate 17) (70 mg, 0.151 mmol, 1 equiv.) was dissolved in a solution of (EtO) ₃ CH (1.5 ml, 9.04 mmol, 60 equiv.) and CH ₃ CO ₂ H (0.43 ml, 7.54 mmol, 50 equiv.). The reaction mixture was stirred and heated in a Biotage microwave initiator at 150°C for 1 hour. The reaction mixture was diluted with water (20 ml), extracted with ethyl acetate (20 ml × 3), washed with brine (10 ml × 3), dried over Na ₂ SO ₄ and filtered on a glass filter. The filtrate was evaporated in vacuo and purified by MPLC (silica gel, 0~5% MeOH/DCM) to obtain 29 mg (yield 40.6%) 3-(2-(methylsulfonyl)ethyl)-8-(pyridin-3-yl) -6-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one (Example 76).

1H-NMR (400 MHz, CDCl ₃ ): δ [ppm] = 9.40 (d, J=1.5 Hz, 1H), 8.74-8.70 (m, 1H), 8, 68 (s, 1H), 8.64 (dd, J=4.9, 1.5 Hz, 1H), 8.44 (t, J=4.1 Hz, 3H), 7.84 (d, J =8.3 Hz, 2H), 7.61 (dd, J=8.0, 4.9 Hz, 1H), 4.58 (t, J=6.5 Hz, 2H), 3.74 (t , J=6.5 Hz, 2H), 3.10 (s, 3H). MS (ESI, m/z): 475.00 [M] ⁺ .

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

Using 2-(methylsulfonyl)ethanamine and (4-chlorophenyl)boronic acid, the title compound was prepared as described for Example 76 (Scheme 5. General Procedure E).

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

Example 78 3H)-on

Using 4-aminotetrahydro-2H-thiopyran-1,1-dioxide and (4-morpholinophenyl)boronic acid, the title compound was prepared as described for Example 76 (Scheme 5. General Procedure E).

1H-NMR (400 MHz, CDCl ₃ ): δ [ppm] = 9.44 (d, J=1.8 Hz, 1H), 8.71 (dd, J=4.8, 1.5 Hz, 1H), 8.57-8.49 (m, 1H), 8.45 (s, 1H), 8.19 (d, J=8.9 Hz, 2H), 8.14 (s, 1H ), 7.46 (dd, J=7.9, 5.1 Hz, 1H), 7.03 (d, J=9.0 Hz, 2H), 5.19-5.08 (m, 1H) , 3.92-3.86 (m, 4H), 3.39-3.20 (m, 8H), 2.70 (dd, J=26.1, 13.0 Hz, 2H), 2.37 (d, J=12.6 Hz, 2H); MS (ESI, m/z): 518.22 [M+H] ⁺ .

Example 79 3-(2-(methylsulfonyl)ethyl)-6-(4-morpholinophenyl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one

Using 2-(methylsulfonyl)ethanamine and (4-morpholinophenyl)boronic acid, the title compound was prepared as described for Example 76 (Scheme 5. General Procedure E).

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

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

Scheme for obtaining a connection according to example 80:

Intermediate 20: 3-(2,2-dimethyl-1,3-dioxan-5-yl)-6-(4-morpholinophenyl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidine -4(3H)-on

Using 2-dimethyl-1,3-dioxan-5-amine and (4-morpholinophenyl)boronic acid, the title compound was prepared as described for intermediate 20 (Scheme 6. General Procedure F).

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

Using 2,2-dimethyl-1,3-dioxan-5-amine and (4-morpholinophenyl)boronic acid, the intermediate was deprotected under 2M HCl in methanol for 3 hours at 40°C to give the title compound according to example 80 (Scheme 6. General procedure F).

^1H NMR (400 MHz, DMCO): δ [ppm] = 9.33 (d, J=1.7 Hz, 1H), 8.68 (dd, J=4.8, 1.5 Hz , 1H), 8.54 (dt, J=8.0, 1.8 Hz, 1H), 8.40 (d, J=4.5 Hz, 2H), 8.15 (d, J=8, 9 Hz, 2H), 7.58 (dd, J=7.9, 4.8 Hz, 1H), 7.10 (d, J=8.9 Hz, 2H), 4.85-4.75 ( m, 1H), 3.91-3.79 (m, 4H), 3.79-3.72 (m, 4H), 3.25-3.21 (m, 4H); MS (ESI, m/z):460.26 [M+H] ⁺ .

Example 81 )-He

Using (R)-3-aminopropane-1,2-diol, pyridin-3-yl-boronic acid (4-(trifluoromethyl)phenyl)boronic acid, general procedure F was followed (Scheme 6). During cyclization step c, according to the results of LC-MS analysis, additional formylation of one of the two hydroxyl groups was observed. The formylated intermediate was deprotected under 2M HCl in methanol for 3 hours at 40°C to give the title compound according to Example 81 (Scheme 6. General Procedure F).

¹ H-NMR (400 MHz, CDCl ₃ ): δ [ppm] = 9.44 (s, 1H), 8.77-8.71 (m, 1H), 8.71 (s, 1H) , 8.66 (d, J=3.8 Hz, 1H), 8.46 (d, J=8.2 Hz, 2H), 8.38 (s, 1H), 7.86 (d, J= 8.3 Hz, 2H), 7.63 (dd, J=7.9, 5.0 Hz, 1H), 4.49 (dd, J=13.6, 3.2 Hz, 1H), 4, 10-3.99 (m, 1H), 3.91 (dd, J=13.6, 8.8 Hz, 1H), 3.66 (d, J=5.2 Hz, 2H); MS (ESI, m/z):443.45 [M+H] ⁺ .

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

Using 3-aminopropane-1,2-diol and (4-morpholinophenyl)boronic acid, general procedure F was followed (Scheme 6). During cyclization step c, according to the results of LC-MS analysis, additional formylation of one of the two hydroxyl groups was observed. The formylated intermediate was deprotected under 2M HCl in methanol for 3 hours at 40°C to give the title compound according to Example 82 (Scheme 6. General Procedure F).

¹ H-NMR (400 MHz, CDCl ₃ ): δ [ppm] = 9.45 (d, J=1.8 Hz, 1H), 8.67 (d, J=3.5 Hz, 1H ), 8.55 (d, J=7.9 Hz, 1H), 8.44 (s, 1H), 8.17 (d, J=8.8 Hz, 2H), 8.14 (s, 1H ), 7.43 (dd, J=7.8, 5.0 Hz, 1H), 7.02 (d, J=8.9 Hz, 2H), 4.30 (d, J=10.2 Hz , 1H), 4.19-4.09 (m, 2H), 3.92-3.87 (m, 4H), 3.76-3.62 (m, 2H), 3.32-3.26 (m, 4H); MS (ESI, m/z): 460.19 [M+H] ⁺ .

Example 83 2-(6-(4-chlorophenyl)-4-oxo-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-3(4H)-yl)propanoic acid, salt 2, 2,2-trifluoroacetic acid

Using methyl 2-aminopropanoate hydrochloride salt, pyridin-3-yl-boronic acid and (4-chlorophenyl)boronic acid, the title compound was prepared as described for Example 80 (Scheme 6. General Procedure F).

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

Example 84 2-(4-oxo-8-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidin-3(4H)-yl)propanoic acid, 2,2,2-trifluoroacetic acid salt

Using methyl 2-aminopropanoate hydrochloride salt, pyridin-3-yl-boronic acid and (4-(trifluoromethyl)phenyl)boronic acid, the title compound was prepared as described for Example 80 (Scheme 6. General Procedure F).

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

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

Scheme for obtaining a connection according to example 86:

Intermediate 21. tert-butyl (2-(3-amino-6-chloro-2-iodoisonicotinamido)propyl)carbamate

3-Amino-6-chloro-2-iodoisonicotinic acid mixture (intermediate 1) (0.8 g, 2.68 mmol, 1 equiv.), EDC (0.617 g, 3.22 mmol, 1.2 equiv.) , HOBT (0.493 g, 3.22 mmol, 1.2 equiv.) and TEA (0.560 ml, 4.02 mmol, 1.5 equiv.) were dissolved in DMF (13.4 ml, 0.2 M) and stirred within 10 min. Tert-butyl (2-aminopropyl)carbamate (0.475 mL, 2.68 mmol, 1 equiv) was then added to the reaction mixture and stirred for 12 hours at 50°C. The reaction mixture was diluted with water (50 ml), extracted with ethyl acetate (20 ml x 3), washed with brine (20 ml x 3), dried over Na ₂ SO ₄ and filtered on a glass filter. The filtrate was evaporated in vacuo and purified by MPLC (silica gel, 0~50% ethyl acetate/hexane) to obtain 0.372 g (31% yield) tert-butyl (2-(3-amino-6-chloro-2-iodoisonicotinamido)propyl)carbamate (intermediate 21).

^1H NMR (400 MHz, CDCl ₃ ): δ = 7.71 (d, J=5.1 Hz, 1H), 7.29 (s, 1H), 6.17 (br, 2H), 5.01 -4.90 (m, 1H), 4.13-4.00 (m, 1H), 3.37-3.19 (m, 2H), 1.45 (s, 9H), 1.23 (d , J=6.5 Hz, 3H); MS (ESI, m/z): 455.08 [M+H] ⁺ .

Intermediate 22. 6-chloro-3-((1R,3S)-3-hydroxycyclopentyl)-8-iodopyrido[3,4-d]pyrimidin-4(3H)-one

tert-Butyl (2-(3-amino-6-chloro-2-iodoisonicotinamido)propyl)carbamate (intermediate 21) (0.372 g, 0.818 mmol, 1 equiv.) was dissolved in a solution of (EtO) ₃ CH (1.226 ml, 7.36 mmol, 9 equiv.) and CH ₃ CO ₂ H (1.226 ml, 20.18 mmol, 25 equiv.). The reaction mixture was stirred and heated in a Biotage microwave initiator at 150°C for 1 hour. The reaction mixture was diluted with water (20 ml), extracted with ethyl acetate (20 ml × 3), washed with brine (10 ml × 3), dried over Na ₂ SO ₄ and filtered on a glass filter. The filtrate was evaporated in vacuo and purified by MPLC (silica gel, 0~50% ethyl acetate/hexane) to give 0.135 g (36%) tert-butyl (2-(6-chloro-8-iodo-4-oxopyrido[3,4 -d]pyrimidin-3(4H)-yl)propyl)carbamate (intermediate 22) and used without further purification.

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

Intermediate 23. Tert-butyl (2-(6-chloro-4-oxo-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-3(4H)-yl)propyl)carbamate

tert-Butyl (2-(6-chloro-8-iodo-4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)propyl)carbamate (intermediate 22) (0.123 g, 0.265 mmol, 1 equiv.), pyridin-3-yl-boronic acid (0.036 g, 0.291 mmol, 1.1 equiv.), 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 equiv.) was dissolved in 1,4-dioxane/water (2.1 ml/0.53 ml, 0.1 M). The reaction mixture was stirred and heated in a Biotage microwave initiator at 130°C for 30 min. The reaction mixture was diluted with water (10 ml), extracted with ethyl acetate (10 ml x 3), washed with brine (10 ml x 3), dried over Na ₂ SO ₄ and filtered on a glass filter. The filtrate was evaporated in vacuo and purified by MPLC (silica gel, 0~5% MeOH/DCM) to give 0.093 g (84% yield) tert-butyl (2-(6-chloro-4-oxo-8-(pyridine-3- yl)pyrido[3,4-d]pyrimidin-3(4H)-yl)propyl)carbamate (intermediate 23).

^1H NMR (400 MHz, CDCl ₃ ): δ = 9.37 (d, J=1.8 Hz, 1H), 8.70 (dd, J=4.8, 1.5 Hz, 1H), 8 .44 (dt, J=8.0, 1.8 Hz, 1H), 8.13 (s, 1H), 8.09 (s, 1H), 7.44 (dd, J=7.9, 4 .8 Hz, 1H), 5.02-4.91 (m, 1H), 4.81-4.72 (m, 1H), 3.66-3.47 (m, 2H), 1.56 ( d, J=7.1 Hz, 3H), 1.29 (s, 9H); MS (ESI, m/z): 416.18 [M+H] ⁺ .

Intermediate 24. Tert-butyl (2-(4-oxo-8-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidin-3(4H)- yl)propyl)carbamate

tert-Butyl (2-(6-chloro-4-oxo-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-3(4H)-yl)propyl)carbamate (intermediate 23) ( 30 mg, 0.072 mmol, 1 equiv.), (4-(trifluoromethyl)phenyl)boronic acid (15.1 mg, 0.079 mmol, 1.1 equiv.), K ₂ CO ₃ (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 equiv.) were dissolved in 1,4-dioxane/water (5.8 ml/1, 4 ml, 0.1 M). The reaction mixture was stirred and heated in a Biotage microwave initiator at 130°C for 30 min. The reaction mixture was diluted with water (10 ml), extracted with ethyl acetate (10 ml x 3), washed with brine (5 ml x 3), dried over Na ₂ SO ₄ and filtered on a glass filter. The filtrate was evaporated in vacuo and purified by MPLC (silica gel, 0~10% MeOH/DCM) to give 29 g (76%) 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).

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

Example 85 one

tert-Butyl (2-(6-(4-chlorophenyl)-4-oxo-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-3(4H)-yl)propyl)carbamate (intermediate product 24) (29 mg, 0.055 mmol, 1 equiv.) was dissolved in 4 M HCl in 1,4-dioxane (138 μl, 4.0 M, 10 equiv.). The reaction mixture was stirred for 30 minutes at room temperature. The reaction mixture was concentrated under reduced pressure and diluted with DCM (10 ml). This solution was carefully basified with 1M NaOH until the pH of the aqueous layer reached 7. The aqueous layer was further extracted with DCM (10 ml x 2) and the combined organic layer was dried over Na ₂ SO ₄ and filtered on a glass filter. The filtrate was evaporated in vacuo and purified by MPLC (silica gel, 0~10% MeOH/DCM) to give 12.2 mg (51% yield) 3-(1-aminopropan-2-yl)-8-(pyridin-3-yl) )-6-(4-(trifluoromethyl)phenyl[3,4-d]pyrimidin-4(3H)-one (Example 85).

¹ H-NMR (400 MHz, CDCl ₃ ): δ [ppm] = 9.47 (d, J=1.7 Hz, 1H), 8.72 (dd, J=4.8, 1, 6 Hz, 1H), 8.61 (d, J=2.7 Hz, 1H), 8.57 (dt, J=7.9, 1.9 Hz, 1H), 8.35 (d, J= 8.2 Hz, 2H), 8.31 (s, 1H), 7.78 (d, J=8.3 Hz, 2H), 7.47 (dd, J=7.8, 4.9 Hz, 1H), 5.09-4.98 (m, 1H), 3.20-3.08 (m, 2H), 1.55 (d, J=7.1 Hz, 3H); MS (ESI, m/z): 426.15 [M+H] ⁺ .

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

3-(1-aminopropan-2-yl)-8-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl[3,4-d]pyrimidin-4(3H)-one (Example 85) (9.8 mg, 0.023 mmol, 1 equiv.) and TEA (3.85 µl, 0.028 mmol, 1.2 equiv.) were dissolved in DCM (115 µl, 0.2 M) and stirred for 5 min. Acetyl chloride (1.97 µl, 0.028 mmol, 1.2 equiv) was added to the reaction mixture and stirred for 30 min at room temperature. The reaction mixture was diluted with water (5 ml), extracted with DCM (5 ml x 3), washed with brine. solution (5 ml x 3), dried over Na ₂ SO ₄ and filtered on a glass filter, the filtrate was evaporated under vacuum and purified by MPLC (silica gel, 0~10% MeOH/DCM) to obtain 4.2 mg (38% yield). N-(2-(4-oxo-8-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidin-3(4H)-yl)propyl)acetamide (example 86).

^1H NMR (400 MHz, CDCl ₃ ): δ [ppm] = 9.46 (d, J=1.7 Hz, 1H), 8.71 (dd, J=4.8, 1.5 Hz, 1H), 8.59-8.54 (m, 2H), 8.33 (d, J=8.2 Hz, 2H), 8.14 (s, 1H), 7.77 (d, J =8.3 Hz, 2H), 7.46 (dd, J=7.8, 4.7 Hz, 1H), 5.94 (t, J=5.9 Hz, 1H), 5.06-4 .96 (m, 1H), 3.89-3.77 (m, 1H), 3.71-3.61 (m, 1H), 1.92 (s, 3H), 1.60 (d, J =7.1 Hz, 3H); MS (ESI, m/z): 468.20 [M+H] ⁺ .

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

Using tert-butyl (2-aminopropyl)carbamate, pyridin-3-yl-boronic acid and (4-chlorophenyl)boronic acid, the title compound was prepared as described for Example 85 (Scheme 7. General Procedure G).

^1H NMR (400 MHz, MeOD): δ [ppm] = 9.41 (d, J=1.7 Hz, 1H), 8.72 (dt, J=8.0, 1.9 Hz , 1H), 8.63 (dd, J=4.9, 1.5 Hz, 1H), 8.58 (s, 1H), 8.39 (s, 1H), 8.23 (d, J= 8.6 Hz, 2H), 7.61 (dd, J=8.2, 4.7 Hz, 1H), 7.53 (d, J=8.6 Hz, 2H), 5.00-4, 91 (m, 1H), 2.36-2.28 (m, 1H), 2.23-2.13 (m, 1H), 1.58 (d, J=7.0 Hz, 3H); MS (ESI, m/z): 392.14[M+H] ⁺ .

Example 88

Using tert-butyl (2-aminopropyl)carbamate, pyridin-3-yl-boronic acid, (4-chlorophenyl)boronic acid and acetyl chloride, the title compound was prepared as described for Example 86 (Scheme 7. General Procedure G).

^1H NMR (400 MHz, MeOD): δ [ppm] = 9.41 (s, 1H), 8.71 (dt, J=8.0, 1.8 Hz, 1H), 8.63 (d, J=3.5 Hz, 1H), 8.57 (s, 1H), 8.35 (s, 1H), 8.23 (d, J=8.6 Hz, 2H), 7.61 (dd, J=7.9, 4.9 Hz, 1H), 7.54 (d, J=8.6 Hz, 2H), 5.08-4.98 (m, 1H), 3.70- 3.63 (m, 2H), 1.84 (s, 3H), 1.59 (d, J=7.1 Hz, 3H); MS (ESI, m/z): 434.16 [M+H] ⁺ .

Example 89

Using tert-butyl (2-aminopropyl)carbamate, pyridin-3-yl-boronic acid, (4-chlorophenyl)boronic acid and methanesulfonyl chloride, the title compound was prepared as described for Example 86 (Scheme 7. General Procedure G).

^1H NMR (400 MHz, CDCl ₃ ): δ [ppm] = 9.35 (d, J=1.5 Hz, 1H), 8.64 (dd, J=4.7, 1.3 Hz, 1H), 8.46 (dt, J=8.0, 1.9 Hz, 1H), 8.30 (s, 1H), 8.14 (s, 1H), 8.03 (d, J =8.7 Hz, 2H), 7.42 (d, J=8.7 Hz, 2H), 7.41-7.37 (m, 1H), 6.07 (t, J=6.5 Hz , 1H), 4.90-4.79 (m, 1H), 3.70-3.59 (m, 1H), 3.50-3.40 (m, 1H), 2.99 (s, 3H ), 1.56 (s, 3H); MS (ESI, m/z): 470.11 [M+H] ⁺ .

Example 90

Using tert-butyl (2-aminopropyl)carbamate, pyridin-3-yl-boronic acid and (4-morpholinophenyl)boronic acid, the title compound was prepared as described for Example 85 (Scheme 7. General Procedure G).

^1H NMR (400 MHz, MeOD): δ [ppm] = 9.39 (d, J=1.6 Hz, 1H), 8.70 (dt, J=8.0, 1.9 Hz , 1H), 8.61 (dd, J=4.9, 1.6 Hz, 1H), 8.46 (s, 1H), 8.31 (s, 1H), 8.14 (d, J= 8.9 Hz, 2H), 7.59 (dd, J=8.0, 4.9 Hz, 1H), 7.09 (d, J=9.0 Hz, 2H), 4.96-4, 88 (m, 1H), 3.86 (t, J=4.8 Hz, 4H), 3.27 (t, J=4.8 Hz, 4H), 3.23-3.19 (m, 1H ), 3.10 (dd, J=13.6, 5.1 Hz, 1H), 1.56 (d, J=7.0 Hz, 3H); MS (ESI, m/z): 443.23 [M+H] ⁺ .

Example 91

Using tert-butyl (2-aminopropyl)carbamate, pyridin-3-yl-boronic acid, (4-morpholinophenyl)boronic acid and methanesulfonyl chloride, the title compound was prepared as described for Example 86 (Scheme 7. General Procedure G).

^1H NMR (400 MHz, MeOD): δ [ppm] = 9.37 (s, 1H), 8.68 (dt, J=8.0, 1.8 Hz, 1H), 8.61 (d, J=4.6 Hz, 1H), 8.42 (s, 1H), 8.27 (s, 1H), 8.11 (d, J=8.9 Hz, 2H), 7.58 (dd, J=7.9, 5.0 Hz, 1H), 7.07 (d, J=8.9 Hz, 2H), 4.96-4.90 (m, 1H), 3.86 ( t, J=4.8, 4H), 3.63 (dd, J=14.4, 7.9 Hz, 1H), 3.50 (dd, J=14.3, 4.7 Hz, 1H) , 3.26 (t, J=4.8, 4H), 2.92 (s, 3H), 1.60 (d, J=7.1 Hz, 3H); MS (ESI, m/z): 521.21 [M+H] ⁺ .

Example 92

Using tert-butyl (2-aminopropyl)carbamate, pyridin-3-yl-boronic acid, (4-morpholinophenyl)boronic acid and acetyl chloride, the title compound was prepared as described for Example 86 (Scheme 7. General Procedure G).

¹ H NMR (400 MHz, MeOD): δ [ppm] = 9.40 (s, 1H), 8.74-8.69 (m, 1H), 8.62 (d, J=4, 8 Hz, 1H), 8.44 (s, 1H), 8.28 (s, 1H), 8.13 (d, J=8.9 Hz, 2H), 7.60 (dd, J=7, 9, 4.9 Hz, 1H), 7.09 (d, J=8.9 Hz, 2H), 5.06-4.98 (m, 1H), 3.86 (t, J=4.8 Hz, 4H), 3.66 (t, J=5.8 Hz, 2H), 3.27 (t, J=4.8 Hz, 4H), 1.84 (s, 3H), 1.58 ( d, J=7.1 Hz, 3H); MS (ESI, m/z): 485.16 [M+H] ⁺ .

Example 93 3-(piperidin-4-yl)-8-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one

Using tert-butyl 4-aminopiperidine-1-carboxylate, pyridin-3-yl-boronic acid and (4-(trifluoromethyl)phenyl)boronic acid, the title compound was prepared as described for Example 85 (Scheme 7. General Procedure G).

^1H NMR (400 MHz, MeOD): δ [ppm] = 9.42 (d, J=1.6 Hz, 1H), 8.72 (dt, J=8.0, 1.9 Hz , 1H), 8.63 (dd, J=5.0, 1.5 Hz, 1H), 8.62 (s, 1H), 8.44 (s, 1H), 8.41 (d, J= 8.2 Hz, 2H), 7.82 (d, J=8.3 Hz, 2H), 7.61 (dd, J=8.0, 4.9 Hz, 1H), 4.85-4, 78 (m, 1H), 3.26 (d, J=12.9 Hz, 2H), 2.82 (td, J=13.0, 2.8 Hz, 2H), 2.12-2.01 (m, 4H); MS (ESI, m/z): 452.19 [M+H] ⁺ .

Example 94 He

Using tert-butyl 4-aminopiperidine-1-carboxylate, pyridin-3-yl-boronic acid, (4-chlorophenyl)boronic acid and methanesulfonyl chloride, the title compound was prepared as described for Example 86 (Scheme 7 General Procedure G).

^1H NMR (400 MHz, CDCl ₃ ): δ [ppm] = 9.44 (d, J=1.6 Hz, 1H), 8.72 (dd, J=4.8, 1.6 Hz, 1H), 8.56-8.53 (m, 2H), 8.19 (d, J=8.7 Hz, 2H), 8.17 (s, 1H), 7.50 (d, J =8.7 Hz, 2H), 7.49-7.44 (m, 1H), 5.03-4.93 (m, 1H), 4.09 (d, J=12.4 Hz, 2H) , 3.00-2.91 (m, 2H), 2.89 (s, 3H), 2.18-2.11 (m, 4H); MS (ESI, m/z): 496.20 [M+H] ⁺ .

Example 95 He

Using tert-butyl 4-aminopiperidine-1-carboxylate, pyridin-3-yl-boronic acid, (4-chlorophenyl)boronic acid and cyclopropanesulfonyl chloride, the title compound was prepared as described for Example 86 (Scheme 7 General Procedure G).

¹ H NMR (400 MHz, CDCl ₃ ): δ [ppm] = 9.48 (s, 1H), 8.74 (s, 1H), 8.59 (d, J=7.9 Hz, 1H), 8.53 (s, 1H), 8.18 (d, J=9.6 Hz, 3H), 7.50 (d, J=8.6 Hz, 3H), 5.04-4, 93 (m, 1H), 4.08 (d, J=12.8 Hz, 2H), 3.14-3.03 (m, 2H), 2.38-2.30 (m, 1H), 2 ,16-2.07 (m, 4H), 1.25-1.20 (m, 2H), 1.06 (sq.d, J=5.4, 0.6 Hz, 2H); MS (ESI, m/z): 522.16 [M] ⁺ .

Example 96

Using tert-butyl 4-aminopiperidine-1-carboxylate, pyridin-3-yl-boronic acid, (4-chlorophenyl)boronic acid and acetyl chloride, the title compound was prepared as described for Example 86 (Scheme 7 General Procedure G).

^1H NMR (400 MHz, CDCl ₃ ): δ [ppm] = 9.43 (d, J=2.0 Hz, 1H), 8.72 (dd, J=4.9,1.6 Hz, 1H), 8.55-8.51 (m, 2H), 8.19 (d, J=8.6 Hz, 2H), 8.13 (s, 1H), 7.50 (d, J =8.7 Hz, 2H), 7.49-7.45 (m, 1H), 5.11-5.01 (m, 1H), 4.94 (d, J=13.7 Hz, 1H) , 4.06 (d, J=13.9 Hz, 1H), 3.33 (t, J=11.8 Hz, 1H), 2.75 (td, J=13.2, 2.1 Hz, 1H), 2.18 (s, 3H), 2.13 (d, J=10.8 Hz, 1H), 2.06 (d, J=10.9 Hz, 1H), 1.98-1, 82 (m, 2H); MS (ESI, m/z): 460.19 [M+H] ⁺ .

In vitro XRE luciferase reporter gene assay (in vitro assay 1, 2, 3)

Activation of the AhR results in the induction of expression of target genes such as CYP1A1 and CYP1B1 by binding of the AhR to AhR-responsive DNA elements, also known as xenobiotic response elements (XREs). The assay for measuring AhR activity herein is a luciferase assay using cell lines transfected with a luciferase reporter plasmid containing an XRE upstream of the reporter gene. Cells transfected with an XRE-luciferase reporter (XRE-Luc) plasmid drive luciferase activity, reflecting AhR activation and inhibition in the cells. In addition to transfection with the XRE reporter vector, cells were co-transfected with a nanoluciferase reporter gene construct (Nano-Luc) containing a constitutively active promoter as an internal control. Kynurenine (an endogenous AhR agonist) was used to stimulate cells to investigate the antagonistic properties of the compounds. The half-maximal inhibitory concentration (IC ₅₀ ) or half-maximal effective concentration (EC ₅₀ ) value was calculated by nonlinear regression (four parameters) using Prism8.0 software (GraphPad).

In Vitro Assay 1: Antagonism in a Human Cell Line

The HepG2 cell line (human hepatoma cell line) with the XRE-luciferase reporter either transiently or permanently (Invivogen) was placed in complete medium and incubated at 37°C in a CO ₂ incubator. After 24 hours, cells were treated with kynurenine (50* or 200 μM) alone (negative control) or test compounds for 6 hours. Luciferase activity was measured using a commercially available kit such as the Promega Luciferase kit or other reagents for measuring luciferase activity. Relative luciferase activity (Firefly/Nano-Luc) was used to calculate _IC50 values. Relative luciferase activity was further normalized using the kynurenine-only group as the maximum control and the vehicle group as the minimum control. The AhR antagonistic activity of the example compounds is shown in Table 1 below. (IC ₅₀ values are grouped into cakes A, B, C and D, with A: IC ₅₀ < 0.01 µM; B: 0.01 < IC ₅₀ < 0.1 µM; C: 0.1 < IC ₅₀ < 1 .0 µM; D: IC ₅₀ > 1.0 µM).

In Vitro Assay 2: Antagonism in a Mouse Cell Line

Hepa1c1c7 cells (mouse liver cancer cell line), cotransfected with xre-luc and Nano-Luc plasmids, were placed in complete medium and incubated overnight at 37°C in a CO ₂ incubator. After incubation, cells were treated with AhR-activating ligands such as kynurenic acid, kynurenine (#) in the presence or absence of test compounds for 6 hours. Firefly luciferase and nanoluciferase activities were measured using the Nano-glo Luciferase kit (Promega), and relative luciferase activity (Firefly/Nano-Luc) was used to calculate IC ₅₀ values. Relative luciferase activity was further normalized using the agonist-only group as the maximum control and the vehicle group as the minimum control. The AhR antagonistic activity of the example compounds is shown in Table 1 below (IC ₅₀ values are grouped as A, B, C and D, with A: IC ₅₀ < 0.01 μM; B: 0.01 < IC ₅₀ < 0.1 μM; C: 0.1 < IC ₅₀ < 1.0 µM; D: IC ₅₀ > 1.0 µM).

In Vitro Assay 3: Agonism in a Human Cell Line

HepG2 cells (a human hepatoma cell line) cotransfected with xre-luc and Nano-Luc plasmids were placed in tryptophan-free medium containing 1% dialyzed fetal bovine serum and incubated overnight at 37°C in a CO ₂ incubator. After 24 hours, cells were treated for 6 hours with test compounds or left untreated. Firefly luciferase and nanoluciferase activities were measured using a Nano-glo Luciferase kit (Promega), and relative luciferase activity (Firefly/Nano-Luc) was used to calculate EC ₅₀ values. As a positive control, cells were incubated with tetrachlorodibenzo-p-dioxin.

(EC ₅₀ values are grouped as A, B, C and D, with A: EC ₅₀ < 0.1 µM; B: 0.1 < EC ₅₀ < 1.0 µM; C: 1.0 < EC ₅₀ < 10 µM; D: EC ₅₀ > 10 µM)

In Vitro Assay 4: Endogenous AhR Activity Assay

HepG2 cells were seeded in a 12-well plate (3×10 ⁵ cells/well). One day after seeding, cells were treated with tetrachlorodibenzo-p-dioxin (10 nM) or compounds (123 nM) alone for 4 hours. Total RNA was extracted using TRIzol (Thermo Fisher Scientific). ctDNA synthesis and quantitative reverse transcription PCR (qRT-PCR) analysis were performed using PrimeScript™ RT Master Mix (TAKARA) and TV Green™ Premix Ex Taq™ II (TAKARA) according to the manufacturer's instructions. To measure endogenous AhR activity, the relative levels of CYP1A1 and CYP1B1 mRNA relative to β(beta)-actin mRNA were quantified using the comparative Ct (ΔΔCt) method. The percentage of inhibition was calculated according to:

The endogenous AhR antagonistic activity of the example compounds is shown in Table 2 below.

Claims (130)

1. A compound of formula (I) or its enantiomer, diastereomer, racemate or pharmaceutically acceptable salt: wherein: Ar ¹ and Ar ² are independently phenyl, monocyclic C _5-6 -heteroaryl containing one or more heteroatoms selected from the group consisting of N, O and S, or monocyclic C _5-6 -heterocycloalkyl containing one or more heteroatoms , selected from the group consisting of N, O and S, where Ar ¹ and Ar ² are unsubstituted or substituted with halogen, hydroxyl, amino, C _1-6 -alkyl, C _1-6 -alkoxy, phenyl, chlorophenyl, methylpiperazine or morpholine where C _1-6 -alkyl or C _1-6 -alkoxy is unsubstituted or substituted with one to three halogens; L is absent (direct bond), represents H, halogen, hydroxy, amino, ether (-O-), sulfonyl (-SO ₂ -), carbonyl (-(CO)-), reverse amido (-NR ² (CO )-), C _1-5 -alkyl, unsubstituted or substituted with halogen or hydroxyl, mono- or bicyclic C _3-10 -cycloalkyl, mono- or bicyclic C _4-10 -heterocycloalkyl containing one or more heteroatoms selected from the group, consisting of N, O and S, mono- or bicyclic C _6-10 -aryl or mono- or bicyclic C _5-10 -heteroaryl containing one or more heteroatoms selected from the group consisting of N, O and S; R ¹ is absent (direct bond), represents H, halogen, hydroxy, amino, NHR ³ , OR ³ , phosphate, unsubstituted or substituted with C _1-6 alkyl, C _1-3 alkyl phosphate, C _1-5 alkyl, carboxylic acid (-(CO)-OH), carbonyl ((-(CO)R ² ), reverse alkylamide (-NH(CO)-R ² ), sulfonate (-SO ₂ -R ² ), C _3-10 - cycloalkyl, C _1-5 -alkylhydroxy, C _1-5 -alkylamine, mono- or bicyclic C _3-10 -heterocycloalkyl containing one or more heteroatoms selected from the group consisting of N, O and S or mono- or bicyclic C _5-10 -heteroaryl containing one or more heteroatoms selected from the group consisting of N, O and S; R ² represents C _1-5 -alkyl or C _3-8 -cycloalkyl; R ³ represents H, C _1-5 -alkylacetyl (alkyl-CO-) or C _1-5 -sulfonylalkyl (alkyl-SO ₂ -). 2. The compound or its enantiomer, diastereomer, racemate or pharmaceutically acceptable salt according to claim 1, wherein Ar ¹ and Ar ² are each independently phenyl, imidazole, pyridine, pyrimidine, piperidine or morpholine, wherein Ar ¹ and Ar ² are unsubstituted or substituted with halogen, hydroxyl, amino, C _1-6 alkyl, C _1-6 -alkoxy, phenyl, chlorophenyl, methylpiperazine or morpholine, wherein C _1-6 -alkyl or C _1-6 -alkoxy is unsubstituted or substituted with one to three halogens. 3. The compound or its enantiomer, diastereomer, racemate or pharmaceutically acceptable salt according to claim 1, in which Ar ¹ and Ar ² are each independently phenyl, monocyclic C _5-6 -heteroaryl containing one or two heteroatoms selected from the group consisting of N, O and S, or monocyclic C _5-6 -heterocycloalkyl containing one or two heteroatoms selected from the group consisting of N, O and S, which is unsubstituted or substituted with halogen, hydroxyl, amino, C _1-3 -alkyl, C _1-3 -alkoxy, phenyl, chlorophenyl, methylpiperazine or morpholine, where C _1-3 -alkyl or C _1-3 -alkoxy is unsubstituted or substituted with one to three halogens. 4. The compound or its enantiomer, diastereomer, racemate or pharmaceutically acceptable salt according to claim 1, in which L is absent (direct bond), is H, halogen, hydroxy, amino, ether (-O-), sulfonyl (-SO ₂ -), carbonyl (-(CO)-), reverse amido (-NR ² (CO)-), C _2-5 -alkyl, unsubstituted or substituted with halogen or hydroxyl, mono- or bicyclic C _3-8 -cycloalkyl, mono- or bicyclic C _3-8 -heterocycloalkyl, mono- or bicyclic C _6-10 -aryl or mono- or bicyclic C _5-8 -heteroaryl, wherein the mono- or bicyclic C _3-8 -heterocycloalkyl and mono- or bicyclic C _5-8 -heteroaryl contain one or more heteroatoms selected from the group consisting of N, O and S. 5. The compound or its enantiomer, diastereomer, racemate or pharmaceutically acceptable salt according to claim 1, in which L is absent (direct bond) is H, C _1-5 -alkyl, unsubstituted or substituted with halogen or hydroxyl, 1,1-dioxidotetrahydrothiopyran, piperidine or mono- or bicyclic C _3-6 -cycloalkyl. 6. The compound or its enantiomer, diastereomer, racemate or pharmaceutically acceptable salt according to claim 1, in which R ¹ is absent, represents H, halogen, hydroxy, amino, N(R ³ ) ₂ , OR ³ , C _1-4 -alkyl, carbonyl (-(CO)R ² ), C _3-8 -cycloalkyl, C _1-4 -alkylhydroxy, C _1-4 -alkylamine, mono- or bicyclic C _3-8 -heterocycloalkyl or mono- or bicyclic C _5-8 -heteroaryl, where mono- or bicyclic C _3-8 -heterocycloalkyl and mono- or bicyclic C _5-8 -heteroaryl contains one or more heteroatoms selected from the group consisting of N, O and S. 7. The compound or its enantiomer, diastereomer, racemate or pharmaceutically acceptable salt according to claim 1, in which R ¹ is absent, represents H, hydroxyl, -NH ₂ , -NH-C(O)CH ₃ , -NH-SO ₂ -CH ₃ , -C(O)OH, -SO ₂ -CH ₃ , - OS(O)-CH ₃ , -O-P(=O)(OSH ₂ CH ₃ ) ₂ or -C(O)CH ₃ . 8. A compound that is selected from any of compounds 1-96, 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) -He; 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]pyrimidine-4 (3H)-on; 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) -He; 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) -He; 16. 3-((1R,2S)-2-hydroxycyclohexyl)-8-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidin-4(3H) -He; 17. 3-((1S,2R)-2-hydroxycytohexyl)-8-(1-methyl-1H-pyrazol-4-yl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-d] pyrimidin-4(3H)-one; 18. 3-((1R,2S)-2-hydroxycyclohexyl)-8-(1-methyl-1H-pyrazol-4-yl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-d] pyrimidin-4(3H)-one; 19. 3-((1R,2S)-2-hydroxycytohexyl)-8-(1-methyl-1H-pyrazol-4-yl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-d] pyrimidin-4(3H)-one; 20. 6-(4-chlorophenyl)-3-((1S,2R)-2-hydroxycyclohexyl)-8-(1-methyl-1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidine-4 (3H)-on; 21. 6-(4-chlorophenyl)-3-((1S,2R)-2-hydroxycyclohexyl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; 22. 8-(1-methyl-1H-pyrazol-4-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4- d]pyrimidin-4(3H)-one; 23. 6-(4-chlorophenyl)-8-(1-methyl-1H-pyrazol-4-yl)-3-(3,3,3-trifluoroP-2-hydroxypropyl)pyrido[3,4-d]pyrimidine -4(3H)-on; 24. 6-(4-chlorophenyl)-8-(pyridin-3-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)pyrido[3,4-d]pyrimidin-4(3H)- He; 25. 8-(pyridin-3-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidine-4( 3H)-on; 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) -He; 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) -He; 30. 6-(4-chlorophenyl)-3-((1R,3S)-3-hydroxycyclopentyl)-8-(1-methyl-1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidine-4 (3H)-on; 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) -He; 34. 6-(4-chlorophenyl)-3-((1S,3R)-3-hydroxycyclopentyl)-8-(1-methyl-1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidine-4 (3H)-on; 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- silt acetate; 37. 2-methyl-1-(4-oxo-8-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidin-3(4H)-yl) propan-2-yl acetate; 38. 6-(4-chlorophenyl)-3-(2-hydroxy-2-methylpropyl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; 39. 3-(2-hydroxy-2-methylpropyl)-8-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one ; 40. 3-(2-hydroxy-2-methylpropyl)-8-(pyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4( 3H)-on; 41. 6-(4-chlorophenyl)-3-(1-hydroxy-3-methylbutan-2-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)- He; 42. 3-(1-hydroxy-3-methylbutan-2-yl)-8-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidin-4( 3H)-on; 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 )-He; 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)-on; 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 )-He; 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) -He; 58. 6-(4-chlorophenyl)-3-((1S,4S)-4-hydroxycyclohexyl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; 59. 3-(1-hydroxypropan-2-yl)-8-(1-methyl-1H-pyrazol-4-yl)-6-(4-(trifluoromethyl)phenyl)-2,3-dihydropyrido[3,4 -d]pyrimidin-4(1H)-one; 60. 6-(4-chlorophenyl)-3-(2,3-dihydroxypropyl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; 61. 6-(4-chlorophenyl)-3-(3-hydroxyphenyl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; 62. 3-(3-hydroxyphenyl)-8-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one; 63. 6-(4-chlorophenyl)-3-(3-hydroxycyclohexyl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; 64. 6-(4-chlorophenyl)-3-(3-hydroxycyclohexyl)-8-(1-methyl-1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; 65. 3-((1R,3S)-3-hydroxycyclopentyl)-8-(pyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin- 4(3H)-one; 66. 3-(2,3-dihydroxypropyl)-8-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one; 67. 6-(4-chlorophenyl)-3-(2,3-dihydroxypropyl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; 68. 3-(2,3-dihydroxypropyl)-6-(4-(4-methylpiperazin-1-yl)phenyl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4( 3H)-on 69. 3-(1,3-dihydroxypropan-2-yl)-8-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidin-4(3H) -He; 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 )-He 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 )-He; 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) -He; 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, salt 2.2 ,2-trifluoroacetic acid; 84. 2-(4-oxo-8-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidin-3(4H)-yl)propanoic acid, salt 2,2,2-trifluoroacetic acid; 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 for use in the prevention and/or treatment of a disease or condition mediated by the aromatic hydrocarbon receptor (AhR), containing a therapeutically effective amount of a compound of formula (I) according to claim 1 or a compound according to claim 8, or an enantiomer, diastereomer, a racemate or a pharmaceutically acceptable salt; and a pharmaceutically acceptable carrier. 10. The pharmaceutical composition of claim 9, wherein the disease or condition mediated by the aromatic hydrocarbon receptor (AhR) is a malignancy, cancerous conditions, tumor, fibrosing disorders or conditions with dysregulated immune responses or other disorders associated with aberrant signal transduction AhR. 11. The pharmaceutical composition of claim 9 for use in inhibiting the proliferation, tissue invasion, metastasis and angiogenesis of cancer cells in a subject with a malignancy, cancerous condition or tumor. 12. The pharmaceutical composition according to claim 11, in which the malignant tumor is selected from the group consisting of breast cancer, squamous cell cancer, lung cancer, peritoneal cancer, hepatocellular cancer, gastric cancer, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer , liver cancer, bladder cancer, hepatoma, colon cancer, colorectal cancer, endometrial or uterine carcinoma, salivary gland carcinoma, kidney or renal cell cancer, prostate cancer, vulvar cancer, thyroid cancer, malignant head tumor and neck, B-cell lymphoma, chronic lymphocytic leukemia; acute lymphoblastic leukemia, hairy cell leukemia and chronic myeloblastic leukemia. 13. The pharmaceutical composition according to claim 10, wherein the fibrosing condition is selected from the group consisting of liver fibrosis, liver cirrhosis, pulmonary fibrosis, endomyocardial fibrosis, nephropathy, glomerulonephritis, interstitial renal fibrosis, fibrotic damage due to diabetes, bone marrow fibrosis, scleroderma , annular scleroderma, keloids, hypertrophied scars, nevus, diabetic retinopathy, proliferative vitreoretinopathy and sarcoidosis. 14. The pharmaceutical composition according to claim 10, wherein the condition with uncontrolled immune responses is selected from the group consisting of sepsis, multiple organ failure, inflammatory kidney disorders, chronic inflammatory bowel disease, pancreatitis, peritonitis, inflammatory skin disorders and inflammatory eye disorders, rheumatoid diseases, systemic lupus erythematosus or multiple sclerosis. 15. A method of modulating AhR activity in a subject, comprising administering a therapeutically effective amount of a compound of formula (I) according to claim 1 or a compound according to claim 8, or an enantiomer, diastereomer, racemate or pharmaceutically acceptable salt thereof. 16. A method of preventing or treating a disease or condition mediated by an aromatic hydrocarbon receptor (AhR) in a subject, comprising administering a therapeutically effective amount of a compound of formula (I) according to claim 1 or a compound according to claim 8, or an enantiomer, diastereomer, racemate or pharmaceutical thereof acceptable salt. 17. The method of claim 16, wherein the disease or condition mediated by the aromatic hydrocarbon receptor (AhR) is a malignancy, cancerous conditions, tumor, fibrosing disorders or conditions with dysregulated immune responses, or other disorders associated with aberrant signal transduction AhR. 18. The method of claim 17, wherein the malignant tumor is selected from the group consisting of breast cancer, squamous cell cancer, lung cancer, peritoneal cancer, hepatocellular cancer, gastric cancer, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, hepatoma, colon cancer, colorectal cancer, endometrial or uterine carcinoma, salivary gland carcinoma, kidney or renal cell cancer, prostate cancer, vulvar cancer, thyroid cancer, malignant head tumor and neck, B-cell lymphoma, chronic lymphocytic leukemia (CLL); acute lymphoblastic leukemia (ALL), hairy cell leukemia and chronic myeloid leukemia. 19. The method of claim 17, wherein the fibrosing disorder is selected from the group consisting of liver fibrosis, liver cirrhosis, pulmonary fibrosis, endomyocardial fibrosis, nephropathy, glomerulonephritis, interstitial renal fibrosis, fibrotic damage due to diabetes, bone marrow fibrosis, scleroderma, annular scleroderma, keloids, hypertrophied scars, nevus, diabetic retinopathy, proliferative vitreoretinopathy and sarcoidosis. 20. The method of claim 17, wherein the condition with uncontrolled immune responses is selected from the group consisting of sepsis, multiple organ failure, inflammatory kidney disorders, chronic inflammatory bowel disease, pancreatitis, peritonitis, inflammatory skin disorders and inflammatory eye disorders, rheumatoid diseases, systemic lupus erythematosus and multiple sclerosis. 21. A method of inhibiting the proliferation, tissue invasion, metastasis and angiogenesis of cancer cells in a subject with a cancer, cancerous condition or tumor, comprising administering a therapeutically effective amount of a compound of formula (I) according to claim 1 or a compound according to claim 8, or an enantiomer thereof , diastereomer, racemate or pharmaceutically acceptable salt.